MALIGNANCY-ASSOCIATED HYPERCALCEMIA - RESOLUTION OF CONTROVERSIES OVER VITAMIN-D METABOLISM BY A PATHOPHYSIOLOGICAL APPROACH TO THE SYNDROME

OBJECTIVE Parathyroid hormone-related protein (PTHrP) is recognized as a major pathogenetic factor of humoral hypercalcaemia of malignancy b ut its action on vitamin D metabolism is controversial. Our aim was to study the relation between serum 1,25-dihydroxyvitamin D and humoral activity in malignancy-associated hypercalcaemia. DESIGN Prospective, cross-sectional, single-centre study of patients with documented solid malignancies, hypercalcaemia and suppressed plasma PTH concentrations . PATIENTS AND METHODS Vitamin D metabolites, PTH, nephrogenous cyclic AMP (N-cAMP), PTHrP and biochemical parameters of calcium and bone me tabolism were measured in 39 patients with solid malignancies and hype rcalcaemia and bone scans were performed. RESULTS In 27 patients plasm a PTHrP levels were elevated (69%) and in 9 patients (23%) serum 1,25- (OH)(2)D concentrations were not appropriately suppressed (>92 pmol/l) . Patients with plasma PTHrP levels below the upper limit of normal (< 1.6 pmol/l) had lower serum 1,25-(OH)(2)D concentrations than those wi th elevated levels (>1.6 pmol/l) (47 +/- 6 vs 70 +/- 7 pmol/l, respect ively; P < 0.04). Serum 1,25-(OH)(2)D concentrations were higher in pa tients with negative bone scans than in those with metastatic bone dis ease (80 +/- 9 vs 50 +/- 5 pmol/l; P < 0.01) and similar levels of pla sma PTHrP. In the patients with negative bone scans there was a signif icant relation between plasma PTHrP and serum 1,25-(OH)(2)D (r = 0.51; P < 0.03) whereas there was no such correlation in those with a posit ive scan. CONCLUSION Contrary to current belief, serum 1,25(OH)(2)D co ncentrations are not generally suppressed in humoral hypercalcaemia of malignancy and PTHrP is a determinant of these levels in the absence of demonstrable bone metastases. These findings provide further insigh ts into the pathophysiology of malignancy-associated hypercalcaemia an d may help in the clinical management of these patients.