TREATMENT OF OSTEOPOROSIS HOLIDAYS OR NO HOLIDAYS? Nelson B. Watts, MD OSTEOPOROSIS AND BONE HEALTH SERVICES CINCINNATI, OHIO

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1 TREATMENT OF OSTEOPOROSIS HOLIDAYS OR NO HOLIDAYS? Nelson B. Watts, MD OSTEOPOROSIS AND BONE HEALTH SERVICES CINCINNATI, OHIO

2 DISCLOSURES Honoraria: Amgen, Merck, Shire Consulting : AbbVie, Amgen, Merck, Radius, Sanofi Research support: Shire

3 FDA-APPROVED MEDICATIONS INDICATIONS Postmenopausal Osteoporosis Glucocorticoid-induced Osteoporosis Men Drug Prevention Treatment Prevention Treatment Estrogen Calcitonin (Miacalcin, Fortical ) Raloxifene (Evista ) Ibandronate (Boniva ) Alendronate (Fosamax ) Risedronate (Actonel ) Risedronate (Atelvia ) Zoledronate (Reclast ) Denosumab (Prolia ) Teriparatide (Forteo )

4 FDA-APPROVED MEDICATIONS EVIDENCE FOR FRACTURE REDUCTION Drug Vertebral Fracture Nonvertebral Fracture Hip Fracture Calcitonin (Miacalcin, Fortical ) No effect demonstrated No effect demonstrated Raloxifene (Evista ) No effect demonstrated No effect demonstrated Ibandronate (Boniva ) No effect demonstrated No effect demonstrated Alendronate (Fosamax ) Risedronate (Actonel, Atelvia ) Zoledronic acid (Reclast ) Denosumab (Prolia ) Teriparatide (Forteo ) No effect demonstrated Evidence for effect but not an FDA-approved indication

5 ACTION OF BISPHOSPHONATES ON OSTEOCLASTS Bind to bone mineral BP Bone BP BP BP Concentrate at sites of bone resorption BP Bone BP BP BP BP BP BP BP Release and intracellular uptake during resorption BP BP BP Bone Loss of resorptive function BP = bisphosphonates Courtesy of Mike Rogers (2005)

6 BISPHOSPHONATES AVAILABLE IN THE US Daily Weekly Monthly IV Alendronate* (Fosamax ) Risedronate (Actonel, Atelvia ) Ibandronate (Boniva ) Zoledronate (Reclast 5 & 10 mg 35 & 70 mg 5 mg 35 mg 150 mg 2.5 mg 150 mg 3 mg q 3 mo 5 mg/yr *Alendronate available as alendronate alone (brand or generic) or 70 mg with vitamin D 2800 or 5600 IU (brand only) Atelvia should be taken once weekly, immediately after breakfast

7 BISPHOSPHONATES SIDE EFFECTS / SAFETY CONCERNS Short-term side effects Hypocalcemia Esophageal irritation (oral) Acute phase response (IV and high-dose oral) Acute renal damage (IV) Musculoskeletal pain* Long-term safety concerns Osteonecrosis of the jaw* Atypical femur fractures* *Reports from post-marketing surveillance

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9 SIDE BENEFITS OF BISPHOSPHONATE THERAPY Decreased risk of breast cancer 1-5 Decreased risk of colorectal cancer 6 Decreased risk of stroke 7 Decreased risk of MI 8 Reduced risk of gastric cancer 9 Decreased overall mortality10, Chlebowski RT et al. J Clin Oncol 2010; 28: Dreyfuss JH. CA Cancer 2010; 60: Newcomb PA et al. Br J Cancer 2010; 102: Rennert G et al. J Clin Oncol 2010; 28: Vestergaard P et al. Calcif Tissue Int 2011; 88: Rennert G, et al. J Clin Oncol 2011; 29: Kang JH et al. Osteoporos Int 2012; [Epub ahead of print] 8. Wolfe F et al, J Bone Miner Res 2013; 28: Abrahamsen B et al. J Bone Miner Res 2012;27: Center JR et al. J Clin Endocrinol Metab 2011; 96: Sambrook PN et al. Osteoporos Int 2011; 22:2551.

10 HOW LONG SHOULD TREATMENT LAST? A question unique to bisphosphonates; no other agent used to treat osteoporosis (or other chronic disease) has a cumulative effect or potential for residual benefit Bisphosphonates have a long residence time in bone Does long-term treatment create safety concerns that limit the duration of treatment? Given the long retention in bone, with release and possibly recycling of drug, does cumulative exposure lead to a reservoir in bone, so that after therapy is stopped, sufficient drug will be released to exert a continuing benefit?

11 OSTEONECROSIS OF THE JAW Exposed necrotic bone in the maxillo-facial region, not healing after 6-8 weeks of appropriate management, often at the site of a dental extraction or other invasive dental procedure or in patients with poorly fitting dentures Over 90% of reported cases have been in cancer patients receiving BP doses 10x higher than used to treat osteoporosis Estimated incidence in osteoporosis: 1:10,000-1:100,000 Current guidelines from the American Dental Assn. (2011) emphasize the health consequences of osteoporosis, the benefits of bisphosphonate treatment and the low risk of ONJ in osteoporosis patients receiving bisphosphonate therapy Woo S-B et al. Ann Intern Med 2006;144: Khosla S et al. J Bone Miner Res 2008;23: Hellstein JW et al. JADA 2011:142:

12 FEMUR FRACTURES TYPICAL FEMUR FRACTURES No warning symptoms Caused by a fall Unilateral Proximal Acute angle (femoral neck, intertrochanteric) May be comminuted *Major features **Required for diagnosis ATYPICAL FEMUR FRACTURES Prodromal thigh or groin pain Little or no trauma* ~30% bilateral Subtrochanteric location** Transverse/oblique, medial spike* Little or no comminution* Begin as a localized periosteal reaction of the lateral cortex* Thick cortices Delayed healing ASBMR Task Force Shane E et al, JBMR 2010;25: Shane E et al, JBMR 2014;29:1-23

13 2014 UPDATE: ASBMR TASK FORCE ON ATYPICAL FEMUR FRACTURES Location: below lesser trochanter, above supracondylar flare Major Features (four of five) Trauma: little or none Direction: lateral transverse, may be oblique on the medial side Comminution: little or none Complete fractures: may have a medial spike; incomplete fractures involve only the lateral cortex Localized periosteal reaction/thickening of the lateral cortex Minor features (none required) Generalized increase in cortical thickness of the shaft Prodromal symptoms such as dull aching pain in groin or thigh Bilateral incomplete or complete fractures and symptoms Delayed fracture healing Shane E et al, JBMR 2014;29:1-23

14 SUBTROCHANTERIC FEMUR FRACTURE This patient had not been on a bisphosphonate or any other treatment for osteoporosis

15 ATYPICAL FRACTURES OF THE FEMUR Watts NB and Diab D, J Clin Endocrinol Metab 2010;95:

16 ATYPICAL FEMORAL FRACTURES 1.5 million women 55 and older with fx from any cause 12,777 (0.9%) had femur fractures Schilcher J et al, N Engl J Med 2011;364:

17 ATYPICAL FEMORAL FRACTURES 10.6% of all femur fractures were in the shaft Schilcher J et al, N Engl J Med 2011;364:

18 ATYPICAL FEMORAL FRACTURES 10.6% of all femur fractures were in the shaft 59 were atypical fractures 0.46% of all femur fractures 4.4% of all shaft fractures Schilcher J et al, N Engl J Med 2011;364:

19 ATYPICAL FEMORAL FRACTURES 10.6% of all femur fractures were in the shaft Atypical fractures accounted for 0.46% of all femur fractures and 4.4% of all shaft fractures. Absolute risk increase: 5 cases per 10,000 pt years Schilcher J et al, N Engl J Med 2011;364:

20 ATYPICAL FEMORAL FRACTURES Only 11% were using bisphosphonates! Assume 35% risk reduction 4,000 fractures could have been prevented 10.6% of all femur fractures were in the shaft Atypical fractures accounted for 0.46% of all femur fractures and 4.4% of all shaft fractures. Absolute risk increase: 5 cases per 10,000 pt years Schilcher J et al, N Engl J Med 2011;364:

21 LONG-TERM EXPERIENCE WITH ALENDRONATE FIT LONG-TERM EXTENSION (FLEX) STUDY Patients who received ~5 years of alendronate in the Fracture Intervention Trial agreed to a second 5-yr study Re-randomized to stay on alendronate (n=672) or changed to placebo (n=437) For those who had 10 years of alendronate compared with stopping after 5 years Overall, clinical vertebral fractures were reduced 55% In women with T-scores -2.5 or below at the start of FLEX, nonvertebral fractures were reduced by 50% Black DM et al, JAMA 2006;296: Schwartz AV et al. J Bone Miner Res 2010;25:

22 CLINICAL VERTEBRAL FRACTURES IN THE FLEX STUDY Cumulative incidence of fractures (%) ALN 5 years Placebo 5 years Alendronate 10 years RR 55% P= % 2.5% Years Since FIT ALN/PLB ALN/ALN Black DM et al, JAMA 2006;296:

23 CLINICAL VERTEBRAL FRACTURES IN THE FLEX STUDY Cumulative incidence of fractures (%) ALN 5 years Placebo 5 years Alendronate 10 years RR 55% P= % 2.5% Years Since FIT ALN/PLB ALN/ALN Black DM et al, JAMA 2006;296:

24 ALGORITHM FOR MANAGEMENT OF POSTMENOPAUSAL WOMEN ON LONG TERM BISPHOSPHONATE THERAPY Adler R. et al, J Bone Miner Res 2016;31:16-35

25 WHEN SHOULD THE HOLIDAY END? YOU ARE ENTERING A DATA-FREE ZONE

26 WHEN SHOULD THE HOLIDAY END? Arbitrary? Longer for drugs with highest skeletal affinity (zoledronic acid), shorter for drugs with lowest skeletal affinity (risedronate) Longer for lower risk patients, shorter for those at high risk Bone turnover markers? Which marker? How high? BMD? Decrease more than the least significant change (LSC) Watts NB and Diab D, J Clin Endocrinol Metab 2010;95:

27 DENOSUMAB (PROLIA ) Human monoclonal antibody to RANKL; blocks binding to RANKL, decreases osteoclast differentiation, function and survival Reduces the risk of spine, hip and other nonvertebral fractures compared with placebo For treatment of osteoporosis, the dose is 60 mg SQ every 6 months Contraindicated in patients with hypocalcemia Can be used without dose adjustment in patients with decreased kidney function Bekker PJ et al. J Bone Miner Res. 2004;19: Boyle WJ et al. Nature. 2003;423: Peterson, et. al. J. Bone Miner. Res. 2003; 18(suppl. 2): S166. Abstract SA393 and poster Cummings SR et al, N Engl J Med 2009;361: Prolia Package Insert

28 DENOSUMAB FREEDOM TRIAL 3-YEAR FRACTURE RESULTS Subjects with New Fractures (%) ,808 postmenopausal women with osteoporosis 68% 20% Placebo Denosumab 40% Vertebral Non-Vert Hip Cummings SR et al, N Engl J Med 2009;361:

29 BMD CHANGE AFTER STOPPING DENOSUMAB 12 Lumbar Spine BMD All discontinued % Change (LS mean ± SE) All discontinued at 36 months Subjects who rec d 30 mg q 3 mos were given 60 mg q 6 mos starting at Month 36 Months Miller PD et al Bone 2008;43:

30 Management of osteoporosis is a longterm proposition, similar to treatment of hypertension or hypercholesterolemia

31 Prepared by Nelson Watts MD YEAR BMD CHANGE WITH DENOSUMAB Percentage Change from Baseline Lumbar spine Total hip Bone HG et al, ASBMR 2015

32 FRACTURES AFER EIGHT YEARS OF DENOSUMAB Papapoulos S et al, Osteoporos Int 2015;epub ahead of print

33 Placebo Years 1-3 D mab Years 4-6 Crossover Group D mab Years 1-3 D mab Years 4-6 Long-term Group Watts NB et al ASBMR 2015

34 LONG-TERM SAFETY WITH D MAB Watts NB et al ASBMR 2015

35 LONG-TERM SAFETY WITH D MAB Watts NB et al ASBMR 2015

36 NONSKELETAL EXPRESSION OF RANKL RANKL Bone marrow stromal cells Activated T cells B cells Fibroblasts Endothelial cells Chrondrocytes Mammary epithelial cells RANK Dendritic cells Chondrocytes Endothelial cells Fibroblasts Macrophages Other cells OPG Bone marrow stromal cells Fibroblasts Endothelial cells Lymphoid cells Smooth muscle cells Mature B cells NOT thymocytes, peripheral blood lymphocytes Kearns AE et al. Endocrine Reviews 2008;29:

37 WHAT ABOUT CONCOMITANT USE OF D MAB AND ANTI-TNF AGENTS? Source: Medicare database Subjects: RA patients, all receiving biologic agents, getting either ZOL (n=4,460) or dmab (n=1,354) Findings: no difference in rates of hospitalization for infection (matched analysis) and similar to reported rates in older patients not receiving dmab or ZOL Dmab 9.4 ( ) cases per 100 patient years ZOL 11.7 ( ) cases per 100 patient years Curtis JR et al, Arthritis & Rheumatol 2015;67:

38 SEQUENTIAL OR CONCOMITANT COMBINATIONS DENOSUMAB AND TERIPARATIDE ` Years 1-2 Years 3-4 Combination Denosumab Teriparatide Denosumab Denosumab Teriparatide Leder B et al Lancet 2015;336:1147

39 SEQUENTIAL OR CONCOMITANT COMBINATIONS DENOSUMAB AND TERIPARATIDE ` Years 1-2 Years 3-4 Combination Denosumab Teriparatide Denosumab Denosumab Teriparatide Leder B et al Lancet 2015;336:1147

40 SEQUENTIAL OR CONCOMITANT COMBINATIONS DENOSUMAB AND TERIPARATIDE Years 1-2 Years 3-4 Combination Denosumab Teriparatide Denosumab Denosumab Teriparatide Leder B et al Lancet 2015;336:1147

41 TREATMENT OF OSTEOPOROSIS HOLIDAYS OR NO HOLIDAYS? Treatment of osteoporosis is a long-term proposition, similar to management of other chronic silent diseases (hypertension, hyperlipidemia and diabetes) Because bisphosphonates accumulate in bone, it is possible to stop administration for a time with continued therapeutic effect during a drug holiday Lower risk patients, 3 years of IV or 5 years of oral Higher risk, 6 years of IV or 10 years of oral No holiday for denosumab or other agent but, depending on drug and situation, changes between agents may be OK.

42 Questions or comments? WILL YOUR BONES LAST AS LONG AS YOU DO?