1. Strewler GJ, Rosenblatt M. Mineral metabolism. In: Felig P, Baxter JD, Frohman LA, eds. Endocrinology and Metabolism, 3rd ed, McGraw-Hill, New York, 1995, pp. 1407-1516.

2. Kovacs CS, Kronenberg HM. Maternal-fetal calcium and bone metabolism during pregnancy, puerpe-rium and lactation. Endocr Rev 1997;18:832-872.

3. Cornish J, Callon KE, Nicholson GC, Reid IR. Parathyroid hormone-related protein-(107-139) inhibits bone resorption in vivo. Endocrinology 1997;138:1299-1304.

4. Callies F, Arlt W, Scholz HJ, et al. Management of hypoparathyroidism during pregnancy—report of twelve cases. Eur J Endocrinol 1998;139:284-289.

5. Salle BL, Berthezene F, Glorieux FH, et al. Hypoparathyroidism during pregnancy: treatment with cal-citriol. J Clin Endocrinol Metab 1981;52:810-813.

6. Caplan RH, Beguin EA. Hypercalcemia in a calcitriol-treated hypoparathyroid woman during lactation. Obstet Gynecol 1990;76:485-489.

7. Dobnig H, Kainer F, Stepan V, et al. Elevated parathyroid hormone-related peptide levels after human gestation: relationship to changes in bone and mineral metabolism. J Clin Endocrinol Metab 1995;80: 3699-3707.

8. Mather KJ, Chik CL, Corenblum B. Maintenance of serum calcium by parathyroid hormone-related peptide during lactation in a hypoparathyroid patient. J Clin Endocrinol Metab 1999;84:424-427.

9. Cundy T, Haining SA, Guilland-Cumming DF, et al. Remission of hypoparathyroidism during lactation: evidence for a physiological role for prolactin in the regulation of vitamin D metabolism. Clin Endo-crinol 1987; 26:667-674.

10. Hoper K, Pavel M, Dorr G, et al. Calcitriol-Gabe in der Scwangerschaft bei partieller Di-Geroge-Anomalie. Deutsche Medizinische Wochenschrift 1994;119:176-178.

11. Eastell R, Edmonds CJ, deDhayal RCS, McFadyen IR. Prolonged hypoparathyroidism presenting as second trimester abortion. Br Med J 1985;291:955-956.

12. Loughead JL, Mughal Z, Mimouni F, et al. Spectrum and natural history of congenital hyperparathy-roidism secondary to maternal hypocalcemia. Am J Perinatol 1990;7:350-355.

13. Friedman WF, Mills LF. The relationship between vitamin D and craniofacial and dental anomalies of the supravalvular aortic stenosis syndrome. Pediatrics 1969;43:12-18.

14. Pylypchuk G, Oreopoulos, Wilson DR, et al. Calcium metabolism in adult outpatients with epilepsy receiving long-term anticonvulsant therapy. Can Med Assoc J 1978;118:635-638.

15. Weinstein RS, Bryce GF, Sappington LJ, et al. Decreased serum ionized calcium and normal vitamin D metabolite levels with anticonvulsant drug treatment. J Clin Endocrinol Metab 1984;58:1003-1009.

16. Hahn TJ, Hendin BA, Scharp CR, Haddad JGJ. Effect of chronic anticonvulsant therapy on serum 25-hydroxycalciferol levels in adults. N Engl J Med 1972;287:900-904.

17. Matheson RT, Herbst JJ, Jubiz W, et al. Absorption and biotransformation of cholecalciferol in drug-induced osteomalacia. J Clin Pharmacol 1976; 16:426-432.

18. Corradino RA. Diphenylhydantoin: direct inhibition of the vitamin D3-mediated calcium absorptive mechanism in organ-cultured duodenum. Biochem Pharmacol 1976;25:863-864.

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An 88-yr-old African-American male diagnosed as having carcinoma of the prostate in 1978 was admitted in July 1980. He had a previous history of type 2 diabetes mellitus, inactive Paget's disease of the bone, status post-right nephrectomy, and chronic renal failure since 1973. His physical examination was remarkable for a generalized decrease in muscle strength and an enlarged prostate. Chvostek's and Trousseau's signs were negative. His admission laboratory data revealed a hemoglobin of 7.6 g/dL, WBC 7900/ mm3, and normal differential. Other laboratory values were as follows: serum Na 142

mEq/L, K 6.9 mEq/L, glucose 320 mg/dL, Cl 116 mEq/L, bicarbonate 17 mEq/L, creatinine 2.3 mg/dL, total calcium (Ca) 4.7 mg/dL (normal 8.6-10.2), phosphorus 3.9 mg/dL (normal 2.5-4.1), magnesium (Mg) 0.9 mEq/L (normal 1.5-2.4), and alkaline phosphatase 1641 mU/mL (normal = 77-260). His plasma ionized Ca was 2.16 mg/dL (normal 3.78-4.66), serum 25(OH) vitamin D3 (25OHD3) 10 ng/mL (normal 10-55) and serum 1,25 dihydroxyvitamin D3 26.1 pg/mL (normal 21-44). His serum parathyroid hormone (PTH) level was at the upper limit or normal. Twenty-four hour urine calcium excretion was 12 mg (normal <200 mg). Selected laboratory data from his previous admission in 1978 were as follows: serum Ca 8.4 mg/dL, phosphorus 3.9 mg/dL, and creatinine 2.5 mg/dL.

X-rays of the skeleton revealed widespread osteoblastic lesions. A bone scan revealed markedly increased generalized skeletal uptake and absent renal uptake. However, a bone scan performed earlier in October 1978 was essentially normal (see Fig. 1). Bone marrow biopsy revealed extensive infiltration by adenocarcinoma cells.

His hypocalcemia failed to respond to treatment with intravenous and oral magnesium replacement despite normalization of the serum magnesium level. The patient received intravenous calcium (15 mg/kg elemental calcium in normal saline over 6 h with minimal change in serum calcium levels (normal expected response is 2.0-3.0 mg/dL increase). The patient was started on oral calcium carbonate (1 g elemental Ca q6hr) and 1,25 dihydroxyvitamin D3 0.5 |g b.i.d. and stilbesterol 1 mg daily. In October 1980, his serum Ca was 5.1 mg/dL and serum Mg was 1.65 meq/L and the patient remained asymptomatic. He was subsequently lost to follow up.


The association of hypercalcemia with cancer is well known. On the other hand, the presence of hypocalcemia in association with malignancy is less well recognized. In several studies of unselected cancer patients hypocalcemia has been observed more frequently than hypercalcemia. Raskin et al. (1) observed that hypocalcemia occurred in16% of patients with cancer with bone metastases, as compared to the occurrence of hyper-calcemia in 9% of patients. In other studies, the prevalence of hypocalcemia ranged from 5-13% in patients with bone metastases, depending on the correction formula used to adjust serum calcium values for protein concentrations (2). However, true hypocalcemia based on ionized calcium measurements is less common (3).

Decreased serum albumin levels are frequently observed in cancer patients. Approximately 45% of serum calcium is bound to proteins, predominantly albumin. Therefore, serum total calcium values may be decreased, whereas serum ionized calcium values are normal in these patients. Various correction formulas have been devised to calculate corrected serum total calcium levels. Most commonly applied formulas make adjustment for serum albumin concentrations. For each 1 g/dL change in serum albumin (from the normal mean value), 0.8 mg/dL is added or subtracted from the observed serum calcium value. While these formulas may accurately reflect the ionized calcium status in certain disease states such as cirrhosis of the liver, they do not perform as well in cancer patients (3-6). Therefore, ionized calcium measurements are frequently necessary to determine whether the patient has true hypocalcemia.

Our patient had hypomagnesemia and renal insufficiency, both of which could lead to hypocalcemia. In magnesium deficiency, there is a defect in parathyroid hormone secretion, which is corrected within minutes of magnesium infusion (7). In addition, there is evidence that skeletal effects of parathyroid hormone are impaired in the presence of

Fig. 1. Posterior views of the bone scan were done in October 1978 (A) revealing a normal skeletal study (right kidney is absent due to previous nephrectomy) and in July 1980, (B) revealing extensive generalized skeletal uptake. (Reprinted with permission from ref. 3.)

magnesium deficiency (7). Hypomagnesemic patients may continue to have tetany, even if serum calcium values are corrected by calcium infusions. Magnesium deficiency is best corrected by parenteral administration of magnesium sulfate (2g MgSO4 as 50% solution Q8h via IM injection or iv infusion 48 meq over 24 h) or oral supplementation with magnesium oxide (300-600 mg/d elemental Mg in divided doses). Our patient received supplementation with both intravenous and oral magnesium with normalization of serum magnesium levels. However, the hypocalcemia persisted. Parenteral, magnesium should be administered very cautiously to patients with impaired renal function to avoid hypermagnesemia.

The hypocalcemia associated with renal insufficiency is multifactoral (8). Patients with renal insufficiency may have a metabolic acidosis, which increases the ionized fraction and therefore, the decrease in serum total calcium may be out of proportion to the decrease in ionized calcium. Hyperphosphatemia resulting from inability to excrete phosphorus leads to a decrease in serum calcium levels. Impaired synthesis of 1,25 dihydroxy-vitamin D by the kidney results in poor calcium absorption from the gut. In addition, there is resistance to the actions of parathyroid hormone. The hypocalcemia seen in renal insufficiency responds to treatment with phosphate binders and 1,25 dihydroxyvitamin D. Our patient had low normal serum 1,25-dihydroxyvitamin D levels, however, the hypocalcemia did not respond to a relatively high dose of 1,25(OH)2 vitamin D3 (0.5 |g BID).

Despite a marked decrease in serum ionized calcium levels, our patient was asymptomatic, and Chvostek's and Trousseau's signs were negative. Acute manifestations of hypocalcemia are related to increased neuromuscular irritability and include paresthesias, muscle cramps, carpopedal spasms, tetany, and seizures. In addition to hypocalcemia, the neuromuscular threshold is decreased by alkalosis and hypomagnesemia and if these are present, the clinical manifestations of tetany may occur at minimally decreased or even normal serum ionized calcium levels. The severity of symptoms is related to whether hypocalcemia is acute or chronic. In some patients with chronic hypocalcemia, there may be a striking paucity of symptoms. In adults, cardiac decompensation with congestive heart failure or cardiogenic shock may develop; these manifestations resolve after successful treatment of hypocalcemia (9).

There are several possible explanations for true hypocalcemia in patients with malignancy. Patients who are critically ill because of sepsis or other conditions, may develop hypocalcemia. The mechanisms that are responsible for this hypocalcemia are poorly understood, although cytokines such as interleukin-1 (IL-1) released by macrophages may be responsible. The frequency of hypocalcemia in critically ill patients varies from 12 to 23% (10). Serum parathyroid hormone levels in these patients may be inappropriately low for the degree of hypocalcemia. There is no clear evidence that demonstrates that correction of hypocalcemia in critically ill patients results in better clinical outcomes. However, it is generally agreed that when hypocalcemia is severe, and especially if heart failure is present, parenteral calcium should be given (11). The presence of large concentrations of citrate in preserved blood may contribute to some decrease in ionized calcium, although in clinical practice, this is not a significant problem.

Patients with malignancy often receive chemotherapeutic agents that might cause hypocalcemia. Common among these is cisplatinum, which directly inhibits bone resorption. In addition, its administration results in renal magnesium losses, resulting in hypomag-nesemia and thus inducing hypocalcemia (12). Parenteral bisphosphonates are used for treatment of hypercalcemia, as well as for prevention of bone disease in normocalcemic patients with multiple myeloma. In general, clinically significant hypocalcemia is uncommon. However, there are a few case reports of patients with underlying hypoparathyroidism who developed hypocalcemia following bisphosphonate therapy. In these patients, the normal compensatory mechanisms, i.e., an increase in parathyroid hormone did not occur, thus resulting in hypocalcemia (13).

In patients with acute leukemia and Burkitt's lymphoma, tumors that are relatively sensitive to chemotherapy, rapid tumor lysis results in sudden release of uric acid, phosphate, and potassium into the circulation. As a consequence of the hyperphosphatemia, there is a precipitation of calcium and phosphate salts as the blood concentration exceeds the calcium phosphate stability product (14). Hypocalcemia during treatment of acute leukemia is especially common in children. The hyperphosphatemia should be managed by adequate fluid administration; in severe cases, dialysis may be indicated for the hyperphosphatemia.

There are several case reports of true hypocalcemia occurring in patients with extensive osteoblastic bone metastases. The tumors that have been associated with this phenomenon are lung, breast, and prostate cancer (15-19). Of these, prostate cancer is the most common. The association of hypocalcemia in patients with acute monocytic leukemia with osteoblastic bone formation and hypocalcemia has also been reported (20). Calcium balance studies have shown that hypocalcemia in patients with osteoblastic metastases results from excessive accretion of calcium into bone. Increased uptake of radioactive calcium in strontium has been demonstrated in these patients. Bone scanning with Tech-netium-99m labeled bisphosphonates reveals extensive skeletal uptake and appearance of "super-scan," as seen in our patient (21). Patients with this syndrome frequently have hypomagnesemia and hypophosphatemia, presumably because of accretion of these ions into the skeleton as well. Urinary calcium excretion is decreased, as was the case in our patient. Serum parathyroid hormone levels may be inappropriately normal for the degree of hypocalcemia, possibly owing to low serum magnesium levels. When serum magnesium is corrected, serum parathyroid hormone levels may increase appropriately.

In prostate cancer, extensive osteoblastic and metabolic consequences appear related to the production of osteoblast stimulating factors by tumor cells. Extracts of hyperplas-tic and neoplastic prostate tissue stimulate thymidine uptake and collagen synthesis by fibroblasts and osteoblasts (22,23). Some studies suggest that the factors may be similar to urokinase (24,25). In a more recent study, culture media from various stages of prostate cancer tissue were shown to stimulate proliferation and activity of osteoblasts in culture. This stimulation was greater with tissues from advanced stages and was not blocked by urokinase inhibitors (26). The exact nature of these factors remains unknown. There are no cases reported where the response of the hypocalcemia to antiandrogen therapy in these patients with prostate cancer has been evaluated.

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