Osteoclast-mediated bone resorption

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]. 

PTH has a dual effect on bone cells, depending on the temporal mode of administration given intermittently, PTH stimulates osteoblast activity and leads to substantial increases in bone density. In contrast, when given (or secreted) continuously, PTH stimulates osteoclast-mediated bone resorption and suppresses osteoblast activity. Further to its direct effects on bone cells, PTH also enhances renal calcium re-absorption and phosphate clearance, as well as renal synthesis of 1,25-dihydroxy vitamin D. Both PTH and 1,25-dihydroxyvitamin D act synergistically on bone to increase serum calcium levels and are closely involved in the regulation of the calcium/phosphate balance. The anabolic effects of PTH on osteoblasts are probably both direct and indirect via growth factors such as IGF-1 and TGF 3. The multiple signal transduction... 

Binds to hydroxyapatite in bone and inhibits osteoclast-mediated bone resorption... 

Takamatsu Y, Simmons PJ, Moore RJ et al. Osteoclast-mediated bone resorption is stimulated during short term administration of granuloc34e colony stimulating factor but is not responsible for hematopoietic progenitor cell mobilization. Blood. 1998 92 3465 3473. 

Bisphosphonates. Bisphosphonates are synthetic compounds designed to function as mimics of pyrophosphate, in which the oxygen atom in P-O-P is replaced with a carbon atom, creating a non-hydrolyzable backbone structure. The bisphosphonates selectively bind to the hydroxyapatite portion of the bone, decreasing the number of sites along the bone surface at which osteoclast-mediated bone resorption can occur. This permits the osteoblasts to lay down well-mineralized new bone without competition from osteoclasts. Clinically employed bisphosphonates include etidronate (8.109), tilu-dronate (8.110), risedronate (8.111), alendronate (8.112), and pamidronate (8.113). 

Inhibits osteoclast-mediated bone resorption, thereby reducing the rate of bone loss and increasing bone density... 

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>. 

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. 

Nevertheless, phosphonocarboxylate derivatives have been considered for treatment of diseases characterized by excessive osteoclast-mediated bone resorption. For example, it has been demonstrated that 3-PEHPC treatment in the 5T2MM model of multiple myeloma prevents the development of myeloma bone disease in vivo and reduces the myeloma burden by inhibiting osteoclastic bone resorption [29]. Similarly, it has been shown that 3-PEHPC dose-dependently increases apoptosis in human myeloma cells similar to risedronate. However, while risedronate causes apoptosis and induces cell cycle arrest in the S-phase, no cell cycle arrest was detected after treatment with 3-PEHPC due to its different mechanism of action [30]. 

Mithramycin (plicamycin) is a potent cytotoxic antibiotic that inhibits osteoclast-mediated bone resorption and thereby reduces hypercalcemia. Mithramycin may be administered at a dose of 25 mcg/kg via intravenous infusion over 4 to 6 hours in saline or 5% dextrose solutions. This therapy may be repeated daily for 3 to 4 days or on alternating days for 3 to 8 doses. ° Serum calcium levels begin to fall within 12 hours of a mithramycin dose, with the peak effect generally occurring within 48 to 96 hours.Single doses are usually well tolerated. Adverse effects of mithramycin include nausea, vomiting, stomatitis, thrombocytopenia, inhibition of platelet function, and renal and hepatotoxicity. Because these adverse effects are more commonly associated with multiple doses, mithramycin is usually limited to short-term therapy in patients who have not responded to alternative therapies. Monitoring parameters include complete blood count, liver function, and renal function. Mithramycin should be avoided in patients with thrombocytopenia and liver and renal insufficiency. ... 

Alendronate sodium (10 mg/day) is indicated for the treatment of osteoporosis in postmenopausal women and of Paget s disease. It acts as a specihc inhibitor of osteoclast-mediated bone resorption. The osteoclasts adhere normally to the bone surface but lack the ruffled border that is indicative of active resorption. Alendronate does not interfere with osteoclast recruitment or attachment, but it does inhibit osteoclast activity. Bones examined 6 and 49 days after ( H)alendronate administration showed that normal bone was formed on top of the alendronate, which was incorporated in bone matrix. Alendronate is not pharmacologically active thus, it must be continuously administered to suppress osteoclasts on newly formed resorption surfaces. Calcium supplements, antacids, and other oral medications will interfere with absorption of Fosamax. Therefore, patients must wait at least one hour before taking Fosamax. 

Osteopetrosis, also known as marble bone disease, describes a group of heritable disorders that are centered on a defect in osteoclast-mediated bone resorption. There are four autosomal recessive and one autosomal dominant forms of osteopetrosis (Table 35.4) (16). It generally is characterized by abnormally dense, brittle bone and increased skeletal mass. Unlike osteoporosis, this disorder results from decreased osteoclast activity, which has an effect on both the shape and structure of the bone. In very extreme cases, the medullary cavity, which houses bone marrow, fills with new bone, and production of hematopoietic cells is hampered. Like osteoporosis, this disease can be detected radiographically and appears as though there is a bone within a bone. There is limited evidence that bisphosphonates can induce osteopetrosis via their inhibition of osteoclast activity (17). 

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