Two-Year Treatment With Denosumab (AMG 162) in a Randomized Phase 2 Study of Postmenopausal Women With Low BMD

Abstract

Denosumab is a monoclonal antibody to RANKL. In this randomized, placebo-controlled study of 412 postmenopausal women with low BMD, subcutaneous denosumab given every 3 or 6 mo was well tolerated, increased BMD, and decreased bone resorption markers for up to 24 mo. Continued study of denosumab is warranted in the treatment of low BMD in postmenopausal women.Introduction: Denosumab is a fully human monoclonal antibody that inhibits RANKL, a key mediator of osteoclastogenesis and bone remodeling. This prespecified exploratory analysis evaluated the efficacy and safety of denosumab through 24 mo in the treatment of postmenopausal women with low BMD. Materials and Methods: Four hundred twelve postmenopausal women with lumbar spine BMD T-scores of -1.8 to -4.0 or femoral neck/total hip T-scores of -1.8 to -3.5 were randomly assigned to receive double-blind, subcutaneous injections of placebo; denosumab 6, 14, or 30 mg every 3 mo; denosumab 14, 60, 100, or 210 mg every 6 mo; or open-label oral alendronate 70 mg once weekly. Outcome measures included BMD at the lumbar spine, total hip, distal one-third radius, and total body; bone turnover markers; and safety. Results: Denosumab increased BMD at all measured skeletal sites and decreased concentrations of bone turnover markers compared with placebo at 24 mo. At the lumbar spine, BMD increases with denosumab ranged from 4.13% to 8.89%. BMD changes with denosumab 30 mg every 3 mo and Ն60 mg every 6 mo were similar to, or in some cases greater than, with alendronate. The incidence of adverse events was similar in the placebo, denosumab, and alendronate treatment groups. Exposure-adjusted adverse events over 2 yr of treatment were similar to those reported during the first year of treatment. Conclusions: In these postmenopausal women with low BMD, treatment with denosumab for 2 yr was associated with sustained increases in BMD and reductions in bone resorption markers compared with placebo.

Prevention of glucocorticoid‐induced bone loss in mice by inhibition of RANKL

“…Denosumab has a rapid onset of action and a long plasma half-life after a single subcutaneous injection, resulting in a sustained clinical effect on bone that lasts for months. In clinical trials, denosumab has been evaluated in postmenopausal women with low bone mass (17,35), women with skeletal metastases due to breast cancer (19,36), and patients with myeloma bone disease (36). In these studies, denosumab increased BMD at the lumbar spine and the proximal femur (17,35) and suppressed biochemical markers of bone turnover (17,19,35,36), findings that are consistent with our study.…”

Effects of denosumab on bone turnover markers in postmenopausal osteoporosis

“…This change in CTX is similar to BTM responses to denosumab reported previously. (2)(3)(4) The mechanism for the apparent greater release over time is not fully understood but does not appear to be related to a change in the pharmacokinetics of denosumab over time. It could relate to greater endogenous RANKL synthesis over time to try to ''overcome'' RANKL inhibition.…”

“…Such changes have been reported for the bone-resorption markers cross-linked C-telopeptide of type I collagen (CTX) and cross-linked N-telopeptide of type I collagen (NTX) and the bone-formation markers serum procollagen N-propeptide of type I collagen (PINP) and bone alkaline phosphatase (BALP). (2)(3)(4) The baseline bone turnover level is related to the bone mineral density (BMD) increase with denosumab (as for alendronate). (5) The effect of denosumab on bone resorption is earlier and of greater magnitude than that of the oral bisphosphonate alendronate, as is the increase in BMD.…”

“…(6) The changes in bone-resorption markers with denosumab do not remain steady over the dosing interval; there is suppression within 12 hours of administration of the drug, with median decreases in bone-resorption markers of 80% or more. (2)(3)(4)6) There is subsequently a resolution of effect before the next injection, and this cycle of marked reduction followed by a release in bone turnover markers (BTMs) occurs after each injection. After stopping treatment, BTM levels return to baseline, and there follows a transient increase in BTMs above the initial baseline that lasts for up to a year, and this is associated with loss of BMD gained during denosumab therapy.…”

“…The aims of this study were (1) to describe in detail the time course of BTM response to denosumab, (2) to identify the determinants of BTM response during treatment with denosumab, (3) to estimate the percentage of women with BTMs below the reference interval for premenopausal women while taking denosumab, and (4) to relate the changes in BTMs to those in BMD.…”