Osteoclast inhibitor

Hypercalcemia can be treated by (1) administering 0.9% NaCl solution plus furosemide (if necessary) renal excretion (2) the osteoclast inhibitors calcitonin, plicamycin, or clodro-nate (a bisphosphonate) bone calcium mobilization i (3) the Ca +chelators EDTA sodium or sodium citrate as well as (4) glucocorticoids. 

Inhibitors of osteoclast activity Stimulators of osteoblast activity... 

KAiiYA H, OKABE K, OKAMOTO F, TSUZUKi T and SOEDA H (2000) Proteiu tyrosiue kinase inhibitors increase cytosolic calcium and inhibit actin organization as resorbing activity in rat osteoclasts. J Cell Phys 183, 83-90. 

GOTO T, MAEDA H and TANAKA T (2002) A Selective inhibitor of matrix metalloproteinases inhibits the migration of isolated osteoclasts by increasing the life span of podosomes. J Bone Miner Metab. 20 (2) 98-105. 

Pamidronate and zoledronic acid are used most commonly and are potent inhibitors of osteoclast activity.29 The choice of bisphosphonate is a difficult one zoledronic acid is more efficacious in terms of response rate and longer duration of nor-mocalcemia but is approximately four times more expensive.30 Regardless of selection, the bisphosphonates should be administered at diagnosis owing to their delayed onset of action. 

Dalgarno DC, Weigele M, Lesuisse D, Sawyer TK, Baron R. Bone-targeted Src SH2 inhibitors block Src cellular activity and osteoclast-mediated resorption. Bone 2001 28 54-64. 

The osteoprotegerin (OPG), also known as OCIF, TR1, or FDCR-1, is the first soluble protein that belongs to the TNF superfamily (Simonet et al. 1997 Kwon et al. 1998 Yun et al. 1998). Unlike RANK and RANKL, OPG is expressed in high concentrations in a variety of tissues and cellular types such as skin, bones, large arteries, and the gastrointestinal tract (Simonet et al. 1997). In bone, OPG is produced by stromal/OB cells (Hofbauer et al. 1999) and works as a decoy receptor for RANKL, competing with RANK for binding RANKL. Therefore, OPG is a potent inhibitor of the OCS. In vitro, OPG inhibits the differentiation and survival of osteoclast precursors, blocks their activation, and induces their apoptosis (Lacey et al. 1998 Yasuda et al. 1998 Hofbauer et al. 

NO is recognized as a mediator of bone cell metabolism, where it regulates osteoblast and osteoclast activity [141-143]. Osteoporosis, which frequently occurs in postmenopausal women, is a systemic skeletal disease associated with abnormal bone resorption. Addition of NO or NO donors to osteoclasts in vitro results in a reduction in bone resorption, whereas NO synthase inhibitors increase bone resorption, both in vitro and in vivo. Further research has shown that NO reduces bone resorption, via inhibition of the cysteine protease cathepsin K, which is believed to be a key protease in bone resorption. Most of the NO donors, i.e., nitroglycerin, 3-... 

AP23451 administration to mice inoculated with MDA-231 breast cancer cells effectively prevents metastasis-induced osteolysis similar to bisphosphonate zoledronic (Zometa ). However, it also significantly reduces the volirme of tumor cells inside the bone marrow cavities of the mice as opposed to a lack of inhibitory effect on tirmor cell volume in mice treated with zoledronic acid. AP23588 is also a bone-targeted Src kinase inhibitor which has been determined to possess both anti-resorptive and anabohc properties in vitro with respect to reducing osteoclast activity and stimulating osteoblast activity, respectively. 

Plicamycin (Mithracin), an inhibitor of RNA synthesis in osteoclasts, reduces serum calcium levels when infused over 4 to 6 hours every 3 to 4 days. Plicamycin s effects are slower than those of the bisphosphonates the drug is a bone marrow suppressant that can complicate clinical management if the patient is already receiving chemotherapy for the malignancy. 

The azepane (3)-3-methyl-l- 3-oxo-l-[2-(3-pyridin-2-ylphenyl)ethenoyl]azepane 4-ylcarbamoyl butylamide is a potent nonpeptide inhibitor of rat cathepsin K (and thus of potential value in the control of osteoclast-mediated bone resorption) <2002MI746>, and an N-substituted azepane-isatin derivative was reported to be a nonpeptide inhibitor of caspase 3 <2001JME2015> another N-substituted azepane-indole derivative was shown to act as an estrogen <2001JME1654>. 

In common with other cellular systems, refilling of Ca2+ stores following their release appears to depend upon a thapsigargin-sensitive Ca2+-ATPase. Furthermore, such store depletion appears to induce a capacitative Ca2+ influx. Thus, the Ca2+-ATPase inhibitor thapsigargin produced the expected elevation of cytosolic [Ca2+] in osteoclasts studied in Ca2+-free extracellular solutions. Restoration of the extracellular [Ca2+] then produced a cytosolic [Ca2+] overshoot. Similar effects followed Ca2+ store depletion by ionomycin in cells bathed in EGTA-containing solutions when extracellular [Ca2+] was similarly restored. Both studies suggested capacitative Ca2+ influx processes from the extracellular space by a cytosolic route (Shankar et al., 1994). 

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. 

Osteoclasts are multinucleated cells found on the endosteal surface of bone, in Haversian systems and periosteal surfaces. PTH activates osteoclasts (indirectly via osteoblasts that possess PTH receptors). Calcitonin is a potent inhibitor of osteoclast activity. Local cytokine factors, including interleukin-1 (IL-1), tumour-necrosis factor (TNF), TGF- 0 and interferon-y (INF-y), are important regulators. Osteoclast resorption of bone releases collagen peptides, pyridinoline cross-links and calcium from the bone matrix, through the action of lysosomal enzymes (collagenases and cathepsins). The collagen breakdown products in serum and urine (e.g. hydroxyproline) can be used as biochemical markers. 

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