Previous studies have suggested a role for adrenergic stimuli in the regulation of PTH secretion. In the present studies, we evaluated the effect of endogenous catecholamine stimulation (by treadmill exercise) on serum calcium (Ca) and immunoreactive PTH (iPTH) in six healthy volunteers. Blood was collected for serum total Ca, ionized Ca, iPTH, cAMP, epinephrine, and norepinephrine before, during, and after exercise. As expected, plasma cAMP and catecholamine levels increased significantly during the exercise. In addition, there was an increase in serum total and plasma ionized Ca. However, serum iPTH levels did not change significantly at any of the times tested during and after exercise. The lack of change in serum PTH despite an increase in plasma catecholamines may be explained by 1) an increase in plasma ionized Ca by a separate mechanism (such as metabolic acidosis), which blocked an increase in serum iPTH, or 2) insufficient increase in plasma catecholamines to stimulate PTH secretion.

No abstract

Serum 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] levels are low in patients with malignancy-associated hypercalcemia (MAH), whereas murine models of MAH have high circulating 1,25(OH)2D3. To determine the effects of a hypercalcemia-producing tumor on circulating 1,25(OH)2D3, in vitro 25-hydroxyvitamin D1-hydroxylase (1OHase) activity was measured in kidneys from BALB/c athymic mice implanted with a hypercalcemia-producing human lung tumor. Twelve days of low-phosphorus diet (LPD) in control animals lowered serum phosphorus to levels found in tumor-bearing mice fed normal phosphorus diet (NPD; 4.1 +/- 0.3 vs. 4.4 +/- 0.7 mg/dl, P = NS) and increased 1OHase activity (1.6 +/- 0.2 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, NPD vs. LPD, P less than 0.05). 1OHase activity was greater in tumor-bearing animals fed NPD compared with control animals fed LPD (8.4 +/- 0.6 vs. 3.9 +/- 0.7 pmol.mg protein-1.5 min-1, P less than 0.01). High-phosphorus intake suppressed 1OHase activity in both control and tumor-bearing animals. Seven days of parathyroid hormone infusion in control animals fed NPD raised serum calcium (9.4 +/- 0.2 vs. 13.3 +/- 1.6 mg/dl, P less than 0.05) and suppressed 1OHase activity (0.25 +/- 0.02 vs. 0.02 +/- 0.002 pmol.mg protein-1.5 min-1, P less than 0.001). The inverse relationship of serum phosphorus and 1OHase activity was much steeper in the tumor-bearing animals, with greater enzyme activity at comparable levels of serum phosphorus. The present study indicates that 1) factors produced by the tumor stimulate 1OHase activity, and 2) hypophosphatemia is required for expression of enhanced enzyme activity.

We performed quantitative bone histomorphometry on lumbar vertebrae in hypercalcemic tumor-bearing athymic mice carrying a human squamous cell carcinoma. For comparison, studies were also performed in athymic mice that received bovine 1-34 parathyroid hormone (PTH) infusion at the rate of 0.167 micrograms/hr for 7 days. In both the PTH-infused and tumor-bearing animals, percent cortical and total bone areas were significantly reduced as compared to controls, whereas trabecular bone was significantly reduced only in the tumor-bearing animals. Trabecular perimeter lined by osteoclasts was significantly increased in both tumor-bearing (1.7-fold) and PTH-infused animals (2.8-fold) compared to control mice. Trabecular perimeter lined by active osteoblasts was significantly reduced in the tumor-bearing animals (to 42% of control) and unchanged in the PTH-infused animals (97% of control). Tumor-bearing animals had significantly reduced resorptive as well as formative surfaces as compared to the PTH-infused animals. Dynamic histomorphometry revealed a marked reduction in bone formation rate (23% of control) in the tumor-bearing animals. The studies therefore demonstrate a marked inhibition of bone formation associated with increased bone resorption in this model of hypercalcemia of malignancy. These observations are similar to those seen in the human syndrome.

We evaluated nephrogenous cyclic adenosine monophosphate ( NcAMP ) levels in 61 normocalcemic patients with documented cancer of various organs and cell types. NcAMP levels were elevated in 17 (28%) and decreased in 13 (21%) of the cancer patients. Both high and low NcAMP levels were seen within the various cancer groups. There was a significant correlation (r = 0.383, P less than 0.01) between NcAMP and serum parathyroid hormone (PTH) levels, suggesting that tumor-related factors affecting NcAMP , may be partially related to native PTH. Alternatively, these factors might be altering the effect of endogenous PTH on renal tubules. A significant negative correlation was also observed between NcAMP and tubular maximum for phosphate (r = -0.356, P less than 0.02) suggesting that either cAMP per se or factors affecting NcAMP alter phosphate excretion. Follow up serum calcium data was available on 48 of the 61 patients. Subsequent hypercalcemia developed independent of the initial nephrogenous cAMP levels. It therefore appears that NcAMP elevation and development of hypercalcemia are two separate paraneoplastic phenomena.