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

Abstract

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.

Hepatocyte Growth Factor Overexpression in the Islet of Transgenic Mice Increases Beta Cell Proliferation, Enhances Islet Mass, and Induces Mild Hypoglycemia

“…Quantitative Islet Histomorphometry-Histomorphometric analysis on insulin-stained sections from normal and transgenic mice was performed as previously reported (40). Briefly, quantitation of islet number and islet volume as a function of pancreatic volume was performed in insulin-stained sections by using a Nikon (Nikon Inc., New York, NY) Labophot microscope coupled to an Osteotablet (Osteometrics, Atlanta GA) planimeter and analyzed with Osteomeasure software package (Osteometrics).…”

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

“…Secondly, while both syndromes have marked increases in osteoclastic bone resorption, many patients with HHM do not have the normally coupled increase in osteoblastic activity that those with 1 HPT experience. Studies using either serum markers of bone turnover (Nakayama et al 1996) or quantitative bone histomorphometry (Stewart et al 1982) have demonstrated this uncoupling of bone resorption from bone formation. Finally, unlike the metabolic acidosis seen in patients with 1 HPT, patients with HHM often have a metabolic alkalosis with a low plasma chloride and high plasma bicarbonate concentration.…”

Changes in bone density after cancer treatment in patients with cervicaland endometrial cancer

“…Several factors are known to be related to the activation of osteoclasts by tumor cells including parathyroid hormone-like peptide [8][9][10] transforming growth factor [11], osteoclast activating factor [12], and prostaglandins [13]. In cancer patients, greater osteoclastic activity, markedly reduced osteoblastic surface, osteoid surface, and osteoid volume have been noted by quantitative histochemical studies of the bone [6,26]. If the reduced bone mass in patients with cancer was related to the bone-resorbing factors secreted by cancer-cell lines, we would expect to develop hypercalcemia.…”