Osteoclast modulators

RGD analogs have been shown to inhibit the attachment of osteoclasts to bone matrix and to reduce bone resotptive activity in vitro. The cell surface integrin, av 33, appears to play a role in this process. RGD analogs may rq resent a new approach to modulating osteoclast-mediated bone resorption and may be useful in the treatment of osteoporosis [9]. 

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Taranta A, Brama M, Teti A, De 1, V, Scandurra R, Spera G, Agnusdei D, Termine JD, Migliaccio S (2002) The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro. Bone 30 368-376... 

Y. Ramasw/amy, D.R. Flaynes, G. Berger, R. Gildenhaar, H. Lucas, C. Holding, H. Zreiqat, Bioceramic composition modulate resorption of human osteoclast, J. Mater. Sci. Mater. Med. 6 (2005) 1199-1205. 

Adebanjo OA, Shankar VS, Pazianas M, Zaidi A, Huang CL-H, Zaidi M. 1994. Modulation of the osteoclast Ca2+ receptor by extracellular protons. Possible linkage between Ca2+ sensing and extracellular acidification. Biochem Biophys Res Communl94 742-747. 

Shankar VS, Pazianas M, Huang CL-H, Simon B, Adebanjo OA, Zaidi M. 1995. Caffeine modulates Ca2+ receptor activation in isolated rat osteoclasts and induces intracellular Ca2+ release. Am J Physiol 268 F447-54. 

The benzothiophene derivative raloxifene (Evista /Lilly) is a selective estrogen receptor modulator (SERM). Raloxifene produces its biological actions via modulation (both activation and blockade) of estrogen receptors that ultimately results in decreased resorption of bone. The bisphosphonate derivative alendronate (Fosamax /Merck), an inhibitor of osteoclast-mediated bone resorption, is also useful in the treatment of osteoporosis. Both raloxifene and alendronate are useful in the treatment of osteoporosis in postmenopausal women. 

Treatment of osteoporosis depends on the cause. In secondary osteoporosis, treatment is directed at the underlying condition. Most therapies for the treatment of postmenopausal osteoporosis are directed at decreasing osteoclastic bone resorption. Antiresorptive therapies include bisphosphoiiates (alendronate and risedronate), estrogen replacement, selective estrogen receptor modulators (raloxifene), and calcitonin (nasal spray or injection). The FDA has recently approved recombinant hPTH(l-34) (injection), the first approved therapy for stimulating bone formation. 

Drugs currently used to treat osteoporosis are classified into those that inhibit osteoclastic bone resorption (including bisphos-phonates, denosumab, and selective estrogen receptor modulators) and those that stimulate bone formation by osteoblasts (parathyroid hormone and derivatives, such as teriparatide). Strontium ranelate may have a dual effect. Other drugs being tested in clinical trials include inhibitors of cathepsin K (an osteoclastic enzyme critical for bone resorption) and of sclerostin (a negative modulator of the Wnt pathway) [21],... 

Both osteoblasts and osteoclasts are derived from osteo-progeni tor cells originating in the bone marrow. Osteoblast precursors are pluripotent mesenchymal stem cells and the osteoclast precursors are hematopoietic cells of the monocyte-macrophage lineage. The development of osteoblasts and osteoclasts is regulated by several growth factors and cytokines whose responsiveness in turn is modulated by systemic hormones. 

Calcitonin therapy results in decreased bone resorption. Osteoclasts have calcitonin receptors and calcitonin inhibits their activity. Sodium fluoride stimulates bone formation by unknown mechanisms. In women with osteoporosis, fluoride therapy produced an increased bone mineral density but no reduction in the rate of vertebral fractures. Other drugs known as selective estrogen receptor modulators (raloxifene, droloxifene, idoxifene, and levormeloxifene) may provide an alternative to estrogen replacement therapy (Chapter 34). Administration of low doses of PTH [or recombinant PTH( 1 -34)] does not affect serum calcium concentration, promotes bone formation, and increases mineral density. This anabolic action of PTH is probably mediated by decreasing osteoblast apoptosis. 

There have been some relatively new developments in the treatment of osteoporosis. Selective oestrogen receptor modulators, for example raloxifene mimic the inhibitory effects of oestrogen on osteoclasts. Teriparatide, which is a recombinant fragment of... 

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