Denosumab: A New Treatment for Osteoporosis
Abstract & Commentary
By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.
Synopsis: Denosumab, a human antibody, effectively increases bone mineral density in postmenopausal women.
Source: Miller PD, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: A randomized blinded phase 2 clinical trial. Bone 2008;43:222-229.
Miller and colleagues, representing 29 study centers in the United States, reported the results of a Phase 2 clinical trial, assessing the impact of denosumab on bone density.1 The participants in this trial were postmenopausal women up to age 80 who had osteoporosis based on low T-scores. For the first two years, the patients were randomized to one of 7 denosumab doses, alendronate, or placebo. After two years, patients in 5 of the treated groups were continued for two more years on 60 mg given subcutaneously only once every 6 months. One treatment arm was discontinued, and then after a year, treatment was resumed with 60 mg denosumab every 6 months. One treatment arm was discontinued after two years and followed. A total of 262 women completed the study. Long-term treatment increased bone density in the spine and hip, whereas the placebo group continued to lose bone density. A reduction in markers for bone turnover was sustained. The group that discontinued treatment after two years lost bone density; after a year, retreatment with denosumab restored the bone to the level of the gain achieved in the first two years, levels similar to the groups who continued treatment for 4 years. No significant differences in the treatment and placebo groups were noted for adverse events.
Welcome to a system confused by the bone world's choice of names. RANKL is secreted by osteoblasts and binds to its receptor, RANK, on the surface of osteoclasts, stimulating the osteoclasts to mature and to resorb bone. OPG is osteoprotegerin, a receptor that competes with RANK and thus counteracts the effects of RANKL, causing osteoclasts to undergo apoptosis. Some method that could act like OPG, therefore, would prevent bone loss.
Denosumab is a human monoclonal antibody to RANKL, that works like OPG, but rather than competing with RANK for its activator RANKL, it binds with great affinity to RANKL thus preventing activation of RANK. This is not the same mechanism as bisphosphonates and estrogens that bind to the surface of bone and interfere with osteoclast activity. Denosumab prevents both maturation of osteoclasts and active bone resorption by osteoclasts. Early results from this clinical trial indicated an increase in bone density at multiple sites; this report summarizes treatment for 4 years. Similar results have been reported in a Phase 3 trial with 332 women in 21 centers in Canada and the United States.2 A fracture trial has been completed; although not yet reported, there is no reason to doubt that, like estrogens and bisphosphonates, the impact on bone density will translate into fracture protection. Keep in mind, that raloxifene has the disadvantage of no effect on hip bone density, presumably because it is less potent than the other drugs.
How do the results compare with bisphosphonates? The increase in bone density at the spine and hip is comparable, but total body bone density, as exemplified by the radius, increases with denosumab, but not with bisphosphonates. The requirement for subcutaneous administration might seem to be an obstacle, but on the other hand, a required visit to the office might increase continuation rates (although it is likely that a self-administration technique would be available). This report demonstrated that after discontinuation of denosumab, bone loss immediately begins. This quick reversibility contrasts with bisphosphonates, which bind tightly and remain in bone for decades, maintaining a long-term effect; this can be an important advantage for denosumab.
There is growing concern that long-term treatment with bisphosphonates begins to accumulate adverse effects, probably because the tight binding to bone over time produces excessive dosage (when bone resorbs and releases bound bisphosphonates, it can act again and add to the dose currently being administered). Thus the quality of bone may eventually deteriorate.
However, there is a problem. The RANKL system operates in other tissues, significantly in the immune system. The number of subjects in the completed trials has been insufficient to achieve the statistical power to reassure us that infections and tumors won't arise in treated patients.
We will see a lot of hype about denosumab in the coming months. It works fast; it's reversible; it needs to be administered only every 6 months; and the bisphosphonates are losing their patent protection. Although denosumab will probably be approved for treatment of osteoporosis, there will be no reason not to use it to prevent osteoporosis. Unfortunately, the risk profile will probably not emerge until there is general use by a large population.
Unlike estrogen treatment with its broad spectrum of benefits, it is currently recommended that the treatment choices that target only bone should be limited to a 5-year duration of exposure. If continued monitoring of bone density detects a resumption of bone loss of 5%-10% in one year, resumption of treatment is indicted.
- Miller PD, et al. Effect of denosumab on bone density and turnover in postmenopausal women with low bone mass after long-term continued, discontinued, and restarting of therapy: A randomized blinded phase 2 clinical trial. Bone 2008;43:222-229.
- Bone HG, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women. J Clin Endocrinol Metab 2008;93:2149-2157.