Calcium Mediates the Phosphaturia in Hypercalcemia of Malignancy

Abstract

Background: Humoral hypercalcemia of malignancy (HHM) is claimed to be caused by circulating parathyroid hormone like peptide (PTHrP) that shares several of the cardinal biochemical and skeletal histological features with hyperparathyroidism (HPT). Both syndromes are characterized by hypercalcemia from increased renal tubular reabsorption of filtered calcium, increased urinary cyclic AMP, renal phosphate wasting and hypophosphatemia, in contrast to low 1,25(OH)2D levels, metabolic alkalosis, and uncoupled bone formation-resorption rate in HHM. The aim of the study was to reassess if phosphaturia of HHM can be attributed to hypercalcemia rather than to humoral effect of PTHrP. Methods: A prospective study was conducted at Mount Sinai Services at Queens Hospital Center, NY. Results: Nine (four females and five males) out of 20 patients with hypercalcemia of malignancy documented having elevated PTHrP, normal renal function, and low PTH levels were finalized for the study. Serum calcium, phosphate, creatinine, albumin, and PTHrP concentration were determined. On the initiation of hydration, 24 h urine for creatinine, calcium and phosphorous were also collected. Blood and urine tests were repeated after serum calcium levels had been decreased by at least 1.5 mg/dL. All patients received vigorous intravenous hydration with normal saline at 200 cc/h. After the first 24 h, small doses of furosemide were given to two out of nine patients for 48 - 72 h. Hydration has shown statistically significant decrease in serum calcium concentration (13.9 ± 2.1 to 10.8 ± 1.48 mg/dL; P < 0.001) and increase in tubular reabsorption of phosphate (TRP) (69.54±8.16% to 77.85±12.24%; P < 0.01). However, PTHrP levels have shown no statistically significant difference on hydration therapy. Conclusion: Improvement of hypercalcemia by hydration reverses phosphaturia without reducing PTHrP levels. It is being proposed that in HHM, PTHrP can lead to hypercalcemia from uncoupled bone formation-resorption rate through a local autocrine or paracrine action produced by bony micrometastases that could not be demonstrated radiologically, rather than from PTHrP’s humoral effect. J Endocrinol Metab. 2017;7(2):55-60 doi: https://doi.org/10.14740/jem402w