Bone remodeling effects

Pruna A, Fournier A. Cyclosporine bone remodeling effect prevents steroid osteopenia after kidney transplantation. 

Westeel FP, Mazouz H, Ezaitouni F, Hottelart C, Ivan C, FardeUone P, Brazier M, El Esper I, Petit J, Achard JM, Pruna A, Fournier A. Cyclosporine bone remodeling effect prevents steroid osteopenia after kidney transplantation. Kidney Int 2000 58(4) I788-96. 

PTH is the most important regulator of bone remodelling and calcium homeostasis. PTH is an 84-amino acid polypeptide and is secreted by the parathyroid glands in response to reductions in blood levels of ionised calcium. The primary physiological effect of PTH is to increase serum calcium. To this aim, PTH acts on the kidney to decrease urine calcium, increase mine phosphate, and increase the conversion of 25-OH-vitamin D to l,25-(OH)2-vitamin D. PTH acts on bone acutely to increase bone resorption and thus release skeletal calcium into the circulation. However, due to the coupling of bone resorption and bone formation, the longer-term effect of increased PTH secretion is to increase both bone resorption and bone formation. 

Diaz Curiel M, Calero JA, Guerrero R, Gala J, Gazapo R, de la Piedra C (1998) Effects of LY-117018 HC1 on bone remodeling and mineral density in the oophorectomized rat. Am J Obstet Gynecol 178 320-325... 

Levormeloxifene induces an increase in lumbar and tibial bone mass in a rat model and is associated with a decrease in osteocalcin and cholesterol levels, while it has a neutral effect on the uterus (Bain et al. 1997 Nowak et al. 1998). In monkeys, a decrease in bone remodeling with prevention of bone loss has... 

Lasofoxifene is a SERM that also protects from bone loss, reduces cholesterol levels, and exerts a positive effect on bone strength in rats, specifically in male models (Ma et al. 2002). This compound is in the final stages of clinical development. Two other SERMs also in advanced phase III trials are bazedoxifene and arzoxifene, both with protective effects against ovariectomy-induced bone loss. Arzoxifene has shown both bone remodeling reduction with positive effects on bone quality as well as a reduction in cholesterol levels in oophorectomized rats (Biskobing2003). 

Johnell O, Scheele WH, Lu Y, Reginster JY, Need AG, Seeman E (2002) Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 87 985-992... 

Wright CD, Garrahan NJ, Stanton M, et al. (1994) Effect of long term Tamoxifen therapy on cancellous bone remodeling and structure in women with breast cancer. J Bone Miner Res 9 153-159... 

The past 3 years have seen tremendous advances in both the design of Cat K inhibitors and in our understanding of the effect of Cat K inhibition on bone remodeling. The structural diversity of Cat K inhibitors has expanded considerably from simple peptidomimetics to non-peptidic derivatives and even non-covalent inhibitors. The potency, selectivity and pharmacokinetic properties of key compounds are very attractive and seem well-suited to further development. The disclosure of clinical validation of the effect of Cat K inhibition on bone mineral density, plus the provocative data suggesting a decoupling of bone resorption and bone formation provides a compelling framework for further development of Cat K inhibitors for the treatment of osteoporosis. 

Minkin, C., Rabadjija, L-, Goldhaber, P. Bone remodeling in vitro The effects of two diphosphonates on osteoid synthesis and bone resorption in mouse calvaria. Calc. Tiss. Res. 14, 161 (1974)... 

Interleukin-6 (IL-6) is a principal cellular regulatory factor, and also plays a role in bone remodeling. IL-6 exercises its effect by binding to a receptor (IL-6R), which leads to signal transduction and activation of intracellular cascades. Information from studies performed both in vitro and in vivo show IL-6 as an autocrine/paracrine factor of the osteoclasts. Recent studies describe especially increased expression of IL-6R mRNA in the osteoclasts engaged in increased bone resorption. It can be judged that IL-6 itself is in a sophisticated way involved in bone resorption, and that especially the expression of its receptor (IL-6R) correlates with resorption activity of the osteoclasts (LI). 

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