New and Emerging Antiresorptive Treatments in Osteoporosis

Lars      Rejnmark; Leif      Mosekilde

Abstract

Bisphosphonates have for many years been the mainstay of antiresorptive treatment, acting predominantly by inducing apoptosis of mature osteoclasts. During recent years, an advanced understanding of the genetic and biological mechanism involved in bone resorption has revealed new therapeutic targets for antiresorptive treatments. Several of these new drugs act by targeting specific pathways within the osteoclastic cells and may reduce bone resorption without a concomitant decrease in bone formation. Such an uncoupling may result in a net bone formation, thereby causing a bone “anabolic” effect through an antiresorptive mechanism. Moreover, in contrast to bisphosphonates several of the new drugs are not deposited within bone and therefore their duration of action is related to their presence in plasma. Accordingly, their antiresorptive effect is quickly reversible, which may be advantageous if reversal of a suppressed bone turnover is warranted under certain clinical conditions such as osteonecrosis of the jaw. In this paper, we will review the pharmacological properties and clinical effects of the drugs that recently have been (denosumab, bazedoxifene, lasofoxifene), or currently are being tested in large phase III clinical trials (Catepsin K inhibitor), as well as drugs that have shown potential beneficial effects in phase I or II trials and may be tested in upcoming phase III trials (integrin antagonists, c-Src kinase inhibitor, inhibitors of the acidification process within the resorption lacuna, and glucagon-like peptide).

Keywords: Antiresorptives, osteoporosis treatment, fracture, denosumab, catepsin K inhibitor, Bisphosphonates, c-Src kinase inhibitor, Osteoclasts, receptor activator of NK-κB ligand, macrophage colony-stimulating factor (M-CSF)