A new comprehensive review by Rachner and colleagues [1] focuses on osteoporosis therapies that have been recently introduced and those with novel mechanisms of action likely to succeed in ongoing clinical trials. The paper is extensively referenced. A discussion of new insights into bone biology precedes the review of clinical trials of new agents. The communication between bone-forming osteoblasts and bone-resorbing osteoclasts has led to novel treatment strategies aimed at inhibiting excessive bone resorption and others aimed at increasing bone formation. The most promising of the new therapies are denosumab, an antiresorptive monoclonal antibody for receptor activator of NF-κB ligand; odanacatib, a specific inhibitor of cathepsin K, the osteoclast protease responsible for the breakdown of bone collagen; and antibodies against osteocyte-expressed sclerostin and dickkopf-1, endogenous inhibitors of bone formation.

Comment
This paper is a good introduction to the new bone biology and an indication of how this understanding will lead to new therapeutic targets for the management of postmenopausal osteoporosis. The concise summary of clinical trials documenting novel effects of these agents on the skeleton helps the reader to understand that there is more to osteoporosis therapy than bisphosphonates. 

The review documents the extensive literature on denosumab antiresorptive therapy. With Phase 3 trials complete, denosumab demonstrates hip, non-vertebral, and vertebral antifracture efficacy. Head-to-head trials against alendronate show superior bone density and bone turnover marker efficacy, with perhaps superior effects on cortical bone.

The authors discuss a likely new category of osteoporosis antiresorptive therapies, the uncoupling antiresorptives. These agents, currently characterized by odanacatib (cathepsin K inhibitor) and saracatinib (lysosine src kinase inhibitor), have the ability to selectively suppress bone resorption without suppression of bone formation. This will potentially show increased antifracture efficacy as compared to the conventional antiresorptive therapies.

The discussion of bone anabolic therapy highlighted novel ways of stimulating the PTH receptor in addition to new pharmacologic targets for therapy. Calcilytic agents bind to the calcium sensing receptor on parathyroid cells, inducing a pulse of PTH similar to the pulse effect of daily subcutaneous teriparatide or PTH injection. The accurate mimicking of the PTH pulse by such agents may lead to a PTH secretogogue oral anabolic therapy. Farther along in clinical trials are antibody therapies against osteoblast inhibiting proteins sclerostin and Dkk-1. These osteocyte proteins suppress osteoblast activity and their suppression may lead to an anabolic response.

Although much of the discussion in this review relates to agents that are yet to be introduced, the perspective of enhanced understanding of new bone biology and novel therapeutic targets is very encouraging for patients suffering from osteoporosis and their treating physicians.

David Kendler
University of British Columbia, Vancouver, Canada

References
1. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet 2011;377:1276–87.
http://www.ncbi.nlm.nih.gov/pubmed/21450337