Background/Purpose: Denosumab, a fully human monoclonal antibody to RANKL, has been shown to increase bone mineral density (BMD) in postmenopausal women with high or low bone turnover,¹ and reduce the risk for new vertebral, non-vertebral, and hip fractures.² ADAMO evaluated denosumab in men with low BMD and demonstrated increases in BMD at all measured skeletal sites and reductions in serum CTX (sCTX).³ We assessed the efficacy of denosumab to increase BMD in men across a range of baseline bone turnover levels in ADAMO.

Methods: ADAMO was a multicenter, randomized, double-blind, placebo-controlled study. Subjects were randomized 1:1 to receive either 60 mg denosumab or placebo administered subcutaneously once every 6 months over a 12-month period. Subjects were included if they were aged 30 to 85 years; had a BMD T-score ≤‑2.0 and ≥‑3.5 at the lumbar spine or femoral neck, or had a prior major osteoporotic fracture and a T-score ≤‑1.0 and ≥‑3.5 at the lumbar spine or femoral neck. Subjects received ≥1000 mg calcium and ≥800 IU vitamin D supplementation daily. Percentage change in sCTX was assessed at day 15. Percentage change in BMD from baseline to month 12 at the lumbar spine, total hip, femoral neck, trochanter, and 1/3 radius was assessed according to baseline tertile of sCTX.

Results: A total of 242 subjects (121, placebo; 121, denosumab) were enrolled. As previously reported, 12 months of denosumab treatment significantly increased BMD from baseline at the lumbar spine, total hip, femoral neck, trochanter, and 1/3 radius compared with placebo (all p<0.02, adjusted for multiplicity). Denosumab reduced sCTX by 81% from baseline vs 7% for placebo at day 15. For each tertile of baseline sCTX, subjects treated with denosumab, compared with placebo, demonstrated greater gains in lumbar spine and total hip BMD at month 12 (Figure). Subjects in the highest tertile of baseline sCTX had the numerically greatest gains in BMD when compared with subjects in the lowest tertile, although differences were not statistically significant. Associations between baseline sCTX and 12-month BMD improvements were weaker at the femoral neck and 1/3 radius, sites with greater variability in BMD measurements.⁴ 

Conclusion: Independent of baseline sCTX, men with low BMD treated for one year with denosumab, compared with placebo, demonstrated greater gains in BMD at key skeletal sites routinely used to diagnose and manage patients with osteoporosis, suggesting that men at all levels of bone turnover may benefit from denosumab therapy.

Figure: Percent Change From Baseline in Mean BMD at 12 Months by Tertiles of Baseline sCTX

1.     Bone, JCEM 2008

2.     Cummings, NEJM 2009

3.     Gruntmanis, ENDO 2012

4.     Brown, ASBMR 2009