Quantitative Bone Histomorphometry in Humoral Hypercalcemia of Malignancy: Uncoupling of Bone Cell Activity*

Humoral hypercalcemia of malignancy (HHM) results from elaboration by tumors of a circulating bone-resorbing factor(s). THe specific mechanism responsible for this bone resorption is poorly understood, and no comprehensive study employing quantitative histomorphometric analyses of bone biopsies obtained from living patients with HHM has been reported. We describe bone histology and quantitative bone histomorphometry in bone biopsies obtained from seven patients defined biochemically (elevated nephrogenous cAMP excretion) and histologically (no tumor in biopsy sample) as having HHM. These biopsies are compared to biopsies from nine patients with primary hyperparathyroidism (HPT). Compared to patients with HPT, those with HHM displayed (mean +/- SD) greater osteoclastic activity (osteoclast surface, 8.6 +/- 6.1% vs. 2.7 +/- 1.5%; P less than 0.001) and more frequent empty lacunae (9.2 +/- 4.0% vs. 5.8 +/- 3.0%; P less than 0.01), but markedly reduced osteoblastic surface (2.5 +/- 3.1% vs. 13.8 +/- 7.0%; P less than 0.001), osteoid surface (12.9 +/- 11.9% vs. 42.0 +/- 15.0%; P less than 0.001), and osteoid volume (0.3 +/- 0.3% vs. 1.3 +/- 1.0%; P less than 0.01). These findings directly confirm the presence of humorally mediated bone resorption and indicate a striking uncoupling of osteoclast and osteoblast activities in bone from patients with HHM. These findings are in sharp contrast to those in HPT patients, where osteoclast and osteoblast activities are tightly coupled, and net skeletal calcium loss is minimal. This uncoupling provides a mechanism for the marked skeletal calcium losses observed in patients with HHM.