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Molecular basis of the spectrum of skeletal complications of neoplasia

  1. David Goltzman M.D.1,2,*,
  2. Andrew C. Karaplis M.D.3,
  3. Richard Kremer M.D.1,2,
  4. Shafaat A. Rabbani M.D.1,2

Article first published online: 20 NOV 2000

DOI: 10.1002/1097-0142(20000615)88:12+<2903::AID-CNCR4>3.0.CO;2-G

Issue

Cancer

Cancer

Supplement: Skeletal Complications of Malignancy

Volume 88, Issue Supplement 12, pages 2903–2908, 15 June 2000

Additional Information

How to Cite

Goltzman, D., Karaplis, A. C., Kremer, R. and Rabbani, S. A. (2000), Molecular basis of the spectrum of skeletal complications of neoplasia. Cancer, 88: 2903–2908. doi: 10.1002/1097-0142(20000615)88:12+<2903::AID-CNCR4>3.0.CO;2-G

Author Information

  1. 1

    Departments of Medicine, McGill University, Montreal, Quebec, Canada

  2. 2

    Calcium Research Laboratory, Royal Victoria Hospital, Montreal, Quebec, Canada

  3. 3

    Lady Davis Research Institute and Jewish General Hospital, Montreal, Quebec, Canada

*Calcium Research Laboratory, Royal Victoria Hospital Room H4.67, 687 Pine Avenue West, Montreal, Quebec, Canada H3A 1A1

Publication History

  1. Issue published online: 20 NOV 2000
  2. Article first published online: 20 NOV 2000
  3. Manuscript Accepted: 10 MAR 2000
  4. Manuscript Received: 2 MAR 2000

Funded by

  • Medical Research Council (MRC) of Canada. Grant Numbers: MT-5775, MT-14101, MT-10839, MT-10630
  • National Cancer Institute of Canada
  • Cancer Research Society

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Keywords:

  • parathyroid hormone-related peptide;
  • urokinase;
  • hypercalcemia of malignancy;
  • phosphate-regulating endopeptidase in x-linked hypophosphatemic rickets;
  • phosphaturia;
  • osteolysis;
  • osteogenesis

Abstract

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.

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