Inhibition of Bone Resorption

Calcitonin is secreted when abnormally high calcium levels occur in plasma. Although plasma concentrations are normally minute (<100 pg/mL), they increase two- to threefold after calcium infusion. Calcitonin has a short plasma half-life (ca 10 min). Certain thyroid tumors are the result of CT concentrations 50—500 times normal. The mechanism of action is a direct inhibition of bone resorption. Calcitonin is used clinically in various diseases in which hypercalcemia is present, eg, Paget s disease (46). 

Studies have demonstrated that treatment with soy or phytoestrogen enriched diets is effective in conserving bone in rodent models of osteoporosis (Anderson and Gamer, 1998 Ishimi et al, 2000 Draper et al, 1997). The mechanism of action of phytoestrogens on bone health is unclear but several mechanisms including inhibition of bone resorption and stimulation of bone formation maybe involved (Fanti etal, 1998 Ishimi e/a/., 1999 Picherit eta/., 2000). Limited data from studies in postmenopausal women have indicated that phytoestrogen supplements have a small, beneficial effect on bone loss in the lumbar spine (Alekel et al, 2000 Potter et al, 1998 Somekawa et al, 2001). 

Flanagan AM, Chambers TJ. Inhibition of bone-resorption by bisphosphonates—interactions between bisphosphonates, osteoclasts, and bone. Calcif Tissue Int 1991 49 407-415. 

Calcitonin release is normally stimulated by rising serum calcium levels and suppressed by hypocalcemia. The major physiological effects of calcitonin are inhibition of bone resorption and deposition of postabsorp-tive calcium into bone following a meal, which prevents postprandial hypercalcemia. 

Neither the increase in cytosolic [Ca2+] nor the associated cell retraction or inhibition of bone resorption appear to involve voltage-dependent L-type Ca2+ channels. These were largely insensitive to both dihydropyridine or phenylalky-lamine Ca2+ channel specific reagents even under depolarizing conditions (Datta et al., 1990 see also Zaidi et al., 1990). The available evidence favours specialist cellular mechanisms that sense ambient [Ca2+] that parallel situations described in... 

Contrary to the original assumption which linked the inhibition of bone resorption solely to physico-chemical adsorption of the BP onto the bone surface, there is new evidence indicating cellular mechanisms of BP action, although a prerequisite of the biological activity is still the adsorption. The bisphosphonates deposited on the bone surface poison the bone-resorbing osteoclasts after being internalized by them. 

Xia, L. et al. 1999. Localization of rat cathepsin K in osteoclasts and resorption pits inhibition of bone resorption cathepsin K-activity by peptidyl vinyl sulfones. Biol. Chem. 380, 679-687. 

Dunford, J.E., Thompson, K., Coxon, F.P., Luckman, S.P., Hahn, F.M., Poulter, C.D., Ebetino, F.H., and Rogers, M.J. (2001). Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296 235-242. 

Although the kidney has been identified as a major target organ for all bisphosphonates at the high doses used in preclinical toxicity studies, a clear therapeutic window still exists, enabhng bisphosphonates to be safely administered in general clinical use for the inhibition of bone resorption. However, there are differences in the therapeutic indices between individual agents and in their pharmacokinetic and pharmacodynamic profiles in patients with both normal and impaired renal function. 

A2. Aliapoulios, M. A., Goldhaber, P., and Munson, P. L., Thyrooalcitonin inhibition of bone resorption induced by parathyroid hormone in tissue culture. Science 161, 330-331 (1966). 

Zoledronic acid is a bisphosphonate that causes inhibition of bone resorption. It is indicated in the treatment of hypercalcemia of malignancy treatment of patients with multiple myeloma and bone metastases from solid tumors in conjunction with standard antineoplastic therapy. 

Spichiger, M., R. Brenneisen, R. Felix, and R. C. Miihlbauer, 2006. The inhibition of bone resorption in rats treated with (-)-menthol is due to its metabolites. PlantaM., 72 1290-1295. 

Calcitonin 10 Thyroid Lowering of blood Ca ". Inhibition of bone resorption... 

Calcitonin is active in the rat in doses of less than 0.05/ag. It lowers plasma calcium by the inhibition of bone resorption (Robinson, Martin, Matthews and MacIntyre, 1967). When given for several weeks to parathyroidectomised rats it increases the radiodensity of tail vertebrae (Foster, Doyle, Bordier and Matrajt, 1966a). 

The affinity of the phosphonates and bisphosphonates to ions led to their application in the treatment of osteoporosis, hypercalcemia, and the inhibition of bone resorption [25]. This property also led to the development of platinum complexes (Fig. 13.7) that have been used to specifically target bone cancer [26, 27]. The bisphosphonate functionality strongly interacts with the bone surface directing the platinum to the tumor. The complexes are active against different cancer cell lines and are more active following addition of Ca " ions and were found to be particularly active against the transplanted osteosarcoma in in vivo studies [28]. 

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