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Molecular basis of the spectrum of skeletal complications of neoplasia
Author(s) -
Goltzman David,
Karaplis Andrew C.,
Kremer Richard,
Rabbani Shafaat A.
Publication year - 2000
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/1097-0142(20000615)88:12+<2903::aid-cncr4>3.0.co;2-g
Subject(s) - osteolysis , medicine , osteoclast , osteoblast , parathyroid hormone related protein , paracrine signalling , bone resorption , cancer research , bone remodeling , endocrinology , pathology , parathyroid hormone , calcium , surgery , biology , receptor , biochemistry , in vitro
BACKGROUND Neoplasia may produce a spectrum of dysregulatory effects on bone and mineral metabolism. The range of these effects and the known molecular mechanisms causing them are reviewed. METHODS The current review is mainly based on previously published scientific reports from North America, Europe, and Japan that were identified from references in the literature. RESULTS Osteolysis is the most common skeletal manifestation of neoplasia and may be focal or generalized. When tumors release abundant parathyroid hormone‐related peptide (PTHrP) into the circulation, this may act as an endocrine substance to produce generalized osteopenia and, ultimately, hypercalcemia. PTHrP also may act in a paracrine manner to enhance focal osteolysis associated with metastasis and to generate hypercalcemia. The increased circulating PTHrP in tumor states also can augment serum calcium by renal mechanisms. PTHrP may contribute to focal osteolysis by tumor metastases, even in the absence of hypercalcemia. Strategies to reduce PTHrP production or PTHrP signaling, therefore, may be useful to treat the tumor‐induced bone resorption induced both in hypercalcemic and nonhypercalcemic states. The most commonly used intervention, bisphosphonates, targets the osteoclast directly. Although osteolytic lesions generally occur with some degree of reactive new bone formation, osteoblastic lesions may be particularly abundant in association with certain tumors, such as prostate carcinoma. The mechanisms underlying these lesions remain unknown; however, a variety of osteoblast growth factors may contribute. These include the urokinase system, which may have growth factor activity as well as enzymatic activity. Finally, osteomalacia may be a manifestation of tumors either through accelerated bone formation with insufficient mineralization or through the production of a phosphaturic substance. CONCLUSIONS Elucidation of the mechanisms underlying the spectrum of skeletal manifestations of neoplasia is yielding important insights into both tumor diagnosis and patient management. Cancer 2000;88:2903–8. © 2000 American Cancer Society.