Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic and osteoblastic metastasis to bone

Abstract

Calcium homeostasis is a tightly regulated process involving the co-ordinated efforts of the skeleton, kidney, parathyroid glands and intestine. Neoplasms can alter this homeostasis indirectly through the production of endocrine factors resulting in humoral hypercalcaemia of malignancy. Relatively common with breast and lung cancer, this paraneoplastic condition is most often due to tumour production of parathyroid hormone-related protein and ensuing increased osteoclastic bone resorption. Although control of hypercalcaemia is generally successful, the development of this complication is associated with a poor prognosis. The metastasis of tumour cells to bone represents another skeletal complication of malignancy. As explained in the 'seed and soil' hypothesis, bone represents a fertile ground for cancer cells to flourish. The molecular mechanisms of this mutually beneficial relationship between bone and cancer cells are beginning to be understood. In the case of osteolytic bone disease, tumour-produced parathyroid hormone-related protein stimulates osteoclasts that in turn secrete tumour-activating transforming growth factor-b that further stimulates local cancer cells. This 'vicious cycle' of bone metastases represents reciprocal bone/ cancer cellular signals that likely modulate osteoblastic bone metastatic lesions as well. The development of targeted therapies to either block initial cancer cell chemotaxis, invasion and adhesion or to break the 'vicious cycle' is dependent on a more complete understanding of bone metastases. Although bisphosphonates delay progression of skeletal metastases, it is clear that more effective therapies are needed. Cancer-associated bone morbidity remains a major public health problem, and to improve therapy and prevention it is important to understand the pathophysiology of the effects of cancer on bone. This review will detail scientific advances regarding this area.

Prognostic significance of disordered calcium metabolism in hormone-refractory prostate cancer patients with metastatic bone disease

“…9 We disclose the limit of not having measured PTHrP but the low PTH levels observed in our hypercalcemic patients are consistent with PTHrP elevation since the IRMA assay we used for PTH evaluation does not cross-react with PTHrP. 9,17,18 Out of 151, two patients (1.3%), however, had elevated levels of both serum calcium and PTH suggesting primary hyperparathyroidism. Hyperparathyroidism is frequent in the aged population, 20 thus the association Disordered calcium metabolism and prognosis M Tucci et al with prostate cancer is not expected to be rare even if precise estimates are not presently available.…”

“…3,4,8 Hypercalcemia in malignancy is mainly due to the tumor production of PTHrP. 9 We disclose the limit of not having measured PTHrP but the low PTH levels observed in our hypercalcemic patients are consistent with PTHrP elevation since the IRMA assay we used for PTH evaluation does not cross-react with PTHrP. 9,17,18 Out of 151, two patients (1.3%), however, had elevated levels of both serum calcium and PTH suggesting primary hyperparathyroidism.…”

“…9 The osteoblastic nature of secondary bone lesions and the relative low frequency of PTHrP elevation due to PSA cleavage predispose bone metastatic prostate cancer patients to hypocalcemia, whereas hypercalcemia is expected to be very rare. In our series of patients in which albumin-corrected serum calcium levels were systematically measured at the onset of hormonerefractory disease, hypocalcemia was observed in about 27% and hypercalcemia in 8.3% of cases, confirming the expectations.…”

“…Cancer cells adversely affect mineral metabolism through a broad spectrum of mechanisms. 9 Neoplasms can cause hypercalcemia through the production of endocrine factors, notably parathyroid hormone-related peptides (PTHrP). Hypercalcemia typically complicates the natural history of bone metastatic patients with predominantly lytic bone lesions, such as those with breast and lung cancer.…”

“…Hypercalcemia typically complicates the natural history of bone metastatic patients with predominantly lytic bone lesions, such as those with breast and lung cancer. 9 In patients with prostate cancer this metabolic disturbance has been described exceptionally. [10][11][12][13] A number of factors could prevent the onset of hypercalcemia in prostate cancer patients.…”