A Randomized, Placebo-Controlled Study of the Effects of Denosumab for the Treatment of Men with Low Bone Mineral Density

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1 ORIGINAL ARTICLE Endocrine Care A Randomized, Placebo-Controlled Study of the Effects of Denosumab for the Treatment of Men with Low Bone Mineral Density Eric Orwoll, Christence S. Teglbjærg, Bente L. Langdahl, Roland Chapurlat, Edward Czerwinski, David L. Kendler, Jean-Yves Reginster, Alan Kivitz, E. Michael Lewiecki, Paul D. Miller, Michael A. Bolognese, Michael R. McClung, Henry G. Bone, Östen Ljunggren, Bo Abrahamsen, Ugis Gruntmanis, Yu-Ching Yang, Rachel B. Wagman, Suresh Siddhanti, Andreas Grauer, Jesse W. Hall, and Steven Boonen Oregon Health and Science University (E.O.), Portland, Oregon 97239; Center for Clinical and Basic Research (C.S.T.), Ballerup 2750, Denmark; Aarhus University Hospital (B.L.L.), Aarhus 8000, Denmark; Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 1033 (R.C.), Université de Lyon, Hôpital Edouard Herriot, Lyon 69003, France; Krakow Medical Center (E.C.), Krakow , Poland; University of British Columbia (D.L.K.), Vancouver, British Columbia V6H 3X8, Canada; University of Liège (J.-Y.R.), Liège 4020, Belgium; Altoona Center for Clinical Research (A.K.), Duncansville, Pennsylvania 16635; New Mexico Clinical Research and Osteoporosis Center (E.M.L.), Albuquerque, New Mexico 87106; Colorado Center for Bone Research (P.D.M.), Lakewood, Colorado 80227; Bethesda Health Research Center (M.A.B.), Bethesda, Maryland 20817; Oregon Osteoporosis Center (M.R.M.), Portland, Oregon 97213; Michigan Bone and Mineral Clinic (H.G.B.), Detroit, Michigan 48236; Uppsala University (O.L.), Uppsala 75185, Sweden; University of Southern Denmark and Gentofte Hospital (B.A.), Odense 5000 and Hellerup 2900, Denmark; Dallas Veterans Affairs Medical Center and University of Texas Southwestern (U.G.), Dallas, Texas 75216; Amgen Inc. (Y.-C.Y., R.B.W., S.S., A.G., J.W.H.), Thousand Oaks, California 91320; and Leuven University (S.B.), Leuven 3000, Belgium Context: Men with low bone mineral density (BMD) were treated with denosumab. Objective: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment. Design, Subjects, and Intervention: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD. Main Outcome Measure: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. Results: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P ). The incidence of adverse events was similar between groups. Conclusions: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed. (J Clin Endocrinol Metab 97: , 2012) ISSN Print X ISSN Online Printed in U.S.A. Copyright 2012 by The Endocrine Society doi: /jc Received March 2, Accepted May 31, First Published Online June 21, 2012 Abbreviations: ADT, Androgen deprivation therapy; AE, adverse events; BMD, bone mineral density; CI, confidence interval; DXA, dual-energy x-ray absorptiometry; FN, femoral neck; LS, lumbar spine; ONJ, osteonecrosis of the jaw; Q6M, every 6 months; 1/3R, one third radius; RANK, receptor activator of nuclear factor -B; SAE, serious AE; sctx, serum C-telopeptide; TH, total hip; TR, trochanter. J Clin Endocrinol Metab, September 2012, 97(9): jcem.endojournals.org 3161

2 3162 Orwoll et al. Denosumab Treatment in Men with Low BMD J Clin Endocrinol Metab, September 2012, 97(9): An estimated 2 million men in the United States have osteoporosis, with over 12 million more who are at risk ( whatmenneedtoknow). Cumulative data indicate that osteoporosis-related fracture risk in men is substantial (2), and studies in the United States suggest that 27 30% of all fractures in individuals over the age of 50 are in men (3, 4). Worldwide, an estimated 39% of all osteoporotic fractures occur in men over the age of 50 (5). Furthermore, mortality after osteoporotic fracture is higher in men than in women (6, 7). Despite these facts, osteoporosis in men remains under-recognized and undertreated (8, 9), even though approximately one in five men over the age of 50 meet the National Osteoporosis Foundation requirements to initiate treatment for osteoporosis (10). With aging of the overall population and increasing longevity of men, fractures (the primary consequence of osteoporosis) and the ensuing health care burdens are expected to greatly increase in coming years (5, 11). Currently approved treatments for osteoporosis in men include bisphosphonates [alendronate (12), risedronate (13), zoledronic acid (14), and teriparatide (15)]. Although available therapies have shown efficacy and safety in the controlled setting of clinical studies, practical concerns limit the usefulness of these therapies. Persistence with long-term bisphosphonate therapy is poor, even with once-weekly dosing (16). Zoledronic acid is administered by once-yearly iv infusion, which increases compliance but reduces practicality in the primary care setting. Thus, despite the availability of generally safe and effective therapies, osteoporosis remains a significant health concern in men, and there remains a need for alternative therapies. Denosumab, a fully human monoclonal antibody that binds to the protein receptor activator of nuclear factor -B (RANK) ligand, has been shown to markedly reduce bone resorption, increase bone mineral density (BMD), and reduce fracture risk in postmenopausal women with osteoporosis (17, 18). In addition, men receiving androgen deprivation therapy (ADT) for prostate cancer who were treated with denosumab had increased BMD and a lower incidence of new vertebral fractures (19). Here we describe results from a randomized placebo-controlled study designed to evaluate efficacy and safety of denosumab in men with low BMD after 1 yr of treatment. Subjects and Methods Study design ADAMO is a 2-yr international, multicenter, randomized, phase 3 study to compare the efficacy and safety of denosumab vs. placebo in males with osteoporosis. The first year of the study was double blind and placebo controlled. Eligible subjects were randomized in a 1:1 ratio within 35 d of screening to receive either 60 mg denosumab or blinded placebo as a sc injection once every 6 months (Q6M) over a 12-month period at d 1 and month 6. The randomization (using randomly permuted blocks of size 2) was stratified by each subject s minimum BMD T-score ( 2.5 vs. 2.5) at either the lumbar spine (LS) or femoral neck (FN), whichever corresponded to the lower T-score. Individual subject s treatment assignment was obtained from the interactive voice response system at the time of the randomization call. After the 12-month double-blinded treatment, all continuing subjects were assigned to receive open-label 60 mg Q6M sc denosumab for 12 more months; the second year of the study remains ongoing at the time of this report. Daily calcium ( 1000 mg elemental calcium) and vitamin D ( 800 IU) supplementation were provided to subjects during the study. The primary endpoint of the study was to assess percent change from baseline in LS BMD at 12 months. Secondary endpoints included the percent change from baseline in BMD of the total hip (TH), FN, hip trochanter (TR), and one third radius (1/3R) at month 12 and the percent change from baseline in serum C-telopeptide of type I collagen (sctx) at d 15. Safety endpoints included the subject incidence of adverse events (AE) at month 12. Subjects Ambulatory men between the ages of 30 and 85 yr (inclusive) were eligible if they had a BMD T-score (based on male reference ranges) less than or equal to 2.0 and more than or equal to 3.5 at the LS or FN or had a previous major osteoporotic fracture and a BMD T-score less than or equal to 1.0 and more than or equal to 3.5 at the LS or FN and had at least two lumbar vertebrae, one femur, and one forearm evaluable by dual-energy x-ray absorptiometry (DXA). Exclusion criteria included any severe or more than one moderate vertebral fracture on screening spinal x-ray, any vertebral fracture or clinical fracture diagnosed within 6 months before screening, any disease known to affect bone metabolism, and serum 25(OH)-vitamin D concentration less than 20 ng/ml. In addition, subjects were excluded if they had received any bisphosphonate treatment for 3 months or more cumulatively in the past 2 yr or for 1 month or more in the past year or during the 3-month period before randomization. Also, men were not eligible if they had any of the following treatments within 3 months before screening: anabolic steroids or testosterone, glucocorticoids, calcitonin, calcitriol or vitamin D derivatives, and other bone-active drugs. Use of these drugs was not permitted during the study. All subjects provided the appropriate written informed consent before any study-specific procedures were conducted. The study was performed in compliance with the International Conference on Harmonization guidelines for Good Clinical Practice standards and approved by an institutional review board or ethics committees for each study site. Study assessments BMD was assessed using DXA of the LS, hip regions (TH, FN, and TR), and 1/3R at baseline and at month 12. Baseline and on-study DXA scans were performed by the local DXA technologist, and the scans were then submitted electronically to a central imaging center (Synarc, Inc., Portland, OR) for final blinded analysis (the central imaging center was blinded to treatment but

3 J Clin Endocrinol Metab, September 2012, 97(9): jcem.endojournals.org 3163 not to sequence). Lateral spine x-rays performed at screening to determine subject eligibility were analyzed by the local radiologist. Lateral spine x-rays performed at screening and at month 12 were analyzed and graded using a semiquantitative grading scale (20). Baseline 10-yr major osteoporotic fracture risk was assessed using the FRAX (version 3.3) algorithm ( Serum samples (drawn before noon on fasting subjects) collected at d 1 and 15 and months 6 and 12 were used to assess sctx [Serum Crosslaps (CTX-1) ELISA; IDS Nordic, Herlev, Denmark] and testosterone levels (free testosterone active RIA; Beckman Coulter, Inc., Brea, CA). All laboratory assessments were done by the same central laboratory (Covance, Indianapolis, IN). Assays for antidenosumab antibodies (22) were performed before administration of the first dose of denosumab and at month 12. AE and the severity of AE were recorded at each study visit. Adjudication of all investigator-reported oral conditions possibly related to or suspicious for osteonecrosis of the jaw (ONJ), was done by the ONJ Adjudication Committee (which remained blinded to treatment group assignment) at the study sponsor site and was conducted according to the sponsor s preestablished and documented criteria and event definition. Statistical analyses A study sample size of 232 subjects in total (116 in each treatment group) would provide at least 99% power to detect a 5.2% difference in LS BMD assuming a SD of 3.8% and a twosided type-1 error rate of 0.01 (a Bonferroni type-1 error allocation was applied). The sample size for this study was determined by relative change in the 1/3R BMD, which had the least power among all primary and secondary endpoints. A sample size of 232 subjects was estimated to provide an 80% power to detect a 1.99% difference at the 1/3R between the treatment groups, assuming a SD of 4.2% and a two-sided type-1 error rate of A 10% dropout rate for the 12-month double-blind treatment duration was assumed. The primary analysis included data from all subjects who were randomized into the study and who had a baseline and at least one post-baseline assessment. Percent change in BMD at each skeletal site was analyzed using analysis of covariance models with treatment and minimum baseline BMD T-score level (randomization strata) as fixed effects. The primary results were based on the point estimate for the least-squares mean and the two-sided 95% confidence interval (CI) for the treatment difference at the 12-month time point. When statistical significance in the primary endpoint (percent change from baseline in lumbar FIG. 1. Disposition of study subjects. spine BMD at 12 months) was achieved, formal statistical inferences on the secondary efficacy endpoints were simultaneously evaluated using the Hochberg step-up procedure for multiplicity adjustment (23). Last observation carried forward imputation was used for BMD endpoints, and observed data were used for sctx endpoints. For BMD endpoints, a sensitivity analysis was conducted using a repeated-measures model with observed data without imputation. Sensitivity analyses on the primary efficacy endpoint were also conducted by controlling for baseline covariates [testosterone level, BMD T-score, 10-yr major osteoporotic fracture risk (calculated from FRAX with BMD), sctx, age, race (Caucasian vs. non-caucasian), geographic region (Europe vs. North America), and previous osteoporotic fracture (yes vs. no)] to evaluate the robustness of the results from the primary analysis. The primary endpoint was also analyzed to assess the efficacy of denosumab within various subgroups: baseline total testosterone levels of less than or more than or equal to 250 ng/dl (prespecified by the study), less than 230 ng/dl, more than or equal to 230 to less than 350 ng/dl, and more than or equal to 350 ng/dl (based on international recommendations for the classification of hypogonadism) (24); minimum baseline BMD T-score ( 2.5 and 2.5); baseline 10-yr major osteoporotic fracture risk (calculated from FRAX with BMD and assessed in tertiles); baseline sctx; age; race; and geographic region. The safety analysis included all randomized subjects who received at least one dose of investigational product. Descriptive statistics calculated for the 12-month endpoint included mean and SD for continuous variables and counts and percentages for categorical variables. Changes in sctx exhibit a nonsymmetric distribution and were summarized using medians and interquartile ranges. Safety results were descriptively summarized by treatment groups. Results Subject baseline characteristics A total of 242 subjects enrolled in the study (121 placebo, 121 denosumab) and 228 (94.2%) completed the 12-month double-blind treatment phase. The first subject enrolled in October 2009, and the last subject completed the month-12 visit in June Fourteen (5.7%; four placebo, 10 denosumab) subjects discontinued the study before completing the first 12 months of treatment (Fig. 1). Reasons for discontinuation were study participation consent withdrawal [one (0.8%) placebo, four (3.3%) denosumab], AE occurrence [zero placebo, three (2.5%) denosumab], ineligibility determined [two (1.7%) placebo, one (0.8%) denosumab], death [one (0.8%) in each group], and other reasons [zero placebo, one (0.8%) denosumab]. Demographics and baseline characteristics of subjects are shown in Table 1.

4 3164 Orwoll et al. Denosumab Treatment in Men with Low BMD J Clin Endocrinol Metab, September 2012, 97(9): TABLE 1. Demographics and baseline characteristics of men randomized in the study Placebo (n 121) Denosumab (n 121) All (n 242) Age (yr) mean (SD) 65.0 (9.1) 64.9 (10.5) 65.0 (9.8) Age group (yr) n (%) 50 5 (4.1) 9 (7.4) 14 (5.8) (21.5) 22 (18.2) 48 (19.8) (40.5) 44 (36.4) 93 (38.4) (28.9) 39 (32.2) 74 (30.6) 80 6 (5.0) 7 (5.8) 13 (5.4) Ethnic group n (%) White 107 (88.4) 121 (100.0) 228 (94.2) Other 14 (11.6) 0 (0) 14 (5.8) Minimum BMD T-score at LS or FN n (%) (46.3) 61 (50.4) 117 (48.3) (53.7) 60 (49.6) 125 (51.7) BMD T-score mean (SD), range Lumbar spine 2.0 (1.0), 3.6 to (1.1), 3.6 to (1.1), 3.6 to 2.3 Total hip 1.4 (0.7), 2.8 to (0.6), 3.5 to (0.6), 3.5 to 0.2 Femoral neck 1.9 (0.6), 3.4 to (0.6), 3.8 to (0.6), 3.8 to 0.7 Trochanter 1.3 (0.7), 2.9 to (0.7), 2.7 to (0.7), 2.9 to 0.6 1/3R 1.7 (1.2), 5.0 to (1.3), 5.1 to (1.2), 5.1 to 1.5 sctx (ng/ml) mean (SD) 0.41 (0.2) 0.40 (0.18) 0.41 (0.19) History of fracture n (%) Any 48 (39.7) 47 (38.8) 95 (39.3) Osteoporotic a 37 (30.6) 23 (19.0) 60 (24.8) Major osteoporotic b 20 (16.5) 16 (13.2) 36 (14.9) Prevalent vertebral fracture 25 (20.7) 30 (24.8) 55 (22.7) 10-yr probability of major osteoporotic fracture (%) c Mean (SD) 9.7 (6.4) 9.9 (6.3) 9.8 (6.3) Range 1.6, , , 42.3 Total testosterone (ng/dl) mean (116.7) (121.0) (118.8) (SD) Total testosterone n (%) 230 ng/dl 14 (11.6) 14 (11.6) 28 (11.6) 250 ng/dl d 19 (15.7) 17 (14.0) 36 (14.9) 350 ng/dl 44 (44.6) 53 (43.8) 107 (44.2) a Defined as either vertebral or nonvertebral fractures with low trauma. b Defined as hip, spine, forearm, or humerus fractures with low trauma. c As assessed by FRAX with BMD (version 3.3). d Testosterone threshold prespecified by the study. The mean (SD) age was 65.0 (9.8) yr, with the majority in the 50- to 79-yr age range. All men in the denosumab group and 88.4% in the placebo group were white. A total of 46.3 and 50.4% of subjects in the placebo and denosumab groups, respectively, had a BMD of less than or equal to 2.5 at either the LS or FN. The mean baseline BMD T-scores were similar between treatment groups for all sites. Mean serum testosterone levels were in the normal range [mean (SD) of (118.8) ng/dl]. Approximately 15% of subjects had testosterone concentrations below 250 mg/dl. A total of 11.6% of subjects had a testosterone level below 230 ng/dl, and 44.2% had a level below 350 ng/dl. Change in BMD A total of 231 men (117 placebo, 117 denosumab) were included in the primary analysis for the percent change from baseline in LS BMD at 12 months. Denosumab increased LS BMD by 5.7% at month 12 compared with an increase of 0.9% with placebo. The difference in mean LS BMD between treatment groups was 4.8% (P ; 95% CI %) (Fig. 2A). LS BMD was significantly higher than placebo (P ) by 6 months of treatment, and the difference continued to increase to 12 months. Denosumab also significantly increased BMD at all other skeletal sites measured including the TH, FN, TR, and 1/3R (P for all comparisons) (Fig. 2, B E). Similar results were found when analyzed using a repeatedmeasures model with observed data. Results of sensitivity analyses on the percent change from baseline in LS BMD at 12 months were consistent with the primary analysis, demonstrating that the results

5 J Clin Endocrinol Metab, September 2012, 97(9): jcem.endojournals.org 3165 Results of subgroup analyses on the percent change from baseline in LS BMD at 12 months by baseline total testosterone levels, by minimum baseline BMD T-score, and by baseline 10-yr major osteoporotic fracture risk are shown in Table 2. Denosumab increased LS BMD in all subgroups (P 0.005). Additional subgroup analyses done by baseline sctx, age, race, and geographic region all showed that denosumab increased LS BMD to a similar degree at month 12 compared with placebo (data not shown; all P for the difference in percent change between denosumab and placebo). Bone turnover markers Treatment with denosumab decreased median sctx concentration compared with placebo at d 15 (adjusted P ). The median percent change from baseline in sctx concentration at d 15 was 7% in the placebo group and 81% in the denosumab group (Fig. 3). FIG. 2. Percent change from baseline in BMD over time at five measurement sites (A E) for the placebo and denosumab groups. Values are least squares means; error bars are 95% CI. P values compare the difference between treatment groups and are based on an analysis of covariance model. Fractures Clinical fractures occurred in two (1.7%) and one (0.8%) subject in the placebo- and denosumab-treated groups, respectively. Two men (one in each treatment group) had a rib fracture, and one placebo-treated man had a humerus fracture. A new vertebral fracture occurred in one (0.8%) man in the placebo group and none in the denosumab group. of the primary analysis were robust. Difference in the percent change in BMD from baseline at month 12 between the denosumab and placebo groups after controlling for baseline testosterone level (4.8%), LS BMD T-score (4.9%), 10-yr major osteoporotic fracture risk (4.8%), sctx (4.8%), age (4.8%), race (4.9%), geographic region (4.8%), and previous osteoporotic fracture (4.8%) were all significant (P for all comparisons). The sensitivity analysis by race confirmed that although the denosumab group had relatively more whites than the placebo group, this difference did not affect the outcomes of the analysis. Safety A total of 240 men (120 placebo, 120 denosumab) received at least one dose of investigational product and were included in the safety analysis (Table 3). Overall, the incidence of AE, serious AE (SAE), and fatal AE was similar between treatment groups. Most AE in both treatment groups were mild or moderate in severity; the most frequent ( 5% incidence) AE were back pain, arthralgia, nasopharyngitis, and constipation. There were no instances of hypocalcemia, adjudicated ONJ, complications of fracture healing, or atypical fem-

6 3166 Orwoll et al. Denosumab Treatment in Men with Low BMD J Clin Endocrinol Metab, September 2012, 97(9): TABLE 2. Percent change in lumbar spine BMD at month 12 as assessed by baseline covariates Covariate n Placebo Least-squares mean (95% CI) n Denosumab Least-squares mean (95% CI) P value Baseline testosterone level 250 ng/dl ( 0.9, 2.4) (3.5, 6.9) ng/dl (0.3, 1.5) (5.1, 6.3) ng/dl ( 0.9, 2.8) (3.0, 6.6) to 350 ng/dl (0.7, 2.9) (4.8, 7.0) ng/dl ( 0.4, 1.0) (4.9, 6.4) Minimum baseline BMD T-score (0.6, 2.4) (5.6, 7.3) ( 0.4, 1.1) (4.1, 5.7) Baseline 10-yr major osteoporotic fracture risk (tertiles) 6.4% ( 0.6, 1.4) (4.5, 6.5) to 11.2% ( 0.2, 2.0) (5.1, 7.2) % (0.4, 2.2) (4.4, 6.2) oral fractures during the 12-month double-blind treatment phase. Events potentially associated with hypersensitivity [three subjects (2.5%) in each group], infections [24 subjects (20.0%) in each group), acute pancreatitis [one subject (0.8%) in each group), and cataract [three subjects (2.5%) in placebo group, two subjects (1.7%) in denosumab group) were balanced between treatment groups. One (0.8%) instance of non-sae of skin infection was reported in the placebo group (none in denosumab), and two (1.7%) of eczema were reported in the denosumab group (none in the placebo). No denosumabtreated subject tested positive for binding antidenosumab antibodies. SAE were reported in 8.3% (10 subjects) and 9.2% (11 subjects) in the placebo and denosumab groups, respectively. Among the SAE, prostate cancer was reported in three men (2.5%) in the denosumab group (zero in placebo group); two of the three men were diagnosed with prostate cancer within 3 wk of receiving the first dose of denosumab, indicating that the cancer was present before treatment initiation. Arterial limb thrombosis SAE were reported in two men (1.7%) in the denosumab group (zero in placebo group). All other SAE were reported in single subjects per group ( 1% per treatment group). Two deaths (one in the denosumab group from myocardial infarction and one in the placebo group from basilar artery thrombosis) were reported during the 12-month double-blind treatment period; neither was considered treatment related. Discussion FIG. 3. Median percent change in serum CTX levels from baseline by study visit. RANK ligand is an essential mediator of osteoclast activity. Denosumab is a fully human monoclonal antibody that binds RANK ligand and prevents the activation of RANK, thereby inhibiting the formation, activation, and survival of osteoclasts. In assessing the effects of osteoporosis therapies, BMD has been used in previous studies to evaluate efficacy of different antiresorptive therapies because it has been shown to be a reliable surrogate for fracture risk in phase 3 osteoporosis studies of those agents. Low BMD is an important and modifiable risk factor for fracture in men. ADAMO is the first study to evaluate the efficacy and safety of 60 mg sc

7 J Clin Endocrinol Metab, September 2012, 97(9): jcem.endojournals.org 3167 TABLE 3. Summary of AE Placebo (n 120) n (%) Denosumab (n 120) n (%) AE regardless of relationship to treatment All 84 (70.0) 86 (71.7) Serious 10 (8.3) 11 (9.2) Fatal 1 (0.8) 1 (0.8) Leading to investigational 0 (0) 4 (3.3) product discontinuation AE with 5% incidence Back pain 8 (6.7) 10 (8.3) Arthralgia 7 (5.8) 8 (6.7) Nasopharyngitis 7 (5.8) 8 (6.7) Constipation 7 (5.8) 0 (0) AE of new vertebral fractures 1 (0.8) 0 (0) AE of any clinical fracture 2 (1.7) 1 (0.8) ONJ 0 (0) 0 (0) Fracture healing 0 (0) 0 (0) complications Atypical femoral fracture 0 (0) 0 (0) n, Number of subjects. Q6M denosumab in a population of men with low BMD. Men who received denosumab over a 1-yr period experienced a significant increase in BMD at the LS, TH, FN, TR, and 1/3R compared with men treated with placebo. Moreover, increases in BMD after denosumab treatment were independent of baseline BMD T-score, estimated 10-yr fracture risk, sctx, testosterone levels, age, race, geographic region, or previous osteoporotic fractures. The consistent results across subgroups demonstrated that denosumab therapy is effective across a spectrum of men. Treatment with denosumab resulted in significant reductions in sctx at d 15; these reductions were maintained at month 6 and month 12. Other studies have been conducted in men with osteoporosis to assess therapeutic response to antiresorptive agents. Studies with oral bisphosphonates have included 2-yr treatment with daily alendronate (12) or weekly risedronate (13) and 1-yr treatment with monthly ibandronate (25) as well as a 2-yr study using annual iv zoledronic acid (14). Although all have been shown to increase LS and proximal femur BMD relative to placebo, these studies did not demonstrate an increase in BMD at the 1/3R, a predominately cortical bone site (26). In the current study, denosumab-treated men showed a significant increase in BMD at the 1/3R, a finding that has been observed in denosumab clinical trials with postmenopausal women (17, 18, 27 29). As postulated by others, differences in mechanism of action between bisphosphonates and denosumab may explain the propensity for increases in both cortical and trabecular bone observed with RANK ligand inhibition (30). Although men lack the rapid phase of bone loss present at menopause in women, they lose substantial amounts of bone with aging. This bone loss results in low bone mass and microarchitectural deterioration with a subsequent increase in bone fragility and susceptibility to fracture (1, 21, 31, 32). Hypogonadism may contribute to bone loss in men (11). In the current study, 15% of men had serum testosterone concentrations below 250 ng/dl. Sensitivity and subgroup analyses indicated that denosumab was effective in increasing BMD similarly in men across a range of testosterone concentrations, a finding that suggests denosumab treatment is effective in men with normal and decreased gonadal function. Denosumab 60 mg Q6M also has been evaluated in the treatment of bone loss in men receiving ADT for nonmetastatic prostate cancer (19). In these men, median testosterone concentration at study entry was 8 ng/dl, consistent with the effect of hormone ablation therapy. Despite this considerable difference in gonadal status, the mean BMD increases observed in AD- AMO were similar to those in the prostate cancer study. Increases in BMD were associated with decreases in new vertebral fractures as early as 1 yr of denosumab treatment initiation in men receiving ADT (19). Results from ADAMO are also consistent with results from the phase 3 pivotal fracture study in postmenopausal women with osteoporosis (FREEDOM) (18). BMD increases in ADAMO were similar to those in postmenopausal women, and gains in BMD were associated with decreases in new vertebral, nonvertebral, and hip fractures (18). Furthermore, significant reduction in sctx with denosumab compared with placebo was observed when first measured 15 d after initiating treatment, and the sustained reduction of bone turnover throughout the 12 months of therapy is consistent with what has been previously demonstrated with denosumab in postmenopausal women with low BMD or osteoporosis (17, 27). All of these findings support the conclusion that 60 mg Q6M sc denosumab is similarly effective in men with low BMD and in postmenopausal women with osteoporosis. Although the current study was not designed with adequate statistical power to assess anti-fracture efficacy, the effects of denosumab on BMD and sctx suggest that effects on fracture risk are likely to be similar in this patient population to those in men with prostate cancer treated with ADT (19) and in women with postmenopausal osteoporosis (18). Consistent with other studies, denosumab was well tolerated for the 12 months in men enrolled in this study. The incidence of AE was similar in the denosumab and placebo groups. No new safety risks associated with denosumab treatment were identified. In summary, 1 yr of Q6M denosumab therapy in men with low BMD resulted in a reduction in bone resorption

8 3168 Orwoll et al. Denosumab Treatment in Men with Low BMD J Clin Endocrinol Metab, September 2012, 97(9): and increases in BMD at all skeletal sites assessed and was well tolerated. These effects were independent of gonadal function level, baseline BMD status, age, and estimated fracture risk. The increases in BMD were similar to those observed in previous studies that demonstrated fracture risk reduction, suggesting that denosumab is efficacious in the treatment of men with osteoporosis. Acknowledgments We thank Yeshi Mikyas (Amgen Inc.) for her assistance in writing this manuscript. S.B. is senior clinical investigator of the Fund for Scientific Research (FWO Vlaanderen) and holder of the Leuven University Chair in Gerontology and Geriatrics. Address all correspondence and requests for reprints to: Eric Orwoll, M.D., Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon orwoll@ohsu.edu. This work was supported by Amgen Inc., Thousand Oaks, CA. This study is registered in ClinTrials.gov under the identifier NCT This work was presented in part as an abstract and oral presentation at the 33rd Annual Meeting of the American Society for Bone and Mineral Research (September 16 20, 2011; San Diego, CA). Disclosure Summary: E.O. received research support or consulting fees from Amgen, Eli Lilly, Merck, and Wright Medical Technology; C.S.T. has no conflict of interest to declare B.L.L. has received research grants, honoraria, or board membership/ consultancy fees from Amgen; R.C. has received honoraria and has been on the Advisory Council board for Amgen; E.C. has received research grants and honoraria from Amgen; D.K. has received research grants or consulting fees from, or has served as a member of the Speaker s Bureau for, Amgen, Biosante, Boehringer, Eli Lilly, GlaxoSmithKline, Johnson&Johnson, Merck, Novartis, Pfizer, and Servier; J.-Y.R. has received research grant, consulting fees, or lecture fees from Amgen, Analis, Bristol Myers Squibb, Ebewee Pharma, Eli Lilly, Genevrier, GlaxoSmith- Kline, IBSA, Merck, Merck Sharp and Dohme, Negma, Nolver, Novartis, NPS Pharmaceuticals, Novo-Nordisk, Nycomed, Roche, Rottapharm, Servier, Teijin, Teva, Theramex, UCB, Zodiac, and Wyeth; A.J.K. has received monetary compensation for speakers programs from Amgen; E.M.L. has received research grants, honoraria, board membership/consultancy fees from, or has been a member of, the Advisory Council or Speaker s Bureau for Amgen, Eli Lilly, GlaxoSmithKline, Merck, Novartis, and Warner Chilcott; P.D.M. has received scientific grants or consulting fees from, or has been a board member for, Amgen, Baxter, Eli Lilly, GE, Merck, Novartis, Procter & Gamble, Radius, Roche, Sanofi-Aventis, Takeda, Warner Chilcott, and Wright; M.A.B. has been a member of the Speaker s Bureau for Amgen; M.R.M. has received research grants or board membership/consultancy fees or has been a member of the Advisory Council for Merck; H.G.B. has received research grants or honoraria or has been a member of the Advisory Council or Speaker s Bureau for Amgen, Azelon, GlaxoSmithKline, Merck, Tarsa, and Zelos; O.L. has received honoraria and been a member of the Advisory Council for Amgen; B.A. has received research grants or consulting fees from, and has been a member of the Speaker s Bureau for, Amgen, Eli Lilly, Merck, Novartis, and Nycomed; U.G. has received research grants from Amgen; Y.-C.Y., R.B.W., S.S., A.G., and J.W.H. are Amgen employees and may own stocks in the company; S.B. has received research grants and honoraria and has been a member of the Advisory Council for Amgen. References 1. Jones G, Nguyen T, Sambrook PN, Kelly PJ, Gilbert C, Eisman JA 1994 Symptomatic fracture incidence in elderly men and women: the Dubbo Osteoporosis Epidemiology Study (DOES). Osteoporos Int 4: Gielen E, Vanderschueren D, Callewaert F, Boonen S 2011 Osteoporosis in men. Best Pract Res Clin Endocrinol Metab 25: King AB, Tosteson AN, Wong JB, Solomon DH, Burge RT, Dawson-Hughes B 2009 Interstate variation in the burden of fragility fractures. J Bone Miner Res 24: Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A 2007 Incidence and economic burden of osteoporosisrelated fractures in the United States, J Bone Miner Res 22: Johnell O, Kanis JA 2006 An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 17: Haentjens P, Magaziner J, Colón-Emeric CS, Vanderschueren D, Milisen K, Velkeniers B, Boonen S 2010 Meta-analysis: excess mortality after hip fracture among older women and men. Ann Intern Med 152: Kannegaard PN, van der Mark S, Eiken P, Abrahamsen B 2010 Excess mortality in men compared with women following a hip fracture. National analysis of comedications, comorbidity and survival. Age Ageing 39: Ebeling PR 2008 Clinical practice. Osteoporosis in men. N Engl J Med 358: Kiebzak GM, Beinart GA, Perser K, Ambrose CG, Siff SJ, Heggeness MH 2002 Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med 162: Dawson-Hughes B, Looker AC, Tosteson AN, Johansson H, Kanis JA, Melton 3rd LJ 2012 The potential impact of the National Osteoporosis Foundation guidance on treatment eligibility in the USA: an update in NHANES Osteoporos Int 23: Khosla S, Amin S, Orwoll E 2008 Osteoporosis in men. Endocr Rev 29: Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, Adami S, Weber K, Lorenc R, Pietschmann P, Vandormael K, Lombardi A 2000 Alendronate for the treatment of osteoporosis in men. N Engl J Med 343: Boonen S, Orwoll ES, Wenderoth D, Stoner KJ, Eusebio R, Delmas PD 2009 Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study. J Bone Miner Res 24: Orwoll ES, Miller PD, Adachi JD, Brown J, Adler RA, Kendler D, Bucci-Rechtweg C, Readie A, Mesenbrink P, Weinstein RS 2010 Efficacy and safety of a once-yearly i.v. infusion of zoledronic acid 5 mg versus a once-weekly 70-mg oral alendronate in the treatment of male osteoporosis: a randomized, multicenter, double-blind, active-controlled study. J Bone Miner Res 25: Kurland ES, Cosman F, McMahon DJ, Rosen CJ, Lindsay R, Bilezikian JP 2000 Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 85: Cramer JA, Gold DT, Silverman SL, Lewiecki EM 2007 A system-

9 J Clin Endocrinol Metab, September 2012, 97(9): jcem.endojournals.org 3169 atic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int 18: Bone HG, Bolognese MA, Yuen CK, Kendler DL, Wang H, Liu Y, San Martin J 2008 Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 93: Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C 2009 Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361: Smith MR, Saad F, Egerdie B, Szwedowski M, Tammela TL, Ke C, Leder BZ, Goessl C 2009 Effects of denosumab on bone mineral density in men receiving androgen deprivation therapy for prostate cancer. J Urol 182: Genant HK, Wu CY, van Kuijk C, Nevitt MC 1993 Vertebral fracture assessment using a semiquantitative technique. J Bone Miner Res 8: Meier DE, Orwoll ES, Jones JM 1984 Marked disparity between trabecular and cortical bone loss with age in healthy men. Measurement by vertebral computed tomography and radial photon absorptiometry. Ann Intern Med 101: Moxness M, Tatarewicz S, Weeraratne D, Murakami N, Wullner D, Mytych D, Jawa V, Koren E, Swanson SJ 2005 Immunogenicity testing by electrochemiluminescent detection for antibodies directed against therapeutic human monoclonal antibodies. Clin Chem 51: Hochberg Y 1988 A sharper Bonferroni procedure for multiple tests of significance. Biometrika 75: Wang C, Nieschlag E, Swerdloff RS, Behre H, Hellstrom WJ, Gooren LJ, Kaufman JM, Legros JJ, Lunenfeld B, Morales A, Morley JE, Schulman C, Thompson IM, Weidner W, Wu FC 2009 ISA, ISSAM, EAU, EAA and ASA recommendations: investigation, treatment and monitoring of late-onset hypogonadism in males. Aging Male 12: Orwoll ES, Binkley NC, Lewiecki EM, Gruntmanis U, Fries MA, Dasic G 2010 Efficacy and safety of monthly ibandronate in men with low bone density. Bone 46: Dempster DW 2006 Anatomy and functions of the adult skeleton. In: Favus MJ, ed. Primer on the metabolic bone disease and disorders of mineral metabolism. 6th ed. Washington, DC: American Society for Bone and Mineral Research; Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Alvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG 2009 Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 24: McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, Peacock M, Miller PD, Lederman SN, Chesnut CH, Lain D, Kivitz AJ, Holloway DL, Zhang C, Peterson MC, Bekker PJ 2006 Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354: Miller PD, Wagman RB, Peacock M, Lewiecki EM, Bolognese MA, Weinstein RL, Ding B, San Martin J, McClung MR 2011 Effect of denosumab on bone mineral density and biochemical markers of bone turnover: six-year results of a phase 2 clinical trial. J Clin Endocrinol Metab 96: Seeman E, Delmas PD, Hanley DA, Sellmeyer D, Cheung AM, Shane E, Kearns A, Thomas T, Boyd SK, Boutroy S, Bogado C, Majumdar S, Fan M, Libanati C, Zanchetta J 2010 Microarchitectural deterioration of cortical and trabecular bone: differing effects of denosumab and alendronate. J Bone Miner Res 25: Melton 3rd LJ, Khosla S, Atkinson EJ, Oconnor MK, Ofallon WM, Riggs BL 2000 Cross-sectional versus longitudinal evaluation of bone loss in men and women. Osteoporos Int 11: Fatayerji D, Cooper AM, Eastell R 1999 Total body and regional bone mineral density in men: effect of age. Osteoporos Int 10:59 65