Osteolysis

Oyajobi BO, Franchin G, Williams PJ, et al. Dual effects of macrophage inflammatory protein-lalpha on osteolysis and tumor burden in the murine 5TGM1 model of myeloma bone disease. Blood 2003 102(1) 311—319. 

Moro T, Takatori Y, Ishihara K et al (2004) Surface grafting of artihcial joints with a biocompatible polymer for preventing periprosthetic osteolysis. Nat Mater 3 829-836... 

Gama,C. andMeira, J.B. Occupational acro-osteolysis, J. Bone Joint Surg. Am., 60,86,1978. 

Metastatic bone disease (MBD) is characterized by very high levels of bone turnover in regions proximal to the tumour [33]. Bone resorption inhibitors such as bisphosphonates represent the current standard of care for the treatment of bone metastases primarily due to breast or prostate cancer and multiple myeloma. It has been proposed that other strong anti-resorptives such as a Cat K inhibitor could be useful in the treatment of bone metastases. Evidence for this has been presented in the form of a preclinical MBD model in which human breast cancer cells are implanted into nude mice. Treatment with a Cat K inhibitor gave a significantly lower area of breast cancer-mediated osteolytic lesions in the tibia [34]. In a separate study, the efficacy of a Cat K inhibitor in the reduction in tumour-induced osteolysis was found to be enhanced in the presence of the bisphosphonate zolendronic acid [35,36]. When prostate cancer cells were injected into the tibia of SCID mice, treatment with a Cat K inhibitor both prevented and diminished the progression of cancer growth in bone [37]. 

Bisphosphonates structurally mimic endogenous pyrophosphate, which inhibits precipitation and dissolution of bone minerals. They retard bone resorption by osteoclasts and, in part, also decrease bone mineralizatioa Indications include tumor osteolysis, hypercalcemia, and Paget s disease. Qinical trials with etidronate, administered as an intermittent regimen, have yielded favorable results in osteoporosis. With the newer drugs clodronate, pamidronate, and alendronate, inhibition of osteoclasts predominates a continuous regimen would thus appear to be feasible. 

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. 

Breast cancer Androgen therapy may cause hypercalcemia by stimulating osteolysis. 

Mechanism of Action Abisphosphonatethat decreases mineral release and matrix in bone and inhibits osteocytic osteolysis. Therapeutic Effect Decreases bone resorption. 

Vinyl chloride causes liver cancer (hemangiosarcoma), narcosis, and Raynaud s phenomenon that comprises scleroderma, acro-osteolysis, and liver damage. The appearance of liver tumors is dose dependent but reaches a maximum at about 22% incidence. This seems to be due to the fact that the metabolism that is necessary for the carcinogenicity, is saturated, and/or inhibited by vinyl chloride. The toxic metabolites produced are the epoxide and chloroacetaldehyde. 

Murray, F.J. SU11248 inhibits tumor growth and CSF-lR-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin. Exp. Metastasis 2003, 20 757-766. 

Pamidronate (Ciba Geigy) Hypercalcemia of malignancy Tumoral osteolysis Paget s disease Osteoporosis -100 1987 25, 312... 

Tiludronate (Sanofi Winthrop) Paget s disease Hypercalcemia of malignancy Tumoral osteolysis Osteoporosis -10 1995 31,350... 

Ibandronate (Boehringer Mannheim) Hypercalcemia of malignancy Tumoral osteolysis OsteoporosisPaget s disease -1000- -10 000 1996 32, 309... 

Croucher, P.I., De Hendrik, R., Perry, M.J., Hijzen, A., Shipman, C.M., Lippitt, J., Green, J., Van Marck, E., Van Camp, B., and Vanderkerken, K. (2003). Zoledronic acid treatment of 5T2MM-bearing mice inhibits the development of myeloma bone disease evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival. J Bone Miner Res 18 482-492. 

A 39-year-old normocalcemic patient with subchnical hypoparathyroidism and bone metastases from breast carcinoma was given pamidronate 60 mg parenteraUy and developed hypocalcemia (1.42mmol/l) and carpopedal spasm (29). Hypocalcemia due to latent hjrpopar-athyroidism had been compensated by extensive osteolysis due to bone metastases. 

Merkel KD, Erdmann JM, McHugh KP, et al. (1999) Tumor necrosis factor-alpha mediates orthopedic implant osteolysis. Am J Pathol 154 203-210... 

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