Emerging Anabolic Treatments in Osteoporosis

Leif      Mosekilde; Ove      Torring; Lars      Rejnmark

doi:10.2174/157488611795684712

Abstract

Anabolic treatment that remodels bone tissue and restores bone biomechanical competence is essential in the treatment of osteoporosis. In addition, long term antiresorptive therapy may have limitations because of the reduced renewal of bone tissue. The only pure anabolic drugs available at present are intact PTH (1-84) (Preotact®) and the truncated PTH (1-34) (Teriparatide, Forteo®) while strontium ranelate may possess antiresorptive as well as anabolic properties. The marketed antiresorptive and anabolic antiosteoporotic drugs have limitations in their use due to adverse effects or to the occurrence of rare but severe late complications. Furthermore, indications may be restricted by coexisting diseases or treatment duration may be limited. However, new anabolic drugs are being developed mimicking the effect of PTH, or targeting the calcium sensing receptor (CaSR) or the Wnt/β-catenin signalling pathway. The PTH mimetics are truncated or altered PTH fragments, parathyroid hormone related peptide (PTHrP) and calcilytics stimulating endogenous PTH secretion. Calcimimetics (e.g. strontium) and calcilytics (e.g. lithium) may also affect bone cells directly through the CaSR. The Wnt pathway that stimulates osteoblastic proliferation, differentiation and function may be activated by neutralizing antibodies to secreted inhibitors of Wnt signalling (e.g. Sclerostin or Dickkopf) or by small molecules (e.g. lithium) that inhibits the glycogen synthase kinase 3β mediated degradation of β-catenin. Finally, blocking of activin A by soluble receptor fusion proteins has been shown to increase bone mass by a dual anabolic-antiresorptive action. The present paper summarises the physiological background and the present evidence for these effects.

Keywords: Activin A, CaSR, dickkopf, osteoporosis, PTH, sclerostin, SOST, Wnt-signalling, Teriparatide, Postmenopausal, cathepsin-K inhibitors