Reducing the Risk of Fracture in Postmenopausal Women: Guidance for Family Physicians

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1 Sturdy Generl Session Reducing the Risk of Frcture in Postmenopusl Women: Guidnce for Fmily Physicins E. Michel Lewiecki, MD Clinicl Assistnt Professor of Medicine University of New Mexico School of Medicine Director, New Mexico Clinicl Reserch nd Osteoporosis Center Aluquerque, New Mexico Eductionl Ojectives By the end of this eductionl ctivity, prticipnts should e etter le to:. Identify ptients t risk of frcture using DXA, FRAX, nd guideline-sed dignostic criteri.. Select pproprite therpies for osteoporosis sed on the ptient s frcture risk, guideline recommendtions, nd emerging dt.. Compre the efficcy, dverse effects, nd mechnism of ction for ville nd emerging phrmcotherpies for the mngement of osteoporosis. Speker Disclosure Dr. Lewiecki hs disclosed tht he hs received grnt support from Amgen, Mereo, PFEnex, nd Rdius; he is consultnt for Alexion, Amgen, Celltrion, Rdius, Sndoz, nd Ultrgenyx; nd he is on the speker s ureu for Alexion nd Rdius. Supporter Disclosure This eductionl ctivity is supported y n eductionl grnt from Amgen. It hs een plnned nd produced y North Crolin Acdemy of Fmily Physicins nd Spire Lerning with Texs Acdemy of Fmily Physicins strictly s n ccredited continuing medicl eduction ctivity.

2 Sponsorship nd Support Reducing the Risk of Frcture in Postmenopusl Women: Guidnce for Fmily Physicins This eductionl ctivity is jointly provided y the North Crolin Acdemy of Fmily Physicins (NCAFP) nd Spire Lerning. This ctivity is supported y eductionl funding provided y Amgen. Plese complete the pressessment efore the session strts. Accredittion Sttements AAFP Prescried Credit: This live ctivity, Reducing the Risk of Frcture in Postmenopusl Women: Guidnce for Fmily Physicins, hs een reviewed nd is cceptle for up to. Prescried credit(s) y the Americn Acdemy of Fmily Physicins. Physicins should clim only the credit commensurte with the extent of their prticiption in the ctivity. AMA/AAFP Equivlency: AAFP Prescried credit is ccepted y the Americn Medicl Assocition s equivlent to AMA PRA Ctegory Credit(s) towrd the AMA Physicin s Recognition Awrd. When pplying for the AMA PRA, Prescried credit erned must e reported s Prescried credit, not s Ctegory. Instructions to Receive Credit To receive credit for your prticiption in this eductionl ctivity: Red the ojectives nd other introductory CME informtion Complete the pressessment prior to the strt of the ctivity Prticipte in the postmenopusl osteoporosis presenttion Complete the postssessment nd evlution t the conclusion of the ctivity Fculty nd Disclosures Activity Chir Felici Cosmn, MD Professor of Clinicl Medicine Columi University College of Physicins nd Surgeons New York, NY Disclosure Sttement: Advisory Bord: Amgen Inc; Eli Lilly nd Compny; Rdius Helth, Inc Grnt Recipient/Reserch Support: Amgen Inc; Eli Lilly nd Compny Promotionl Speker s Bureu: Amgen Inc; Eli Lilly nd Compny; Rdius Helth, Inc. Fculty nd Disclosures (Cont.) Fculty Presenter E. Michel Lewiecki, MD, FACP, FACE Clinicl Assistnt Professor of Medicine University of New Mexico School of Medicine Director, New Mexico Clinicl Reserch & Osteoporosis Center Aluquerque, NM Disclosure Sttements: Assocition Bord Memer: Ntionl Osteoporosis Foundtion; Interntionl Society for Clinicl Densitometry; Osteoporosis Foundtion of New Mexico Consulting: Alexion Phrmceuticls Inc.; Amgen, Inc; Celltrion; Rdius Helth, Inc; Sndoz; Ultrgenyx Phrmceuticl Inc. Reserch Grnt Support: Amgen Inc; Mereo BioPhrm; Pfenex Inc; Rdius Helth, Inc. Speker s Bureu: Alexion Phrmceuticls Inc.; Rdius Helth, Inc.

3 Off-Lel nd Disclimer Sttements This eductionl ctivity my contin discussion of pulished nd/or investigtionl uses of romosozum for the mngement of postmenopusl osteoporosis tht re not indicted y the FDA. Plese refer to the officil prescriing informtion for ech product for discussion of pproved indictions, contrindictions, nd wrnings. Further, prticipnts should pprise the informtion presented criticlly nd re encourged to consult pproprite resources for ny product or device mentioned in this progrm. Levels of Evidence Recommendtion Description Grde A Homogeneous evidence from multiple, well-designed, rndomized, controlled trils with sufficient sttisticl power Homogeneous evidence from multiple, well-designed, cohort-controlled trils with sufficient sttisticl power conclusive level pulictions demonstrting enefit >> risk B Evidence from well-designed clinicl tril, cohort- or cse-controlled nlytic study, or metnlysis No conclusive level pulictions; conclusive level pulictions demonstrting enefit >> risk C Evidence sed on clinicl experience, descriptive studies, or expert consensus opinion No conclusive level or pulictions; conclusive level pulictions demonstrting enefit >> risk No conclusive risk t ll nd no conclusive enefit demonstrted y evidence D Not rted No conclusive level,, or pulictions demonstrting enefit >> risk Conclusive level,, or pulictions demonstrting risk >> enefit Source: AACE Criteri for Grding Recommendtions. Cmcho PM, et l. Endocr Prct. ;(suppl ):-. Lerning Ojectives At the conclusion of this live ctivity, lerners should e etter le to: Identify ptients t risk of frcture using prior frcture history, verterl imging, DXA, nd FRAX. Select pproprite therpies for osteoporosis sed on n ssessment of the ptient s imminent or long-term frcture risk. Compre the efficcy, dverse effects, nd mechnism of ction for ville nd emerging phrmcotherpies for the mngement of osteoporosis. Employ gol-directed therpy, sequentil therpy, nd drug holidys to chieve tretment gols. Definition of Osteoporosis A chronic progressive skeletl disorder chrcterized y Compromised one strength predisposing to n incresed risk of frcture Bone strength reflects the integrtion of two min fetures: Bone density Bone qulity Risk Fctors: Estrogen deficiency nd ging Genetics: fmily history, ethnicity Chronic diseses nd medictions Lifestyle: nutrition, exercise, smoking, lcohol Norml Bone Osteoporotic Bone NIH Consensus Development Conference. Helth Consequences of Osteoporosis Osteoporosis-relted frctures Frctures in people > yers of ge tht occur in the setting of trum equl to or less thn fll from stnding height Exceptions re fingers, toes, fce, nd skull Lifetime osteoporosis-relted frcture risk in women Up to in men Ech yer in the US, verterl frctures, wrist frctures, hip frctures, pelvic frctures 7, other frctures (humerus, ri, ptell, clvicle, etc.) Consequences of Hip Frcture Hip frctures require surgicl repir nd hospitliztion % mortlity in the yer following the frcture, deths in the US ech yer % require t lest temporry sty in nursing home Over % permnently disled Over -fold risk of ecoming destitute Ry NF, et l. J Bone Miner Res. 997;():-.

4 Consequences of Verterl Frcture Acute ck pin in %-% Incresed risk of mortlity Chronic ck pin Height loss/kyphosis Disility relted to poor multion, loss of lnce, nd high flling risk Pulmonry symptoms relted to restrictive lung disese Adominl symptoms Verterl Frcture Identifiction Most spine frctures do not come to clinicl ttention t the time of the event (7%). Proctive trgeted screening spine imging recommended to identify those with spine frctures Courtesy of the Interntionl Society for Clinicl Densitometry. Culey JA, et l. Bone. ;88:-9. Cosmn F, et l. Osteoporosis Int. ;():9-8. Cosmn F, et l. Osteoporosis Int. ;():9-8. Prevlence of Spine Frctures y Age Overll prevlence is.% History of Self-Reported Spine Frcture Compred to VFA Dignosis Of those reporting history of spine frcture % (9% CI ) hd positive VFA Of those dignosed with spine frcture y VFA 8.% (.,.) reported history of frcture History of self-reported spine frcture* VFA dignosis Cosmn F, et l. Osteoporosis Int. 7;8(8):9-. *Numers in figure re unweighted. VFA, verterl frcture ssessment. Cosmn F, et l. Osteoporosis Int. 7;8(8):9-. Dignosis of Osteoporosis Osteoporosis Cn Be Dignosed y Presence of Frcture nd/or BMD Criteri Osteoporosis cn e dignosed y*: Occurrence of low-trum hip frcture - Occurrence of low-trum spine, humerus, or pelvis frcture in person with osteopeni - BMD T-score -. spine, totl hip, femorl neck - T-score compres n individul s BMD with the men vlue for young dults nd expresses the difference s stndrd devition score, Norml -. nd ove Low one mss (osteopeni) -. to -. Osteoporosis -. nd elow?? Elevted frcture risk, e.g., y FRAX - This pproch is eing pplied in mny countries where the osteoporosis intervention threshold is sed on frcture risk *Grde B BMD, one minerl density.. Siris E, et l. Osteoporos Int. ;: Siris E, et l. Osteoporos Int. ;:9-.. Cmcho PM, et l. Endocr Prct. ;(suppl ):-.. WHO Study Group. World Helth Orgn Tech Rep Ser. 99;8:-9.. WHO Scientific Group. Assessment of Osteoporosis t Primry Helth Cre Level. Pulished 7.

5 Who Should Hve Bone Density Test? AAFP nd NOF Guidelines Women ge nd older Men ge 7 nd older Postmenopusl women nd men ges -9 with clinicl risk fctors Adults who hve frcture fter ge Adults with condition (e.g., rheumtoid rthritis) or tking mediction (e.g., glucocorticoids) ssocited with low one mss or one loss Who Should Hve Verterl Frcture Assessment? Women ge 7 nd men ge 8 if BMD T-score is -. t the spine, totl hip, or femorl neck Women ge -9 nd men ge 7-79 if BMD T-score is -. t the spine, totl hip, or femorl neck Postmenopusl women nd men ge with specific risk fctors Low trum frcture during dulthood (ge +) Historicl height loss of. inches or more ( cm) Prospective height loss of.8 inches or more ( cm) Recent or ongoing long-term glucocorticoid tretment If one density testing is not ville, verterl imging my e considered sed on ge lone AAFP, Americn Acdemy of Fmily Physicins; NOF, Ntionl Osteoporosis Foundtion.. Sweet MG, et l. Am Fm Physicin. 9;79():9-.. Cosmn F, et l. Osteoporos Int. ;():9-8. Cosmn F, et l. Osteoporos Int. ;():9-8. Cmcho PM, et l. Endocr Prct. ;(Suppl ):-. Limittions of FRAX Not vlid to monitor ptients on tretment Only femorl neck BMD considered Risk is yes/no without considertion of dose (e.g., glucocorticoids, smoking) Not ll risk fctors included (e.g., risk of flling) Mny diseses nd medictions not included No considertion of time from frcture No considertion for multiple frctures Do ptients with high FRAX scores enefit from mediction? (Unknown) Mny Ptients With Frctures Do Not Hve Osteoporosis y BMD Criteri Women Nonverterl frctures % Osteoporosis Rotterdm Study % Norml BMD % Low BMD % % 8% Men Nonverterl frctures Ptients With Prior Frctures Are High Risk Prior frcture is the most importnt risk fctor for nother frcture Hzrd Rtios for Groups of Incident Frctures Previous frcture site Any one Hip Spine Any prior frcture.9..9 frcture.8.. frctures > frctures Hip frctures % Norml BMD % Low BMD % Osteoporosis 9% % 8% Hip frctures Approximtely % of hip frcture ptients hve prior frcture y history (often spine, wrist) Trget these ptients t younger ge fter the first frcture to prevent hip frctures Risk is highest within first few yers fter first frcture Suggests n urgency for tretment Schuit SC, et l. Bone. ;:9-.. Knis JA,et l. J Bone Miner Res. ;9: Gehlch S, et l. J Bone Miner Res. ;7():-.. Blsurmnin A, et l. Osteoporos Int. ;7():9-9.

6 Asolute Risk of Recurrent Frcture 77, women > yers with first clinicl frcture (excluding fingers, toes, fce, skull) identified from Medicre Dtse Recurrent Frctures, % Totl. Hip 8 Time (yers) Yers -: Annulized rtes ll fx:.%/yer Annulized rtes hip fx:.%/yer // Mngement of Osteoporosis Fx, frcture. Blsurmnin A, et l. Astrct presented t: ASBMR, Atlnt, GA, Sept -7,. Universl Recommendtions Counsel on the risk of frctures Et diet rich in fruits nd vegetles nd clcium (supplemented if necessry) to totl clcium intke of: mg per dy for men -7 mg per dy for women mg per dy for men 7 Vitmin D intke should e 8- IU per dy (ge ), supplemented if necessry Regulr weight-ering nd muscle-strengthening exercise Fll prevention evlution nd trining Cesstion of tocco use nd voidnce of excessive lcohol intke Whom to Tret: NOF Guidelines T-score -. in the lumr spine, totl hip, or femorl neck or Hip or spine frcture (clinicl or rdiogrphic) YES Cndidte for TREATMENT Women nd men 7 (younger with risk fctors) DXA test YES T-score etween -. nd -. FRAX -y frcture risk % for hip frcture or % for mjor osteoporotic frctures Cosmn F, et l. Osteoporos Int. ;:9-8. Cosmn F, et l. Osteoporos Int. ;:9-8. ACP Guidelines Phrmcologic tretment with lendronte, risedronte, zoledronic cid, or denosum to reduce risk for hip nd verterl frctures in women with known osteoporosis Tret osteoporotic women with phrmcologic therpy for yers BMD screening not recommended during the -yer tretment period for osteoporosis in women Menopusl estrogen therpy ± progesterone therpy or rloxifene not recommended for the tretment of osteoporosis in women Consider tretment in osteopenic women yers of ge who re t high risk for frcture sed on ptient preferences, frcture risk profile, nd enefits, hrms, nd costs of medictions Limittions* No tretments without specific hip frcture efficcy were included Recommends tretment holidy for denosum No discussion of long-term tretment decisions eyond yers Anolic therpy not included The 7 ACP guidelines re endorsed y the AAFP. *Expert opinion. ACP, Americn College of Physicins. Qseem A, et l. Ann Intern Med. 7;(): AACE/ACE Guidelines for Tretment Prior frgility frctures or indictors of higher frcture risk* Denosum, teriprtide, zoledronic cid** Alternte therpy: lendronte, risedronte Ressess t lest yerly for response to therpy nd frcture risk Denosum Continue therpy or consider dding teriprtide if progression of one loss or recurrent frctures Teriprtide for up to yers Sequentil therpy with orl or injectle ntiresorptive gent Zoledronic cid If stle, continue therpy for yers*** If progression of one loss or recurrent frctures, consider switching to teriprtide *Indictors of higher frcture risk in ptients with low BMD would include dvnced ge, frilty, glucocorticoids, very low T-scores, or incresed fll risk. **Medictions re listed lpheticlly. ***Consider drug holidy fter yers of IV zoledronic cid. During the holidy, nother gent such s teriprtide or rloxilene could e used. ACE, Americn College of Endocrinology; AACE, Americn Assocition of Clinicl Endocrinologists; IV, intrvenous. Cmcho PM, et l. Endocr Prct. ;(Suppl ):-.

7 Different Tretments for Ptients t Different Risk Levels Moderte-risk ptients Ptients with one density in the mild osteoporosis rnge who hve not hd osteoporosisrelted frctures do not need nolic therpy Could e served with ntiresorptive therpy* High-risk ptients People with rdiogrphic verterl frcture People with history of ny clinicl osteoporosis-relted frcture, especilly if recent (high imminent risk) People with very low BMD (high long-term risk) Consider nolic therpy versus ntiresorptive therpy Evidence for Frcture Reduction Drug Verterl Frcture Nonverterl Frcture Hip Frcture Clcitonin Rloxifene Indronte Alendronte Risedronte Zoledronic cid Denosum Teriprtide Aloprtide *Expert opinion. Overview Dt for One Bisphosphonte nd Other Potent Agents Zoledronic Acid (HORIZON Tril): Intrvenous Bisphosphonte, dministered once yerly Denosum (FREEDOM Tril): Monoclonl Antiody to Rnk Lignd, dministered sucutneously every months Teriprtide (Frcture Prevention Tril): -PTH, dministered dily sucutneously Aloprtide (ACTIVE Tril): -PTH-relted peptide nlogue, dministered dily sucutneously Romosozum* (FRAME Tril): Monoclonl Antiody to Sclerostin, dministered monthly sucutneously Zoledronic Acid Reduced -Yer Risk of Morphometric Verterl Frctures (Strtum I) % Ptients With New Verterl Frctures.7% (/8) Plceo %*.% (/8) Zoledronic cid 7.7% (/8) 7%*.% (/8).9% (/8) Yers 7%*.% (9/8) *Romosozum is n investigtionl gent nd is not pproved y the FDA for the tretment of osteoporosis. PTH, prthyroid hormone. *P<., reltive risk reduction vs plceo (9% confidence intervl). Adpted from Blck DM, et l. N Engl J Med. 7;:89-8. Zoledronic Acid Reduced Cumultive -Yer Risk of Clinicl Verterl nd Nonverterl Frctures (Strt I + II) Cumultive Incidence (%) Plceo (n = 8) Zoledrondic Acid (n = 87) %* Time to First Hip Frcture (months) *P=., reltive risk reduction vs plceo (9% confidence intervl). **Reltive risk reduction vs. plceo. Adpted from Blck DM, et l. N Engl J Med. 7;:89-8. Cumultive Incidence (%) 8 Cumultive Risk of Nonverterl Frcture (Strt I + II) P< Months %** Plceo (n = 8) Zoledronic Acid (n = 87) Sfety Informtion Contrindictions: Hypoclcemi Cretinine clernce < ml Acute renl impirment Adverse Rections: Pyrexi Mylgi Hedche Arthrlgi Pin in extremities Flu-like symptoms Nuse Vomiting Dirrhe Eye inflmmtion Other Concerns: Osteonecrosis of the jw Atypicl femur frcture Severe one, joint, nd muscle pin US FDA. CDER. Zoledronic cid NDA 87. Lel 7/7/7.

8 Zoledronic Acid mg Reduced Susequent Frcture Risk Over Time Event Rte (%) 8 8 Plceo %* (%, %).9% (9/) 8.% (9/) Clinicl Frctures Zoledronic cid mg 7% (%, %).7% (7/) 7.% (79/) Nonverterl Frctures.8% (9/) % (8%, 8%).7% (/) Clinicl Verterl Frctures *P=.; P=.8; P=., reltive risk reduction vs. plceo; NS = not significnt. Vlues ove rs re cumultive event rtes sed on Kpln-Meier estimtes t Month. Lyles KW, et l. N Engl J Med. 7;7(8): % (/) % NS (-%, 9%).% (/) Hip Frctures Zoledronic Acid mg Reduced Risk of All-Cuse Mortlity y 8% Over Time 8 Hzrd Rtio,.7 (9% CI,.-.9) 8% P=.7 Asolute Risk Reduction,.7% 8 Zoledronic cid mg (n = ) Plceo (n = 7) 8 8 No. t Risk Month ZOL mg Plceo Cumultive Incidence (%) Lyles KW, et l. N Engl J Med. 7;7(8): Effects of Denosum Tretment on Lumr Spine BMD nd New Verterl Frctures Through Yers Percentge Chnge From Bseline Plceo Long-term Denosum Cross-over Denosum FREEDOM Lumr Spine Extension.7% c.% c Study Yer Yerly Incidence of New Verterl Frctures (%) Yerly Incidence of New Verterl Frctures (%) FREEDOM...7 FREEDOM Extension / d 7/8d 9/d Yers of Denosum Tretment. Extension / d /d /7 d Yers of Denosum Tretment BMD dt re LS mens nd 9% confidence intervls. P<. vs FREEDOM seline. P<. vs FREEDOM nd Extension selines. c Percentge chnge while on denosum tretment. d Annulized incidence: (-yer incidence) /. Lterl rdiogrphs (lumr nd thorcic) were not otined t yers, 7, nd 9 (yers,, nd of the Extension). Bone HG, et l. Lncet Dietes Endocrinol. 7;(7):-. Effects of Denosum Tretment on Totl Hip BMD nd Nonverterl Frctures Through Yers Percentge Chnge From Bseline Plceo Long-term Denosum Cross-over Denosum Totl Hip FREEDOM Extension Study Yer 9.% c 7.% c Yerly Incidence of Nonverterl Frctures (%) Yerly Incidence of Nonverterl Frctures (%) FREEDOM FREEDOM Extension Yers of Denosum Tretment BMD dt re LS mens nd 9% confidence intervls. Percentges for nonverterl frctures re Kpln-Meier estimtes. P<. vs FREEDOM seline. P<. vs FREEDOM nd Extension selines. C Percentge chnge while on denosum tretment. Bone HG, et l. Lncet Dietes Endocrinol. 7;(7):-..8. Extension Yers of Denosum Tretment Sfety Informtion Contrindictions: Hypoclcemi Adverse Rections: Bck pin Pin in extremities Hypercholesterolemi Musculoskeletl pin Cystitis Other Concerns: Skin rsh Osteonecrosis of the jw Atypicl femur frcture Multiple verterl frctures upon withdrwl US FDA. CDER. Denosum NDA. Lel //. Effects of Teriprtide on Verterl nd Nonverterl Frctures Percentge of Women 7 Verterl Frcture Plceo PTH, µg Frcture > Frcture Moderte or severe frcture Rdiogrphic of New Verterl Frctures ARR, solute risk reduction; RRR, reltive risk reduction. Neer RM, et l. N Engl J Med. ;(9):-. Percentge of Women Nonverterl Frcture ARR =.9% RRR= % P. vs plceo Plceo PTH, µg 7

9 Aloprtide Bckground Aloprtide is -mino cid osteonolic peptide Synthetic nlogue of PTH-relted peptide In preclinicl nd clinicl studies: Improved BMD, microrchitecture nd strength incresed Unique mechnism of ction t the PTH receptor Stimultes one formtion with limited clcium moiliztion nd one resorption Optimized osteonolic profile Httersley G, et l. Endocrinology. ;7:-9. ACTIVE: Risk of New Verterl Frctures Modified ITT Popultion* N=8 Reltive Risk Reduction -8% -8% Proportion (%) of Ptients With New Verterl Frctures.% (n=).8% (n=).8% (n=) Plceo Aloprtide Teriprtide n=7 n=9 n=77 *Includes ll ITT ptients who hd pretretment nd post-seline evlule rdiologic ssessments. P<. vs plceo ITT, intention-to-tret. Miller PD, et l. JAMA. ;:7-7. ACTIVE: Time to First Nonverterl Frcture ITT Popultion N= Proportion (%) of Ptients With Nonverterl Frcture Kpln-Meier Curve Time to event (dys) Plceo Teriprtide Log-rnk P vlue =. vs plceo Aloprtide Log-rnk P vlue =.9 vs plceo Sfety Informtion for Teriprtide nd Aloprtide Rodent Osteosrcom Hyperclcemi Hyperclciuri Hyperuricemi Orthosttic Hypotension Adverse Rections Arthrlgi Pin Nuse Miller PD, et l. JAMA. ;:7-7. US FDA. CDER. Teriprtide NDA 8. Lel //8. US FDA. CDER. Aloprtide NDA 87. Lel //8. Full ACTIVExtend Study (. yers) Compred to the plceo/lendronte group, the loprtide/ lendronte group experienced t oth months nd months into the extension study: Sustined reduced risk for verterl, nonverterl, clinicl, nd mjor osteoporotic frctures Similr incidence of dverse effects, no cses of AFF or ONJ Romosozum Bckground Monoclonl ntiody tht inds nd inhiits sclerostin Sclerostin inhiition hs dul effect on one Stimultes one formtion y promoting osteolst numer nd ctivity Reduces one resorption y inhiiting RANK lignd expression Increses BMD mrkedly FRAME is phse, rndomized, plceo-controlled FRActure study in postmenopusl women with osteoporosis yer linded denosum vs plceo nd then trnsition to yer denosum in ll ptients Cosmn F, et l. Myo Clin Proc. 7;9:-. Bone, HG. J Clin Endocrinol Met. 8 My. doi:./jc.8-. [Epu hed of print].. Cosmn F, et l. N Engl J Med. ;7:-. 8

10 New Verterl Frcture Incidence Through Month (Co-Primry Endpoint) Suject Incidence (%).% Plceo (N=9).%.%.% Romosozum (N=89).8% RRR = % P =..% RRR = 7% P = <..8%.%.% Through Month Through Month / / 9/ / n/n = n/n = numer of sujects with frctures/numer of sujects in the primry nlysis set for verterl frcture. P vlue sed on logistic regression model djusted for ge (<7, 7) nd prevlent verterl frcture. Cosmn F, et l. N Engl J Med. ;7:-. Time to First Clinicl Frcture Through Month Sujects Experiencing Event (%) Plceo n = Romosozum n = Plceo (N=9) Romosozum (N=89) Study Month RRR = % P =.8 Nonverterl nd symptomtic verterl frcture. Nonverterl frctures comprised the mjority (more thn 8%) of clinicl frctures. Kpln-Meier curve sed on dt through month ; n=numer of sujects t risk for event t time point of interest P vlue sed on RRR. Cosmn F, et l. N Engl J Med. ;7:-. Nonverterl Frcture Incidence Through Month in Ltin Americ vs. Rest of the World Suject Incidence (%) % % % % Plceo Romosozum Tretment-y-sugroup interction (P =.).% RRR = -% P =.7.7% RRR = % P =..%.% Adverse Rections No significnt difference in the incidence of osteorthritis, hyperostosis, cncer, hypersensitivity, nd serious crdiovsculr events Hypersensitivity rections oserved over the -month period in the romosozum group Mild injection-site rections oserved in the romosozum group (.%) nd plceo group (.9%) ONJ ws reported in ptients from the romosozum group % Ltin Americ Rest of the World* 9/ / /7 /9 n/n = *Regions excluding Ltin Americ grouped post hoc. n/n = numer of sujects with frctures/numer of sujects in the full nlysis set. Cosmn F, et l. N Engl J Med. ;7:-. Cosmn F, et l. N Engl J Med. ;7:-. Limittions of Antiresorptives for the High-Risk Ptient Nonverterl frcture risk reductions for ntiresorptives At est %-% Tkes yers to see significnt decline Long-term efficcy of ntiresorptives is uncler With isphosphontes Effect on frctures eyond - yers inconsistent BMD plteus fter - yers If BMD remins <-., ptients still t risk Limittions of Antiresorptives for the High-Risk Ptient (Cont.) With denosum Continued increse in BMD yers - Low frcture rtes during the extension study yers (ut no long-term plceo group), Hip BMD ttined during denosum tretment is predictive of lower risk of susequent incident nonverterl frcture Rre ut significnt long-term sfety risks for oth BPs nd Denosum (AFFs, ONJ). Cosmn F, et l. J Clin Endocrinol Met.;99:-.. Bone H, et l. Lncet Dietes Endocrinol. 7;:-.. Ferrri S. Astrct presented t: ASBMR 7; Sept, 7; Denver, CO. Astrct 7. 9

11 Frcture Outcome Comprison Studies: Anolic vs. Antiresorptive Agents In glucocorticoid-induced osteoporosis: Teriprtide reduced verterl frctures y 9% compred to lendronte over 8 months In ptients with cute symptomtic verterl frctures: Teriprtide reduced verterl frctures y % compred to risedronte In ptients with prevlent verterl frcture (VERO): Teriprtide reduced verterl nd ll clinicl frctures vs. risedronte over yers In ptients with prevlent spine (or hip) frcture (ARCH) : Romosozum reduced risk of verterl, clinicl, nonverterl, nd hip frctures with romosozum compred to lendronte Potentil sfety issues (crdiovsculr serious AEs) hve resulted in dely of pprovl Rtionle for Anolic Therpy First Line If imminent frcture risk is high Anolic gents provide fstest protection ginst frctures ( to 8 months for oth verterl nd nonverterl risk reductions) If very low BMD (T-score <-) even without prior frcture Best initil tretment is still nolic Incresed skeletl mss nd improved microrchitecture Lrgest effects when nolic followed y ntiresorptive. Sg KG, et l. N Engl J Med. 7;7:8-9.. Hdji P, et l. Osteoporos Int. ;:-.. Kendler, DL, et l. Lncet. 7; pii: S-7(7)7-. [Epu hed of print]. Sg KG, et l. N Engl J Med. 7;77():7-7. Cosmn F, et l. J Bone Miner Res. 7;:98-. Tretment Sequence Mtters Potentil Tretment Trgets for Osteoporosis Tretment Trgets Are the Inverse of Tretment Indictions Orl Bisphosphonte (men. yr), Lngdhl et l 8 Alendronte (men.8 yr)* TPTD ( mo) -.8% -.% - - Remin free of frcture (first or recurrent) for yers For recurrent frcture, frcture-free durtion trget might vry sed on site of initil frcture After incident spine or hip frcture, possily longer trget Must include ssessment of verterl frcture Verterl imging needed t eginning nd end Attin BMD T-scores ove osteoporosis rnge Reduce frcture proilities to elow tretment indictions TPTD, teriprtide.. Cosmn F, et l. J Bone Miner Res. 7;:98-.. Lngdhl BL, et l. Lncet. 7;9():8-9. Cummings SR, et l. J Bone Miner Res. 7;:-. Tretment Trgets Affect Selection of Initil Tretment nd Tretment Sequence For highest-risk ptients, especilly those t high imminent risk (e.g., those with recent frctures) Produce rpid reduction in osteoporosis-relted frcture Provide foundtion for greter strengthening effect nd BMD improvement Growing consensus tht nolic therpy should e given first line for highrisk ptients Use non-isphosphonte ntiresorptive (denosum) second line To help chieve frcture-free intervl of - yers To help chieve BMD gols (T-scores ove -.) Cummings SR, et l. J Bone Miner Res. 7;:-. Tretment Trgets Affect Tretment Sequence Decisions nd Decisions Aout Drug Holidys If using non-isphosphonte medictions When tretment is stopped, BMD is lost rpidly Either continue these gents indefinitely or switch to mintennce therpy Mintennce therpy Use isphosphontes t end of tretment sequence If tretment gols met, consider mediction holidy Intermittent isphosphontes cn e used to mintin BMD* e.g., single zoledronic cid infusion Repet tretment when/if needed Monitor frctures/bmd/iochemicl turnover mrkers* Repet sequentil monotherpy s needed Sequentil monotherpy^ Cn minimize exposure to phrmcology while mximizing enefits on strength nd BMD *Grde A. ^Grde A for teriprtide followed y n ntiresorptive gent. Cummings SR, et l. J Bone Miner Res. 7;:-.

12 Tke-Home Messges Osteoporosis is common disese with serious consequences due to frctures Frcture numers re expected to hit crisis rnge Tools to dignose osteoporosis nd identify ptients for phrmcologicl therpy re ville chep nd without risk Phrmcologicl gents reduce frcture risk Tretment decisions for inititing nd continuing therpy should e individulized sed upon the expected enefit nd potentil risk for ech ptient Different medictions re pproprite t different ges nd stges of disese Secondry frcture prevention should e priority Questions? Thnk You! Appendix Plese complete the post ssessment nd evlution for this session. FDA-Approved Medictions Osteoporosis Glucocorticoidinduced Postmenopusl Mle Drug Prevent Tret Prevent Tret Estrogen/HT/BZD Clcitonin (Miclcin ) Rloxifene (Evist ) Indronte (Boniv ) Alendronte (Fosmx ) Risedronte (Actonel ) Risedronte (Atelvi ) Zoledronte (Reclst ) Denosum (Proli ) Teriprtide (Forteo ) Aloprtide (Tymlos ) Di DL, et l. Endocrinol Met Clin North Am. ;():-7. Denosum: Exposure-Adjusted Suject Incidence of Adverse Events (Rtes per Suject-Yers) Extension Yers 7 ) Long-term Cross-over Denosum (N = Denosum (N = ) Yer 7 7 Serious infections Mlignncies FREEDOM Yers Extension Yers 7 Plceo (N = 88) Cross-over Denosum (N = ) Long-term Denosum (N = ) All AEs Infections Mlignncies... Eczem..9.9 Hypoclcemi <. <. <. Pncretitis <. <. <. Serious AEs... Infections... Cellulitis or erysipels <. <. <. Ftl AEs Osteonecrosis of the jw <. <. Atypicl femorl frcture <. <. Multiple verterl frctures...8 upon discontinution N = numer of sujects who received dose of investigtionl product. Tretment groups re sed on the originl rndomized tretments received in FREEDOM. AEs coded using MedDRA v.. Cumultive osteonecrosis of the jw cses: cross-over, 7 long-term. Cumultive typicl femorl frcture cses: cross-over, long-term. Cummings SR, et l. N Engl J Med. 9;(8):7-7. Cummings SR, et l. J Bone Miner Res. 8;():9-98.

13 ACTIVE: BMD Chnges t Spine nd Hip ITT Popultion N= Percentge Chnge From Bseline Aloprtide Teriprtide Lumr Spine BMD Totl Hip BMD 9 *. * *. 8 * * 7. *. * * *.. * * * Months From Rndomiztion Plceo Femorl Neck BMD * * * * * * 8 ACTIVE nd ACTIVExtend Tril Design Rndomiztion ACTIVE N= ACTIVExtend N=9 Representing 9% of ptients eligile to enroll month plnned interim nlysis 9* Plceo (n=8) Aloprtide 8 μg dily (n=8) Teriprtide μg dily SC (n=88) Months 8 Alendronte 7 mg QW (n=8) Alendronte 7 mg QW (n=8) Full durtion of extension, months *P<. compred with plceo; P<. compred with teriprtide. Missing BMD ws imputed using lst oservtion crried forwrd. Miller PD, et l. JAMA. ;:7-7. *-month gp in tretment llowed for rollover from ACTIVE to ACTIVExtend. Investigtors nd ptients remined linded to originl tretment ssignment for the first months of the extension study. Cosmn F, et l. Myo Clin Proc. 7;9:-. ACTIVExtend: New Verterl Frctures ACTIVE: Sfety nd Adverse Events Modified ITT Popultion N=* ACTIVExtend first months ACTIVE + ACTIVExtend Cumultive Incidence t months Proportion (%) of Ptients With New Verterl Frctures.% (n=7) Plceo/ Alendronte n=8 % (n=) Aloprtide/ Alendronte n=.% (n=) Plceo/ Alendronte n=8 Reltive Risk Reduction -87%.% (n=) Aloprtide/ Alendronte n= *All ptients from the ACTIVE mitt popultion who hd Month evlule rdiologic ssessments. P<. vs. plceo/lendronte. Cosmn F, et l. Myo Clin Proc. 7;9:-. Miller PD, et l. JAMA. ;:7-7. FRAME: Adverse Events Cosmn F, et l. N Engl J Med. ;7:-.

14 Mediction Index Reducing the Risk of Frcture in Postmenopusl Women: Guidnce for Fmily Physicins The following medictions were discussed in this presenttion. The tle elow lists the generic nd trde nme(s) of these medictions. Generic Nme Aloprtide Alendronte Clcitonin Denosum Indronte Rloxifene Risedronte Romosozum Teriprtide Zoledronic Acid Trde Nme Tymlos Binosto, Fosmx Miclcin Proli, Xgev Boniv Evist Actonel, Atelvi Evenity Forteo Reclst, Zomet

15 Notes

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