The Pathogenesis and Management of Malignancy-Associated Hypercalcaemia

Traditionally, accelerated bone resorption has been considered to play the principal pathogenic role in malignancy-associated hypercalcaemia (MH), by one of two basic mechanisms. Hypercalcaemia in patients with metastatic bone disease, is thought to be due to the local release of skeletal calcium at a rate in excess of that which can be excreted by the kidney. In patients without bone metastases, hypercalcaemia is also thought to arise as the result of bone resorption, in this case stimulated by humoral mediators, which are released by the primary tumour. Although both humoral and metastatic mechanisms of hypercalcaemia could in theory coexist, the demonstration of bone metastases has conventionally been considered to provide reason enough for the occurrence of hypercalcaemia without invoking an additional humoral component. The humoral mediators responsible for MH are at present poorly defined, but have been generally been considered to differ from parathyroid hormone (PTH) both structurally and functionally. Previous investigators have failed to find evidence of increased renal tubular calcium reabsorption or stimulation of 1,25 dihydroxyvitamin (1,25(OH)2D3) synthesis in MH. The skeletal effects of these humoral mediators have also been considered to be distinct from PTH, in causing "uncoupling" of bone cell activity, with greatly increased osteoclastic bone resorption and depressed bone formation. While metastatic bone disease has traditionally been considered to be the commonest cause of MH, a retrospective study of 195 cancer patients undergoing bone scan examinations showed no correlation between the extent of skeletal involvement and serum calcium values. These observations, indicated that, in most cases, the development of hypercalcaemia could not simply have been explained on the basis of local bone destruction, but rather may have been due to humoral mechanisms (chapter 3.1). A further prospective study of bone scan appearances in 87 consecutive cancer patients confirmed these results but in addition, showed that other biochemical indices of bone resorption were significantly higher in hypercalcaemic when compared with normocalcaemic patients, and were disproportionately raised with respect to the extent of metastatic disease seen on the bone scan. These observations indicated that in MH, bone resorption was largely occurring on a systemic, humorally mediated basis, rather than on a local "metastatic" basis (chapter 3.2). Further studies compared renal tubular reabsorption of calcium in MH, primary hyperparathyroidism (HPT) and normal subjects undergoing acute calcium infusions. While immunoreactive PTH levels were invariably low or undetectable in the cancer patients, renal tubular reabsorption of calcium was raised to a level comparable with that in HPT. These observations raised the possibility that there frequently may be released a humoral mediator in MH which, although immunologically distinct from PTH, did possess a "PTH-like" effect on renal tubular reabsorption of calcium (chapter 4.1). Studies of renal tubular calcium reabsorption in patients with benign, non-parathyroid hypercalcaemia revealed generally normal results, excluding the possibility that the raised levels of renal tubular calcium reabsorption in malignancy may simply have been the result of chronic hypercalcaemia per se (chapter 4.2). Further studies also excluded the possibility that the raised levels of renal tubular reabsorption of calcium in malignancy may have been due to sodium depletion, since the renal handling of sodium in relation to renal tubular calcium reabsorption was similar in MH and HPT (chapter 4.3). Studies performed during the surgical exploration of tumours associated with humoral hypercalcaemia (HHM) demonstrated that a fall in renal tubular calcium reabsorption was the major factor responsible for the normalisation of serum calcium values after surgical resection (chapter 6.1). A comparison of the mechanisms of hypercalcaemia in patients with early and advanced HHM showed that in the early stages, increased renal tubular reabsorption of calcium was the most important pathogenic mechanism, often occurring in the absence of increased bone resorption. With progression of the tumour and increasing immobilisation however, accelerated osteoclastic bone resorption with depressed bone formation became more apparent. This indicated that, the HHM-associated humoral factor, like PTH itself, had more potent effects on the kidney than on osteoclastic bone resorption. A possible explanation for the increased bone resorption and depressed bone formation associated with advanced tumours may however have been due to the synergistic effects of immobilisation and HHM-associated humoral factors on bone cells (chapter 6.2)