Effect of denosumab on bone mineral density and biochemical markers of bone turnover: 8-year results of a phase 2 clinical trial

Abstract

SummaryIn a phase 2 study, continued denosumab treatment for up to 8 years was associated with continued gains in bone mineral density and persistent reductions in bone turnover markers. Denosumab treatment was well tolerated throughout the 8-year study.IntroductionThe purpose of this study is to present the effects of 8 years of continued denosumab treatment on bone mineral density (BMD) and bone turnover markers (BTM) from a phase 2 study.MethodsIn the 4-year parent study, postmenopausal women with low BMD were randomized to receive placebo, alendronate, or denosumab. After 2 years, subjects were reallocated to continue, discontinue, or discontinue and reinitiate denosumab; discontinue alendronate; or maintain placebo for two more years. The parent study was then extended for 4 years where all subjects received denosumab.ResultsOf the 262 subjects who completed the parent study, 200 enrolled in the extension, and of these, 138 completed the extension. For the subjects who received 8 years of continued denosumab treatment, BMD at the lumbar spine (N = 88) and total hip (N = 87) increased by 16.5 and 6.8 %, respectively, compared with their parent study baseline, and by 5.7 and 1.8 %, respectively, compared with their extension study baseline. For the 12 subjects in the original placebo group, 4 years of denosumab resulted in BMD gains comparable with those observed during the 4 years of denosumab in the parent study. Reductions in BTM were sustained over the course of continued denosumab treatment. Reductions also were observed when the placebo group transitioned to denosumab. Adverse event profile was consistent with previous reports and an aging cohort.ConclusionContinued denosumab treatment for 8 years was associated with progressive gains in BMD, persistent reductions in BTM, and was well tolerated.

Changes in Bone Turnover Marker Levels and Clinical Outcomes in Patients with Advanced Cancer and Bone Metastases Treated with Bone Antiresorptive Agents

“…Therefore, modalities that reduce bone turnover rates might impact tumor growth, thus limiting DPB and improving survival (20,21). Denosumab and zoledronic acid are potent bone antiresorptive agents that have been shown to significantly reduce the levels of BTMs such as uNTx and sBSAP (33,34). As such, decreased levels of uNTx and sBSAP after treatment with denosumab or zoledronic might be an indicator of reduced tumor growth in the bone due to reduced bone turnover rates, whereas high levels of these BTMs might indicate continued tumor growth.…”

“…Both denosumab and zoledronic acid have been shown to significantly reduce uNTx and sBSAP levels (33,34), and these two BTMs have been investigated as potential prognostic factors for monitoring patients with cancer who are receiving bone antiresorptive agents. A recent study in 1,901 men with castration-resistant prostate cancer demonstrated that decreased baseline levels of uNTx and sBSAP were associated with improved overall survival (OS; ref.…”

Periprosthetic osteolysis after total hip replacement: molecular pathology and clinical management

“…Gene therapy has also been proposed for the treatment of periprosthetic osteolysis [44][45][46] . However, although agents such as bisphosphonates and a human monoclonal antibody to RANKL, denosumab, have shown efficacy in reducing the systemic bone loss of osteoporosis 47 , an evidence base for using these agents clinically in established periprosthetic osteolysis is so far lacking. To evaluate the role of these and other potential treatments for 6 periprosthetic osteolysis, treatment protocols will need to be based on the severity of the osteolysis and its rate of progression and, importantly, accurate measurement of osteolysis will be required for such treatments to be properly evaluated.…”

Postmenopausal osteoporosis treatment with antiresorptives: Effects of discontinuation or long-term continuation on bone turnover and fracture risk—a perspective

“…(73) Longer follow-up is currently underway, (72) but data from a 4-year extension of a 4-year phase II study found the long-term safety profile of denosumab was generally similar to that reported previously. (77) No neutralizing antibodies to denosumab have been reported. ONJ has been reported in patients in the extension study of FREEDOM.…”