Examples of New Osteoporosis Targets and New Mechanisms of Action
The discovery of the receptor activator of the nuclear factor-kappa B ligand RANKL/RANK/osteoprotegerin (OPG) pathway has opened new ways to target osteoclastic bone resorption. Clinical trials indicate that denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is effective in suppressing bone resorption, resulting in an increase in BMD in postmenopausal women with low BMD.[172–175] The effect of denosumab on BMD and markers of bone remodeling was more pronounced than with weekly alendronate. The effects on fracture reduction in postmenopausal osteoporosis are awaited from the recently finished FREEDOM (Fracture REduction Evaluation of Denosumab in Osteoporosis Every 6 Months) study of nearly 8,000 women. As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture by 68%, with a cumulative incidence of 2.3% in the denosumab group versus 7.2% in the placebo group (risk ratio 0.32, 95% CI 0.26 to 0.41; P < 0.001). Denosumab significantly reduced the risk of hip fracture by 40% and also reduced significantly the risk of nonvertebral fracture by 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw.
In clinical trials with denosumab, overall adverse events were similar to placebo or comparators, indicating a favorable safety profile in these diseases, which are, up until now, available up to 4 years. Since the RANKL/RANK/OPG pathway is involved in the development of the immune system, data on long-term safety, particularly with respect to bacterial infection and neoplasms, will be needed.[172–176,178]
Catepsin K Inhibition
Cathepsin K is the most abundant cysteine protease expressed in the osteoclast and is believed to be instrumental in the bone matrix degradation necessary for bone resorption. Cathepsin K inhibitors represent a novel target for developing agents to treat osteoporosis and other disorders characterized by increased bone resorption.
The discovery that the Wnt signaling is a major pathway in osteoblast activity has resulted in a revolution in our understanding of the molecular mechanisms that are involved in bone formation. Preclinical studies have shown that sclerostin has a pivotal role as a negative regulator of bone formation in the aging skeleton and, furthermore, suggest that antibody-mediated inhibition of sclerostin represents a promising new therapeutic approach for the anabolic treatment of bone-related disorders, such as postmenopausal osteoporosis.
Arthritis Res Ther. 2009;11(5):251 © 2009 BioMed Central, Ltd.
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Cite this: Progress in Osteoporosis and Fracture Prevention: Focus on Postmenopausal Women - Medscape - Oct 14, 2009.