Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives

Abstract

Osteoporosis is defined as low bone mineral density associated with skeletal fractures secondary to minimal or no trauma, most often involving the spine, the hip, and the forearm. The decrease in bone mineral density is the consequence of an unbalanced bone remodeling process, with higher bone resorption than bone formation. Osteoporosis affects predominantly postmenopausal women, but also older men. This chronic disease represents a considerable medical and socioeconomic burden for modern societies. The therapeutic options for the treatment of osteoporosis have so far comprised mostly antiresorptive drugs, in particular bisphosphonates and more recently denosumab, but also calcitonin and, for women, estrogens or selective estrogen receptor modulators. These drugs have limitations, however, in particular the fact that they lead to a low turnover state where bone formation decreases with the decrease in bone-remodeling activity. In this review, we discuss the alternative class of osteoporosis drugs, i.e. bone anabolics, their biology, and the perspectives they offer for our therapeutic armamentarium. We focus on the two main osteoanabolic pathways identified as of today: PTH, the only anabolic drug currently on the market; and activation of canonical Wnt signaling through inhibition of the endogenous inhibitors sclerostin and dickkopf1. Each approach is based on a different molecular mechanism, but most recent evidence suggests that these two pathways may actually converge, at least in part. Whereas recombinant human PTH treatment is being revisited with different formulations and attempts to regulate endogenous PTH secretion via the calcium-sensing receptor, antibodies to sclerostin and dickkopf1 are currently in clinical trials and may prove to be even more efficient at increasing bone mass, possibly independent of bone turnover. Each of these anabolic approaches has its own limitations and safety issues, but the prospects of effective anabolic therapy for osteoporosis are indeed bright.

Nmp4/CIZ Suppresses the Parathyroid Hormone Anabolic Window by Restricting Mesenchymal Stem Cell and Osteoprogenitor Frequency

“…A significant drawback to the use of PTH as an osteoporosis drug is that its anabolic potency declines within a relatively short period of time, which is particularly problematic in treating a chronic degenerative disease [21]. The cellular and molecular mechanisms underlying this closing of the PTH anabolic window are unknown.…”

Mechanically stimulated bone cells secrete paracrine factors that regulate osteoprogenitor recruitment, proliferation, and differentiation

“…However, bone anabolic therapeutics may act as an important adjunct for advanced osteoporosis to regenerate lost tissue [3,4]. Given the limited lifespan of the osteoblast [5], bone anabolism requires the continued replenishment of the exhausted osteoblast from an osteoprogenitor population [6][7][8].…”

Bone anabolics in osteoporosis: Actuality and perspectives

“…The first human phase Ⅰ clinical trial, studying a humanized monoclonal sclerostin antibody in healthy men and postmenopausal women, showed that this new compound had effects on bone formation and resorption after a single month similar to those showed by rhPTH after 6 months, but with greater effects on bone mass than rhPTH [39] . Such data are, then confirmed, in a phase II study in more than 400 postmenopausal osteoporotic women who showed a significantly increase in BMD at the lumbar spine compared with placebo and teriparatide [40] . Antagonists to inhibitors of the Wnt pathway have show to have positive effect on osteoblast activity regardless of osteoclasts and bone resorption.…”