The pathogenesis of
cancer-associated
hypercalcemia is not yet completely understood. This syndrome appears to be a consequence of the
tumor production of humoral factors, mainly
parathyroid hormone related protein (
PTHrP). However, patients with
humoral hypercalcemia of malignancy have features suggesting that factors other than
PTHrP might play a role in this syndrome. We performed a case-control study in
cancer patients with and without
hypercalcemia. A total of 105 patients with a variety of
tumors, 60 of them with
hypercalcemia (corrected serum
calcium over 2.6 mmol/l), and 45 without
hypercalcemia. In a previous study, we demonstrated that plasma
PTHrP was highly associated with
hypercalcemia in these patients. In the present study, we measured the plasma levels of various bone
cytokines:
interleukin-1beta (IL-1beta),
interleukin-6 (IL-6),
transforming growth factor (
TGF) alpha, and
tumor necrosis factor (
TNF) alpha, in these
cancer patients. We also determined C-terminal
type I procollagen (
PICP) and
C-terminal telopeptide of type I collagen (ICTP), bone formation and
bone resorption markers, respectively, in serum in these patients. We found that these osteolytic
cytokines do not increase in plasma by the presence of
hypercalcemia. In fact, using a logistic regression analysis, a significant (P<0.02) association was found between the low plasma levels of IL-1beta and
TGFalpha and
hypercalcemia, independent of plasma
PTHrP and the presence of bone
metastasis, in these patients. No significant association between the plasma levels of
IL-6 or
TNFalpha and
hypercalcemia was found in these
cancer patients. Serum ICTP correlated (r=0.35; P=0.008) with
hypercalcemia in these patients, but none of the
cytokines studied in plasma correlated with either ICTP or
PICP in these hypercalcemic patients. Our data indicate that the circulating levels of several bone
cytokines are not enhanced by
PTHrP in hypercalcemic
cancer patients. The mechanism responsible for the association between the low plasma levels of some of these
cytokines and
hypercalcemia in these patients remains obscure. However, this finding does not rule out the possible local bone effects of these
cytokines, contributing to
hypercalcemia in
cancer patients.