Day 1 – Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention

Day 1 – Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention


I’M DAVID MURRAY. OUR OFFICE SPONSORS PATHWAYS TO PREVENTION PROGRAM. WE’RE VERY HAPPY TO WELCOME YOU HERE TODAY FOR OUR P2P FOR OSTEOPOROTIC FRACTURE PREVENTION. I WILL SPEAK TO YOU A LITTLE BIT FURTHER IN A MOMENT, BUT MY MAIN TASK RIGHT NOW IS TO JUST GET EVERYBODY IN THEIR SEATS AND TO INTRODUCE DR. STEVE KATZ, THE DIRECTOR OF THE NATIONAL INSTITUTE FOR ARTHRITIS, MUSCULOSKELETAL AND SKIN DISORDERS. DR. KATZ CAME TO ME ALMOST TWO YEARS AGO ENCOURAGING MY OFFICE TO PUT THIS WORKSHOP TOGETHER, HE AND I ARE BOTH DELIGHTED WE’RE HERE TODAY HAVING THE WORKSHOP. DR. KATZ.>>THANKS VERY MUCH, DAVID. I WANT TO THANK DR. ALBERT SIU FOR TAKING ON THE RESPONSIBILITY HE DIDN’T KNOW WAS QUITE SUCH A RESPONSIBILITY WHEN HE AGREED. WE TELL YOU IN TRICKLES AS TO WHAT THE RESPONSIBILITIES ARE. GOOD MORNING TO EVERYBODY. MY FRIENDS, MANY OF MY COLLEAGUES FROM THE INSTITUTES, AND MANY FORMER COUNCIL MEMBERS HERE. I DO WANT TO REINFORCE THE FACT THAT DR. SIU HAS LED THIS WORKSHOP IN THE EXPERT PANEL AND WILL BE ISSUING A REPORT AT THE END OF THIS DAY AND A HALF MEETING. IT’S NOT UNLIKE THE MEETINGS THAT WE USED TO HAVE, CONSENSUS CONFERENCES BUT FAR MORE SOPHISTICATED WITH A BETTER FOCUS. IT’S MY PLEASURE TO WELCOME YOU TO THE PATHWAYS TO PREVENTION WORKSHOP AND APPROPRIATE USE OF DRUG THERAPIES FOR OSTEOPOROTIC FRACTURE. THIS STARTED BY A DISCUSSION WE HAD AT COUNCIL MEETING. I WAS FORTUNATE TO HAVE ELIZABETH SHANE AND SUNDEEP KHOSLA ON THE COUNCIL. AFTER OPEN REMARKS WE OPENED THE FLOOR FOR DISCUSSION, ABOUT A YEAR AND A HALF, IT WAS CLEAR THINGS WERE NOT GOING WELL IN THE AREA OF OSTEOPOROSIS PREVENTION. WHAT COULD BE DONE? THE SBIR WHICH I’LL REFERRED TO COULD DO SOMETHING ABOUT IT. THE NIH IS THE PLACE YOU CAN GET A NON-BIASED ASSESSMENT OF WHAT IS REALLY GOING ON IN THE FIELD. WE TOOK THOSE SUGGESTIONS AND THAT DISCUSSION, ELIZABETH AND SUNDEEP WITH THE FIRST SPEAKERS AT THIS CONFERENCE SO WE RECOGNIZE IT’S AN IMPORTANT ISSUE AND MANY STRATEGIES WERE NOT BEING USED. THERE WAS ENORMOUS FLURRY IN IN TERMS OF ADVERSE EVENTS. WE PARTNERED WITH THE NATIONAL INSTITUTE OF AGING AND DISEASE PREVENTION, TO EXPLORE DISCUSSION. I WANT TO ACKNOWLEDGE FAYE CHEN, DR. JOSEPH, FOR LEADING THE DEVELOPMENT. THOSE WHO RECEIVED HUNDREDS OF E-MAILS KNOW HOW MUCH WORK GOES INTO THIS. NIH COMPONENTS OF LEADING THE EFFORT, I MUST NOTE THE DIVERSITY OF NIH ENTITIES AND FEDERAL AGENCIES THAT ARE COMMITTED TO REDUCING THE BURDEN OF FRAGILITY FRACTURES, IT’S IMPORTANT TO GET A SENSE OF INTEREST IN THIS AREA. DIE DIGESTIVE AND KIDNEY DISEASES, TRANSLATIONAL SCIENCES, INTEGRATIVE HEALTH, NIH OFFICE OF BEHAVIORAL AND SOCIAL SCIENCE RESEARCH, NIH OFFICE OF RESEARCH ON WOMEN’S HEALTH, FDA, CENTERS FOR MEDICARE AND MEDICAID SERVICES, ADMINISTRATION FOR COMMUNITY LIVING, HHS OFFICE OF WOMEN’S HEALTH, DEPARTMENT VETERANS AFFAIRS, AND EVIDENCE-BASED REPORT AROUND WHICH THIS REPORT IS BASED. AS I TOLD DR. SIU AND A FEW OTHERS, THERE ARE BIG HOLES IN THE AUDIENCE BUT THEY ARE FILLED BY PEOPLE WHO ARE ON THE VIDEOCAST, SINCE WE STARTED VIDEOCASTING WE HAVE ENORMOUS AUDIENCE, AT SOME POINT WE’LL BE ABLE TO TELL YOU HOW MANY ARE ON THE VIDEOCAST. NIH IS WIDELY RECOGNIZED AS LEADING GOVERNMENT AGENCY THAT SUPPORTS BIOMEDICAL RESEARCH, AS SUCH WE NEED TO CONTINUE TO FILL THIS SIGNIFICANT GAPS IN KNOWLEDGE REGARDING THE USE OF DRUGS AND MUST PLAY A ROLE IN DISSEMINATING INFORMATION WHAT IS ALREADY KNOWN ABOUT OSTEOPOROTIC FRACTURE PREVENTION. WHILE THE FEDERAL GOVERNMENT MAY BE A PART OF NATIONAL ENDEAVOR TO REDUCE THE BURDEN OF OSTEOPOROSIS AND IMPROVE AMERICANS’ BONE HEALTH, LEADERSHIP HAS TO BE SHARED. I COMMEND THE AMERICAN SOCIETY FOR BONE AND MARROW RESEARCH FOR EMBRACING A LEADERSHIP ROLE IN SUCH EFFORTS BY DEVELOPING THE COORDINATED CALL TO ACTION TO AGGRESSIVELY REDUCE FRACTURE RISK IN AGING POPULATION. I HEARD THE FIRST REPORT THAT TASK FORCE IN MONTREAL JUST A FEW WEEKS AGO, AND THEY REALLY HAVE A CALL TO ACTION AND APPLAUD THAT VERY MUCH. MORE THAN 30 ORGANIZATIONS HAVE SIGNED ON TO THE EFFORT, TO INTENSIFY EFFORTS, INCREASE TESTING AND DIAGNOSING, TO BETTER EDUCATE PATIENTS ON OPTIONS. MANY ORGANIZATIONS ARE REPRESENTED HERE TODAY AND WE HOPE APPLY THE REPORT THAT WILL EMERGE FROM DISCUSSIONS DURING THIS WORKSHOP INTO MANY OF THEIR ACTIVITIES. SO THIS IS A TEAM SPORT, NOT JUST AN NIH SPORT. IN CLOSING I WANT TO THANK THE EXPERT PANEL IN ADVANCE FOR WHAT IS GOING TO BE A HECTIC FEW DAYS TO YOU, HECTIC YEOMAN’S EFFORT TO CONSOLIDATE EVERYTHING YOU HEAR TODAY, TOMORROW, INTO A COHESIVE REPORT THAT THE NIH CAN THEN USE TO MAKE RECOMMENDATIONS, NEXT STEMS IN DRUG BASED INTERVENTIONS. I’M NOT ABLE TO STAY FOR ENTIRE WORKSHOP, A FAMILY MEMBER RECENTLY BROKE HER HUMERUS, I’M LOOKING AFTER HER, OSTEOPOROTIC FRACTURE. I MUST SAY THAT I HAVE A VESTED INTEREST IN THIS. I’VE ALWAYS HAD A VESTED INTEREST IN THIS. WE ALL HAVE A TESTED INTEREST IN WHAT GOES ON HERE IN THE NEXT FEW DAYS. WE THANK YOU VERY MUCH IN ADVANCE FOR YOUR DELIBERATIONS, NOT ONLY DELIBERATIONS DURING THE TWO DAYS BUT ALSO FOR YOUR ADVANCEDs STUDIES OF ALL THE MATERIALS YOU’VE BEEN SENT. AND EXPLORING WAYS WE CAN WORK ACROSS THE NIH WITH PROFESSIONAL SOCIETIES AND OTHER STAKEHOLDERS TO BETTER HELP PEOPLE RECEIVE APPROPRIATE MEDICAL CARE IS THE GOAL. THANK YOU FOR BEING HERE. THANK YOU TO ALL THE SPEAKERS FOR COMING, FOR PRESENTING EVIDENCE AND THE PANEL WHOSE DELIBERATIONS WE’LL LOOK AT VERY CAREFULLY. I AM DAVID MURRAY, ASSOCIATE DIRECTOR FOR PREVENTION. A LITTLE BIT ABOUT OUR OFFICE, OUR MISSION IS TO IMPROVE PUBLIC HEALTH BY INCREASING THE SCOPE, QUALITY, DISSEMINATION, IMPACT OF PREVENTION RESEARCH SUPPORTED BY NIH. WE’RE LOCATED IN THE OFFICE OF THE DIRECTOR, WE WORK WITH ALL OF THE INSTITUTES AND CENTERS SO WE’RE NOT FOCUSED ON A PARTICULAR DISEASE OR RISK FACTOR. OUR ROLE IS PROVIDE LEADERSHIP FOR DEVELOPMENT, COORDINATION, IMPLEMENTATION OF PREVENTION RESEARCH IN COLLABORATION WITH THE OTHER INSTITUTES AND CENTERS ON CAMPUS. WE HAVE JUST RELEASED OUR NEW STRATEGIC PLAN FOR FY19 TO 23. YOU CAN FIND OUT MORE ABOUT ON OUR WEBSITE, THE LINK SHOWN HERE. WE HAVE SIX PRIORITIES FOR THE NEXT FIVE YEARS. WE ARE VERY INTERESTED IN CONDUCTING PORTFOLIO ANALYSIS, LOOKING AT THE PREVENTION RESEARCH PORTFOLIO THAT NIH HOLDS, AND EVALUATING THE IMPACT OF THE PREVENTION RESEARCH THAT NIH SUPPORTS. VERY MUCH RELATED TO THIS WORKSHOP, WE’RE VERY INTERESTED IN IDENTIFYING RESEARCH GAPS, AREAS THAT NEED ADDITIONAL ATTENTION AND THAT’S ONE OF THE MAIN PURPOSES OF THE WORKSHOP, TO DETERMINE WHAT KINDS OF RESEARCH ARE NEEDED TO MOVE THIS AREA FORWARD. WE’RE VERY INTERESTED IN IMPROVING THE QUALITY OF THE RESEARCH METHODS THAT ARE USED IN PREVENTION RESEARCH, SUPPORTED BY NIH, WE’RE NOT GOING TO ADVANCE THE SCIENCE IF WE DON’T USE THE BEST POSSIBLE METHODS. WE’RE ALWAYS INTERESTED IN PROMOTING COLLABORATIVE RESEARCH. THAT’S WHY ALL OF THESE WORKSHOPS ARE SPONSORED BY TWO INSTITUTES OR CENTERS AT NIH. WE VERY INVOLVED IN TOBACCO RESEARCH, PARTICULARLY REGULATORY SCIENCE RESEARCH, SUPPORTED BY THE FDA BUT IMPLEMENTED BY THE NATIONAL INSTITUTES OF HEALTH. FINALLY WE’RE INTERESTED IN COMMUNING RESULTS WITH NIH LEADERSHIP AND IN THE EXTRAMURAL COMMUNITY ACROSS THE COUNTRY. THIS PATHWAYS TO PREVENTION WORKSHOP ADDRESSES OUR INTEREST UNDER PRIORITY 2, IDENTIFYING RESEARCH GAPS. OUR GOAL IS TO IDENTIFY NEW DIRECTIONS FOR RESEARCH TO IMPROVE THE USE OF OSTEOPOROTIC DRUG THERAPY FOR FRACTURE PREVENTION. THIS STARTS WITH EVIDENCE REVIEW, THE REPORT IN THE HANDS OF THE WORKSHOP PANEL SO THEY HAVE HAD A CHANCE TO STUDY IT, IT REVIEWS THE LITERATURE FOR THIS CONTENT. WE COME TOGETHER THEN FOR A DAY AND A HALF, HAVING STUDIED THE EVIDENCE REVIEW TO HEAR PRESENTATIONS FROM EXPERTS IN THE FIELD WHO WORKED IN THIS AREA EVERY DAY. WE HAVE PARTICIPATION BY THOSE OF YOU IN THE ROOM, ALSO PARTICIPATION OVER E-MAIL AND TWITTER, FROM PEOPLE WATCHING THE VIDEOCAST. AS DR. KATZ MENTIONED WE’LL HAVE FAR MORE PEOPLE ON THE VIDEOCAST THAN WE HAVE IN THE ROOM. IT USED TO BE THE ROOMS WERE FULL TO OVERFLOWING WITH KIOSKS, IN THE BACK, BUT WE STARTED VIDEOCASTING AND PEOPLE STARTED WATCHING FROM THEIR OFFICES INSTEAD OF COMING TO CAMPUS. MANY PEOPLE ARE WATCHING OVER THE VIDEO. THE PANEL THEN NEEDS TO PUT ALL OF THIS INFORMATION TOGETHER. THE WORK FROM THE EVIDENCE REVIEW, FROM THE PRESENTATIONS, INPUT FROM THE AUDIENCE. AND THEY WILL SPEND A LOT OF TIME OVER THE NEXT TWO DAYS PREPARING A DRAFT PANEL REPORT. IT WILL BE LIKE ALL-NIGHTERS IN COLLEGE. THE PANEL REPORT WILL GET POSTED FOR COMMENT FOR A PERIOD. AND THEN THE PANEL WILL HAVE A CHANCE ON REVISE IT. THE FINAL REPORT WILL BE PUBLISHED IN THE PEER-REVIEWED LITERATURE. WE AT THE OFFICE OF DISEASE PREVENTION ARE VERY INTERESTED IN EVALUATING THE IMPACT OF THIS WORKSHOP SERIES. WE HAVE ONE OR TWO P2P WORKSHOPS EVERY YEAR, PROGRAM REGISTRANTS REPRESENT A BROAD SPECTRUM OF SCIENTISTS AND STAKEHOLDERS, WE ALWAYS PUBLISH THE PANEL REPORT, EVIDENCE REVIEW, PEER-REVIEWED LITERATURE, OFTEN DRAWING ATTENTION SHOWN IN THIS GRAPH AS THE RELATIVE CITATION RATIO FOR SOME OF THE REPORTS THAT HAVE BEEN OUT FOR A FEW YEARS. A SCORE OF 1 MEANS IT’S AVERAGE IN TERMS OF IMPACT. A STORE OF 2 OR 3 MEANS IT’S VERY MUCH ABOVE AVERAGE. TO HIT 56.6 AS WE DID WITH OPIOID AND CHRONIC POINT IS REMARKABLE. WE HARDLY EVER SEE NUMBERS OF THAT MAGNITUDE. WE HAVE A NUMBER OF PEOPLE KEY PARTICIPANTS IN THESE WORKSHOPS, THE INSTITUTE COORDINATORS YOU’LL HEAR FROM LATER TODAY ARE INVOLVED FROM THE VERY BEGINNING, IDENTIFYING THE TOPICS TO BE COVERED, IDENTIFYING THE SPEAKERS, WORKING CLOSELY WITH MY STAFF, THE AHRQ EVIDENCE-BASED PRACTICE CENTER, IN THIS CASE TWO PRACTICE CENTERS, PERFORM THE EVIDENCE REVIEWS AND PROVIDE THAT MATERIAL TO THE PANEL. WE HAVE THE PANEL ITSELF AND I’LL INTRODUCE THEM IN A MOMENT. THEN WE HAVE THE PRESENTERS WHO ARE HERE IN THE ROOM, AND THE AUDIENCE INCLUDING BOTH THE GENERAL PUBLIC AND THE SCIENTIFIC COMMUNITY. THE EVIDENCE-BASED PRACTIC CENTER, CENTERS IN THIS CASE, CONDUCT SYSTEMATIC EVIDENCE REVIEWS UNDER CONTRACT WITH AHRQ. WE PAY FOR THAT, AND WORKING WITH THE INSTITUTE COORDINATORS, I.C. COORDINATORS, PROVIDE GUIDANCE FOR HOW THE REVIEW IS TO BE DONE. AS I INDICATED FOR THIS WORKSHOP WE HAVE TWO EPCs PRESENTING, FROM MINNESOTA IS ONE WE COMMISSIONED FOR THIS WORKSHP ON LONG-TERM USE OF DRUG THERAPIES. THE SECOND ONE WE RECOGNIZE WE SHOULD INCLUDE NOT BECAUSE WE COMMISSIONED IT FOR THE WORKSHOP BUT BECAUSE IT WAS UNDERWAY, UNDER COMMISSION FROM THE U.S. PREVENTIVE SERVICES TASK FORCE. IT WAS SO CLEARLY RELATED TO THE MATERIAL AND COVERS SHORT-TERM USE OF DRUG THERAPY, WE’LL HEAR FROM BOTH OF THOSE PANELS. THE INDEPENDENT PANEL, WE HAVE FIVE OUTSTANDING SCIENTISTS WITH US TODAY. THEY HAVE NO FINANCIAL OR INTELLECTUAL CONFLICTS OF INTEREST, THAT’S ON PURPOSE. PEOPLE OFTEN SAY, DAVID, NONE OF THESE PEOPLE ARE EXPERTS IN THE CONTENT AREA THAT YOU’RE TALKING ABOUT. THAT IS ON PURPOSE. WE DON’T WANT THEM TO BE PEOPLE KIND OF CONFLICT OF INTEREST. THEY DO, HOWEVER, HAVE EXPERTISE IN METHODS AND CLINICAL PRACTICE, ACADEMIC RESEARCH, PUBLIC HEALTH. THEY ARE NOT FEDERAL REPRESENTATIVES, AND THEY PRODUCE A REPORT DETAILING THE METHODOLOGICAL AND OTHER WEAKNESSES IN THE AREA AND MAKE RECOMMENDATIONS FOR FUTURE RESEARCH. LET ME GIVE THE CHARGE TO THE PANEL. I WOULD ASK THAT YOU LISTEN TO EVERYTHING THAT IS PRESENTED TODAY, VERY CLOSELY. ATTEND ALL THE EXECUTIVE PANEL WRITING SESSIONS NO MATTER HOW LATE THEY MAY GO. PREPARE A DRAFT PANEL REPORT WITHIN TWO DAYS OF THE WORKSHOP CLOSURE. WE WOULD ASK YOU TO REVIEW AND INCORPORATE PUBLIC COMMENTS THAT WE RECEIVE ON THAT DRAFT REPORT AFTER ITS POSTED, AND WE COLLECT THOSE COMMENTS FOR A PERIOD OF TIME AFTER THE INITIAL POSTING. FINALLY, WE ASK YOU TO PREPARE A FINAL PANEL REPORT THAT SUMMARIZES THE WORK SHOP PROCEEDINGS AND MAKES RECOMMENDATIONS PUBLISHED IN THE PEER-REVIEWED LITERATURE IN SIX TO NINE MONTHS FROM NOW. I’M PLEASED TO INVITE THE MEMBERS OF THE PANEL TO COME UP AND TAKE A SEAT AT THE TABLE. DR. ALBERT SIU, WHO IS THE PANEL CHAIR. I WILL INTRODUCE MORE FORMALLY IN A MOMENT. PLEASE HAVE A SEAT. DR. HEATHER ALLURE FROM YALE SCHOOL OF PUBLIC HEALTH, DR. DARRELL BROWN FROM DREXEL, DR. SUSAN CHARLES FROM UNIVERSITY OF CALIFORNIA AT IRVINE, DR. MATTHEW LOWMAN FROM UNIVERSAL OF SOUTH CAROLINA ARNOLD SCHOOL OF PUBLIC HEALTH. SO WELCOME TO ALL OF YOU. THANK YOU VERY MUCH FOR YOUR PARTICIPATION. AND THANK YOU IN ADVANCE FOR ALL THE HARD WORK THAT YOU’RE GOING TO DO AND LATE NIGHTS. I HOPE YOU GOT PLENTY OF SLEEP BEFORE YOU ARRIVED IN BETHESDA. THANK YOU VERY MUCH. [APPLAUSE] THE SPEAKERS HAVE BEEN ASKED TO DISCLOSE ALL RELEVANT FINANCIAL AND OTHER CONFLICTS AND TO READ HERE IS DISCLOSURES ALOUD SO YOU’LL BE HEARING THOSE OVER THE COURSE OF THE NEXT DAY AND A HALF. PLEASE REFER TO THE DISCLOSURE STATEMENTS TO GET INFORMATION. THE PANELISTS ARE CHOSEN BECAUSE THEY DON’T HAVE ANY CONFLICTS OF INTEREST. SO WE VET PANELISTS VERY CAREFULLY AND HAVE JUDGED THEY HAVE NO RELATIONSHIPS PERTINENT TO THE WORKSHOP TOPIC. I WANT TO THANK DR. FAYE CHEN AND DR. JOSEPH AND DR. JANELLE DRUGAN FROM NIH FOR ALL THE WORK THEY HAVE DONE TO HELP ORGANIZE THE CONFERENCE. I THANK REPRESENTATIVES FROM THE AGENCY FOR HEALTH CARE RESEARCH AND QUALITY FOR COORDINATING THE WORK OF THE EPCs. I WANT TO CERTAINLY THANK THE TWO EPCs THAT MAY BE PRESENTING AT THIS WORKSHOP. I THANK ALL THE SPEAKERS AND THE PANEL MEMBERS, THE STAFF WHO HELPED TAKE CARE OF THE LOGISTICAL ACTIVITIES RELATED TO THE WORKSHOP AND MEMBERS OF MY STAFF, PARTICULARLY KEISHA, DEBRA LANGER, AND KERRY WHO HAVE BEEN — AND KATE, WHO HAVE BEEN VERY INVOLVED IN ALL THE ACTIVITIES BRINGING THIS WORKSHOP TOGETHER. IT’S NOW MY PLEASURE TO INTRODUCE ALBERT SIU WHO IS GOING TO CHAIR THE PANEL AND LEAD THE SHIFTS OVER THE NEXT DAY AND A HALF. HE’S PROFESSOR OF THE BROOKDALE DEPARTMENT AT THE ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI, DIRECTOR OF THE GERIATRIC RESEARCH EDUCATION AND CLINICAL CENTER, JAMES PETERS VETERANS AFFAIRS MEDICAL CENTER, M.D. FROM YALE, MASTERS IN PUBLIC HEALTH UNIVERSITY OF CALIFORNIA LOS ANGELES, COMPLETED RESIDENCY IN INTERNAL MEDICINE AND ROBERT WOOD JOHNSON CLINICAL SCHOLAR FELLOWSHIP AT UCLA. HE WAS CHAIR FOR 14 YEARS OF THE DEPARTMENT OF GERIATRICS AND PALLIATIVE MEDICINE, ONE OF THE LARGEST IN THE COUNTRY. PRINCIPAL INVESTIGATOR ON THE NATIONAL INSTITUTE OF AGING CLAUDE PEPPER CENTER AT MOUNT SINAI, RESEARCH AIMS TO IMPROVE THE QUALITY AND DELIVERY OF CARE PROVIDED TO GERIATRIC POPULATIONS, FOCUSING ON IMPROVEMENT OF FUNCTIONAL OUTCOMES AND EVALUATION OF SYSTEM INTERVENTIONS TO IMPROVE THEIR CARE FOR CHRONIC ILLNESS. IMPORTANTLY, DR. SIU SEARCHED FOR 12 YEARS ON THE U.S. PREVENTIVE SERVICES TASK FORCE, AS A MEMBER, VICE CHAIR AND FINALLY CHAIR. HE’S A SENIOR ASSOCIATE EDITOR AT HEALTH SERVICES RESEARCH. PLEASE JOIN ME IN WELCOMING DR. ALBERT SIU. [APPLAUSE]>>THANK YOU, DR. MURRAY AND DR. KATZ. WELCOME, EVERYBODY, TO THIS P2P WORKSHOP TO CONSIDER OSTEOPOROTIC DRUG TREATMENT, OTC, NOT TO BE CONFUSED WITH ODP, AS WE CONSIDER OVER THE NEXT COUPLE DAYS HOW WE MIGHT PREVENT, YOU KNOW, VERTEBRAL FRACTURES, CVF, RVF, BY THE END OF THE MORNING YOU’LL BE FAMILIAR WITH ALL THE ACRONYMS. LET ME SEE IF I CAN ADVANCE THE SLIDES. LET ME TRY THIS. I HAVE NO FINANCIAL OR NON-FINANCIAL DISCLOSURES TO REPORT. LET ME TAKE THIS OPPORTUNITY TO THANK MY FELLOW PANELISTS WHO HAVE BEEN INTRODUCED BEFORE. WE WILL BE SITTING UP AT THE FRONT AND BE AVAILABLE TO TAKE ON OUR CHARGE AS DR. MURRAY INDICATED. WHAT WE WILL BE DOING OVER — WE READ EPC REPORT, SYSTEMATIC EVIDENCE REVIEW PREPARED FOR US. OVER THE NEXT COUPLE DAYS, THE NEXT TWO DAYS, WE’LL BE CONSIDERING THE EVIDENCE FROM THE SPEAKERS AND COMMENTS FROM THE AUDIENCE, WE’RE LOOKING FORWARD TO PUBLIC DISCUSSION TODAY. OVER THE NEXT TWO OR THREE DAYS WE’LL BE DRAFTING A PANEL REPORT IN WHICH WE WILL BRIEFLY SUMMARIZE THE CURRENT LITERATURE, BRIEFLY ADDRESS THE EVIDENCE FROM THE SPEAKERS, WHAT WE KNOW ABOUT OSTEOPOROTIC DRUG TREATMENT AND OUTLINE 5 TO 10 RECOMMENDATIONS OF GAPS FOR FUTURE RESEARCH AREAS WHERE WE DON’T KNOW AND WHERE IT IS IMPORTANT TO FIND OUT, YOU KNOW, WHAT TO DO TO GO FORWARD. AS WELL AS TO HIGHLIGHT WHAT SHOULD BE PRIORITIZED TO MOVE THE FIELD FORWARD. AS DR. MURRAY INDICATED WE’LL DRAFT AN EVIDENCE REPORT. THIS PANEL PROCESS IS EXEMPT FROM IRB REVIEW BECAUSE I DON’T THINK ANY OF US WOULD HAVE AGREED TO DO THIS IF WE HAD BEEN FULLY INFORMED IN ADVANCE WHAT WAS GOING TO BE REQUIRED OF US. THE DRAFT REPORT WILL BE OPEN FOR PUBLIC COMMENT ON THE ODP WEBSITE. AND AS DR. MURRAY INDICATED, IT WILL APPEAR IN A PEER-REVIEWED JOURNAL AS WELL AS COMPANION PIECE FOR THE EPC SYSTEMATIC EVIDENCE REVIEWS LATER THIS MORNING. THE EPC SYSTEMATIC EVIDENCE REVIEW COVERS THE BENEFITS AND RISKS OF LONG-TERM OSTEOPOROTIC DRUGS. WE WILL HAVE SPEAKERS WHO WILL COVER SHORT-TERM AND LONG-TERM USE, ONE OF THE — AS DR. MURRAY INDICATED, ONE OF THE OTHER EPC REPORTS WILL ALSO DISCUSS SHORT-TERM BENEFITS AS WELL. EACH SESSION ADDRESSES ONE OF THE WORKSHOP KEY QUESTIONS. THE FIRST TALK OF EACH SESSION WILL SUMMARIZE, SUBSEQUENT TALKS ADDRESS RESEARCH GAPS OR PROVIDE OTHER INFORMATION. I WILL BE ASKING EACH SPEAKER TO INTRODUCE THEMSELVES, NAME, TITLE, AFFILIATION, PRESENTATION AND TITLE, AS WELL AS THEIR DISCLOSURES. AND EACH SESSION ENDS WITH A 40-MINUTE DISCUSSION IN PERSON AMONG THOSE OF YOU IN THIS ROOM AS WELL AS REMOTE ATTENDEES WHO ARE ENCOURAGED TO PARTICIPATE. I’M GOING TO ASK EVERYBODY TO HOLD THEIR QUESTIONS AND COMMENTS UNTIL THE DISCUSSION AT THE END OF EACH GROUP OF SPEAKERS. AT THAT POINT, THE PANEL WILL BE ALLOWED TO ASK QUESTIONS FIRST. THERE’S NO TIME LIMIT FOR THE PANEL QUESTIONS. EACH PUBLIC COMMENTER IS RESTRICTED TO THREE MINUTES. COMMENTS SUBMITTED BY VIDEOCAST WILL BE READ AT THE MICROPHONE, IF TIME PERMITS, AND GIVEN TO THE PANEL FOR CONSIDERATION IF NOT READ. AND THERE WILL BE A 10-MINUTE BREAK BETWEEN SESSIONS. SESSIONS WILL START ON TIME. I’M GOING TO ASK ALL THE OUR SPEAKERS OUT OF CONSIDERATION TO SPEAKERS THAT FOLLOW YOU TO TRY TO STAY WITHIN YOUR ALLOTTED TIME LIMITS. I’VE BEEN TO CONFERENCES WHERE — WHICH HAVE RUN OVER TIME AND WHERE SPEAKERS AT THE END OF THE DAY HAVE BEEN ASKED TO RESTRICT THEIR PREPARED REMARKS TO HALF THEIR LENGTH, AND WE DON’T WANT THAT TO HAPPEN. SO, THOSE ARE THE GROUND RULES FOR TODAY. AS DR. MURRAY INDICATED, COMMENTS ARE ENCOURAGED ON TWITTER, BY E-MAIL, YOU KNOW, AND OTHER FORMS. AND ANONYMOUS COMMENTS CAN ALSO BE SUBMITTED BY LAPTOP COMPUTER LOCATED OUTSIDE THE AUDITORIUM. SO, THANK YOU. WE ARE RELATIVELY ON TIME. AND I BELIEVE THAT WE’RE GOING TO KICK THIS OFF WITH AN OVERVIEW OF OSTEOPOROTIC DRUG TREATMENT AND LISTEN TO SHANE AS THE FIRST SPEAKER.>>THANK YOU VERY MUCH. I WOULD LIKE TO SAY THAT I’M VERY EXCITED TO BE HERE TODAY. I’M ELIZABETH SHANE, PROFESSOR OF MEDICINE AT COLUMBIA UNIVERSITY COLLEGE OF PHYSICIANS AND SURGEONS IN NEW YORK. AND I JUST THINK IT’S A VERY EXCITING TIME TO SEE WHAT HAPPENED AT COUNCIL A YEAR AND A HALF AGO COME TO FRUITION IN THIS WONDERFUL CONFERENCE AND THANK EVERYBODY INVOLVED FOR BRINGING IT TO PASS. HERE ARE MY DISCLOSURES, INDUSTRY SUPPORT TO MY INSTITUTION FROM LILLY, AMGEN AND MERCK. OBJECTIVES TO HAVE SUMMARIZE EFFECTS ON OLDER MEN AND WOMEN IN THE UNITED STATES. IN SO DOING TO PRESENT RATIONALE FOR HOLDING THIS CONFERENCE AT THIS TIME. I HOPE YOU’LL PERMIT ME AS SOMEONE WHO GREW UP IN CANADA IF I BORROW A PHRASE FROM THE DECLARATION OF INDEPENDENCE, THESE TRUTHS WE HOLD TO BE SELF EVIDENT. I WILL PRESENT EVIDENCE DURING MY TALK ABOUT EACH OF THE FOLLOWING TRUTHS THAT WILL SERVE AS OUTLINE OF MY TALK. OSTEOPOROTIC FACTS AFFECT MILLIONS OF OLDER MEN AND WOMEN IN THE UNITED STATES. LOW BONE MINERAL DENSITY, A MAJOR PREDICOR OF FRACTURES, AFFECTS MILLIONS MORE. FRACTURES BEGET MORE FRACTURES. WOMEN AND MEN WHO FRACTURE HAVE SIGNIFICANTLY INCREASED MORTALITY AND MORBIDITY. DECREASED QUALITY OF LIFE AND THEY DON’T LIVE INDEPENDENTLY. FRACTURES ARE ASSOCIATED WITH GREATLY INCREASED HEALTH CARE COSTS. THEY CAN BE PREVENTED WITH EFFECTIVE MEDICATIONS, BUT THESE MEDICATIONS ARE NOT BEING USED EFFECTIVELY. THESE STATEMENTS CAN BE CONSIDERED TRUTHS BECAUSE THEY ARE SUPPORTED BY A WEALTH OF EVIDENCE AVAILABLE BECAUSE OF THE CONTRIBUTIONS OF THOUSANDS OF MEN AND WOMEN OF ALL RACES, ETHNICITIES AND NATIONALITIES WHO VOLUNTEERED FOR HIGH QUALITY EPIDEMIOLOGIC STUDIES OF OS OSTEOPOROSIS, RANDOMIZED TRIALS, EFFORTS OF THOUSANDS OF BASIC INVESTIGATORS WORLDWIDE, AND HUNDREDS OF MILLIONS OF RESEARCH DOLLARS THAT HAVE BEEN DIRECTED TOWARDS CONQUERING OSTEOPOROSIS. FRACTURES AFFECT MILLIONS IN THE UNITED STATES. THERE ARE 1 1/2 TO 2 MILLION FRACTURES ALONE EVERY YEAR, VERTEBRA, HIP, FOREARM AND PELVIS MOST COMMON. WOMEN SUSTAIN ABOUT 70% OF THESE FRACTURES, AND MEN MAINLY NON-HISPANIC WHITE MEN SUSTAIN ABOUT 30%. AND 50% OF WOMEN OVER 50, 25% OF MEN OVER 65 ARE GOING TO SUSTAIN ONE OR MORE OSTEOPOROTIC FRACTURES DURING THEIR REMAINING LIFE. AND THIS MEANS THAT EITHER YOU OR SOMEONE YOU KNOW IS GOING TO HAVE AN OSTEOPOROTIC FRACTURE. LOW BONE MINERAL DENSITY, A MAJOR PREDICTOR OF FRACTURES, AFFECTS MILLIONS MORE. THE PREVALENCE OF OSTEOPOROSIS AND LOW BONE MASS IN THE UNITED STATES BASED ON BONE MINERAL DENSITY OF THE SPINE AND FEMORAL NECK WAS RECENTLY UPDATED, USING NHANES DATA FROM 2005 TO 2010, RECENT UPDATE FOUND 10% OF ADULTS OVER 50 HAVE OSTEOPOROSIS DEFINED BY T SCORE BELOW MINUS 2.5. THIS MEANS THERE ARE ABOUT 10.2 MILLION PEOPLE WITH OSTEOPOROSIS, AND ABOUT 43 MILLION WITH LOW BONE MASS. AND YOU CAN SEE THAT WOMEN MAKE UP THE MAJORITY BUT MEN ARE SUBSTANTIALLY REPRESENTED IN THESE NUMBERS. USING THE NATIONAL BONE HEALTH ALLIANCE CRITERIA, THE PREFERENCE OF OSTEOPOROSIS MAY BE HIGHER, THESE CRITERIA ARE A HIP OR SPINE T SCORE BELOW MINUS 2.5, LOW BONE MASS, MORE THAN 20% FOR A MAJOR OSTEOPOROTIC FRACTURE. 30% OF WOMEN OVER AGE 50 AND 16% OF MEN OVER AGE 50 HAVE OSTEOPOROSIS AS SO DEFINED, INCIDENCE INCREASES STEEPLY WITH INCREASING AGE. LOW FEMORAL NECK BONE DENSITY PREDICTS INCIDENT FRACTURES, AND THIS IS EVIDENCED BY MAINLY POST MENOPAUSAL WOMEN
IN THIS COUNTRY. SHOWING LOW BMD PREDICTS FRACTURES. IN A META-ANALYSIS OF 9,000 MEN AND 29,000 MEN FROM 12 COHORTS, AT THE AGE OF 65 FOR EVERY ONE STANDARD DEVIATION, THERE’S A THREE-FOLD INCREASE RISK OF HIP FRACTURE, 40% INCREASED RISK OF ALL OSTEOPOROTIC FRACTURE. FURTHER EVIDENCE THAT IT PLAYS A ROLE IN FRACTURE RISK WAS RECENTLY PUBLISHED IN THE BRITISH MEDICAL JOURNAL, IN THE FORM OF METANALYSIS OF GWAS FROM 25 INTERNATIONAL COHORTSA LARGE STUDY WITH GENOTYPE M FRACTURE DATA ON 565,000 PEOPLE. THE GWAS EXAMINED 15 GENETICALLY DETERMINE RISK FACTORS FOR FRACTURE. ALL OF THE 15 LOCI ASSOCIATED WERE LINKED TO BONE DENSITY. 55% INCREASE IN FRACTURE RISK PER 1 STANDARD DEVIATION AT THE FEMORAL NECK, 43% INCREASE PER 1 STANDARD DEVIATION DECREASE AT THE LUMBAR SPINE. FRACTURES BEGET MORE FRACTURES, INCREASING THE RISK BY FIVE-FOLD OF INCIDENT, HIP BY THREE-FOLD, ANY NON-VERTEBRA FRACTURE BY TWO-FOLD. ALSO A PREVALENCE PREDICTED SECOND FOR UP TO 15 YEARS. 26% OF WOMEN WITH AN INCIDENT VERTEBRAL FRACTURE HAD A SECOND FRACTURE WITHIN ONE YEAR. IN THE GLOW STUDY WOMEN WITH HIP FRACTURE HAD HIGHER WELCOME, 17% OF PATIENTS OVER 65 AND 12% OF PATIENTS OVER 50 HAD A SECOND FRACTURE WITHIN ONE YEAR OF AN INDEX FRACTURE WITH INCREASED MORTALITY AND MORBIDITY. THIS IS MOST — THE MOST EVIDENCE AFTER HIP FRACTURE, I’LL SHOW ONE STUDY OF A METANALYSIS OF 49 INTERNATIONAL COHORTS OF MEN AND WOMEN OVER AGE 50, A FIVE TO EIGHT-FOLD INCREASED RISK FOR ALL CAUSE MORTALITY IN THE FIRST THREE MONTHS, THAT MORTALITY — SORRY, PERSISTED FOR MORE THAN TEN YEARS. IT WAS HIGHER IN MEN THAN WOMEN, HIGHER IN AFRICAN-AMERICANS. INCREASED MORTALITY HAS ALSO BEEN REPORTED IN ASSOCIATION WITH OTHER FRACTURES, MAINLY BASED ON SOF IN WOMEN. VERTEBRAL FRACTURES INCLUDING INCIDENT, PREVALENT AND CLINICAL VERTEBRAL FRACTURES HAVE BEEN ASSOCIATED WITH INCREASED MORTALITY AS HAS PELVIS, FEMUR, TIBIA, MULTIPLE RIB FRACTURES, EVEN MINOR FRACTURES. NOW TURNING TO QUALITY OF LIFE, ABILITY TO LIVE INDEPENDENTLY, AFTER HIP FRACTURE IT’S BEEN REPORTED THAT 50% OF PATIENTS HAVE WALKING DISABILITIES AT 12 AND 24 MONTHS AFTER THE EVENT. SIGNIFICANTLY MORE TRANSFERRING DIFFICULTY. OLDER PATIENTS, BLACK AND HISPANIC HAVE WORST OUTCOMES. VERTEBRAL TRACTS ASSOCIATED WITH BACK PAIN, DISABILITY, LIMITED ADLs, AND THIS IS TRUE WHETHER CLINICAL OR ASYMPTOMATIC, WHETHER INCIDENT OR PREVALENT, AND IT IS WORSE WITH INCREASING NUMBER AND SEVERITY OF VERTEBRAL FRACTURES. THIS IS IMPORTANT BECAUSE VERTEBRAL FRACTURES AFFECT YOUNGER PEOPLE. A FIGURE SHOWS FROM A STUDIED IN KOREA, THAT SHOWS HEALTH RELATED QUALITY OF LIFE IN THE GENERAL POPULATION, PATIENTS WERE OSTEOPOROSIS HAVE A LOWER QUALITY OF LIFE, SIGNIFICANTLY, AS TO PATIENTS WITH ANY FORM OF FRACTURES. THE LOWEST IS PATIENTS WHO HAVE HAD TWO OR MORE FRACTURES. NOW TURNING TO THE INCREASED HEALTH CARE COSTS ASSOCIATED WITH OSTEOPOROSIS, IN 2005 THERE WERE 2 MILLION INCIDENT FRACTURES IN THIS COUNTRY THAT ENGENDERED $17 BILLION IN ANNUAL COSTS. WITH THE AGING OF THE U.S. POPULATION, BY 2025 THIS IS ESTIMATED TO INCREASE TO 3 MILLION INCIDENT FRACTURES, $25 BILLION IN HEALTH CARE COSTS. HEALTH CARE COSTS HAVE ALSO BEEN ESTIMATED IN ASSOCIATION WITH DIFFERENT FRACTURE TYPES. THE ESTIMATED PER PATIENT DIRECT COST FOR FIRST YEAR AFTER FRACTURE IS $30,000 FOR HIP, 11 FOR NON-HIP, NON-SPINE FRACTURE, 8,000 FOR VERTEBRAL FRACTURE. HOWEVER, BECAUSE THERE ARE SO MANY MORE NON-HIP, NON-SPINE FRACTURES, FIVE TIMES MORE, THEY ACTUALLY ARE MORE COSTLY THAN FRACTURES — THAN HIP FRACTURES. IN ABOUT 50,000 MEDICARE PATIENTS RECENTLY TOTAL ANNUAL DIRECT COST 70% HIGHER IN FRACTURE THAN NON-FRACTURED CONTROLS. MOREOVER NOT SURPRISINGLY FRACTURE PATIENTS WHO GO ON TO HAVE A SECOND FRACTURE HAVE EVEN HIGHER TOTAL HEALTH CARE COSTS, 1.75-FOLD HIGHER IN MEDICARE PATIENTS, 2-FOLD HIGHER IN COMMERCIALLY INSURED PATIENTS. OSTEOPOROSIS CAN BE — FRACTURES CAN BE PREVENTED WITH EFFECTIE MEDICATION. I WOULD LIKE TO POINT OUT THAT IT IS VERY IMPORTANT TO ENCOURAGE ADEQUATE CALCIUM, VITAMIN D AND EXERCISE AND TO IMPLEMENT FALL PREVENTION FRACTURES STRATEGIES BEFORE AND AFTER OSTEOPOROSIS IS DIAGNOSED. BUT ONCE THIS DISEASE HAS DEVELOPED, DRUG THERAPY IS NECESSARY TO PREVENT FRACTURES. AND WE HAVE HAD — FORTUNATE TO HAVE SEVERAL FDA-APPROVED MEDICATIONS THAT HAVE BEEN SHOWN IN THE SHORT-TERM, THREE YEARS TO FIVE YEARS, TO DECREASE FRACTURE RISK IN LARGE RANDOMIZED PLACEBO CONTROLLED TRIALS. I’M NOT GROWING TO SPEND A LOT OF TIME ON THIS BECAUSE IT WILL BE ADDRESSED BY OTHER SPEAKERS, BUT JUST TO SHOW THIS TABLE OF SHORT-TERM USE OF FDA APPROVED OSTEOPOROSIS THERAPIES, BY FRACTURE TYPE, AND BY CLASS, YOU CAN SEE THAT WE DO HAVE ABUNDANCE OF THERAPIES. HOWEVER, WE REALLY NEED MORE EVIDENCE TO GUIDE LONG-TERM USE OF OSTEOPOROSIS THERAPY AND THAT IS GOING TO BE AN IMPORTANT TOPIC OF THIS WORKSHOP. THESE EFFECTIVE MEDICATIONS ARE NOT BEING USED EFFECTIVELY. HERE WE HAVE A GRAPH OF ORAL BISPHOSPHONATE USE SINCE APPROVAL IN 1990s, PREVALENCE OF THEIR USE ROSE TO A PEAK IN 2006, AND SINCE 2008 THERE’S BEEN A STEEP 50% DECLINE. THIS DECLINE FOLLOWED MEDIA REPORTS OF OSTEONECROSIS OF THE LAW AND ATYPICAL FEMUR FRACTURES. WE SHOULD POINT OUT A PORTION OF THIS DECLINE MAY BE ENTIRELY AND IS PROBABLY ENTIRELY APPROPRIATE RELATING TO OUR ABILITY TO MORE PRECISELY LEARN HOW TO MORE PRECISELY TARGET THERAPIES TO THOSE AT HIGHEST RISK OF FRACTURE AND ALSO MAY SPEAK TO PRACTICE OF INITIATING DRUG HOLIDAYS. HOWEVER, OSTEOPOROSIS USE HAS DECLINED EVEN AFTER HIP FRACTURES WHICH EVERYBODY AGREES ARE A MANIFESTATION OF OSTEOPOROSIS. WE HAVE TWO RECENT STUDIES, EACH INCLUDING 100,000 HIP FRACTURE PATIENTS OVER 50, BOTH SHOWING DECLINE IN INITIATION OF OSTEOPOROSIS DRUG THERAPY AFTER HIP FRACTURE, THE STUDY BY SOLOMON WHICH IS PUBLISHED IN 2014, PATIENTS WERE BEING INITIATED ON TREATMENT AT RATE OF 40% AFTER HIP FRACTURE, IN 2002, AND 20% IN 2011. MORE RECENT STUDY THAT SHOWED THAT PATIENTS WERE BEING INITIATED AT A RATE OF ONLY 10% IN 2004, AND ARE DOWN TO 3% IN 20125 R. 15 — 2015. RECENTLY, EVEN MORE CONCERNING DATA HAS BEEN PUBLISHED SHOWING THAT THE DECLINING HIP FRACTURE 2002 TO 2012 MAY BE LEVELINGES- OFF. THIS IS AN ANALYSIS OF MEDICARE CLAIMS FRACTURE FOR HIP FRACTURE IN WOMEN OVER 65, AND YOU CAN SEE THAT HIP FRACTURE RATES HAVE STEADILY DECLINED FROM 2002 TO 2012, BUT PLATEAUED AT HIGHER THAN EXPECTED RATES IN 2013, 14 AND 15. AND FOR THE FIRST TIME IN 30 YEARS, HIP FRACTURE INCIDENTS RATES INCREASED 2 1/2 IN PATIENTS 60 TO 69, 4% IN 70 TO 74. THIS LEVELING OFF DURING THIS PERIOD HAS RESULTED IN ALMOST 11,500 MORE HIP FRACTURES, $459 MILLION MORE IN MEDICAL COSTS, AND ALMOST 2300 MORE DEATHS. SOME ATTRIBUTE THIS 50% — THIS DECLINE IN HIP FRACTURE RATES OR THIS LEVELING OFF IN HIP FRACTURE RATES TO A 70% DECREASE IN REIMBURSEMENT FOR OFFICE-BASED THAT HAS OCCURRED SINCE 2002. WHICH WAS TEMPORALLY ASSOCIATED WITH DECLINE DEXA TESTING AND DECLINE IN DIAGNOSING OSTEOPOROSIS. IN MY CLINICAL EXPERIENCE, SIDE EFFECTS LOOM LARGE FOR BOTH PATIENTS AND PHYSICIANS. PARTICULARLY OSTEONECROSIS OF THE JAW AND ATYPICAL FEMUR FRACTURES. THIS WAS BROUGHT HOME TO OUR SCIENTIFIC COMMUNITY BY THE FAMOUS 2016 “NEW YORK TIMES” ARTICLE THAT REPORTED HOW OSTEOPOROSIS DRUGS WERE BEING SHUNNED BY PATIENTS AND DOCTORS WERE AFRAID OF THESE RARE SIDE EFFECTS. AND IT WAS FURTHER BROUGHT HOME TO OUR SCIENTIFIC COMMUNITY BY THE PUBLICATION WHICH SHOWED THE MARKET SPIKES IN INTERNET SEARCH ACTIVITY THAT OCCUR IMMEDIATELY AFTER MEDIA REPORTS OF SAFETY CONCERNS, AND WHICH I SHOULD POINT OUT THAT THE SPIKES ARE RELATED TO THE LAY PRESS IN RED, FOUR TIMES HIGHER THAN THOSE RELATED TO SCIENTIFIC REPORTS IN BLUE FROM THE AMERICAN SOCIETY OF BONE AND MINERAL RESEARCH AND EVEN THE FDA. SO WE HAVE TO FIND A WAY OF PUBLICIZING THE GOOD THINGS ABOUT OSTEOPOROSIS TREATMENT TO THE COMMUNITY. AND WE KNOW FROM MULTIPLE SOURCES THAT THE RISK OF MAJOR OSTEOPOROTIC FRACTURES DWARFS ONJ IN A TYPICAL FEMUR FRACTURE. HERE WE SHOW THE RISK OF A MAJOR OSTEOPOROTIC IN HIGH, MODERATE AND LOW RISK WOMEN COMPARED TO THE RISK OF OSTEONECROSIS OF LAW OF JAW AND ATYPICAL FEMUR FRACTURES AFTER TWO OR EIGHT YEARS OF BISPHOSPHONATE THERAPY. AND YET THAT IS NOT REALLY HOW PATIENTS SEE IT OR THE PUBLIC SEES IT. WITH THIS EDITORIAL, SHORTLY AFTER THE KOLATA ARTICLE WAS PUBLISHED, ABOUT 35 PATIENTS RESPONDED BY E-MAIL, EACH DESCRIBING THEIR AFF EXPERIENCE, AND AS PHYSICIANS THESE ACCOUNTS WERE VERY HARROWING FOR US TO READ AND WE REALIZED WE HAD NOT TRULY BEEN LISTENING TO PATIENTS AND THAT EVEN WORSE WE’D LOST THE TRUST OF MANY OF THEM. BECAUSE AFF PATIENT’S VIEW, THESE FRACTURES ARE NOT RARE. THEY BELIEVE THEY ARE UNDERREPORTED AND POINT OUT RISK IS LOW UNTIL IT HAPPENS TO YOU. ONE PARTICULARLY COGENT REMARK WAS IT APPEARS THE PRESUMED NUMBER OF FRACTURES THAT MAY HAPPEN WITHOUT TREATMENT IS A STATISTIC OF MORE VALUE TO YOUR SOCIETY THAN THE REAL PEOPLE WHO LOST THEIR HEALTH BY MANY LEVELS, LOST THEIR DREAMS, SPENT RETIREMENT FUNDS ON MEDICAL BILLS AND IN MOST CASES LIVE IN PAIN EVERY DAY. SO, THE CENTRAL GOAL OF THE P2P CONFERENCE IS TO CONDUCT UNBIASED EXAMINATION OF THE SCIENCE UNDERPINNING THE DIAGNOSIS, PREVENTION AND TREATMENT OF OSTEOPOROTIC FRACTURES, AS CLINICIANS AND SCIENTISTS WE MUST LISTEN TO CONCERNS ABOUT SIDE EFFECTS, UNDERSTAND THE BARRIERS TO TREATMENT INITIATION AND ADHERENCE, FIND THE EFFECTIVE WAYS TO COMMUNICATE THAT OSTEOPOROTIC TOO HAVE DEVASTATING EFFECTS ON PEOPLE’S LIVES, RECOGNIZE THAT SIMPLY QUOTING STATISTICS IS NOT GOING TO CONVINCE PEOPLE TO TAKE DRUGS IF THEY ARE AFRAID OF THEM. AND USE THE KNOWLEDGE THAT WE’VE GAINED OVER THE PAST TEN YEARS SINCE THESE SIDE EFFECTS BECAME RECOGNIZED, TO PREVENT THEM BY IDENTIFYING PEOPLE AT HIGH RISK AND USING TECHNOLOGY TO DETECT SIDE EFFECTS BEFORE THEY OCCUR. SO TO SUM UP, OSTEOPOROTIC FRACTURES ARE COMMON, COSTLY, DEBILITATING, DISABLING AND DEADLY. ALTHOUGH WE HAVE DRUGS THAT PREVENT THEM, DRUGS ARE NOT BEING USED. THERE ARE MANY REASONS FOR THIS. BUT THEY MAY INCLUDE CONCERNS ABOUT SIDE EFFECTS AND LACK OF EVIDENCE SUPPORTING LONG-TERM USE. AND THESE ARE THE REASONS FOR HOLDING THIS P2P CONFERENCE AT THIS TIME. THANK YOU VERY MUCH MY TALK IS ON REVIEWING THE FDA APPROVED PHARMACOLOGIC OPTIONS FOR FRACTURE PREVENTION. THESE ARE MY DISCLOSURES. NON-PAID CONSULTANT FOR ON THE SCIENTIFIC ADVISORY BOARD OF A BIOTECH COMPANY. THIS PRESENTATION WILL NOT INCLUDE DISCUSSION OF UNLABELED PRODUCTS. SO WE WERE ASKED TO PROVIDE A SUMMARY SLIDE THAT SUMMARIZED OUR FINDINGS. AND MY MAIN MESSAGE IS THAT I’LL EXPAND UPON IN THE NEXT FEW MINUTES THAT THE PAST 30 YEARS HAVE TRULY WITNESSED REMARKABLE PROGRESS IN THE DEVELOPMENT OF NEW DRUGS TO PREVENT OR TREAT OSTEOPOROSIS. DESPITE THIS REMARKABLE PROGRESS, HOWEVER, THERE REMAIN PROFOUND CHALLENGES AS ELIZABETH HAS ALLUDED TO IN OSTEOPOROSIS TREATMENT DRIVEN IN PART BY CONCERNS ABOUT RARE SIDE EFFECTS, RELATED PRINCIPALLY TO BISPHOSPHONATE USE. I THINK ADDRESSING THESE CHALLENGES BY ENHANCING APPROPRIATE USE OF EXISTING DRUGS AND DEVELOPING NEW DRUGS THAT BOTH LACK THESE SIDE EFFECTS AND PERHAPS EVEN MORE EFFECTIVE IN REVERSING OSTEOPOROSIS REMAINS AN IMPORTANT GOAL FOR RESEARCH AND CLINICAL PRACTICE. SO I JOIN THE FACULTY OF MAYO CLINIC IN 1988, AND WHEN I WENT TO THE OSTEOPOROSIS CLINIC BASICALLY I WOULD OFFER WOMEN CALCIUM AND VITAMIN D, AND ESTROGEN AT THAT TIME, ORAL ESTROGEN. WE HAD LITTLE TO OFFER MEN. WE COULD USE A BISPHOSPHONATE OFF LABEL AND SOME PEOPLE USED CALCITONIN, IT’S RARELY USED TODAY. SO THAT WAS IN 1988. THIS IS WHERE WE ARE TODAY IN 2018 WHERE WE HAVE A NUMBER OF OPTIONS, TWO DIFFERENT FORMULATIONS OF ESTROGEN, A SELECTIVE ESTROGEN RECEPTOR MODULATOR, RALOXIFEN, AN ANTI-BODY, PTH AND PTHR. I COULD PUT CALCITONIN ON THE LIST. I DON’T, IT’S RARELY USED IN THE U.S., AND STRONTIUM IS NOT APPROVED IN THE U.S., RARELY USED NOW IN EUROPE I BELIEVE. ON THE HORIZON IS ANOTHER IMPORTANT DRUG THAT WILL BE REVIEWED BY THE FDA AND WE ALMOST HAD ANOTHER DRUG THAT UNFORTUNATELY DESPITE A HUGE INVESTMENT ON THE PART OF PHARMA WAS FINALLY PULLED FROM MARKET BECAUSE OF UNFORESEEN CARDIOVASCULAR SIDE EFFECTS. SO, IN TERMS OF ESTROGEN AND SERUM, I WANT TO REVIEW HOW WE GOT TO THESE DRUGS AND HOW THE PROCESS OF DRUG DEVELOPMENT HAS CHANGED. ESTROGEN GOES BACK MORE THAN — BACK TO 1940s, IN THE DAYS OF FULLER ALBRIGHT, WHERE HE FIRST OBSERVED THAT WOMEN WHO HAD HAD MENOPAUSE OOPHORECTOMY, HE COULD PREVENT BONE LOSS, THIS VERY OLD DRUG WAS DEVELOPED BASED ON ASTUTE CLINICAL OBSERVATIONS BY DR. ALBRIGHT. FOLLOWING THAT, MODERATORS WERE DEVELOPED USING MEDICINAL CHEMISTRY APPROACH, FABLED EFFECTS ON BONE, NEUTRAL EFFECTS ON BREAST TISSUE AND UTERUS, SO PRESUMABLY HAVE A BETTER SAFETY PROFILE THAN USING ESTROGEN. THE OTHER DRUGS, THE FIRST OF WAS WAS ALENDRONATE, THE BISPHOSPHONATES, OF INTEREST BECAUSE THEY HAD BEEN KNOWN FOR MANY YEARS AS AN A LOGS OF PYROPHOSPHATE COMPOUNDS, NATURALLY OCCURRING PYROPHOSPHATES, ENDOGENOUS WATER SOFT ENSURE IN THE BODY. EARLY USE OF BISPHOSPHONATES WAS NOTHING TO DO WITH MEDICINE. IT WAS CORROSION INHIBITORS, COMPLEXING AGENTS IN OTHER INDUSTRIES. THEY WERE SUBSEQUENTLY ALMOST ACCIDENTALLY FOUND TO INHIBIT CALCIFICATION AND LATER FOUND TO INHIBIT BONE RESORPTION, AND IN FACT EVEN THOUGH DRUGS HAVE BEEN WIDELY USED, THEIR UNDERLYING MECHANISMS WERE WORKED OUT DECADES AFTER THEIR CLINICAL USE HAD BEEN INITIATED. THESE DRUGS HAD EXTREMELY EFFECTIVE, YOU CAN SEE FOR VERTEBRAL OR HIP FRACTURES, FOR VERTEBRAL FRACTURES FROM 40 TO 70% REDUCTION, FROM 40 TO 50% REDUCTION IN HIP FRACTURES. THE BISPHOSPHONATES CAME ABOUT AS AN OPPORTUNISTIC DISCOVERY, COMPOUNDS USED FOR SOMETHING ELSE WERE FOUND TO HAVE OPPORTUNISTIC EFFECT ON BONE. PTH AND PTHRP INCREASE BONE MASS, ALL OF THESE INHIBIT BONE RESORPTION. THESE TWO APPROVED DRUGS RELATED TO EACH OTHER THAT CAN BUILD BONE MASS. THE DISCOVERY OF THESE DRUGS ACTUALLY ALSO GOES BACK TO FULLER ALBRIGHT, HE MADE AN IMPORTANT CLINICAL OBSERVATION THAT IF YOU HAD CHRONIC PARATHYROID HORMONE EXCESS IT CAUSED BONE LOSS BUT NOTED INCREASES IN BONE FORMATION, AND THEN ANIMAL AND HUMAN STUDIES SHOWED THAT IN CONTRAST TO CONTINUOUS EXPOSURE TO PTH IF YOU GAVE PTH INTERMITTENTLY, ONCE A DAY, THAT INCREASED BONE FORMATION WITH SMALLER INCREASES IN BONE RESORPTION, AND OF COURSE PIVOTAL CLINICAL TRIAL WAS DONE IN 2001 SHOWING IMPORTANT FRACTURE RISK REDUCTION, AND THE ANALOG OF PTHRP HIGHLY RELATED TO PTH, THAT MAY HAVE SOME ADVANTAGES IN TERMS OF GREATER INCREASES IN BONE MASS BUT OVERALL SIMILAR. IMPORTANTLY, DESPITE INVESTIGATION THE UNDERLYING MECHANISMS FOR THE ANABOLIC EFFECTS OF PTH ON THIS BONE TO THIS DAY REMAIN UNCLEAR. THIS FALLS IN IN TERMS OF CLINICAL OBSERVATIONS LEADING TO ANIMAL AND THEN HUMAN STUDIES AS A NEW DRUG WAS DEVELOPED. THE FIRST DRUG THAT CAME ABOUT WAS THE RANK LIGAND ANTIBODY, DEVELOPED BY TWO GROUPS, BASED ON THE DISCOVERY OF A RELATED MOLECULE OSTEOPROTOGERIN, OPG DISCOVERED BY THE AMGEN AND JAPANESE GROUP. THE DRUG DISCOVERY PROCESS WAS INTERESTING IN THE AMGEN GROUP AT THE TIME HAD NO INTEREST IN BONE. THEY WERE INTERESTED IN MOLECULES RELATED TO THE TNF FAMILY, MAKING TRANSGENIC MICE OVEREXPRESSING DIFFERENT TNF MOLECULES. ONE OF THE MICE HAPPENED TO HAVE A MARKED INCREASE IN BONE MASS AND THAT’S IN FACT HOW THAT DRUG COMPANY GOT INTO IN BONE BECAUSE MOSTLY INTERESTED IN INFLAMMATION. WHEN THEY KNOCKED OUT OPG THESE MICE HAD SEVERE OSTEOPOROSIS AS WELL AS INTERESTINGLY ARTERIAL CALCIFICATIONS. THEY THEN USED OPG AS A PROBE TO IDENTIFY OGR, RANK LIGAND, IT BECAME CLEAR WITH M-CSF, THIS DISCOVERY COMING OUT OF REALLY GENOMICS DISCOVERY OPENED UP A WHOLE NEW AREA OF BONE BIOLOGY, AND WHEN YOU KNOCKED OUT RANK LIGAND HAD SEVERE INCREASE IN BONE MASS AND DEFECTS IN MAMMARY GLAND DEVELOPMENT. RANK WAS EASILY IDENTIFIED BECAUSE IT WAS ALREADY KNOWN AS THE RECEPTOR FOR RANK LIGAND. IF YOU KNOCK OUT RANK THEY HAD INCREASE IN BONE MASS. SO THIS LED TO UNRAVELING THE PATHWAY OF RANK LIGAND DRIVING OSTEOCLAST DEVELOPMENT, OPG IS A NATURAL LIGAND THAT NEUTRALIZES, AND DENOSUMAB IS THE MONOCLONAL ANTIBODY WHICH BLOCKS THIS PROCESS. DENOSUMAB IS EFFECTIVE. THESE ARE THE FRACTURE DATA FOR NON-VERTEBRAL FRACTURES. YOU CAN SEE ALMOST 70% REDUCTION IN NON-VERTICAL BRACKS WITH DENOSUMAB, EFFECTS VERY EARLY, ARE SUSTAINED TO THREE YEARS. IN CONTRAST TO THESE DRUGS HERE IT WAS FUNDAMENTAL BONE BIOLOGY DISCOVERY SCIENCE DRIVING NOVEL THERAPEUTIC, AND THIS IS ALSO TRUE OF THE NEW DRUG ON THE HORIZON, THIS IS RELATED TO WNT SIGNALING AND BONE. AND THE DEVELOPMENT OF THIS DRUG ACTUALLY GOES BACK AS INCREASINGLY COMMON TO RARE FAMILIES WITH AN ACTIVATING MUTATIONS IN LRP 5, RECEPTOR FOR WNTs, RESULTING IN OSTEOPOROSIS. ACTIVATING MUTATIONS IN LRP 5 LED TO HIGH BONE MASS, ALSO ASSOCIATED WITH INACTIVATING MUTATIONS IN A PROTEIN THAT PREVENTS BINDING WNTs TO LRP 5. IF YOU KNOCK OUT OST, YOU EXPECT INCREASE IN BONE MASS. THIS IS AT 12 AND 24 MONTHS, A VERY EFFECTIVE THERAPY, RARE BONE DISEASE TO FUNDAMENTAL BONE BIOLOGY TO NOVEL THERAPEUTIC. I DON’T HAVE TIME TO GO INTO
THE TOULOUSE-LAUTREC SYNDROME DRIVING THIS NOVEL THEY ARE MUTIC. — THERAPEUTIC. 2000 WAS A WATERSHED YEAR. PRIOR, MOST DRUGS REALLY CAME OUT OF THE ASTUTE CLINICAL OBSERVATIONS OR OPPORTUNISTIC DISCOVERIES, MEDICINAL CHEMISTRY, SINCE 2000 IT’S BEEN EITHER FUNDAMENTAL BIOLOGY OR RARE BONE DISEASES THAT HAVE DRIVEN THE NEW DRUG DEVELOPMENT IN OSTEOPOROSIS. AND THESE DRUGS ARE AS EFFECTIVE OR MORE THAN THE EARLIER DRUGS THAT HAD BEEN DEVELOPED. SO, COMPARED TO WHEN I WENT TO THE OSTEOPOROSISES ON CLINIC IN 1988, NOW I CAN OFFER ESTROGEN, RALOXIFENE. I PARADIGM FOR DRUG DEVELOPMENT HAS SHIFTED FROM OBSERVATIONAL AND OPPORTUNISTIC TO PATHWAY DRIVEN BY ADVANCES IN FUNDAMENTAL BONE BIOLOGY, TO A LARGE EXTENT GREAT AND RARE HAPPENING IN THE CARDIOVASCULAR FIELD, FOR EXAMPLE, AND WHEN I GIVE TALKS HERE OR TO MY COLLEAGUES AT NIH, I SAY OSTEOPOROSIS ACTUALLY IS A REALLY GOOD EXAMPLE OF HOW INVESTING IN DISCOVERY SCIENCE BY FEDERAL RESOURCES AND PHARMA PAID OFF AND TRANSLATED INTO NOVEL THERAPEUTICS THAT WOULD NOT HAVE BEEN THERE WITHOUT THE DISCOVERY. HERE IS THE PROBLEM. ELIZABETH ALLUDED TO THIS. THIS WAS IN JUNE 2016. A COUPLE WEEKS BEFORE THE NIAMS COUNCIL THAT ELIZABETH AND I ATTENDED. THIS PAPER BY GINA KOLATA, MILLIONS TAKE THEIR CLANSES WITH OSTEOPOROSIS. AS DR. KATZ MENTIONED, THIS WHAT WE TOOK TO COUNCIL. AND MANY THANKS TO DR. KATZ AND OTHERS WHO TOOK OUR CONCERNS SERIOUSLY AND REALLY LED TO THIS EFFORT AS WELL AS THE ASBMR EFFORT WITH THE CENTER FOR MEDICAL TRANSLATION POLICY. SO, THE PROBLEM, BISPHOSPHONATE USE PEAKED AROUND 2006 AND 2007, DECLINED EVER SINCE. I THINK GIVEN THE FACT THAT WE HAVE SO MANY TERRIFIC OPTIONS FOR THE TREATMENT OF OSTEOPOROSIS, YET TREATMENT IS DECLINING AND FRACTURE RATES INSTEAD OF CONTINUING TO DECLINE ARE STARTING TO PLATEAU OR GO UP I THINK NOW IS THE TIME FOR ACTION. SOMEHOW WE HAVE TO FIGURE OUT HOW TO ENHANCE APPROPRIATE USE OF EXISTING DRUGS, IT INVOLVES ALL OF THE THINGS THAT ELIZABETH MENTIONED, ENGAGING PRIMARY CARE PHYSICIANS, LISTENING TO OUR PATIENTS, I HAVE TO ECHO ELIZABETH’S SENTIMENTS AFTER WE WROTE OUR PAPER IN THE JOURNAL OF BONE AND MINERAL RESEARCH ON THE CRISIS IN OSTEOPOROSIS, THE LETTERS THAT WE GOT WERE TRULY HEART WRENCHING. THESE WERE PATIENTS WHO HAD SUFFERED REALLY BAD SIDE EFFECTS FROM THESE DRUGS. AND YET THEY WERE A PROFOUND MINORITY COMPARED TO THOUSANDS OF FRACTURES, HUNDREDS OF THOUSANDS OF FRACTURES THAT HAD BEEN PREVENTED WORLDWIDE. SO WE HAD TO KEEP IN MIND ALL OF THE GOOD THAT THESE DRUGS HAVE DONE AGAINST THE RARE SIDE EFFECTS, AND HOW CAN WE USE THESE DRUGS BETTER TO MINIMIZE OR PREVENT THOSE SIDE EFFECTS FROM OCCURRING. I STILL THINK THAT DESPITE THAT, WE NEED NEW DRUGS THAT LACK SIDE EFFECTS AND HAVE GREATER SKELETAL EFFICACY. IF YOU WANT TO REVERSE THE DISEASE ALMOST ALL THE DRUGS PREVENT FURTHER BONE LOSS BUT IF YOU WANT TO CURE OSTEOPOROSIS, YOU WANT TO BUILD THE BONE BACK UP, TELPERATD TO TO EXTENT, BUT THE EFFECT OF THOSE DRUGS OVER SIX TO NINE MONTHS. WE’LL NOT HAVE A DRUG THAT CAN TAKE A PATIENT OF A T SCORE OF MINUS 3 AND BRING IT BACK TO MINUS 1 POINT 1 — 1.5. THERE NEEDS TO BE CONTINUED SEARCH FOR NEW DRUGS THAT ARE ACTUALLY ABLE TO FULLY CURE OSTEOPOROSIS. WITH THAT ALL STOP.>>GOOD MORNING. SO I’M FAYE CHEN, AS DR. KATZ AND DR. MURRAY HAVE INTRODUCED. DR. JOSEPH AND I WERE THE SCIENTIFIC ORGANIZERS. IN THE NEXT TEN MINUTES I WANT TO GIVE YOU A SENSE OF NIH ACTIVITIES INFORMING OSTEOPOROTIC FRACTURE PREVENTION. I WANT TO THANK OUR PANEL FOR ALL THE HARD WORK YOU’RE PUTTING INTO THE WORKSHOP, WE WANT TO THANK OUR SPEAKERS FOR YOUR TIME AND EFFORT, THANK OUR LEADERSHIP AND COLLEAGUES FOR HELPING, FOR SUPPORTING US IN BRINGING THIS MEETING TOGETHER. WE HAVE NO CONFLICTS OF INTEREST TO DISCLOSE. MY TALK FOCUSES ON RESEARCH PORTFOLIO BUT I WILL NOTE TWO OTHER IMPORTANT ACTIVITIES OF NIH, ONE IS TRAINING THE NEXT GENERATIONS OF RESEARCHERS, AND THE OTHER ONE IS DISSEMINATING THE RESEARCH FINDINGS AND THE OTHER RELATED HEALTH INFORMATION TO AMERICANS. NIH INVESTMENT GOES TO SUPPORT BASIC TRANSLATION AND CLINICAL RESEARCH AT INSTITUTIONS AROUND THE NATION. NIMS AND NIA ARE THE LARGEST FUNDERS OF OSTEOPOROTIC RESEARCH, MANY OTHER INSTITUTES AND CENTERS ALSO SUPPORT WORK IN THIS AREA AS YOU CAN SEE ON THE PIECHART ON THE LEFT-HAND SIDE. RESEARCH COVERS A WIDE RANGE OF TOPICS, BONE QUALITY, BONE FORMATION, AND TURNOVER AND RAW MECHANICAL LOADING AND BONE HEALTH JUST TO NAME A FEW. IN ADDITION TO FUNDING RESEARCH, NIH ALSO INVESTS IN TRAINING THE NATION’S NEXT GENERATION OF RESEARCHERS. YOU CAN SEE ON THE RIGHT-HAND SIDE WE USE DIFFERENT GRANT MECHANISMS TO TRAIN AT DIFFERENT STAGES OF THEIR CAREER DEVELOPMENT. NOW LET ME GIVE YOU A FEW EXAMPLES HOW NIH-SUPPORTED RESEARCH CONTRIBUTES TO OUR UNDERSTANDING OF FRACTURE PREVENTION. WE KNOW THE WOMEN’S HEALTH INITIATIVE, THE RESULTS FROM THE STUDY HAVE SHAPED OUR CURRENT USE OF HORMONE THERAPIES. AND WE KNOW NIH HAS SUPPORTED THIS RESEARCH. WHI HAS STRONG OSTEOPOROSIS AND BONE COMPONENTS. , FOR EXAMPLE, IT HAS SHOWN EFFECT OF CALCIUM PLUS VITAMIN D, AND THERAPY AS WELL AS WHAT HAPPENS TO THE FRACTURE RISK IF ONE DISCONTINUES FORMAL THERAPY. DR. REBECCA JACKSON, WHO IS HERE, WHO LED WHI BONE STUDIES, WILL TALK ABOUT THE CONSIDERATIONS OF USING HORMONE THERAPY FOR PREVENTING AND TREATING OSTEOPOROSIS LATER. ALSO SUPPORTED LARGE EPIDEMIOLOGY STUDIES, SUCH AS STUDY OF OSTEOPOROTIC FRACTURE IN WOMEN AND FRACTURES IN MEN TO NAME A FEW. STUDIES REVIEWED MANY OF THE RISK FACTORS WE KNOW NOW ON OSTEOPOROSIS AND FRACTURE PREVENTION. FOR EXAMPLE, VERY IMPORTANT FINDINGS, THE FIRST STUDIES TO SHOW BONE MINERAL DENSITY BMD STRONGLY PREDICTED WHETHER A MAN OR WOMAN WILL SUFFER AN OSTEOPOROTIC FRACTURE. AS YOU MAY KNOW AFTER YOU PROCESS DRUG TRIALS FOR FDA APPROVAL, SO FAR HAVE USED FRACTURE AS OUTCOMES. THIS REALLY REQUIRES A LARGE NUMBER OF TRIALS, PATIENTS TO BE INVOLVED FOR A RELATIVELY LONG TIME AND THAT CAUSE OF THE TRIALS CAN BE VERY HIGH. TO ADDRESS THIS ISSUE, NIH ALONG WITH FDA HAVE COLLABORATED IN A PUBLIC/PRIVATE PARTNERSHIP IN THE BONE QUALITY PROJECT WITH MANY OF THE PHARMACEUTICAL COMPANIES WHO HAVE BROUGHT THE OSTEOPOROSIS DRUGS INTO CLINICAL USE. SO THE GOAL OF THIS PROJECT IS TO USE PATIENT-LEVEL DATA TO DEVELOP SURROGATE ENDPOINTS FOR FRACTURES. THIS SHOULD SIGNIFICANTLY DECREASE THE RESOURCES AND COST REQUIRED FOR DEVELOPING OSTEOPOROSIS DRUGS FOR FDA APPROVAL. INITIAL DATA LOOKED PROMISING, AND YOU’LL HEAR MORE ABOUT THIS PROJECT LATER AT THE MEETING. SO WITH UNPRECEDENTED ACCESS TO SUCH A HUGE AMOUNT OF DATA, AND WITH EXTRA INVESTIGATORS INCLUDING OUR SPEAKERS, DR. DENNIS BLACK, AND ALSO OUR NIAMS OWN PROJECT CHAIR WE’RE LOOKING FORWARD TO THIS PROJECT COMING TO FRUITION. NOW, WE’LL TALK ABOUT BMD IS ONE OF THE MOST IMPORTANT RISK FACTORS AND PREDICTORS FOR FUTURE FRACTURES. HOWEVER, BMD DOES NOT ALWAYS RELIABLY PREDIC FRACTURE RISK. FOR EXAMPLE, AS ILLUSTRATED HERE TWO BONE PIECES HAVE SIMILAR BMDs, DIFFERENT MICROARCHITECTURE, DIFFERENT BONE STIFFNESS. SO HAS STIMULATED RESEARCH FOR OTHER FACTORS THAT CONTRIBUTE TO BONE FRAGILITY AND BONE STRENGTH AND WE SUPPORT A ROBUST RESEARCH PORTFOLIO FOCUSING ON THIS AREA. NIH-SUPPORTED STUDIES LOOKING AT BETTER USE OF THE DRUGS WE HAVE AVAILABLE NOW, FOR EXAMPLE STUDIES EXPLORED POTENTIAL BENEFICIAL EFFECTS OF COMBINING ANABOLICS AND RESORPTIVE DRUGS, CAN BE IMPORTANT AS BLUNTING EFFECTS CAN BE OBSERVED WHEN PTH IS SOMETIMES USED, BISPHOSPHONATE, AND THIS IS POSSIBLY DUE TO THE COUPLING EFFECT OF BONE RESORPTION WITH BONE FORM ACE. MANY SUPPORT FUNDAMENTAL MECHANISMS GOVERNING BONE REMODELING PROCESS INCLUDING RESORPTION PROCESS WITH THE CELLS, AND EFFECTORS REGULATING THEM. THERE ARE A LOT OF EXAMPLES HOW KNOWLEDGE FROM NIH FUNDED BASIC RESEARCH AND NIH FUNDED INVESTIGATORS HAVE CONTRIBUTED CRITICAL INFORMATION TO EVENTUAL OSTEOPOROSIS DRUG DEVELOPMENT, FOR EXAMPLE WE KNOW FROM SUNDEEP THE RANK LIGAND IS AN EFFECTIVE RESORPTIVE. THE OTHER EXAMPLE VERY NICELY RELATED TO THE STUDY OF THE RARE BONE DISEASES, CAUSED BY MUTATIONS AND INVESTIGATION INTO THE WNT SIGNALING. THAT IS CURRENTLY BEING REVIEWED BY FDA AS POTENTIAL DRUG. YOU’VE HEARD FROM DR. SHANE AND WILL HEAR MORE LATER SERIOUS ADVERSE EVENTS ASSOCIATED WITH OSTEOPOROSIS THERAPIES BEING HEAVY PATIENTS AND PHYSICIANS MINDS, A TYPICAL FEMUR FRACTURE IS ONE OF SUCH EVENTS. NIH IS RECEIVING AND SUPPORTING RESEARCH ON RELATED TOPICS SUCH AS RISK FACTORS FOR ASF, PRODROMAL SYNDROME THAT MAY SERVE AS HARBINGER, AND INFLUENCE DRUG TREATMENT DURATION AND DRUG HOLIDAYS ON THE PATIENT’S RISK. DR. DENNIS BLACK, BOB ELLIS AND CONSTANT WILL ADDRESS TYPICAL FEMORAL FRACTURE LATER AT THIS MEETING. OSTEO NECROSIS OF THE JAW IS ANOTHER RARE BUT SERIOUS COMPLICATION. NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH NIDCR SUPPORTS INVESTIGATION ON THIS TOPIC. SO INFORMATIONING THAT WHEN THIS TOPIC FIRST CAME UP NIDCR ISSUED PROGRAM ANNOUNCEMENTS, NIH STIMULUS WILL USE TO STIMULATE RESEARCH IN A PARTICULAR TOPIC. MUCH INSIGHT HAS BEEN GAINED FROM RESEARCH SUPPORTED BY THIS PROGRAM ANNOUNCEMENT, ALONG WITH THOSE FROM THE DENTAL PRACTICE BASED RESEARCH NETWORK CONDUCTING RESEARCH AT THE FRONT LINE IN REAL WORLD DENTAL PRACTICE. AS WELL AS INVESTIGATOR RESEARCH. WE KNOW ABOUT MULTI-FACTOR RISK, MECHANISM OF ONJ, HOW TO MANAGE AND WHAT CAN BE DONE TO DECREASE IN THE FIRST PLACE. YOU’LL HEAR MORE ON THIS TOPIC LATER. NOW, I’VE SHOWN YOU A FEW IMPORTANT STUDIES RELATED TO THIS WORKSHOP FOCUS. IT IS ESSENTIAL THAT WE GET THIS RESULT AND RESULTS FROM OTHER STUDIES AND IMPORTANT BONE HEALTH INFORMATION OUT TO THE COMMUNITY FOR INFORMATION DISSEMINATION. WHAT DO WE STILL NEED TO KNOW TO GET PEOPLE TO APPROPRIATELY USE THE MEDICATIONS THAT CAN PREVENT OSTEOPOROTIC FRACTURES AND WHAT CAN BE DONE TO MAXIMIZE BENEFIT AND MINIMIZE RISKS? THIS IS THE FOCUS OF THIS MEETING. WE LOOK FORWARD TO HEARING THE DISCUSSIONS OVER THE NEXT DAY AND A HALF, AND ALSO LOOKING FORWARD TO THE PANEL REPORT AND RECOMMENDATIONS BECAUSE WE DO INTEND TO USE THEM TO FOSTER RESEARCH THAT WILL MOVE THE FIELD FORWARD. THANK YOU VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] [APPLAUSE]>>I’M THERESA KEHOE, CENTER OF DRUG EVALUATION AND RESEARCH AT FOOD AND DRUG ADMINISTRATION, OUR CONCENTRATION IS ON THE BONE DRUGS. I’M GOING TO TALK TODAY ABOUT HOW FDA PROCEEDS WITH THE TRANSLATIONAL PIPELINE. I CAN’T TELL YOU MUCH ABOUT THE TRANSLATIONAL PIPELINE BECAUSE THAT’S CONFIDENTIAL COMMERCIAL INFORMATION. SO WHAT I’M GOING TO DO IS WALK YOU THROUGH HOW THE FDA GETS TO THE POINT OF A NEW DRUGS BEING APPROVED FOR MARKETING IN THE UNITED STATES, THIS PATHWAY HAS EXISTED FOR ALL THE DRUGS YOU’VE HEARD ABOUT ALREADY FROM DR. KHOSLA AND NEW DRUGS COMING UP THE PIPELINE. I HAVE NO INFORMATION TO DISCLOSE EITHER FINANCIAL INTERESTS AND THE PRESENTATION WILL NOT INCLUDE UNLABELED USE. I HAVE A DISCLAIMER, BEING FROM THE FOOD AND DRUG ADMINISTRATION, THAT THE VIEWS EXPRESSED HERE REALLY ARE MINE AND NOT THE OFFICIAL POSITION OF THE U.S. FOOD AND DRUG ADMINISTRATION. WHAT YOU HEARD FROM DR. KHOSLA, IT’S A VERY ACTIVE AND DYNAMIC BASIC SCIENCE INTEREST IN BONE THAT WILL TRANSLATE INTO DRUGS COMING EVENTUALLY TO THE MARKET. BEFORE REACHING THE FDA, DEVELOP A NEW AND NOVEL THERAPIES REALLY BEGINS WITH THAT BASIC SCIENCE. UNDERSTANDING THE TARGETS, WHETHER IT’S BASED ON A RARE DISEASE OR SOME OTHER FORM OF THE SCIENCE, AND CREATING THERAPIES THAT CAN TARGET, INTERACT WITH THE TARGET IN A BENEFICIAL WAY. BUT ALSO THE BASIC SCIENCE CAN PROVIDE SOME INSIGHT INTO POTENTIAL SIDE EFFECTS THAT ONCE WE AT FDA ARE LOOKING AT THIS DRUG WE CAN MAKE SURE ARE TARGETED AND EVALUATED DURING THE CLINICAL RESEARCH PIPELINE. SO THIS IS JUST A — LET’S SEE. I MIGHT NEED HELP WITH THIS ONE. THIS IS A GRAPHIC OF THE TIME LINE FOR A DRUG DEVELOP. WITH THE FIRST PART OF THIS GROUP IT’S ALL THE PRE-CLINICAL RESEARCH. THIS IS ALL HAPPENING BEFORE WE EVER SEE THE APPLICATION. WHEN WE SEE IT, IT IS AN INVESTIGATIONAL NEW DRUG APPLICATION, AND IND IS REQUIRED WHEN UNAPPROVED DRUG IS ADMINISTERED TO HUMAN SUBJECTS IN THE UNITED STATES. OUR OBJECTIVE WHEN WE SEE A NEW IND IS TO ASSURE THE SAFETY AND RIGHT OF THE SUBJECTS IN ALL PHASES OF INVESTIGATION ARE BEING UPHELD AND IN LATER STAGES OF DEVELOPMENT TO HELP ASSURE THE QUALITY OF THE SCIENTIFIC ASSESSMENTS ARE ADEQUATE TO PERMIT US TO MAKE AN EVALUATION OF THE PRODUCT SAFETY AND EFFECTIVENESS. BY THE TIME WE GET AN IND APPLICATION FOR NEW THERAPY IT CONTAINS ANIMAL STUDIES IN TWO SPECIES THAT SUPPORT SAFETY FOR THE FIRST DOSE TO BE GIVEN IN A HUMAN. WE REVIEW THAT ANIMAL DATA AND DETERMINE IF THE HUMAN DOSING IS SAFE TO PROCEED. WE’RE LOOKING AT THE DOSE, THE LEVEL, THE TIMING, AND SOMETIMES THE ANIMAL DATA WILL TELL US SAFETY EVALUATIONS THAT NEED TO OCCUR IN THOSE EARLY STUDIES. BUT SPECIFIC TO OSTEOPOROSIS DRUGS, THESE ANIMAL INVESTIGATIONS ALSO INCLUDE STUDIES SPECIFIC TO BONE. THAT IS BIOMECHANICAL STUDIES, AND MINERALIZATION STUDIES, THAT ARE IMPORTANT FOR LATER DEVELOPMENT. SO, WHEN WE GET IN THE CLINICAL RESEARCH FOR DRUG DEVELOPMENT, WE START WITH THE PHASE 1 STUDIES AND THESE START WITH THE FIRST IN HUMAN, AND PROGRESS ON. AND THIS IS USUALLY 20 TO 100 VOLUNTEERS, HEALTHY PATIENTS USUALLY, CAN OCCUR OVER SEVERAL MONTHS, AND THE MOST IMPORTANT FOCUS HERE IS SAFETY WITH SOME ON DOSE. WHEN YOU HAVE A NEW PRODUCT THAT YOU’RE STARTING TO CLINICALLY DEVELOP AS A NEW DRUG, ONLY ABOUT 70% OF THESE THAT ENTER AT PHASE 1 ACTUALLY MOVE TO PHASE 2. SO PHASE 2 IS WHERE YOU GET INTO THE LONGER-TERM MULTI-DOSE STUDIES THAT USUALLY TAKE SEVERAL HUNDRED PATIENTS, AND CAN TAKE MONTHS TO YEARS DEPENDING ON THE PROGRAM. AND YOU’RE STARTING TO LOOK AT EFFICACY AS WELL AS SAFETY.& THE DOSE FINDING STUDY IS PROBABLY THE MOST IMPORTANT PHASE 2 STUDY. GENERALLY A LONGER TERM STUDY. AND 33% OF THESE PRODUCTS WILL MOVE ON TO THE NEXT PHASE. PHASE 3 IS REALLY THE KEY PIVOTAL EFFICACY STUDIES. AND THEY CAN ENROLL 300 TO 3,000 OR AS WE KNOW WITH OSTEOPOROSIS DRUGS MANY MORE THOUSAND PATIENTS THAN THAT, TEND TO BE 1 TO 4 YEARS IN DURATION, THE FOCUS IS EFFICACY AND ALSO ADVERSE EVENT PROFILE TO BE ABLE TO LABEL THE DRUG. AND THEN WE WOULD GET A MARKETING APPLICATION. AND THE PHASE 4 STUDIES AFTER MARKETING. SO, FDA REALLY FOLLOWS THE SAFETY PATTERN OF A DRUG THROUGHOUT THE DEVELOPMENT STARTING IN PHASE 1 WITH THOSE ANIMAL STUDIES. WE CAN IMPOSE A CLINICAL HOLD AT ANY TIME IF LATER IN DEVELOPMENT, AS DEVELOPMENT PROGRESSES, THERE’S A SAFETY SIGNAL OF SUCH CONCERN WE DON’T THINK THE DRUG COULD BE USED IN HUMANS. YOU CAN DO A FULL HOLD WHERE THE DRUG HAS TO STOP, OR PARTIAL HOLD, IF YOU’RE LOOKING AT CERTAIN SUBSETS OF PATIENTS, YOU DON’T THINK SHOULD RECEIVE THE DRUG. IN LATER PHASES OF A CLINICAL DEVELOPMENT WE ALSO WORK WITH SPONSORS ON THE EFFICACY ENDPOINTS AND TRIAL DESIGN, AS I BRIEFLY SPOKE ABOUT. AND BONE MINERAL DENSITY CHANGES FOR US, WE FREQUENTLY USE THESE FOR DOSE FINDING STUDIES. BUT WHEN WE GET INTO OUR EFFICACY TRIALS, WE REALLY AT THIS POINT REQUIRE FRACTURE REDUCTION, BE THE PRIMARY ENDPOINT. THAT’S MORPHOMETRIC WITH RADIOGRAPHIC EVIDENCE OF VERTEBRAL FRACTURE. NON-VERTEBRAL FRACTURE AND HIP FRACTURES ARE OPTIONAL. AND AS WE KNOW, WHEN YOU START LOOKING AT THESE OPTIONAL ENDPOINTS OF NON-VERTEBRAL FRACTURE AND HIP FRACTURE THAT’S REALLY WHAT DRIVES THE NUMBER OF PATIENTS REQUIRED IN THIS STUDY. THE LARGEST STUDY FOR OSTEOPOROSIS DRUG THAT WE’VE SEEN HAS BEEN REQUIRED 17 TO 18,000 PATIENTS BE ENROLLED. SO WHEN YOU START TO LOOK AT A HIP FRACTURE ENDPOINT AGAINST EVEN PLACEBO, YOU LOOK AT VERY LARGE TRIALS OVER A NUMBER OF YEARS TO ANSWER THAT EFFICACY QUESTION. BONE MINERAL DENSITY IS DONE AS A SECONDARY ENDPOINT IN MOST ALL OF OUR STUDIES, AS YOU HEARD FROM DR. CHEN THERE IS AN ACTIVE LOOK AT TRYING TO FIND A SURROGATE ENDPOINT TO REQUIRING THESE FRACTURES. THERE’S HISTORY OF WHY WE DO BUT WE DO FEEL FROM OUR PERSPECTIVE THAT THERE IS PERHAPS NOT AS MUCH INTEREST IN PURSUING THESE THERAPIES, BECAUSE BY THE TIME YOU GET INTO PHASE 3 IT’S A VERY LARGE TRIAL WHICH REQUIRES A LARGE AMOUNT OF FUNDING SOME COMPANIES MAY NOT BE WILLING TO PROGRESS WITH. DEMONSTRATION OF SAFETY IS THE SECOND PART OF WHAT MAIN FOCUS, RELYING ON ICH GUIDELINES, GUIDELINES FOR CHRONIC DISEASE 500 TO 1500 PATIENTS EXPOSED TOTAL SO 300 TO 600 PATIENTS FOR SIX MONTHS, 100 PATIENTS EXPOSED FOR A YEAR WE ARE WELL AHEAD OF THE CURVE LOOKING AT SAFETY AND ADVERSE EVENTS BUT WHEN YOU LOOK AT CHRONIC TRIALS SAFETY EVALUATIONS IN CLINICAL DEVELOPMENT ARE NOT EXPECTED TO CHARACTERIZE RARE EVENTS LIKE WE’VE SEEN WITH OSTEOPOROSIS DRUGS. YOU’RE LIKING TO CHARACTERIZE EVENTS IN MORE THAN 1 IN A THOUSAND PATIENTS. VERY RARE EVENTS EVEN WITH THE VERY LARGE TRIALS WE HAVE ARE NOT SUFFICIENT. THESE TRIALS ARE NOT SUFFICIENT TO CAPTURE THOSE RARE EVENTS. WE’RE SUING UP TO 8,000 PATIENTS EXPOSED FOR TWO YEARS, WELL BEYOND WHAT THE ICH GUIDANCE CALLS FOR. NOW WE’RE READY FOR A MARKETING APPLICATION. A NEW APPLICATION FANTASTIC A SMALL MOLECULE OR BIOLOGICS LICENSE APPLICATION, REGULATIONS DIFFER SLIGHTLY BUT ARE PRETTY MUCH THE SAME. IT’S A COMPLETE APPLICATION THAT CON TAINTS ALL THE INFORMATION TO SUPPORT THE SAFETY AND EFFECTIVE USE OF THE DRUGS, THAT’S THE CHEMISTRY MANUFACTURING AND CONTROLS, NON-CLINICAL DATA, CLINICAL PHARMACOLOGY DATE AND CLINICAL SAFETY AND EFFECTIVENESS DATA AND ANY DATA ON A DEVICE, IF A DEVICE IS PART OF THE WAY THAT THE DRUG NEEDS TO BE ADMINISTERED. FDA IS RECEIVING STUDY REPORTS AND DATA SUBMITTED. OUR GOAL IS WHETHER THE DRUG IS SAFE AND EFFECTIVE FOR PROPOSED USE AND WHETHER THE BENEFITS OF THE DRUG OUTWEIGH RISK. WHETHER LABELING, PACKAGE INSERT IS APPROPRIATE AND WE FREQUENTLY WILL CHANGE WHAT WE FEEL NEEDS TO BE CONTAINED IN THAT LABELING, WHETHER ADDITIONAL RISK MITIGATION STRATEGIES ARE BEYOND — NEEDED BEYOND THE LABELING, AND THEN WHETHER THE METHODS USED IN THE MANUFACTURING OF THE DRUG AND CONTROLS USED TO MAINTAIN THE DRUG’S QUALITY ARE ADEQUATE TO PRESERVE. WE HAVE 6 TO 12 MONTHS REVIEW TIME LINE FOR AN APPLICATION LIKE THIS. OUR DECISION TO APPROVE ARE PRODUCT LABELING OR COMPLETE RESPONSE, IF THE APPLICATION CANNOT BE APPROVED. SO IN A COMPLETE RESPONSE WE’LL OUTLINE TO THE APPLICANT ISSUES THAT PRECLUDE APPROVAL AND ACTIONS THEY CAN TAKE TO PLACE THE APPLICATION IN THE CONDITION FOR APPROVAL. FOR US THAT INFORMATION IS NOT PUBLICLY AVAILABLE. MA THAT WILL GO TO THE SPONSOR, WHAT THEY RELEASE IS UP TO THEM. ONCE A DRUG IS MARKETING, IN THE POST MARKETING SITUATION, A MAJOR PART OF OUR FOCUS ESPECIALLY FOR PUBLIC HEALTH IS TO MONITOR SAFETY SIGNALS ONCE THAT DRUG GETS INTO THE GENERAL PUBLIC. THE MONITORING TOOLS FDA HAS, FDA ADVERSE EVENT REPORTING SYSTEM REPORTS THAT PATIENTS, PHYSICIANS, DRUG COMPANIES WITH SUBMIT IF THEY FEEL THEY HAVE HAD AN ADVERSE EVENT TO THE DRUG. WE MONITOR PUBLISHED STUDIES AND CASE REPORTS, ALSO NEWER IN THE ARM MEN TARE YUM IS THE SENTINEL. EVEN SENTINEL WOULD NOT PICK UP RARE EVENTS WE’VE SEEN WITH THE OSTEOPOROSIS DRUGS. ONCE WE SEE A SAFETY SIGNAL FDA HAS ABILITY TO UPDATE THE DRUG LABEL, REQUIRE NEW SAFETY STUDIES, REQUIRE A RISK EVALUATION MITIGATION STRATEGY, WE CAN REMOVE THE INDICATION OR THE DRUG FROM THE MARKET IF THINGS ARE SO DIRE AND CAN ISSUE PUBLIC SAFETY COMMENTS, COMMUNICATION, THIS IS A SCREEN SHOT OF THE FDA PUBLIC — THE DRUG SAFETY PAGE, IT’S ALSO THE SAME PAGE THAT HAS THE DRUG SHORTAGES INFORMATION. YOU CAN SEE DRUG SAFETY COMMUNICATIONS YOU CAN EASILY CLICK THE LINK TO. OF COURSE WE’VE HEARD ABOUT OSTEONECROSIS, ATYPICAL FEMORAL FRACTURES. FOR FDA OSTEONECROSIS WAS NOTED IN THE BISPHOSPHONATES IN THE ONCOLOGY SETTING, THE FDA BEGAN THEIR EVALUATION IN 2003. AND THE WARNING IN ALL OSTEOPOROSIS BISPHOSPHONATE LABELS HAPPENED IN 2005. NOW FOR ATYPICAL FEMORAL FRACTURES FDA BECAME AWAR AND STARTED EVALUATION IN 2008, WE HAD A SAFETY COMMUNICATION THAT WAS IN RESPONSE TO A MAJOR NEWS PUBLICATION, AND MARCH OF 2010 WE WERE WORKING CLOSELY WITH THE ASBMR TASK FORCE, REQUESTED A SAFETY CHANGE AND HAD DRUG SAFETY COMMUNICATION IN OCTOBER OF 2010. AND THIS IS OUR VIEW OF WHAT HAPPENED TO THE BISPHOSPHONATE PRESCRIPTIONS. A LITTLE BIT DIFFERENT, THIS IS BY PRESCRIPTION, NOT BY PATIENT. AND AS YOU CAN SEE THERE ARE APPROXIMATELY 30 MILLION PRESCRIPTIONS FROM 2006 TO 2008, AND THEN THINGS REALLY STARTED TO TAIL OFF AND CONTINUED TO DWINDLE THROUGH 2017. BECAUSE A PATIENT GOT A PRESCRIPTION DOESN’T NECESSARILY MEAN THEY ARE TAKING IT. SO IN SUMMARY, THE BASIC SCIENCE AND TRANSLATIONAL PIPELINE IS ACTIVE MANY YEARS BEFORE FDA BECOMES INVOLVED IN PRODUCT DEVELOPMENT, FDA DOES ASSIST IN GUIDING DRUG DEVELOPMENT THROUGHOUT THE IND FACE AND WE BEGIN MONITORING DRUG SAFETY IN THE IND PHASE. ONCE STUDIES ARE COMMITTEE FDA WILL RECEIVE A DECISION IN A YEAR AND AFTER APPROVAL REMAIN ACTIVE IN SAFETY SURVEILLANCE FOR ALL MARKETED DRUGS. I’D LIKE TO THANK YOU FOR YOUR ATTENTION AND I BELIEVE THAT TAKES US TO OUR FIRST BREAK. [APPLAUSE] AND WE WILL RECONVENE AT 10:10. [APPLAUSE] WE’RE STARTING THE NEXT SEGMENT, WE’RE GOING TO KICK IT OFF WITH A PRESENTATION FROM ONE DR. MEERA VISWANATHAN.>>SO THANK YOU FOR INVITING ME TO THIS P2P WORKSHOP TO TALK ABOUT TREATMENTS TO PREVENT OSTEOPOROTIC FRACTURE. I’M MEERA VISWANATHAN SPEAKING ON BEHALF OF THE RTI-UNC EVIDENCE-BASED PRACTICE CENTER HERE TO PRESENT THE FINDINGS OF A SYSTEMATIC REVIEW WE DID FOR U.S. PREVENTIVE SERVICES TASK FORCE, WHICH WAS RECENTLY PUBLISHED. DISCLOSURES BEFORE I GET STARTED, WE HAVE NO CONFLICTS INTEREST, NONE OF THE AUTHORS HAVE FINANCIAL OR NON-FINANCIAL CONFLICTS OF INTEREST. THE WORK WAS FUNDED BY AHRQ, PUBLISHED ON THE AHRQ WEBSITE AND IN JAMA IN JUNE OF THIS YEAR. THANK YOU ON BEHALF OF THE TEAM, NAMES ARE LISTED HERE. SO THE NEXT SLIDE WHAT I’M GOING TO SAY OVER THE NEXT 20 MINUTES. I WILL START REQUEST — WITH A FAIR BIT OF CONTEXT, THE PURPOSE IS DIFFERENT FROM THE ONE YOU’LL HEAR LATER TODAY. LATER YOU’RE HEAL FROM LONG-TERM TREATMENTS FROM THE MINNESOTA EPC. I WOULD REFER TO THEM AS THE USBSDF, BECAUSE OUR AUDIENCE DETERMINED OUR QUESTIONS, ANALYTIC FRAMEWORK AND METHODS, KEEP DIFFERENCES IN MIND AS YOU LISTEN TO MY PRESENTATION, THAT WILL INFLUENCE MIGHT DIFFER FROM THE MINNESOTA EPC. AFTER CONTEXT I’LL GO OVER ANALYTICS, METHODS, FRAMEWORK, RESULTS, LIMITATION, CONCLUSION, OUR REVIEW IS INDEPENDENT PRECEDED BY SEVERAL MONTHS, THE USBSDF ASKED US TO CONDUCT A SYSTEMATIC REVIEW TO UPDATE THE GUIDELINES ON SCREENING TO PREVENT OSTEOPOROTIC FRACTURES. NOW, BECAUSE THIS SYSTEMATIC REVIEW IS MEANT TO ANSWER THE QUESTION DOES SCREENING IMPROVE HEALTH OUTCOMES, THE OVERARCHING QUESTIONS DOES SCREEN REDUCE FRACTURE AND MORBIDITY AND MORTALITY. DIRECT EVIDENCE IS LINKING YOU OFTEN HAVE TO GO TO INDIRECT LINKS, THE FIRST BEING ON THE VALIDITY OF SCREENING ON IDENTIFYING THOSE AT RISK, AND THEN MOVING TO TREATING THOSE AT RISK. BECAUSE REVIEW FOCUSING ON THAT PATHWAY, ALL OF OUR STUDIES HAVE TREATMENT DURATION UNDER FIVE YEARS BUT A FEW OF THEM DID HAVE TREATMENT DURATION BETWEEN THREE AND FIVE YEARS, AND AS I GO THROUGH THE REVIEW ALL OF THE RESULTS THAT PERTAIN THAT INTERMEDIATE DURATION TRIAL MARKED WITH RED BOX AND SO YOU’LL KNOW WHAT THOSE ARE. SO HERE IS WHAT OUR ANALYTIC FRAMEWORK LOOKED LIKE. YOU’LL SEE OVERARCHING ARROW FROM SCREENING TO TREATMENT, THAT’S THE OVERARCHING LING. WE LOOKED AT INDIRECT PATHWAY, HOW WELL RISK ASSESSMENT PERFORMS, HOW WELL TREATMENT WORKS. BECAUSE OF THE NATURE OF WHAT WE’RE DOING WE’RE TRYING TO SUPPORT THE USPSTF SCREENING, WE START WITH POPULATION OF ADULTS WITHOUT LOW TRAUMA FRACTURE AND WITHOUT STEROID USE; ONCE YOU IDENTIFY THOSE AT RISK YOU DEFER THE RISK ASSESSMENT AND ATTEMPT TREATMENT IN THEM. SO THE POPULATION I’M GOING TO TALK ABOUT TODAY IS ADULTS WITHOUT LOW TRAUMA FRACTURES, WITHOUT ENDOCRINOPATHY, WITHOUT STEROID USE BUT AT INCREASE IN FRACTURE. WE LOOK AT TREATMENT QUESTIONS, QUESTIONS AROUND EFFICACY AND HARM. I’M GOING TO PRESENT THREE QUESTIONS, THE FIRST IS HOW EFFECTIVE IS THERAPY REDUCING FRACTURE IN MORBIDITY AND MORTALITY, THE SECOND RELATES TO HOW THE EFFICACY — HOW THAT VARIES SPECIFICALLY BY MENOPAUSE, AGE, SEX, BASELINE BMD AND BASELINE FRACTURE RISK. THE THIRD IS HARMS OF PHARMACOTHERAPY. OUR METHODS, WE REVIEWED A VARIETY OF PUBLISHED SOURCES. WE HAND SEARCHED THE LITERATURE. UPDATES, WE DID FORMAL AND SYSTEMATIC SEARCHING THROUGH OCTOBER OF 2016 AND CONTINUE TO SURVEY LITERATURE THROUGH MARCH OF 2018, SYSTEMATIC REVIEW PUBLISHED IN JUNE. I’M GOING TO GO OVER THESE — THESE ARE STUDY COLLECTION CRITERIA, I WON’T GO OVER EVERY LINE BUT WILL POINT OUT SPECIFIC CRITERIA FOR THE LIMITATIONS, THE FIRST IS ABOUT POPULATION, I ALREADY MENTIONED THAT. WE LOOKED AT THOSE WHO WERE AT INCREASED RISK, BUT WITHOUT TRAUMA, TRAUMA FRACTURES. THE SECOND TO PAY ATTENTION TO, AGAIN, KEEP IN MIND THIS IS BEING DONE FOR THE USPSTF, THE QUESTION IS SHOULD WE SCREEN OR NOT, AND THEREFORE THE APPROPRIATE TREATMENT GROUP BY COMPARISON WAS AN ACTIVE COMPARISON AGAINST A PLACEBO FOR BENEFITS, AND AGAINST PLACEBO OR NO TREATMENT FOR HARMS. WE DID NOT COMPARATIVE TREATMENT SO THERE’S NO COMPARATIVE EFFECTIVENESS DATA IN WHAT I’M GOING TO PRESENT TO YOU. NOW, THIS SLIDE STUDY SELECTION CRITERIA, I WILL FOCUS ON THE TWO ISSUES THAT SERVE THIS CONSTRAINT TO WHAT WE DID. THE FIRST IS WE FOCUSED ON VERY HIGHLY DEVELOPED COUNTRIES, HUMAN DEVELOPMENT INDEX. THE SECOND IS WE RESTRICTED EVIDENCE BASE TO STUDY THE QUALITY. SO MUCH FOR THE METHODS. I’M NOW TALKING ABOUT MEANS. WE RAN THE SEARCHES FROM THE LAST REVIEW, DONE I BELIEVE IN 2013 I THINK. SO WE RAN THE SEARCH TO UPDATE THAT EVIDENCE REVIEWS, PICKED UP 4700 CITATIONS, 744 MERIT FURTHER REVIEW, FROM THOSE IDENTIFIED 129 STUDIES TO MAKE IT INTO OUR REVIEW. OF THOSE 129, ONLY 22 ARE RELEVANT FOR THE BENEFITS QUESTION, KEY QUESTION 4. AND 49 FOR HARMS QUESTION. SO THAT’S WHAT YOU’LL HEAR ME TALK ABOUT FOR THE REMAINDER OF THE PRESENTATION. I WANTED TO TALK ABOUT DURATION OF TREATMENT, DISTINCTION SHORT SHORT AND LONG IS IMPORTANT FOR TODAY. OF THE 22 BENEFIT STUDIES, 21 HAD DURATION TREATMENT UNDER 3 YEARS, ONLY ONE STUDY WITH TREATMENT DURATION OF 4 YEARS, RALOXIFEN. 45 OF THE 49 STUDIES HAD TREATMENT DURATION UNDER 3 YEARS OR LESS, AND TWO ALENDRONATE BETWEEN 3 AND 5 YEARS, ONE DIDN’T SPECIFIC, A FOURTH ON RALOXIFEN HAD TREATMENT DURATION OF 4 YEARS. SO THOSE STUDIES BETWEEN 3 AND 5 YEARS, POSSIBLY ONES WITH SOME DEGREE OF OVERLAP BETWEEN MY PRESENTATION AND MINNESOTA PRESENTATION, YOU’LL SEE ALL THOSE RESULTS HIGHLIGHTED WITH THE RED BOX AS WE GO THROUGH THE RESULTS. NOW I’VE GONE THROUGH THE METHODS AND YIELDS, I’M GOING THROUGH RESULTS. THE FIRST I PRESENT ON THE BENEFITS QUESTION. AND WHAT I DO IS GIVE YOU THE BOTTOM LINE FIRST AND PRESENT SOME SLIDES TO SUPPORT THAT BOTTOM LINE. IF PEOPLE HAVE QUESTIONS LATER I HAVE PLENTY OF BACKUP SLIDES. SO THERE’S A LOT OF TEXT HERE. I’M NOT GOING TO EXPECT YOU TO READ ALL OF IT. I WILL READ IT OUT LOUD BUT I WANT TO POINT OUT A FEW KEY THINGS. THE FIRST OF THESE IS A LOT MORE EVIDENCE OF BENEFIT FOR WOMEN THAN MEN. WHEN THERE’S EVIDENCE ON MEN AND WOMEN THE FINDINGS ARE CONSISTENT IN DIRECTION BUT NOT IN THE SIZE OF THE EFFECT OR STATISTICAL SIGNIFICANCE. THE SECOND IS — I’M SORRY. THE SECOND IS THERE’S A LOT MORE EVIDENCE ON BISPHOSPHONATES, AND ON VERTEBRAL FRACTURES THAN THERE IS ON OTHER DRUGS, AND ON OTHER OUTCOMES. SORRY, I’M TRYING TO GET THIS TO HIGHLIGHT. NOPE? I’M TRYING TO SCROLL DOWN, IT’S NOT WORKING. SO, WE’LL KEEP GOING. THE THIRD THING TO POINT OUT, THE EVIDENCE DOMINATED BY LARGE STUDIES, TYPICALLY ONE FOR EACH BODY OF EVIDENCE. FINALLY THE OTHER THING I WANT TO POINT OUT ON THIS SLIDE DECK IS THAT WE USED MANY CRITERIA TO COME UP WITH JUDGMENTS ABOUT HOW EFFECTIVE THESE DRUGS ARE, SO WHAT WE CAME UP WITH AFTER LOOKING AT THE EFFECT SIZE, RISK OF BIAS, CONSISTENCY
AND PRECISION, STRENGTH OF EVIDENCE GRADING, SO WE JUDGED THE EVIDENCE WAS MORBID FOR RALOXIFENE FOR VERTEBRAL FRACTURES. AND
ON RALOXIFENE THERE’S EVIDENCE FROM STUDIES WITH TREATMENT DURATION BETWEEN 3 AND NOW THE NEXT FEW SLIDES WILL PRESENT SOME OF THE EVIDENCE IN MORE DETAIL. SO AT LEAST THREE OUTCOMES FROM POOLED ANALYSES FOR VERTEBRAL, NON-VERTEBRAL HIP FRACTURE, BISPHOSPHONATE IN WOMEN, AND STRONGEST FOR VERTEBRAL FRACTURE, LESS EFFECT SIZE, CONFIDENCE INTERVALS FOR HIP FRACTURE. FOR BISPHOSPHONATE FOR MEN AS FOR WOMEN STRONG EFFECTIVE OF BISPHOSPHONATE ON VERTEBRAL FRACTURE. FOR RALOXIFENE ONE STUDY PROVIDED FIVE — 3 TO 5-YEAR TREATMENT, AND FOUND A SIGNIFICANT DIFFERENCE OF VERTEBRAL AND NON-VERTEBRAL FRACTURES FOR WOMEN. FOR DENOSUMAB. NOW I’M GOING TO MOVE TO SUBGROUP ANALYSES FOR BENEFITS AS A REMINDER WE LOOKED AT WHETHER THE EFFECT VARY BY CHARACTERISTIC, AGE, BASELINE BMD, PRIOR FRACTURE. SO HERE IS THE BOTTOM LINE. WE DIDN’T OBSERVE DIFFERENCE BY GROUP. SOME OF THE DETAILED THAT HELP SUPPORT THIS, A FEW THINGS TO NOTE, FIRST ALL OF THESE RESULTS CAME FROM SINGLE STUDIES. VERY LIMITED DATA HERE. THE SECOND IS NOT ALL OF THE RESULTS CAME FROM TEST AND INTERACTION, ALENDRONATE, FOR EXAMPLE, RESULTS CAME FROM COMPARING RESULTS IN THE OVERALL TRIAL WITH A SUBGROUP ANALYSIS. FOR THE OTHER THREE DRUGS LISTED HERE, DID COME FROM INTERACTION. AND THEN THE THIRD SET OF RESULTS, MY FINAL SET OF RESULTS FOR TODAY ON HARMS. SO I WANT TO START AT THE BOTTOM LINE. A LOT OF TEXT DOWN HERE, I’LL POINT OUT KEY THINGS. FIRST, FOR HARMS SUCH AS DISCONTINUATION, FEARS, ADVERSE EVENTS, UPPER G.I. AND CARDIOVASCULAR EVENTS, THE CONFIDENCE INTERVAL, FOR OSTEOPOROSIS AND ATYPICAL FEMUR INFRASTRUCTURES WE DIDN’T FIND EVIDENCE THAT SUGGESTED A HARM BUT KEEP IN MIND OUR FRAME OF REFERENCE, THE INCLUSION CRITERIA WERE RELATIVELY NARROW. AND THEN A COUPLE OTHER POINTS TO NOTE. ONE IS THAT AS BENEFITS, EVIDENCE ON MEN IS VERY LIMITED. �DOMINATED BY SINGLE TRIALS, BODIES OF EVIDENCE AND THEN FINALLY THERE’S SOME EVIDENCE FROM TREATMENT STUDIES, DURATION BETWEEN 3 AND 5 YEARS, MARKED AS WE GO THROUGH THE REMAINDER OF THE SLIDES. THE NEXT FEW SLIDES WILL EXPLICATE THE BOTTOM LINE FOR HARM, HELP PROVIDE SUPPORT OF THE FINDINGS. THE FIRST OF THESE IS ON BISPHOSPHONATES. WE DID — WERE ABLE TO DO ANALYSES ON DISCONTINUATION AND UPPER G.I. EVENTS. AS YOU CAN SEE FROM THE NUMBERS, THESE ARE A LOT OF PATIENTS. WE DIDN’T HAVE A PROBLEM WITH PRECISION. THESE STUDIES WERE — THE POOL ESTIMATES WERE PRECISE. BUT THEY FAILED TO FIND AN EFFECT OF THE CONFIDENCE INTERVAL SPANNED FOR ALL THREE OF THESE OUTCOMES. THE NEXT ONE, RALOXIFENE, FOR RALOXIFENE WE WERE ABLE TO DO POOLED ANALYSES. WE DID FIND HARMS, INCREASED INCIDENCE OF HOT FLASHES AND LEG CRAMPS. BUT NOT FOR DVT AND DISCONTINUATIONS. THE OTHER THING TO NOTE ABOUT THIS IS THAT THESE RESULTS DID IN FACT INCLUDE ONE TRIAL BETWEEN 3 AND 5 YEARS. AND THEN THE NEXT SET OF SLIDES, DENOSUMAB, THREE TRIALS GAVE US EVIDENCE ON DISCONTINUATION, SERIOUS ADVERSE EVENTS AND SERIOUS INFECTION, IN ALL CASES CONFIDENCE INTERVAL SPANNED THE NULL. FOR PARATHYROID HORMONE WE FOUND ONE TRIAL IN WOMEN WHICH INDICATED HARM — INCREASED INCIDENCE OF DISCONTINUATION. FOR MEN THE RESULTS DID NOT INDICATE THAT THERE WAS INCREASED RISK OF DISCONTINUATION, BUT THAT’S WHEN YOU LOOK AT THE FDA-APPROVED DOSE OF 20 MICROGRAMS. THE STUDY ALSO DID LOOK AT 40-MICROGRAM DOSE, THAT DID HAVE INCREASED RISK OF DISCONTINUATION. AND THERE WAS NO REPORTED RISK, INCREASED RISK OF CANCERS. NOW, ON TO OSTEONECROSIS OF THE JAW, NO STUDIES THAT MET INCLUSION CRITERIA REPORTED INCREASE IN OSTEONECROSIS OF THE JAW, AGAIN BECAUSE OF THE POPULATION WE LOOKED AT, WHEN WE LOOKED AT SYSTEMATIC REVIEW THAT WASN’T RESTRICTED TO PRIMARY PREVENTION WE FOUND THAT THEY DID REPORT AN INCREASED INCIDENCE, MODULATING INCREASED INCIDENCE WHEN COMPARED TO GENERAL POPULATION, BUT ONCOLOGY POPULATION, IT WAS MORE. THE STUDIES WE INCLUDED DIDN’T REPORT INCREASED INCIDENCE BUT FROM STUDIES THAT WERE RESTRICTED, AS WE WERE THERE WAS QUITE A LOT OF HETEROGENEITY IN THE RESULTS. SO WHAT ARE LIMITATIONS? OUR REVIEW IS LIMITED BY FRAME OF REFERENCE WE TOOK ON. WE WERE SEEKING TO ADDRESS THE PREVENTION QUESTION, REGARDING LIMITATION OF EVIDENCE WAS A LOT OF UNDERLYING HETEROGENEITY, IN BASELINE RISK, PRIOR FRACTURES, PRIOR TREATMENT AND DURATION OF FOLLOW-UP BUT VERY LIMITED EVIDENCE. SO REGARDING FUTURE RESEARCH DIRECTION, NOT ENOUGH TREATMENT TRIALS IN MEN. DATA ON SUBGROUPS PARTICULARLY AGE, BASELINE BMD AND BASELINE FRACTURE RISK IS INSUFFICIENT. AND EVIDENCE AND HARMS IS LACKING. TREATMENTS REDUCE RISK OF VERTEBRAL AND NON-VERTEBRAL FRACTION. WE DID NOT FIND CONSISTENT INCREASE IN HARMS FROM INCLUDED STUDIES. RARE HARMS SUCH AS OSTEONECROSIS MAY EXIST BUT WE DIDN’T FIND EVIDENCE OF THAT. THANK YOU. [APPLAUSE]>>I’D LIKE TO THANK THE ORGANIZERS FOR ASKING ME TO TALK. I’M GOING TO DO SOMETHING A LITTLE DIFFERENT, AND THAT IS PROVIDE YOU SOME EVIDENCE FROM SOME ORIGINAL DATA SETS. OKAY, GREAT. SO, THAT’S THE WRONG TALK. ALL RIGHT. GREAT. THANK YOU. ALL RIGHT. SO, I’M GOING TO TALK ABOUT SOME OF THE SHORT-TERM DRUG THEIRS FOR OSTEOPOROTIC FRACTURE. MY TALK ABOUT BE MORE LIMITED TO FEMALES, IT WILL ALSO INVOLVE PEOPLE AT HIGHEST RISK. THIS WILL GIVE YOU SOME DISTINCTION BETWEEN THE OVERALL EVIDENCE-BASED REVIEW AND WHAT WE SEE FROM SOME OF THE CLINICAL TRIALS, IN INDIVIDUALS AT HIGH RISK. I’M GOING TO EMPHASIZE THAT SEVERAL TIMES. I HAVE NO DISCLOSURES. SO FIRST I’LL DEFINE SHORT-TERM THERAPY AND REALLY FOCUS ON WHO IS AT RISK FOR FRACTURES BECAUSE THOSE ARE THE PEOPLE WHO BENEFIT THE MOST FROM THERAPY. I’LL GO TRUE A COUPLE OF THE ANTI-RESORPTIVE AND ANABOLIC THERAPIES, FINISH WITH ANOTHER EPIC STUDY THAT WAS DONE AT THE MAYO CLINIC, EVIDENCE-BASED REVIEW, TO LOOK AT THE DATA, AND FINISH WITH SOME CONCLUSIONS. SO, MY SUMMARY IS SIMILAR TO THE PREVIOUS TALK. SHORT-TERM TREATMENT FOR OSTEOPOROSIS SHOULD BE FOCUSED AT WOMEN IN HIGHEST RISK INCLUDING ALL ETHNIC AND RACIAL GROUPS. IT’S DIFFERENT FROM PRIMARY PREVENTION, AND HERE WE’RE FOCUSED ON THE HIGHEST RISK INDIVIDUALS. ALGORITHMS AS WELL AS BONE DENSITY CAN PREDICT WOMEN AT HIGHEST RISK OF FRACTURE. ANTI-RESORPTIVE THERAPY REDUCE RISK, VERTEBRAL AND NON-VERTEBRAL FRACTURES SHOWN IN THE PREVIOUS TALK, AND I’LL TALK ABOUT ANABOLIC THERAPIES. AND THERE ARE SOME ON AND OFF TARGET SIDE EFFECTS FROM SHORT-TERM ANTI-RESORPTIVE THERAPY THAT I’LL MENTION. SO SHORT-TERM THERAPY FOR OSTEOPOROSIS IS DEFINED AS THREE YEARS OR LESS OF TREATMENT, THAT’S REALLY DUE TO THE REGISTRATION TRIALS MANDATED TO BE 3 YEARS, THERESA MENTIONED THEY COULD GO 1 TO 4 YEARS. SHORT TERM IS 3 YEARS, BEYOND THAT IS LONG TERM. THIS IS SOMEWHAT ARBITRARY BUT THIS IS WHAT WE’RE LEFT WITH. SO, WHO SHOULD BE TREATED TO PREVENT OSTEOPOROTIC FRACTURES? IN THE ALGORITHM, IT’S THOSE AT THE HIGHEST RISK. I’M GOING TO FOCUS ON DATA SHOWING YOU WHY WE FOCUS ON THE WOMEN AT HIGHEST RISK, BECAUSE THE DRUGS THAT ARE MOST EFFICACIOUS ARE THE ONES THAT WORK IN THOSE INDIVIDUALS WHO ARE AT THE HIGHEST RISK OF FRACTURE. SO, TWO COMPONENTS ARE PRESENT ON THIS SLIDE. GENDER IS EXTREMELY DIFFERENT IN TERMS OF RISK. AND SECOND, THAT AGE IS AN INDEPENDENT RISK FACTOR FOR FRACTURE. AND HERE YOU CAN SEE THAT AGE BY ITSELF INCREASES FRACTURE RISK IMMENSELY. SO AGE AND BEING A WOMAN ARE TWO MAJOR RISK FACTORS FOR FRACTURE. WHAT ELSE CAN WE USE TO PREDICT FRACTURES IN THOSE AT HIGHEST RISK IN THIS IS FROM THE STUDY OF OSTEOPOROTIC FRACTURES THAT YOU HEARD ABOUT PREVIOUSLY. AND THIS DATA DEMONSTRATES THAT THOSE WOMEN IN THE LOWEST BMD QUARTILE HAVE THE HIGHEST RISK OF FRACTURE, A SINGLE BONE MINERAL DENSITY 25 YEARS OUT CAN PREDICT THOSE INDIVIDUALS AT HIGHEST RISK. BONE DENSITY IS A HIGH — A STRONG PREDICTOR OF SUBSEQUENT FRACTURE. AND AS ELIZABETH POINTED OUT, PREVIOUS FRACTURES BEGET NEW FRACTURES. SO THE ABSOLUTE RISK OF RECURRENT FRACTURE AFTER A FIRST FRACTURE REALLY MANDATES TREATMENT. HERE YOU CAN SEE THAT OVER TIME, OVER FIVE YEARS AFTER A FRACTURE, THE RISK OF HAVING A RECURRENT FRACTURE IS CONSIDERABLY INCREASED, BOTH FOR TOTAL FRACTURES AND ALSO IMPORTANTLY FOR HIP FRACTURES. SIMILARLY, THE HIP FRACTURE INCIDENCE AFTER A NON-VERTEBRAL FRACTURE IS GREATER IF YOU HAD A NON-VERTEBRAL FRACTURE. AGAIN, HIP FRACTURE IS VERY SIGNIFICANT ENDPOINT, AS ELIZABETH POINTED OUT IN TERMS OF MORBIDITY AND MORTALITY, AND SO A SEMINAL EVENT IN AN INDIVIDUAL AFTER THE AGE OF 65 THAT HAS A NON-VERTEBRAL FRACTURE IS POTENTIAL RISK FOR A SUBSEQUENT HIP FRACTURE. WE TALKED ABOUT AGE AND WE TALKED ABOUT GENDER, AND WE TALKED ABOUT PREVIOUS FRACTURE AND BONE DENSITY. THESE CAN BE COMBINED IN AN ALGORITHM IN THE UNITED STATES, PRESENT IN DIFFERENT ALGORITHMS USEDTY POINT OF CARE, THEY INTEGRATE A NUMBER OF RISK FACTORS THAT HELP US PREDICT WHO ARE THE INDIVIDUALS WHO ARE AT GREATEST RISK, THOSE ARE THE INDIVIDUALS WE WANT TO FOCUS ON THAT CAN PREVENT FRACTURES BUT NOT ONLY THAT HAVE THE HIGHEST DEGREE OF SUCCESS IN REDUCING THOSE FRACTURES. THAT EXCLUSION LIE RACE OR ETHNICITY IS NOT SOMETHING SHOULD THINK ABOUT. IT’S TRUE OTHER INDIVIDUALS CAN FRACTURE BESIDES WHITE NON-HISPANIC WOMEN, AND HERE YOU CAN SEE FROM THE WOMEN’S HEALTH INITIATIVE JUST THE DIFFERENCES IN HIP FRACTURE RATES AMONG DIFFERENT RACIAL AND ETHNIC GROUPS. SO EXCLUDING THOSE INDIVIDUALS BECAUSE OF THEIR BACKGROUND IS NOT A REASONABLE APPROACH TO UNDERSTANDING THOSE AT HIGHEST RISK, AND, AGAIN, THESE ALGORITHMS HELP US PROVIDE THOSE THAT WE’RE FOCUSED ON TREATING. SO, WITH THAT IN MIND, THE SHORT-TERM THERAPEUTIC OPTIONS WE HAVE, SHORT TERM BEING 3 YEARS, INCLUDE ANTI-RESORPTIVES AS WELL AS ANABOLIC AGENTS, TERRAPERATIDE AND ALOPERATIDE. YOU’LL HEAR FROM REBECCA JACKSON ESTROGENS HAVE A PROFOUND EFFECT, SANDEEP MENTIONED AS WELL, ON REDUCING FRACTURE. THIS IS THE CALCIUM AND VITAMIN D STUDY, RANDOMIZED TO CALCIUM AND VITAMIN D, ESTROGEN OR NO ESTROGEN, A 45% REDUCTION IN HIP FRACTURES IN INDIVIDUALS ON ACTIVE HORMONE THERAPY AND CALCIUM AND VITAMIN D. ESTROGEN LONG ESTABLISHED TO HAVE SIGNIFICANT EFFECT ON FRACTURES. I SHOULD POINT OUT IN THIS TALK I’M NOT TALKING AT ALL ABOUT CHANGES IN BONE DENSITY, YOU WILL ONLY SEE FRACTURE DATA BECAUSE THESE ARE PATIENT-SPECIFIC OUTCOMES WE’RE INTERESTED IN. YOU’VE HEARD ABOUT RALOXIFENE, I WANT TO TALK ABOUT THE MOORE TRIALA VERY LARGE TRIAL OVER 7,000 WOMEN, AND ONE OF THE MOST IMPORTANT POINTS ABOUT THIS SLIDE, ABOUT THIS STUDY, WAS THAT THE DIFFERENCE IN THE RATE OF INCIDENT VERTEBRAL FRACTURES WAS ALMOST FOUR-FOLD GREATER IN THOSE WOMEN WHO HAD A PREEXISTING VERTEBRAL FRACTURE, AND SO THE EFFICACY WAS QUITE SIGNIFICANT IN BOTH GROUPS BUT AS YOU CAN SEE THESE INDIVIDUALS WERE AT THE HIGHEST RISK. SO THE MOORE TRIAL RECRUITED PEOPLE WHO BOTH HAD FRACTURES AND THOSE THAT DID NOT HAVE FRACTURES. HERE YOU CAN SEE THE SEPARATION IN TERMS OF RISK OVER THE FOLLOW-UP OF THE TRIPE. IN THE FRACTURE INTERVENTION TRIAL OF DENNIS BLACK AND STEVE CUMMINGS THEY SHOWED A VERY SIGNIFICANT REDUCTION IN FRACTURES IN WOMEN WITH EXISTING VERTEBRAL FRACTURES, SO IN FIT ONE, WHICH WAS ONE COMPONENT, YOU HAD TO HAVE A FRACTURE TO GET IN, THE RISK REDUCTION WAS SIGNIFICANT, AND THIS ALSO HOLDS FOR HIP FRACTURES. ALTHOUGH IN THE PRIMARY PREVENTION META-ANALYSIS AND SYSTEMATIC REVIEW DIDN’T APPEAR TO HAVE AN EFFECT, FIT 1 AND FIT 2. HIGHEST RISK INDIVIDUALS WITH EXISTING VERTEBRAL FRACTURE 50% REDUCTION IN HIP FRACTURE. IT WAS SHOWN TO REDUCE VERT AND NON-VERTEBRAL FRACTURES, ANOTHER REGISTRATION TRIAL OVER 3 YEARS. REDUCED HIP FRACTURES IN ELDERLY WOMEN, BETWEEN 70 AND 90 YEARS OF AGE, RISK REDUCTION FOR HIP FRACTURES INDEPENDENT OF BONE DENSITY BUT VERY DEPENDENT ON AGE. THE HORIZON TRIAL WAS PERFORMED AND PUBLISHED IN 2007, 5 MILLIGRAMS A DAY, 5 MILLIGRAMS, ONCE A YEAR, RISEDRONATE, YEARLY, 3 YEARS, HAZARD RATIOS ARE SIGNIFICANT. IN ADDITION, A TRIAL ALSO USING ZOLEDRONRATEE CAME IN WITH HIP FRACTURES, ADMINISTERED ZOLEDRONRATEE. YOU CAN PREVENT 71 SPINE FRACTURES WITH BISPHOSPHONATE, 29 NON-VERTEBRAL, 11 VERTEBRAL. HIGH RISK INDIVIDUALS THAT FIT THE TRIAL AND REGISTRATION. THIS DECREASED NON-VERTEBRAL FRACTURES BY 20%, AND REDUCED HIP FRACTURE RISK BY 40%. AGAIN, THE FREEDOM TRIAL RANDOMIZED THE NUMBER OF INDIVIDUALS WHO WERE AT VERY HIGH RISK FOR SUBSEQUENT FRACTURE. THE TERIPARATIDE STUDIES SHOWED SIGNIFICANT RISK REDUCTION, NEW VERTEBRAL FRACTURES, WOMEN, AND NON-VERTEBRAL FRACTURES, AS ALLUDED TO IN PREVIOUS TALK THERE WAS NO STATISTICAL SIGNIFICANCE BECAUSE OF THE SMALL NUMBER OF HIP FRACTURES TO SHOW EFFICACY FOR HIP FRACTURE REDUCTION. HOWEVER, THE STUDY BY PAUL MILLER AND COLLEAGUES SHOWED REDUCED RISK OF ALL FRACTURES, VERY SIMILAR TO TERIPARATIDE, IN SOME CASES BETTER IN REDUCING RISK OF CLINICAL FRACTURES, NON-VERTEBRAL, MAJOR OSTEOPOROTIC AND NEW VERTEBRAL FRACTURES ABALOPARATIDE. FROM A EVIDENCE-BASED REVIEW BY THE MAYO CLINIC GROUP, AS PART OF THE ENDOCRINE SOCIETY, OVER A 2 1/2 YEAR PERIOD TO UNDERSTAND HOW BENEFIT AND RISK EVOLVED IN THE TREATMENT OF POST MENOPAUSAL WOMEN FOR OSTEOPOROTIC FRACTURES. SEVERAL PEOPLE IN THE AUDIENCE WERE INVOLVED IN THIS, DR. ESTYL, BLACK, SHOWBACK, MYSELF, I WANT TO SHOW OUR DIAGRAM OF THE VERTEBRAL FRACTURE RISK REDUCTION SHOWS VERY CONSISTENT EFFECT FOR VIRTUALLY ALL THERAPIES I’VE MENTIONED AS WELL AS SOME OTHER ONES, BASED ON AGAIN SYSTEMATIC REVIEW. THIS IS CURRENTLY IN PRESS, TO BE PUBLISHED SOON. SIMILARLY FOR HIP FRACTURE ONE CAN SEE THAT SEVERAL OF THE TRIALS SHOW A SIGNIFICANT RISK/BENEFIT RATIO. SO WHAT ARE THE RISKS FROM SHORT-TERM THERAPY? ON-TARGET EFFECT IN THE SKELETAL, ONJ, MENTIONED VERY RARE BUT OFTEN SEEN WITH CANCER PATIENTS TREATED WITH BISPHOSPHONATES, AND THEN ATYPICAL FEMORAL FRACTURES, YOU’LL HEAR A LOT ABOUT THAT FROM DR. BLACK AND OTHERS, POTENTIAL RISK ASSOCIATED WITH THAT AND THE DURATION, BUT LESS FREQUENTLY AS YOU’LL SEE WITH SHORT-TERM THEY WERE. THERE ARE MODEST OFF-TARGET EFFECTS THAT SHOULD BE CONSIDERED, BARRETT’S ESOPHAGUS LESS COMMONLY REPORTED, FREQUENCY OF USE IS LESS, MUSCLE PAIN DOES OCCUR, ATRIAL FIBRILLATION INCREASED, CARDIOVASCULAR EFFECTS DR. JACKSON WILL MENTION THIS AS WELL, ESTROGEN AS YOU ALL KNOW MAY HAVE A NEGATIVE EFFECT ON THE CARDIOVASCULAR SYSTEM, AND OF COURSE DVTs WHICH PLAY A RISK, SOMETHING TO DISCUSS WITH PATIENTS IN TERMS OF USE OF EITHER SERMs OR ESTROGEN. THE ROLE OF BISPHOSPHONATES IN CARDIOVASCULAR DISEASE REMAINS AN OPEN QUESTION. THERE ARE SOME DATA SUPPORTING NO EFFECT FROM BISPHOSPHONATES AND THERE’S AT LEAST ONE OR TWO NEW PAPERS SUGGESTING THERE MAY BE SOME RISK REDUCTION. SO STAY TUNED FOR THAT BECAUSE I THINK THAT STILL REMAINS AN AREA OF ACTIVE INVESTIGATION. I WANT TO SHOW ONE SLIDE FROM THE ATYPICAL FEMORAL FRACTURE, NEW DATA THAT YOU’LL HEAR A LOT ABOUT FROM DR. BLACK, A PIONEER IN THE FIELD, LOOKING AT USE OF BISPHOSPHONATE AND RISK OF FRACTURES, THAT DRIVES PATIENTS TO NOT TAKE MEDICINE OR NOT GET A PRESCRIPTION IN THE FIRST PLACE. HERE YOU CAN SEE THAT THE FREQUENCY OF THESE EVENTS IS MUCH GREATER AS YEARS GO ON WITH USE OF BISPHOSPHONATE. BUT MUCH MORE WILL BE TALKED ABOUT BY DR. BLACK IN TERMS OF CHARACTERIZING THOSE WILL BE MENTIONED, IDENTIFYING PEOPLE AT HIGHEST RISK. WHO SHOULD TREATED SHORT TERM? WE THINK ANYBODY WITH PREVIOUS FRACTURE, POST MENOPAUSAL WOMEN, INCIDENT FRACTURES WITHIN THE PAST YEAR, ANY HIP FRACTURE, AND THAT’S REALLY CRITICAL BECAUSE MOST FRACTURE PATIENTS LEAVE WITHOUT A PRESCRIPTION FOR TREATMENT, HIGH RISK INDIVIDUALS WITH LOW DENSITY PREVIOUS FRACTURE, EVEN REMOTE FRACTURES, OVER THE AGE OF 65 WITH OTHER RISK FACTORS, PREVIOUS FRACTURE, STEROID USE, MAYBE DIABETES, AND INFLAMMATORY DISORDERS. WHO WE DON’T WANT TO TREAT ARE PEOPLE WITH BONE DENSITY ABOVE MINUS 2.5 NO RISK FACTORS, PRE-MENOPAUSAL WITH OSTEOPENIA WITH NO RISK FACTORS, AND CHILDREN. THERE ARE EFFICACIOUS TREATMENT PARTICULARLY SHORT TERM IN INDIVIDUALS AT HIGH RISK. CONFIRMING RISK REDUCTION IN INDIVIDUALS PART OF THE REGISTRATION TRIAL AND I’D LIKE TO MAKE THAT DISTINCTION FROM THE LARGER EVIDENCE BASED PRESENTATION YOU HEARD WHERE IT WAS ON PRIMARY PREVENT AND INCLUDED IN THOSE NOT AT HIGH RISK. LONG TERM RISK IS CONSIDERED SEPARATELY. SCREENING AT HIGH RISK OF FRACTURE IS ESSENTIAL FOR OPTIONAL OPTIMAL TREATMENT PARADIGMS, SHORT RESORPTIVE OR ANABOLIC WITH HIGHEST RISK, INCLUDING PREVIOUS FRACTURE, AND ANABOLIC TREATMENTS CAN BE USED FOR SHORT TERM THERAPY. THANK YOU VERY MUCH.>>I’M JIM GILL, FAMILY PHYSICIAN, SMALL PRACTICE IN WILMINGTON, DELAWARE, RESEARCH IN QUALITY AND OUTCOMES PRIMARILY FOCUSING ON PRIMARY CARE. AND I WANT TO TALK TODAY ABOUT TREATMENT, SCREENING AND TREATMENT OF OSTEOPOROSIS IN THE PRIMARY CARE SETTING. I’M ALSO A MEMBER OF THE BOARD OF THE NATIONAL OSTEOPOROSIS FOUNDATION, AND I GUESS THAT’S — I CARE ABOUT OSTEOPOROSIS SO I GUESS THAT’S SORT OF A DISCLOSURE. WHAT I WANT TO TRY TO TALK ABOUT, I WANT TO SUMMARIZE FIRST ABOUT WHAT I’M GOING TO TELL YOU, AND FIRST WHILE MOST DIAGNOSIS AND TREATMENT OF OSTEOPOROSIS OCCURS IN THE PRIMARY CARE SETTING, RATES OF SCREENING AND TREATMENT OF OSTEOPOROSIS IN PRIMARY CARE ARE SUBOPTIMAL. THAT’S PROBABLY NO SURPRISE TO ANYONE HERE BECAUSE THAT’S WHY WE’RE ALL HERE. WHAT I BELIEVE IS THAT THE MAIN BARRIERS IN PRIMARY CARE ARE NOT ABOUT KNOWLEDGE ABOUT OSTEOPOROSIS BUT RATHER THE LOGISTICS. MEANING PUTTING GUIDELINES INTO PRACTICE. AND I’LL SHOW HOW USING A STRUCTURED APPROACH TO TREATMENT OF OSTEOPOROSIS OR SCREENING CAN IMPROVE THIS, AND WHAT MIGHT BE PARTICULARLY EFFECTIVE IS USING A TEAM-BASED APPROACH TO CARE. MEANING RELYING ON OFFICE STAFF, CHRONIC CARE MANAGEMENT NURSES, AND OTHER STAFF TO FACILITATE SCREENING AND TREATMENT. AND WHILE EDUCATION OF PRIMARY CARE PHYSICIANS AND OTHER CLINICIANS ABOUT OSTEOPOROSIS IS IMPORTANT, I BELIEVE THAT IT’S LESS HELPFUL IN GETTING US TO WHERE WE WANT TO BE. SO FIRST TO TALK ABOUT WHAT I’M GOING TO FOCUS ON HERE, I’M GOING TO FOCUS ON PRIMARY PREVENTION IN WOMEN. SO TREATMENT OF OSTEOPOROSIS IN WOMEN WITH NO PREVIOUS HISTORY OF A LOW IMPACT FRACTURE. NOW, CERTAINLY OTHER COMPONENTS OF OSTEOPOROSIS SUCH AS TREATMENT OF OSTEOPOROSIS IN MEN, AND TREATMENT OF OSTEOPENIA IN WOMEN AT HIGH RISK ARE IMPORTANT BUT LESS IN PRIMARY CARE SO I WON’T FOCUS ON THOSE. MOST DIAGNOSIS AND TREATMENT OF OSTEOPOROSIS IN WOMEN WHICH I’M FOCUSING ON OCCURS IN THE PRIMARY CARE SETTING. WHEN I SAY PRIMARY CARE, I’M TALKING ABOUT FAMILY MEDICINE, PRIMARY CARE, INTERNAL MEDICINE, PRIMARY CARE GERIATRICS. TO SOME EXTENT IT COULD HAPPEN IN GYNECOLOGY SETTINGS AND SOMETIMES OTHER SPECIALTIES BUT LESS SO. SO I’M SAYING THAT KNOWLEDGE GAPS ARE LESS IMPORTANT. LET’S TALK ABOUT THAT FOR A MINUTE. I BELIEVE THAT GENERALLY PRIMARY CARE PHYSICIANS KNOW THE BASICS. SO THEY KNOW OSTEOPOROSIS IS COMMON. THEY KNOW THAT IT LEADS TO POOR HEALTH OUTCOMES. THEY KNOW THAT POST MENOPAUSAL WOMEN SHOULD BE SCREENED AND WE’LL TALK ABOUT THE GUIDELINES. AND THAT TREATMENT PREVENTS FRACTURES. THE KNOWLEDGE IS NOT PERFECT, BUT I THINK PHYSICIANS AND OTHER PRIMARY CARE CLINICIANS KNOW THE BASICS. THERE ARE GOOD RECENT GUIDELINES FROM THE AMERICAN COLLEGE OF PHYSICIANS THAT ARE VERY HELPFUL IN TERMS OF TREATMENT AND BASICALLY SAY BISPHOSPHONATES ARE THE FIRST CHOICE. DESPITE WHAT I THINK IS RELATIVELY REASONABLY GOOD KNOWLEDGE, SIGNIFICANT GAPS EXIST. SO I’M A FAMILY PHYSICIAN. AND THE AMERICAN ACADEMY OF FAMILY PHYSICIANS FOLLOWS THE U.S. PREVENTIVE SERVICES TASK FORCE GUIDELINES IN THIS AREA WHICH RECOMMENDS ALL WOMEN 65 AND OVER BE SCREENED FOR OSTEOPOROSIS, WITH A DEXA AS WELL AS WOMEN AT HIGH RISK, I’LL TALK ABOUT THAT LATER. BUT WE KNOW ONLY ABOUT 1/4 OF WOMEN 65 TO 79 GET SCREENED, AND IT’S EVEN LOWER FOR OLDER WOMEN. AND CERTAINLY TREATMENT RATES FOR WOMEN WITH KNOWN OSTEOPOROSIS ARE ALSO LOW. WHAT’S THE PROBLEM? I BELIEVE THE PROBLEM IS IN THE IMPLEMENTATION. AND THAT MEANS PUTTING EVIDENCE INTO PRACTICE. WHY IS THAT? PRIMARY CARE IS THE MOST COMPLEX HEALTH CARE SETTING, AND PHYSICIANS AND OTHER CLINICIANS MANAGE A BROAD — THE BROADEST ARRAY OF PROBLEMS, EVEN IN A SINGLE VISIT, IT’S NOT UNCOMMON TO HAVE SIX OR 5EU9 EIGHT PROBLEMS IN A SINGLE VISIT AND IT CAN GET LOST. THERE WERE STUDIES AT DUKE, TO CARE FOR PREVENTIVE, ACUTE AND CHRONIC CARE THAT’S NEEDED FOR TYPICAL PHYSICIAN’S PANEL OF PATIENTS WOULD TAKE 22 HOURS PER DAY. EVEN THE SCREENING PART IS COMPLEX. IF YOU LOOK AT SCREENING, THE SIMILAR DUKE STUDY SHOWED IT TAKES 7.4 HOURS PER DAY JUST TO DO ALL OF THE SCREENING AND PREVENTION RECOMMENDED BY THE U.S. PREVENTIVE SERVICES TASK FORCE FOR A TYPICAL PANEL OF PATIENTS. UNTIL RECENTLY, MEDICARE WHICH IS THE INSURANCE FOR MOST WOMEN WE’RE TALKING ABOUT DID NOT EVEN PAY FOR PREVENTIVE CARE VISITS. THIS IS WHY JUST TELLING PHYSICIANS OR TRYING TO EDUCATE THEM ABOUT IMPORTANCE OF OSTEOPOROSIS IS NOT GOING TO GET US TO WHERE WE WANT TO BE. SO GIVEN THIS IS LOGISTICALLY IMPOSSIBLE HOW DO WE IMPROVE IT? WELL, FIRST I THINK A STRUCTURED APPROACH. SO WHAT DO I MEAN BY THAT? ONE EXAMPLE IS HAVING VISITS DEDICATED TO PREVENTION, THIS SOUNDS LIKE A NO-BRAINER, WE’VE BEEN DOING PREVENTIVE CARE, AND, QUOTE, PHYSICALS FOR NON-MEDICARE PATIENTS FOR YEARS. RECENTLY, MEDICARE INTRODUCED THE MEDICARE WELLNESS VISIT. I THINK THAT’S A GOOD MODEL. IT CAN HELP CATCH UP ON PREVENTION. BUT EVEN JUST FOR THIS, IT’S HAVING A VISIT DEDICATED TO PREVENTION THERE’S STILL NOT ENOUGH TIME. I’LL SHOW YOU IN A MINUTE WHY THAT’S TRUE. BUT THE OTHER REASON IS THAT VERY FEW PATIENTS ACTUALLY COME IN SPECIFICALLY FOR A MEDICARE WELLNESS VISIT. THE WAY PHYSICIANS DEAL WITH THIS BECAUSE WE’RE NOW MEASURED BY HOW MANY MEDICARE WELLNESS VISITS AND PREVENTIVE SERVICEES WE DO, WE DO MEDICARE WELLNESS VISITS AS AN ADD-ON TO A PROBLEM VISIT. WHEN A PATIENT IS THERE FOR DIABETES, DEPRESSION, AND I FELL DOWN YESTERDAY, WE ADD A MEDICARE WELLNESS VISIT AT THE SAME TIME. AS YOU CAN SEE, THIS MAKES THE TIME EVEN MORE LIMITED. YOU CAN HAVE TEMPLATES, A CHECKLIST. IN THE AIRLINE INDUSTRY WE WOULD NEVER SAY TO PILOTS, YOU NEED TO BE EDUCATED ABOUT ALL THE THINGS YOU NEED TO DO TO KEEP THE AIRPLANE SAFE. AND WE’RE GOING TO RELY ON YOU TO TRY TO REMEMBER TO DO THAT EACH TIME BEFORE YOUR PLANE TAKES OFF.& WE HAVE A CHECKLIST. WE NEED THE SAME THING IN PRIMARY CARE. IN OUR OFFICE WE FOLLOW WHAT’S CALLED THE AMERICAN ACADEMY OF FAMILY PHYSICIANS GUIDELINES, ALMOST IDENTICAL TO THE U.S. PREVENTIVE SERVICES TASK FORCE. THIS IS OUR CHECK LIST. YOU CAN SEE THAT THERE ARE A WHOLE LOT OF THINGS, THAT’S WHY I SAID THAT EVEN IF YOU JUST HAVE A VISIT DEDICATED TO PREVENTION, IT’S STILL EXTREMELY COMPLEX. SO JUST IF YOU CHECK THROUGH THE THINGS THAT ARE NEEDED FOR PATIENTS OVER THE AGE OF 65 THERE’S FOUR — AT LEAST FOUR VACCINES RECOMMENDED, IF YOU DEBT GET INTO SCREENING, THERE’S COLON CANCER SCREENING, THREE DIFFERENT OPTIONS. CHOLESTEROL SCREENING. HEPATITIS C SCREENING. SOME VARY DEPENDING ON YOUR AGE. BREAST CANCER SCREENING. AND THEN ALSO OSTEOPOROSIS SCREENING. AGAIN, ON OUR CHECK LIST WE HAVE WHAT’S RECOMMENDED BY THE AFT, THAT ALL WOMEN 65 AND OVER GET A DEXA. FOR MEN AORTIC ABDOMINAL SCREENING. I THINK IF HAVING ALL THESE THINGS ON ONE SHEET ALLOWS OR PREVENTS I SHOULD SAY KIND OF A BIAS, THERE’S SOME SENSE DOCS THINKS OSTEOPOROSIS ISN’T AN IMPORTANT. IF YOU HAVE IT IN A CHECKLIST, IT HELPS TO PROTECT AGAINST THAT. I WOULD ACTUALLY ARGUE SOME OF THE THINGS ON THIS LIST GET DONE EVEN LESS COMMONLY THAN OSTEOPOROSIS SCREENING, FOR EXAMPLE AAA SCREENING FOR MEN 65 TO 75 RATES ARE EXTREMELY LOW, HEPATITIS C UNTIL THE COMMERCIALS CAME ON ON TV THOSE RATES WERE EVEN LOWER. IT’S GREAT TO HAVE THE CHECKLIST BUT THE PHYSICIAN CAN’T DO IT ALONE. THESE ARE OFTEN ADD-ONS, I’M HERE FOR DIABETES, DEPRESSION, VAGINAL BLEEDING AND I HURT MY ARM YESTERDAY, IMPOSSIBLE FOR A PHYSICIAN TO DO THIS. WHAT YOU NEED TO DO IS A TEAM-BASED APPROACH. HAVE THE STAFF FOCUS ON THE PREVENTION, WHILE THE PHYSICIAN IS FOCUSING ON MANAGEMENT OF OTHER PROBLEMS. SO IN OUR OFFICE WE HAVE A CLERICAL PERSON WHO PREPARES THE CHECKLIST BEFORE THE PATIENT GETS THERE. AT THE BEGINNING OF THE OFFICE VISIT WHEN A MEDICAL ASSISTANT ROOMS THE PATIENT, THEY GO OVER EACH OF THE PREVENTIVE SERVICES I TALKED ABOUT, LOOK IN THE CHART, WHAT WAS DONE, NOT DONE, AND THEN PREPARE A PRELIMINARY PLAN. THEN THE DOCTOR IS THERE PRIMARILY TO ANSWER QUESTIONS AND OUR STUDIES, AGAIN, THE SAME DUKE STUDIES, SHOW THAT NON-PHYSICIAN, NON-CLINICIAN STAFF CAN DO ABOUT 80% OF WHAT’S REQUIRED FOR PREVENTION. AND THEN THE FINAL PLAN IS GIVEN TO THE PATIENT AFTER THAT’S FINISHED. THAT HELPS THE PATIENT TO NOT FORGET TO GET DONE THE THINGS THAT ARE SUPPOSED TO GET DONE AND THAT ARE AGREED TO. BUT OF COURSE PATIENTS STILL FORGET. SO, IT’S IMPORTANT TO DO THE FOLLOW-UP. THAT’S THE NEXT STEP OF THE TEAM-BASED APPROACH. MEDICARE ALSO HAS SOMETHING CALLED CHRONIC CARE MANAGEMENT. MEDICARE ESTIMATES 70% OF PATIENTS QUALIFY, I WOULD STATEMENT MORE LIKE 90, A VAST MAJORITY OF PATIENTS QUALIFY. YOU CAN HAVE A CHRONIC CARE MANAGEMENT NURSE OR OTHER CLINICAL STAFF FOLLOW UP ON WHETHER THAT DEXA THAT WAS ORDERED ACTUALLY GETS DONE. IF IT WASN’T DONE THEY CAN HELP THE PATIENT FACILITATE GETTING IT DONE. IF IT WAS DONE AND NORMAL, THEY COMMUNICATE TO THE PATIENT AND UPDATE THE PATIENT’S CHART. IF IT WAS ABNORMAL THEY NOTIFY THE PHYSICIAN OR OTHER CLINICIAN AND SCHEDULE THE PATIENT TO DISCUSS TREATMENT. THAT’S WHAT WE DO IN OUR OFFICE. BY THE WAY, THE CHECKLIST CAME UP, YOU MIGHT HAVE NOTICED IF YOU’RE FAMILIAR WITH THE U.S. PREVENTIVE SERVICES TASK FORCE GUIDELINES THERE’S SOMETHING THAT WAS MISSING ON OUR CHECK LIST. THAT’S SCREENING IN POST MENOPAUSAL WOMEN UNDER AGE 65. WE DID NOT PUT THAT ON OUR CHECK LIST HERE. AND I WOULD ARGUE HERE THAT PROBABLY THE KNOWLEDGE GAP IS GREATER. I WOULD SAY SPECIFICALLY MOST PHYSICIANS PROBABLY DON’T KNOW THAT SIMPLY BEING A THIN WHITE WOMAN MAKES PUTS YOU AT HIGH RISK. THE GUIDELINES ARE ALSO HELPFUL HERE, THEY HAVE A NUMBER OF SUGGESTED RISK SCORES INSTRUMENTS TO HELP DETERMINE WHICH PATIENTS ARE AT HIGH ENOUGH RISK TO DO DEXA ON EVEN IF THEY ARE UNDER 65. THIS IS THE TABLE THAT THEY HAVE. THEY HAVE FIVE DIFFERENT SCORING INSTRUMENTS YOU CAN DO. AS YOU CAN TELL AGAIN WE’RE TALKING ABOUT LOGISTICS, MOST OF THESE ARE ACTUALLY FAIRLY COMPLICATED. THERE’S ONE UP HERE THAT’S REALLY SIMPLE. AND I WOULD ARGUE THAT THAT’S THE ONE WE SHOULD BE USING. NOW, NOT ARGUIN THE OTHER ONES CAN’T BE USED, BUT ISN’T THAT PRETTY SIMPLE TO SAY THE OSTEOPOROSIS SELF ASSESSMENT MEASURE JUST SAYING IS MY — I’M A WOMAN UNDER 65, POST-MENOPAUSAL, IF MY WEIGHT IN KILOGRAMS IS NOT 10 GREATER THAN MY AGE, I’M AT HIGH RISK. THAT’S PRETTY SIMPLE. THAT CAN ACTUALLY BE PUT INTO AN EHR, FOR EXAMPLE, AND THAT CAN HELP GET THESE WOMEN WHO ARE NOT OVER THE AGE OF 65 BUT ARE HIGH RISK. I WOULD ARGUE SOME OF THE OTHER TOOLS THAT PHYSICIANS PROBABLY ARE MORE FAMILIAR WITH LIKE THE FRAX IS MORE COMPLICATED AND CUMBERSOME IN PRIMARY CARE. THESE CAN BE INSERTED IN THE EHR. LOOK AT EACH WOMAN AT EACH AGE, SHOW ME THE WOMEN WHOSE WEIGHT IN KILOGRAMS IS NOT 10 GREATER THAN THEIR AGE, THAT WILL BRING UNTHE UP THE WOMEN NOT CAUGHT AT THE WELLNESS VISITS. WE DID THAT AND FOUND LOTS OF WOMEN IN OUR OFFICE. OKAY. SO ONCE OSTEOPOROSIS IS DIAGNOSED, THEN HOW ABOUT TREATMENT? I WOULD ACTUALLY ARGUE THAT THE KNOWLEDGE GAPS ARE NOT THE PRIMARY PROBLEM HERE. WE HEAR ABOUT DIFFERENT OPTIONS WITH OSTEOPOROSIS TREATMENT AND PRO AND CONS. THE ACP GUIDELINES GIVE GOOD GUIDANCE, BOTTOM LINE BISPHOSPHONATE ARE THE FIRST CHOICE. MOST PRIMARY CARE, BISPHOSPHONATES WILL BE APPROPRIATE AND ACCEPTABLE IN THE LARGE MAJORITY OF WOMEN. AGAIN, THE ISSUE IS IMPLEMENTATION. GETTING WOMEN TO START THE MEDICATION THAT WAS ORDERED, AND THEN STAY ON IT ONCE YOU’RE ON IT. THIS IS A BIG ISSUE FOR SURE. BUT I’D ARGUE IT’S REALLY NOT THAT MUCH DIFFERENT THAN ALL THE OTHER DISEASES THAT WE WORK WITH IN PRIMARY CARE. PARTICULARLY THE ONES THAT ARE THE SILENT CHRONIC DISEASES, DIABETES, HYPERTENSION, WHICH WE DEAL WITH ALL THE TIME. AND THAT MEANS, FOR EXAMPLE, WOMEN WHO NEVER START THE THERAPY OR WHO STOP BUT DON’T TALK TO THEIR CLINICIAN. THE WOMEN WHO HAVE A SIDE EFFECT AND THEY ARE NOT SURE IF THAT’S FROM THE MEDICATION OR NOT. AN EXAMPLE MIGHT BE ACHING IN MY LEGS, IS THAT FROM POTENTIALLY IMPENDING ATYPICAL FEMORAL FRACTURE OR JUST BECAUSE OF THE STATIN THAT I’M ON? THERE’S OTHER THINGS LIKE WHEN TO RETEST, ET CETERA. BUT I WOULD ARGUE THAT TEAM-BASED APPROACH, DON’T RELY PRIMARILY ON THE PHYSICIAN TO FIGURE THIS OUT. USE THE CHRONIC CARE MANAGEMENT NURSES TO HELP TALK TO THE PATIENTS, AND ALSO TO FACILITATE DISCUSSIONS WITH THE PHYSICIAN. OKAY. SO, WE’RE SUPPOSED TO TALK ABOUT WHERE ARE THE GAPS. I WOULD ARGUE IN PRIMARY CARE, MOST OF THE RESEARCH GAPS ARE GOOD LOGISTICS. AND THAT’S IMPLEMENTATION SCIENCE. SO, FOR EXAMPLE, WHAT’S THE BEST MODEL FOR IMPLEMENTING SCREENING AND TREATMENT OF OSTEOPOROSIS IN PRIMARY CARE? IS IT THE OLD MODEL OF CLINICIAN-DRIVEN ENCOUNTERS? I DON’T THINK SO BUT I DON’T KNOW IF WE’VE EVER STUDIED THAT. IS IT A TEAM HAD BEEN BASED APPROACH USING TEMPLATES FOR SCREENING? IS IT USING STAFF AND OFFICE VISITS TO FIGURE OUT WHO IS DUE FOR TESTING? CHRONIC CARE STAFF FOR PATIENTS TO FOLLOW UP A AFTER PATIENTS GET TESTED OR TREATED. HOW ABOUT WOMEN UNDER 65? I THINK THERE’S PROBABLY A SIGNIFICANT KNOWLEDGE GAP THERE, IS THAT TRUE? I DON’T KNOW IF WE HAVE THE SCIENCE FOR THAT. WHAT’S THE KNOWLEDGE ABOUT VALID SCREENING TOOLS? WHAT’S THE BEST SCREENING TOOL TO USE, LOU TO INTEGRATE IN PRIMARY CARE? LASTLY I THINK THERE’S GOING TO BE A LOT OF UNDERLYING ASSUMPTION THAT WE TREAT OSTEOPOROSIS DIFFERENT, IS THAT TRUE? DO PRIMARY CARE PHYSICIANS REALLY TREAT OSTEOPOROSIS DIFFERENTLY THAN ANYTHING ELSE BY GIVING LOW PRIORITY? I DON’T THINK WE HAVE THE RESEARCH BASE FOR THAT EITHER. HOW ABOUT FOR TREATMENT? WHAT PERCENTAGE OF WOMEN STOP TREATMENT IN PRIMARY CARE? THE STUDIES NEED TO BE DONE IN PRIMARY CARE IN ORDER FOR THIS TO BE VALID. WHAT ARE THE EFFECTIVE WAYS TO IDENTIFY WOMEN AND INTERVENE? AND IS ADHERENCE TO OSTEOPOROSIS MEDICATIONS ANY DIFFERENT THAN ADHERENCE TO BLOOD PRESSURE MEDICINES, DIABETES MEDICINES, OTHER THINGS THAT WE DO FOR SILENT DISEASES? IN SUMMARY I THINK THE BOTTOM LINE IS IN PRIMARY CARE WE HAVE PROBLEMS. WHAT DO WE NEED TO DO? FIRST, FOCUS ON THE BASICS. INITIAL SCREENING AND TREATMENT, THAT’S WHERE THE LARGE MAJORITY IS FALLING THROUGH THE CRACKS. I THINK WE SHOULD IMPLEMENT MODELS TO PUT GUIDELINES INTO PRACTICE PARTICULARLY STRUCTURED APPROACHES, TEAM-BASED APPROACH USING STAFF, CHRONIC CARE MANAGEMENT NURSES, OTHER STAFF TO HELP WITH SCREENING AND IDENTIFY PATIENTS WHO NEED SCREENING, BUT ALSO IN TREATMENT, FOLLOWING UP PATIENTS WITH TREATMENT. AGAIN, I DON’T WANT TO DIS THE IMPORTANCE OF KNOWLEDGE AMONG PHYSICIANS AND OTHER CLINICIANS, IN ORDER FOR THIS TO WORK, PHYSICIANS AND OTHER CLINICIANS NEED TO BUY IN. CNA ABOUT OSTEOPOROSIS IS NOT GOING TO GET THE JOB DONE, WHEN WE DO CME AND INFORMATION FOR PHYSICIANS WE NEED TO FOCUS ON AREAS WHERE, DEFINING HIGH RISKING, AND FOCUS LESS ON GENERAL KNOWLEDGE ABOUT OSTEOPOROSIS, THAT’S WHAT’S GOING TO HELP GET US WHERE WE NEED TO BE. THANK YOU VERY MUCH. [APPLAUSE] I’M STU SILVERMAN, A RHEUMATOLOGIST AT CEDARS-SINAI UCLA. WE HEARD A GOOD TALK BY DR. GILL ABOUT THE ROLE OF THE CLINICIAN AND HEALTH CARE TEAM. LET’S FLIP TO THE OTHER SIDE AND TAKE A LOOK AT THE PATIENT. MY DISCLOSURES, SPEAKERS BUREAU, CONSULTANT, GRANT SUPPORT. AND THE SUMMARY IS THAT PATIENTS MAKE DECISIONS BASED ON THEIR INDIVIDUAL PERCEPTIONS OF RISK AND BENEFITS. AS WE’LL SEE, THESE DECISIONS ARE SURPRISING TO SOME OF US BECAUSE DESPITE THE PATIENT’S BEING AT HIGH RISK OF FRACTURE, THEY FREQUENTLY CHOOSE NOT TO INITIATE THERAPY. BASING THIS ON THEIR PERCEPTION OF RISK AND BENEFITS. THE RISK INCLUDES RISK OF EVENTS, AS WELL AS RISK OF PERCEIVED, AND/OR EXPERIENCED ADVERSE EVENTS. THERE ARE MULTIPLE FACTORS WE’LL DISCUSS. I’LL TRY TO USE SOME FINDINGS FROM COGNITIVE SCIENCE TO HELP US IN THAT REGARD. PATIENTS PERCEIVE BENEFITS OF THERAPY DIFFERENTLY. AND COMMUNICATING THAT GETS CHALLENGING TO US. AS I MENTIONED, PATIENTS FREQUENTLY CHOOSE NOT TO INITIATE OSTEOPOROSIS MEDICATION DESPITE HAVING HIGH RISK OF FRACTURE. SO GLOW, FOR EXAMPLE, THERE WERE 32% OF 28,000 PARTICIPANTS AT HIGH RISK, YET ONLY 35%, A LITTLE OVER A THIRD, REPORTED TREATMENT WITH ANTI-OSTEOPOROSIS MEDICINE. IN ANOTHER STUDY AT KAISER, COST WAS NOT AN ISSUE, ONLY ABOUT 30% OF PATIENTS FILLED PRESCRIPTIONS, WE LOOK AT HEALTH RECORDS TO SEE WHETHER THE PRESCRIPTIONS HAPPENED. THERE’S CLEARLY A NEED TO UNDERSTAND LACK OF WILLINGNESS OF PATIENTS AT HIGH RISK TO START OSTEOPOROSIS MEDS. WHY ARE PATIENTS NOT WILLING TO START? FIRST HAVE TO UNDERSTAND HOW PATIENTS MAKE MEDICAL DECISIONS AND MAKE DECISIONS BASED ON PERCEPTION OF THAT PERCEIVED RISK AND RELATIONSHIP TO PERCEIVED BENEFIT. RISK IS THE PRODUCT OF THE PROBABILITY OF HAZARDOUS OUTCOME, INTERPRETED BY PATIENTS, BASED ON INDIVIDUAL PERCEPTION, LIKELIHOOD OF THAT OUTCOME. PERCEPTION OF RISK INCLUDES PERCEPTION OF RISK OF EVENT, AM I AT RISK OF FRACTURE, ALSO RISK OF PERCEIVED OR EXPERIENCED ADVERSE EVENT. PERCEIVED RISK IS BASED ON THE PATIENT’S UNDERSTANDING OF THE MEDICAL INFORMATION, THAT THESE CLINICIANS PROVIDE TO THEM. UNFORTUNATELY, 40 TO 80% OF THE INFORMATION THAT WE GIVE THEM IS FORGOTTEN IMMEDIATELY. THE GREATER THE AMOUNT OF INFORMATION WE GIVE OUR PATIENTS, THE LOWER IS RECALLED. SOMETIMES FORGET WE HAVE UNDERSTANDING THAT PATIENTS AS UNDERSTANDING OF RISK RESULTS NOT FROM COMPLETE INFORMATION BUT WHAT THEY PERCEIVE IS GIST OR CENTRAL MESSAGE OF THE INFORMATION. SO THE GIST AND DETAILED CONCEPT ARE PARALLEL BUT INDEPENDENT. WE FORGET PRECISE DETAILED FACTS ABOUT RISK MAY NOT NECESSARILY BE EFFECTIVE IN ENCOURAGING HEALTH BEHAVIOR. PATIENTS GET FACTS RIGHT, BUT THEY DON’T GET THE PROPER MEANING. THEY MAY TAKE A NUMERIC ESTIMATE, SUCH AS 1%, 15%, FOR SOME PEOPLE THAT’S SMALL, OTHER PEOPLE THAT’S LARGE. SO RISK IS INFLUENCED BY MULTIPLE FACTORS. THE SOURCE OF INFORMATION, WE’LL DISCUSS THE PHARMACIST, MEDIA COVERAGE, HEARSAY, TRUST IN THE HEALTH CARE PRACTITIONERS, IMMEDIACY OF THAT INFORMATION, BIASES, FRAMING EFFECTS, EMOTIONS, DENIAL, FINALLY DISEASE PERCEPTION. WELL, AS YOU WOULD EXPECT, INFORMATION IS JUDGED MORE LIKELY IF YOU REMEMBER IT. IT’S EASILY BROUGHT TO MIND, RECENTLY HEARD. SOMETHING RECENTLY COVERED IN THE MEDIA, WELL, PUBLIC MEDIA, YOU WILL REMEMBER THAT. THERE’S ALSO SOCIAL MEDIA, GOOGLE SEARCHES, FACEBOOK, ROLE OF INFLUENCERS, I JOKE THAT DR. GOOGLE IS OFTEN CONSULTED AS A SECOND OPINION WHENEVER I TALK TO A PATIENT. THE RELATIONSHIP AS WE HEARD BETWEEN MEDIA COVERAGE AND NUMBER OF PRESCRIPTIONS THAT ARE FILLED. WE ALL APPRECIATE PATIENTS ARE NOW MUCH MORE LIKELY TO SUGGEST THEIR OWN TREATMENT PLAN. THE ENDLESS SUPPLY OF INFORMATION, MEDICAL APPS, SEARCH THE INTERNET, BRING TO MY OFFICE, PRINTOUTS, COME ON WITH MORE RESEARCH IDEAS THAN SUGGESTION. THIS CAN BE GOOD. BUT IT CAN ALSO BRING CHALLENGES WHEN AN ONLINE SERVICE ISN’T TRUSTY OR DOESN’T ACCOUNT FOR INDIVIDUALITY OF OUR PATIENTS. HEALTH IS HELPING ON MAJOR SOCIAL NETWORKS. 30% OF PATIENTS SAY THEY HAVE USED SOCIAL MEDIA TO FIND HEALTH-RELATED CONSUMER REVIEWS, TREATMENTS OR PHYSICIANS. ABOUT A THIRD USE YouTube, FACEBOOK, AND TWITTER, AND GOOGLE SEARCHES DEFINE MEDICAL INFORMATION, RESEARCH, SHARE SYMPTOMS AND LOOK AT OPTIONS ABOUT DOCTORS’ TREATMENTS, ET CETERA. WE ALSO RECOGNIZE SOCIAL MEDIA HAS LIMITATIONS. I WON’T GO THROUGH ALL BUT WE RECOGNIZE THERE’S A LACK OF RELIABILITY, QUALITY CONCERNS, THERE MAY BE RISKS ASSOCIATED WITH USE OF INCORRECT DEVICE, INFORMATION OVERLOAD, NOT SURE HOW TO APPLY INFORMATION FOUND ONLINE. TRUST IN THE HEALTH CARE PRACTITIONER, PATIENTS ARE MORE LIKELY TO BELIEVE INFORMATION THEY GET AND FOLLOW THAT HEALTH CARE PRACTITIONERS’S ADVICE. IN STUDIES THAT I PARTICIPATED IN, IN FOCUS GROUPS OF PATIENTS TRUST IS IDENTIFIED AS A CRITICAL DOMAIN OPTIMISM BIAS, THAT PERSON, THEY ARE GOING TO BE THE ONE TO GET THE FRACTURE, NOT ME. AGAIN, THERE’S THE PESSIMISM BIAS. I KNOW IT’S EXTREMELY RARE AND RISK IS 1 IN A THOUSAND OR 1 IN 10,000 BUT YOU KNOW ME, WHATEVER IS A SIDE EFFECT, I’M THE ONE. FRAMING EFFECTS, WE NEED TO STATE WHAT A TREATMENT IS, 97% EFFECTIVE IS MORE IMPRESSIVE THAN SAYING IT’S ONLY 3% INEFFECTIVE. MOST IS DETERMINED BY EMOTION. THE FRACTURE HAS GOTTEN CONCERNS, IT’S CATASTROPHIC, MY JAW IS FALLING OFF, THERE’S A FRACTURE. UNFORTUNATELY THE OTHER PROBLEM WE MIGHT SEE A SIDE EFFECT WITH ONE CLASS OF OSTEOPOROSIS MEDICATIONS, EVEN THROUGH OTHER CLASSES THAT DON’T HAVE THAT SAME SIDE EFFECT, PATIENTS TEND TO GENERALIZE ACROSS MEDICATION INDICATION, THAT’S CALLED CATEGORICAL BIAS. WE PUT PATIENTS ON HOLIDAYS. WELL, OBVIOUSLY IF YOU HAVE TO TAKE ME OFF THAT DRUG AFTER A COUPLE YEARS, THAT MEANS IT MUST BE RISKY. OF COURSE THE MALE FEELS LESS MASCULINE TAKING MEDICINE. THIS MAY BE HELPFUL TO AVOID CONCERNS, MIGHT BE A COPING METHOD. THIS SHOWS THERE IS A DIFFERENCE BETWEEN PATIENT AND PHYSICIAN SEVERITY. ON THE LEFT IS PATIENT-PHYSICIAN AGREEMENT, YOU REQUEST SEE 14% OF PATIENTS RATE DISEASES MORE SEVERE, 20% LESS SEVERE. 30% RATE GREATER CONCERN ABOUT OSTEOPOROSIS THAN THEIR PHYSICIAN, AND 21% REPORTED LOWER CONCERN. IN GLOW, ONLY 11% OF WOMEN WITH LOWER BASELINE WERE TAKING MEDICINES FOR OSTEOPOROSIS COMPARED WITH HALF OF WOMEN WITH HIGHER PERCEIVED FRACTURE RISK. AND USE OF MEDICINES WAS INCREASED IN YEARS AFTER A FRACTURE, AND WHAT’S IMPORTANT IS WOMEN WITH A LOWER SELF PERCEIVED FRACTURE RISK WHO FRACTURED STILL REPORTED LOWER USE OF OSTEOPOROSIS MEDS THAN WOMEN WITH OR WITHOUT A FRACTURE WITH A HIGHER PERCEIVED RISK. SIDE EFFECTS CAN BE PERCEIVED OR NOT YET EXPERIENCED, INDIVIDUALIZED BUT PLAY VARY BY RACE AND ETHNICITY BUT IF YOU CORRECT FOR AGE, SOCIOECONOMIC STATUS AND GENDER THAT SENDS TO DISAPPEAR. IN TERMS OF BENEFIT, PATIENTS SAY IS OSTEOPOROSIS REALLY TREATABLE? IT’S A DISEASE OF AGING. ARE THERE REALLY MEDICINES THAT WORK? HOW EFFECTIVE ARE THAT? HOW LONG HAVE THEY BEEN STUDIED? A COUPLE YEARS? THAT DOESN’T SOUND LONG ENOUGH. DO THEY WORK IN EVERYONE? ONE THING THAT’S IGNORED, PATIENTS DO NOT MAKE A DECISION ALONE. IN SOME CULTURES WE FIND, FOR EXAMPLE, THAT THE WOMAN HAS TO CONSULT WITH HER HUSBAND FIRST, WHO MAY AGREE OR DISAGREE WITH THE DECISION, OR THERE MAY BE YOUR CHILDREN WHO YOU HAVE TO TALK TO. OR SOCIAL GROUPS. ANOTHER STUDY LOOKED AT ESTROGEN, 28 DAYS TO FILL THE PRESCRIPTION, WOMEN TENDED TO CONSULT PEER GROUP, WALKING GROUP, MAH-JONGG GROUP, THE ROLE OF “OTHER.” WE’RE LOOKING AT PHYSICIANS, THE PATIENT ALONE IS NOT THE ONLY ONE MAKING THAT DECISION. TAKE TAKING A MEDICINE IS LEARNED BEHAVIOR. SO, PATIENTS NOT TAKING ANY, HESITANT, THIS MEANS I’M REALLY SICK. OR PATIENTS WITH SO MANY MEDICINES, I DON’T WANT TO TAKE ANOTHER ONE. AS INFLUENCED BY GENDER WITH WOMEN, TAKING LONGER TO FILL A PRESCRIPTION THAN MEN. HOW CAN WE COMMUNICATE RISK? YOU OUGHT TO BE CAREFUL ABOUT USING VERBAL TERMS.. IT DOESN’T COMMUNICATE RISK EFFECTIVELY. USE NUMERICAL. SOME PATIENTS, BIGGER RISK THAN 1 IN 25. WE TALKED ABOUT FRAMING. IT’S EASY TO GET CONFUSED ON PERCENTAGES OR INTERPRETING STATEMENTS, THREE TIMES MORE LIKELY TO CURE WITH TREATMENT A THAN B. USES VISUAL AIDS. WE NEED TO MAKE SURE THE DECISION IS BASED ON INFORMATION, GIVING DATA ALONE IS NOT INFORMATION. DO VISUAL AIDS HELP? I REFER TO THE MAYO TRIAL, DECISION COMPARED TO FRAX, TWICE AS MANY RECEIVED AND FILLED PRESCRIPTIONS IN THE DECISION-MADE ARM, THIS IS REALLY HELPFUL. THE NEXT SPEAKER, DEBBIE GOLD, EXPLAINED MEDICATION ADHERENCE AT SIX MONTHS IS NO DIFFERENT ACROSS ARMS. WHO ARE THE LOW RISK PATIENTS WHO REQUEST OSTEOPOROSIS MEDS? IN MY PRACTICE, PROBABLY SOME HAVE THAT PESSIMISM BIAS, CONVINCED IT’S GOING TO BE THEM. THE FRIGHTENED DAUGHTER WHO DOESN’T WANT TO BE BENT OVER LIKE MOTHER OR GRANDMOTHER. SO WHAT ARE MY KEY RECOMMENDATIONS? WELL, WE’VE BEEN TOLD THAT ACTUALLY OUR GOALS AS CLINICIANS IS FIRST OF ALL TO GIVE INFORMATION TO OUR PATIENTS. TO SHARE INFORMATION WITH THEM. THEN TO CHANGE THEIR BELIEFS, AND THEN CHANGE THEIR BEHAVIOR . WE NEED TO SHARE TO BETTER UNDERSTAND HOW THE PATIENT PERCEIVES RISK AND BENEFITS. WE’VE HEARD ABOUT THIS INFORMATION, THAT IT’S PROBABLY BETTER YOU COULD START VERBAL BUT WANT TO GET NUMERICAL, AVOID NUMBER NEEDED TO TREAT, USE ABSOLUTE NUMBERS AND RISK, RELATIVE RISK, BUT EVEN THEN THAT’S NOT ENOUGH. IN MY LAST BULLET POINT, ACTUALLY ONE OF THE THINGS I FIND MOST IMPORTANT IS FOR PATIENTS TO UNDERSTAND WHAT THE CONSEQUENCES ARE TO THEM. THESE THINGS ARE ABSTRACT CONCEPTS, WE’RE TALKING IN ASYMPTOMATIC DISEASE UNTIL YOU FRACTURE. PATIENTS, YOU NEED TO SPEND TIME WITH PATIENTS. VERY OFTEN THAT MIGHT BE MORE THAN ONE VISIT WHERE YOU CAN UNDERSTAND WHAT IS A PATIENT’S PRIORITY? YOU MIGHT BE ABLE TO CONVINCE A PATIENT GREATER THAN ANY VERBAL DESCRIPTION, NUMERICAL DESCRIPTION, BY HAVING THEM UNDERSTAND RISK OF NO TREATMENT VERSUS RISK OF TREATMENT, TO THEIR ROLES AS WIFE, HUSBAND, PARENT, DAUGHTER, SON. IT’S VERY IMPORTANT IF I FIND OUT THAT THEY ARE LOOKING FORWARD TO THEIR GRANDCHILDREN, IF YOU FRACTURE YOU MAY NOT BE ABLE TO PLAY WITH YOUR GRANDCHILDREN, AS YOU’VE BEEN ANTICIPATING. YOU’VE BEEN LOOKING FORWARD TO HAVING GRANDCHILDREN BUT MAY NOT BE ABLE TO PLAY WITH THEM IF YOU FRACTURE. WE HAVE TO FIND OUT WHAT RESONATES. THAT’S ONE OF OUR GREAT CHALLENGES, IN A VERY SHORT TIME, TO FIGURE OUT WHAT IS IMPORTANT TO OUR PATIENTS AND GO LOOK AT IT FROM THEIR PERSPECTIVE. AND THEN WE NEED TO IMPROVE OUR COMMUNICATION WITH OUR PATIENTS. WE NEED TO BETTER UNDERSTAND THE ROLE OF THE OTHER. I WANT TO EMPHASIZE THERE’S A DEARTH OF EVIDENCE IN TERMS OF HOW SOCIAL MEDIA WORKS FOR DECISION MAKING. I CERTAINLY — I THINK THAT WE NEED TO LOOK, FOR EXAMPLE, AT PATIENT LISTENING, THERE ARE NOW EFFORTS IN SOME DISEASES RIGHT NOW, FOR EXAMPLE, IN HIV TO LOOK AT PATIENT CONVERSATIONS ON SOCIAL MEDIA. WE HAVE THE ABILITY TO LOOK ACROSS ALL MEDIA, FACEBOOK, ET CETERA, UP TO GOOGLE SEARCHES IN OUR OLDER PATIENTS. AND UNDERSTAND WHAT THEY ARE THINKING AND SAYING WE NEED TO BE ABLE TO WORK WITH THEM IN TERMS OF SOCIAL MEDIA AS WELL. I THINK ONE OF THEIR PROBLEMS, WE TALK RIGHT NOW IN OUR CONVERSATION NATIONALLY ABOUT MISINFORMATION, POLITICALLY. WELL, THERE’S A LOT OF MEDICAL INFORMATION AND WE’RE JUST STARTING TO WORK ON WHAT A LOT OF US CALL CYBER HYGIENE, HOW TO LABEL PERHAPS MISINFORMATION ABOUT FACTS, WE HAVEN’T DONE THAT AS WELL. FOR EXAMPLE, FACEBOOK NOW WILL HAVE LIKE, DISLIKE, OR QUESTION THAT DATA. WE NEED TO DO THE SAME THING EXACTLY WITH MEDICAL INFORMATION AS WELL. THAT’S NOT STARTED. SOCIAL MEDIA RELIES ON ONLINE COMMUNITIES. I’M VERY EXCITED TO LOOK AT NON-PROFIT ADVOCACY GROUP, LOOKING TOWARD GOALS TO ESTABLISH ONLINE COMMUNITIES, WHICH CAN BE MONITORED AND CAN BE BETTER INFORMATION FOR OUR PATIENTS. THE SAME TIME I THINK WE MENTIONED EARLIER ABOUT INFORMATION, I WOULD LIKE TO POINT OUT THAT VISUAL AIDS MIGHT BE HELPFUL, WEB BASE AND ONLINE WOULD BE GREAT TO HAVE THOSE VISUAL AIDS THAT CLINICIANS TO USE TO TALK TO PATIENTS OR PATIENTS COULD LOOK AT TO UNDERSTAND RISK OF FRACTURE AND ALSO UNDERSTAND BENEFITS OF TREATMENT. THIS IS AN AREA WE NEED TO EXPLORE. SO, AGAIN, MY EMPHASIS, WE NEED TO WORK ON PATIENT-CLINICIAN COMMUNICATION, AND INCREASE TRUST IN THE HEALTH CARE PROVIDER AND TEAM. THANK YOU. [APPLAUSE]>>I’M DEBRA GOLD, PROFESSOR OF MEDICAL SOCIOLOGY AT DUKE UNIVERSITY MEDICAL CENTER. AND I’M HERE TO TALK TO YOU TODAY ABOUT WHAT MAY BE THE MOST IMPORTANT ASPECT OF DRUG THERAPY AND THAT IS ACTUALLY GETTING THE PATIENTS TO TAKE THE DRUGS. I’M CONSULTANT FOR AMGEN, LILLY, RADIUS, SPEAKER FOR AMGEN AND LILLY AND WOULD LIKE TO SHOW WE HAVE SUBSTANTIAL DATA THAT SHOWS ADHERENCE WITH OSTEOPOROSIS EDICATIONS IS EXTREMELY POOR. VERY FEW INTERVENTIONS NO MATTER HOW WELL CONCEIVED ARE CARRIED OUT HAVE MADE ANY DIFFERENCE, PERCEPTIONS BY PATIENTS AND PHYSICIANS NEEDS TO CHANGE. THIS IS NOT A NORMAL CONSEQUENCE OF AGING. IT IS A DISEASE. WE NEED TO REDUCE COST OF TREATMENT AND HYPERTENSION PATIENTS UNDERSTAND RISKS OF NOT TAKING MEDICATIONS WHICH THEY DON’T YET UNDERSTAND. WE’VE DONE A WONDERFUL JOB IN THE LAST 25 YEARS OF PROVIDING PATIENTS WITH OPTIONS IN TAKING THEIR OSTEOPOROSIS MEDICATION. FIRST NON-HORMONAL WAS ALENDRONATE IN 1995, ORAL BISPHOSPHONATE WITH ANTI-RESORPTIVE THERAPIES. MOST RECENT FDA APPROVED MEDICATION WAS A DAILY INJECTABLE PARATHYROID HER MONEY APPROVED IN 2017, BUILD BONE. IN BETWEEN THE TWO APPROVALS, SIX OTHER MEDICATIONS RECEIVED FDA APPROVAL, AND THEN PREVIOUSLY TWO HORMONAL MEDICATIONS HAD ALREADY BEEN APPROVED. HERE IS A LIST OF MEDICATIONS AND THE TYPE THAT THEY ARE, NOT ONLY DO WE GIVE CHOICES OF MEDICATIONS WE GIVE THEM CHOICES OF HOW TO TAKE THE MEDICATIONS. YOU CAN TAKE THEM DAILY. WEEKLY. EVERY TWO WEEKS. EVERY MONTH. EVERY TWO MONTHS. EVERY THREE MONTHS, EVERY SIX MONTHS, EVERY YEAR. IN FACT, MY BELIEF IS WE GAVE PEOPLE TOO MANY OPTIONS IN TAKING OSTEOPOROSIS MEDICATIONS. AND THEN THE QUESTION CAME DO ALL THE OPTIONS MAKE A DIFFERENCE? AND WE KNOW ADHERENCE WITH ALL OF THE MEDICATIONS IS REALLY POOR, TRUE FOR HYPERTENSION, HYPER CHOLESTEROLEMIA, ADHERENCE IS NOT GOOD WITH THOSE MEDS. THE EARLY MEDICATIONS, ORAL BISPHOSPHONATES ARE CONVOLUTED DESK REGIMENS THAT SET THE PHONE FOR THE REST OF THE MEDICATIONS THAT PATIENTS FOUND BURDENSOME. AS YOU’VE HEARD FROM I BELIEVE EVERY SPEAKER WHO HAS TALKED, THOSE SIDE EFFECTS THAT ARE SO RARE BUT SCARY FRIGHTEN PEOPLE OFF THESE MEDICATIONS. A NOW CLASSIC REVIEW BY LEE AND COMPANY WHICH LOOKED AT 1970 TO 2009, DOSING INTERVAL WAS NOT THE PRIMARY FACTORS. FACTORS MORE IMPORTANT THAN DOSING WERE DRUG EFFECTIVENESS, SIDE EFFECTS, ROUTE OF ADMINISTRATION. FACTORINGS EQUALLY AS IMPORTANT AS DOSING WERE MEDICATION COST, AVAILABILITY OF PATIENT SUPPORT PROGRAMS. SO THAT ENTIRE LIST OF DAILY, WEEKLY, MONTHLY, YEARLY RAISES THE QUESTION WHY DID WE DO THAT WHEN IT DOESN’T SEEM TO MATTER TO PATIENTS HOW OFTEN YOU WANT TO TAKE THE MEDICATION, HOW WELL IT WORKS, HOW BAD THE SIDE EFFECTS ARE, PERCEIVED SIDE EFFECTS. RECENT STUDIES HAVE SHOWN ADHERENCE IS POOR ACROSS ALL MEDICATIONS, ACROSS MULTIPLE PATIENT GROUPS, EVEN USING VARIETY OF INTERVENTIONS. THERE WAS ONE STUDY RECENT IN THE OSTEOPOROSIS INTERNATIONAL JOURNAL THAT SHOWED OLDER ASIAN WOMEN HAD 29% GOOD ADHERENCE, 71 POOR ADHERENCE, WITH ASIAN STEREOTYPES POSITIVE ABOUT DOING THINGS TO MAKE THEMSELVES BETTER. ADHERENCE LEVELS HAVEN’T CHANGED SINCE THE YEAR 2000. DESPITE THE MANY INTERVENTIONS THAT HAVE BEEN DEVELOPED AND TRIED. ANOTHER FROM 2012 TO 2017, FLS AND PHARMACIST-BASED INTERVENTIONS HAD MODEST SUCCESS, BEHAVIORAL INTERVENTION DID NOT FAIR SO WELL. THE NATIONAL OSTEOPOROSIS FOUNDATION IS SUPPORTIVE OF FLS, DATA SHOWS IT WAS A GOOD DECISION. SO MANY OTHER INTERVENTIONS WE’RE TRYING ARE NOT WORKING. NOW, PATIENT BELIEFS ARE POWERFUL, IN MAKING THE THE DECISION TO START A MEDICATION THAT IS PRIMARY ADHERENCE, AND THEN TO CONTINUE THE MEDICATION, SECONDARIED Y ADHERENCE. IT’S STILL STUNNING 20 YEARS LATER WOMEN ARE SAYING MY MOTHER HAD IT, MY GRANDMOTHER HAD IT, IT’S A DISEASE OF AGING, I DON’T NEED TO TAKE MEDICATION. THE NEXT BELIEF MAY BE TRUE, OSTEOPOROSIS MEDICATIONS ARE EXPENSIVE, AND MOST PEOPLE CAN’T AFFORD THEM, PREVENTS PEOPLE FROM EVEN GOING TO DOCTORS AND ASKING TO BE CONSIDERED. COMPLEX DOSING REGIMENS OR DELIVERY METHODS, THERE ARE MILLIONS OF PEOPLE IN THE COUNTRY AFRAID OF NEEDLES, ARE OVERWHELMING, AND PERCEPTION THAT PHYSICIANS ARE NOT WORRIED ABOUT THIS DISEASE IF YOU GO TO A PHYSICIAN’S OFFICE YOU HAVE SEVEN MINUTES, NINE CONDITIONS, IT MAY BE THAT OSTEOPOROSIS GETS LEFT OFF AT THE END. THAT’S UNFORTUNATE. IN TERMS OF SCREENING, I’VE NEVER BEEN SCREENED BEFORE SO I DON’T NEED TO BE. IT’S IT LOGICAL BUT MANY REPORT WHY THEY HAVEN’T BEEN SCREENED FOR THE DISEASE. PHYSICIAN FACTORS CAUSE POOR ADHERENCE. CHANGING ATTITUDES TOWARDS PHYSICIANS CAN RESULT IN COMPROMISED RELATIONSHIPS WITH THEIR PATIENTS. WHEN I WAS A CHILD, DOCTORS WERE GODS. SORRY, GUYS, NOT THAT WAY ANYMORE. AND AS STUART MENTIONED, THE DR. GOOGLE BEING RATED THE NUMBER ONE PHYSICIAN RATED IN THE UNITED STATES IT’S DIFFICULT TO GET PATIENTS TO LISTEN AND CARRY ON A CONVERSATION WITHOUT THEIR PRETENDING THEY HAVE BETTER MEDICAL KNOWLEDGE THAN PHYSICIANS. SOMETIMES ORAL BISPHOSPHONATES ARE THE FIRST CHOICE BUT MANY PEOPLE CAN’T THEM THEM. WE HAVE TO SPEND EFFORT TO GET PEOPLE ON MEDICATIONS THAT WILL HELP THEM WITHOUT CAUSING PROBLEMS. AND THEN SOME SYSTEM FACTORS THAT HAVE LED TO THE REDUCTION IN VISIT LENGTH, LESS TIME TO DEVELOP A RELATIONSHIP, LESS TIME TO FOCUS ON OSTEOPOROSIS AS A PROBLEM, AND MUCH LESS TIME TO EDUCATE PEOPLE ABOUT THIS DISEASE AND ITS CONSEQUENCES. SO WHAT DO WE DO NOW? THOSE OF US WHO HAVE DONE ADHERENCE RESEARCH AND THERE ARE MANY SITTING IN THE AUDIENCE TODAY, HAVE THOUGHT OVER TIME WE’D GET A WAY TO HAVE PATIENTS PAY ATTENTION, LISTEN, TAKE THEIR MEDICATION. HASN’T WORKED. GIVEN THE POOR OUTCOMES OF THE INTERVENTION TRIALS THAT HAVE BEEN DONE TO THIS POINT, WHAT& SHOULD WE DO NEXT? UNFORTUNATELY, BEHAVIOR CHANGES AND EDUCATION ARE NOT LIKELY TO MAKE SIGNIFICANT CHANGES IN ADHERENCE. SOME ADHERENCE INFORMATIONS WORK ONLY IN THE SHORT THEY TERM, YOU HEARD ABOUT THAT BUT JUST TALKING AT PEOPLE WILL NOT WORK. WE NEED TO MAKE MEDICATION TAKING INTO A HABIT. IS DEVELOPING HABITS EASY? NO, NOT EVER. ASK ANYBODY WHO EVER TRIED TO DEVELOP A GOOD HABIT OF RUNNING EVERY MORNING, DOING EXERCISES, IT’S NOT SIMPLE. REMEMBER WHEN YOU TRIED TO TEACH YOUR KIDS TO BRUSH THEIR TEETH EVERY DAY? IT’S TERRIBLE. EARLIER IT WAS A FIGHT. NOW THEY ARE DOING IT. WE HOPE. [LAUGHTER] AND TWO CHALLENGES IN PARTICULAR ARE RESPONSIBLE FOR MAKING ADHERENCE TO OSTEOPOROSIS MEDICATIONS DIFFICULT TO ACHIEVE. CHALLENGE NUMBER ONE, THE MEDIA PERCEPTIONS AND INFORMATION ABOUT OSTEOPOROSIS. WE’VE SEEN THE ORAL IN THE “NEW YORK TIMES” ON THE SCREEN TWICE TODAY BUT I WOULD ARGUE SINCE THE AWARENESS OF OSTEOPOROSIS BY MEDICAL PERSONNEL HAS INCREASED, THE MEDIA HAVE WORKED TIRELESSLY TO MISCONSTRUE AND MISINFORM THE PEOPLE ABOUT THE DISEASE AND ITS TREATMENTS. THERE’S A RECENTLY PUBLISHED REVIEW ARTICLE THAT DID AN EXCELLENT JOB OF TALKING ABOUT MEDIA’S PROBLEMS. AWARENESS OF OSTEOPOROSIS AS A MAJOR HEALTH PROBLEM, PERCEPTION OF EFFECTIVENESS OF MEDICATION AND FEAR OF ADVERSE EVENTS. THE AUTHOR SAID IN CONTINUATION SEVERAL TRUTHS ABOUT THE MEDIA. ABUNDANCE OF DATA SHOW THAT ALARMING REPORTS ABOUT OSTEOPOROSIS MEDICATION IN TODAY’S MEDIA HAVE RAPIDLY BEEN FOLLOWED BY THE REDUCTION IN THE USE OF THESE MEDICATIONS. WE SAW THAT IN CHART FORM A MINUTE AGO. STARTED HERE, CAME DOWN TO HERE. SECOND, THE CURRENT CRISIS OF OSTEOPOROSIS CARE IS IN PART DUE TO THE MEDIA’S REPORTING. I DON’T KNOW WHY PATIENTS BELIEVE THEIR NEWSPAPERS OR THEIR COMPUTERS MORE THAN THEY DO THEIR DOCTORS. BUT THEY DO. FINALLY, THE PRESENCE AND/OR ABSENCE OF MEDIA REPORTS CAN STRONGLY INFLUENCE THE LEVEL OF AWARENESS OF OSTEOPOROSIS. AND ALSO THE LEVEL OF CONCERN ABOUT FRACTURE RISK. SO THEY CAN UNDERREPORT AND PATIENTS UNDERPERCEIVE. THE SECOND CHALLENGE HAS TO DO WITH DEMOGRAPHIC OR SOCIAL FACTORS. MANY OF THESE FACTORS AFFECT WHETHER PEOPLE FEEL THAT THEY CAN OR SHOULD TAKE THESE MEDICATIONS. ONE IS POOR EDUCATION AND POOR HEALTH LITERACY. ANOTHER LOW INCOME. ANOTHER HIGH COST. INADEQUATE UNDERSTANDING OF THE DISEASE AND ITS MEDICATIONS, AND UNCERTAINTY ABOUT MEDICATION SAFETY. NOW, YOU’LL NOTICE I’VE FOLLOWED EACH OF THESE FACTORS WITH AN “OR.” SO POOR EDUCATION OR LOW INCOME OR HIGH COST, ET CETERA, BUT THE TRUTH IS IN THE REAL WORLD, THEY SHOULD BE FOLLOWED BY “AND.” IT’S POOR EDUCATION AND LOW INCOME AND HIGH COST AND INADEQUATE UNDERSTANDING OF THE DISEASE. THE CUMULATIVE EFFECT OF THESE FACTORS IS OVERWHELMING. AND REQUIRES LONG-TERM MULTI-DISCIPLINARY INTERVENTIONS THAT ARE NOT LIMITED TO SIMPLY THE TAKING OF MEDICATION BUT TO CHANGE PEOPLE’S PERCEPTIONS ABOUT THEIR HEALTH AND WHAT THEY CAN DO TO IMPROVE IT. IF I LOOK AT LITERATURE ON ADHERENCE WITH ALL MEDICATIONS, NOT JUST OSTEOPOROSIS INCENTIVIZING CHANGE THROUGH ECONOMIC MEANS IS MORE EFFECTIVE THAN ANY OTHER STRATEGY. LET ME TRANSLATE FOR YOU. MONEY. MONEY. MONEY. IF WE REDUCE COST WE’RE MORE LIKELY TO BRING PATIENTS IN LINE. NEGOTIATE DRUG PRICES AS HAPPENS IN VIRTUALLY EVERY OTHER COUNTRY, AND WHEN I SAT WITH TWO OF MY BRITISH FRIENDS AT DINNER LAST NIGHT AND LISTENED TO COSTS OF MEDICATIONS THERE I SHOOK MY HEAD AND THOUGHT WHY THE U.S. IS SUPPORTING THE WORLD’S MEDICATION USE. THIS ISN’T A MAGIC BULLET BUT COULD INITIATE SYSTEMWIDE CHANGES THAT COULD MUCH IMPROVE ADHERENCE. FOR MANY MEDICATIONS, STATINS, ET CETERA, NOT JUST OSTEOPOROSIS DRUGS. AND FINALLY, IT WAS SAID IN THE “NEW YORK TIMES” AT THE END OF 2007, HIGH TECH APPROACHES AND REMINDER PACKAGING DON’T WORK WELL TO IMPROV ADHERENCE. REDUCING PRICES DOES. AND IT MAY BE THE ONLY WAY TO MAKE A SIGNIFICANT DIFFERENCE IN HOW WE EFFECTIVELY TREAT OSTEOPOROSIS AND IMPROVE THE BONE HEALTH OF AMERICANS. THANK YOU VERY MUCH. [APPLAUSE]>>COULD I ASK ALL THE SPEAKERS TO COME UP. WE’RE GOING INTO THE FIRST OF OUR DISCUSSION SESSIONS THIS MORNING WHILE I WAIT FOR THE SPEAKERS TO COME UP. AND THE PANELISTS GET THE FIRST CRACK IN TERMS OF ASKING QUESTIONS. LET’S GIVE EVERYBODY A FEW MINUTES. ET>>LET ME OPEN TO THE PANEL.>>DR. SHANE SHARED WITH US THAT FRACTURES OCCURRING WITHIN ONE YEAR OF AN INITIAL FRACTURE WAS VERY HIGH. WE HEARD ABOUT A NUMBER OF DIFFERENT THERAPEUTIC APPROACHES. CAN ANY OF YOU SHARE WITH ME WHAT YOU KNOW ABOUT WHETHER THERAPIES THAT ARE APPLIED SHORTLY AFTER A FRACTURE, ANY PART OF THE BODY, WOULD HAVE AN EFFECT OF REDUCING THAT SECOND FRACTURE WHICH SEEMS TO BE MOST LIKELY WITHIN A GIVEN YEAR?>>I THINK I’LL START AND JUST SAY THAT THE KEN LILES TRIAL, 5 MILLIGRAMS ZOLEDRONIC ACID, A VERY CHARGE TRIAL OF ZOLEDRONIC ACID OR PLACEBO, SHOWED SIGNIFICANT REDUCTION IN ALL FRACTURES AFTER SUBSEQUENT TREATMENT WITH ZOLEDRONIC ACID, IN ADDITION TO 27% REDUCTION IN MORTALITY WHICH I DON’T THINK ANY OF US QUITE UNDERSTAND BUT THAT WAS PROBABLY THE MOST NOTABLE AND LARGEST POPULATED TRIAL TO LOOK AT POST-FRACTURE INTERVENTION.>>I HAVE ANOTHER QUESTION ABOUT THE FDA BUT I DON’T SEE OUR SPEAKER UP ON THE PANEL BUT WE’LL DO OUR BEST. SO NOW WITH THE INCLUSION ACROSS THE AGE SPAN, AND WITH THE FDA, IT SEEMS LIKE THERE HAS BEEN A MISMATCH BETWEEN WHO IS IN TRIALS IN THE GENERAL POPULATION THAT’S MOST AT RISK OF FRACTURES. MANY OF THE TRIALS DID NOT HAVE THE PROPORTIONS OF PERSONS 80 AND OLDER, AND WE REALLY DON’T HAVE THE POWER OF THE STUDIES TO UNDERSTAND RACIAL AND ETHNIC GROUPS. ONE OF YOU SHOWED A SLIDE OF 2010 JAG STUDY WITHIN NATIVE AMERICANS THEY HAD THE HIGHEST, I HAVEN’T SEEN OTHER INFORMATION ON THE HIGH RISK GROUPS BEYOND A FRAX SCORE, SOME OTHER MEASURES; COULD YOU COMMENT ABOUT WHAT THE NIH IS FUNDING AND THE TRUE POPULATION AT RISK?>>DR. KEHOE.>>THIS IS THERESA KEHOE. FARCE WHAT YOU SEE IN THE FDA TRIALS ESPECIALLY MOST RECENT TRIALS WE’RE UP AGAINST THE DECLARATION AT HELSINKI, TALKING ABOUT IS IT ETHICAL TO HAVE TRIALS, PLACEBO-CONTROLLED TRIALS THAT HAVE THE POTENTIAL TO HARM SUBJECTS WHEN THERE ARE ADEQUATE THERAPIES ON THE MARKET. WHAT HAS HAPPENED TO THE POP LAPPINGS OF PATIENTS THAT ARE ABLE TO BE ENROLLED IN THE TRIALS, BASED ON THE INSTITUTIONAL REVIEW BOARDS AND THE ETHICS OF THE SITUATION IS THAT THE WOMEN THAT ARE ENROLLED IN THE FRACTURE TRIALS NOW ARE MUCH LESS AT RISK, LOWER RISK PATIENTS THAN THERE WERE WITH THE INITIAL TRIALS. WHEN YOU GO BACK TO THE 1990s, AND LOOK AT THE EARLY BISPHOSPHONATE TRIALS, AND EVEN THE RALOXIFENE AND FORTEO TRIALS, OVER 90% HAD A FRACTURE AT BASELINE. YOU DO NOT SEE THAT ANYMORE BECAUSE FRANKLY ITS UNETHICAL TO ENCONTROL THEM IN A PLACEBO-CONTROLLED TRIAL. THAT’S WHY THERE’S A PARADIGM SHIFT IN WHAT WE SEE IN THE TRIALS, THE DRUG REGISTRATION TRIALS. OUR BELIEF IS THE DEMONSTRATION OF FRACTION REDUCTION EFFICACY IN THAT LOWER RISK POPULATION WOULD TRANSLATE A SIMILAR FRACTURE REDUCTION RISK IN HIGHER RISK POPULATION. THAT’S THE PREMISE THAT WE’VE WE OPERATE UNDER. DOES THAT ANSWER YOUR QUESTION?>>THAT ANSWERS WITH NEW DRUG FORMULATIONS BUT NOT WHEN TALKING ABOUT THE AMERICAN PUBLIC THAT’S FUNDING THIS RESEARCH, A DIFFERENT SORT OF QUESTION.>>I COULD JUST START BY SAYING THAT MOST OF THE TRIALS YOU HEARD ABOUT AND EVIDENCE IS FROM INDUSTRY-SPONSORED TRIALS FOR FRACTURE EFFICACY. NIH HAS NOT BEEN INVOLVED IN MANY FRACTURE INTERVENTION TRIALS. WOMEN’S HEALTH INITIATIVE IS ONE OF THE BIGGEST ONES THAT HAD MULTIPLE. MOST LOOK AT BONE DENSITY. HERE WE DEPEND ON INDUSTRY, FOR THAT, FOR REGISTRATION TRIALS, BEST APPROACHES TO GET THOSE PEOPLE INTO HIGHEST RISK, WHAT WAS PREVIOUSLY SAID FROM THE FDA IS AS WE MOVE ALONG WE’RE LESS LIKELY TO INVOLVE HIGH RISK INDIVIDUALS IN A PLACEBO-CONTROLLED RANDOMIZED TRIAL BECAUSE OF THE ETHICAL IMPLICATIONS OF NOT ALLOWING THEM TO GET ADEQUATE TREATMENT. IT’S A TRICKY BALANCE. YOU DID MAKE ONE REALLY IMPORTANT POINT ABOUT ETHNIC AND RACIAL INPUT, WE’VE NOT DONE A GOOD JOB OF RECRUITING MINORITIES FROM THESE TRIALS, THEY CLEARLY CAN POSE A RISK POPULATION AND NEED TO BE INVOLVED IN, SO THIS IS AN IMPORTANT RESEARCH GAP THAT REALLY HAS TO BE FILLED IN. I THINK IT’S DIFFICULT AT TIMES TO DO THAT, PARTICULARLY IF THE NIH IS NOT FUNDING THESE TRIALS BECAUSE THE FRACTURE TRIALS ARE SO EXPENSIVE. THE TRIAL WAS MENTIONED WHICH SHOWED TREMENDOUS EFFICACY, OFF-TARGET EFFECTS, OVER A BILLION DOLLAR TRIAL AND SO IT’S LESS LIKELY THESE KINDS OF TRIALS ARE EVER GOING TO OCCUR AGAIN. WE DO HAVE A NEW TRIAL COMPARED TO ALENDRONATE, THOSE ARE& PROBABLY WHAT WE WILL SEE IN THE FUTURE.>>MANY OF YOU TREAT PATIENTS, SOME OF OUR OTHER SPEAKERS MAY ALSO TREAT PATIENTS. IT SEEMS THAT THOSE WITH MULTIPLE CHRONIC CONDITIONS THAT ARE TAKING MULTIPLE MEDICATIONS, WE WERE JUST HEARING ABOUT, IF YOU’RE TAKING NO MEDICINES, MULTIPLE MEDICINES YOU MAY BE LESS LIKELY TO TAKE MEDICINES. NO ONE DISCUSSED CONCERNS AMONG PEOPLE THAT HAVE MULTIPLE MORBIDITIES, WHEN WE HEARD SOME INFORMATION ABOUT SUBGROUPS, I HAVE NO IDEA IF THEY WERE PROPERLY POWERED TO MEASURE SUBGROUPS. BUT HOW DO YOU FEEL ABOUT MANY OF THESE OLDER ADULTS MAY BE AT HIGHEST RISK, MAY ALSO HAVE OTHER CHRONIC CONDITIONS, MAY BE ON MULTIPLE MEDICATIONS?>>SURE, I CAN ANSWER THAT. YEAH, IT’S DEFINITELY TRUE. MY PERSONAL PRACTICE IS SKEWED TOWARD KIDS, I TAKE CARE OF A FAIR NUMBER OF ELDERLY PEOPLE AS WELL. PEOPLE ARE ON MULTIPLE MEDICATIONS. HONESTLY, I DON’T SEE THE SAME CONCERNS IN PRACTICE BROUGHT UP HERE. FOR THE MOST PART PATIENTS DO WHAT THEIR DOCTOR RECOMMENDS THEY DO, IF, ACKNOWLEDGE I THINK DR. SILVERMAN BROAD UP THE ISSUE OF TRUSTING YOUR PHYSICIAN. THAT CERTAINLY IS AN ISSUE. I DON’T THINK IT’S AS BIG OF AN ISSUE WITH MULTIPLE COMORBIDITIES, AS THE ISSUE OF GETTING TO SOMEONE THAT YOU TRUST, AND WORKING WITH THEM. USUALLY IN THOSE CASES PATIENTS DO WHAT THEIR DOCTOR RECOMMENDS.>>LET ME JUMP IN HERE FOR A SECOND. I DON’T THINK — HERE WE GO. LET ME JUMP IN FOR A SECOND AND FOLLOW UP ON THAT A LITTLE BIT. I DON’T KNOW, TO WHAT EXTENT DID SHORT-TERM TRIALS THAT YOU REVIEWED INCLUDE INDIVIDUALS WITH MULTIPLE CHRONIC CONDITIONS, ET CETERA, I UNDERSTAND THAT THEY WERE DONE WITHIN THE CONTEXT OF TRYING TO DO THIS FOR THE USPSTF AND PRIMARY PREVENTION QUESTION, BUT WERE THESE INDIVIDUALS IN THE 12s?>>SO THE TRIALS WERE REPRESENTATIVE OF A POPULATION AS LONG AS THEY ARE NOT AT HIGHER RISK OF FRACTURE. THEY HAD — THEY DIDN’T HAVE RISK FACTORS, THEY WOULD BE INCLUDED, SO ON THE WHOLE I CAN’T TELL YOU, I DIDN’T GO BACK AND LOOK AT WHAT PROPORTION HAD MULTIPLE CHRONIC CONDITIONS BUT THOSE WERE NOT EXCLUSIONS IN THE STUDIES WE LOOKED AT.>>GREAT. THANK YOU.>>I HAVE A QUESTION ABOUT ADHERENCE. AND SO YOU MENTIONED TWO LARGE BARRIERS TO PEOPLE TAKING THE MEDICATIONS, AND ONE IS SILENT DISEASE, THE SECOND ONE IS THERE’S A VERY LOW PROBABILITY OF SOME VERY SERIOUS ASF AND ONJ, AND WITH THAT PAINFUL STORIES WE’LL HEAR MORE ABOUT THAT AFTER LUNCH TODAY. I’M JUST WONDERING ABOUT THAT COMBINATION OF THOSE TWO FACTORS, AND WHETHER YOU SEE THIS COMBINATION UNIQUE TO OSTEOPOROSIS OR NOT, AND IF NOT IS IT THE SAME, BETTER OR WORSE WHEN YOU COMPARE THE CONSTELLATION OF SILENT DISEASE PLUS LOW PROBABILITY OF SOMETHING VERY SERIOUS AND THE OUTCOME.>>IT’S PRETTY CLEAR THAT SILENT DISEASES GIVE BIRTH TO POOR ADHERENCE. YOU SEE IT IN THE HYPERTENSION LITERATURE, AND A NUMBER OF OTHER AREAS. AND THAT IS CERTAINLY TRUE. BUT I SIT AND SEE COMMERCIALS ON TELEVISION FOR NEW DRUGS, AND THE LITANY OF SIDE EFFECTS THEY RECITE VERY FAST BEFORE THE COMMERCIAL GOES OFF, IT DOESN’T SEEM SOMEHOW TO BE AS SERIOUS A PROBLEM AS PERCEIVED BY THE PATIENTS AS IT IS IN OSTEOPOROSIS. WE WATCHED WOMEN GO LIKE THIS OVER THEIR LIFE COURSE AND WE THOUGHT IT WAS BECAUSE THEY WERE GETTING OLD. AND TO TRY TO CONVINCE THAT AUDIENCE THAT, NO, THAT WAS A DISEASE, TAT’S WHY YOU NEED TO TAKE THE MEDICINE, WAS DIFFICULT. THEN ONCE THE ONJ PROBLEM CAME UP, THE MEDIA REALLY RAN WITH IT AND THAT WAS THE BEGINNING OF A VERY DIFFICULT TIME TRYING TO GET PATIENTS TO EVEN CONSIDER TAKING AN OSTEOPOROSIS DRUG. THE OTHER FACTOR IS THAT THEY BELIEVE ALL OF THE SIDE EFFECTS RESULT FROM ALL OF THE DRUGS. THAT IS NOT TRUE. IN SOME WAYS AGAIN THE MEDIA AND THEIR OWN CONVERSATIONS MAKE THEM THINK THAT. WE ALSO HAVE THE PROBLEM OF LISTENING TO PEOPLE WHO DON’T KNOW ANYTHING. SO, OUR DEAR FRIEND ETHYL SIGHERS FROM COLUMBIA SAID I’M NOT GOING TO TAKE THE DRUG ANYMORE BECAUSE MY CLEANING WOMAN SAID IT’S NOT GOOD FOR ME. SHE SAID IN RESPONSE, WHERE DOES YOUR CLEANING WOMAN GO TO MEDICAL SCHOOL? SHE LISTENED TO THE CLEANING WOMAN RATHER THAN HER FIGURES. — HER PHYSICIAN.>>SOME EXCELLENT WORK BY JEFF CURTIS, POORL ADHERENT PUTS THEM AT RISK FOR ADHERENCE TO OSTEOPOROSIS DRUG.>>THE WHOLE THING WITH STATINS AND RHABDOMYALYSIS, INVOCANA, NOT SUPPOSED TO USE BRAND NAMES, RISK OF AMPUTATION, THESE THINGS HAPPEN IN OTHER CONDITIONS, HONESTLY YOU DEAL WITH IT. IT’S NOT — I DON’T PARTICULARLY PERCEIVE IT DIFFERENT THAN OTHER CONDITIONS. THERE ARE RISKS, MAYBE HIGHER HERE, HIGHER PERCEIVED THAN OTHER CONDITIONS, BUT IN AGGREGATE NOT MUCH DIFFERENT THAN OTHER THINGS WE DEAL WITH.>>I WOULD ARGUE THAT OTHER CONDITIONS DON’T RESULT IN THE DENTISTS, WHEN I GO TO THE DENTAL OFFICE, SAYING TO ME YOU’RE RESPONSIBLE FOR ALL THE ORAL HEALTH PROBLEMS IN THE UNITED STATES BECAUSE YOU WORK ON OSTEOPOROSIS. AND I JUST THINK THERE’S A VERY POWERFUL COMBINED GROUP OF PEOPLE WHO HAVE MADE THIS THEIR MISSION, IF YOU GET ONLINE AND LOOK UP BONE BABE, FOR EXAMPLE, I DON’T KNOW WHO SHE IS BUT SHE THINKS SHE KNOWS EVERYTHING ABOUT OSTEOPOROSIS AND HOW AWFUL MEDICATIONS ARE. SHE HAS NO QUALIFICATIONS TO MAKE THOSE STATEMENTS. YET PEOPLE SWEAR BY THEM.>>DR. LOOM, DR. BROWN.>>OKAY. A FEW QUESTIONS. I’M TRYING TO UNDERSTAND THE CONTEXT OF SCREENING TODAY. GIVEN THE MANAGED CARE ENVIRONMENT, IS THE SCREENING ISSUE PASSIVE OR ARE WE LOOKING AT SOME SORT OF THING LIKE IN DISEASE MANAGEMENT WHERE YOU WANT TO HAVE YOUR PATIENTS GET THOSE RECOMMENDED SCHEDULED SCREENINGS, SO WHAT’S IT LIKE? HELP ME UNDERSTAND WHAT A PATIENT WOULD BE –>>YEAH, SO IT’S NOT DIFFERENT THAN OTHER CONDITIONS. AGAIN, OTHER THAN THE FACT THAT THERE MIGHT BE A PERCEIVED — YOU KNOW, IT’S LESS FOR MOST IN THE MINDS OF PRIMARY CARE PHYSICIANS BUT IT’S REALLY NO DIFFERENT. THERE IS ONE ISSUE, I THINK YOU MAY BE GETTING AT IT WITH MANAGED CAR, QUALITY AND HEDIS MEASURED BY MANAGED CARE, MEDICARE SHARED SAVINGS ACO SCREENING FOR OSTEOPOROSIS IS NOT ONE OF THE MEASURES THAT’S USUALLY USED, NOR IS TREATMENT OF OSTEOPOROSIS ONCE IT’S DIAGNOSED. SO THERE MIGHT BE AN ISSUE THAT IT’S NOT ON THE RADAR OF PEOPLE WHO MEASURE QUALITY OR IMPLEMENT THOSE QUALITY MEASURES AS MUCH AS A1c FOR DIABETES AS MUCH AS COLORECTAL SCREENING, MAMMOGRAMS FOR PEOPLE. IT’S NOT ON THE RADAR AS MUCH.>>BUT THERE IS IN THOSE MEASURES THE INDICATOR FOR FALLS, SO IS FALLS A PRIMARY PRECURSOR TO THE FRACTURES THAT MAY BE DUE TO OSTEOPOROSIS OR, NO, BECAUSE MY QUESTION ALMOST TO THAT LINE IS THAT IF WE UNDERSTAND THAT WOMEN HAVE A GREATER RISK FOR OSTEOPOROSIS THAN MEN, IS THERE GREATER RISK FOR FALLS DIFFERENTIATING BETWEEN MEN AND WOMEN?>>IS THERE RISK OF FALLS DIFFERENT? FALLS IS A MEASURE WE LOOK AT IN OUR ACO. CERTAINLY PEOPLE WHO FALL, IF YOUR RISK OF FALLS AND YOU HAVE OSTEOPOROSIS YOU’RE THE HIGHER RISK OF FRACTURE, BUT I’M SAYING NO ONE’S CHECKING TO SEE, NO ONE’S LOOKING TO SEE AS A MEASURE DID YOU CHECK FOR OSTEOPOROSIS, DID YOU SCREEN FOR OSTEOPOROSIS OR NOT. BUT I THINK YOUR QUESTION IS A LITTLE DIFFERENT. ARE PEOPLE WHO ARE –>>IT FALLS — IF FALLS ARE A KEY ELEMENT, MEN ARE NOT AS HIGHER RISK FOR FALLS, I’M SORRY, OSTEOPOROSIS FOR WOMEN, IS FALLS THAT MAGIC BULLET WE COULD BE LOOKING AT?>>SO I WOULD ARGUE THAT IT’S PROBABLY ONE OF THE MOST IGNORED HISTORY-TAKING ASPECTS THAT WE DO, ESPECIALLY IN OLDER INDIVIDUALS. SO WOMEN LIVE LONGER THAN MEN, SO FALLS ARE GREATER OBVIOUSLY. BUT CLEARLY FALLS ARE A MAJOR RISK FACTOR FOR FRACTURE AND IT’S OFTEN THE TARGET OF A THERAPY AND MORE ON TO PREVENTION AND QUESTIONING AND WHAT’S THE RUG SITUATION AT THE HOUSE, WHAT IS — HOW DO THEY USE SLIPPERS, ALL THESE THINGS THAT ARE SO IMPORTANT. MY MOM’S 95, GREAT BONE DENSITY BUT FALLS THREE OR FOUR TIMES A YEAR. TRYING TO UNDERSTAND EACH RISK FACTOR FOR FALLS IS VERY IMPORTANT BECAUSE SHE WILL ULTIMATELY FRACTURE. I THINK IT’S REALLY AN ESSENTIAL COMPONENT, I THINK PROBABLY NEEDS TO BE ON THE PREVENTION SCALE BUT TIME IS A LIMITING FACTOR AND REQUIRES CAREFUL QUESTIONING.>>I WAS TO SAY IF YOU LOOK AT FRAX, DID NOT INCLUDE FALLS, THE MAJOR REASON, I WAS PART OF THE FRAX STEERING COMMITTEE WE HAVE NO MEDICATION TO REDUCE RISK OF FALLING. THERE ARE ALGORITHMS WHICH DO INCLUDE FALLS AND MANY OF US USE WHEN WE SEE A PATIENT WHO IS NOT SURE OF THERAPY, IF YOU ADD FALLS AND THE LIKE, MULTIPLE FRACTURES, YOU INCREASE THE RISK. SO I THINK WE REALLY OFTEN IGNORE FALLS. I DON’T REALLY SEE VERY WELL I GUESS DR. GILL THAT ASSESSING PATIENTS’ BALANCE UNFORTUNATELY IS NOT DONE ROUTINELY. WE CAN REDUCE RISK OF FRACTURE PERHAPS 50% BUT THE OTHER 50% IS NOT FALLING.>>A COUPLE QUESTIONS. IN TERMS OF COST, I WANT TO UNDERSTAND THIS. IN CANCER, THE DIAGNOSIS OF THE DISEASE EXTENDS TO THE PAYMENT OF IMMUNOTHERAPY, CHEMOTHERAPY, WHAT NOT FOR THOSE DRUGS. IT DOESN’T WORK THAT WAY WITH THE DIAGNOSIS OF OSTEOPOROSIS.>>FIRST LINE TREATMENT IS ALL BISPHOSPHONATES, IT’S NOT UNTIL YOU FAIL THAT, IN MANY INSURANE SITUATIONS, THAT YOU BECOME ELIGIBLE TO TRY SOME OF THE OTHER THINGS. LOOK, I’M GOING TO GIVE YOU A CHOICE. CAN YOU HAVE CANCER OR OSTEOPOROSIS. WHICH ONE DO YOU WANT? AND THAT’S WHAT PEOPLE DO AND THEY SEE IT AS NOT ANYWHERE NEAR AS IMPORTANT, AND SO WHY SHOULD WE SPEND MONEY ON THE DRUGS LIKE WE DO ON CANCER DRUGS. BUT THE FACT IS THERE ARE A BUNCH OF PEOPLE IN THIS COUNTRY WHO ARE MISERABLE OR DEAD BECAUSE OF OSTEOPOROSIS. IT JUST DOESN’T GET THAT SAME LEVEL OF ATTENTION. LOOK AT ALL THE PEOPLE IN OUR STATE HOMES, BED BOUND, WHEELCHAIR BOUND, DOESN’T TAKE LONG FOR BONE DENSITY TO DROP ONCE YOU BECOME UNABLE TO AMBULATE ON YOURSELF. AND YET I DON’T SEE PEOPLE RUNNING ON ZOLEDRONRATEE ASSED — ASSED. THEY ARE IN A NURSING HOME, THEY WILL BE DEAD SOON ANYWAY.>>THERE’S A RHYTHM AS A PRACTITIONER PRESCRIBING DRUGS, COST DOES BECOME A FACTOR, INSURANCE REIMBURSEMENT IS A BIG FACTOR. ALENDRONATE IS A FIRST LINE DRUG, THEY DON’T GET THE PRESCRIPTION, DON’T ADHERE, THEY HAVE ANOTHER FRACTURE, SECOND LINE DRUGS THAT ARE EXPENSIVE, TERIPARATIDE, $9,000, NOW $30,000 A YEAR FOR THE SAME DRUG, TO GET INSURANCE TO PAY FOR THAT AS A SECOND LINE FAILURE SO THEY ARE FAILING BECAUSE THEY FRACTURED AGAIN. IT’S A REAL CONUNDRUM FOR US IN PRACTICE BECAUSE WE HAVE TO JUMP THROUGH ALL THE HOOPS TO GET THAT APPROVED. THIS BECOMES A REAL ISSUE OF COST AND TIME SPENT TO TRY TO GET REIMBURSEMENT TO MOVE INTO THOSE SECOND LINE THERAPIES.>>ANOTHER QUESTION, ONE OF THE SLIDES PRESENTED THE BONE ABSORPTION AND — I’M SORRY, RESORPTION AND BONE FORMATION. CAN YOU HAVE IT ALL?>>I THINK THE BODY IS DESIGNED TO BALANCE RESORPTION AND FORMATION. SO IN THE NORMAL SITUATION AFTER PUBERTY WHEN YOU HAVE A LITTLE MORE FORMATION THAN RESORPTION YOU’RE BUILDING BONE. THEN HAVE YOU ACQUISITION, A MAINTENANCE PHASE. AND IT’S REALLY AFTER 60 OR 55 OR AFTER MENOPAUSE THAT BALANCE GETS DISTURBED AND SO THERE’S MORE RESORPTION THAN FORMATION, EITHER BECAUSE THE BONE IS NOT FORMING AS WELL OR THERE’S ACCELERATED RESORPTION. AND THAT’S WHAT LEADS TO THE DROP IN BONE MASS AND THE BONE LOSS WHICH PREDICTS SUBSEQUENT FRACTURE. YOU’LL HEAR SOME OF THE SURROGATES FROM DR. BAUER TOMORROW ABOUT MEASURING SOME OF THOSE RESORPTION INDICES TO PREDICT PEOPLE THAT WILL LOSE BONE AND ULTIMATELY FRACTURE.>>I WANTED TO PIGGYBACK ON A PRIOR QUESTION. WE HEARD A LOT ABOUT PATIENT PERCEPTION AND ESPECIALLY THE MEDIA, AND DRIVING PATIENT PERCEPTION AND HOW THAT AFFECTS INITIATION AND ADHERENCE FOR THESE DRUGS. HEARD A LITTLE BIT ABOUT THE PHYSICIAN’S ROLE IN ADDRESSING THAT ISSUE BUT I WAS WONDERING IF YOU COULD SPEAK MORE DEEPLY ABOUT POTENTIAL ROLE OF RESEARCH IN ADDRESSING THOSE ISSUES OF ADHERENCE AND PATIENT PERCEPTION.>>AS A NON-PHYSICIAN, I’D BE HAPPY TO TALK ABOUT THE PHYSICIAN ROLE. [LAUGHTER] BUT AT ANY RATE, RESEARCH IS OBVIOUSLY VERY IMPORTANT. IT’S SOMETHING THAT IS READ WIDELY BY SCIENTISTS WHO HAVE AN INTEREST IN THE AREA. BUT IN ORDER TO GET RESEARCH RESULTS TO PATIENTS, ONE OF TWO THINGS HAS TO HAPPEN. EITHER THEIR PHYSICIANS HAVE TO HAVE THE TIME TO DO THAT, OR THE MEDIA OR SOME OTHER SOURCE HAS TO TRANSLATE THAT INTO UNDERSTANDING. WE JUST ARE DEALING WITH A VERY DIFFICULT CONCEPT TO UNDERSTAND WHICH IS BONE DENSITY. WE’RE DEALING WITH A NEGATIVE STANDARD DEVIATION WHICH PATIENTS DON’T GET AND YOU SAY IT’S LESS THAN NEGATIVE 2.5, AND THEY ARE CONFUSED ALREADY. BUT THE PHYSICIANS I KNOW WHO WORK ON THIS WORK THEIR TAILS OFF TRYING TO HELP PATIENTS UNDERSTAND THE REALITY, NOT WHAT’S GOING TO HAPPEN IF YOU TAKE THE DRUG BUT WHAT MIGHT HAPPEN IF YOU DON’T TAKE THE DRUG. AND THAT’S WHERE WE’VE HAD A LOSS OF REAL UNDERSTANDING LATELY. THEY ARE SO BUSY WORRYING ABOUT ONJ AND ASF THAT THE IDEA OF A HIP FRACTURE IS LOST IN THE CONTEXT. AND JIM HAS SAID SEVERAL TIMES THAT THERE DOESN’T SEEM TO BE DIFFERENCE BETWEEN OSTEOPOROSIS AND OTHER CONDITIONS IN TERMS OF SIDE EFFECT, ET CETERA. THAT’S NOT THE WAY I SEE IT, IN TALKING TO THE PEOPLE WHO GO TO PHYSICIANS AND WHO HEAR THE RESULTS FROM THEIR PHYSICIANS, AND WHO INTERPRET IT OR LISTEN TO THEIR CLEANING WOMEN AND DON’T GET IT. PHYSICIANS HAVE TO BE GIVEN A CERTAIN AMOUNT OF REALLY TIME TO BE ABLE TO DO WHAT YOU’RE SAYING, TRANSLATE THE RESEARCH FOR THE PATIENT SO THEY UNDERSTAND WHAT THE CONSEQUENCES, WHAT THE RISKS, AND OUTCOMES ARE. AND THEY DON’T HAVE IT RIGHT NOW.>>YEAH, I WOULD ALSO ADD ANOTHER PART OF THAT IS WHAT ABOUT RESEARCH AND UNDERSTANDING IT A LOT BETTER, I’M AFRAID AT THIS MOMENT DEBBIE AND I BOTH AGRE ADHERENCE, PRIMARY OR SECONDARY, IS STILL A BLACK BOX. WE DON’T UNDERSTAND IT AND DON’T KNOW THE BEST WAY TO COMMUNICATE RISK. WE TRULY NEED A LOT MORE HELP IN TERMS OF HOW WE AS CLINICIANS CAN COMMUNICATE BETTER WITH OUR PATIENTS. WHETHER IT’S — AS I SAID WEB-BASED ONLINE VISUAL AIDS, WE DON’T KNOW. WE NEED MORE WORK ON IMPROVING PHYSICIAN-PATIENT COMMUNICATION.>>AND YOU CAN MAKE ALL THE WONDERFUL MEDICATIONS IN THE WORLD, EVEN PAY FOR THEM, BUT IF PEOPLE WON’T TAKE THEM THEY DON’T DO ANY GOOD.>>SOME OF US WROTE AN EDITORIAL THAT CONCLUDED IT’S ALL A MATTER OF CHOICE.>>JUST ONE OTHER COMMENT ABOUT — SO I THINK — I DO THINK THE SIDE EFFECT THING IS IMPORTANT, PROBABLY PERCEIVED GREATER BUT THE ISSUE IS THAT IN THE SCHEME OF THINGS IT’S A RELATIVELY SMALL PART OF THE PROBLEM. WE HAVE TO REMEMBER 3/4 OF WOMEN AREN’T EVEN GETTING SCREENED. SO NO ONE’S TALKING ABOUT ADHERENCE, PERCEPTION OF MEDS, YOU KNOW, SIDE EFFECTS, COST. THREE-QUARTERS OF WOMEN AREN’T EVEN GETTING STEP ONE. LET’S FOCUS ON STEP ONE. AT LEAST AS PART OF WHAT WE’RE DOING, A SIGNIFICANT PART OF WHAT WE’RE DOING. LET’S NOT PUT ALL THE FOCUS ON THE SMALL PERCENTAGE OF WOMEN WHO ARE GETTING SCREENED AND SMALL PERCENTAGE OF WOMEN DIAGNOSED AND THEN PERCENTAGE OF THEM WHO HAVE MISPERCEPTIONS ABOUT SIDE EFFECTS. YES, THAT’S IMPORTANT. BUT DON’T MISS THE THREE-QUARTERS OF WOMEN NOT EVEN GETTING SCREENED. THAT’S THE BIG BUCKET.>>IN MY COMMUNITY WOMEN ARE NOT SCREENED BECAUSE THE DECREASE IN DEXA REIMBURSEMENT, ALMOST ALL THE GYNECOLOGISTS IN MY COMMUNITY WHO HAD DEXAs AND WERE SCREENING GAVE UP THE MACHINES BECAUSE IT DIDN’T MAKE FINANCIAL SENSE. I THINK WE HAVE TO FACE ONE OF THE BIGGEST PROBLEM FOR SCREENING IS LACK OF REIMBURSEMENT. WHICH IS WHAT THE FOCUS FOR ISCD AND STILL REMAINS SO.>>LET ME JUST JUMP IN WITH A COUPLE QUICK QUESTIONS ON THE EVIDENCE PRESENTED TODAY. TO RELATED QUESTIONS. THE FIRST ONE WAS THAT AT LEAST THE FIRST PART OF THE SEGMENT WAS TITLED ABOUT SHORT-TERM TREATMENTS. CORRECT ME IN I’M WRONG, TRIALS WERE NOT NECESSARILY DONE WITH THE INTENT OF SELECTING PATIENTS WHO MIGHT BENEFIT FROM SHORT-TERM TREATMENT AND THAT IT WOULD BE ENDED AT THE — AFTER THREE TO FIVE YEARS. THESE WERE REALLY TRIALS WITH PERHAPS, YOU KNOW, LONGER INTENT.>>AND, YES, YOU’RE COMPLETELY CORRECT IN THE TITLE, TO DISTINGUISH WHAT WE WERE DOING FROM WHAT YOU’RE GOING TO HEAR LATER IN THE DAY. THERE IS — IT WAS NOT AT ALL THE INTENT TO TREAT THEM FOR A SHORT DURATION OF TIME. THAT WAS JUST WHAT WAS IN THE TRIALS.>>RIGHT. DR. ROSEN, EVEN THOUGH YOU TALK ABOUT, YOU KNOW, TREATING THE HIGHEST RISK OF FRACTURE, YOU DON’T REALLY THINK ARE YOU REALLY THINKING THAT THERE ARE PATIENTS THAT WE OUGHT TO SELECT OUT FOR SHORT-TERM TREATMENT ONLY?>>WELL, I THINK THAT ABSOLUTELY IF YOU HAVE SOMEBODY WHO HAS A FRACTURE, THEN OBVIOUSLY SHORT-TERM TREATMENT IS INDICATED BECAUSE THEIR RISK OF SUBSEQUENT FRACTURE IS SO HIGH. WHEN THESE TRIALS ARE DESIGNED, THEY ARE DESIGNED TO POWER FOR THE MOST EFFICACIOUS — FOR THE BEST EFFECT, WHICH WOULD BE IN THOSE INDIVIDUALS WHO ARE AT HIGHEST RISK. SO THEIR RECRUITMENT IS GOING TO BE THOSE INDIVIDUALS WHO HAD A PREVIOUS FRACTURE, BONE DENSITY LOWER THAN T SCORE MINUS 2.5, DIFFERENT THAN SCREENING EVERYBODY BECAUSE AS DR. BLACK PROVED IN THE FRACTURE INTERVENTION TRIAL, BACK IN 1996, IN FIT 2, IF THEY WERE NOT AT HIGH RISK THE EFFICACY OF ALENDRONATE WAS MUCH LESS, NOT STATISTICALLY SIGNIFICANT. SO, FROM A DESIGN POINT OF VIEW, YOUR GOAL IS TO SHOW THE MOST PRONOUNCED EFFECT, AND THAT WOULD REQUIRE RECRUITING INDIVIDUALS, PARTICULARLY INDIVIDUALS AS THERESA SAID WHO HAD A PREVIOUS FRACTURE.>>THE CONDITION DOES NOT GO AWAY.>>ABSOLUTELY NOT. IT’S ARTIFICIAL. I MADE THAT DEFINITION AT THE BEGINNING. THREE YEARS IS ARTIFICIAL. IT’S REGISTRATION TRIALS THAT SET IT UP AS THREE YEARS. IT’S NOT BECAUSE WE DECIDED THAT SHORT TERM MEANS THREE YEARS AND THEREFORE THE RISK GOES AWAY. IN FACT IT DOESN’T GO AWAY.>>RIGHT.>>AS YOU GO ON FURTHER. SO THE IDEA THAT SOMEHOW, WELL, WE’LL STOP AT THREE YEARS, BUT BISPHOSPHONATES ARE DIFFERENT, YOU’LL HEAR ABOUT THAT THIS AFTERNOON, THERE ARE DRUG HOLIDAYS, BUT THERE’S AN OVERALL RISK THAT CONTINUES.>>RIGHT.>>I WANT TO CLARIFY SOMETHING ABOUT THE SYSTEMATIC REVIEW WE DID. TO CLARIFY THAT WE DIDN’T LOOK AT PEOPLE ESTABLISHED RISK FACTORS SUCH AS LOW TRAUMA FRACTURES, ENDOCRINEOPATHY, ALL HAD INCREASED TYPICALLY DEFINED AT LOW BONE MASS, OSTEOPOROSIS, BUT NOT NECESSARILY FRACTURE, BUT NOT FRACTURES.>>OKAY.>>I THINK IT’S ALSO IMPORTANT TO EMPHASIZE TREATMENT OF OSTEOPOROSIS IS A LIFE-LONG MANAGEMENT. WE HAVEN’T SAID THAT CLEARLY. YOU KNOW, POINT IS IF WE MIGHT HAVE SHORT-TERM THERAPY, BISPHOSPHONATE HOLIDAY IS A HOLIDAY, NOT RETIREMENT. ONCE SOMEBODY HAS DECLARED THAT THEY ARE AT HIGH RISK, HAD A FRACTURE, LIKE SOMEBODY WHO HAS BLOOD PRESSURE, YOU HAVE TO CONTINUE TO FOLLOW THEM. YOU MAY MAKE DECISIONS LATER TO CONTINUE THERAPIES. WE MIGHT INDUCE SOME INCREASED BONE MASS PERHAPS WITH ANABOLIC BUT YOU STILL MAINTAIN IT WITH BISPHOSPHONATE. THIS IS A LIFE-LONG JOURNEY FOR OUR PATIENTS AT INCREASED RISK. WE NEED TO EMPHASIZE THAT. THAT’S SOMETHING THAT’S OFTEN MISSED IN OUR DISCUSSIONS.>>AND THE SECOND FOLLOW-UP ON TRIAL RESULTS IS WHAT DO WE KNOW ABOUT ADHERENCE OF PARTICIPANTS IN THE TRIAL? YOU KNOW, THESE OUTCOMES AND HARMS, WERE THEY ASSOCIATED WITH POOR ADHERENCE TO BEGIN WITH?>>I DO NOT RECOLLECT SEEING IN THOSE TRIALS THAT WE LOOKED AT STATISTICS THAT CONSISTENTLY MEASURED THOSE. BUT I THINK OTHER PEOPLE ON THE PANEL MIGHT BE ABLE TO SPEAK TO THAT.>>ADHERENCE IN TRIALS IN BETTER THAN IN REAL LIFE. AND THE WAY THESE MEDICATIONS WORK IS THEY — ON ADHERENCE IN THE STUDIES THAT DOESN’T TRANSLATE UNFORTUNATELY INTO THE COMMUNITY.>>WHICH PROBABLY WASN’T PERFECT EITHER.>>EXACTLY.>>IN A CLINICAL TRIAL YOU’RE MONITORING WITH VISITS, MAYBE PHONE CALLS WHICH WE DON’T DO IN PRACTICE BUT EFFORTS TO MINIMUM MIMIC IN PRACTICE HAS NOT SHOWN DRAMATIC INCREASES IN ADHERENCE.>>DR. BROWN?>>(INAUDIBLE) TESTING. THERE WE ARE. OKAY. FROM THE RESEARCH VEIN, ANY SENSE OF QUALITY FROM ONE MEDICINAL APPROACH VERSUS ANOTHER?>>MAYBE YOU CAN CLARIFY THAT A LITTLE BIT. YOU ARE MEAN IN TERMS OF COMPARATIVE EFFECTIVENESS TRIAL?>>AND OUTCOME BEING QUALITIES.>>QUALITIES, OKAY, OKAY. I DON’T KNOW. STU, DO YOU KNOW WHETHER THERE’S BEEN ANY –>>BASED ON COST PER QUALITY, YEAH, WE’VE BEEN ABLE TO LOOK AT THAT. THAT’S BEEN LOOKED AT. YEAH, THE QUESTION IS IF YOU ENRICHED A CERTAIN POPULATION, FOR EXAMPLE, THAT ARE AT VERY, VERY HIGH RISK WHO ALREADY HAD A FRACTURE, SUGGESTS ANABOLIC MIGHT BE PREFERABLE TO START OFF WITH BECAUSE YOU HAVE SUCH A HIGH FREQUENCY OR INCIDENCE OF THE EVENTS HAPPENING FAIRLY QUICKLY, THERE’S SEVERAL TRIALS THAT LOOKED AT THAT EARLY INTERVENTION WITH ANABOLIC AND VERY, VERY HIGH PATIENTS WILL REDUCE RISK OF FRACTURES, HOSPITALIZATIONS, ACTUALLY BE PREFERABLE TO MAYBE USING ANOTHER DRUG SUCH AS BISPHOSPHONATE, YEAH, THAT’S BEEN DONE.>>GREAT. ANYTHING ELSE FROM THE PANELIST BEFORE WE GO TO THE AUDIENCE?>>I’LL MAKE A POINT, IT WAS BROUGHT UP BY THE FIRST PANELIST, AND IN A IS WE — THAT IS WE HAVE RESEARCH GAP, YOU ASKED ABOUT MEDICATIONS CONFOUNDING WITH OTHER MEDICATIONS, A BIG ISSUE WE’VE NOT STUDIED. COMBINATION OF TWO OR THREE FREQUENTLY USED DRUGS, JONATHAN SKINNER HAS DONE SOME WORK ON LOOKING AT THE COMBINATION OF OPIOIDS AND PPIs, PPIs HAVE BEEN SHOWN TO HAVE INCREASED RISK, WE DON’T UNDERSTAND THE MECHANISM. BUT WHEN YOU SEE THESE COMBINATION USAGE IN MEDICARE DATA BASE AND RISK OF FALLS AND FRACTURES GOING UP, PARTIALLY OF COURSE DUE TO SEDATION OR CONFUSION, BUT ALSO FRACTURES GOING UP, WE NEED TO INVESTIGATE WHAT THOSE MECHANISMS ARE AND THEY ARE EXTREMELY IMPORTANT BECAUSE POLYPHARMACY IS A STATE OF LIFE FOR ELDERLY INDIVIDUALS. IT’S A RESEARCH GAP WE’VE NOT SYSTEMATICALLY WORKED OUT.>>RIGHT. NO OTHER QUESTIONS IN THE PANELISTS, LET ME OPEN UP TO THE AUDIENCE STARTING WITH — THE ONE ON THE RIGHT.>>HI. I HAVE A COMMENT AND QUESTION. DEBRA GAFFEY, NATIONAL CANCER INSTITUTE. THIS IS NOT MY AREA OF EXPERTISE BUT I HAVE A COMMENT. I HAVEN’T HEARD ANY DISCUSSION OF EDUCATION ACROSS MEDICAL DIS MEDICAL DISCIPIPLINE. THEY GO TO THE ORAL SURGEON, I CAN’T TAKE THIS DRUG, MY ORAL SURGEON DIDN’T GOING TO TREAT ME, WE’RE NOT GOING TO GIVE YOU ANY OTHER DRUG BECAUSE YOU’RE DOING WELL ON THIS DRUG AND THE OTHER DRUGS COST A LOT OF MONEY. OR YOU HAVE GASTROENTEROLOGISTS TREATING PATIENTS WITH GERD OR ULCERATIVE FOR COLITIS FOR EXTENDED PERIODS OF TIME, THEY DO NOT TELL PATIENTS THEY SHOULD BE SCREENED FOR OSTEOPOROSIS, SO I’D LIKE SOME DISCUSSION ABOUT THAT BEFORE I ASK MY NEXT QUESTION.>>I’LL SAY IT’S A BIG PROBLEM IN PRACTICE. IT’S A HUGE PROBLEM. I THINK THE INTERPHYSICIAN OR INTERPROVIDER COMMUNICATION IS MISERABLE AT TIMES.>>(INAUDIBLE).>>FOR ME GOOD EXAMPLE FOR ME, MEN. WE HAVE NOW GUIDELINES FOR WOMEN ON AROMATOSE INHIBITORS, WE DON’T HAVE GOOD GUIDELINES FOR MEN. YES, THERE’S CLEARLY A NEED TO REACH OUT OUR FELLOW SPECIALISTS AND START DEVELOPING, INCREASE AWARENESS. YOU’RE RIGHT.>>OKAY. AND MY QUESTION WHICH IS REALLY A PIE IN THE SKY BECAUSE I’M SURE I KNOW THE ANSWER IS, IN THIS DAY AND AGE ELECTRONIC HEALTH RECORDS IS REALLY KIND OF AN EMERGING AREA, IT’S NOT REALLY WELL ESTABLISHED, YOU HAVE A PATIENT WHO TRAVELS A LOT FOR BUSINESS OR PLEASURE, HAS THREE FRACTURES IN FIVE YEARS, SIMPLE FRACTURES, FORGETS TO TELL THEIR PRIMARY CARE PHYSICIAN BECAUSE IT’S 11 MONTHS AFTER THEY SAW THEM, SIMPLE FRACTURE, NO SURGERY. IS THERE ANY WAY TO HARNESS THE INSURANCE COMPANIES SO THAT INSURANCE COMPANY WHO SEES ALL THIS INFORMATION CAN RED FLAG THAT PERSON AND SAY, HEY, YOU NEED TO GO IN FOR OSTEOPOROSIS SCREENING?>>YOU’RE RIGHT, IT’S CLEAR. I OFTEN SEE PATIENTS WHO HAVE BEEN TO AN E.R. WITH A WRIST FRACTURE, E.R. DIDN’T NOTIFY ME AND NOW THAT WE HAVE EHR THAT COVERS OUR WHOLE HEALTH SYSTEMS WE ARE BEGINNING TO GET NOTICE OF THOSE EFFECTS, THEY ARE BEING SCREENED BY FRACTURE LIAISON SERVICES. THAT’S CORRECT. BUT I THINK, YES, INSURANCE COMPANIES DO PLAY A ROLE RIGHT NOW. I HAVE SEEN GOTTEN NOTICES THAT YOUR PATIENT IS ON STEROIDS, HAS NOT BEEN STARTED ON OSTEOPOROSIS MEDS. I THINK THEY NEED TO STEP UP TO THAT ROLE, THAT’S A GOOD SUGGESTION.>>I’M GOING TO ASK WE TRY TO MOVE THE — KEEP THE QUESTIONS SHORT AND ANSWERS SHORT, WE HAVE NINE MINUTES LEFT.>>THIS QUESTION COMES FROM AN ONLINE VIEWER. THEY NOTED IT’S DIRECTED TOWARDS DR. ROSEN, BUT COULD BE ANSWERED BY OTHERS. HOW DOES ONE MAKE TREATMENT DECISIONS ABOUT THOSE WOMEN WHO FALL IN THE MIDDLE BETWEEN THOSE AT HIGHEST RISK, BASED ON THE RISK FACTORS YOU DISCUSSED AND THOSE WHO SHOULD NOT BE TREATED, AND GIVEN THAT WE DON’T HAVE DATA ON THE BENEFITS OF LONG-TERM THERAPY IS IT BETTER TO WAIT UNTIL A WOMAN IS OVER 65 OR OLDER IF SHE HAS SOME RISK FACTORS SUCH AS A BMD SCORE BELOW NEGATIVE 2.5 BUT NOT OTHER RISK FACTORS FOR EXAMPLE A PREVIOUS FACTOR.>>A COMPLICATED QUESTION THAT REPRESENTS A SUMMATION OF CLINICAL SCIENCE AND SOME ART THAT’S INVOLVED IN PATIENT TO PHYSICIAN OR PATIENT TO PROVIDER INTERACTIONS BUT I THINK YOU HAVE TO HAVE TO WEIGH THE RISK FACTORS. STUART MENTIONED SOME DIFFERENT RISK PREDICTORS THAT WE HAVE. BUT GENERALLY ONCE AN INDIVIDUAL IS OVER 65, THEIR BONE DENSITY IS LOWER THAN MINUS 2.5 THEY ARE EMERGING INTO THE RISK FACTOR SITUATION WHERE THERAPY SHOULD BE CONSIDERED, OR AT LEAST DISCUSSED WITH THE PATIENT, BECAUSE EVEN IF THEY ARE AT HIGH RISK, ONE HAS TO SPEND A FAIR AMOUNT OF TIME MAKING SURE THAT THEIR SHARED DECISION MAKING THAT EVERYBODY’S ON BOARD WITH THE CONCEPT THERE SHOULD BE AN INTERVENTION, AND I THINK IT’S AS MUCH OF A CHALLENGE THAN ANYTHING ELSE. THERE ARE INTERMEDIATE PEOPLE WHO DON’T FALL INTO THAT. OFTENTIMES DOING NO HARM AND EDUCATING BUT NOT TREATING IS A REASONABLE APPROACH. I THINK SOMETIMES AS PHYSICIANS WE WANT TO DO EVERYTHING, WE WANT TO TREAT THE BONE DENSITY SCORE AND THAT’S IT. AND IT’S MUCH WISER TO SAY LET’S WATCH THIS, WE CAN DO FOLLOW-UP, WE CAN TALK MORE ABOUT DECISION MAKING. IT DOESN’T HAVE TO BE AN ABSOLUTE THING.>>YEAH, I’M GOING TO COMMENT. SOMETIMES SOMEONE IS AT HIGH RISK BUT WHICH IS THE PREFERRED THERAPY, I’LL MAKE A CONTRACT, WOULD YOU MIND CONTRACTING TO REPEAT YOUR BONE DENSITY IN ONE OR TWO YEARS AND IF YOU FALL CAN WE RECONSIDER TOGETHER?>>YOU’VE BEEN WAITING.>>SO I HAVE TWO BRIEF COMMENTS THAT MAY BE HELPFUL. JIM’S POINT ABOUT SCREENING, THE PROBLEM WE HAVE IS THAT BEYOND SCREENING THERE ARE SO MANY PATIENTS WHO HAVE ALREADY HAD A FRAGILITY FRACTURE WHO AREN’T A APPROPRIATE TREATMENT, THE FOCUS IS SECONDARY PREVENTION, A HIP OR VERTEBRAL FRACTURE BE ON FRACTURE — OBVIATES A NEED FOR DEXA. THE
OTHER POINT, THIS IS PERHAPS HELPFUL FOR THE PANEL IN TERMS OF HISTORY, THE REASON WE’RE IN A BIT OF A MESS WE ARE IS BECAUSE WE ACTUALLY IN THE ’90s REALLY WENT FOR PRIMARY PREVENTION SIMILAR TO THE USE OF STATINS FOR M.I. AND SO FORTH. SO MANY OF US WHEN ALENDRONATE CAME OUT STARTED TO TREAT WOMEN WITH OSTEOPENIA WITH ALENDRONATE BECAUSE WE DIDN’T WANT THEM TO GET OSTEOPOROSIS. NOW, THE FIELD GOT REALLY BAD PRESS BECAUSE OF AN NPR PERSPECTIVE ON DRUG COMPANY KIND OF EXPANDING THE USE OF DEXA TESTING AND PUSHING THE CONCEP OF OSTEOPENIA IN THEIR MIND TO ENHANCE DRUG SALES. IT TURNS OUT A LOT OF THOSE WOMEN WHO WERE TREATED FOR OSTEOPENIA ENDED UP GETTING ATYPICAL FEMUR FRACTURES FOR A DRUG THEY PROBABLY DIDN’T NEED TO BE ON. WE LEARNED MORE HAD ABOUT HOW TO USE THE DRUGS, WHEN NOT TO USE THE DRUGS. DENNIS HAS DATA SHOWING THOSE WOMEN WITH BETTER BONE DENSITIES THAT WERE TREATED IN THE ’90s THAT MAY BE MOST PRONE TO GETTING ATYPICAL FEMUR FRACTURES. THERE’S A LIEUTENANTS — A HISTORY THAT GOT US HERE. THE PROBLEM IS NEGATING ALL THAT BY SAYING WE’VE LEARNED WE’RE DOING BETTER, WE KNOW HOW TO DO THIS BETTER, WE’RE GOING TO FOCUS ON SECONDARY PREVENTION, THAT IS A CHALLENGE FOR US.>>GOOD.>>DOUG KEEL, BOSTON HARVARD MEDICAL SCHOOL. HEARING THIS MORNING’S SESSION I THINK I’VE COME AWAY AGREEING THAT WE HAVE A LOT OF EVIDENCE THAT SUPPORTS THE EFFICACY AND LOW SIDE EFFECT PROFILE OF THE APPROVED DRUGS. AND WHAT I’M HEARING IS THAT WE DON’T KNOW HOW TO IMPLEMENT IN REAL PATIENTS WHO ARE NOT SCREENED FOR CLINICAL TRIALS HOW TO GET THERAPIES INTO USE. IN THOSE SITUATIONS IT SEEMS THAT PRAGMATIC CLUSTER RANDOMIZED TIMES OF EFFORTS NEED TO BE UNDERTAKEN TO TEST ALL THESE THINGS THAT THE PANELISTS HAVE SAID WE JUST DON’T KNOW. WE DON’T KNOW HOW TO IMPROVE ADHERENCE. WE DON’T KNOW HOW TO ASSESS PATIENT BELIEFS. WE DON’T KNOW THE BEST WAY TO SCREEN, GIVEN THE BUSY PRIMARY CARE SCHEDULES. IT SEEMS TO ME THAT’S A VERY OBVIOUS GAP IN IMPLEMENTATION SCIENCE.>>COMMENTS?>>ABSOLUTELY AGREE.>>THANK YOU FOR A GREAT SESSION THIS MORNING. I THINK WHEN I’M SITTING WITH PATIENTS I OFTEN SHOW THEM THE SLIDE FROM THE MAYO CLINIC TO SHOW THE ANNUAL COST FOR DISEASE IN THE UNITED STATES, ANNUAL COST IN THE LAST 10 YEARS. HEART ATTACKS, BREAST CANCER, STROKES, AND FRACTURES EXCEEDS THE REST. THEY DROP THEIR MOUTHS AND PALE. THEY HAVE NO SENSE OF WHAT THIS — THIS KIND OF INFORMATION. WHY DON’T THEY? WE DON’T HAVE A SPOKESPERSON, THIS IS A GAP. WE DON’T HAVE A HERO FOR OSTEOPOROSIS. BOB DOLE FOR PROSTATE CANCER, REAGAN FOR ALZHEIMER’S, WE NEED A PERSON TO STAND AND NOT SAY THEY HAVE WORD PERCEIVED BY THE PUBLIC AS BEING OLD AND FRAIL BECAUSE IT DIDN’T WIN VOTES.>>DR. SHANE, I’M GOING TO LET YOU HAVE THE LAST WORD BEFORE LUNCH.>>OKAY. THANK YOU. THIS IS REALLY TO GO BACK TO THE ISSUE OF SHORT-TERM AND LONG-TERM FOR THE PANEL. I THINK THE SHORT-TERM DATA ARE VERY STRONG BECAUSE THEY REFLECT THE DURATION OF MOST OF THE RANDOMIZED CONTROL CLINICAL TRIALS. AND THEY DEFINITELY SHOW BENEFIT. AND THE ISSUE OF LONG TERM, I THINK IN THE OLD DAYS WE THOUGHT THAT WE WOULD JUST CONTINUE THESE DRUGS THAT THEY WERE SAFE. AND DIDN’T SEEM TO HAVE VERY MANY ADVERSE EFFECTS BECAUSE WE DIDN’T SEE ANY ADVERSE EFFECTS IN THE SHORT TERM. AND THEN THE LONG TERM DATA ARE IT’S REALLY AN ARTIFICIAL CONSTRUCT, BASED ON THE FACT THAT WE HAVE VERY LITTLE LONG-TERM DATA BECAUSE THOSE WERE NOT CAPTURED BY RANDOMIZED CONTROLLED CLINICAL TRIALS SO WE HAVE VERY LITTLE IN THE WAY OF PLACEBO-CONTROLLED LONG-TERM DATA. AND THE OTHER POINT ABOUT THE LONG-TERM ISSUE VERSUS SHORT TERM, IT WAS IN THE LONG TERM IT BECAME APPARENT THAT PATIENTS WERE AT HIGHER RISK FOR THESE SIDE EFFECTS IN THE LONG TERM. SO I THINK SHORT TERM VERSUS LONG TERM IT’S MORE A MATTER OF STUDY DESIGNS, WHAT WE DO AND DON’T KNOW BECAUSE OF HOW STUDIES WERE DESIGNED AND WHAT DATA FROM PLACEBO-CONTROLLED TRIALS, THE MOST HIGHLY VALUE AND RELEVANT, AND YET APPRECIATION AS TIME WENT ON THAT IT WAS THE PEOPLE ON VERY LONG-TERM THERAPY WHO WERE ON — AT GREATER RISK FOR SIDE EFFECTS, EVEN THOUGH THAT RISK WAS STILL RELATIVELY LOW COMPARED TO RISK OF FRACTURE, I WANTED TO CLARIFY, SHORT TERM, LONG TERM, THROUGH THE RETRO SCOPEHOW WE REALLY INTENDED TO DO THINGS.>>VERY GOOD. WE’RE BREAKING FOR AN HOUR FOR LUNCH. WE’LL RECONVENE AT 1:30. THANK YOU. GOOD AFTERNOON. I’M CARRIE KLABUNDE, I’M TEAM LEAD IN OFFICE OF DISEASE PREVENTION FOR THE PATHWAYS TO PREVENTION PROGRAM. OVER THE NEXT 20 MINUTES WE ARE GOING TO TAKE A PAUSE FROM THE SCIENTIFIC PRESENTATIONS TO HEAR FROM THREE PATIENTS ABOUT THEIR EXPERIENCES WITH OSTEOPOROSIS, OSTEOPOROTIC FRACTURES AN DRUG THERAPY. SO WE HAVE HEARD THIS MORNING THE CONCERNS THAT MANY PEOPLE WHO ARE AT RISK FOR OSTEOPOROTIC FRACTURES ARE NOT BEING PRESCRIBED. MEDICATIONS THAT COULD PREVENT FRACTURES AND SOME PATIENTS WHO DO RECEIVE RECOMMENDATION TO GO ON DRUG THERAPY ARE NOT TAKING THE MEDICATIONS THAT HAVE BEEN PRESCRIBED FOR THEM. THE MAIN PURPOSE OF THIS WORKSHOP IS TO IDENTIFY RESEARCH GAPS AND SHAPE A RESEARCH AGENDA, WE HAVE A NUMBER OF RESEARCHERS AN CLINICIANS HERE WHO ARE SHARING THEIR DATA AND THEIR PERSPECTIVES. CLARIFYING RESEARCH NEEDS AND GAPS ALSO MEANS UNDERSTANDING THE PATIENT’S ROLE, THEIR PREFERENCES AN BARRIERS THEY MAY FACE IN DECIDING WHETHER OR NOT TO GO AND STAY ON TREATMENT. SO THIS AFTERNOON WE HAVE THREE PATIENT REPRESENTATIVES WHOSE WILL SHARE THEIR UNIQUE EXPERIENCES. EACH WILL HAVE FIVE MINUTES TO TALK AND IN PRESENTATION ORDER THEY’RE GERRY O’CONNER, BARBARA HANNAH GRUFFERMAN AND NANCY OSTROVE. THE WORKSHOP PLANNING COMMITTEE IDENTIFIED THESE INDIVIDUALS THROUGH OUTREACH TO ONE OF OUR CONSENT AREA EXPERTS AS WELL AS TO THE NATIONAL OSTEOPOROSIS FOUNDATION AN AMERICAN SOCIETY FOR BONE AND MINERAL RESEARCH. WE ARE VERY PLEASED TO HAVE THEM HERE WITH US THIS AFTERNOON. AND WE ARE GOING TO START WITH GERRY O’CONNOR.>>HERE WE GO. HI, EVERYONE. I’M VERY HAPPY TO BE HERE TO SHARE MY STORY. SO THAT WOMEN CAN GET THE RIGHT INFORMATION THEY NEED FROM THEIR DOCTORS. I KNOW THAT EVERY PATIENT’S JOURNEY IS NOT THE SAME. AND IT WAS VERY DIFFERENT FOR ME AND IN FACT I FELT LIKE THE SYSTEM — THERE WAS A BROKEN WHEN IT CAME TO MY CARE AND I FACED MANY UNEXPECTED HURDLES ALONG THE WAY. FIRST I WOULD LIKE TO SHARE I’M CURRENTLY AN EMPLOYEE OF RADIUS HEALTH. THE VIDEO YOU BE SEE IN A FEW MOMENTS WAS PRODUCED AND PAID FOR BY RADIUS BUT REFLECTS MY OWN PERSONAL JOURNEY. MY JOURNEY TOOK PLACE A YEAR BEFORE I JOINED RADIUS. SO THE STORY I TELL HAPPENED BEFORE I JOINED THE COMPANY. THIS IS MY DATA SLIDE. IS BELL AND SOFIA YOU’LL LEARN I CALL THEM THE CULPRITS BUT THE DATA I THINK IS EVIDENT TWO DOGS ARE GOING TO INCREASE YOUR RISK OF A FRACTURE. YOU’RE GOING TO HEAR MORE ABOUT THAT. THE TRUTH IS, I LOVE TO TAKE LONG WALKS WITH THE DOGS BUT THEY CAN MISBEHAVE WHEN THEY SEE OTHER DOGS. I WOULD LIKE TO TELL YOU ABOUT MY BACKGROUND. I HAD ALWAYS BEEN VERY PHYSICALLY ACTIVE AND IN MY 40s A DEVELOPED A PASSION FOR COMPETITIVE ROWING AN DISTANCE RUNNING. LATER MANY MY 50 MY PLAN WAS TO MIGRATE TO YOGA AND PERHAPS CYCLING BUT SINCE I BROKE MY HIP I HAVE STOPPED ALL STRENUOUS EXERCISES AND FACT WHEN I HEAR THERE’S A REPORT OF BAD WEATHER ANXIOUS ABOUT IT. AND YOU WILL LEARN WHY. WHEN I WAS DIAGNOSED WITH OSTEOPOROSIS MY TREATMENT OPTION TO ME SEEMED VERY UNCLEAR. PLEASE DON’T GET ME WRONG, I LOVE ALL MY DOCTORS, I CONTINUE TO SEE THEM BUT WHAT I HAVE DONE IS ADDED AN OSTEOSPECIALIST TO MY HEALTHCARE TEAM. YOU WILL SEE WHY.>>I WAS ACTUALLY DIAGNOSED ABOUT TEN YEARS AGO WITH OSTEOPENIA. AT THE TIME I WAS TOLD IT’S THE PRECURSOR TO OSTEOPOROSIS. ABOUT TEN YEARS LATER I WENT TO SEE MY GYNECOLOGIST AND SHE SAID MAYBE IT’S TIME TO DO ANOTHER BONE DENSITY STUDY. A FEW DAYS LATER I LEARNED I DO HAVE OSTEOPOROSIS. I WENT TO MY PCP, SHE SAID I HAVE NEVER TREATED OSTEOPOROSIS, WHY DON’T YOU GO FOR A YEAR AND WE’LL RE-EVALUATE. AND I’M THINKING CHILIES, HOW SERIOUS IS THIS CONDITION? I DON’T HAVE SYMPTOM, MY DOCTOR ISN’T SURE WHAT TO TELL ME TO GO ON. I’M THINKING OSTEOPOROSIS, IT’S AN OLDER PERSON’S DISEASE. I THINK I’LL BE OKAY. I WAS BORN THE TAKE — GOING TAKE MY DOGS OUT FOR LAST WALK OF THE EVENING AND SLIPPED ON THE WET GREAT AND LANDED ON MY LEFT HIP. AT THE TIME I THINK I WAS IN SHOCK, I THOUGHT I HAVE JUST SPRAINED MY THIGH, I WILL BE FINE. NOT SURE HOW MUCH LONGER I SAT OUT THERE. BUT I CRAWLED BACK IN TO MY PLACE AND MADE SURE DOGS WERE OKAY, CRAWLED UP AND DOWN THE STAIRS A COUPLE OF TIMES AND BY THE MIDDLE OF THE NIGHT THE PAIN WAS SO EXCRUCIATING I KNEW I HAD SOMETHING MORE THAN A SPRAIN. AT 6 A.M. I CALLED AN AMBULANCE, TAKEN TO THE HOSPITAL, BY 8 A.M. I WAS DIAGNOSED WITH A BROKEN HIP, I HAD A PARTIAL HIP REPLACEMENT, I WAS OVERWHELMED WE MOTION AND CONCERN ABOUT HOW I WAS GOING TO HANDLE THIS. WHILE I WAS IN THE HOSPITAL TWO ORTHOPEDIC SURGEONS ON TEAM SAID YOU NEED TO TREAT THIS. YOU NEED TO BE ON MEDICATION. I CAN TELL YOU WHEN I WENT BACK TO THE TYN OFFICE AND SHARED MY STORY, THAT POSITION SAID THERE’S A LOT OF CONFUSION IN THE FIELD HOW TO TREAT OSTEOPOROSIS. YOU CAN BE HELPING YOUR MOM, YOUR GRANDMA, YOUR SISTER, YOUR WIFE,>>SO ONE THING WE DIDN’T TALK ABOUT THIS MORNING, THERE’S A PHYSICAL ASPECT TO OSTEOPOROSIS, THERE’S EMOTIONAL, WHEN YOU DO EXPERIENCE THE TYPE OF FRACTURE I DID. BUT HOW I PERSONALLY THINK YOU CAN CONTINUE TO HELP IS TO CONTINUE TO EDUCATE DOCTORS ABOUT THE SERIOUSNESS OF THIS DISEASE. IF A WOMAN IN HER 50s FALLS DOWN SHE’S IN THE JUST BEING CLUMSY, SHE COULD HAVE OSTEOPOROSIS. ALSO ASK DOCTORSES TO THINK ABOUT ALL THE RISK FACTORS NOT JUST THE MOST COMMON ONES THAT COULD BE AFFECTING A WOMAN, I USED TO GIVE A LIST OF MEDICATIONS AND THEY WOULD MEASURE MY HEIGHT AND THEY NEVER MADE THE LINK TO OSTEOPOROSIS. FOR ME. AT THE END OF THE DAY I DO REMAIN VERY OPTIMISTIC AND UNOFFICIAL PATIENT ADVOCATE FOR THIS DISEASE STATE BECAUSE I THINK TOGETHER WE CAN EMPOWER WOMEN TO UNDERSTAND THE DISEASE, THEIR TREATMENT OPTIONS AN TO HAVE A GOOD BONE HEALTH PLAN IN PLACE. THANK YOU VERY MUCH. [APPLAUSE]>>THAT’S A VERY TOUGH ACT FOLLOW. IT WAS A GREAT VIDEO, THANK YOU SO MUCH AN THANK YOU RADIUS FOR HELPING ME MAKE IT. I’M BARBARA HANNAH GRUFFERMAN, I’M A WRITER, SPEAKER, I FOCUS ON WOMEN’S HEALTH AND WELL BEING AND I’M ALSO A TRUSTEE, BOARD MEMBER OF THE NATIONAL OSTEOPOROSIS FOUNDATION. HAVE BEEN FOR A COUPLE OF YEARS. I’M VERY DEEPLY INVOLVED IN THIS ISSUE OF OSTEOPOROSIS AN BONE HEALTH. MY STORY, I MUST BE BRIEF, I DON’T THINK A VIDEO OR ANYTHING, I SHOULD HAVE A PHOTO OF MY DOGS UP THERE TOO BECAUSE MY DOG WAS INVOLVED IN MY LITTLE ACCIDENT WHEN I BROKE MY ARM. WHEN I WENT THROUGH MENOPAUSE ABOUT 49 I STARTED TO EXPERIENCE A LOT OF WHAT MANY WOMEN EXPERIENCE, THAT’S WEIGHT GAIN AND FEELING WHAT I CALL MY LUMPY GRUMPY FRUMPY AND EVERY OTHER UMPY YOU CAN THINK OF SO I TOOK SOME ACTION AND I DID SEE A LOT OUT THERE AND THAT’S’S WHEN I WROTE MY FIRST BOOK FOR WOMEN OVER 50. I STARTED AN EXERCISE PROGRAM, FOLLOWED THE RECOMMENDATIONS FROM THE EXPERTS I INTERVIEWED ON ONE OF THESE JOHN MY THEN DOG WHO IS NOW UP IN DOG HEAVEN I JUST STUMBLED OVER MY OWN TWO FEET AS WE WERE WALKING HOPE. I CAN’T BLAME HIM, IT WAS ME. AND TURNS OUT I HAD — DID BREAK MY ARM. AND I WAS ABOUT 50. LUCKILY I DO HAVE A PCP, DR. GAIL YOU’LL BE HAPPY TO HEAR THIS, HE DID RECOMMEND EVENTUALLY WHEN I SAW HIM FROM MY NEXT PHYSICAL SO IT TOOK A WHILE TO GET MY FIRST BONE DENSITY TEST. AT THAT TIME SHOWED THAT I WAS OSTEOPEENIC AN LOW BONE MASS. MY TOTAL HIP WAS ABOUT 1.2, MINUS 1.2. EXCUSE ME. AND SO I, WITH HIS BLESSING AND IN PARTNERSHIP WITH MY DOCTOR, TOOK ALL THE STEPS I FELT WAS REALLY RIGHT FOR ME AN APPROPRIATE AT THAT TIME. INCREASE CALCIUM, CALCIUM RICH FOODS, VITAMIN D INTAKE, I TAKE 2000 A DAY, THAT’S MY OWN RECOMMENDATION TO MYSELF, SEEMS TO BE WORKING. INCREASE MY STRENGTH TRAINING, AND I ALSO STARTED TO RUN. WHEREAS BEFORE I WAS JUST WALKING. IN FACT I’M PROUD TO TELL YOU THAT I’M RUNNING IN THE NEW YORK CITY MARATHON ON SUNDAY, FIVE DAYS FROM NOW AN IT WILL BE MY SIXTH MARATHON ALL SINCE TURNING 50. ALL SINCE THIS TIME SO I’M REALLY VERY EXCITED ABOUT THAT. IT’S NEVER TOO LATE AS I ALWAYS LIKE TO SAY. TY PERIODICALLY GET MY BONE DENSITY TESTS PER MY DOCTOR’S RECOMMENDATION. IF LAST ONE I HAD WAS A LITTLE LESS THAN A YEAR AGO AND I DOES — YOU KNOW, EACH PASSING TEST I GET DOES SHOW SOME DECREASE IN BONE DENSITY. EVEN THOUGH I’M DOING EVERYTHING I FEEL I SHOULD BE DOING IN TERMS OF LIFESTYLE. TO ADDRESS THE ISSUE. HOWEVER MY LAST ONE DID SHOW FOR EXAMPLE BY COMPARISON THE TOTAL HIP WAS MINUS 1.7. SO IN THIS CASE MY PCP SAID KEEP DOING WHAT YOU’RE DOING, HE WAS COMFORTABLE WITH EVERYTHING AS IT WAS. I THEN SAID BEING EXTREMELY PROACTIVE ESPECIALLY NOW THAT I’M FOCUSED ON WOMEN’S HEALTH AND WELL BEING AND I I’M A HEALTH FREAK, I DID SAY LET ME TAKE THESE NUMBERS TO A SPECIALIST AND LET’S GET SOMEONE ELSE TO WEIGH IN ON THIS, HE WAS TOTALLY COOL WITH THAT AND OFF WE WENT. THIS END DRINKNOLOGIST AGREED — ENDOCRINOLOGIST CONTINUED TO MONITOR ME. I HAVE TO TELL YOU BASED ON EVERYTHING WE HAVE HER SO FAR, LEARNED SO MUCH MORE AND SO CONNECTED TO THIS ISSUE BECAUSE OF MY ROLE AT NOF, MY INVOLVEMENT AND MY ENGAGEMENT WITH ALL THE WONDERFUL, WONDERFUL MEMBERS OF THE BOARD. MEDICAL SIDE BUT I FOUND I LEARNED SO MUCH MORE TODAY AND QUITE FRANKLY I’M REALLY WONDERING IF THE PATH I’M ON RIGHT NOW IS THE RIGHT PATH FOR ME. AND I AM ALWAYS TO MEDICATION AN TREATMENT. I WANT TO BE CLEAR ABOUT THAT. BUT I’M NOT ON THAT PATH BECAUSE OF THE RECOMMNDATION FROM TWO DOCTORS I WILL CONTINUE TO BE OPEN MINDED. IN THE INTERIM SINCE THIS LAST BONES DENSITY TEST ACTUALLY THIS PAST JANUARY MY TO MOTHER WHO IS 81 FELL AN BROKE HER HIP, SHE HAD EMERGENCY SURGERY AND SHE WAS MOBILE. SHE WAS SEMIINDEPENDENT AND NOW SHE IS NOT REALLY MOBILE. SHE CAN’T GO FROM HERE TO THERE WITHOUT HELP OF A PERSON OR A WALKER. SHE IS NO LONGER LIVING INDEPENDENTLY. AND I LOOK AT THAT AND I SAY NO. THIS IS NOT THE LIFE I WANT FOR MYSELF AS I GET OLDER. MY GOAL NOW AS I’M 61 WHEN I THINK ABOUT ALL THE THINGS I DO FOR MYSELF AND WHAT I WRITE ABOUT AND TALK ABOUT AND ENCOURAGE OTHERS TO DO SO I CAN BE MOBILE AND INDEPENDENT FOR AS LONG AS POSSIBLE. I DO NOT WANT TO FALL AN BREAK A BONE AND BECOME OTHER THAN MOBILE. SO THAT IS THE PATH I’M ON, THANK YOU FOR LISTENING TO ME STORY. THANK YOU FOR ALL THE GOOD WORK THAT YOU CONTINUE TO DO. I APPRECIATE IT. THANK YOU. [APPLAUSE]>>OKAY. SO MY TURN. HI. AFTERNOON TO EVERYONE. I’M NANCY OSTROVE. I GOT A DOCTORATE IN EXPERIMENTAL SOCIAL PSYCHOLOGY, I WAS AN FDA RISK COMMUNICATIONS RESEARCHER AN POLICY DEVELOPER FOR 21 YEARS. THAT’S MY BACKGROUND. I HAVE HAD AT LEAST TWO, PROBABLY THREE LUMBAR WEDGE COMPRESSION FRACTURES. AFTER I HAD BEEN TREATED FOR OSTEOPOROSIS ABOUT THEN HAD A STOP BECAUSE I GOT BETTER. I’M BACK ON TREATMENT NOW BUT I’M EVEN SHORTER THAN I STARTED WHICH AT MY HEIGHT, HARD TO LOSE THAT. I’M A LITTLE BIT PARANOID ABOUT FRACTURING MORE VERTEBRA ESPECIALLY AFTER THE ORTHOPEDIST SAID IF I HAVE THAT PAIN AGAIN I CAN ASSUME IT’S ANOTHER FRACTURE. NOW, IN THE EVEN BEFORE MENOPAUSE I KNEW I WAS HIGH RISK FOR OSTEOPOROSIS, NOT A BIG CALCIUM CONSUMER AND THYROID TO BOOT BUT I WAS ALWAYS ACTIVE, I CAN’T SIT OR STAND STILL FOR LONG PERIODS OF TIME, I’M A FAST WALKER, I TEACH, AND I TAKE TAI CHI. BACK IN MY 40s I STARTED TAI QWON, DO WITH MY KIDS RANS GOT MY SECOND DEGREE BLACK BELT, BEFORE I STOPPED I WAS ON SCHOOL DEMONSTRATION TEAM. I WAS DIAGNOSED AT DIFFERENT TIMES WITH OSTEOPOROSIS AND OSTEOPINIA MAINLY LOWER SPINE THOUGH NOW IT AFEARS MY FOREARM IS OSTEOPOROTIC AS WELL. THE BASED DISTINCTION BETWEENS THESE TWO CONDITIONS IS REALLY CONTRIBUTED TO THE FRACTURES THAT I EXPERIENCED. I FIRST TRIED TO ADDRESS MY CONCERNS ABOUT OSTEOPOROSIS AND THE FACT I WAS DIAGNOSED WITH OSTEOPENIA BY ENROLLING IN A CLINICAL STUDY FOR RALOXIFENE. I NOW DID NOT GET THE DRUG BECAUSE THE PLACEBO WAS — AND I NEVER HAD HEART BURN BEFORE IN MY LIFE UNTIL I STARTED THAT CLINICAL STUDY. THAT WAS DESPITE CAREFULLY FOLLOWING THE INSTRUCTIONS ABOUT LESSENING RISK. PLUS MY BMD DIDN’T IMPROVE. FOLLOWING THAT STUDY I ENROLLED IN OPEN LABEL TRIAL OF DENOSAMAB. AFTER TWO YEARS MY NUMBERS IMPROVE SIGNIFICANTLY SO I CONTINUED AFTER THE TRIAL ENDED THEN MY T SCORE IMPROVED SUFFICIENTLY WHERE I WAS NO LONGER OSTEOPOROTIC. MY PHYSICIAN ENDOCRINOLOGIST COULDN’T JUSTIFY CONTINUING TREATMENT BECAUSE I WAS NO LONGER OSTEOPOROTIC AND FEDERAL EMPLOYEE PROGRAM IS GENEROUS BUT THEY NEEDED AN OSTEOPOROSIS DIAGNOSESIS. SO A YEAR AND A HALF LATER I FRACTURED L 1 AND L 2 DESPITE MY CONTINUING ACTIVE LIFESTYLE. ORTHOPEDIST THOUGHT I FRACTURED L-4 AFTER THE INITIAL TWO FRACTURES SO HOW DID THAT HAPPEN? I DIDN’T FALL. I WAS PLAYING WITH MY GRANDDAUGHTER ON SOME PLAYGROUND EQUIPMENT. I TOOK HER WEIGHT AND I TWISTED MY BACK, THE WRONG WAY OBVIOUSLY. AND BOOM, THAT WAS IT. AT THE TIME I JUST FIGURED I PULLED SOME MUSCLES, I THOUGHT I HEARD A CRACKING NOISE BUTTY HAD TORN LIGAMENTS SPRAINED MUSCLES BEFORE AND FIGURED IT WAS MY IMAGINATION. AFTER A MONTH OF THE INTENSE PAIN I HAD EVERY TIME I CHANGED POSITION AN INSISTING I DIDN’T NEED TO GO TO THE DOCTOR MY HUSBAND FINALLY CONVINCED ME TO GO TO THE DOCTOR. SO PREDNISONE FOR SPASMING BACK MUSCLE AND MRI LATER IT WAS NOT A MUSCLE SPRAIN. ULTIMATELY I HAD A LOCATE A RHEUMATOLOGIST ON MY OWN. BECAUSE MY ORTHOPEDIST KNEW NOTHING ABOUT TREATING OSTEOPOROSIS. THIS IS AN ORTHOPEDIC SURGEON. AND MY PRIMARY CARE DOC ALSO DIDN’T HAVE A REFERRAL FOR ME. I HAD NO IDEA WHAT KIND OF SPECIALIST I SHOULD SEE AND APPARENTLY NEEDED A DAY. THEY WERE BOTH MEN BUT I’M IN THE HOLDING THAT AGAINST THEM. THE RHEUMATOLOGIST PUT ME ON A YEAR OF TERPERTIDE INCREASING THE SPINAL BMD THAT IT WAS OSTEOPEENIC. HOWEVER I’M STILL GETTING DEKNOX HAS BEEN INJECTIONS BECAUSE I HAD FRACTURE AND THEREFORE CONSIDERED HIGH RISK SO TESTIMONY INSURANCE PLAN AT THIS POINT DOESN’T BALK AT PAYING THE EXPERIENCE TO TREAT ME. IF THEY LET ME CONTINUE TAKING IT IN THE FIRST PLACE THIS WOULDN’T HAVE HAPPENED SO WHAT ARE THE TAKE AWAYS? I DID EVERYTHING I COULD, I TRIED TO GET SUFFICIENT CALCIUM AN VITAMIN D I EXERCISE ON REGULAR BASIS NONE OF THAT PREVENTED IT. I DIDN’T FALL, THIS WAS NOT IF THE TRADITIONAL FALLING. MY DOCS DIDN’T KNOW WHAT KIND OF SPECIALIST TREATS OSTEOPOROSIS AND COULDN’T OFFER REFERRALS. MY PRIMARY CARE SPECIALIST AT MY PRIMARY CARE DOC TRIED MEACAL SIN BUT IT DIDN’T DO ANYONE. MEDICATIONS HELPED, THIS IS GOOD. REAL BIG ONE, MAKING SURE T SCORE BASED DICTIONS BETWEEN OSTEOPENIA AND OSTEOPOROSIS FOR CLINICAL INSURANCE RELATED DECISIONS DOESN’T MAKE SENSE FROM A TREATMENT STANDPOINT THOUGH SURE IT MAKES SENSE FROM A COST PERSPECTIVE. I UNDERSTAND THAT ARBITRARY CUT OFFS ARE SOMETIMES NEEDED BUT THERE ALSO NEEDS TO BE CONSIDERATION OF RANGES RATHER THAN SPECIFIC NUMBERS AND A GREATER EMPHASIS BASED ON ASSESSING RELATIVE RISK AND BENEFITS OF BOTH THE CONDITION AND THE MEDICATIONS USED TO TREAT IT. THANK YOU, VERY MUCH. [APPLAUSE]>>CAN YOU HEAR? OKAY. I’M HOWARD FINK, I’M A PHYSICIAN AND RESEARCHER FROM THE MONEY YAP POLICE VA CENTER, I’M GOING AN INVESTIGATOR WITH THE MINNESOTA EVIDENCE BASED PRACTICE CENTER. I’M GOING TO BE PRESENTING THREE PRESENTATIONS TAKEN FROM OUR EVIDENCE REVIEW. THE FIRST ONE IS ON THE LONG TERM BENEFITS AN EFFECT MODIFIERS OF BENEFITS AND — HERE IS THE — — AND THEN YOU WILL SEE OKAY. SO DISCLAIMERS, SO THIS PRESENTATION IS BASED ON MINNESOTA EVIDENCE BASED PRACTICE CENTER, RESEARCH, CONTRACTED TO AHRQ. THE FINDINGS ARE OURS, I HAVE NO FINANCIAL INTERESTS OR RELATIONSHIPS. TO STATE AND THEN WE’RE NOT GOING TO BE DISCUSSING UNLABELED OR INVESTIGATIONAL USES, MEDICATIONS IN THE REVUE ARE ALL FDA APPROVED FOR AT LEAST SOME INDICATION. SO THE GOALS OF THE SYSTEMATIC REVIEW ARE TO THE OVERALL REVIEW, REVIEW EVIDENT ON BENEFIT AN HARM OF OSTEOPOROSIS DRUG THERAPY AN OSTEOPOROSIS DRUG THERAPY HOLIDAYS AND NON-FACTORS THAT MAY MONEY THESE EFFECTS. SO WHETHER THE TREATMENT EFFECTS VARY AS A FUNCTION OF DIFFERENT FACTORS, THE FIRST TALK THIS AFTERNOON IS GOING TO BE FOCUSED ON LONG TERM TREATMENT BENEFITS AND THEIR POSSIBLE EFFECT MODIFIERS. THE KEY QUESTION FOR THIS PART OF THE REVIEW IS AMONG MEN AN POST MENOPAUSAL WOMEN AGE 50 OR OLDER WITH OSTEOPOROSIS OR OSTEOPENIA, WHAT IS THE EFFICACY OF LONG TERM OSTEOPOROSIS DRUG TREATMENT RISK OF INCIDENT FRACK CHU AND ON CHANGE IN BONE MINERAL DENSITY, AS PEOPLE TALKED EARLIER, IT’S A LITTLE ARBITRARY BUT LONG TERM FOR THIS REVIEW IS DEFINED AS GREATER THAN THREE YEARS. AND THEN THE SECOND THING WAS DOES EFFICACY OF LONG TERM DRUG TREATMENT FOR REDUCING RISK INCIDENT FRACTURE VARY BY PATIENT, BONE OR OSTEOPOROSIS DRUG CHARACTERISTICS. SO JUST REAL BRIEF BACKGROUND, AS YOU HEARD FROM A NUMBER OF SPEAKERS EARLIER, THIS MORNING, THERE ARE MULTIPLE OSTEOPOROSIS DRUG TREATMENTS THAT REDUCE FRACTURE RISK SHORT TERM TREATMENT, DATA ARE LARGELY FROM POST MENOPAUSAL WOMEN, THE BENEFITS OF LONG TERM TREATMENT ARE LESS CLEAR AND UNDERSTANDING FACTORS THAT MODIFY THE LIKELY HOOF BENEFIT WITH LONG TERM TREATMENT MAY INFORM TREATMENT DECISION. SO THAT’S A REASON FOR LOOKING AT THESE PO TERMIAL EFFECT MODIFIER. POTENTIAL EFFECT MODIFIERS. SO THE METHODS OF REVIEW INVOLVED IN ELECTRONIC, SEARCH OF ELECTRONIC DATABASES, GOING BACK FAR ENOUGH TO GET THE EARLIEST TRIALS AN THROUGH JUNE OF THIS YEAR TO — WE HAVE BEEN SEARCHING LITERATURE SINCE THEN TO UPDATE IT, HAVE INCORPORATED SOME STUDIES PUBLISHED SINCE THEN INTO THE PRESENTATION. WE ALSO LOOKED AT REFERENCES OF SYSTEMATIC REVIEWS, THE POPULATIONS OF INTEREST FOR THE REVIEW ADULTS, 50 OR OLDER WITH OSTEOPOROSIS OR OSTEOPENIA, TREATED TO PREVENT FRACTURES SO THAT COULD HAVE PREVENTED THE WHOLE POPULATION, MET THAT CRITERIA OR STUDY REPORTED ON A SUBGROUP THAT MET CRITERIA. WE EXCLUDED STUDIES THAT WERE FOCUSED ON PATIENTS WITH KNOWN SECONDARY CAUSE OF OSTEOPOROSIS WHO HAD METASTATIC CANCER, OR TREATMENT, THE PURPOSE WAS TO LOOK AT THAT TIME THE EFFECT ON BONE HEALING, AS I MENTIONED BEFORE. THE LONG TERM TREATMENT WAS DEFINED AS MORE THAN THREE YEARS, WE LOOKED AT FDA APPROVED TREATMENTS. FDA APPROVED DRUGS. (INDISCERNIBLE) IS NOT INCRUDED IN OUR REVIEW BECAUSE IT’S NOT YET FDA APPROVED. FOR LOCKING AT THE AFFECT ON INCIDENT FRACTURE WE LOOKED STRICTLY AT RANDOMIZED CONTROL TRIALS AND CONTROL CLINICAL TRIALS AND WE DID NOT LOOK AT OBSERVATIONAL STUDIES FOR EFFICACY. THE PRIMARY EFFICACY OUTCOME WE LOOKED AT WAS INCIDENT CLINICAL FRACTURE, HERE ARE SOME OF THESE ABBREVIATIONS. ANY INCIDENT CLINICAL FRACTURE IS CF AND I MADE THAT ABBREVIATION SHEET THAT I THINK EVERYBODY GOT WITH THEIR HAND OUT BUT THERE’S HIP FRACTURE, NON-VERTEBRAL FRACTURE AND CLINICAL VERTEBRAL FRACTURE. THE SECONDARY FOR FRACTURE AND THEN IN OUR REPORT, OUR THIRD OUTCOME WAS CHANGED IN BMD BUT I’M NOT TALKING ABOUT BMD OUTCOMES IN THIS PRESENTATION. BECAUSE IT’S LESS PATIENT IMPORTANT OUTCOME. NOT A PATIENT REPORTED OUTCOME. SO THE POSSIBLE EFFECT MODIFIERS THAT WE LOOKED AT IN OUR REVIEW WE WERE IN THREE CATEGORIES PATIENT FACTORS, BONE FACTORS AN DRUG TREATMENT FACTORS. THE PATIENT FACTORS THAT WE LOOKED FOR TO SEE IF STUDIES PROVIDED DATA LOOKING AT WHETHER THESE FACTORS AFFECTED THE TREATMENT OUTCOMES OR WHETHER THE TREATMENT EFFECTS VARIED AS FUNCTION OF AGE, SEX, RACE, OSTEOPOROSIS CATEGORIES, THAT’S LIKE WHETHER THEY WERE OSTEOPOROTIC OR OSTEOPEENIC. IF THEY HAD A PAST FRACTURE HISTORY, THEIR FRACTION SCORE, ESTIMATED RISK OF HIP OR FRACTURE OVER NEXT TEN YEARS AN COMORBIDITIES. FOR BONE WE LOOKED AT BMD, BONE MARKERS AND FOR THE DRUG TREATMENT WE LOOKED AT WHETHER TREATMENT EFFECTS VARIED BY DOSE, FREQUENCY, DURATION OR ROUTE. WHEN WE EVALUATED THE STRENGTH OF EVIDENCE FOR OUR FINDINGS IT WAS BASED ON LOOKING AT SEVERAL DOMAINS, THE QUALITY OF INDIVIDUAL STUDIES, WHETHER THE STUDIES PROVIDED EVIDENCE THAT DIRECTLY LINKED THE INTERVENTION TO THE OUTCOME WHETHER THE RESULTS WERE CONSISTENT BETWEEN STUDIES, WHETHER THE ESTIMATE EFFECT WAS PRECISE AND WHETHER WE COULD DETECT ANY REPORTING BIAS. SO HIGH STRENGTH OF EVIDENCE IS GENERALLY WHEN WE HAVE HIGH CONFIDENCE THAT THE ESTIMATE IS CLOSE TO THE TRUE EFFECT AN FINDINGS ARE LIKELY STABLE AND ADDITIONAL STUDIES WOULD BE UNLIKELY TO CHANGE EITHER THE DIRECTION, MAGNITUDE AND GOING THE OTHER EXTREME INSUFFICIENT STRENGTH OF EVIDENCE WOULD BE WHEN THERE’S NO EVIDENCE, WHEN THE EVIDENCE IS SO LIMITED THAT WE’RE UNABLE TO ESTIMATE EFFECT OR WE HAVE NO CONFIDENCE IN IT. THE DECISIONS ABOUT WHETHER SOMETHING IS HIGH VERSUS MODERATE, LOW OR INSUFFICIENT, ULTIMATELY INVOLVE JUDGMENT IN SOME SUBJECTIVITY THOUGH WE ATTEMPTED TO MAINTAIN CONSISTENCY IN OUR PROCESS. START OUT WITH THE TREATMENTS IN OUR REVIEW INCLUDING THE LONG TERM BENEFITS HARMS AND DRUG HOLIDAYS, WE IDENTIFIED ABOUT 58 DIFFERENT STUDIES, WHEN YOU — WE ANALYZED ONLY THOSE THAT WE CONSIDERED TO HAVE JUST LOW OR MEDIUM RISK OF BIAS, IF SOMETHING WAS THOUGHT TO BE HIGH RISK OF BIAS WE DIDN’T ANALYZE IT AND THEN WITHIN THAT MOST OF THE DATA WERE BASED ON A SMALL NUMBER OF TRIALS AN OBSERVATIONAL STUDIES ABOUT LESS THAN TEN INDIVIDUAL TRIALS SOME WITH MULTIPLE REPORTS AND A DOZEN OBSERVATIONAL STUDIES, FOR THE EFFICACY OR PEOPLE ASKED ABOUT PATIENT POPULATIONS IN THE TRIALS THEY WERE US A POST MENOPAUSAL WOMEN NEARLY ALL WERE WHITE VERY LITTLE REPORTING OF CO-MORBID CONDITIONS MOST STUDIES DIDN’T REPORT ANY TELL YOU THAT HA VERY LOW PREVALENCE CO-MORE BY CONDITIONS. FOR ELANDERNATE ONE TRIAL PROVIDED LISTENING TERM DATA THIS WAS THE FIT 2 STUDY, IT WAS A FOUR YEAR TRIAL CONDUCTED IN POST MENOPAUSAL WOMEN AGE 54 TO 81. THEY WERE WERE OSTEOPOROTIC OR OSTEOPENIC BY BMD. THE PORTION HAD NO RADIOGRAPHIC FOR VERTEBRAL FRACTURE. THE MAIN FINDING IS THAT THERE WAS ABOUT A 45% RELATIVE REDUCTION IN RISK OF RADIOGRAPHIC VERTEBRAL FRACTURE, STATISTICALLY SIGNIFICANT, THE RED BOXES ARE AROUND RESULTSES THAT ARE STATISTICALLY SIGNIFICANT. THE ABSOLUTE RISK REDUCTION WAS TWO SO THAT CONVERTS TO ABOUT A NUMBER NEEDED TO TREAT OF 50 TO TREAT FOUR YEARS TO PREVENT ONE RADIOGRAPHIC VERTEBRAL FRACTURE. FOR THE OTHER OUTCOMES, CLINICAL OUTCOMES NONE OF THEM WERE STATISTICALLY SIGNIFICANTLY DIFFERENT BETWEEN ELENDERNATE AND PLACEBO. THE HAZARD RATIO WERE LESS THAN ONE BUT NONE WERE STATISTICALLY SIGNIFICANT SO WE LOOKED AT WHETHER THE RESULTS DIFFERED AS A FUNCTION OF DIFFERENT CRITERIA AND THE EFFECT ON THE RISK OF INCIDENT FRACTURES VARIED BY BASELINE BMD. IN THE SUBGROUP WITH OSTEOPOROSIS BEFORE THE DATA WAS OPENED, THEY CHOSE TO LOOK AT WHETHER EFFECTS ON CLINICAL FRACTURE AND RADIOGRAPHIC VERTEBRAL FRACTURE VARIED AS A FUNCTION OF BMD. THE GROUP WITH OSTEOPOROSIS, T SCORE OF MINUS TWO AND A HALF OR WORSE, REDUCTION IN RISK OF CLINICAL FRACTURE RADIOGRAPHIC VERTEBRAL FRACTURE WAS SIGNIFICANTLY REDUCED IN THE OSTEOPENIC GROUPS, THERE WAS NO SIGNIFICANT REDUCTION IN RISK OF RADIOGRAPHIC VERTEBRAL FRACTURE. SO IF YOU LOOK AT THE — IN THE T MINUS TWO AND A HALF TO MINUS 2 HA CZAR RATIO FOR RAY OWE GRAPHIC VERTEBRAL FRACTURE IS SIMILAR TO THAT IN THE OSTEOPOROTIC GROUP BUT THEY HAD FEWER EVENTS THE COMPETENCE RULES ARE WIDER AND RESULTS WERE NOT STATISTICALLY SIGNIFICANT. IN THE COLUMN, STRENGTH OF EVIDENCE COLUMN JUST SO YOU KNOW HERE, WE WE LISTED HIGH MODERATE LOW RISK OF BIAS AND MG IS NOT GRADED. THERE’S A FEW THAT WERE NOT GRADED YET. OKAY. IN WOMEN WITH OSTEOPOROSIS WE FOUND NO ELIGIBLE TRIALS OF LONG TERM OLENDRENATE THAT REPORTED WHETHER FRACTURE EFFICACY VARIED BY TREATMENT BONE CHARACTER THES. BUT WOMEN WITH OSTEOPENIA VERSUS PLACEBO ON RISK OF INCIDENTS AN FRACTURE DID NOT VARY BY PAST NON-VERTEBRAL FRACTURE, BASE LIKE FRAC SCORE BASELINE BONE TURN OVER MARKERS. THERE’S A TRIAL PUBLISHED EARLIER THIS MONTH, SIX YEAR TRIAL IN 2000 POST MENOPAUSAL WOMEN 65 OR OLDER DESCRIBED AS OSTEOPOROTIC BY HIP BMD BUT BETWEEN 13 AND 21% WOULD BE CATEGORIZE AS OSTEOPOROTIC BY MOST DEFINITIONS AND THEY EITHER HAD A BASELINE RAY YES GRAPHIC VERTEBRAL FRACTURE OR T SCORE HIP OR SPINE THAT WAS WORSE THAN MINUS 2 AND A HALF. IN THIS STUDY GROUP TREATED WITH SELENDRENATE 18 MONTHS FOR SIX YEARS HAD REDUCTIONS IN CLINICAL FRACTURE, NON-VERTEBRAL FRACTURE AND CLINICAL VERTEBRAL FRACTURE. HIP FRACTURE HAZARD RATIO IS .66 BUT THEY’RE ONLY 20 HIP FRACTURES IN THE STUDY. AND-NOT STATISTICALLY SIGNIFICANT. THEY LOOKED AT WHETHER RESULTS VARIED AS A RESULT OF DIFFERENT CHARACTERISTIC AND THEY FOUND THAT IN THE WHOLE GROUP EFFICACY DID NOT VARY BY BASELINE RAID YES GRAPHIC VERTEBRAL FRACTURE, THEY DID A NUMBER OF ANALYSES WHERE THEY FOUND THE RESULTS WERE SIMILAR TO OVERALL AFTER THEY EXCLUDED PEOPLE WITH BASELINE RADIOGRAPHIC VERTEBRAL FRACTURE OR BASELINE BMDT SCORE AND THEN WHEN THEY EXCLUDED PEOPLE WHO HAD A FRAC SCORE GREATER THAN 3% AT THE HIP OR 20% FOR MAJOR OSTEOPOROTIC FRACTURES AND EXCLUDED PEOPLE AT PAST FRACTURE REDUCTION IN RISK OF FRAGILITY FRACTURE AND NON-VERTEBRAL FRACTURE WAS SIMILAR TO OVERALL. FOR RALOXIFENE, THIS WAS A FOUR YEAR TRIAL OR THREE YEAR TRIAL ONE YEAR EXTENSION IN POST MENOPAUSAL WOMEN WHO WERE OSTEOPOROTIC BY DMD AND/OR PAST RADIOGRAPHIC VERTEBRAL FRACTURE, AN AFTER FOUR YEARS THE RISK OF CLINICAL VERTEBRAL FRACTURE RADIOGRAPHIC VERTEBRAL FRACTURE WAS REDUCED 35 TO 40%. THERE WAS NO DIFFERENCE IN RISK OF ANY OTHER FRACTURE OUTCOME. THE RESULTS BETWEEN RALOXIFENE AND PLACEBO DIDN’T VARY AS FUNCTION OF AGE BASELINE BMD AND BASELINE RADIOGRAPHIC VERTEBRAL FRACTURE. FOR DENOSMAB THERE WAS ONE FOUR YEAR PHASE 2 DOSE FINDING STUDY THAT ENROLLED POST MENOPAUSAL WOMEN WITH OSTEOPOROSIS OR O PENIA BY BMD. IN THIS CASE THEY REPORTED CLINICAL OSTEOPOROTIC FRACTURES AS ADVERSE EVENTS, THEY — BECAUSE THE RESULTS FOR THE DENOSMAB LONG TERM TREATMENT GROUP WERE POOLD WITH OTHER TREATMENT ARMS WHICH DENOSMAB WAS STOPPED OR IT WAS STOPPED AND RESTARTED, IT WAS NOT POSSIBLE TO COMPARE THE CONTINUOUS TREATMENT DIRECTLY WITH PLACEBO. BUT THE GROUP DENOSMAB STUDIES HAD ARMS SIMILAR RISK OF FRACTURES. COMPARED TO PLACEBO. FOR ESTROGEN, THE — THIS IS FROM WHI, THERE IS A SEVEN YEAR TRIAL AND A LITTLE OVER 10,000 POST MENOPAUSAL WOMEN UNSELECTED BY FRACTURE HISTORY OR BMD, DIDN’T HAVE VERTEBRAL FRACTURES MEASURED BASELINE AND STATUS POST HYSTERECTOMY. IN THE OVERALL WHI POPULATION, THERE WAS A SIGNIFICANT REDUCTION IN RISK OF CLINICAL FRACTURE, HIP FRACTURE, AND CLINICAL VERTEBRAL FRACTURE, THEY DID SUBGROUP ANALYSES ONE IN WHICH THEY REPORTED THE RESULTS IN PEOPLE WHO HAD HAD A — REPORTED A PAST FRACTURE AT BASELINE. RESULTS WERE SIMILAR IN THIS GROUP WHERE THEY HAD A SIGNIFICANT REDUCTION WITH ESTROGEN COMPARED TO PLACEBO AN SIGNIFICANT REDUCTION IN CLINICAL FRACTURE AND IN HIP FRACTURE. THEY MEASURED BMD FEWER THAN 10% PEOPLE SO THEY REPORTED THE RESULTS IN A SMALL NUMBER WHO ARE OSTEOPOROTIC AT BASELINE BUT THE DATA WAS INSUFFICIENT TO DRAW ANY CONCLUSIONS. THEY LOOKED AT A LOT OF DIFFERENT FACTORS TO SEE IF RESULTS ON RISK FRACTURE VARIED AS A FUNCTION OF DIFFERENT BASELINE CHARACTERISTICS, THE TWO THAT WERE CONSISTENT FOR BOTH THE HIP IN ANY CLINICAL FRACTURE OUTCOMES WERE HIGHER BASELINE FRACTURE RISK SCORE AN MORE THAN TEN YEARS SINCE MENOPAUSE HAD SIGNIFICANT INTERACTIONS WITH TREATMENT OUTCOME. THERE’S THE OLDER AGE NON-SMOKERS, HAD ONE FOR ONE OF THE OUTCOMES AND THEN THE — ON THE RIGHT FALL HISTORY CALCIUM INTAKE OTHER FACTORS — THE RESULTS DIDN’T DIFFER AS A RESULT OF THOSE CHARACTERISTICS. FROM FOR ESTROGEN AND PROJESTIN THIS IS ANOTHER WHI TRIAL IN THIS CASE. A LITTLE OVER 16,000 WOMEN, 50 TO 79 POST MENOPAUSAL WOMEN WERE RANDOMIZED TO ESTROGEN PROGESTINS FROM PLACEBO FOR FIVE OR SIX YEARS. UNSELECTED BY FRACTURE HISTORY BMD, NO VERTEBRAL FRACTURES AT BASELINE AND THESE WHERE WOMEN WHO HAD INTACT UTERUS. RESULTS WERE SIMILAR TO THE ESTROGEN STUDY AN OVERALL THERE WAS REDUCTION IN CLINICAL FRACTURES HIP FRACTURES AN CLINICAL VERTEBRAL FRACTURES. THE RESULTS WERE SIMILAR IN MAGNITUDE FOR A CLINICAL FRACTURE AND HIP FRACTURES IN THE PAST FRACTURE GROUP BUT NOT STATISTICALLY SIGNIFICANT FOR HIP FRACTURE. THE RESULTS ON WHAT FACTORS AFFECTED THE TREATMENT OUTCOMES WERE NOT CONSISTENT WITH THE ESTROGEN GROUP, ESTROGEN STUDY. SO THIS IS A SUMMARY, AN ATTEMPT TO SUMMARIZE THE RESULTS, YOU CAN SEE THAT FOR HIP FRACTURE ESTROGEN AN ESTROGEN PROYES, SIR TIN, BASICALLY A GREEN AND A DOWN ARROW IS THAT THERE’S LOW STRENGTH EVIDENCE IT SIGNIFICANTLY REDUCES RISK OF FRACTURE AND ZERO IS INSUFFICIENT EVIDENCE OR NO DATA. RED ARROW TO THE SIDE IS THAT THERE’S NO DIFFERENCE AND THERE’S AT LEAST LOW STRENGTH EVIDENCE FOR THAT. AND THEN THE DOWN YELLOW QUESTION MARK IS THERE SOME DATA, LEANING THAT DIRECTION BUT IT’S NOT STATISTICALLY SIGNIFICANT OR IT’S NOT CONSISTENT. SO THE LIMITATIONS, THERE WERE FEW LONG TERM TRIALS, THERE’S ONLY ONE EACH OF SIX AGENTS, ONLY TWO HAD INCIDENT FRACTURE AS PRIMARY OUTCOME. THERE WERE NO DATA ON LONG TERM FRACTURE EFFICACY OF SEQUENTIAL TREATMENTS AND TRIALS HAD LOW POWER FOR INCIDENT HIP FRACTURE. ANOTHER LIMITATION IS TRIALS ARE GENERALLY HEALTHY LARGELY WHITE POST MENOPAUSAL WOMEN, GENERALIZABILITY AND OTHER POPULATIONS UNKNOWN, AS I MENTION THE L,NDRONATE DIDN’T PUBLISH DATA ON NICO MORBIDITIES, THE RALOXIFENE HAD FIVE PERCENT OR FEWER WITH DIABETES CARDIOVASCULAR DISEASE SO IT’S A HEALTHY POPULATION. ANOTHER LIMITATION ANALYSIS OF POSSIBLE EFFECT MODIFIERS MOSTLY POST HOCK. SO FUTURE RESEARCH RECOMMENDATIONS WOULD BE ADDRESS ING THESE IDEALLY THAT THE TRIALS WOULD BE POWERED TO ASSESS CLINICAL FRACTURE ENPOINTS, EVALUATE ADDITIONAL AGENTS INCLUDING SEQUENTIAL THERAPY. THEY INCLUDE MAN NON-WHITES INDIVIDUALS WITH COMORBIDITIES, INCLUDE POPULATIONS AT HIGH RISK BUT MAY NOT MEET DEFINITION FOR OSTEOPOROSIS NOW. AND SPECIFY EFFECT MODIFIERS TO EXAMINE A PRIORI. THEN GIVEN THE DIFFICULTY OF DOING SOME OF THESE TRIALS WITH LARGE OR WITH THE CLINICAL END POINTS ANALYSES ONGOING ANALYSES TO LOOK AT THE POSSIBILITY OF BONE DENSITY CHANGES AND BONE TURN OVER CHANGES ON TREATMENT AS POSSIBLE SURROGATES OR IMPORTANT. THIS IS OUR TEAM AND PEOPLE HELPED WORK ON THIS, THANK YOU. I HAD A MISUNDERSTANDING WHEN QUESTIONS WOULD BE ASKED SO THIS IS JUST MY LAST SLIDE BUT THANKS. [APPLAUSE]>>OKAY. GREAT. THANK YOU. TAKING A SLIGHTLY DIFFERENT TACK, RATHER THAN TALKING ABOUT RANDOMIZE TRIALS I’M GOING TO ANSWER SOME OF THE SAME QUESTIONS BUT BY LOOKING SPECIFICALLY AT MORE FROM OBSERVATIONAL PERSPECTIVE. THESE ARE MY DISCLOSURES I HAVE CONSULTED FOR RADIUS AN MS. DUNAI: SYMPOSIA FOR AMGEN. SKIP SUMMARY IN THE INTEREST OF TIME AND COME BACK TO IT. AT THE END. SO I’M GOING TO TALK ABOUT TWO THINGS. I’M GOING TO TALK ABOUT PRIMARILY OBSERVATIONAL STUDIES THE EFFECT OF LONG TERM CONTINUEDIOUS OF TREATMENT AND THE IMPACT OF DRUG HOLIDAYS, TWO TOPICS BOTH IN TERMS OF EFFECT ON THREE FRACTURE TYPES, HIP, NON-VERTEBRAL AND A TYPICAL FEMUR FRACTURES. I THOUGHT I WOULD TRY TO INCLUDE NEW RESULTS FROM ASBMR IN RECENT PUBLICATIONS TO SUPPLEMENT THINGS THAT HAVE BEEN PRESENTED. IN TERMS OF LONG TERM CONTINUED USE OF MEDICATION, THE CHALLENGE AS YOU JUST HEARD IS THERE ARE NOT MANY RANDOMIZED TRIALS. IDEALLY WE WOULD HAVE LONG TERM 10 TO 15 YEAR RANDOMIZE TRIALS OF ACTIVE VERSUS PLACEBO BUT THAT’S NOT POSSIBLE DUE TO BOTH PRACTICAL AN ETHICAL CONCERNS. THE DATA WE HAVE IS LIMITED THREE TO FOUR YEAR PLACEBO CONTROLLED RCTs FOLLOWED BY NON-RANDOMIZED HE CAN TENSION, TWO FOR DENOSMAB. THAT I EAR NOT CONTROLLED AND THERE ARE SELECTION BIASES IN THOSE WHO CONTINUE. SO THESE ARE AS FAR FROM PERFECT. FOR LENDERNATE THIS IS EXTENSION OF PHASE 3 TRIAL YOU CAN SEE — POINTER HERE. YOU CAN SEE IN THE BEGINNING HERE THIS IS THE RATE THAT WAS SEEN IN THE ELENDERNATE GROUPS IN THE RANDOMIZE PART OF THE TRIAL, THAT COULD BE COMPARED TO THE RATES SEEN FOR NON-VERTEBRAL FRACTURES, FOR THE GROUP IN YEAR 6 TO 10. YOU CAN SEE THEY’RE FAIRLY SIMILAR. THEY CAME UP WITH AN ESTIMATED PLACEBO GROUP HERE YOU CAN SEE BAR IS HIGHER SUGGESTING THAT THE RATE FOR NON-VERTEBRAL WAS LOWER THAN IT PROBABLY WOULD HAVE BEEN BECAUSE PEOPLE WERE OLDER. SUGGESTING CERTAINLY NON-VERTEBRAL FRACTURES REMAINED LOW, MAYBE WERE LOWER THAN THEY WOULD HAVE BEEN. WE CAN ALSO LOOK AT THIS IN THE FIT AND THE FLEX TRIALS, I EXPECTED HOWARD TO TALK ABOUT THESE TRIALS. JUST A BRIEF SUMMARY, FIT WAS A RANDOMIZED TRIAL OF ELENDRENATE YOU LETTER ABOUT, FLEX WAS A RANDOMIZED EXTENSION HALF PEOPLE CONTINUED, HALF DIDN’T. FOR THE PEOPLE WHO GOT, THE RATE IN THE ORIGINAL FIT TRIAL IS 3.5% VERTEBRAL NON-VERTEBRAL FRACTURES ANNUALLY, AND THE RATE OF THE FLEX TRIAL WAS SIMILAR. AGAIN WOMEN IN THE FLEX TRIAL WERE FIVE YEARS OLDER SO YOU EXPECT A MUCH HIGHER RATE, AGAIN SUPPORTING THE IDEA THAT RATES DO REMAIN LOW OVER LONG TERM TREATMENT WITH POSSIBLY LOWER THAN THEY WOULD HAVE BEEN. THESE ARE SOME DATA FOR DENOSMAB. THE BLUE BAARS REPRESENT THE RATES OF NON-VERTEBRAL FRACTURES, AND THEN YOU CAN SEE THE FIRST THREE YEARS IS RANDOMIZE PART AND EXTENSION IS SHOWN. IF ANYONE RATES SEEM A BIT LOWER. AGAIN WORTH KEEPING IN MIND IT’S NOT CONTROLLED AND THAT ONLY ABOUT 36% OF THE RANDOMIZED PATIENTS COMPLETED THE TEN YEAR TRIAL. ON THE RIGHT HAND SIDE YOU SEE THE CUMULATED RATES NON-VERTEBRAL FRACTURE WAS 6.5% OVER THE THREE YEARS, THAT’S OVER THREE YEARS, IN THE FREEDOM TRIAL 9.3% EXTENSION, BUT THAT’S OVER SEVEN YEARS. AND ONCE AGAIN, THEY USED THE VIRTUAL TWIN METHOD ESTIMATE WHAT THE PLACEBO RATE WOULD HAVE BEEN SUGGESTING THAT THE RATE REMAINED LOWER IN THE EXTENSION AS WELL. SO WHAT ABOUT THE THEIR TYPE OF FRACTURE AFS? I WANTED TO GO ON, THIS IS MY CURRENT PASSION SO I APOLOGIZE IF YOU INDULGE ME, LET ME TALK ABOUT THIS A LITTLE BIT. AFS STUDIED IN MANY EPIDEMIOLOGIC STUDIES, BUT THERE ARE SIGNIFICANT LIMITATIONS, IF YOU’RE INTERESTED I WOULD POINT YOU TO A NICE ENDOCRINE REVIEWSES THAT A GROUP OF US JUST COMPLETED AND PUBLISHED, IT’S NICE TALKING ABOUT THIS. IN YOU GAVE 20 HOURS INSTEAD OF 20 MINUTES I WOULD TALK BUT THERE ARE LIMITATIONS AND WE ALL AGREE NOW THE MOST INFORMATIVE STUDY OF AFF ARE POPULATION BASED STUDIES WITH RADIO GRAPHS FOR AFF ASSESSMENT PREFERABLY USING ARCSB CRITERIA, AND THERE ARE ONLY THREE OR FOUR SUCH STUDIES. ONE OF THE STUDY MOST INFLUENTIAL YOU HER ABOUT TODAY IS A STUDY DONE AT KEISER AND SOUTHERN CALIFORNIA WHICH IS A BIG HMO DONE BY RICK DELL OVER A PERIOD OF FOUR YEARS AND THEY FOUND 142 CASES. WHAT YOU CAN SEE IS THAT IF YOU LOOK AT THE DURATION ON THE HORIZONTAL AXIS AND THE RISK WHICH IS THE INCIDENCE PER 100,000 PERSON YEARS, THERE IS INCREASE SEEN PARTICULARLY AFTER ABOUT SIX OR SEVEN YEARS IN THE RISK OF AFF. HOWEVER AS AN EPIDEMIOLOGIST, I REALLY THIS STUDY IS NOT VERY SATISFACTORY, THERE WAS NO CONTROL FOR CONFOUNDING OTHER THAN AGE, THE HIGH RISK OF AFF THAT YOU SEE IN THOUGHT OUTYEAR MAYBE BECAUSE OF PATIENT CHARACTERISTICS, NOT NECESSARILY BECAUSE OF TREATMENT. SO FOR EXAMPLE, DID THOSE WOMEN WHO WERE TREATED FOR A LONGER PERIOD OF TIME HAVE LOW BMD OR FRACTURE HISTORY? SO THOSE ARE IMPORTANT LIMITATIONS. TO GET AROUND THOSE LIMITATIONS AND THE LIMITATIONS OF THE OTHER STUDIES WE DID THIS ONE STUDY WHICH I’M GOING TO TALK ABOUT THAT WAS PRESENTED IN ASBMR. I WOULD LICK TO SAY THIS IS FIRST NEW GENERATION THREE LARGE STUDIES BEING DONE CONCURRENTLY THAT YOU WILL HEAR ABOUT OVER THE NEXT YEAR OR TWO, WE’RE IN THE DOING THEM ALL. SO THIS STUDY BASICALLY WE LOOKED OVER 11 YEARS WE ADJUDICATED TEMPORAL SHAFT USING ASB MARK CRITERIA YIELDING TOTAL OF 306 AFF. VERY IMPORTANTLY THIS STUDY WAS DONE AS A PERSPECTIVE ANALYSIS WITH ADJUSTMENT FOR CO-VARIANTS SO THE HYPOTHESIS WAS ADJUSTMENT WOULD ATTENUATE AFFECTS OF DURATION. AND ACTUALLY JUST GO BACK ONE, THE DATA I’M GOING TO SHOW YOU IS FROM A SUBGROUP OF PATIENTS, ABOUT 200,000 WHO HAD ALMOST ALL THE AFFs, THOSE ARE PATIENT WHOSE HAD AT LEAST ONE PRESCRIPTION OF BUSINESS PHOSPHONATE DURING 11 YEARS OF THE TRIAL. THESE ARE THE AFF DURATION, INCIDENCE PER TEN THOUSAND PERSON YEARS BY BPU CATEGORIES, THIS IS UNADJUSTED, YOU CAN SEE IT SHOWS THE SAME GENERAL EFFECT THAT WAS SHOWN IN THE OTHER STUDY, THAT IS THERE’S INCREASE PRIMARILY AFTER FIVE YEARS WHERE IT DOUBLES THE RISK ABOUT DOUBLES AND EIGHT YEARS IT DOUBLES AGAIN, SO QUITE A DRAMATIC RELATIONSHIP TO DURATION. IT’S INFORMATIVE TO LOOK AT ACTUAL RATES, HERE YOU SEE THE RELATIVE HAZARDS. THIS IS THE RELATIVE RISK, AGAIN UNADJUSTED YOU SEE DOUBLING AFTER FIVE YEARS THEN A DOUBLING AGAIN. WE ADJUSTED FOR AGE, HEIGHT, BMI, ETHNICITY, PRIOR FRACTURE, TIME SINCE LAST BIS PHOSPHATE USE CORTICOID USE, ALL SIGNIFICANT PREDICTORS WE DID FIND THE RISK WAS ATTENUATED BUT A STRONG INCREASE AFTER ABOUT FIVE YEARS. UNLIKE OUR HYPOTHESES, THERE DOES SEEM TO BE SOME RELATIONSHIP BETWEEN LONGER DURATION OF USE INCREASE IN AFF. WE ALSO WERE ABLE IN SUBGROUP TO ADJUST FOR PRE-TREATMENT BONE DENSITY WHICH WE THOUGHT WOULD MAKE A DIFFERENCE BUT THAT MADE NO FURTHER DIFFERENCE. SO TO SUMMARIZE TEN YEARS OF CONTINUOUS OSTEOPOROSIS THERAPY, SUGGEST NON-VERTEBRAL FRACTURE RISK REMAINS LOW AND MAY EVEN CONTINUE TO DECREASE. HOWEVER AFF RISK INCREASES GREATLY WITH LONGER BP DURATION ESPECIALLY BEYOND FIVE TO EIGHT YEARS. LET ME GO ON AND TALK DRUG HOLIDAYS AND WHAT IS THE IMPACT OF DRUG HOLIDAYS ON FRACTURE RISK. PRIMARILY FOCUS ON BIS PHOSPHONATE. I WILL SAY A WORD ABOUT OTHER THERAPIES. TALK ABOUT NON-VERTEBRAL HIP AND AFF. THERE REALLY FOUR SOURCES OF EVIDENCE THAT I WAS AWARE OF FOR THESE. TWO RANDOMIZED TRIALS, THE FLEX TRIAL AND HORIZON TRIAL BOTH OF THESE WERE CONTINUOUS TREATMENT FOR CERTAIN PERIOD OF TIME FOLLOWED BY RANDOMIZED PLACEBO VERSUS CONTINUING. THE FLEX IS FIVE AND FIVE, HORIZON IS THREE AND THREE. THERE ARE TWO OBSERVATIONAL STUDIES, THOSE ARE VERY NEW. KEISER SOUTHERN CALIFORNIA DATA WAS A STUDY THAT WAS PUBLISHED IN JBMR, IN SPRING. MEDICARE DATA WAS PRESENTED BY KEN SAG AND JEFF CURTIS AT ASBMR MEETING LAST MONTH. A QUICK SUMMARY OF THE RESULTS FOR NON-VERTEBRAL FRACTURE SHOWN HERE, IT’S A LITTLE FOREST PLOT SHOWING FLEX TRIAL THE HORIZON TRIAL AND THEN KEISER TRIAL, ALL SHOWED THAT ON A DRUG HOLIDAY THERE WAS NO INCREASE IN THE RISK OF NON-VERTEBRAL FRACTURES. AND THIS CONTINUED AGAIN FOR THREE TO FIVE YEARS, HOLIDAY. IN THESE STUDIES. THE KEISER STUDY IS NOT SPECIFICALLY RANDOMIZED TO DRUG HOLIDAY, JUST PEOPLE WITH DISCONTINUED BIS PHOSPHONATE THERAPY. IN TERMS OF HIP FRACTURES, AGAIN, THE LENDRENATE TRIAL AND THE KEISER TRIAL SHOWED NO INCREASE IN HIP FRACTURE RISK AFTER DISCONTINUATION OF BIS PHOSPHONATE. THE MEDICARE DATA SHOWS A SMALL INCREASE, ABOUT 25%, INCREASE IN HIP FRACTURE, UP TO FOUR YEARS OF HOLIDAY. SO IT’S A LITTLE BIT DISCREPANT SO ONE — MY CONCLUSION HERE IS WE NEED MORE DATA TO DEFINITIVELY DETERMINE WHAT’S GOING ON HERE IN TERMS OF HIP FRACTURES. SO IN TERMS OF AFFs WHAT HAPPENS AFTER YOU STOP BIS PHOSPHONATE? THERE’S TWO SOURCES OF DATA HERE. THERE WAS A SWEDISH STUDY PUBLISHED IN 2014, THAT SHOWED A FAIRLY DRAMATIC DECLINE IN THE RISK OF AFF AFTER STOPPING, ABOUT 70% DECREASE IN THE FIRST YEAR, 90% DECREASE IN YEARS ONE TO FOUR AND THAT SEEMS SORT OF PLAUSIBLE — IMPLAUSIBLE BUT WE LOOKED IN THE KEISER STUDY I TALKED ABOUT BEFORE PRESENTING AT ASBMR AND SHOWED SOMETHING ALMOST AS LARGE, ABOUT 44% DECREASE IN AFF RISK IN THE FIRST YEAR, ABOUT 80% DECREASE UP TO FOUR YEARS. OF A DRUG AFTER DRUG DISCONTINUATION. SO USEFUL DATA LENDS IMPORTANT INFORMATION TOWARDS SUPPORTING THE USEFULNESS OF A DRUG HOLIDAY. TO SUM RIDES THE EFFECT — SUMMARIZE FOR NON-VERTEBRAL FRACTURES THERE’S NO RISK INCREASE ON BIS PHOSPHATE HOLIDAY AS FAR AS WE KNOW. FOR HIP FRACTURES THERE WAS NO OR VERY SMALL RISK INCREASE ON HOLIDAY, WE NEED MORE DATA HERE. THEN FORAFT THE TWO STUDY AVAILABLE SUGGEST WE HAVE LARGE DECREASE IN RISK, WITHIN THE FIRST YEAR OF A DRUG MOLL HOLIDAY. SO WHAT I WOULD LIKE TO DO IS SPEND JUST A MINUTE TRYING TO MAKE SENSE OF ALL THESE RESULTS AND WHAT SHOULD THEY LEAD US TO IN TERMS OF HOW WE DEAL WITH THIS DATA CLINICALLY, THESE ARE SOME DATA LOOKING AT DIFFERENT RISK GROUPS, I WILL SHOW YOU HERE, THESE ARE THE WOMEN IN THE KYESER STUDY OVER 85 YEARS OF AGE, THE ORANGE BAR SHOWS HIP FRACTURE RISK AND THE WHITE BAR WHICH IS SMALL, THE BLUE BAR VERY SMALL SHOWS AFF RISK. YOU CAN SEE THAT THE AFF RISK IS VERY SMALL COMPARED TO THE RISK OF HIP FRACTURE. SUGGESTING THAT IF WE WERE TO CALCULATE WHICH WE WILL DO IN THE FUTURE, RISK VERSUS BENEFIT WOULD BE FAVORABLE IN THIS OVER 85 POPULATION. HOWEVER IF YOU LOOK AT THE YOUNGER WOMEN, THE WOMEN 50 TO 64 THE RATIO IS ONLY ABOUT ONE TO TEN. SO MUCH LESS FAVORABLE. THAT SUGGESTS THAT GIVEN THAT WE KNOW THAT RISK WILL INCREASE GREATLY AFTER FIVE YEARS, THE YOUNGER WOMEN MIGHT BE A GOOD CANDIDATE FOR DRUG HOLIDAYS. ANOTHER RISK GROUP THAT WE LOOKED AT IN THIS STUDY WORRIESK GROUPS DEFINED BY RACE, YOU SEE CAUCASIANS ON THE RIGHT, AGAIN IN A FAVORABLE BENEFIT OF A IF,F TO HIP FRACTURE RISK. WHEREAS THE ASIANS HAVE A MUCH HIGHER RISK OF AFF, SHOWN BY SEVERAL STUDIES, AT THE SAME TIME HAVE A MUCH LOWER RISK OF HIP FRACTURES. SO IN THE ASIAN POPULATION, AGAIN, THE AFF TO HIP FRACTURE RATIO IS NOT NEARLY AS FAVORABLE, AGAIN SUGGESTING THEY MIGHT BE BETTER CANDIDATES FOR A DRUG HOLIDAY. SO THAT KIND OF BRINGS ME TO THE CONCEPTION HERE WHAT I WILL LIKE TO PROPOWS THAT WE AS A FIELD TRY TO DEVELOP A MORE SOPHISTICATED ASSESSMENT FOR WHO SHOULD HAVE A DRUG HOLIDAY THAT TAKES INTO ACCOUNT RISK OF AFF AS WELL AS RISK OF OSTEOPOROTIC FRACTURE. SO IF WE’RE GOING TO EVALUATE WOMEN AFTER FIVE YEARS OF BIS PHOSPHATE THERAPY, SAY YOU HAVE A POPULATION WHO WE MIGHT KNOW IN THE FUTURE HIGH RISK OF AFF BUT LOW RISK OF OSTEOPOROTIC FRACTURES, THOSE MIGHT BE WOMEN WHO WOULD BE MUCH MORE PRE-DISPOSED BENEFIT BY A DRUG HOLIDAY WHEREAS THOSE WHO HAVE LOW AFF RISK BUT HIGHER RISK OF OSTEOPOROTIC FRACTURES MIGHT BE A GROUP WHO COULD CONTINUE TAKING BIS PHOSPHONATE. WE LOOKED AT THREE RISK FACTORS, I TOLD YOU AGE AND RACE, AN BONE DENSITY, SAW SOMETHING SIMILAR. LINE OF REASONING WOULD BE FEMORAL GEOMETRY, THERE’S DATA OUT OF KOREA AND JAPAN SUGGESTING MORE FEMURS AND THE HIP ANGLE ALSO MAYBE PRE-DISPOSING FACTOR, MAY EXPLAIN THIS HIGHER RISK IN ASIA. ALSO THERE’S A LOT OF PROMISE FINDING GENETIC FACTORS THAT MIGHT EXPLAIN THIS, EVENTUALLY MIGHT COMPILE A LONG LIST OF RISK FACTORS WE CAN DEVELOP A FRAX SCORE FOR AFF AND USE THAT TO BALANCE AGAINST RISK OF OTHER FRACTURES. JUST TO SAY A WORD ABOUT DRUG HOLIDAYS FOR NON-BIS PHOSPHONATE THERAPIES FOR ANABOLIC THERAPIES DENOXMAB, THE ANSWER IS DRUG HOLIDAYS DON’T APPLY, THE BENEFITS ARE QUICKLY LOST AFTER DISCONTINUATION FOR ALL THESE. DRUG HOLIDAYS ARE NOT APPROPRIATE AND THESE THERAPIES SHOULD BE FOLLOWED BY SOME KIND OF ANTI-RESORPTIVE OR POSSIBLY BIS PHOSPHONATE. I THINK I HAVE FOUR MINCE LEFT BECAUSE I STARTED COUPLE OF MINUTES LATE. I’M ALMOST DONE. I WILL FINISH IN TWO MINUTES. HERE IS MY SUMMARY. LONG TERM THERAPY NON-VERTEBRAL HIP AND ATYPICAL FEMUR FRACTURES RISK OVER TEN YEARS OF CONTINUOUS THERAPY NON-VERBAL FRACTURE RISK REMAINS LOW MAY CONTINUE TO DECREASE, AFF RISK INCREASES WITH LONGER DURATION OF ORAL BIS PHOSPHONATE. DURING DRUG BISES IF FOENATE HOLE THEYS NON-VERTEBRAL FRACTURE THERE’S NO INCREASE IN RISK FOR THREE TO FIVE YEARS. HIP FRACTURE LIKELY KNOW INCREASE IN RISK OR NOT A LARGE INCREASE, THERE IS UNCERTAINTY, WE NEED MORE DATA HERE. FOR AFF THE TWO STUDIES AVAILABLE SO FAR SUGGEST A LARGE DECREASE STARTING IN YEAR ONE AT THE HOLIDAY. THEN IN THE FUTURE I HOPE WE WILL DEVELOP RISK BENEFIT ANALYSES TO GIVE INDIVIDUALIZED APPROACH THAT TAKES INTO ACCOUNT AFF RISK IN DECIDING ON DRUG HOLIDAYS. IN TERMS OF RESEARCH RECOMMENDATIONS IN TERMS OF BES PHOSPHONATE HOLIDAYS, AGAIN I’M STRONGLY IN FAVOR OF DEVELOPING ALGORITHMS TO PREDICT RISK. THAT NEEDS TO BE DONE. I THINK WE NEED TO DETERMINE THE OPTIMAL LENGTH OF THE BIS PHOSPHONATE HOLIDAY. THAT’S SOMETHING I THINK WE’LL TALK ABOUT TOMORROW. MY POINT OF VIEW, KEEP IT SIMPLE AND PERHAPS ONE FIXED DRUG HOLIDAY MIGHT BE SIMPLER THAN TRYING TO CALIBRATE THEM, I THINK IS A LITTLE BIT CHALLENGING. A VERY IMPORTANTLY WE NEED MORE DATA ON HIP AN NON-VERTEBRAL FRACTURE, ON BISES IF FOENATE HOLIDAYS AND SOMETHING WE KNOW NOTHING ABOUT RISKS AN BENEFITS TO RESTARTING BIS PHOSPHONATE AFTER BIS PHOSPHONATE HOLIDAY. THESE ARE IMPORTANT RESEARCH NEEDS. LASTLY, IN TERMS OF AFF RISK, AGAIN, AFF RISK FACTORS AN RISK PREDICTION, WE HAVE SOME DATA FROM THIS INITIAL STUDY, TWO OTHER STUDIES ARE IN PROGRESS BUT WE NEED A LOT MORE DATA THERE. WE NEED TO UNDERSTAND THE PATHOGENESIS OF AFF BETTER. THERE’S A ROLE FOR HIP GEOMETRY, POSSIBLY GENETICS, POSSIBLY OTHER FACTORS AS WELL. SIMILARLY FOR ASIANS WHY DO THEY SEEM TO BE FOUR TO FIVE TIMES HIGHER RISK EVEN AFTER ADJUSTMENT. THEN LASTLY, I THINK THIS WAS MENTIONED BUT WE KNOW THERE’S A RELATIONSHIP BETWEEN DENOSMAB AN ZELENDRENATE IN TERMS OF A FORF BUT DON’T KNOW IF IT’S IN TERMS OF SIMILAR MAGNITUDE WHICH ORAL BIS PHOSPHONATE. PRIMARILY WHAT I HAVE BEEN TALK ABOUT SO A VERY IMPORTANT THING THAT SHOULD BE MORE RESEARCHED MORE COMPLETELY. WITH THAT I WOULD LIKE TO THANK YOU VERY MUCH. [APPLAUSE]>>MY NAME IS REBECCA JACKSON, FROM THE OHIO STATE UNIVERSITY. I’M A LITTLE SHORT, THE LIFT BROKEN. SO MANY OF YOU CAN JUST WATCH THE SLIDES RATHER THAN TRYING TO LOOK DOWN HERE AT RELATIVELY SHORT ME I’M GOING TO TALK TODAY ABOUT MENOPAUSAL HORMONE THERAPY SELECTIVE ESTROGEN RECEPTOR MODULATORS AN TISSUE SELECTIVE COMPLEXES AND THE RISK AND BENEFITS OF THOSE THERAPIES FOR THE MANAGEMENT FOR THE PREVENTION AND TREATMENT OF POST MENOPAUSAL OSTEOPOROSIS. I HAVE DISCLOSURES TO REPORT TODAY. AND TO REVIEW SUMMARY OF FINDINGS AND THEN THE DATA THAT ARE GOING TO SUPPORT THESE, FIRST IS THAT POST MENOPAUSAL HORMONE THERAPY IS EFFECTIVE AT PREVENTING BONE LOSS AN DECREASING RISK FOR FRACTURES. HOWEVER, THE BALANCE OF RISK AN BENEFITS ARE SUCH THAT IT SHOULDN’T BE USED FOR THE PRIMARY PREVENTION OF OSTEOPOROSIS IN OLDSER WOMEN. SECOND, FOR YOUNGER WOMEN USING HORMONE THERAPY FOR THE MANAGEMENT OF MENOPAUSAL SYMPTOMS, POST MENOPAUSAL HORMONE THERAPY DOES APPEAR TO REDUCE RISK OF BONE LOSS AN SUBSEQUENTLY TO DECREASE RISK OF FRACTURES. TRANSDERMAL LOW DOSE ESTROGEN REDUCE BONE LOSS BUT DATA TO DATE ARE INCONCLUSIVE REGARDING THERE’S MORE BENEFICIAL BALANCE OF RISK AND BENEFIT FOR THESE DOSES OR REGIMENS OF THERAPY, AND LASTLY, RELOX PHONE IS EFFECTIVE AT PREVENTING BONE LOSS REDUCING RISK FOR VERTEBRAL FRACTURE BUT EVIDENCE REGARDING NON-VERTEBRAL FRACTURE REDUCTION IS STILL LACKING. LET’S PUT THIS BACK INTO PERSPECTIVE FOR ALL OF YOU. AS YOU PROBABLY ARE AWARE OVER THE PAST 20 TO 30 YEARS THE AVERAGE AGE OF MENOPAUSE IS CONSTANT ABOUT 51 YEARS OF AGE. WHAT HAS CHANGED IS LENGTH OF LIFE EXPECTANCY FOR WOMEN. SO AT THIS TIME POST MENOPAUSAL WOMEN REACHING AGE 50 IS EXPECTED TO SPEND ONE-THIRD OF HER LIFE SPAN IN A PERIOD OF TIME WITH SIGNIFICANTLY REDUCED ESTROGEN LEVELS. WHEN YOU BRING THAT INNER PLAY OF AGING ASSOCIATED WITH THE ESTROGEN EFFICIENCY ASSOCIATED WITH MENOPAUSE, WE SEE AN INCREASE RISK OF A NUMBER OF DISEASES THAT COULD BE MODULATED BY THESE CONCURRENT CHANGES INCLUDING GYNECOLOGIC CHANGES, POST MENOPAUSAL BASAL MOTOR SYMPTOMS OSTEOPOROSIS, ATHEROSCLEROTIC DISEASE AND COGNITIVE IMPAIRMENT IN THE DEVELOPMENT OF DEMENTIA. ALMOST 40 YEARS AGO — I’M SORRY, ALMOST IN THE 1940s ASSOCIATES BETWEEN DECLINE OF ESTROGEN AT MENOPAUSE AND DEVELOPMENT OF OSTEOPOROSIS WAS FIRST NOTED BY FULLER AL BRIGHT WHEN HE COINED THE PHRASE POST MENOPAUSAL OSTEOPOROSIS. SUBSEQUENTLY THERE’S BEEN MANY STUDIES THAT DEMONSTRATE ACCENTUATED BONE LOSS IN PERIMENOPAUSAL YEARS AN PROCEED INTO AGING. CONCURRENT WITH THIS DECREASE IN ESTROGEN LEVELS IS INCREASE IN THE RISK OF FRACTURES. FIRST BEING SEEN WITH THAT INCREASE IN THE RISK OF VERTEBRAL AND RISK FRACTURES, AND THEN 10 TO 15 YEARS LATER INCREASE IN RISK O HIP FRACTURES. THOSE FRACTURES ASSOCIATE WITH GREATEST MORE MORBIDITY MORTALITY AND LOSS OF QUALITY OF LIFE. AS A RESULT OF THE DATA SUGGESTING THAT THERE WAS A CONTRIBUTORY FACTOR OF ESTROGEN DEFICIENCY ASSOCIATED WITH THE DEVELOPMENT OF OSTEOPOROSIS, THERE’S BEEN A GREAT DEAL OF INTEREST WHETHER POST MENOPAUSAL HORMONE THERAPY REPLACEMENT MIGHT BE AN IMPORTANT THERAPEUTIC MODULATION FOR THE REDUCTION OF THIS DISEASE. BUT TO UNDERSTAND THIS MORE FULLY WE NEED TO PUT THIS INTO A PRECISION MEDICINE INITIATIVE. SO HOW DO WE APPLY THE SCIENTIFIC EVIDENCE TO OSTEOPOROSIS CARE TO DETERMINE THE RIGHT TREATMENT FOR THE RIGHT WOMAN AT THE RIGHT TIME? WHAT’S THE APPROPRIATE TIMING FOR THE INITIATION OF HORMONE THERAPY? DOES IT HAVE SAME RISKS AND BENEFITS ACROSS THE ENTIRE LIFE SPAN? ARE THERE OTHER FORMS OF HORMONE THERAPY DURATION OR REGIMENS THAT MIGHT BE MORE EFFECTIVE OR GIVE MORE VALUABLE RISK TO BENEFIT RATIO? OVER THE LAST 20 YEARS WE HAVE SEEN STUDIES OF ESTROGEN THERAPY CONSISTENTLY SHOWN THAT’S STROW GENERAL ARE AN ANTI-RESORPTIVE AGENT ACTUALLY SLOWING RATES OF BONE REMODELING OR TURN OVER AN RESTORING THAT BALANCE BETWEEN BONE RESORPTION HERE SHOWN BY CTL PEPTIDE AN BONE FORMATION AS DEPICTED BY BONE SPECIFIC ALKALINE PHOSPHATASE. FURTHERMORE, WHEN ESTROGEN THERAPY IS GIVEN TO POST MENOPAUSAL WOMEN ORALLY OR TRANSDERMALLY AS SEEN IN THIS SLIDE, IT PREVENTS ADDITIONAL BONE LOSS AS DETERMINED BY DEXA FINDINGS NOT ONLY AT THE SPINE BUT IN FACT AT THE HIP TOTAL BODY AN RADIAL SITES AS WELL. SO RESTORING THE BALANCE OF THESE INTERMEDIATE BIOMARKERS OF THERAPEUTIC EFFICACY, REDUCTION IN THE RATES OF BONE REMODELING, PREVENTION OF THE RATES OF BONE LOSS ARE CERTAINLY IMPORTANT BUT WHAT MATTERS TO US IS CLINICIANS AND WHAT MATTERS TO OUR PATIENTS IS WHETHER OR NOT POST MENOPAUSAL HORMONE THERAPY IS IN FACT EFFECTIVE AT REDUCING THE RISK OF PATIENT CENTERED OUTCOME. WHICH IS THE CLINICAL FRACTURE. SO THE WHI WAS REALLY DESIGNED TO ACTUALLY ADDRESS THIS ANSWER. THIS IS A CLINICAL TRIAL OF 27,000 POST MENOPAUSAL WOMEN AGE 50-69 YEARS, AVERAGE AGE 63,AGE LENGTH OF TIME SINCE MEN PAUSE TRANSITION 13 YEARS THAT WANTED TO ADDRESS THE BENEFITS AS WELL AS THE RISKS OF POST MENOPAUSAL HORMONE THERAPY. AS YOU CAN SEE IN THIS SLIDE, ESTROGEN THERAPY WITH OR WITHOUT PROYES, SIR TIN WAS ASSOCIATED WITH A SIGNIFICANT REDUCTION IN HIP FRACTURES, CLINICAL VERTEBRAL FRACTURES AND IN FACT TOTAL FRACTURES ALMOST EQUALLY WITH BOTH FORMS OF THERAPY. THIS BENEFIT WAS SEEN WITHIN THE FIRST 12 TO 24 MONTHS INITIATION OF THERAPY AND WAS MAINTAINED THROUGHOUT THE THERAPY. SIMILARLY, RESULTS WERE RECENTLY PRESENTED IN THE U.S. PREVENTATIVE TASK FORCE DATA WHICH SHOWS SIMILAR TYPES OF REDUCTIONS OF ABOUT 44 FRACTURES PER TEN THOUSAND WOMEN YEAR REDUCTION WITH ESTROGEN PLUS PROYES, SIR TIN, THE ESTROGEN ALONE DATA WAS DOMINATED BY THE WHI DATA SO REALLY DOESN’T SHOW SIGNIFICANT CHANGES. THE NEXT QUESTION THAT WAS DETERMINED WHO IS HORMONE THERAPY EFFECTIVE FOR? IN LOOKING AT THIS, WE ACTUALLY LOOKED AT INDIVIDUALS BY FRACTURE RISK SCORE BECAUSE AS YOU KNOW IN WHI WE DIDN’T SELECT INDIVIDUALS AT HIGH RISK FOR FRACTURE WE TOOK INDIVIDUALS IN THE NORMAL COMMUNITY AN VARYING GROUPS. SO SUBGROU ANALYSES SHOW HORMONE THERAPY IS EFFECTIVE AT REDUCING RISK OF FRACTURES BOTH HIP FRACTURES AND TOTAL FRACTURES AND INDIVIDUALS AT HIGH RISK FOR FRACTURES BUT IT WAS EQUALLY EFFECTIVE AT REDUCING FRACTURES IN THOSE INDIVIDUALS AT LOWER RISK. THESE DATA ACTUALLY SUPPORT THAT THE BENEFIT OF MENOPAUSAL THERAPY IS USEFUL AS A PREVENTIVE STRATEGY, PRIMARY PREVENTIVE STRATEGY FOR OSTEOPOROTIC FRACTURE IN POST MENOPAUSAL WOMEN. DESPITE THESE UNEQUIVOCAL RESULTS THAT SHOW A BENEFIT OF HORMONE THERAPY IN TERMS OF REDUCTION OF FRACTURE RISK AND MAINTENANCE OF BONE RISK IT’S WELL KNOWN THE ESTROGEN RECEPTOR IS EXPRESSED ON MULTIPLE TISSUES AND THEREFORE IT’S IMPORTANT TO UNDERSTAND THE RISKS AND BENEFITS OF THIS ALMOST UBIQUITOUS THERAPY. OUR UP UNTIL WHI WE HAD RELATIVELY LIMITED DATA PRIMARILY LOOKING AT INTERMEDIATE VARIABLES OR SOME SMALL STUDIES THAT SUGGEST OUTCOME DATA. SO THE WHI WAS REALLY DESIGNED AGAIN TO RIGOROUSLY EXAMINE THE RISKS AND BENEFITS OF POST MENOPAUSAL HORMONE THERAPY ON THE ABSOLUTE PREDICTED OUTCOME. AS YOU CAN SEE IN THIS SUBSEQUENT ANALYSIS, THIS IS ANALYSIS OVER THE COURSE OF THE ENTIRE WHI TRIALS, IN ANALYSIS PUBLISHED THE LAST TWO YEARS. HORMONE THERAPY ESTROGEN WITH OR WITHOUT PROGESTIN WAS ASSOCIATED WITH A CONSISTENT BENEFIT IN REDUCING THE RISK OF HIP AND TOTAL FRACTURE AS WELL AS UNFORTUNATELY A CONSISTENT RISK OF 33% INCREASE RISK FOR STROKE. IN ADDITION ESTROGEN PLUS PROGESTERONE WAS ASSOCIATED WITH NON-SIGNIFICANT INCREASE IN KERNARY HEART DISEASE, 24% INCREASE IN RISK OF BREAST CANCER, AND INCREASE IN PULMONARY EMBOLIST AND VENUS THROMBOLIC DISEASE AN DEMENTIA IN WOMEN OVER AGE 65. FOR ESTROGEN ALONE, THIS BALANCE OF RISK AND BENEFITS IS MORE BALANCE WHERE WE DID NOT FIND ANY INCREASE IN RISK OF CORONARY HEART DISEASE AND NO INCREASE IN THE RISK OF INVASIVE BREAST CANCER. AS A RESULT OF THE BODY OF EVIDENCE THAT CAME FROM THE WHI, IN THE MID 2000s, MANY WOMEN DISCONTINUED ESTROGEN THERAPY. AND ALTHOUGH SOME EARLY OBSERVATIONAL STUDIES SUGGESTED THAT THERE MAYBE AN INCREASE IN THE RISK OF FRACTURES ASSOCIATED WITH THIS DISCONTINUATION, SUBSEQUENT STUDIESS FROM THE WHI PUBLISHED IN THE LAST YEAR AND A HALF SHOWED NO DIFFERENCE IN RISK OF HIP OR TOTAL FRACTURE AFTER DISCONTINUATION. MOST OTHER RISKS AN BENEFITS HOWEVER AFTER DISCONTINUATION OF HORMONE THERAPY GRADUALLY WANED EXCEPT FOR BREAST CANCER WHICH IS MAINTAINED IN INDIVIDUALS WHO ARE EXPOSED TO THE INCREASE RISK WITH ESTROGEN PLUS PROYES, SIR TIN THERAPY. SO IN SUMMARY, THOUGH ESTROGEN IS AN EFFECTIVE DRUG FOR MANAGEMENT OF POST MENOPAUSAL OSTEOPOROSIS, THE OVERALL BALANCE OF RISK AN BENEFITS OF THERAPY DO NOT SUPPORT ITS USE FOR THE PRIMARY MANAGEMENT OF POST MENOPAUSAL OSTEOPOROSIS IN OLDER POST MENOPAUSAL WOMEN. SO ALTHOUGH WHI CERTAINLY GAVE US A GREAT AMOUNT OF UNDERSTANDING, IN THE ROLE OF MENOPAUSAL HORMONE THERAPY, IT DIDN’T ANSWER THE QUESTION THAT MANY PHYSICIANS AND WOMEN WANTED WHICH IS ESTROGEN IS OFTEN PRESCRIBED FOR MANAGEMENT OF MENOPAUSAL SYMPTOMS. IS THERE A DIFFERENTIAL RESPONSE TO MORE MOAN THERAPY, WHEN GIVEN EARLY IN TIME OF MENOPAUSE OR GIVEN IN WOMEN AT SOMEWHAT YOUNGER AGE. SO SEEN IN THIS SLIDE WHAT YOU CAN SEE IS IN WOMEN WHO HAD A HYSTERECTOMY WHO RECEIVED CONJUGATE E POINT IN WHI THERE WAS NO INCREASE IN CARDIO VAS CHEW LAR EVENTS IN YOUNGER WOMEN RELATIVE TO OLDER WOMEN WHERE YOU SEE A SLIGHTLY INCREASED TREND TOWARDS CARDIOVASCULAR DISEASE. IN 2013 WE EXTEND THOSE ANALYSES FURTHER BY LOOKING AT ESTROGEN PROYES, SIR TIN TRIALS LOOKING AT COMPOSITE CARDIOVASCULAR OUTCOMES WITH ESTROGEN PLUS PROYES, SIR TIN THERAPY WE SAW INTERACTION WHEN YOU LOOK AT YEARS POST MENOPAUSE AND RISK FOR MYOCARDIAL INFARCTION AND REVASCULARIZATION PROCEDURES. THE ESTROGEN ALONE TRIAL WHERE THE RISK WAS SOMEWHAT LOWER, THERE WAS SIGNIFICANT INTERACTION BETWEEN ADVANCING AGE AND THE RISK FOR CARDIOVASCULAR EVENTS. TO EXTEND THESE FINDINGS FURTHER THREE ADDITION AL STUDIES ARE WORTH HIGHLIGHTING IN THE FIRST OF THESE IS STUDY BY HODES AND ASSOCIATES WHICH STRATIFY MORE THAN 600 WOMEN INTO INDIVIDUALS WHO WERE LESS THAN SIX YEARS POST MENOPAUSE OR GREATER THAN TEN YEARS POST MENOPAUSE AND THEN RANDOMIZE THEM TO AN ORAL ESTROGEN BE VAGINAL PROYES, SIR TIN VERSUS PLACEBO. AND STUDY CAROTID THICKNESS. WHAT YOU CAN SEE IS IN THE YOUNGER INDIVIDUALS THAT THERE APPEAR TO SEE SOME BENEFIT IN TERMS OF A DECREASE IN CIMT RELATIVE TO THE OLDER INDIVIDUALS. THE KEEP STUDY WAS A STUDY THAT RANDOMIZED WOMEN WITHIN THE FIRST THREE YEARS OF MENOPAUSE TO EITHER A LOWER DOSE OF CONJUGATED EQUINE ESTROGEN OR TRANSDERMAL ESTROGEN THERAPY VERSUS PLACEBO, THAT SHOW NO INCREASE IN CORONARY EVENTS, CIMT, OR PROGRESSION OF SCORES DURING THE THREE YEAR PERIOD OF TIME. FINALLY, THE DOCK STUDY, THE DANISH OSTEOPOROSIS PREVENTION STUDY WHICH IS AN OPEN LABEL ESTROGEN STUDY SHOWED THAT WOMEN WHO TOOK THIS FOR MORE THAN EIGHT YEARS HAD A SIGNIFICANTLY LOWER RATE OF CARDIOVASCULAR MORTALITY ASSOCIATED WITH THERAPY. WHAT ABOUT RISK FOR BREAST CANCER, WHICH IS ANOTHER CONCERN WITH ESTROGEN PLUS PROYES, SIR TIN THERAPY? LIKE WHI THE MILLION WOMEN STUDY CONFIRMED THE FINDINGS THAT THE RISK OF REST CANCER IS HIGHER AMONG USERS OF ESTROGEN PLUS PROYES, SIR TIN RELATIVE TO estrogen alone but extended findings to suggest that in terms of this timing hypothesis this the earlier one starts hormone therapy, that the greater the risk associated with breast cancer incidence and we are talking about invasive breast cancer. THEN FINALLY IN SUMMARY, WHEN YOU LOOK AT THE OVERALL BALANCE OF THE REISES AN BENEFITS OF CONJUGATED EQUINE ESTROGEN AN ESTROGEN PLUS PROYES, SIR TIN AND LOOK AT THAT RELATIVE TO AGE THE IMPORTANT FINDING IS EVEN THOUGH THERE IS SOME RISK IN YOUNGER WOMEN LOW MAGNITUDE LOW PREVALENCE IS SUCH THAT IT APPEARS FOR SHORT TERM USE OF MENOPAUSAL SYMPTOMS THERE WILL BE BOTH BENEFIT IN TERMS OF REDUCTION IN OSTEOPOROTIC FRACTURE RISK AND PREVENTION OF BONE LOSS AS WELL AS MANAGEMENT OF MENOPAUSAL SYMPTOMS. SO IN SUMMARY, FOR WOMEN WHO ARE IN THEIR EARLY MENOPAUSAL THERAPY, EXCUSE ME. MENOPAUSAL PERIOD, THE BENEFITSs STROW GIN PLUS PROYES, SIR TIN IS MORE FAVORABLE THAN OTHER WOMEN THOUGH VENUS THROMBOLIC DISEASE IN STROKE PERSIST FOR WOMEN WHO HAVE UNDERGONE HYSTERECTOMY TAKING ESTROGEN ALONE, THE BALANCE IS MORE FAVORABLE AND BASED UPON SUCH EVIDENCE IN WOMEN WHO REQUIRE MENOPAUSAL HORMONE THERAPY FOR THE MANAGEMENT OF SEVERE MENOPAUSAL SYMPTOMS, HORMONE THERAPY DOES PROVIDE PREVENTION BONE LOSS REDUCTION OF RISK FRACTIONS AND SO ADDITIONAL TREATMENT FOR THE MANAGEMENT OF THEIR OSTEOPOROSIS IS PROBABLY NOT NECESSARY. SO WHAT ABOUT DOSING? THERE’S A LOT OF INTEREST WHETHER THERE’S A DOSE RESPONSE AN CAN WE GET DOSE OF ESTROGEN LOW ENOUGH TO MAINTAIN THE BENEFIT FOR OSTEOPOROSIS REDUCE THE RISK OF SOME OF THE NEGATIVE EFFECTS. SO LARGE BODY OF DATA SHOWING LOW DOSE ESTROGEN ARE EQUALLY EFFECTIVE AT PREVENTING BONE LOSS AN MORE RECENTLY ULTRA LOW DOSE ESTROGENS 17 BETA ESTRADIOL, REDUCES BIOCHEMICAL MARKERS, BONE TURN OVER TO A DEGREE THAT’S SIMILAR TO THAT SEEN WITH HIGHER DOSES, SUGGESTING A BONE BENEFIT. TRANSDERMAL ESTROGEN ALSO HAS SIMILAR BENEFITS TO ORAL ESTROGEN. HOWEVER, BY AVOIDING THE FIRST PASS METABOLISM BY THE LIVER, THERE IS POTENTIAL THAT IT HAS A LOWER RISK IN TERMS OF VENUS THROMBOLIC DISEASE AND STROKE AND THEREFORE MORE FAVORABLE RISK TO BENEFIT RATIO. WHEN ONE LOOKS AT THIS IN A LITTLE BIT MORE DETAIL BECAUSE OF THE LOWER DOSE HT AN TRANSDERMAL ESTROGEN WAS ASSOCIATED WITH LOWER THROMBOTIC RISK THERE WAS A HYPOTHESIS THAT THIS WOULD BE ASSOCIATED WITH A LOWER RISK OF ISCHEMIC STROKE. WHAT IS A LARGE FRENCH MEDICATION DATABASE THAT WAS RECENTLY PUBLISHED THEY WERE ABLE TO SHOW THAT ORAL ESTROGEN SIGNIFICANTLY INCREASE RISK IN A DOSE DEPENDENT RELATIONSHIP OR LOWER THE DOSE OF ESTROGEN THE LOWER RISK OF STROKE AND THAT TRANSDERMAL ESTROGEN DISPLAYED NO INCREASE RISK OF STROKE SO THE FIRST OUTCOME DATA SUGGESTING THAT LOWER DOSE ESTROGEN AND TRANSDERMAL ESTROGEN MAY HAVE A MORE FAVORABLE RISK TO BENEFIT RATIO. SO IN SUMMARY, THOUGH BOTH LOW DOSE AN TRANSDERMAL HORMONE THERAPY PREVENT BONE LOSS AND HAVE A FAVORABLE EFFECT UPON INTERMEDIATE BIOMARKERS, FOR EXAMPLE LIPID PROFILE AND OTHERS THERE’S NO DEFINITIVE DATA OTHER THAN THE STROKE DATA I PRESENTED THAT THERE’S A GREATER BENEFIT TO RISK RATIO IN TERMS OF EFFECT ON FRACTURES, BREAST CANCER RISK, DEMENTIA OR CORONARY HEART DISEASE. FINALLY, THERE’S BEEN A GREAT DEAL OF INTEREST IN HARNESSING THIS POTENTIAL BENEFIT OF HORMONE THERAPY FOR OSTEOPOROSIS MANAGEMENT AND MENOPAUSAL SYMPTOMS. SO ADVANCES IN OUR UNDERSTANDING OF ESTROGEN RECEPTOR AN WAYS TO MODULATE THIS HAVE RESULTED IN THO POUTIC CLASSIFY CASES OF DRUGS — THERAPEUTIC CLASSIFICATIONS OF DRUGS THAT OPTIMIZE RECEPTOR ACTIVITY, THOSE SELECTIVE ESTROGEN RECEPTOR MODULATORS AND THE TISSUE SELECTIVE ESTROGEN COMPLEXES. THE FIRST WE’RE GOING TO DISCUSS IS RALOXIFENE, THE ONLY ESTROGEN RECEPTOR MODULATOR THAT INDEPENDENTLY IS APPROVED FOR MANAGEMENT OF POST MENOPAUSAL OSTEOPOROSIS AS BY SEVERAL SPEAKERS TODAY, THE PIVOTAL MOORE TRIAL DEMONSTRATED SIGNIFICANT REDUCTION IN VERTEBRAL FRACTURES BOTH INDIVIDUALS AND HIGH RISK FOR OSTEOPOROSIS IS DEFINED BY HAVING ONE OR MORE PRIOR VERTEBRAL FRACTURES AS WELL AS IN THOSE INDIVIDUALS SIGNIFICANTLY LOWER RISK. THE CORE STUDY OR THE CORE TRIAL WHICH IS THE CONTINUING OUTCOMES RELATIVE TO EVISTA TRIAL FURTHER EXTENDED OUR KNOWLEDGE ABOUT THE RISKS AND BENEFIT RATIO OF RALOXIFENE. SO OVER EIGHT YEARS THE BENEFIT IN TERMS OF VERTEBRAL FRACTURE REDUCTION AND PREVENTION OF BONE LOSS WAS MAINTAINED BUT THERE WAS NO REDUCTION IN NON-VERTEBRAL FRACTURES AS YOU CAN SEE IN HAZARDS RATIO, THAT DOESN’T CROSS ONE, THERE’S NO INCREASE IN CARDIOVASCULAR BENEFITS BUT BREAST CANCER RATES DID SIGNIFICANTLY DECLINE. UNFORTUNATELY VENUS THROMBOLIC DISEASE CONTINUE TO BE MAINTAINED. SO FINALLY, ONE HYPOTHESIZE COULD YOU USE BENEFITS TO ANTAGONIZE THE ESTROGEN AT THE UTERUS WHILE ADDING THE ESTROGEN TO GET ADDITIONAL BENEFITSES THAT MIGHT BE PRESENT? THAT COMBINATION OF BRING IT TOGETHER A SELECTIVE ESTROGEN RECEPTOR MODULATOR TOGETHER WITH AN ESTROGEN IS WHAT A TISSUE SELECTIVE ESTROGEN COMPLEX IS. THE ONLY ONE THAT IS CURRENTLY FDA APPROVED IS THE BASO DOCKS FEEBLE, A THYROGEN RATION ESTROGEN RECEPTOR MODULATOR WITH EQUINE ESTROGEN WHICH HAS UNIQUE TISSUE ACTIVITY IN A NUMBER OF DIFFERENT TISSUES. SOME OF THE SMART TRIALS WHAT WE SEE IS WE SEE A SIGNIFICANT IMPROVEMENT IN VASOMOTOR SYMPTOMS, A STABILIZATION TO SMALL IMPROVEMENTS IN BONE MINERAL DENSITY, AN IMPROVEMENT IN LIPID PROFILES BUT TO DATE WE HAVE ABSOLUTELY NO DATA SUPPORTING PATIENT-CENTERED OUTCOME OF FRACTURE, STROKE AN DEMENTIA. SO WHAT ARE THE RECOMMENDATIONS, WHERE ARE GAPS IN OUR KNOWLEDGE TODAY? I THINK THE FIRST OF THIS IS THAT WE REALLY HAVE RELATIVELY LITTLE DATA AN UNDERSTANDING THE BALANCE OF RISKS AN BENEFITS OF HORMONE THERAPY WITH WOMEN WITH PRE-MATURE MENOPAUSE. HOW LONG DO WE TREAT THEM AND WHAT KINDS OF DOSES SHOULD WE TRANSITION AT THE AGE OF 50 OR DO WE CONTINUE TO USE IT LONGER THAN THAT BECAUSE THEY ACT MUCH MORE TAKING ESTROGEN DURING THE MENOPAUSE TRANSITION. SECOND IS THAT ALTHOUGH TRANSDERMAL HORMONE THERAPY LOW DOSE HORMONE THERAPY SHOW PROMISE THAT MAINTAIN BONE MASS, AND SOME REDUCTION POTENTIALLY IN THE RISK FOR STROKE, ARE THEY EFFICACIOUS REDUCING FRACTURES? DO THEY REALLY HAVE A SUPERIOR RISK TO BENEFIT RATIO WHEN CONSIDERING THESE PATIENT CENTERED OUTCOMES INCLUDING AT RISK OF DEMENTIA. THIRD, IS THERE A BENEFIT OF OTHER ESTROGEN LIKE COMPOUNDS IN THE PREVENTION TREATMENT OF OSTEOPOROSIS, BIOIDENTICAL HORMONES, SOMETHING WE’RE NOT GOING TO TALK ABOUT BUT CERTAINLY A LOT OF WOMEN ARE ASKING QUESTIONS ABOUT, SOME MORE SELECTIVE ESTROGEN RECEPTOR MODULATORS OR OTHER TISSUE SELECTIVE ESTROGEN COMPLEXES IN COMBINATIONS GIVE YOU A MORE FAVORABLE BENEFIT TO RISK RATIO AND THEN LASTLY, IN THAT PRECISION PERSONALIZED MEDICINE APPROACH, CAN WE IDENTIFY BIOMARKERS, CLINICAL RISK FACTORS, OR OTHER PREDICTORS THAT WILL ACTUALLY MODULATE THE RISK OF HORMONE THERAPY TO PROVIDE A MORE INDIVIDUALIZED APPROACH TO INFORM REGARDING HORMONE THERAPY AN SELECTIVE ESTROGEN RECEPTOR MODULATORS. THANK YOU VERY MUCH FOR LISTENING TO ME TODAY. I’M SORRY I’M SO LOW. AS EVERYBODY KNOWS AS WE FINISH EVERY TALK. GO BUCKS. [APPLAUSE]>>WELL, THANK YOU FOR INVITING ME TO SPEAK HERE TODAY. MY NAME IS FELICIA COSMAN, I’M AN ENDOCRINOLOGIST FROM COLUMBIA UNIVERSITY. I DO HAVE SEVERAL RELATIONSHIPS WITH THE PHARMACEUTICAL INDUSTRY INCLUDING AMJEN ELY LILLY MERCK RADIUS. WHAT I’M GOING TO TRY TO DO TODAY IS DEFINE THE HIGHEST RISK PATIENTS, WE HAVE HEARD ABOUT HIGH RISK, I’M GOING TO DECLINE THE HIGHEST RISK I THINK. AND TALK A LITTLE BIT ABOUT THE RATIONALE FOR USING ANABOLIC THERAPY AS INITIAL THERAPY IN THESE HIGHEST RISK PATIENTS. CONCENTRATING ON A FEW OBSERVATIONS, LOOKING ACROSS DIFFERENT PIVOTAL TRIALS, AND FOCUSING ON FRACTURE TRIALS THAT COMPARE ANABOLIC AND ANTI-RESORPTIVE THERAPIES. WE’LL TALK ABOUT OPTIMAL AND SUBOPTIMAL TREATMENT SEQUENCES AND THE LIMITED TREATMENT ROLE FOR COMBINATION THERAPY. SO WE KNOW THAT PRIOR FRACTURE IS THE MOST IMPORTANT RISK FACTOR FOR ANOTHER FRACTURE, WE HAVE TALKED ABOUT THIS MANY TIMES. BUT THE KEY POINT OF THIS LARGE DATABASE STUDY 377,000 PLUS WOMEN WITH FIRST FRACTURE, IS TO SUGGEST THAT THESE ARE THE PEOPLE WHO REALLY HAVE AN OSTEOPOROSIS EMERGENCY. BECAUSE THE EMINENT RISK IN THE NEXT TWO YEARS OF ANOTHER FRACTURE IS SO EXCEEDINGLY HIGH IN THIS GROUP OF PATIENTS, SO IF YOU LOOK AT THE PURPLE BARS YOU LOOK — THE ABSOLUTE RISK OF RECURRENT FRACTURE IS 10% IN THE FIRST YEAR AN 18% IN THE FIRST TWO YEARS. THEN THE RISK STARTS TO FALL OFF ABOUT FOUR 1/2 PERCENT PER YEAR OVER THE ENSUING THREE YEARS. CUMULATIVE RISK OVER FIVE YEARS IS 31%. THERE ARE SIMILAR TRENDS IF YOU LOOK JUST AT HIP FRACTURE AS THE RECURRENT FRACTURE TWO 1/2% RISK IN THE VERY NEXT YEAR, FIVE PERCENT RISK IN THE NEXT TWO YEARS THEN FALSE OFF A BIT. THESE ARE THE PEOPLE WHO INDEED ARE AT REALLY, REALLY HIGH RISK FOR MORE FRACTURES. IT’S ALSO TRUE WHEN YOU LOOK AT RADIOGRAPHIC VERTEBRAL FRACTURES. IF YOU FOCUS ON THE PURPLE BAR THESE ARE THE — THIS IS THE RISK THE ONE YEAR RADIOGRAPHIC VERTEBRAL FRACTURE INCIDENT RISK IN PEOPLE WHO HAVE A PREVALENT VERTEBRAL FRACTURE OF UNKNOWN TIMING. THAT’S ABOUT FIVE PERCENT AND FIVE FOLD HIGHER PEOPLE WHO DID NOT HAVE PREVALENT VERTEBRAL FRACTURE. LOOK AT THOSE WHO WERE DIAGNOSED WITH A RECENT VERTEBRAL FRACTURE WITHIN THE PROCEEDING YEAR, THE RISK OF ANOTHER RADIOGRAPHIC VERTEBRAL FRACTURE IN THESE PEOPLE IS ABOUT 20%. A RECENT FRACTURE IS MUCH BIGGER PREDICTOR OF FUTURE RISK THAN THE PREVALENT FRACTURE. NOW, IT’S ALSO KEY, AND I I’M DISMAYED BY THE FACT THAT WE HAVE BEEN HERE FOR ABOUT SIX HOURS, WE HAVE TALKED A LOT ABOUT BONE DENSITY TESTING AND THERE HASN’T BEEN A SINGLE MENTION OF USING VERTEBRAL IMAGING TO FIND VERTEBRAL FRACTURES. AND THESE DATA COME FROM N HAYNES STUDY THAT WAS PUBLISHED LAST YEAR USING VERY STRICT CRITERIA FROM HARRY AND LOOKING AT A POPULATION BASED 3,000 PLUS INDIVIDUALS. WE SEE THAT PRESENCE OF VERTEBRAL FRACTURES AT 5% IN PEOPLE BEFORE 60, ABOUT 10% IN THE 70s, 20% IN THE 80s. FEWER THAN 10% PEOPLE IN THIS STUDY HAD A KNOWN HISTORY OF VERTEBRAL FRACTURE. SO THE ONLY WAY WE’RE GOING TO FIND FRACTURES IS IF WE GO OUT AND LOOK FOR THEM USING TARGETED SPINE IMAGING CRITERIA. AND THE NATIONAL OSTEOPOROSIS FOUNDATION, THE INTERNATIONAL OSTEOPOROSIS FOUNDATION, ACE AND ISCD ALL HAVE SUBMITTED CRITERIA THAT ARE CONSISTENT WITH EACH OHER. TO FIND THESE FRACTURES BECAUSE THESE ARE THE PEOPLE WHO NEED TO BE TREATED. MULTIPLE FRACTURES IF NOT RECENT SUGGEST HIGH RISK. AND PEOPLE WITH VERY LOW BONE MASS ESPECIALLY YOUNG PEOPLE WITHOUT RISK FRACK CHUS MAY NOT HAVE A HIGH RISK BUT VERY HIGH REMAINING LIFETIME FRACTUR RISK AND THESE ARE ALSO IN THE HIGH RISK CATEGORY AND WE SHOULD CONSIDER ANABOLIC THERAPY BUT PERHAPS FOR DIFFERENT REASONS. SO NOW ONCE IDENTIFIED VERY HIGH RISK PATIENTS WHAT ABOUT ANTI-RESORPTIVE THERAPY FOR THEM? LOOKING AT THE TWO MOST POTENT THERAPIES (INAUDIBLE) ACID FROM THE — FREEDOM TRIAL YOU SEE IN FACT THERE IS NO SIGNIFICANT REDUCTION IN RISK OF NON-VERTEBRAL FRACTURE BEFORE THREE YEARS, AND AT BEST AT THE END OF THREE YEARS, YOU HAVE RISK REDUCTIONS FOR NON-VERTEBRAL FRACTURES 20 TO 25%. IN CONTRAST, IF YOU LOOK AT THE TWO ANABOLIC THERAPIESES THAT ARE CURRENTLY AVAILABLE AND ANOTHER THERAPY THAT’S IN DEVELOPMENT YOU SEE OVER A MUCH SHORTER PERIOD OF TIME WE SEE REDUCTIONS IN VERTEBRAL FRACTURES BUT NON-VERTEBRAL FRACTURES. FOR — OVER 18 MONTHS AND ROAMSOSAMAB A STRONG TREND TO REDUCE NON-VERTEBRAL FRACTURE WITHIN ONE YEAR. OF COURSE WE HAVE TO BE CAUTIOUS WHEN COMPARE ACROSS PIVOTAL TRIALS, DIFFERENT PATIENT CHARACTERISTICS, RISK OF THE POPULATION, DIFFERENT DEFINITION OF FRACTURE, SO FORTH. SO THE BEST STUDIES TO LOOK AT ARE THE ONES THAT ARE HEAD TO HEAD OF COURSE. THERE WERE TWO OLDER STUDIES WHERE FRACTURE OUTCOMES WERE ASSESSED BUT THEY WERE NOT PRIMARY ENPOINT. ONE WAS THE GLUE DOE CORTICOID TRIAL WHERE TERPERTIDE WAS COMPARED WITH LENDRENATE AND ACUTELY PAINFUL VERTEBRAL FRACTURES WHERE IT WAS COMPARED WITH RESE DLENADE AND THEY BOTH SHOWED SIGNIFICANTLY LOWER RISK OF VERTEBRAL FRACTURE WITH TERPERTIDE COMPARED TO THE BIS PHOSPHONATE. BUT THE BEST DATA COME FROM THE TWO TRIALS WHERE FRACTURE OUTCOMES WERE THE PRIMARY END POINTS, FIRST IS THE VERO TRIAL. THIS STUDY ENROLLED 1360 POST MENOPAUSAL WOMEN WHO HAD SEVERE OSTEOPOROSIS, PREVALENT FRACTURE WHICH IS AT LEAST TWO MODERATE FRACTURES OR ONE SEVERE VERTEBRAL FRACTURE AS WELL AS LOW BONE MASS AT SPINE HIP OR TEMPORAL NECK RANDOMIZED TO RECEIVE TERPERT ISHDE OR — AND THE DATA SHOW WITHIN ONE YEAR ABOUT A 50% REDUCTION IN OCCURRENCE OF VERTEBRAL FRACTIONTURES WITH TERP YOU KNOWRTIDE COMPARED TO RESIDRENATE IN RED AND OVER TWO YEARS 56% REDUCTION IN OCCURRENCE OF NEW VERTEBRAL FRACTURES WITH — COMPARED TO THE ACTIVE ARM. WE ALSO SEE THE TERPERTIDE REDUCES NON-VERTEBRAL FRACTURES WITHIN ABOUT SIX MONTHS COMPARED TO RESEDRENATE OVER TWO YEAR PERIOD OF TIME, A STRONG TREND P VALUE IS .1. IF YOU LOOK AT NON-VERTEBRAL FRACTURE COUNT WHAT RATHER THAN SUBJECT INCIDENCE OF NON-VERTEBRAL FRACTURE, SINCE THERE WERE MANY PEOPLE IN THE RESIDRENATE GROUP WITH MULTIPLE FRACTURES THE TOTAL NUMBER WAS SIGNIFICANTLY REDUCED WITH TERPERTIDE COMPARED WITH RESEDRINAT SO SUPPORTIVE OF THE TREND THAT BESEE FOR SUBJECT INCIDENCE OF NON-VET FRACTURE. ONE OTHER POINT IS THERE WERE NUMBER OF PLAN SUBGROUPS ASSESSED IN THIS STUDY, AND NONE SHOWED SIGNIFICANT TREATMENT BY SUBGROUP INTERACTION, I CALL YOUR ATTENTION TO THE CATEGORY OF RECENT BICS PHOSPHONATE NEWS BECAUSE THE WAY THEY DEFINE THIS I THINK WAS OVERLY LIBERAL. IT WAS A TOTAL CUMULATIVE USE OF SIX MONTHS ORRILL BIS PHOSPHONATE OVER THREE YEAR PERIOD OF TIME PROCEEDING ENROLLMENT IN THE TRIAL AN I DON’T THINK THAT REALLY QUALIFIES AS WHAT MOST OF US WOULD CONSIDER TO BE RECENT USE. THE SECOND HEAD TO HEAD STUDY IS THE ARCH TRIAL COMPARED ONE YEAR OF ROAMASOSAMAB FOLLOWED BY TWO YEARS OR MORE OF OPEN LABEL ELENDRENATE IN BOTH GROUPS, ENROLLED 4,093 SUBJECTS, SEVERE PATIENTS WITH EITHER A PREVALENT MODERATE OR SEVERE VERTEBRAL FRACTURE OR AT LEAST TWO MILD FRACTURES OR RECENT HIP FRACTURE WITHIN THE TWO YEARS PRIOR TO ENTRY INTO THE TRIAL. THE DATA HERE ALSO SHOW THAT ROMASOSOMAB REDUCE THERYK OF VERTEBRAL FRACTURE IN THE FIRST YEAR AN REDUCED THE RISK OVER TWO YEAR PERIOD OF TIME, BY ABOUT 50% COMPARED TO THE ELENDRENATE ARM. SIMILARLY THERE’S A REDUCTION IN OCCURRENCE OF BOTH NON-VERTEBRAL FRACTURE AND HIP FRACTURE IN THE ROAMSOSAM AAB GROUP COMPARED TO ELENDRENATE GROUP. FOR THOSE PATIENTS AT HIGH IMMINENT RISK OF FRACTURE, THE DATA CLEARLY SHOW THAT ANABOLIC AGENTS REDUCE FRACTURES FASTER AND TO A GREATER EXTENT THAN ANTI-RESORPTIVE AGENTS AND SHOULD BE CONSIDERED AS FIRST LINE FOR THESE PATIENTS. BUT A KEY POINT IS WHETHER THE ANTI-FRACTURE EFFECTS ARE SUSTAINED AFTER TRANSITION TO ANTI-RESORPTIVE THERAPY. IF YOU SEE IT JUST DURING THE FIRST YEAR OR TWO YEARS, AND THEY’RE NOT SUSTAINED THEN MAYBE YOU’RE NOT GAINING THAT MUCH. AND FOR THIS QUESTION DRAW YOUR ATTENTION TO THE ACTIVE AND ACTIVE EXTEND TRIAL IN THIS STUDY, PLACEBO WAS COMPARED WITH — TERPERTIDE FOR 18 MONTHS AND PLACEBO IN GROUPS TRANSITION TO ELINDRANATE FOR TWO YEARS OUT OF THE TOTAL THREE AND A HALF YEAR TRIAL. THE DATA SHOW ON THE LEFT SET OF BAARS THE RESULTS FOR NEW VERTEBRAL FRACTURE DURING THE INITIAL TRIAL. SHOWING AN 86% RELATIVE RISK REDUCTION FOR COMPARED TO PLACEBO FOR VERTEBRAL FRACTURE AND IF YOU LOOK JUST AT EXTENSION PERIOD NOW, SO THE PATIENTS ARE NOW ON ELENDRENATE ALL OF THEM AND ONLY DIFFERENCE IS ABERPERTIDE GROUP RECEIVED ONE AND A HALF YEARS COMPARED TO PLACEBO, YOU SEE THERE IS A SIMILAR RELATIVE RISK REDUCTION OVER THE ENTIRE PERIOD OF THE EXTENSION STUDY. THIS IS ALSO TRUE FOR THE NON-VERTEBRAL FRACTURE INCIDENCE, WHERE THERE IS A REDUCTION OF SOME 40 TO 50% IN THE FIRST 18 MONTHS AND THAT RISK REDUCTION IS MAINTAINED OVER THE ENTIRE TIME PATIENTS ARE ON ELENDRINATE IN THE EXTENSION STUDY. SO IT’S CLEAR THE ANTI-FRACTURE EFFECTS ARE FASTER AND GREATER& IN OUR SUSTAINED AFTER TRANSITION TO ANTI-RESORPTIVE THERAPY. NOW, WHAT ABOUT BMD BUILDING? WE KNOW NOW BONE DENSITY ESPECIALLY IN THE HIP IS MAJOR PREDICATOR OF FUTURE RISK OF FRACTURE IN PEOPLE ALREADY TREATED. WE HAVE KNOWN FOR A LONG TIME IT’S A MAJOR PREDICTOR OF FRACTURE IN UNTREATED PATIENTS AS WELL BUT THESE DATA OPT LEFT ARE FROM THE — ON THE LEFT FROM THE DENNIS FLEX TRIAL SHOWING THE BONE DENSITY ATTAINED AFTER FIVE YEARS PREDICTS YOUR RISK OF FRACTURE OVER THE ENSUING FIVE YEARS ON PLACEBO. AND THE SAME WAS SEEN IN THE EXTENSION STUDY WITH ZODIDRONIC ACID, THE T SCORE IN THE HIP AFTER THREE YEARS OF ZOLIDRONIC ACID A PREDICTOR OF SUBSEQUENT RISK OF FRACTURE WHILE ON PLACEBO OVER THE NEXT THREE YEARS AND ALSO TRUE WITH DENOSMAB IN THE FREEDOM AND FREEDOM EXTENSION STUDIES WHERE THE TOTAL HIP T SCORE THAT YOU ACHIEVE PREDICTS YOUR RISK OF SUBSEQUENT NON-VERTEBRAL FRACTURE. WE PRESENTED DATA AT ASBMR LAST MONTH TO SHOW THAT THIS WAS ALSO TRUE FROM THE AHRQ STUDY WHERE THE 12 MONTH TOTAL HIP T SCORE ACHIEVED ONE YEAR WAS A PREDICTOR OF SUBSEQUENT RISK OF NON-VERTEBRAL FRACTURE AND THIS WAS TRUE FOR BOTH SUBJECTS ON ROMASOSAMAB AS WELL AS ON ELENDRANATE FROM THE AHRQ STUDY, SO CLEARLY THE IDEA OF BUILDING BMD TO THE GREATEST EXTENT PARTICULARLY IN THE HIP SHOULD BE ONE OF THE GOALS FOR PEOPLE WHO ARE AT HIGHEST RISK FOR FRACTURE. TOWARD THIS END TREATMENT SEQUENCE MATTERS AND YOU GET THE BEST BMD GAIN IN THE HIP PARTICULARLY WHEN YOU USE ANABOLIC FIRST LINE FOLLOWED BY ANTI-RESORPTIVE SECOND LINE. THESE DATA ARE TOTAL HIP BMD RESULTS FROM ACTIVE AND ACTIVE EXTENSION STUDY SHOWING ABOUT A 7% GAIN WITH A YEAR AND A HALF OF — FOLLOWED BY TWO YEARS OF ELANDRANATE. IN CONTRAST WHEN YOU USE TER,APERTIDE SECOND LINE AFTER PHOSPHATE OR DENOSMAB YOU SEE CONSISTENT DECLINE IN HIP BMD FOR THE FIRST 12 TO 18 MONTHS. WE REVIEWED THAT LAST YEAR IN JBMR LOOKING AT COHORTS OF PEOPLE ON ELENDRANATE OR DENOSMAB AND SWITCHING THEN TO TERPERTIDE. THE SIX MONTH CHANGE AND 12 MONTH CHANGE IN TOTAL HIP BMD WAS UNIFORMLY NEGATIVE IN ALL OF THESE STUDIES. BY 18 MONTHS IT STARTS TO TURN AROUND, FOR THE BIS PHOSPHONATE COHORTS, BUT NOT FOR THE DENOSMAB COHORT. ONE STRATEGY THAT WE CAME UP WITH A NUMBER OF YEARS AGO, TO TRY TO DEAL WITH THIS DISAPPOINTING HIP BMD OUTCOME, IS TO COMPARE A STRATEGY OF ADDING TERPERTIDE TO ONGOING ELANDRONATE IN PINK VERSUS THE GROUP THAT SWITCHED FROM ELENDRANATE TO TERPERTIDE, IN YELLOW YOU SEE RANDOMIZED STUDY YOU SEE DEFINE IN BMD IN THE SWITCH GROUP AT SIX MONTHS AND THE INCREASE IN THE ED GROUP AND DIFFERENCE IS STILL SIGNIFICANT OVER 18 MONTHS WITH COMBINATION GROUP DOING BETTER THAN THE SWITCH GROUP. SO THE WAY I THINK WE CAN INTERPRET THIS CLINICALLY, IS FIRST FOR PEOPLE WITH REMOTE EXPOSURE TO BICSS IF — BISES IF PHENATE, THE EFFECT YOU GET IS PROBABLY SIMILAR TO WHAT YOU SEE IN TREATMENT NAIVE INDIVIDUALS BUT ONE QUESTION IS WHEN DOES RECENT EXPOSURE BECOME REMOTE, I WILL SUGGEST PROBABLY TWO YEARS FROM THE EXPOSURE WOULD QUALIFY AS REMOTE, MAYBE ONE YEAR, WE DON’T KNOW. BUT FOR PEOPLE WHO ARE CURRENTLY ON BIS PHOSPHONATE. FOR THOSE WHO HAVE INCIDENCE SPINE FRACTURE OR VERY LOW SPINE BMD BUT THE HIP BMD IS OKAY, IT MAY BE FINE THE SWITCH TO TERPERTIDE. BUT FOR THOSE PATIENT ON BIS PHOSPHONATE WHO HAVE INCIDENT HIP FRACTURE OR ANY FRACTURE AND HAVE LOW HIP BMD, I THINK THE STRATEGY OF SWITCHING TO A PTH RECEPTOR AGONIST MIGHT NOT BE THE BEST PLAN AN INSTEAD WE SHALL CONSIDER ADDING WHILE CONTINUING THE ANTI-RESORPTIVE THERAPY. WHAT ABOUT ROAMSUSIMAB? THERE WAS A STUDY BY LENDEL AN COLLEAGUES WHERE A GROUP OF WOMEN, 400 WOMEN WERE SWITCHED TO TERPERTIDE IN BLUE OR ROMAS OOSAMAB IN GREEN AND TESTIMONY CHARACTERISTIC DECLINE IN BMD IS SEEN FOR THE FIRST YEAR, AND THOSE WHO SWITCH TO TERPERTIDE BUT FOR WOMEN WHO WERE RANDOMIZED TO ROMASOSAMAB THERE WAS INCREASE IN HIP BMD, SIGNIFICANT INCREASE IN SIX AND IS THE MONTHS, CERTAINLY MORE FAVORABLE RESPONSE AN THIS WAS BACKED UP BY QCT DATA, VOLUME METRIC BMD OF THE HIP AS WELL AS FINITE ELEMENT MODELS. OF THE PCT FINDINGS. OUR BIGGEST PROBLEM REALLY WHAT HAPPENS WITH DENOSMAB IN PATIENTS WHO MIGHT REQUIRE ANABOLIC THERAPY, THESE DATA COME FROM DAN LEADER AN COLLEAGUES AND THE DATA TRIAL. IN YOU COMPARE THE RED LINE, FOCUS ON TOTAL HIP THAT’S MOSTLY WHAT WE HAVE BEEN LOOKING AT HERE ON THE RIGHT SIDE, PEOPLE GET IT FOR TWO YEARS AND THEN SWITCH TO TERPERTIDE FOR TWO YEARS, HAVE A PRECIPITOUS DECLINE IN BMD OF THE HIP AND THIS IS A MUCH BIGGER DECLINE THAN WHAT I SHOWED YOU FOR THE BIS PHOSPHONATE SWITCH COHORTS, IN FACT AT THE END OF TWO YEARS, THERE’S STILL NOT A BMD THAT GETS TO THE BASELINE POST DENOSMAB BASELINE, COMPARE THAT TOO THE SEQUENCE IN BLUE WERE PATIENTS RECEIVE TERPERTIDE FIRST FOR TWO YEARS FOLLOWED BY DENOSMAB WHERE ENDING HIP BMD LEVEL AT END OF FOUR YEARS IS TWICE THAT. WHAT WE SEE WITH THESE SEQUENCE OF DENOSMAB FIRST. THE GREEN LINE ON THIS GRAPH LOOKS AT THE COMBINATION DE NOVOOF DENOSMAB AND TERPERNTIDE AND THEIR HIP — IS THE GREATEST AND FOUR YEARS SLIGHTLY GREATER THAN WHAT YOU SEE WITH THE TERPERTIDE FOLLOWED BY DENOSM ABB SEQUENCE. THIS FINDING IN FACT IS TOTALLY CONSISTENT WITH EVERY SINGLE COMBINATION THERAPY STUDY, SOME OF WHICH I HAVE DONE AND SOME WHICH HAVE BEEN DONE BY MY COLLEAGUES. THAT’S ALWAYS BETTER TO DO TERPERTIDE AND ANTI-RESORPTIVE AS DE NOVO FOR HIP BMD OUTCOME REALISTICALLY IF FRACTURE DATA ARE SO GOOD WITH ANABOLIC THERAPY ALONE FOR THE FIRST 18 MONTHS OR 12 MONTHS, IT’S SUCH A CHALLENGE TO GET PEOPLE ON THERAPY ONE THERAPY I THINK WE SHOULD PROBABLY FOCUS MORE ON JUST THE BEST SEQUENCE RATHER THAN DE NOVO COMBINATIONS. SO WHAT IS THE STRATEGY JOY FOR PEOPLE WHO NEED ANABOLIC THERAPY, WE HAVE NO DATA LOOKING AT THE SPECIFIC GROUP. I THINK BY VIRTUE OF ALLERGY WITH WHAT I SHOWED YOU WITH BIS PHOSPHONATES IN THESE PATIENTS AND DEKNOW SLOW COMBINATION OF TERPERDIDE THAT WE CAN CONSIDER ADDING THEM IN CONTINUING DENOSMAB, THAT’S ONE APPROACH. WHAT ABOUT ROMASOSAMAB AFTER DENOSMAB? I HEAR IF YOU JUST FOCUS THIS AS A COMPLICATED GRAPH BUT FOCUS ON THE RIGHT SIDE THIS IS FROM PHASE 2 STUDY, WHERE YOU SEE THE PATIENTS RECEIVED DENOSMAB FOR A YEAR IN THE PINK AND THEN RECEIVED ROMASOSMAB AND BONE DENSITY GOES UP NICELY IN THE SPINE DURING THAT ROMASOSAMAB YEAR. NOW IF YOU LOOK IF THE TOTAL HIP AFTER DENOSMAB IN PINK WITH ROMASOSAMAB THERE’S NOT INCREASE IN HIP BMD, BUT AT LEAST THERE IS NO PRECIPITOUS DECLINE WITH WE GAIN BMD IN THIS CASE. WHILE- THERE ARE SAFETY CONSIDERATIONS FOR ANABOLIC AGENTS AS SHOWN HERE. SO WHAT ARE THE KEY RECOMMENDATIONS FOR USE OF ANABOLIC THERAPY? I THINK THE OPTIMAL TREATMENT FOR THE HIGHEST RISK PATIENTS, THOSE WITH RECENT FRACTURES, CLINICAL AND RADIOGRAPHIC FRACTURES AS WELL AS THOSE WITH MULTIPLE FRACTURES AND THOSE WHO START WITH VERY LOW BMD WITH OR WITHOUT RISK FACTORS, OPTIMAL TREATMENT IS TO BEGIN WITH ANABOLIC AND TRANSITION TO POTENT ANTI-RESORPTIVE. THIS WILL PROVIDE THE FASTEST LARGEST ANTI-FRACTURE EFFECTS AND THE BEST SEQUENCE TO ATTAIN THE GREATEST BMD, PARTICULARLY IN THE HIP. FOR PATIENT WHOSE ARE CURRENTLY ON DENOSMAB OR BIS PHOSPHONATE WHO REQUIRE AN BOT UK AGENT CONSIDER RATHER THAN SWITCHING TO PTH RECEPTOR AGONIST PARTICULARLY IN INCIDENT OF HIP FRACTURE OR LOW HIP BMD, MORE DATA TO CONFIRM VALIDITY AN ROMASOSMAB MIGHT BE AN OPTION IN SOME PATIENTS FOR MONOTHERAPY. THANK YOU VERY MUCH FOR YOUR ATTENTION. [APPLAUSE] THIS IS PART TWO OF THE INFORMATION FROM OUR EVIDENCE REPORT, PART TWO IS GOING TO BE FOCUSING ON HARMS AN LONG TERM OSTEOPOROSIS DRUG THERAPY AN EFFECT MODIFIERS OF THOSE TREATMENT HARMS. MY DISCLAIMERS ARE UNCHANGED FROM HOUR AND A HALF AGO. I HAVE NONE. THE GOALS OF THE SYSTEMATIC REVIEW AGAIN TO REVIEW EVIDENCE ON BENEFITS AND HARMS OF LONG TERM OSTEOPOROSIS DRUG THERAPY AND DRUG HOLIDAYS AND FACTORS THAT MODIFY THESE FOR THIS PART. THIS IS KEY QUESTION 2B LOOKING AT HARMS AND POSSIBLE EFFECT MODIFIERS OF HARMS. LIKE BEFORE SAME POPULATION MEN AN POST MENOPAUSAL WOMEN AGE 50 OR GREATER WITH OSTEOPOROSIS OR OSTEOPENIA BEING IN THE TRIAL DATA BEING TREATED FOR FRACTURE PREVENTION WE ALSO LOOKED AT OBSERVATIONAL DATA FOR INFORMATION ON HARMS. SO LISTENING TERM TREATMENT BEFORE DEFINED HERE AS MORE THAN THREE YEARS OF TREATMENT WE LOOKED WHETHER THE HARMS OF TREATMENT VARIED BY PATIENT OSTEOPOROSIS DRUG CHARACTERISTICS. THE BACKGROUND AS YOU HAVE HEARD IN DETAIL, SOME DRUGS ASSOCIATED WITH SIDE EFFECTS, VERY BRIEFLY BICSS PHOSPHONATE IS WITH REGARD ATYPICAL TEMPORAL FRACTURE, STENOSIS OF THE JAW, RELOX FENIAN HORMONE THERAPY INCREASES THROMBO SIN AND STROKE, NOT COMPREHENSIVE BUT THE UNDERSTAND OF FACTORS THAT MODIFY THE LIKELIHOOD OF HARMS WITH LONG TERM DRUG PERIPYEMA INFORM TREATMENT DECISIONS WHICH IS MOTIVATION FOR LOOKING AT POSSIBLE EFFECT MODIFIERS. THE METHODS ARE MOSTLY THE SAME, I’LL HIGHLIGHT THE DIFFERENCES. LOOKING AT HARMS THE POPULATION WE LOOKED A IF THE SAME POPULATION PEOPLE TREATED TO PREVENT FRACTURE, PEOPLE WITH OSTEOPOROSIS OR OSTEOPENIA TREATED TO PREVENT FRACTURE. FOR RARE HARMS WE EXPANDED THE POPULATION TO INCLUDE ANYBODY REGARDLESS OF OSTEOPOROSIS STATUS KNOWING THAT MANY OF THE OBSERVATIONAL STUDIES WOULD NOT PROVIDE INFORMATION ON THE INITIAL INDICATION FOR THE PATIENT TREATMENT. WE HAD THE SAME EXCLUSION SECONDARY OSTEOPOROSIS METASTATIC CANCER AN BONE HEELING. FOR STUDY DESIGNS WE LOOK AT RCTs AND CONTROL CLINICAL TRIALS BUT WE ALSO FOR HARMS LOOK AT CONTROLLED OBSERVATIONAL STUDIES. SO THEY HAD CONTROL GROUP FOR MOST HARMS, INCLUDE AT LEAST A THOUSAND PARTICIPANTS BUT RARE HARMS LIKE AFF AND OMJ WE INCLUDED STUDIES THAT WERE SMALL AS 100 PARTICIPANTS. FOR THIS PRESENTATION NOT TALKING SIDE EFFECTS LIKE GI, WE’RE FOCUSING MORE ON THE HARMS SEEM TO BE GREATEST INTEREST FOR THIS WORKSHOP ATYPICAL FEMORAL FRACTURE. THEN SUBFEMORAL SHAFT FRACTURE WHERE STUDIES DID NOT CONFIRM FRACTURES HAD RADIOGRAPHIC AFF FEATURES. OSTEONECROSIS OF THE JAW AND SERIOUS ADVERSE EVENTS. POTENTIAL AFFECT MODIFIERS ARE SAME AS BEFORE, PATIENT BONE OSTEOPOROSIS DRUG CHARACTERISTICS. SO TALK IS ORGANIZED BY DRUG AND THEN WITHIN THAT BY THE HARMS. THE SLIDES ARE LAID OUT SIMILAR LY SO LEFT COLUMN SO THE TITLE GIVES YOU THE DRUG OF INTEREST, LEFT COLUMN IS THE CONTROL GROUP. CONTROL TREATMENT GROUP, YEARS FOLLOW-UP DURATION THEN STUDY DESIGN INDICATING WHETHER IT’S A TRIAL OR OBSERVATIONAL STUDY. RC IS RETROSPECTIVE COHORT, THERE’S OTHER STUDIES ON WHOOPS. THAT WERE CASE CONTROL LABELED CC, DESCRIBES POPULATION HAZARD RATIO OR WHATEVER ESTIMATE RISK IS. THE ABSOLUTE RISK REDUCTION AND STRENGTH OF EVIDENCE. WE DIDN’T FIND ANY ELIGIBLE STUDIES THAT YOU ARE THE REPORTED ON EVIDENCE OF CONFIRMED AFF ONE LOOKED AT BUT RARELY HAD RADIOGRAPHIC — ABLE TO GET RADIO GRAPHS SO IN — SO WHAT WE FOUND WERE STUDIES THAT REPORTED SUBFEMORAL SHAFT FRACTURES WITHOUT CONFIRMATIONAL RADIOGRAPHIC FEATURES. THERE WAS ONE TRIAL FROM THE FIT STUDY, AND HAZARD RATIO OF ONE THAT WERE VERY FEW EVENTS AND THE DATA WERE IN INSUFFICIENT TO DRAW CONCLUSIONS. WE FOUND TWO OBSERVATIONAL STUDIES, LOOKING AT THE RISK OF THESE FEMORAL SHAFT OR FRACTURES WITH ELENDRENATE COMPARED TO NO OSTEOPOROSIS DRUG TREATMENT. ONE STUDY IN A — BOTH IN NATIONAL DATABASES AND THEY HAD DIFFERENT COMPARISON GROUPS IN TERMS OF THE FRACTURE OUTCOME. ONE STUDY SHOW NO SIGNIFICANT INCREASE BUT NO STATISTICALLY SIGNIFICANT DIFFERENCE BUT WE FELT THE STRENGTH OF EVIDENCE IS INSUFFICIENT TO DRAW CONCLUSION AND THEN THE LARGER STUDY BROKE RESULTS OUT FEMORAL SHAFT FRACTURE SIGNIFICANTLY BOTH SIGNIFICANTLY INCREASED. IN RISK WITH — COMPARED TO NO TREATMENT. FOR ONJ WE FOUND THREE STUDIES, ONE COMPARED OLENDRENATE TO RELOX PHONE AND IN THIS CASE THEY HAD BOTH RADIO LOGIC AND PATHOLOGIC CONFIRMATION OF OMJ DIAGNOSIS, THIS WAS AN OBSERVATIONAL STUDY. DONE IN ONE HOSPITAL AND THE RESULTS WERE STATISTICALLY SIGNIFICANT SHOWED A LARGE HAZARD RATIO BUT THE CONFIDENCE INTERVALS WERE VERY WIDE AND WE DIDN’T FEEL FROM THIS STUDY WE COULD DRAW CONCLUSIONS, THERE WERE TWO OTHER STUDIES THAT REPORTED ONJ BASED ON DIAGNOSTIC CODES, ONE COMPARED TO NO TREATMENT AND ONE COMPARED TO OLENDRENATE TO SOME OTHER OSSEOPROSIS DRUG TREATMENT, MOST COMMONLY RELOX PHONE ORCAL SHY TOE ANYONE. — CALCITONIN. FIRST COMPARED TO NO TREATMENT SHOWED THREE FOLD INCREASE IN RISK AND THERE WAS SIGNIFICANT WE THOUGHT THE STRENGTH OF EVIDENCE FOR THIS FINDING WAS LOW, SECOND STUDY REPORTED A HA CZAR RARE — RATIO —
HAZARD RATIO OF .9. GREATER THAN ONE BUT WE HAVEN’T BEEN ABLE TO RECONCILE THAT BUT IN EITHER CASE THE RESULTS WERE NOT STATISTICALLY SIGNIFICANT. FOR SOLENDRENATE, THIS IS BASED ON THIS RECENTLY PUBLISHED SIX YEAR TRIAL IN PATIENTS WITH MOSTLY OSTEOPENIA AND THERE WERE NO STATISTICALLY SIGNIFICANT DIFFERENCES BETWEEN THE SELENDRA GROUP AND PLACEBO GROUP IN SERIOUS ADVERSE EVENTS, COMPOSITE VASCULAR OUTCOME, MORTALITY THOUGH THE ODDS RATIOS WERE ALL LESS THAN ONE FOR CANCER THEY REPORTED STATISTICALLY SIGNIFICANT REDUCTION IN RISK. FOR AFF THEY REPORTED NO EVENTS OMJ THEY REPORTED NO EVENTS SO IMPOSSIBLE TO DRAW ANY CONCLUSIONS FOR THOSE OUTCOMES AND FOR ATRIAL FIBRILLATION THEY RECORDED THAT HAZARD RATIO OF ONE. THERE ARE A NUMBER OF OBSERVE INVESTIGATIONAL STUDIES THAT REPORTED RESULTS FOR BIS PHOSPHONATE AS A CLASS. THERE WERE TWO OF THEM THAT REPORTED ON THE RISK OR LIKELIHOOD OF AFF IN WHICH THEY CONFIRMED AFF RADIO LOGIC FEATURES USING ASBMR CRITERIA. AND THE FIRST ONE WAS NATIONAL FROM A NATIONAL DATABASE THEY PERFORMED BOTH RETROSPECTIVE COHORT ANALYSES AND CASE CONTROL ANALYSES. THEY COMPARED THE CASES WERE RADIO LOGICALLY CONFIRMED AFF, THE CONTROLS OR CONTROL OUTCOMES WERE FEMORAL SHAFT FRACTURES NOT RADIO ALMOSTICALLY CONFIRMED SO TREATMENT THAT LOWERS THE RISK OF OTHER FRACTURES WOULD LOWER DENOMINATOR AND YOU GET VERY HIGH ESTIMATES OF EFFECT IN THIS STUDY, YOU CAN SEE RETROSPECTIVE COHORT HAS OR RELATIVE RISK OVER 100 AND THEN THE CASE CONTROL THEY LOOKED AT EXPOSURE FOR THREE TO FOUR YEARS COMPARED TO NO BIS PHOSPHONATE AND FOUR TO FIVE YEARS VERSUS NO BIS TOES KNOWNATE AND GREATER THAN FIVE. WHAT I’M NOT SHOWING YOU IS THEY ALSO IN THE PAPER REPORTED EXPOSURE FOR LESS THAN THREE YEARS AND THAT THERE APPEARED AN INCREASE IN RISK WITH LONGER EXPOSURE. THE SECOND OBSERVATIONAL STUDY WAS LOOKING AT BISES IF FOENATE VERSUS PAST B YOU KNOWS PHOSPHONATE USE. AT LEAST SIX MONTHS EARLIER FOR AT LEAST A YEAR. THEY RAN A NUMBER OF DIFFERENCE MODELS BUT ALL SHOWED A RISK, THREE TO FIVE FOLD INCREASE IN RISK. WE CONCLUDED THAT THE STRENGTH OF EVIDENCE FOR BOTH OF THESE FINDINGS INCREASE IN RISK OF ATYPICAL FEMORAL FRACTURES WITH BIS PHOSPHONATE WITH LOW. FOR — THERE WERE SOME OBSERVATIONAL STUDIES THAT REPORTED ON FEMORAL SHAFT FRACTURES WITHOUT CONFIRMATION OF AFF FEATURES AND ALL HAD DIFFERENT COMPARISON GROUPS NO BIS PHOSPHONATE, PAST BIS TOES KNOWNATE OR ANOTHER ACTIVE TREATMENT. THEY WERE DONE IN DIFFERENT DATA SETS AND DIFFERENT RESULTS, FIRST STUDY COMPARED TO NO TREATMENT HAD RISK ESTIMATE OF ALMOST TENFOLD INCREASE, THE SECOND ONE YOU CAN SEE NO SIGNIFICANT INCREASE IN THREE TO FIVE YEARS FOLLOW-UP BUT THREE FOLD INCREASE WITH FIVE YEARS OF BIS PHOSPHONATE TREATMENT. THE COMPARISON VERSUS ACTIVE TREATMENT THERE WEREN’T A LOT OF EVENTS AND 34 CASES, HAZARD RATIOS ARE GREATER THAN ONE. THE RESULTS WERE NOT STATISTICALLY SIGNIFICANT. FOR RELOX PHONE, THESE DATA ARE FROM THE MORE AND THE CORE STUDY. MOST RESULTS FIRST TWO ROWS T SO FOR SERIOUS ADVERSE EVENTS REPORTED EIGHT YEARS AT END OF CORE STUDY, THERE WAS NO DIFFERENCE BETWEEN TREATMENT GROUPS FOR DVT THERE WERE MUTT BILL PAPERS DERIVED FROM MOORE AND CORE STUDY THAT RECORDED ABOUT THREEFOLD INCREASE IN RISK OF DVT THAT WAS SIGNIFICANT RESULTS FOR PE WERE REPORTED IN MULTIPLE MOORE AN CORE PAPERS ALL ALSO INCREASED COMPARED TO PLACEBO. THERE WAS ONE DATABASE STUDY THAT REPORTED ON RISK OF RELOX PHONE COMPARED TO NO OSTEOPOROSIS DRUG TREATMENT AND THEY REPORTED NO DIFFERENCE HA CZAR — NO STATISTICALLY SIGNIFICANT DIFFERENT IN RISK OF FRACTURES FEMORAL FRACTURES, TOO FEW ONJ EVENTS TO CONCLUDE ANYTHING AND THERE WAS NO STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN TREATMENT& GROUPS AND ATRIAL FIBRILLATION. FOR DENOSMAB THESE ARE DATA FROM THIS PHASE 2 DOSE FINDING STUDY THAT I MENTIONED EARLIER, THEY HAD SEVERAL ARMS OF PEOPLE WHO HAD DENOSMAB FOR FOUR YEARS, THERE WAS ONE ARM DENOSMAB TWO YEARS, THEN OFF TWO YEARS AND THERE WAS A THIRD — ANOTHER ARM WITH DENOSMAB OFF FOR TWO, BACK ON FOR ONE, ALL RESULTS FOR THOSE THREE ARMS WERE POOLED COMPARED TO PLACEBO. SO IT’S NOT POSSIBLE TO TELL WHAT THE RISK OF CONTINUOUS LONG TERM DENOSMAB ARE COMPARED TO PLACEBO. THIS RELATIVE RISK IS BASED ON THOSE THREE ALL DENOSMAB GROUPS POOLED, IT MAYBE DIFFERENT BETWEEN THE DENOSMAB CONTINUOUS VERSUS DENOSM AB HOLIDAYS SO THAT PROBABLY I WOULD GO BACK AND SAY THAT’S PROBABLY INSUFFICIENT EVIDENCE TO DRAW A CONCLUSION. THERE WERE NO DATA REPORTED ON AFF OR OMJ IN THIS PAPER. FOR ESTROGEN, YOU HEARD FROM DR. JACKSON ABOUT THE RISKS CARDIOVASCULAR DISEASE ESTROGEN AND ESTROGEN PLUS PROYES, SIR TIN. FOR THEs ESTROGEN PROGESTERONE FOR BREAST CANCER, NOT GOING INTO THAT HERE BUT THE E ESTROGEN STUDY IN LOOKING TO SEE IF — SO THE RESULTS ON REDUCTION IN TOTAL FRACTURES AN HIP FRACTURES WERE PRETTY CLEAR BUT THEN THERE ARE THESE RISKS SO THEY HAVE THIS MEASURE, GLOBAL INDEX SWITCH LOOKED AT THE TIME TO FIRST EVENT OF COMBINATION COMPOSITE OF CORONARY HEART DISEASE INVASIVE BREAST CANCER, STROKE, PE, COLORECTAL CANCER, HIP FRACTURE OR DEATH FROM SOME OTHER CAUSE. AND YOU CAN — THEY LOOKED AT IT IN TERTILE SO THEY DEFINED BASED ON SOFT BASE CALCULATOR HIGHEST MYING AN LOWEST TERTILE OF RISK FOR INCIDENT FRACTURE AND THEY FOUND THAT THE RISK OF REACHING THAT GLOBAL INDEX DIDN’T DIFFER BETWEEN TERTILE AND THERE WAS MOTHER TILE WHICH BENEFIT OF REDUCED HIP FRACTURE OUTWEIGHED INCREASE IN RISK OF OTHER EVENTS. THE RESULTS WERE THE SAME, THE GLOBAL INDEX WAS NOT REDUCED BY HIP FRACTURES OUTWEIGHING OR EVANS IN ANY TERTILE. STATISTICALLY SIGNIFICANTLY WAS INCREASED IN THE MIDDLE TERTILE. WE LOOKED FOR WHETHER LONG TERM TREATMENT HARMS VARIED AS FUNCTION OF PATIENT BONE OR DRUG TREATMENT CHARACTERISTIC AND DIDN’T FIND A LOT OF INFORMATION FOR COMPARISON BETWEEN ANY BIS PHOSPHONATE TREATMENT AND CONTROL WHETHER NO TREATMENT OR PAST BIS PHOSPHONATE TREATMENT OR ANOTHER ACTIVE THERAPY, RESULTS FROM THREE DIFFERENT OBSERVATIONAL STUDIES THAT HAD LONG TERM FOLLOW-UP THAT WERE INCLUDED IN OUR REVIEW THAT SUGGESTED THE RISK INCREASED WITH LONGER TREATMENT DURATION. STUDIES ALL COMPARED REPORTED DATA STRATIFIED BY TREATMET DURATION. WHERE THE RISK APPEARED HIGHER WITH MORE THAN FIVE YEARS TREATMENT COMPARED WITH TREATMENT TO THREE TO FIVE YEARS SO NONE DIRECTLY TESTED OR REPORTED TEST FOR INTERACTION BY TREATMENT DURATION. FOR ESTROGEN OR PROGESTIN, IT APPEARING SIMILAR ACROSS THE FRACTURE RISK SCALE, LITTLE DATA FOR OTHER TREATMENT. ANOTHER ATTEMPT AT SUMMARY. FIGURE. AND IT’S — DOESN’T COVER ALL HARMS BUT YOU CAN SEE ANY BIS PHOSPHONATE WAS THE ONLY CATEGORY WHERE THEY REPORTED ARCFF WITH RAID YES GRAPHIC CONFIRMATION BY ASBMR CRITERION RISK WAS HIGHER FOR THE SUBTRO CANTERIC FRACTURES WITHOUT RADIOGRAPHIC CONFIRMATION, BIS PHOSPHONATE INCREASED THE RISK FORM ELENDRENATE THERE WAS MIXED RESULTS THAT SUGGESTED THE RISK MAYBE INCREASED IN THE SAME WENT FOR ONJ. THEN RELOX PHONE INCREASED VENOUS THROMBO EMBOLISM. IT MAY INCREASE RISK OF DEATH, RELOXINE ON DEATH IS JUST IN THE SUBGROUP. THAT I THINK WAS ON 60 MILLIGRAMS THE WHOLE TIME, HAD FOLLOW-UP THROUGH EIGHT YEARS. HARD TO KNOW WHAT TO MAKE OF THAT. HAD NO DIFFERENCE IN RISK OF DEATH AND FOR SERIOUS ADVERSE EVENTS, SELENDRENATE WAS BORDERLINE FOR POSSIBLY DECREASED AND OTHERS DIDN’T SHOW A DIFFERENCE BETWEEN TREATMENT. SO LIMITATIONS, HARMS REPORTING BETWEEN STUDIES WAS INCONSISTENT OFTEN INCOMPLETE, PARTICULARLY FOR THE OBSERVATIONAL STUDIES REPORTING AFF FEMORAL SHAFT FRACTURES INCONSISTENCY IN THOSE STUDIES IS REALLY ADDRESS MORE IN BULLET THREE BUT THAT THEY HAD VARIABLE DEFINITIONS OF WHAT CONSTITUTED A CASE. WHAT TREATMENT INTERVENTION WAS WHAT THE CONTROL GROUP WAS, THEY ADJUST DIFFERENTLY FOR POSSIBLE SELECTION BIAS AND OTHER RISK FACTORS FOR THESE OUTCOMES. SO WE DIDN’T TRY TO MATHEMATICALLY POOL THESE STUDIES BECAUSE THERE’S HETEROGENEITY. THERE WAS NO DATA OTHER THAN WHAT I REPORTED THERE WASN’T DATA ON LONG TERM HARMS OF OTHER INDIVIDUAL STUDIES, THOUGH WE HADN’T INCORPORATED THE SELEDRENATE RESULTS YET OR CONSENSUAL DRUG TREATMENT LARGELY WHITE POST MEMBER PAUSAL WOMEN. THE OBSERVATIONAL STUDIES WERE MOSTLY WOMEN 84 TO 100% WOMEN AND GENERALIZABILITY TO OTHER POPULATION IS UNKNOWN. LIKE WITH THE TREATMENT EFFICACY, THE ANALYSES ON POSSIBLE TREATMENT OF HARMS MODIFIERS ARE ALMOST ALL POST HOCK. FROM SO FUTURE LONG TERM OSTEOPOROSIS DRUG TREATMENT STUDIES LOOKING A HARMS SHOULD COLLECT USING STANDARD DEFINITIONS. FOR EXAMPLE FOR AFF AND ONJ USING A SB CRITERIA. USE STANDARD ASCERTAINMENT METHODS AFTER COMPLETE FOLLOW-UP, COHORT STUDIES LOOKING AT RISK SHOULD USE STANDARD DEFINITIONS OR THEIR NON-CASE EXPOSURE CONTROLS. ADEQUATELY ADJUST FOR SELECTION BIAS. AND FOR RISK FACTORS INCREASE RISK OF FRACTURE AND THESE HARMS OUTCOMES. EVALUATION OF OTHER AGENTS AND SEQUENTIAL THERAPY HARMS WOULD BE USEFUL. FUTURE STUDY INCLUDE MEN NON-WHITE WITH COMORBIDITIES NOT REPPED OR UNDER-REPRESENTED IN THESE STUDIES. POPULATIONS WHO DO NOT MEET CRITERIA FOR OSTEOPOROSIS BUT HIGH RISK FOR FRACTURE MAYBE CONSIDERED FOR TREATMENT MAYBE STUDIED AND IF THEY’RE GOING TO LOOK WHETHER RESULTS VARY AS A FUNCTION OF DIFFERENT CHARACTERISTICS, THEY SHOULD SPECIFY THESE IN ADVANCE. SO IT WOULD BE POSSIBLE TO USE DATA FROM EXISTING STUDIES TO LOOK AT DO PERFORM EXPLORATORY ANALYSES ON MODIFIERS HARMS GENERATE HYPOTHESES FOR FUTURE STUDIES. COORDINATION BETWEEN DIFFERENT STUDIES TO USE COMMON METHODS OR VALIDATE FINDINGS TO LOOK AT HARMS WOULD BE USEFUL. THIS IS THE TEAM, THE SAME AS BEFORE. THAT IS IT. THANK YOU. [APPLAUSE]>>GOOD AFTERNOON. MY NAME IS ROBERT ADLER, BOB ADLER. I’M ENDOCRINOLOGIST AT THE VA MEDICAL CENTER IN RICHMOND AND VIRGINIA COMMONWEALTH UNIVERSITY. HERE ARE MY DISCLOSURES MY INSTITUTION IS REAPING REWARDS OF MY HARD WORK FOR THE TRAVERSE ADAM STUDIES, SAFETY STUDY OF TESTOSTERONE IN STUDY OF PERTI DODE IN MEN. I WILL MENTION SOME POTENTIAL NOVEL ADMINISTRATION SCHEDULES FOR FDA APPROVED MEDICATIONS. THE OPINIONS EXPRESSED WILL BE MINE AND NOT NECESSARILY THOSE OF DEPARTMENT OF VETERANS AFFAIRS. TO SUMMARIZE PATHOGENESIS OF AF REMAINS UNCLEAR. IDENTIFYING PATIENTS AT RISK STILL INCOMPLETE, WE CLEARLY NEED NEW TOOLS TO DETERMINE RISK AN BENEFITS OF TREATMENT AND IN THOSE PATIENTS WHO HAVE AFF BUT STILL HAVE OSTEOPOROSIS, THEIR TREATMENT IS CHALLENGING. HERE ARE ALL THE TOPICS I’M GOING TO ATTEMPT TO COVER IN THIS SHORT TIME. WITH THE RESEARCH AGENDA. THE ORIGINAL DEFINITION BY THE ASB TASK FORCE LED BY DR. SHANE AN BURG IS LISTED ON ONE SIDE THEN THE UPDATED 2014 DEFINITION ON THE OTHER SIDE. AND MAJOR DIFFERENCE WAS THE DIRECTION OF THE FRACTURE. THIS MAY TURN OUT TO BE A SOMEWHAT IMPORTANT IN TERMS OF THE NUMBER OF ATYPICAL FRACTURES. THIS IS A STUDY FROM KEISER LOOKING AT THE DIFFERENT ASPECTS OF ASBMR UPDATED DEFINITION AND WHAT PROPORTION OF 240 FEMORAL SHAFT FRACTURE PATIENTS HAD THESE DIFFERENT ABNORMALITIES AS PART OF THE UPDATED DEFINITION. INTERESTINGLY ONLY A SMALL PROPORTION OF THE PATIENTS WITH ATYPICAL — WE MORAL SHAFT FRACTURES MET ALL FIVE CRITERIA OR EVEN FOUR OUT OF FIVE CRITERIA. SO I THINK ONE OF THE TAKE HOME POINTS IS THERE ARE A LOT OF SHAFT AND SUBTROCANTERIC FRACTURES THAT ARE NOT NECESSARILY ATYPICAL FRACTURES AND THE DEFINITION IS ACTUALLY IMPORTANT. EVEN — THEREFORE AGENERAL DA RESEARCH BE SURE SOME THAT DIDN’T QUITE MAKE THE NEW DEFINITION SHOULD BE LOOKED AT MORE CAREFULLY. WE HAVE CHANGED THE DEFINITION ONCE AND MAYBE IMPORTANT SOME POINT TO REVISIT THE DEFINITION AND BE SURE THAT WE ARE NOT MISSING SOME POTENTIAL PATIENT WHOSE MAY NOT QUITE MEET ALL THE CRITERIA. IF YOU LOOK AT KEISER DATA, LOOK AT THE YELLOW AN GREEN BAARS HERE, WITH THE — BARS HERE, WITH THE MORE PERMISSIVE 2010 DEFINITION, THE INCIDENCE OF ATYPICAL FRACTURES PER 100,000 PATIENT YEARS IN OLDER ADULTS IS REALLY VERY LOW. EVEN WITH THE MORE PERMISSIVE DEFINITION. I THINK THIS IS ILLUSTRATED EVEN MORE DRAMATICALLY IN THIS TWO OBSERVATIONAL STUDIES BUT LARGE OBSERVATIONAL STUDIES, ONE FROM ITALY, ONE FROM KOREA. ONE FROM ITALY WAS FROM CONSORTIUM OF HOSPITALS IN WHICH THEY LOOK AT ALL OF THE TYPICAL NECKTROCANTERI OSTEOPOROTIC FRACTURES IN ORANGE AND SUBTRO CANTERIC SHAFT FRACTURES IN YELLOW. YOU CAN SEE MANY MORE OF THE FRACTURES THAT OCCUR IN THE CLASSIC PLACES THAT WE LOOK FOR OSTEOPOROTIC FRACTURES. BUT THE SHAFT FRACTURES SHOWN IN YELLOW INCLUDE ALL SORTS OF SHAFT FRACTURES BUT THESE ARE ALL LOW TRAUMA. IN KOREA, THIS WAS ONE HUGE REFERRAL CENTER AND OVER A FIVE YEAR PERIOD THEY HAD A TREMENDOUS NUMBER OF TYPICAL HIP FRACTURES AND SIGNIFICANT NUMBER OF SHAFT FRACTURES AS WELL. NOW WE’RE GOING TO LOOK AT JUST THE SHAFT FRACTURES SHOWN IN THIS NEXT SLIDE. IN ITALY THESE WERE COMPATIBLE WITH OSTEOPOROTIC FRACTURES ALL LOW TRAUMA. AND ONLY A SMALL PERCENTAGE WERE ATYPICAL, HOWEVER, IN KOREA, THERE WERE MORE ATYPICAL FRACTURES AMONG THE FRACTURES THAT OCCURRED IN THE SUBTROCANTERIC OR SHAFT AREA. THIS IS AN INTERESTING ETHNIC ASPECT WHICH WILL COME BACK TO A LITTLE LATER. SO OUR AGENDA FOR THE INCIDENCE, EPIDEMIOLOGY ETHNICITY OF ATYPICAL FRACTURES MEANS WE NEED MORE LARGE POPULATION OBSERVATIONAL STUDIES. WE NEED TO COMPARE TYPICAL OSTEOPOROTIC FRACTURES AN ATYPICAL ONE, THIS MAY ACTUALLY HELP IN OUR MANAGEMENT OF PATIENTS SHOWING THEM BRINGS UP THE IMPORTANCE ADJUDICATING THOSE FRACTURES AND NOT JUST TAKING ADMINISTRATIVE DATABASES WITHOUT LOOKING AT THE IMAGES. WHETHER WE WILL HAVE ICD 10 CODE THAT WILL BE GOOD ENOUGH SO THAT WE CAN USE ADMINISTRATIVE DATABASES WITHOUT CORROBORATION BY LOOKING AT THE ACTUAL IMAGES I DON’T KNOW. I’M NOT PARTICULARLY OPTIMISTIC. WHAT ABOUT THE PATHOGENESIS OF ATYPICAL FEE MORAL FRACTURES? THERE ARE — FEMORAL FRACTURE? THERE ARE A LOT OF CONTRIBUTORS. THEY SEEM SOME RESPECTS TO BE STRESS FRACTURES THERE’S SUPPRESSION OF TURN OVER AN HOMOGENEITY OF TISSUE. MAYBE LOCALIZED INCREASE MICROCRACKS INCREASE BRUTALNESS IMPAIRED FRACTURE HEALING GEE METRIC QUALITIES, MAYBE VERY IMPORTANT I’LL COME BACK TO THAT. THERE ARE SOME SUGGESTION OF ABNORMALITY OF THE CORTEX OSTEOPOROSIS MAY PLAY A ROLE. THESE ARE OCCURRING IN PEOPLE WITH OSTEOPOROSIS. PATIENTS ON GLUCOCORTICOIDS APPEAR TO BE AT HIGHER RISK MAYBE THOSE ON PROTON PUMP INHIBITORS. DIABETES MELITIS MAY PLAY A ROLE IN THE ACRONYM AGE HERE IS NOT AGE BUT RATHER A VANCE GLYCATION END PRODUCTS WHICH MAY PLAY A ROLE IN THE PROTEIN CONTENT OF BONE. FINALLY THERE MAYBE UNDERLYING GENETIC VARIANT WE GOT A HINT OF THAT FROM THE OBSERVATIONAL DATA. OBVIOUSLY I CAN’T GO INTO THIS BUT YOU WANT TO SHOW YOU A RECENT STUDY FROM MARY BOXHIME’S LABORATORY WHICH THEY LOOKED AT SOME NAIVE PATIENTS NAIVE OF OSTEOPOROSIS BIS PHOSPHONATE TREATMENT. LONG TERM BIS PHOSPHONATE WITHOUT FRACTURES, HIP FRACTURE PATIENTS AND PATIENTS WHO HAD HAD ATYPICAL FRACTURES NAIVE PATIENT WERE THE YOUNGEST, THE HIP FRACTURE PATIENTS WERE THE OLDEST. THEY DID AN INDENTATION TECHNIQUE IN VIVO, MEASURED DEXA AND LOOKED AT HRPQCT TO LOOK AT THE CORTEX. OF THE PATIENTS IN THIS STUDY. SUBJECTS IN THE STUDY. THE DURATION OF BIS PHOSPHONATE USE WAS SEVEN YEARS LONG TERM GROUP, IN THE HIP FRACTURE GROUP THERE WERE A FEW PATIENTS WHO WERE ON BIS PHOSPHONATE AVERAGING FOUR YEARS AN FEMORAL FRACTURE PATIENTS HAD BEEN ON BIS PHOSPHONATE EIGHT YEARS. NO DIFFERENCES IN THE INDENTATION TECHNIQUE IN DEXA OF THE FEMORAL NECK OR TOTAL HIP AND WHILE THERE WAS A TREND TOWARDS INCREASE CORTICAL FOR OSTY IN THE HIP FRACTURE PATIENTS NO DIFFERENCE IN LONG TERM BIS PHOSPHONATE GROUP WHO HAD ATYPICAL FRACTURE VERSUS THOSE WHO DID NOT. THE OTHER MEASURES OF CORTICAL ANATOMY WERE REALLY NO DIFFERENT AS WELL. SO WE DIDN’T GET WHAT WE HOPED IN TERMS OF A NEW WAY TO IDENTIFY PATIENTS AT RISK. HOWEVER, THIS AREA OF FEMORAL GEOMETRY WHICH DENNIS BLACK MENTIONED IS KIND OF IMPORTANT. IT TURNS OUT THAT EVEN HAVING BILATERAL FRACTURES IS A HINT THAT GEOMETRY IS IMPORTANT. BOEING ALIGNMENT SHORTER ANGLE BETWEEN THE SHAFT AND THE NECK SEEMS TO BE IMPORTANT. THIS INCREASE INCIDENCE OF ATYPICAL FEMORAL FRACTURE IN ASIANS WHO HAVE MORE FRACTURE BOEING SUGGEST A GENETIC COMPONENT AND RECENT STUDY, USING CADAVER BONES LOOK AT LATERAL STRAIN, TENSION ON THE LATERAL ASPECT OF THE FEMUR THAT LATERAL BOEING IN THE DIAMETER OF THE SHAFT HAD THE GREATEST IMPACT ON DIEFESIAL STRAIN. THEN THERE IS AN INTERESTING STUDY REVIEW FROM PETER EBLING GROUP LOOKING AT GENETIC DISORDERS ONLY A FEW OF WHICH WERE TREATED APPROPRIATELY WITH BIS PHOSPHONATE, MOST ARE NOT TREATED WITH THAT. AND ATYPICAL FEMORAL FRACTURE HAVE BEEN REPORTED IN EACH ONE OF THIS VERY, VARIED GROUP OF RARE BONE DISORDERS. FASCINATING. IT SUGGESTS THE GENES ARE CLEARLY PLAYING A ROLE IN THE PROPENSITY TO ATYPICAL FEMORAL FRACTURES. SO IS ATYPICAL FEMORAL FRACTURE A PERFECT STORM? BY GEOMETRY TENSION IS ON LATERAL CORTEX BUT IT’S A BONE THAT IS HOMOGENOUS THAT MAY HAVE INCREASE BRITTLENESS, THERE MAYBE INCREASE MICROCRACKS, LOCALLY GENERAL DECREASE IN REMODELING AND IN UNDERLYING GENETIC RISK DO ALL OF THESE COMPONENTS COME TOGETHER TO MAKE THOSE VERY FEW PATIENTS AT HIGH RISK FOR A TYPICAL FEMORAL FRACTURE. RESEARCH AGENDA, NOT SURE THAT MORE HISTOMORPHOMETRIC ANALYSES WILL ENLIGHTEN US SO I’M OPEN MINDED TO THAT, IT WOULD BE GREAT IF WE CAN FIND AN ANIMAL MODEL WHERE WE CAN PUT STRAIN ON THE LATERAL CORTEX OF THE FEMUR. NOT SURE THAT’S POSSIBLE. WE CLEARLY NEED MORE DOES CITIES OF GENETIC VARIANT, THIS MAYBE ANOTHER INSTANCE WHERE OUR STUDY OF RARE BONE DISEASE IS GOING TO LEAD US TO INSIGHTS IN THE COMMON BONE DISORDERS. WE NEED NEW ASSESSMENTS OF BONE. WE HAVE TO FIND WAYS TO STUDY GEOMETRY IN A EASY POTENTIALLY CLINICALLY AVAILABLE, SOME ANTHROPOE MORPHIC MEASUREMENT THAT MIGHT TIP US OFF TO FEMUR GEOMETRY THAT MIGHT BE VERY HELPFUL AND I WILL MENTION LATER LOOKING AT IMAGES OF FEMURS IN PATIENTS ON LONG TERM BIS PHOSPHONATE THERAPY MAYBE HELPFUL AS WELL. SO HOW DO WE PREDICT IT? WELL, SHOULD WE RAISE THE THRESHOLD FOR TREATMENT IN PEOPLE WITH FEMORAL BOEING OR VARIOUS ALIGNMENT OR ASIAN ETHNICITY? BECAUSE YOU HAVE A T SCORE MINUS 2.5 DOES THAT MEAN THAT’S AN AUTOMATIC PRESCRIPTION FOR TREATMENT? MAYBE NOT. WE OUGHT TO THINK TWICE, SHOULD WE DO X-RAY FOR FEMORAL GEOMETRY FIRST? ARE THERE ANTHROPOE MORPHIC THAT’S HELPFUL, AS DR. COSTMAN MENTIONED CONSIDER USING AN BOLLICS FOR A LONGER PERIOD OF TIME AND SAVE GLUCOCORTICOID INDUCED OSTEOPOROSIS WHERE RISK FOR TYPICAL FRACTURE MAYBE A GREATER. AFTER ALL, THE SAG STUDY SHE ALLUDED TO WAS ACTUALLY A THREE YEAR STUDY OF ALENDRENATE VERSUS TERPERTIDE MAYBE THINK ABOUT THAT. SHOULD WE DO DECKSA, ON FEMURS I’LL SHOW YOU THAT IN A MINUTE. MY BONE CLINIC EVERY PATIENT ON LONG TERM BIS PHOSPHONATE THERAPY IS ASKED ABOUT PRODROMAL, THEY DON’T USE THAT WORD, WE ASK THEM ABOUT A THIGH OR GROWING PAIN AT EVERY VISIT BESIDES LOOKING AT THEIR MOUTHS. WILL THERE SOME DAY BE GENETIC TESTING AS WE FIND OUT WHICH OF THE MANY POTENTIAL TARGET GENES MAY BE CONFIRMED RISK. THESE ARE A COUPLE OF VERY SUBTLE FINDINGS, I HOPE YOU CAN FIND THEM IN THESE TWO IMAGES ONLY ONE ON YOUR RIGHT, SHOWS UP WELL. THIS IS NOT ENOUGH TO MAKE A DIAGNOSIS OF AFF. IT’S ENOUGH TO SEND YOUR PATIENT FOR BETTER IMAGES AND WE HAVE STARTED DOING THIS ROUTINELY ON ALL OF OUR LONG TERM PATIENTS. I CAN DO THIS BECAUSE I WORK IN THE VA. AND I READ ALL THE BONE DENSITY. SO WE’RE DOING THIS NOW, I HAVE DONE THIS NOW FOR A YEAR, I HAVEN’T PICKED UP ANY. WHETHER OR NOT THAT TURNS OUT TO BE COST EFFECTIVE WAY TO LOOK PATIENTS AT RISK I DON’T KNOW BUT IT CERTAINLY IS A TOOL. SO WHAT IS OUR RESEARCH AGENDA FOR PREDICTING ATYPICAL FEMORAL FRACTURES? WE NEED PREDICTION TOOLS. AS DENNIS SUGGESTED WE NEED DEVELOPMENT OF A TEN YEAR ATYPICAL FEMORAL FRACTURE PREDICTION CALCULATOR THAT WE COULD DISCUSS WITH THE PATIENT WHEN WE’RE COMPARING IT WITH THE TEN YEAR OSTEOPOROTIC FRACTURE RISK CALCULATOR. WE NEED PERHAPS TOOLS FOR PATIENT EDUCATION TO REMIND THEM ABOUT THIGH AND GROW GROIN PAIN. AND AGAIN DOES ANABOLIC TREATMENT DECREASE RISK OF ATYPICAL FRACTURE, WILL WE DEVELOP A SIMPLE GENETIC TEST WOULD THIS BE A GOOD USE OF PERSONALIZED MEDICINE TO DETERMINE WHICH PATIENTS ARE AT HIGH RISK. SO WHAT ABOUT TREATMENT TO LOWER RISK. AGAIN, SHOULD WE USE ANABOLIC AGENTS MORE OFTEN? SHOULD WE TRY TO TREAT TARGET MORE QUICKLY SHOULD WE USE ANABOLIC OR IF WE FOLLOW THE DATA FROM THE DATA SWITCH STUDY, MAYBE WE OUGHT TO USE ANABOLIC PLUS DENOSMAB AND BIS PHOSPHONATE. SHOULD WOE DO CYCLIC TREATMENT WITHANT RESORPTIVES. THESE ARE ALL POTENTIAL WAYS WE MIGHT CHANGE THE SIDE EFFECT PROFILE OF LONG TERM TREATMENT. RESEARCH AGENDA IS LISTED HERE, IT’S BASICALLY WHAT I HAVE SAID. SHOULD WE CHANGE OUR TREATMENT PARADIGM PARTICULARLY THOSE AT THE VERY HIGHEST RISK FOR OSTEOPOROTIC FRACTURE AND WILL THAT CHANGE THE SIDE EFFECT PROFILE. THESE ARE NOT GOING TO BE EASY STUDIES TO DO BUT THESE ARE THINGS WE SHOULD BE AT LEAST THINKING ABOUT. SO WHAT ABOUT MANAGEMENT OF ATYPICAL FEMORAL FRACTURES? THIS IS STILL BASICALLY SURGERY. I WILL NOT GO INTO THAT. I DON’T HAVE ANY EXPERTISE. WHAT ABOUT MEDICAL THERAPY? SHOULD THESE PATIENTS ALSO BE GIVEN ANABOLIC AGENT? WE DON’T HAVE ANY GOOD RANDOMIZE CONTROL TRIALS, I DON’T KNOW IF WE EVER WILL HAVE ANYTHING LIKE THAT. WHAT DO IF YOUR PATIENT WHO SUFFERED ATYPICAL FEMORAL FRACTURE STILL HAS OSTEOPOROSIS AND IS STILL AT RISK FOR ANOTHER OSTEOPOROTIC FRACTURE? SO WE NEED RANDOMIZE CONTROL TRIALS OF AN BOLLICS AFTER ATYPICAL FEMORAL FRACTURE. WE NEED TO DISCUSS THE LENGTH OF APPROXIMATE BOLLIC TREATMENT AFTER ATYPICAL FRACTURE. WE HAVE TO CONSIDER CYCLES AND MAYBE USE OF THE LESS POTENT ANTI-RESORPTIVES SUCH AS RELOX PHONE OR BASAL DOCK PHONE OR CONSIDER PERHAPS HORMONE REPLACEMENT THERAPY IN SOME PEOPLE AND WE HAVE TO DETERMINE REASONS WHY THERE’S GREAT VARIABILITY IN THE REHABILITATION RESPONSE OF OUR PATIENTS AFTER ATYPICAL FEMORAL FRACTURE. THEN THERE ARE THESE OTHER DISORDERS. I MENTION RARE BONE DISEASE BUT WHAT ABOUT PERRY PROSTHETIC FRACTURE, SOME OF WHICH HAVE SOME CHARACTERISTICS OF ATYPICAL FEMORAL FRACTURES AND WHAT ABOUT CANCER PATIENTS WHO ALSO ARE AT RISK. DO WE NEED TO GO BACK TO DOSING SCHEDULE FOR CANCER PATIENTS AND MAYBE DECREASE THE AMOUNT THAT THEY’RE GETTING SHOULD THE PERIPROSTHETIC FRACTURES BE CONSIDERED AFFs WHAT ABOUT SCREENING WITH ALKALINE PHOSPHATASE LOOKING FOR HYPOPHOSPHOTASIA. I WANT TO CONCLUDE WE MADE SOME PROGRESS IN DIAGNOSIS AN PATHOGENESIS, WE MADE SOME PROGRESS IN IDENTIFYING PATIENTS AT RISK. SOME PATIENTS ARE NOT BEING PRESCRIBED ANTI-RESORPTIVES. THE GOOD THING IS SOME YOUNG WOMEN WITH OSTEOPENIA ARE NOT GETTING TREATED TODAY, GOOD. OLDER PATIENTS HIGH RISK REFRACTORY ARE NOT GETTING TREATED. WE NEED TO CONSIDER OUR OVERALL TREATMENT PARADIGM, WE HAVE TO THINK ABOUT THE DEFINITION AND GET MORE LARGE OBSERVATIONAL STUDIES AND WE HAVE TO LEARN ABOUT ATYPICAL FRACTURES FROM RARE BONE DISEASES. SO MY KEY RECOMMENDATIONS ARE TO TRY TO TREAT OSTEOPOROSIS PATIENT WITH HIGHEST BENEFIT TO RISK RATIO, CONTINUE OUR STUDY, DO SOME GENETIC STUDIES TO TRY TO FIND PRE-DISPOSITIONS GENES AND PERHAPS IDENTIFY NEW TREATMENT PARADIGMS. THANK YOU VERY MUCH FOR YOUR ATTENTION. [APPLAUSE]>>GOOD AFTERNOON. GOOD AFTERNOON, THANK YOU SO MUCH FOR YOUR ATTENTION AND FOR STICKING AROUND AND STAYING SO ENGAGED. I’M GOING TO TALK ABOUT THE ELEPHANT IN THE ROOM. NOW THIS AFTERNOON. SO ABOUT OSTEONECROSIS OF THE JAW, I’M ORAL MAX OWE FACIAL SURGEON AT UCLA, I SEE 350 PATIENTS WITH ONJ SO THAT’S A LOT OF DISCUSSION ABOUT THAT IT’S VERY RARE AND IN FACT IT IS, AN BUT IN MY PRACTICE I SEE QUITE A LOT. SO THESE ARE MY DISCLOSURES I WAS PART OF THE AMERICAN ASSOCIATION OF ORAL MAXILLO FACIAL SURGEONS POSITION PAPER IN 2014 AND HAVE RECEIVED SOME FUNDING AN ADS CONSULTANT IN THE PAST FOR AMJEN. SO THIS IS THE DEFINITION AND ALL THE FOLLOWING HAVE TO BE PRESENT. WE HAVE TO HAVE BONE PREVIOUS TREATMENT WITH ANTI-RESORPTIVE MEDICATION. DENOSMAB OR BIS PHOSPHONATE, IT’S NOT NECESSARILY EXPOSED BUT THE BONE CAN BE PROBED THROUGH A FISTLA FROM THE OUTSIDE OF COURSE NOT TO HAVE HISTORY OF RADIATION THERAPY TO THE JAWS BECAUSE THEN WE WOULD BE TALKING ABOUT OSTEORADIO NECROSIS. OF COURSE AS YOU ALREADY SIGNED I’M GOING TO SHOW A FEW GROUPS OF PICTURES AND BUT AGAIN MOST OF THESE SOMETIMES LOOK A BIT WORSE THAN THEY ARE, SO ONE OF THE GOALS HERE IS TO REALLY SHOW WITH THIS IT CAN BE DEVASTATING COMPLICATION OF THESE MEDICATIONS THERE ARE SOME WAYS DEFINITELY TO MANAGE THIS FAIRLY EASILY AND LOT OF IT IS ABOUT EDUCATION. EDUCATION TO THE DENTISTS, EDUCATION TO THE PHYSICIANS AND DEFINITELY EDUCATION TO THE PATIENTS. SO THIS IS REALLY LOOKING AT THE PREVALENCE AND IN OSTEOPOROSIS THE PREVALENCE IS VERY LOW AS WE HAVE HEARD MULTIPLE TIMES TODAY. IT’S TRUE, BUT AS WE HAVE ALSO HEARD. WHEN THE PATIENTS SEE WHEN PATIENTS HAPPEN TO THEM IT’S MEANINGFUL AND CAN BE DEVASTATING SO ONE THING THAT I THINK I TOOK HOME FROM TODAY ALREADY IS THAT IT’S ABOUT EDUCATION, ABOUT THESE HONEST DISCUSSIONS WITH YOU ARE PATIENTS, NOT TO MAKE IT SEEM LIKE THIS WILL NEVER HAPPEN TO YOU, SO WE DON’T NEED TO DISCUSS IT BUT BRING IT UP TO DISCUSS, SAY IF IT DOES HAPPEN WE’LL TAKE CARE OF IT AS FAST AS WE CAN BEFORE IT HAPPENS. SO YOU CAN SEE THAT IF PATIENTS HAVE DENTAL DISEASE OR IF THEY’RE ON LONGER TERM THERAPY OF ANTI-RESORPTIVE THAN PREVALENCE INCREASES. IT MAY BE UNDERDIAGNOSED OR EVEN POTENTIALLY UNEXPOSED VARIANT WHY THE SCREENING IS SO IMPORTANT, BOTH BEFORE ANTI-RESORPTIVE THERAPY IS INITIATED AND AS IT’S ONGOING ESPECIALLY LONGER TERM. WITH DENOXMAB WE ARE SEEING THESE NUMBERS BUT BECAUSE IT’S SO NEW, THERE’S FEW PATIENTS THAT HAVE NOT HAD A PREVIOUS RESPONSE, IT’S DIFFICULT TO DETERMINE THE EXACT PREVALENCE HERE. SO ONE OF THE THINGS THAT MY LAB AND MY RESEARCH BOTH CLINICALLY AN TRANSLATIONALLY FOCUSES ON IS WHY ARE TEETH EXTRACTED, IT’S NOT NECESSARILY THE TRAUMA FROM THE DENTAL EXTRACTS OR THE SURGICAL PROCEDURE, BUT THE DISEASE THAT HAPPENS BEFORE THAT, SO THAT’S A LOT OF WHAT I HAVE BEEN STUDYING. IN FACT IN A LOT OF CLINICAL STUDIES THAT HAVE SHOWN PATIENTS HAVE POOR ORAL HYGIENE OR REALLY DON’T HAVE GOOD DENTAL TREATMENT, THEN THEIR INCIDENCE IS HIGHER. AND THEN REALLY GOING BEYOND THAT, IF THEY COME TO THE DENTIST REGULARLY, THEY’RE LESS LIKELY TO DEVELOP OSTEONECROSIS OF THE JAW. MORE PREVENTIVE MEASURES ARE UNTAKEN THIS IS A PATIENT THAT HAD A DENTAL INFECTION SO REALLY HE’S ALREADY AT RISK FOR ONJ, THIS HAS TO BE TREATED SOONER RATHER THAN LATER. WHAT HAPPENS IF YOU HEAR THE COMMERCIALS ON TELEVISION THEY’LL SAY NO DENTAL WORK, TO DENTAL TREATMENT, THIS IS REALLY THE OPPOSITE OF WHAT THE MESSAGE THAT WE SHOULD BE SENDING. THERE SHOULD BE MORE DENTAL VISITS, MORE TREATMENT IN THE PREVENTATIVE FASHION SO THAT WE PREVENT PATIENTS FROM NEEDING TO HAVE TEETH EXTRACTED OR HAVE ANY SURGERY. FEW STAGES, STAGE ONE WHICH BASICALLY SHOWS THAT THERE’S SOME EXPOSED BONE BUT THERE ISN’T ANY SYMPTOM ASSOCIATED WITH THAT, NO PAIN, NO BLEEDING NO SCIENCE OF INFECTION. STAGE TWO WE START GETTING MORE UNAPPEALING OF COURSE IF YOU LOOK IN THE MOUTH AND YOU SEE THIS YOU CAN SEE A LOT OF PLAQUE IN BACTERIA. THIS IS DEAD BONE NECROTIC BONE SO BACTERIA AN PLAQUE JUST REALLY ATTACH VERY WELL TO THAT. SO THE PATIENTS WHAT THEY DO IS AVOID THIS AREA COMPLETELY, NO DENTIST WANT TO TOUCH THIS, NOBODY WANTS TO SEE IT, AND OF COURSE THAT CAN MAKE IT PROGRESS AN BECOME MORE UNCOMFORTABLE AND MORE INFECTED. MOVE TO STAGE 3 IT’S MUCH MORE SEVERE AND SIGNIFICANT. YOU CAN IMAGINE HOW PAINFUL SOMETHING LIKE THIS WOULD BE. BE THE SEA OF PUSS IN YOUR MOUTH WITH LOT OF INFLAMMATION AND IT CAN PROGRESS IN SOME CASES WITH A FRACTURE OF THE JAW. WHEN THIS STAGE YOU GET TO THIS STAGE OFTEN TIMES THERE HAS TO BE SURGERY DONE OR SOME KIND OF MORE INVASIVE THERAPY. THIS IS THE LEAST COMMON MUCH MORE COMMON STAGE ONE AN TWO. AND SO WE CAN DEFINITELY INTERVENOR QUICKLY AND PREVENT THIS FROM HAPPENING. THIS IS MUCH MORE RARE THAN THE OTHER STAGES. SO THESE ARE THE TREATMENT GUIDELINES DEVELOPED BY THE AMERICAN ASSOCIATION OF ORAL MAXILLO PATIENT SURGEONS AND I’LL DRAW YOUR ATTENTION TO STAGE ONE. REALLY TRYING TO GET THE PATIENT TO BE COMFORTABLE TO BE OUT OF PAIN AND MAKE SURE THAT WE KEEP ANY PLAQUE AN BACTERIA FROM THE AREA. SO AN ANTIBACTERIAL RINSE AND GOOD FOLLOW-UP IN PATIENT EDUCATION. IF WE ARE LOOKING STAGE TWO THIS IS WHERE WE HAVE TO MANAGE [email protected] AS WELL. USE OF ANTIBIOTICS ARE CONSIDERED AND THEN THE AOMS GUIDELINES WILL OFTEN DISCUSS DEBRISMENT AS WELL, DIFFERS FROM HOW I TREAT PERSONALLY AND I WILL GO OVER THAT IN A MINUTE. THEN STAGE 3 WHEN GETTING INTO SOMETIMES MORE SURGICAL THERAPY, MEANING SURGICAL DEBELIEVEMENT RESECTION OF PORTION OF THE JAW. SO REALLY WHAT EVIDENCE CAN WE LEARN FROM TRANSLATIONAL STUDIES? THIS IS WHERE CLINICIAN AND SIGNTIS HAS IMPACTED MY LIFE SIGNIFICANTLY IN TREATING THESE PATIENTS WHERE IDENTIFYING A PROBLEM IN THE CLINIC TAKING IT BACK TO THE LAB, GOING FROM THE BASIC TO THE TRANSLATIONAL STUDIES ANT THEN TAKING SOME OF THAT INFORMATION BACK TO THE PATIENT. AND WAYLY I THINK THAT THE PATIENT’S BENEFIT A LOT FROM THIS TYPE OF APPROACH WHICH IS WHY GETTING TOGETHER AND HAVING SUCH CONFERENCE LIKE THIS AND WORKSHOP IS VERY HELPFUL FOR ALL PEOPLE INVOLVED. FIRST THING TO DO IS MINIMIZE THE RISK. HOW CAN WE DO THAT? DENTAL DISEASE IS A BIG PREDICTOR OF PATIENTS THAT ARE GOING TO DEVELOP ONJ, NOT ALWAYS WHEN PATIENTS HAVE EXTRACTS BUT IT’S OFTEN DENTAL DISEASE ITSELF, WHETHER PERIODONTAL DISEASE OR PERIAPICAL DISEASE WHEN THEY NEED A ROOT CANAL. THIS IS SHOWN IN SOME OF OUR ANIMAL STUDIES WHERE WE LOOKED AT TOGETHER WITH THE RAT RODENT AND PATIENT THAT WE GET SIMILAR RAID GROW GRAPHIC FEATURES. THESE ARE COMING CT SCANS WE OFTEN DO NOWADAYS ALMOST ALL MY PATIENTS GET THIS SORT OF LICK WHAT WAS SAID EARLIER GETTING SOME OF THE LOOKING AT THE JAWS TO SEE IF WE CAN DETERMINE ANY OF THESE VIDEO GRAPHIC FEATURES. BOTH IN PATIENTS THAT ARE SYMPTOMATIC AND ALSO AS PREDICTIVE MEASURE. SO WE CAN SEE THE FEATURES LOOK SIMILAR, THE MORE DENSE BONE, THE PERIOSTEOBONE FORMATION AN SEQUESTRATION OF THE BONE. IF WE LOOK AT HISTOLOGICAL ANALYSIS WE SEE NECROTIC BONE VERY SIMILAR TO THE ANIMAL STUDIES AND THE HUMAN STUDIES TOGETHER THAT WE HAVE DONE. IF WE GO ON TO TREATMENT OF THE LESIONS ONCE THEY HAVE HAPPENED WE’RE GETTING INTO A LITTLE BIT OF A DIFFERENT REALM. HERE WE CAN LOOK AT SOME OF THE TREATMENT OPTIONS SO I OFTEN HAVE EXACTLY WHAT WAS MENTIONED EARLIER, WHAT IF YOU HAVE PATIENTS THAT HAVE THESE PROBLEMS AND THEY STILL NEED TO BE ON SOME TYPE OF TREATMENT FOR OSTEOPOROSIS. WHAT CAN WE DO? ANIMAL STUDIES WE CAN LOOK AT PARATHIGH ROAD HORMONE AN EFFECT. WHEN WE LOOK AT STUDIES IF WE HAVE IT IT INCREASES THE BONE REMODELING TO HEAL AN EXTRACTION SOCKET, THIS IS IN A MOUSE MODEL AND IF YOU HAVE DEXAMETHASONE BASICALLY EMPTY EXTRACTS SOCKETS THAT HAVE NOT HEALED BUT USE PARATHYROID HORMONE YOU CAN INCREASE THAT REMODELING AND THE BONE FORMATION IN HEALING. AND HAS THAT BEEN FOLLOWED UP IN ANY STUDIES CLINICALLY. AND THE ANSWER TO THAT IS YES. PATIENTS HAVE BOTH WITH STAGE 2 AND 3 TREATED WITH PTH WHEN THEY HAVE OSTEONECROSIS OF THE JAW IMPROVING THE CLINICAL AND THE RADIOGRAPHIC OUTCOME IN THESE PATIENTS, BUT OF COURSE THESE AT THIS POINT ARE ONLY CASE SERIES AND CASE REPORTS BUT OFTEN TIMES THIS IS HOW SOME OF THE RESEARCH STARTS. WE HAVE HEARD A BIT ABOUT THE ANABOLIC THERAPY AND POTENTIAL PROBLEMS AND WE KNOW THAT THEY’RE CON THAT INDICATED IN PATIENTS WITH CANCER. — CONTRAINDICATED WITH RISK OF CANCER. THERE’S RISK OF OSTEOSARCOMA, LIMITED HOW MUCH TIME TO BE ON IT AND COST IS SIGNIFICANT. SO THIS SOMETIMES A LOT OF WHAT I HAVE HEARD TODAY IS A LOT OF THE CLINICAL RECOMMENDATIONS THAT WE WANT TO MAKE REALLY DON’T GO ALONG WITH EITHER WHAT’S COVERED BY INSURANCE OR MEDICARE AND WHAT PATIENTS CAN REASONABLY AFFORD. HOW ELSE DO WE TREAT THIS? NON-OPERATIVE THERAPY STUDIED EXTENSIVELY, WE CAN SEE HERE VARIOUS RANGE OF SUCCESS RATES WITH NON-SURGICAL THERAPY. SOME OF THE NUMBERS ARE NOT GOOD WHEN YOU LOOK. WE HAVE 20%, SOME 60%, 80% BUT IF PATIENTS AND SURGEONS LOOK AT THIS, THEY’RE GOING TO SAY WELL, WE REALLY DON’T HAVE A VERY GOOD TRACK RECORD WITH SOME OF OUR CONSERVATIVE OR NON-OPERATIVE THERAPY. BUT THESE STUDIES ARE LIMITED, AND WHAT DEFINES SUCCESS? ARE WE THINKING COMPLETE HEALING, TRYING TO GET THE PATIENTS OUT OF PAIN? AND REALLY, THESE STUDIES ARE NOT WELL STANDARDIZED. NOW, WHAT HAS BEEN SHOWN IS SURGICAL THERAPY IS EFFECTIVE. AND YOU CAN SEE THE NUMBERS HERE ARE MUCH BETTER IN GENERAL AND THERE ARE MORE STUDIES SHOWING THAT IF THERE’S INVOLVED SURGICAL DEBELIEVEMENT OR SURGICAL RESECTION THEN THE STUDIES ARE PRETTY EFFECTIVE. BUT AGAIN, A LOT OF THESE PATIENTS ARE NOT GOING TO BE UP FOR THIS. IT’S A VERY INVASIVE PROCEDURE, GENERAL ANESTHESIA, THEN ONE SURGICAL THERAPY IS DONE THE BONE IS RESECTED AND OFTEN CAN’T BE REINSTRUCTED — RECONSTRUCTED SO LEAVES DEBILITATED PATIENT. SO WHEN LOOKING AT THAT, PATIENTS AND CAN THEY TOLERATE SURGERY, IS THERE SOME OTHER THINGS WE CAN DO THAT WAS REALLY ONE OF THE FOCUSES OF WORKING WITH THESE PATIENTS AND TRYING TO SEE IF WE CAN GET SOMETHING ALTERNATIVE. WHAT DO WE KNOW SO FAR? INFLAMMATION OR INFECTION FROM DENTAL DISEASE PLUS ANTI-RESORPTIVE THERAPY IN SOME CASES WILL LEAD TO OSTEONECROSIS OF THE JAW. AGAIN LIKE I SAID IN OSTEOPOROTIC PATIENTS THE PREVALENCE IS LOW. .1 TO .01%, VERY RARE BUT NOT ZERO. SO THIS IS MY SURGICAL INSTRUMENT AND I GET MADE FUN OF A LOT, AS YOU CAN IMAGINE SURGICAL CONFERENCES, BECAUSE I USE Q TIP, IT’S TO DECREASE THAT INFLAMMATION INFECTION IN THE AREA SO THAT WE CAN GET RID OF ALL THE BACTERIA AROUND THE WOULDN’T. SO THE PATIENTS ARE REALLY TOLD BY ME TO SCRUB THE AREA, KEEP ALL THE PLAQUE IN THE BACTERIA OFF OF IT AS MUCH ADS POSSIBLE. SO YOU CAN SEE HERE I HAVE A LITTLE SHORT VIDEO FOR YOU TO SEE AND HOPEFULLY NOT TOO GRAPHIC FOR ANYONE BUT I WANT YOU TO SEE HOW AGGRESSIVE I WANT PATIENTS TO BE. SO THEY’RE SCRUBBING AROUND THIS. OVER TIME WITH THE BETTER THAT THEY KEEP IT CLEAN, THEN I’M GOING TO BE ABLE TO COME IN AND REMOVE IT WITH A COTTON PRIOR THAT’S NOT SURGICAL AT ALL TO REALLY WIGGLE THE BONE OUT WHEN ALREADY SEQUESTERING AN REMOVE IT VERY EASILY. I KNOW THIS SEEMS GRUESOME BUT IF THIS IS THE MORE AGGRESSIVE SURGERY WE ARE DOING WE’RE IN GOOD SHAPE. SO THEN THIS IS WHAT HAPPENS. WE HAVE OUR PATIENTS THAT HAVE EXPOSED BONE, THIS IS STAGE 1 EVENTUALLY EXPOSES MORE BECAUSE WE CAN SEE PRE-OPERATIVELY OR PRE-DEBELIEVEMENT WE HAVE A PRETTY LARGE SEQUESTER IN THE COMB CT SCAN SO GETTING THAT SCAN TELLS US THAT IF IT EXPOSES MORE TELLING PATIENT NO, IT’S NOT GETTING WORSE, IT WAS ALREADY THERE THAT LARGE AND IT JUST OPEN MORE AND YOU’RE ABLE TO ACCESS IT BETTER SO YOU CAN CLEAN IT. AND OVER TIME WHAT HAPPENS IS THIS BONE COMES OUT, IT’S STARTLING TO THE PATIENT OF COURSE IF THIS HAPPENS BUT THEN IT HEALS VERY WELL WITH REALLY COMPLETE MUCOSAL COVERAGE. THIS IS RECENTLY PUBLISHED ACTUALLY THIS MONTH IN THE JOURNAL OF ORAL AND MAXILLO FACIAL SURGERY. SO WHEN WE BASICALLY LOOK AT AFTERWARDS THE BONE IS STILL NOT NORMAL. WE HAVE LOST THAT PART OF BONE, IT’S NOT REGENERATING BUT IT DOESN’T CAUSE FRACTURE OF THE BONE, THE PATIENT NOW HAS AN AREA OF MUCOSA COMPLETELY HEALED AN THEY CAN CONTINUE WITH THEIR REGULAR HYGIENE. WITHOUT SURGERY. SO WE LOOKED AT 117 PATIENTS IN THIS STUDY. YOU CAN SEE WE HAVE PATIENTS WITH STAGE ONE AN MUCH LESS WITH STAGE 3 DISEASE. WE HAD BASICALLY YOU CAN SEE COMPLETE DISEASE RESOLUTION IN 71% OF PATIENTS, ANOTHER 22% DISEASE IMPROVEMENT AND ONLY 8% WHERE WE DIDN’T. THESE NUMBERS WERE AT LEAST AS GOOD IF NOT BETTER THAN SURGICAL THERAPY. SO YOU CAN SEE THAT THE BETTER THEIR WOUND CARE WAS THE FASTER WAS THE TIME TO RESOLUTION. BUT WE HAVE TO HAVE A VERY, VERY COMPLIANT PATIENT PATIENT BECAUSE IT TAKES QUITE SOME TIME FOR DISEASE RESOLUTION AS YOU CAN SEE. SO I WANT TO CONCLUDE WITH SOME THINGS TO TAKE HOME AND DISCUSS WITH OUR PATIENTS, TRYING TO GET THEM INTO A PRE-ANTI-RESORPTIVE PREVENTIVE DENTAL VISIT TO TAKE CARE OF THE ACTIVE DENTAL DISEASE AS MUCH ADS POSSIBLE. ENCOURAGE HYGIENE INCREASE DENTAL MAINTENANCE AND WORK THE SPEAK AND WORK TOGETHER WITH OUR DENTAL COLLEAGUES SO THAT WE REALLY IMPROVE THE EDUCATION THROUGHOUT AND IS ONLY GOING TO BENEFIT OUR PATIENTS. DISCUSS THE RISK AND BENEFITS OF OSTEOPOROSIS THERAPY, I SPEND TIME TELLING ME PATIENT NOT TO GO OFF THEIR MEDICATION RATHER THAN TELLING THEM THEY SHOULD BECAUSE THEY COME AND WANT TO GO OFF SO WHAT I’M DOING IS TELLING THEM THE BENEFITS AND WHY THEY SHOULD NOT STOP. THEN OF COURSE THE EDUCATION ABOUT IF THEY DO DEVELOP ONJ WE HAVE A TEAM IN PLACE THAT CAN DEAL WITH THAT. AND IDENTIFYING PATIENTS AT RISK WITH RADIOGRAPHIC FEATURES THAT WE CAN GET EARLY ON OR WITH DISEASE PROCESSES OR PATIENTS THAT HAVE OTHER COMORBIDITIES. OF COURSE DIAGNOSING AN TREATING IT ADS EARLY ADS POSSIBLE. OF COURSE IF WE DO GET IT, IF WE CAN CONSIDER NON-SURGICAL THERAPY. SO I WANT TO END WITH SOME KEY RECOMMENDATIONS, WE DO HAVE A LOT OF KNOWLEDGE GAPS, WHAT IS TRUE PREVALENCE BECAUSE OFTEN TIMES WITH SUCH A RARE DISEASE WE NEED THOUSANDS OF PATIENTS TO TELL US WHAT THE TRUE PREVALENCE IS. THIS IS DIFFICULT TO DO IN MOST STUDIES. WE NEED THE DIAGNOSE KNOW EARLY AND USE SOME OF THESE TOOLS THAT WE’RE STARTING TO GET TO DETERMINE PREVALENCE AND IDENTIFY THESE PATIENTS AS EARLY AS POSSIBLE. THEN RESEARCH RECOMMENDATIONS WOULD BE TO DO EXACTLY THAT, DETERMINE PATIENTS AT RISK. GET SOME TOOLS AN VALIDATE THESE TOOLS FOR EARLY DIAGNOSIS. AND THEN VALIDATE MORE SOME OF THESE NON-INVASIVE TREATMENT PROTOCOLS WITH MULTI-CENTER STUDIES. THEN MAYBE ALSO ONE OF THE THINGS WE ARE WORKING IN IN OUR LAB WITH ANIMAL MODELS IS TO IDENTIFY MOLECULAR TARGETS WHERE WE CAN IDENTIFY AT RISK SITUATIONS OR DIAGNOSE VERY EARLY. SO WITH THAT, I WANT TO THANK YOU FOR YOUR ATTENTION. [APPLAUSE]>>GOOD AFTERNOON. MY NAME IS JULIET COMPSTON, BONE DOCTOR FROM CAMBRIDGE BIOMEDICAL CAMPUS IN THE UK. THESE ARE MY DISCLOSURES NO FINANCIAL CONFLICTS OF INTEREST, I DO HAVE ASSOCIATIONS OR ACTIVITIES WITH PROFESSIONAL ASSOCIATIONS IN THE UK AND US AS SHOWN ON THIS SLIDE. A NUMBER OF SIDE EFFECTS HAVE BEEN ASSOCIATED WITH ANTI-RESORPTIVE THERAPY. THOUGH THE EVIDENCE IN SOME OF THESE IS CONFLICTING, AND PROOF OF CAUSALITY IS NOT ESTABLISHED IN ALL CASES, THESE ARE THE SITED EFFECTS I’M GOING TO DISCUSS AB OFTEN OBVIOUSLY FEMORAL FAGTORS NECROSIS OF THE JAW HAVE BEEN COVERED BY EXTENSIVE RESEARCH AND CONCENTRATE ON UPPER GASTROINTERSOMETIME CANCER, CARDIOVASCULAR DISEASE AND MORTALITY. HERE IS A SUMMARY OF THE FINDINGS, FIRST THE ESTIMATED INCIDENCE OF ATYPICAL FEMORAL FRACTURES IS ONE TO 50 PER 100,000 PATIENT CARES IN PEEP TREATED BIS PHOSPHONATE AND RISK INCREASES WITH LONGER DURATION OF THERAPY. OSTEONECROSIS OF THE JAW IS VERY RARE, WITH ESTIMATED INCIDENCE OF NOT.NOT, NOT 1 TO NOT POINT ONE, ONE PERCENT THESE TWO SIDE EFFECTS STRONG CONSENSUS THERE IS A LINK REPORTED BY THE ASOCIO IATION PLAUSIBLE S. PHYSIOLOGICAL. FOR OSTEONECROSIS PATIENTS HIGH DOSES OF BIS PHOSPHONATE, HAVE SIGNIFICANTLY HIGHER INCIDENCE OF THESE COMPLICATIONS. INTERESTINGLY DOSE RESPONSE IS NOT REALLY APPARENT FOR ATYPICAL FRACTURES. AND THIS MAY SUGGEST. FOR THE OTHER SIDE EFFECTS MOST EVIDENCE DOES NOT SUPPORT FOR BIS PHOSPHONATE CANCER. DAY TWO FIBRILLATION IS CONFLICTING. AND ASSOCIATIONS TREATING BIS PHOSPHONATE AND
CARDIOVASCULAR DISEASE AND MORTALITY REQUIRE FURTHER INVESTIGATION. NOW MOST OF THE DATA I’M GOING TO SHOW OUR ON LONG TERM EFFECTS COME FROM LONG TERM CLINICAL TRIALS OR OBSERVATIONAL STUDIES, THESE TWO SOURCES OF DATA HAVE BOTH THEIR OWN STRENGTH AND LIMITATIONS. FOR CLINICAL TRIALS THE ADVANTAGES ARE OBVIOUSLY THAT THERE’S RANDOMIZE TREATMENT ASSIGNMENT SO THE PROBABILITY OR POSSIBILITY OF CONFOUNDING IS MINIMIZED, THERE IS BLINDED AND PRE-SPECIFIED DOCUMENTATION ABOUT THOSE EVENTS. BUT AS WE HAS BEEN DISCUSSED EARLIER TODAY CLINICAL TRIALS MAY HAVE LIMITED GENERALIZABILITY IN TERMS OF THE PATIENTS TREATED, TIME SCAN IS LIMITED TO THREE YEARS. RARE ADVERSE EVENTS MAY NOT BE DETECTED PARTICULARLY IF NOT EXPECTED AND IF THEY’RE RELATED TO DURATION. OBSERVATIONAL STUDIES HAVE ADVANTAGES OF MUCH GREATER GENERALIZABILITY YOU CAN HAVE VERY LARGE NUMBERS IN OBSERVATIONAL STUDIES AN LONGER DURATION OF THERAPY. BUT THEY ARE SUBJECT TO CONFOUNDING AND SOME OF THE FACTORS ARE SHOWN ON THIS SLIDE. WITH THESE DIFFERENCES BETWEEN CLINICAL TRIALS AND OBSERVATIONAL STUDIES, WE MAY SOMETIMES GET DIFFERENT ANSWERS IF WE LOOK AT THESE TWO SOURCES OF DATA FOR THE SAME OUTCOMES OBSERVATION A.M. STUDIES CLEARLY MORE SOPHISTICATED STATISTICAL METHODS FOR TRYING TO ADJUST FOR CONFOUNDING BUT IT’S NOT POSSIBLE TO DO THIS COMPLETELY. STRIKING EXAMPLE HOW CON FOUNDING MAY INFLUENCE CONCLUSIONS DRAWN FROM OBSERVATIONAL DATA IS SHOWN ON THIS SLIDE. THIS SLIDE SHOWS DATA FROM WOMEN TREATED WITH PLACEBO IN THE WHI STUDY. WOMEN WERE DIVIDED INTO HIGH GREATER THAN 18% OR LOW ADHERENCE LESS THAN 80% TO PLACEBO. WITHIN THEY LOOK AT NUMBER OF OUTCOMES HIP FRACTURE MYOCARDIAL INFARCTION CANCER DEATH AND ALL CAUSE MORTALITY, YOU CAN SEE THERE ARE SIGNIFICANT REALLY QUITE LARGE BENEFITS IN THE HEALTHY — HIGH ADHERERS COMPARED TO LOW ADHERERS SO CLEARLY THIS EFFECT MAY NEED TO OVERESTIMATION TO TREATMENT BENEFITS. I SHOULD SAY IN THIS STUDY WHAT I’M SHOWING YOU HERE OUR HAZARD RATIO ADJUSTED FOR OVER 30 POTENTIAL CONFOUNDERS AND PROBLEM LOOKING AT OBSERVATIONAL DATA IS THERE MAY BE UNKNOWN CONFOUNDERS. SO FOR BIS PHOSPHONATE ASSOCIATED ATYPICAL FEMORAL FRACTURES BUT HEARD THIS, I WON’T GO THROUGH THE POINTS. ONE THING I WOULD LAKE TO STRESS IS THE HIGH MORBIDITY OF THESE FRACTURES, THEY ARE QUITE OFTEN BILATERAL, THEY MAY TAKE LONG TIME TO HEAL. SO IN IN CONSIDERING RISK BENEFIT BALANCE IT MAY NOT BE APPROPRIATE TO EQUATE SAY ONE HIP FRACTURE WITH ONE ATYPICAL FEMORAL FRACTURE. HERE AGAIN REALLY REPETITION YOU HAVE HER ABOUT OSTEONECROSIS OF THE JAW. THERE HAS ALSO BEEN VERY RARELY REPORTED OSTEONECROSIS OF EXTERNAL AUDITORY CANAL. THIS HAS BEEN REPORTED WITH BOTH BIS PHOSPHONATE THERAPY AND DIMOSNAB USE AND MORE COMMON IN PEOPLE WITH CHEMOTHERAPY OR LOWCAL INFECTION OR TRAUMA. THESE ARE INCREDIBLY RARE COMPUTATIONS. I PERSONALLY HAVE NEVER SEEN OSTEONECROSIS OF THE JAW OR OF THE EXTERNAL AUDITORY CANAL. IN PEOPLE TREATED WITH BIS PHOSPHONATE FOR OSTEOPOROSIS. THE DATA WE HAVE FOR DIMOSNAB MAY COME FROM THE FREEDEN TRIAL THE ACT SECTION STUDY RUNS TOGETHER FOR UP TO TEN YEARS, THERE’S A LONG TERM GROUP WHO HAD IT FOR TEN YEARS. AN ACROSS OVER GROUP WHO HAD PLACEBO THE FIRST THREE YEARS, FOLLOWED BY DENOSMAB THE NEXT SEVEN YEARS. THERE WAS HIGH DROPOUT RATE IN THIS STUDY, 42%, AND JUST WORTH REMEMBERING THERE’S NO PLACEBO GROUP IN THE FINAL SEVEN YEARS OF THE STUDY. SO IN THE FIRST THREE YEARS OF THE STUDY THE PLACEBO CONTROLLED TRIAL THERE WAS NO CASES EITHER ONJ OR ATYPICAL FEMORAL FRACTURES. ATYPICAL FEMORAL FRACTURES OCCURRED IN TWO WOMEN UP TO 3, 7 YEARS TREATMENT IN THE EXTENSION STUDY. THERE WERE 13 CASE OF ONJ EIGHT JOINED FIVE YEARS OFENINGS TENSION, FIVE JOINED YEARS 8 TO 10. PERHAPS SUGGESTING ASSOCIATION BETWEEN RISK OF ONJ AND DURATION THERAPY. TURNING TO BICS PHOSPHONATE UP PER GI CANCER, INTEREST IN THIS STIMULATED BY REPORT TO THE FDA OF 23 CASES OF ESOPHAGEAL CANCER ASSOCIATED WITH USE, REPORTED IN THE NEW ENGLAND JOURNAL OF MEDICINE. A NUMBER OF OBSERVATIONAL STUDIES, 13 AND 3 META ANALYSES WHICH PRODUCE CONFLICTING RESULTS. OF THE META ANALYSES TO NEGATIVE THERE IS A FOURTH META ANALYSIS IN 2015 WHICH ADDED TWO FURTHER STUDIES AT MOST RECENT ONE, THE RESULTS ARE SHOWN HERE YOU CAN SEE OVERALL RISK WAS NOT SIGNIFICANT. THE AUTHORS DO POINT OUT LIMITATIONS THE STUDIES INCLUDED IN THIS META ANALYSIS THOUGH INADEQUATE DATA ABOUT CONFOUNDERS FOR EXAMPLE ONE STUDY HAD NO DATA ON SMOKING, THERE WAS VARIATION DURATION OF THE STUDIES, AND VARIATION IN THE OUTCOMES IN TERMS OF HISTOLOGICAL SUBTYPES AN THESE SITES OF THE CANCER. SO THIS IS AN AREA FURTHER STUDIES ARE NEEDED TO GET TO DEFINITIVE ANSWER BUT THE EVIDENCE TO DATE DOES NOT SUGGEST ASSOCIATION. AN WITHIN ASSOCIATION LIKELIHOOD OF CAUSALITY IS INCREASED IF THERE ARE PLAUSIBLE BIOLOGICAL MECHANISMS AND REALLY THIS IS NOT THE CASE FOR BIS PHOSPHONATE IN CANCER ESOPHAGEAL CANCER. WE KNOW NITROGEN CONTAINING BIS PHOSPHONATE LOCALIZED EFFECTS ON ESOPHAGEAL AND GASTRIC MUCOSA. THIS IS THOUGHT TYPICAL ESOPHAGITIS BY CONTACT OF THE PILL ON THE ESOPHAGEAL MUCOSA. IT CERTAINLY REDUCED THOUGH NOT ELIMINATED BY ENSURING COMPLIANCE WITH THE DOSING REGIMEN AND ALSO AVOIDING USE OF ALL BIS PHOSPHONATE WITH PEOPLE AT RISK OF UPPER GICS DISEASE. NO EVIDENCE IN PRE-CLINICAL DATA FOR CARCINOGENIC PROPERTIES IN THE GI TRACT AND A LARGE COHORT STUDY FROM ME CARE RECENT WILL I FOUND A NEGATIVE ASSOCIATION BETWEEN ALL BIS PHOSPHONATE USE AND BARRETT’S ESOPHAGUS. THAT’S A META PLASTIC CONDITION WHICH PRE-DISPOSES TO ADENOCARCINOMA OF THE ESOPHAGUS, IT MIGHT BE EXPECTED IF THERE WAS POTENTIAL MECHANISM LINKING ORAL BIS PHOSPHONATE WITH CANCER, THE RISK MIGHT BE INCREASED BUT THIS SEEMS NOT TO BE THE CASE. NOW I’M TURNING TO BI SIXTH PHOSPHONATE AND ATRIAL FIBRILLATION. THE INTEREST STARTED IN THE HORIZON TRIAL A SIGNIFICANT INCREASE IN AFIB FIBRILLATION REPORT AS SERIOUS ADVERSE EVENT WITH REPORTED BY DENNIS BLACK AND COLLEAGUES IN 2007, YOU CAN SEE THE ABSOLUTE RISK 1.3%S FROM NULL .5%. STEVEN CUMMINGS ENDED ANALYSIS OF DATA FROM THE FIT TRIAL, REPORT AD SIMILAR NOT STATISTICALLY SIGNIFICANT TREND WITH THE USE OF OLENGOLATE THERE’S INCONSISTENT RESULTS META ANALYSES REPORTED FOR POTENTIAL ASSOCIATION. ARE THERE MECHANISMS WHICH COULD EXPLAIN THIS? AT FIRST BECAUSE OF THE PHARMACOKINETICS OF BIS PHOSPHONATE, VERY LOW CONCENTRATION IN BLOOD TAKEN UP BY BONE, SYSTEMIC SIDE EFFECTS WOULD SEEM UNLIKELY. WITH INTRAVENOUS ACID OBVIOUSLY YOU HAVE HIGHER CONCENTRATIONS IN THE BLOOD BUT FOR SHORT PERIODS OF TIME. OCCASIONALLY CLINICAL HYPERCAL SEEMIA CAN OCCUR THOUGH RARE. HOWEVER SMALL FLUCTUATIONS IN SERUM CALCIUM OCCUR AFTER ADMINISTRATION OF ORAL OR INTRAVENOUS BIS PHOSPHONATE. IT’S POSSIBLE THESE DOWN SUFFICIENT TO ALTER TRANSPORT OF CALCIUM AND CATIONS IN CARDIAC MYOSITES. THEN THE USUAL POSSIBLE OTHER EFFECTS WHICH MIGHT CONTRIBUTE FIBROTIC PRO-INFLAMMATORY AND ANTI-ANGIOGENIC EFFECTS. THIS SHOWS TWO META ANALYSES AT PHOSPHONATE AND ATRIAL FIBRILLATION IN DAN SOLOMON’S GROUP ON THE THESE ARE IN AGREEMENT, THIS META ANALYSIS IS FOR BIS PHOSPHONATE SHOWS SIGNIFICANT INCREASE OR DECREASE IN RISK ASSOCIATION WITH BIS PHOSPHONATE. IN THE META ANALYSIS OF RANDOMIZE CONTROL TRIALS, AGAIN NO INCREASE IN RISK. THERE WAS A SUGGESTION WHEN THEY LOOKED AT ACID THERE’S A TREND TOWARDS INCREASE IN RISK OF ATRIAL FIBRILLATION HERE THOUGH THIS IS NOT STATISTICALLY SIGNIFICANT. NOW ATRIAL FIBRILLATION ARE NOT INCLUDED AS CONTRAINDICATION FOR BIS PHOSPHONATE THERAPY NOR INCLUDED IN THE SPECIAL PRECAUTIONS. BUT IT MAY BE PRUDENT JUST TO CONSIDER WHEN YOU ARE CHOOSING THERAPY FOR PATIENT IF YOU HAVE A PATIENT WHO IS ALREADY AT HIGH RISK OF ATRIAL FIBRILLATION. AND HERE ARE SOME OF THE RISK FACTORS WHICH YOU WILL BE FAMILIAR WITH. FOR ATRIAL FIBRILLATION. SO TURNING NOW TO CARDIOVASCULAR DISEASE, HERE ARE THE DATA VERY INTERESTING BECAUSE THERE ARE SUGGESTION FROM SOME DATA OF PROTECTIVE EFFECT ON CARDIOVASCULAR DISEASE THOUGH THIS IS BY NO MEANS CONSISTENT FINDING. SO THERE WERE THREE OBSERVATIONAL STUDIES IN GROUPS OF PATIENTS, ONE WAS RHEUMATOID ARTHRITIS, ANOTHER WAS CHRONIC KIDNEY DISEASE, THE OTHER I THINK IS POST MENOPAUSAL OSTEOPOROSIS, DECREASE RISK OF ACUTE MYOCARDIAL INFARCTION AND STROKE WERE REPORTED BUT THESE FINDINGS WERE NOT UNIVERSAL BY ANY MEANS AND THERE WERE OTHER STUDIES THAT REPORTED NEUTRAL OR NEGATIVE EFFECTS. THERE WERE THEN TWO META ANALYSES OF RANDOMIZE CONTROL TRIALS, WHICH REPORTED NO EFFECT ON CARDIOVASCULAR DISEASE. I WILL SHOW YOU ONE OF THESE IN A MOMENT. THE ONE OF CROHNENBURG INCLUDED PATIENTS TREATED FOR CANCER WITH HIGHER DOSES SO PERHAPS LESS RELEVANT. THEN POTENTIAL MECHANISM THERE’S CERTAINLY SOME WHICH CAN BE INVOKED. SO DECREASE VASCULAR CALCIFICATION HAS BEEN SHOWN TO BE ASSOCIATED WITH BIS PHOSPHONATE THERAPY BOTH ANIMAL AND HUMAN STUDIES SHOWN THIS. BIS PHOCINENATE THERAPY IMPROVES THE LIPID PROFILE IN THE BLOOD. THEY HAVE ANTI-INFLAMMATORY EFFECTS WHICH COULD CONTRIBUTE. IN ANIMAL THOUGH THERE AREN’T HUMAN DATA, BENEFICIAL EFFECTS ARE BEING SHOWN ON CARDIAC MUSCLE. THIS SHOWS THE RESULT OF META ANALYSIS OF RANDOMIZE CONTROL TRIALS. AGAIN FROM DAN SOLOMON’S GROUP. WHAT YOU HAVE HERE IS VARIOUS OUTCOMES, MYOCARDIAL INFARCTION STROKE CARDIOVASCULAR MORTALITY AND ADVERSE CARDIOVASCULAR EVENTS. YOU CAN SEE THAT IN NO CASE IS THERE ANY SIGNIFICANT EFFECT. AND THE ABSOLUTE RISK OF BIS PHOSPHONATE VERSUS PLACEBO IS SHOWN IN THE LAST COLUMN. NOW, THESE DATA CONTRAST WITH STUDY WHICH IS RECENTLY REPORTED BEING REPORTED IN JBMR LOOKING AT CARDIAC DISEASE MORTALITY IN PATIENTS WITH HIP FRACTURE RECENT HIP FRACTURE TREATED WITH BIS TOES KNOWNATE. THESE OBSERVATIONAL DATA FROM DATABASE IN HONG KONG. 35,000 PATIENTS WITH NEWLY DIAGNOSED HIP FRACTURE WHOM ONLY 4 1/2 THOUSAND TREATED SO TREATMENT RATE OF 13% CONFIRMING VERY LOW TREATMENT RATES. AND MEAN AGE IN THIS COHORT OF 80 YEARS, LOOKING AT QUITE A FRAIL ELDERLY COHORT. IF WE LOOK AT OUTONLIES IN THE RED — OUTCOMES IN THE RED YOU HAVE INCIDENT MYOCARDIAL INFARCTION, PURPLE INCIDENCE STROKE AND IN THE TURQUOISE COLUMN, CARDIOASCULAR MORALITY. THEY LOOK AT THESE YEAR ONE, THREE, FIVE, TEN, HERE I’M SHOWING DATA FOR ALL BIS PHOSPHATASE. YOU CAN SEE REALLY LARGE BENEFITS IN ALL THESE OUTCOMES AT ALL THE TIME POINTS, THINK THEIR STRONGEST IN YEAR ONE THEN TEND TO DECLINE SLIGHTLY OVER TIME. THESE KIND OF EFFECTS ON INCIDENT MYOCARDIAL INFARCTION ARE MUCH HIGHER THAN YOU SEE STATINS. THOUGH THE AUTHORS IN THE STUDY DID THEIR — MADE THE BEST POSSIBLE EFFORT TO ADJUST FOR CONFOUNDERS, IT’S HARD TO BELIEVE THERE ISN’T SOME INFERENCE OF CONFOUNDING IN THESE DATA. BUT WE SHOULD ALSO KEEP OUR MINDS OPEN TO THE POSSIBILITY IN THIS PARTICULAR POPULATION ELDERLY FRAIL POPULATION, THERE MIGHT BE BENEFITS ON CARDIOVASCULAR DISEASE AND MORTALITY THAT AREN’T SEEN IN RANDOMIZED CONTROL TRIALS. WHERE GENERALLY THE POPULATION BEING TREATED IS MUCH HEALTHIER. I WANT TO END BY LOOKING AT WHETHER BIS PHOSPHONATE THERAPY IS ASSOCIATED WITH REDUCE OR ALL CAUSE MORTALITY, WE HAVE SEEN EARLIER TODAY FRACTURES PARTICULARLY HIP AND FRACTURES AND OTHERS ARE ASSOCIATED WITH INCREASE IN MORTALITY. THE INTEREST IN THIS AREA SUBJECT CAME WITH THE STUDY FROM LYLES ET AL SHOWING 28% REDUCTION IN MORTALITY WITH SOLID TONIC ACID IN HIP FRACTURE PATIENTS MIXTURE OF MEN AND WOMEN. SUBSEQUENTLY THERE WAS A META ANALYSIS SHOWING SIGNIFICANT 11% REDUCTION IN MORTALITY FOR ALL OSTEOPOROSIS TREATMENT, THERE WASN’T ACTUALLY SIGNIFICANT BIS PHOSPHONATE ALONE. IN A MOMENT YOU’LL SHOW YOU A VERY RECENT META ANALYSIS FROM STEVE CUMMINGS WHICH DID NOT SHOW ANY SIGNIFICANT REDUCTION. THERE’S BEEN A LOT OF OBSERVATIONAL STUDIES, I WON’T GO INTO DETAIL ABOUT ALL THESE. BUT A NUMBER OF THESE HAVE SHOWN REDUCTION IN MORTALITY, PARTICULARLY IN PATIENTS WITH RECENT HIP FRACTURE TREATED WITH BIS PHOSPHONATE BUT OTHER SETTINGS, FOR EXAMPLE FACTORY LIAISON SERVICES WHERE THE FRACTURE SITES ARE MIXED. THESE ARE THE DATA FROM STUDY BY LYLES ET AL SHOWING THIS 28% MORTALITY AFTER THREE YEARS. YOU CAN SO E THE SEPARATION OF HE LINE BEGINS AROUND 18 MONTHS. APPEARS TO PERHAPS INCREASE THEREAFTER. THEY WERE UNABLE TO PIN DOWN THE CAUSE, IT WASN’T DUE TO A REDUCTION IN SUBSEQUENT FACTOR THOUGH THAT MAY PLAY A ROLE. THESE STEVE CUMMINGS META ANALYSIS. VERY UP TO DATE INCLUDES THE RECENT DATA FROM IAN REED ONZOAL TONIC ACID. HE EXCLUDED (INDISCERNIBLE) FROM THIS META ANALYSIS AND ALSO STUDIES HE CAN CLUED FROM PRIMARY ANALYSIS. WHAT IT SHOWS IS NO REDUCTION IN MORTALITY, OVERALL RISK WAS 1.98. THIS WAS UNCHANGED BIS PHOSPHONATE CONSIDERED. SO IN TERMS OF KEY RECOMMENDATIONS, THERE ARE OBVIOUSLY MANY POSSIBLE ONES BUT ATYPICAL FEMORAL FRACTURES, VERY IMPORTANT TO WORK TOWARDS CONSENSUS ON OPTIMUM CASE DEFINITION BASED ON RADIOGRAPHIC FEATURES. APART FROM OTHER THINGS WE CAN DEFINE MORE ACCURATELY THE INCIDENCE OF THESE FRACTURES. IMPROVED UNDERSTANDING OF PATHOPHYSIOLOGY AND RISK FACTORS. CARDIOVASCULAR DISEASE, THIS IS A HUGE AREA, GREAT INTEREST I THINK, CLARIFICATION OF POTENTIAL RISKS AN BENEFITS. AND FURTHER INVESTIGATIONS OF POTENTIAL MECHANISMS BOTH IN HUMAN AN ANIMAL STUDIES. CLEARLY FURTHER STUDIES REQUIRE ON POTENTIAL ASSOCIATION OF BICSS IF FOENATE THERAPY WITH MORTALITY APPROXIMATE HOW THIS MIGHT BE MEDIATED. AND FINALLY, I THINK SAFETY DATA IN SUBGROUPS, AGAIN THIS IS COME UP SEVERAL TIMES TODAY IS REALLY IMPORTANT. WE HAVE RELATIVELY FEW SAFETY DATA IN MEN, IN PEOPLE TREATED WITH STEROIDS, STEROID TRIALS ARE USUALLY RELATIVELY SHORT. TYPE 2 DIABETES PROBABLY THE COMMON SECONDARY CAUSE OF OSTEOPOROSIS. AN ASSOCIATED WITH NUMBER OF COMORBIDITIES. THE OLEST OLD AND FRAIL PEOPLE. THANK YOU FOR YOUR ATTENTION. [APPLAUSE]>>AT THIS POINT IF I COULD ASK ALL THE SPEAKERS TO COME UP TO THE STAGE.>>HERE WE GO. WE HAVE DR. JACKSON AS WELL.>>AS WITH THE EARLIER SESSION, I’M GOING TO OPEN THIS WITH QUESTIONS FROM THE PANEL.>>I WOULD ROIC TO THANK YOU ALL FOR YOUR — LIKE THE THANK YOU ALL FOR YOUR PRESENTATIONS. WE HAVE LEARNED QUITE A BIT. SO I WOULD LIKE TO REALLY BE RESPONSIVE TO OUR PATIENT’S PERSPECTIVE. BECAUSE WE HEARD ABOUT HOW THEIR LIVES WERE CHANGED AND HOW THE LIVES OF OTHER PEOPLE THAT HAVE DIFFERENT SORTS OF OSTEOPOROTIC FRACTURES OR EVENTS MAYBE CHANGED. SO ONE THING I WONNER ABOUT IS MANY OF YOU TALKED ABOUT THE NEED FOR CONSISTENT DEFINITIONS FOR DIFFERENT SORTS OF FRACTURES OR OSTEONECROTIC JAW DISEASE, NUMBER OF THINGS YOU ARE LOOKING FOR THOSE CONSISTENCIES. CAN YOU MAKE ANY COMMENTS ABOUT IMPORTANT FUNCTIONAL OUTCOMES OF EITHER YOU HAVE RECORDED OR OTHERS STUDIES TRIALS MAY HAVE HAD A SECONDARY OUTCOMES? AND HOW YOU WOULD LIKE TO SEE THE PATIENT PERSPECTIVE INCORPORATED INTO FUTURE RESEARCH?>>JUST I CAN’T ANSWER THE WHOLE QUESTION BUT IN TERMS OF SECONDARY OUTCOMES I KNOW IN SOME OF THE TRIALS WE HAVE DONE WE LOOK AT THINGS LIKE BACK PAIN, ACTIVITY LIMITATIONS, DUE TO BACK PAIN, OUTCOMES IN TRIALS. THEY’RE SHOWN TO BE REDUCED ALONG WITH VERTEBRAL FRACTURES. DOESN’T FULLY ADDRESS THE QUESTION BUT YES.>>GREAT. SO I THINK ONE OF THE THINGS I HAVE LEARNED IN IN AGING RESEARCH IS THAT ORAL CARE IS VERY POORLY COVERED. SO HEARING THE IMPORTANCE OF THE PRESENTATION ON ORAL CARE AN HYGIENE, AN OFTEN WE FIND IAN NURSING HOME RESIDENTS AS WELL AS OLDER FRAIL PEOPLE PERSONS WITH ALZHEIMERS DISEASE AND RELATED DEMENTIA, REDUCED ABILITY TO HAVE ORAL CARE. WHAT WOULD BE YOUR RECOMMENDATIONS AN GAPS YOU SEE, ARE YOU SEEING THAT YOUR SPECIALTY IS AMONG THE MORE FRAIL?>>YES. THAT’S A GREAT QUESTION. I THINK WE CAN LEARN A LOT FROM WHAT HAS HAPPENED WITH OSTEORADIO NECROSIS RISK WHEN PATIENTS HAD HEAD AND NECK RADIATION THEY NOW UNDERGO COMPLETE DENTAL EVALUATION BEFORE THEY START RADIATION THERAPY. AND A LOT OF THAT NOW IS COVERED BY CERTAIN MEDICAL INSURANCE, AT LEAST THE INITIAL PART. THEN SOME OF THE CARE ESCALATES — WHEN YOU GET TO THIS IT BECOMES MORE MEDICAL RATHER THAN DENTAL, SO THERE’S A BIG CROSS OVER. SO I THINK THAT STARTING TO REALLY TALK TO INSURANCE COMPANIES AN MEDICARE AND SOME OF THOSE KEY PARTNERS IN THIS, IT’S VERY IMPORTANT AND A BIG STEP FORWARD TO TRY TO GET THOSE PATIENTS SCREENED AND EVALUATED MAYBE WITH A VISIT BEFORE THEY START THE THERAPY TO GET THINGS UNDER CONTROL AND ALSO HAVE THIS EDUCATIONAL VISIT SO THEY CAN UNDERSTAND WHAT TO LOOK FOR AND THAT THE FOLLOW-UP IS EXTREMELY IMPORTANT. BUT THESE ARE DIFFICULT BECAUSE AS YOU KNOW, MOST PEOPLE DON’T HAVE DENTAL INSURANCE AND WILL BE OUT OF POCKET SO THEY DON’T SEEK THAT CARE UNTIL IT’S A PROBLEM.>>A LOT OF OLDER AMERICANS DON’T REALIZE THAT MEDICARE DOESN’T COVER DENTAL PROBLEMS. AND THIS IS A BIG HOLE IN OUR INSURANCE SYSTEM.>>I KNOW THIS IS AN UNFAIR QUESTION BECAUSE WE DON’T HAVE THE DATA BUT TALK DRUG HOLIDAYS BECAUSE AS WE HEARD AS THE DRUG HOLIDAY BECAUSE IT’S NOT DRUG RETIREMENT,, DO YOU HAVE ANY PREDICTION ABOUT WHEN SOMEONE GOES BACK ON PARTICULARLY BICS PHOSPHONATES AND PARTICULAR RISKS, OR AND BENEFITS THAT MIGHT COME AFTER A DRUG HOLIDAY? DO YOU HAVE ANY IDEAINGS HOW LONG THOSE DRUG HOLIDAYS WOULD BE? QUESTION DIDN’T SEE A DIFFERENCE IN NON-VERTEBRAL FRACTURES, WE SAW THEM HAVE BENEFIT. WHAT YOU SAW WITH THESE SECONDARY ENPOINTS, BONE MINERAL DENSITY WEPT DOWN OVER FIVE YEARS SO SOME IT WAS BACK WHERE IT WAS BEFORE TREATMENT AND TURN OVER MARKERS WENT UP THOUGH SOME CASES NOT QUITE TO PRE-TREATMENT LEVEL SO I THINK I MEAN FROM THAT I WOULD SAY THINK FIVE YEARS WOULD BE OUTSIDE PERIOD FOR A DRUG — AND>>AND THEN BACK ON WOULD YOU EXPECT THE SAME RESPONSE ADS INITIAL RESPONSE?>>THERE’S REALLY NO DATA AS FAR AS I KNOW. THERE’S NO DATA. JUST BE SPECULATING. THE CONCERN WOULD BE THAT IF YOU IMAGINE SOMEONE HIGH RISK SAY AFF YOU GO BACK ON THEY MIGHT IMMEDIATELY BECOME HIGH RISK AGAIN. WE JUST DON’T KNOW THAT.>>I JUST WANT TO ASK ANOTHER THING BEFORE I PASS IT TO YOU. SO I WILL WONDERING WE HEARD DIFFERENT SPEAKERS TALK ABOUT SEQUENTIAL TREATMENT THERAPIES. I THINK WE CAN LEARN A LOT FROM OUR COLLEAGUES IN IN CANCER RESEARCH WHERE THEY DO A LOT OF OF ADAPTIVE TRIALS, THEY ARE COMPARING AGAINST OTHER MARKETED THERAPIES, THEY — THERE’S A NUMBER OF TRIAL DESIGNS SATELLITE IF YOU HAVE A FAILURE, YOU HAVE A PRE-SPECIFIED SECONDARY. HAVE ANY OF YOU, WE HEARD SOME OF THE RESULTS OF THINGS ON SEQUENTIAL TRIALS, DO YOU HAVE ANY PARTICULAR RECOMMENDATIONS OF SEQUENCES, HOW LONG SEQUENCES SHOULD BE, WE HEARD SOME THINGS ABOUT TRYING TO PICK PATIENTS THAT MAYBE APPROPRIATE FOR DIFFERENT SEQUENCES.>>I WANT TO THREE TO SIMPLIFY THIS. THE RIGHT SEQUENCE IS AN ANABOLIC TREATMENT, COURSE FOR CURRENT DRUGS WE GOT, BETWEEN 18 AND 24 MONTHS THEN MOVING TO A GOOD ANTI-RESORPTIVE DRUG. THAT IS THE PREFERRED SEQUENCE. HOW LONG THE ANTI-RESORPTIVE DRUG SHOULD BE, WHAT TO DO IF REACH YOUR GOAL AND THE GOALS I THINK ARE BOTH REMAINING FREE OF FRACTURE FOR AT LEAST FIVE YEARS PROBABLY, AND ALSO ACHIEVING A T SCORE ESPECIALLY IN THE HIP PERHAPS IN THE SPINE AS WELL. WHICH USUALLY SUGGESTS MINIMIZATION OF SUCK WENT FRACTURE RISK. THOSE WOULD BE THE TWO TARGETS THAT I USUALLY TRY TO ATTAIN. AND ONCE YOU GET THERE, IF YOU’RE ON DENOSMAB, THERE HAS TO BE SOME KIND OF TRANSITIONING TO GET TO A BISES IF FOENATE IN ORDER TO MAINTAIN THE GAINS AND WE DON’T KNOW EXACTLY WHAT THAT REGIMEN IS BUT THERE ARE STUDIES ONGOING TO LOOK AT THAT. IF THE PERSON IS ALREADY ON BISES IF FOENATE AND HAS ACHIEVED — BIS PHOSPHONATE AND ACHIEVED THESE GOALS, STOPPING TEMPORARILY IS THE RIGHT APPROACH ONCE THOSE TARGETS ARE ACHIEVED. NOW, WHAT YOU DO A FEW YEARS LATER IF THE PERSON APPEARS AT RISK AGAIN OR HIGH RISK AGAIN MIGHT BE ANOTHER COURSE OF ANABOLIC THERAPIES CURRENTLY WE HAVE A RECOMMENDATION, FDA RECOMMENDATION THAT WE NOT USE PTH RECEPTOR AGONIST TREATMENTS FOR MORE THAN TWO YEARS TOTAL USE. SO WE HAVE LIMITATION THERE, WE DO NEED OTHER ANABOLIC THERAPIES TO HELP BE AVAILABLE FOR PATIENTS WHO MIGHT NEED ANOTHER COURSE OF ANABOLIC THERAPY OR PERHAPS TENOSMAB AT THAT POINT IF A PERSON IS AT RISK AGAIN. MY PERSONAL VIEW ABOUT THIS IS THAT THE TREATMENTS NEED TO BE INDIVIDUALIZED. THAT I DON’T THINK WE CAN IN GENERAL SAY FIVE YEARS THERAPIES IS THE APPROPRIATE DURATION OF THERAPY AND THEN FIVE YEARS OFF IS AN APPROPRIATE DURATION OF DRUG HOLIDAY. I THINK THIS ALL NEEDS TO BE INDIVIDUALIZED, WE CAN HAVE CERTAIN GUIDELINES, HOW TO MAKE THOSE DECISIONS. BUT I THINK THE DECISIONS NEED TO BE INDIVIDUALIZED. BUT IN TERMS OF SEQUENCES, THE BEST SEQUENCE IF YOU IDENTIFY THE HIGH RISK PATIENT START WITH ANABOLIC AND THEN MOVE TO ANTI-RESORPTIVE, NOTHING ELSE WE SHOULD THINK IS OPTIMAL. TO STRESS, THIS WAS MENTIONEDD- EARLIER TODAY THAT OSTEOPOROSIS IS A CHRONIC DISEASE AND MANY PEOPLE NEED LIFE LONG THERAPY BECAUSE AGE IS SUCH A STRONG INDEPENDENT RISK FACTOR FOR FRACTURE IF YOU HAVE BEEN ON AND HAD THEM CORRECTED THAT’S ONE THING YOU CAN’T CORRECT. FIRST FIVE YEARS OF TREATMENT PRETTY GOOD EVIDENCE FOR EFFICACY AND RISK BENEFIT BALANCE. SOME TEN AN BEYOND TEN THERE’S NOTHING AT ALL AT THE MOMENT. THAT’S A HUGE RESEARCH GAP BECAUSE MANY WOMEN IF THEY STOP TREATMENT THE AGE OF 70, 75 OR LONGER THAN TEN YEARS. FROM>>JUST ONE MORE COMMENT ABOUT YOUR ANALOGY WHICH I REALLY LIKE YOU BROUGHT UP SOME OF THE THINGS WE MIGHT DO WITH CANCER TREATMENT, I HAVE USED THAT ANALOGY MYSELF IN THINKING ABOUT PATIENTS AT HIGH RISK OF SEVERE OSTEOPOROSIS. WE USE ANABOLIC THERAPY TO PUT THEM INTO REMISSION. TO REALLY LIFT THEM OFF THIS HIGH RISK CURVE. THEN WE USE ANTI-RESORPTIVE THERAPY TO HELP MAINTAIN AND SUGGESTION STAIN MINIMIZED RISK. MAKE FURTHER DECISIONS DOWN THE LINE. INDUCING REMISSION AND MAINTAINING THE REMISSION CONCEPT.>>PEOPLE HAVEN’T MENTIONED IN TERMS OF LONG TERM TREATMENT, THAT IS THE POSSIBILITY OF ESPECIALLY IN TERMS OF BIS PHOSPHONATE USING A LOWER DOSE. AND IN FOR EXAMPLE IN THE FLEX STUDIES WE HAVE TO PATIENTS WHO CONTINUE HAD HALF THE DOSE BUT NO INDISTINGUISHABLE DIFFERENCE IN EFFICACY BETWEEN HALF THE DOSE AND FULL DOSE. SO THAT DOES SUGGEST AFTER INITIAL QUARTERS YOU MIGHT BE ABLE TO DO JUST AS WELL WITH A SHORTER COURSE, IN TERMS OF ZLODRONIC ACID THERE’S FEWER INFUSIONS THROUGH TIME. SO INSTEAD I MEAN I WOULDN’T IMAGINE WANT THE NEED TO CONTINUE ANNUAL INFUSIONS FOR EXAMPLE TEN YEARS. IT WILL — ACID BASE SHOWED NO DIFFERENCE IN THE SECOND THREE YEARS WHETHER YOU GOT THREE MORE INFUSIONS OR NOT. SO THAT’S ANOTHER WAY TO THINK ABOUT THIS VERY LONG TERM GOING MORE GINGERLY WITH LOWER DOSES. (OFF MIC) ONE REASON TO CONSIDER ANABOLIC TREATMENT FIRST IN HOPES THAT THE AMOUNT OF TIME THAT PATIENT WOULD BE ON BIS PHOSPHONATE MIGHT BE SHORTENED OR THEY MIGHT GO TO LOWER DOSE OR MIGHT GO TO EXTENDING THE TIME BETWEEN ZOLODRONIC ACID AND INFUSION. WE HAVE A STEP UP BY GETTING ANABOLIC THERAPY FIRST. THE MAIN STUMBLING BLOCK, THERE ARE TWO. THE MAIN STUMBLING BLOCK IS THE COST. THE SECOND STUMBLING BLOCK IS THE NUISANCE OF A DAILY INJECTION. I DEAL WITH MEN, MOSTLY AND THEY’RE BIGGER BABIES IN GENERAL. AS FAR AS GETTING THEM TO TAKE A DAILY INJECTION THAN LIMIT THOSE ARE THE TWO STUMBLING BLOCKS BUT IF WE COULD ELIMINATE THEM SOMEHOW, IF WE HAD ALTERNATE ROUTE OF ANABOLIC TREATMENT AND TWO IF THE COST CAME DOWN, I DON’T THINK ANY OF US ON THIS PANEL WOULD HESITATE FOR A MOMENT OF USING ANABOLIC THERAPY FIRST IN A GREAT NUMBER OF OUR PATIENTS.>>I MIGHT ADD ONE MORE CAVEAT THOUGH BECAUSE WE’RE TALKING ABOUT LONG TERM USE AN INTERMITTENT OR — WE HAVE RELATIVELY LITTLE DATA AN TREATMENT OF INDIVIDUALS IN 8TH AND 9TH DECADES SO WE KNOW THAT AGE AN FRAILTY AND RISK FORMALS AN MULTIPLE OTHER FACTORS ARE AS IMPORTANT OR POTENTIALLY MORE IMPORTANT THAN BONE REMODELING AND CHANGES THAT ARE OCCURRING THERE FOR FRACTURE RISK IN DISABILITY THAT OCCURS. BALANCING OR THINKING ABOUT THOSE THINGS THINKING WHERE THERE MIGHT BE OTHER APPROACHES TO REDUCE SARCOPENIA AND FRAILTY AND THE THINGS THAT GO ALONG WITH RISK BECOME INCREASINGLY IMPORTANT TO ADD IN PART OF THE TREATMENT ARMAMENTARIUM AS YOU GET INTO THOSE LATER ADULT YEARS. BEFORE WE LEAVE THIS TOPIC LET ME GIVE DR. — A MOMENT HERE TO COMMENT. I THINK THAT NUMBER OF DIFFERENT APPROACHES HAVE BEEN DISCUSSED IN TERMS OF SEQUENCING TREATMENTS. BUT I WANTED TO CLARIFY THAT AT LEAST FROM YOUR REVIEW I SENSE STRENGTH OF EVIDENCE WAS LACKING FOR SOME OF THIS.>>WE DIDN’T FIND ANY TRIALS OF SEQUENTIAL THERAPY THAT WERE MORE THAN THREE YEARS RANDOMIZE PEOPLE TO ONE SEQUENCE VERSUS CONTROL GROUP THAT WERE MORE THAN THREE YEARS THAT MET ELIGIBILITY. SO I GUESS EVIDENCE WAS COMPLETELY LACKING. EVIDENCE THAT MET OUR ELIGIBILITY CRITERIA I SHOULD QUALIFY THAT.>>JUST A QUESTION ABOUT HORMONE REPLACEMENT THERAPY. GIVEN THAT YOU HAVE ALL THE INDICATIONS CAME DOWN THAT WHI STUDY THE BENEFIT RECEIVE ALSO FROM THE HORMONE REPLACEMENT THERAPY IN ADDITION TO OSTEOPOROSIS, MY QUESTION IS HOW DO YOU COUNCIL WOULD YOU COUNCIL SOMEONE WHO WANTS TO STAY ON ESTROGEN REPLACEMENT THERAPY FOR THE FIRST HOT FLASHES THEN LATER ON OSTEOPOROSIS ISSUES.>>THE CONVENTIONAL WISDOM HASN’T CHANGED DRAMATICALLY FOR A WOMAN WITH SEVERE UNREMITTING MENOPAUSAL SYMPTOMS THAT CAN’T BE MANAGED WITH OTHER FORMS OF LIFESTYLE CHANGES. THAT HORMONE THERAPY FOR SHORTEST DURATION POSSIBLE IS APPROPRIATE AND THAT THE EDITION OF ANOTHER TREATMENT FOR OSTEOPOROSIS PREVENTION IS LIKELY UNNECESSARY. BECAUSE ESTROGEN PLUS PROGESTIN ARE REDUCING BONE LOSS RISK FOR FRACTURES. THE CO-NUMBER DRUM IS HOW LONG, THAT’S A PROBLEM WHETHER DEALING WITH PREMATURE OVARIAN FAILURE HOW LONG YOU CONTINUE THAT, WHETHER THAT’S DEALING WITH SOMEBODY FOR FIVE THE TEN YEARS, AFTER THE AGE OF MENOPAUSE. WHAT WE DON’T KNOW IS IF YOU START THAT’S STROW GENERAL AT THE AGE OF 50 AND YOU CONTINUE IT CONSISTENTLY INTO THE SIX, 7, 8TH DECADE ARE YOU GOING TO LOOK MORE LIKE THOSE INDIVIDUALS WE HAD IN WHI WHO HAD AN AVERAGE AGE OF 63 STARTED HORMONE THERAPY ESTROGEN ALONE OR PLUS PROJESTIN AND HAD INCREASE. THE RISK IS CONSISTENT AND SEEN ACROSS EVERYTHING SO THE STROKE RISK UNLESS YOU LOOK AT TRANSDERMALS OR THOSE VERY LOW DOSES OF ESTROGEN AND THE PROBLEM IS YOU DON’T HAVE OBJECTIVE EVIDENCE IN TERMS OF OUTCOME TO BE CERTAIN SO WE DON’T KNOW THE THRESHOLD THAT GIVES US REDUCTION IN STROKE RISK OR OTHERS AND UNTIL WE HAVE THAT DATA WHICH WE MAY NEVER HAVE, UNTIL WE HAVE THAT WE MAKE THE BEST GUESS AND BEST RECOMMENDATIONS WITH THE DATA THAT WE CURRENTLY HAVE.>>WE HAVE CONSIDERABLE EVIDENCE IN TERMS OF WHAT HAPPENS TO PATIENTS WITH HIP FRACTURE VERTEBRAL FRACTURES, ET CETERA, IN TERMS OF WHAT THE COURSE OF THEIR DISEASE IS, AS DESCRIBED THIS MORNING. AND I UNDERSTAND THE DATA ARE OBVIOUSLY MORE SPARSE WITH THE MORE UNUSUAL SIDE EFFECTS. EVEN IN THE — I THINK IT WAS 360 PATIENTS WITH AFF, THE KEISER SERIES. WHAT DO WE KNOW ABOUT THE CHARACTERISTICS OF THESE PATIENTS ABOUT THEIR COURSE, THEIR FUNCTION, HOSPITALIZATIONS AFTER THEIR AFF.>>IN THAT STUDY IN TERMS OF CHARACTERISTICS OF THE PATIENTS BEFORE THE FRACTURE, THAT — I CAN TELL YOU FOR EXAMPLE HALF THE PATIENT, EVEN THOUGH ASIANS REPRESENT ONLY TEN PERCENT OF THE KEISER POPULATION HALF AFF OCCUR IN — THAT’S AN IMPORTANT CHARACTERISTIC, THEY ALSO TENDED TO BE OLDER, MIDDLE OLDER AGES LIKE IN THEIR 60s AND 70s SO THEY WEREN’T 85 YEARS OLD, KIND OF WHAT I SHOWED SO THOSE ARE IN TERMS OF CHARACTERISTICS IN TERMS OF WHAT HAPPENS AFTERWARDS THAT’S NOT SOMETHING THAT WE STUDIED YET IT’S POSSIBLE THOUGH I’M NOT SURE THAT KEISER IS NECESSARILY THE BEST VENUE FOR STUDYING FUNCTIONAL OUTCOMES AFTER AFF. BUT PERHAPS YOU MIGHT HAVE SOMETHING YOU MENTIONED SOMETHING ABOUT AFF MORBIDITY.>>MORBIDITY. WELL, I MEAN, BASED ON THE PATIENTS I HAVE SEEN, THIS IS ANECDOTAL SORT OF EVIDENCE I HAVE BEEN REALLY STRUCK BY THE HIGH MORBIDITY, I HAVE SEEN PEOPLE WHO HAVE TAKEN TWO OR THREE YEARS TO HEAL AND BE — OTHER THING THAT STRUCK ME IS THEY’RE RELATIVELY HEALTHY PEOPLE, PEOPLE WHO WERE PREVIOUSLY VERY ACTIVE, WALKING GO UP MOUNTAINS, THIS SORT OF THING. SO IT’S A HUGE IMPACT FROM THAT. THAT’S WHAT STRUCK ME BUT IT’S ANECDOTAL AND THEY ARE DIAGNOSED EARLIER AND TREATED EARLIER. SO THE OUTCOMES MAY HAVE IMPROVED A BIT.>>I THINK ALL WE HAVE RK SERIES AND THERE’S GREAT VARIABILITY SOME OF THE PATIENTS TREATED WITH ANABOLIC TREATMENT WITH VARIABLE RESULTS, BUT IT’S ALL ANECDOTAL AS FAR AS I KNOW THERE’S NO SYSTEMATIC STUDIES OUTCOMES. BUT IT’S VERY VARIABLE.>>I HAVE A QUESTION ABOUT THE EUROPEAN PERSPECTIVE. ARE THE TREATMENT REGIMENS THE SAME, ARE THE ISSUES THE SAME? Z FROM IS WHAT WE HAVE HERE.>>THE SIMILARITIES, THE SITUATIONS ARE NOT IDENTICAL. WE DON’T HAVE — THAT WAS DECLINED BY EMA. THEY APPEALED TRYING SO WE DON’T HAVE A (INDISCERNIBLE) BUT WE HAVE THE OTHER DRUGS THAT HAVE BEEN MENTIONED. THE COST OF DRUGS IN THE UK IS CONSIDERABLY LESS GENERALLY SPEAKING THAN IN THE US. SO ALENDRELATE IS TEN POUND A YEAR. SO CHINESE ACID FOR THE ACTUAL DRUG ITSELF IS ABOUT 80 POUNDS. TEN POUND A YEAR. RIGHT. COME DOWN THE GATE BUT YOU HAVE THE COST OF IV INFUSION. STILL VERY LITTLE. IT’S RUN 2000 A YEAR. WHEREAS WHAT NOW? 3,000. $3,000 PER MONTH.>>PER MONTH. I’M TALKING PER YEAR. HUGE DIFFERENCE IN THE PRICE OF THOSE DRUGS. ADS I’M SURE IS THE CASE IN THE U.S. COST EFFECTIVENESS IS REALLY A VERY IMPORTANT CRITERIA IN DECIDING WHAT TREATMENTS TO GIVE. I THINK THOSE ARE PROBABLY THE MAIN DIFFERENCES QUITE BIG ONES ACTUALLY. DR. COMES STONEY MAY HAVE MISUNDERSTOOD YOU BUT I THOUGHT YOU WERE SUGGESTING ONE OF YOUR SLIDES ONJ WAS NOT RELATED TO DURATION OF TREATMENT? YET A SUBSEQUENT SLIDE SEEMED LIKE PERHAPS IT WAS.>>I DIDN’T SAY THAT, I SAID FOR DENOSMAB AND THE DATA WERE LIMITED BECAUSE WE DIDN’T HAVE THE DATA FROM THE PREVIOUS STUDY. THERE IS A HINT THAT THERE IS AN ASSOCIATION WITH DURATION OF THERAPY. WITH DENOSM AP. FOR BIS PHOSPHONATE THERE’S SOME EVIDENCE RISK IS RELATED TO NEARLY AS STRONG AS ATYPICAL FEMORAL FRACTURES BUT SO I THINK YOU MUST HAVE MISHEARD ME, I HOPE I DIDN’T SAY THAT.>>LET ME OPEN UP TO THE AUDIENCE.>>IS THERE A ROLE FOR PEOPLE WHO ARE ON POTENT ANTI-RESORPTIVE DRUGS WHO NEED A DENTAL EXTRACTS OR IMPLANT FOR PROPHYLACTIC USE OF ANTIBIOTIC RINSE OR ORAL SYSTEMIC ANTIBIOTIC PERIOPERATIVELY? YES. BECAUSE OF THE ROLE OF INFLAMMATION AND INFECTION IF I HAVE TO DO THAT I DO GIVE PROPHYLACTIC ANTIBIOTIC BEFORE AND AFTER. AND SYSTEMIC AND RINSE?>>YES. BUT OF COURSE THAT’S ALL ANECDOTAL.>>DR. COSMAN.>>I AGREE WITH JULIET. THREE TO FIVE YEARS IN TERMS OF EFFICACY IS ABOUT AS STRONG AS BUT SEE ANY AREA. OUT TO TEN YEARS, WE’RE RELYING MORE ON OBSERVATIONAL DATA THAT DENNIS PRESENTED. THE QUESTION I HAVE IS THAT WHEN YOU LOOK AT OTHER CHRONIC DISEASES, HYPERTENSION, DIABETES, MICS, STROBE, HOW MANY AREAS IS THERE DATA OUT TO TEN YEARS AND BEYOND IN TERMS OF PREVENTING THAT PRIMARY END POINT? I WANT TO MAKE SURE THAT IN OSTEOPOROSIS WE DON’T SET OURSELVES UP FOR UNREALISTIC STANDARDS THAT ARE HARD TO REACH IN TERMS OF THE KIND OF DATA THAT DR. FINK WOULD WANT TO BE INCLUDED IN THOSE TYPES OF NAIL CEASE. MAYBE THE BEST DATA IS THAT DATA. CURIOUS YOUR THOUGHTS.>>I THINK DATA AS LONG AS WE ARE TALKING ABOUT IDEALLY WANTING OSTEOPOROSIS, NOT COMMON IN OTHER AREAS AND DOING A REVIEW ON DEMENTIA TYPICAL TRIALS ARE 24 WEEKS AND THREE YEARS IS AN OUTLIER FOR BEING THAT LONG AND FOR CARDIO VASCULAR TRIALS, NOT TEN YEARS, AND A LOT OF THINGS WITH ANTI- HYPOTENSIVES AND STATINS APPROXIMATE PEOPLE GET STARTED ON THESE BASED ON TRIALS OF INTERMEDIATE LENGTH. SEVERAL YEARS. AND STAY ON THEM FOR DECADES.>>I WAS GOING TO SAY ONE OF MY FAVORITE EXAMPLES IS ANTIDEPRESSANTS, TYPICALLY STUDIED FOR MAYBE THREE MONTHS AND 200 PEOPLE AND I’M SURE WE KNOW LOTS OF PEOPLE WHO HAVE BEEN TAKING THEM FOR MANY, MANY YEARS, THERE’S NO RANDOMIZE DATA, NO COHORT DATA.>>I THINK THOSE PATIENTS DOCTORS NEED TO REVISIT WHETHER THEY STILL NEED TO BE ON IT I THINK A LOT OF PEOPLE ON DRUGS THAT THEY MAY HAVE HAD AN INDICATION FOR ONE POINT BUT THEY DON’T PROBABLY HAVE IT ANY MORE.>>MAKING GOOD POINT, WE’RE IN THIS FIELD SETTING OURSELVES TOO HIGH A STANDARD THAT OTHER FIELDS DON’T REACH.>>PRIMARY CARE PHYSICIAN AND PATIENTS TO PRESCRIBE MEDICATIONS FOR WHICH WE HAVE BETTER EVIDENCE THAN IN MANY OTHER AREAS OF CHRONIC DISEASES I GUESS. THAT’S REALLY THE IRONY WE HAVE THE DEAL WITH I GUESS.>>UNIVERSITY KRISTIN BEAVERS WAKE FOREST UNIVERSITY. SO MY INSTITUTION WE DO A LOT OF GERIATRIC WEIGHT LOSS TRIALS AND THERE’S CONCERN IN THIS POPULATION THAT THE WEIGHT LOSS THEY EXPERIENCE CAUSES BONE LOSS AN EXACERBATE FRACTURE RISK. I KNOW THIS WASN’T TOPIC WASN’T DIRECTLY DISCUSSED BUT IN CONSIDERATION OF THE TITLE OF THE WORKSHOP I’M WONDERING WHAT THE PANEL THINKSN’T THE USE OF OSTEOPOROTIC OR DRUG THERAPY TO MINIMIZE WEIGHT LOSS ASSOCIATED BONE LOSS, POTENTIAL FRACTURE RISK.>>INTERESTING WAY, VERY DIFFICULT QUESTION TO ANSWER. PRESUME YOU TALK UNINTENTIONAL WEIGHT LOSS. INTENTIONAL WEIGHT LOSS IN PEOPLE WHO WERE PREVIOUSLY OVERWEIGHT. IS THAT CORRECT? OKAY. THEY DO LOSE BONE, IT’S KIND OF PHYSIOLOGICAL ADAPTATION TO HAVING LOWER WEIGHT. BUT THERE’S ALSO SOME EVIDENCE THEY HAVE INCREASE IN FRACTURE RISK AS A RESULT OF THAT. IS THERE’S SOME DATA THAT SUGGESTS IF YOU COMBINE EXERCISE REGIMENS WITH WEIGHT LOSS THEN THAT DOES AT LEAST ATTENUATE BONE LOSS, THERE AREN’T FRACTURE DATA. PARTICULARLY IN ELDERLY FRAIL POPULATION YOU WERE DESCRIBING, EXERCISE REGIMEN MAY NOT BE REALLY APPROPRIATE. THEY MAY BE SAFETY AND CERTAINLY BASIS OF COMPLIANCE. SO IT’S A DIFFICULT ONE BECAUSE THE WEIGHT LOSS IS BENEFICIAL FOR MANY POINTS OF VIEW BUT FROM THE POINT OF VIEW BONE DISEASE SKELETON, THERE IS BONE LOSS, THERE INCREASE IN FRACTURE RISK. INTENTIONAL WEIGHT LOSS, SAY 10, 12 KILOGRAMS OR ABOVE. AND MITIGATING THAT BONE LOSS AN REDUCING THAT FRACTURE RISK IS DIFFICULT, SHOULD YOU GIVE BIS PHOSPHONATE? I THINK THAT WOULD BE DECISION TO MAKE ON AN INDIVIDUAL PATIENT BASIS BUT IT WOULD BE DIFFICULT TO RECOMMEND SIMPLY PROPHYLACTIC MEASURE FOR PEOPLE WHO LOSING WEIGHT.>>AS A COURTESY TO THE FOUR PEOPLE WHO ARE ASKING QUESTIONS I’M GOING TO ASK US TO MOVE IT ALONG.>>ELIZABETH SHANE. I JUST — DRUG HOLIDAYS. AS YOU KNOW I DON’T THINK THIS WAS STATED SOMEBODY WAS THINKING ABOUT FIVE YEARS MIGHT BE A DURATION OR LESS THAN FIVE YEARS AND THERE’S CERTAIN BIS PHOSPHONATES THAT ARE SHORTER ACTING SUCH AS RESDRI NEXTATE ONE WOULD NOT WANT TO PERHAPS WAIT AS LONG IN ONE OF THE SHORTER ACTING DRUGS TO END A DRUG HOLIDAY. SO THAT IS THERE ARE DIFFERENCES AMONG THE BIS PHOSPHOMATES AND DENOSMAB WE SHOULDN’T GIVE DRUG HOLIDAY AFTER THAT POINT WAS MADE. MY SECOND QUESTION WAS REALLY FOR DENNIS ABOUT WHEN YOU TALKED ABOUT DRUG HOLIDAYS AND FRACTURE RISK YOU FOCUSED ON NON-VERTEBRAL FRACTURES, I DON’T HEAR MUCH ABOUT VERTEBRAL FRACTURES, YOU HAVE SHOWN IN YOUR WORK THAT VERTEBRAL FRACTURES MAYBE MORE AN ISSUE AND ALSO THAT THERE ARE SOME BONE DENSITY TARGETS THAT MIGHT BE RELEVANT WHETHER ONE MIGHT RECOMMEND A DRUG HOLIDAY SO I THOUGHT THAT WAS IMPORTANT AND YOU MIGHT COMMENT ABOUT THAT.>>I EXPECTED THAT THE REVIEW WOULD COVER THE FLEX AND THE TALK ABOUT THE VERTEBRAL FRACTURE. SO I DIDN’T SAY ANYTHING ABOUT IT. SO JUST TO REITERATE WHAT YOU SAID, THE ONE FRACTURE BENEFIT THAT WE FOUND AND YOU REALLY IN BOTH EXTENSION RANDOMIZE TRIALS WAS THAT THE PEOPLE THAT CONTINUED HAD REDUCED RISK OVERT PRIAL FRACTURE COMPARED TO THOSE THAT STOP THAT LED US TO MAKE THE RECOMMENDATION THAT WOMEN WHO ARE PARTICULARLY HIGH RISK OF VERTEBRAL FRACTURES THAT WOULD COUNT TOWARD THEM MORE LIKELY TO CONTINUE ON THERAPY FOR LONGER BECAUSE OF THAT RISK OF VERTEBRAL FRACTURE. SO THAT WOULD MEAN PARTICULAR WOMEN MULTIPLE VERTEBRAL FRACTURES ALREADY OR WOMEN WHO HAVE VERY LOW BONE DENSITY ALREADY. MIGHT BE BETTER CANDIDATES TO NOT HAVE A DRUG HOLIDAY.>>MAKING THE POINT DRUG HOLIDAY DOESN’T MAKE TAKING THE HOLIDAY FROM THE CLINICIAN. IF YOU’RE GOING TO DO THAT YOU NEED TO SEE THE PATIENT ANNUALLY AND CONSIDER A DESA, MAYBE EVERY TWO YEARS, BUT IT DOESN’T MEAN FOR GETTING ABOUT YOUR PRIOR FRACTURE RISK.>>(INAUDIBLE) WITH FOGARTY INTERNATIONAL CENTER. SEVERAL YEARS AGO FOGARTY PUT OUT A REQUEST FOR INFORMATION ON ROLE OF LEAD EXPOSURE IN COGNITIVE FUNCTION AND BONE HEALTH SO WE IDENTIFIED A NUMBER OF GAPS FOR RESEARCH PARTICULARLY WANT TO POINT OUT COUPLE OF THINGS THAT CAME OUT OF THAT. THERE ARE A NUMBER OF STUDIES THAT SHOW HOW WITH AGE LEAD COMES OUT OF BONES AND GETS RECIRCULATED. ONE OF THE DATA POINTS WE HAVE IDENTIFIED IS ACTUALLY BIS PHOSPHONATE REDUCE BLOOD LEAD LEVELS SO THE RECENT STUDIES THAT HAVE CALLED ATTENTION TO THE ROLE OF RELATIVELY LOW LEVEL LEAD EXPOSURE IN CARDIOVASCULAR DISEASE RISK, SO ONE OF MY POINTS IS THAT POTENTIALLY COULD BE MECHANISM IF THERE IS A PROTECTIVE EFFECT OF BIS PHOSPHOMATE ON CARDIOVASCULAR DISEASE, THAT IS ONE POSSIBLE PATHWAY THAT IT MIGHT WORK THROUGH. ONE OTHER POINT I WOULD ALSO RECOMMEND AS PART OF THE FUTURE STUDIES THAT YOU CONSIDER ADDING MEASUREMENTS OF BLOOD LEAD AS ANOTHER INDICATOR OF BREAKDOWN OF BONE AND ALSO ADDITIONAL RISK FACTOR FOR OTHER OUTCOMES. THANK YOU.>>PAUL MILLER FROM DENVER. I SEE A LARGE NUMBER OF VERY SICK PATIENTS. MULTIPLE FRACTURES, VERTEBRAL CENTER FROM DENVER AND WE USE EXCEPTIONALLY LARGE AMOUNT OF AN BOLLICS. AND HAVE NOW FOR 17 YEARS. I WOULD LIKE TO HAVE THE GROUP AT LEAST HAVE A RESPONSIBLE DISCUSSION SOMETIME MAYBE NOT THIS PARTICULAR SESSION OF TO CONSIDER DISCUSSING WITH THE FDA REMOVING THE BLACK BOX WARNING FROM TERPERTIDE, THE FLAW COMA IS NOT SEEING IN REMODELED BONES LIKE HUMANS HASN’T BEEN SEEN IN 17 YEARS ANY HIGHER THAN BACKGROUND INCIDENT RATE AND THE BIGGEST PROBLEM WITH IT IS NOT — BECAUSE OFTEN WE WANT TO USE IT BEYOND YEARS P 1 P — PEEP ON HIGH DOSE STEROIDS MULTIPLE FRACTURES, THEY STOP FRACTURING QUALITY OF LIFE IS BETTER. THE BIG PROBLEM IS INSURANCE COMPANIES USE THAT AS THEIR EXCUSE NOT TO PAY FOR IT BEYOND TWO YEARS AND THAT RESTRICTS OUR CARE. SO I WANT JUST FOR CONSIDERATION NOT A VOTE. I THINK THERE’S ENOUGH EVIDENCE FOR US TO BEGIN DISCUSSION. IN THAT WAY.>>RAISE ONE POINT ABOUT WHETHER LONG TERM ADMINISTRATION TERPERTIDE YOU MAINTAIN THE EFFICACY, THERE ARE DATA WHICH SUGGEST THE EFFICACY WEARS OFF AFTER 18 MONTHS TWO YEARS. WE CERTAINLY DON’T REALLY HAVE THE EVIDENCE AT THE MOMENT LONG TERM ETHNICITY.>>GOOD POINT. I THINK OF COURSE THERE ARE PEOPLE WHO LIVE IN THE WORLD OF THE WENT PATHWAY WHO BELIEVE IF YOU HAMMER THE PATHWAY LONG ENOUGH YOU MAY DIRECT IT INTO A BAD PATHWAY. I DO THINK WE NEED THAT DATA AND I DO THINK CONSIDERATION, OUT IN THE REAL WORLD OF MEDICINE WE ARE DEALING WITH THIS ISSUE ALL THE TIME.>>IT MIGHT BE THAT INSTEAD OF CONTINUING IT BEYOND TWO YEARS RIGHT THE TIME YOU CONSIDER ANOTHER COURSE OF ANABOLIC THERAPY A FEWIERS LATER IF YOU NEED IT WHEN YOU REGENERATE YOUR OSTEOBLAST PRECURSORS YOU DON’T HAVE AS MANY INHIBITORS OF WINT SIGNALING THAT MIGHT BE INDUCED DURING THE INITIAL COURSE OF THERAPY.>>TO THE RIGHT.>>TERRY O’CONNOR FOX COUNTY PA. EVERYBODY STATED WHERE THEY’RE COMING FROM. TWO COMMENTS, ONE REGARDING ADHERENCE IF YOU AN LOOK BY PATIENT AGE BECAUSE I HAVE BEEN MOTIVATED TO STAY ADHERENT TO DRUGS THAT WAS RECOMMENDED FOR ME, I TURNED 60 LAST MONTH, I HAVE A LOT TO LIVE VERSUS IF I WAS 80, MAYING NOT BE AS ADHERENT SO TO THINK ABOUT LOOKING AT ADHERENCE BY AGE, MY SECOND COMMENT WAS WHEN I WAS DIAGNOSED I WAS MOTIVATED TO FIND A DOCTOR AND I COULDN’T FIND ONE UNTIL AFTER I HAD THAT FRACTURE. SO IF THERE’S IN I WAY — I MEAN OBVIOUSLY EVEN IN THE AUDIENCE IS PASSIONATE ABOUT THIS DISEASE, IF THERE’S IN I WAY THE PANEL TOGETHER WITH THE NIH CAN HELP IDENTIFY PHYSICIANS THAT ARE WILLING TO TREAT THIS DISEASE OR EDUCATE DOCTORS THAT IF THEY’RE GOING TO DIAGNOSE AND NOTE TREAT IT TO REFER OUT BUT THAT’S WHERE I THINK THERE WAS A MISSTEP FOR ME BECAUSE CANCER, YOU GO TO ONCOLOGIST, CARDIAC, GO TO CARDIOLOGIST BUT IN THIS CATEGORY NO SPECIALTY OWNS THE DISEASE. THANK YOU.>>MY NAME IS ART SATTURA, I WORK FOR MERCK AND CLINICAL RESEARCH 27 YEARS UNTIL I RESTYRED FROM MERCK LAST YEAR. SO NOW I HAVE THE OPPORTUNITY TO ASK SOME QUESTIONS, I ALWAYS WANTED TO ASK, ACTUALLY THIS IS NOT REALLY A QUESTION, JUST A REQUEST. THERE’S AN EXCELLENT REVIEW IN ONJ BUT FOR PEOPLE IN THE BONE BUSINESS,? PATIENTS, IT WOULD BE TERRIFIC TO DESCRIBE EPIDEMIOLOGY OF ONJ IN PEOPLE TAKE OSTEOPOROSIS DRUG AND PEOPLE TO DEVELOP ONJ HAS I THINK DRAMATICALLY DIFFERENT FROM WHAT ONE WOULD DO IN A CANCER PATIENT, AND HAVE UNDERLYING RISK FOR INFECTION AND A VARIETY OF OTHER CONDITIONS. YOU JUST CAN’T STOP THE THERAPY IN CANCER PATIENTS. SO THAT WAS MY REQUEST. THANK YOU, VERY MUCH FOR CONSIDERATION.>>GREAT POINT AND SOMETHING POTENTIALLY TO DO IN THE NEXT POSITION PAPER BUT ONE OTHER THINGS THAT I THINK WOULD BE DIFFICULT IS THERE’S NOT ENOUGH EVIDENCE TO MAKE RECOMMENDATIONS BECAUSE LIKE I SAID YOU HAVE TO HAVE THOUSANDS OF PATIENTS TO EVEN GET INCIDENCE AND THEN FROM THERE TO TEST. SO EXPERT OPINION WHICH COULD BE DONE BUT WOULDN’T BE SCIENTIFIC BUT MAYBE THAT’S SOMETHING THAT HAS TO BE DONE AS A FIRST STEP. THANK YOU. LAST QUESTION.>>DOUG KEEL BOSTON. AS I WAS THINKING OF THE REASON FOR THIS P 2P CONTEST THAT SANDEEP AND OTHERS SHARED WITH A LARGE NUMBER OF PATIENTS WHO CONTACTED ABOUT RARE SIDE EFFECTS AND THE TREATMENT GAP THAT WE SAW IN THE INTRODUCTORY SESSION AND BOB’S ENLESS SLIDES SAYING WHAT WE DON’T KNOW ABOUT ATYPICAL FEMUR FRACKTURES WOULD SEEM — FRACTURES, IT WOULD SEEM SOMEWHAT A POSITIVE APPROACH WOULD BE TO CREATE GOING FORWARD A REGISTRY OF FEMUR FRACTURES WELL CHARGIZED ESPECIALLY IF WE SUCK — CHARACTERIZED IF WE SUCCEED AT CLOSING THE TREATMENT GAP WE MIGHT SEE MORE ATYPICAL FEMUR FRACTURES. SO I’M WONDERING IF ANYONE THOUGHT THIS COULD BE A RESEARCH GAP THAT NEEDS TO BE FILLED?>>GREAT IDEA DOUG. CERTAINLY PUT THAT ON RESEARCH AGENDA.>>DOUG, I MIGHT FOLLOW-UP IN THAT THAT I THINK THIS IS A REAL OPPORTUNITY TO LEVERAGE THE CLINICAL DATA RESEARCH NETWORKS AND EMR AND BE ABLE TO LOOK AT THESE THINGS THIS WAS EARLIER DISCUSSION. AS WE GET STANDARDS AND DEFINE BETTER WITHIN THAT, THE ABILITY TO USE THE ELECTRONIC HEALTH RECORD IN A CONCEPT OF LEARNING HEALTH SYSTEM TO BE ABLE TO MOVE FORWARD, NOT JUST AT A SINGLE INSTITUTION BUT AT NATIONAL PERSPECTIVE, CAN REALLY DRIVE DECISIONS, IT WILL DRIVE THINGS SUNDEEP WAS WORRIED ABOUT WE CAN’T HAVE RANDOMIZE TRIALS GOING ON FOR 20 YEARS BUT WE CAN LEVERAGE WELL CHARACTERIZED COHORTS WITH GOOD DEFINITION AND MULTIPLE OUTCOMES SO WE DON’T HAVE TO SPEND HE $750 MILLION COST TO DO WHI TO ANSWER THOSE QUESTIONS. BUT WE ALSO BE ABLE TO USE REAL LIFE DATA IN ORDER TO BE ABLE TO UNDERSTAND RISKS AND BENEFITS OF ALL THE DIFFERENT DRUGS WE HAVE AVAILABLE.>>WITH THAT, LET ME TAKE THIS OPPORTUNITY TO THANK ALL OUR SPEAKERS TODAY. DR.s COSMAN, FINK, AGHALOO TOMORROW WE’LL GO BACK TO SESSION OF DRUG HOLIDAYS. DR. FINK WILL DO PART THREE OF MINNESOTA EPC PRESENTATION ON THAT AND WE’RE GOING TO SPEND SESSION AS WELL TALKING ABOUT PATIENT AND CLINICIAN FACTORS THAT RELATE TO THE PRESCRIBING OF OSTEOPOROTIC DRUG TREATMENTS. SO WITH THAT, LET ME THANK ALL OF YOU FOR THE STAMINA OF SITTING THROUGH ALL THIS THIS AFTERNOON. ALL DAY. I RECOGNIZE MANY PEOPLE IN THE AUDIENCE WHO ARE NOT SPEAKERS. THANK YOU.

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