Immunochemical localization of parathyroid hormone in cancer tissue from patients with ectopic hyperparathyroidism.

Immunoreactive parathyroid hormone (PTH) in nonparathyroid malignant tumors associated with hypercalcemia and hypophosphatemia in the absence of demonstrable bone metastases was determined by radioimmunoassay and immunofluorescent techniques. Six of seven tumors contained material with immunological cross-reactivity to bovine PTH by radioimmunoassay and immunofluorescence. The intensity of the immunofluorescent stain varied considerably in the different tumors. From 15 to 90% of neoplastic cells were stained specifically with fluorescein-labeled anti-PTH. In contrast, normal parathyroid glands and parathyroid adenomas showed uniform distribution of immunofluorescence in all parenchymal cells. In one malignant tumor, PTH was localized also by immunoautoradiography. In every case PTH was detected only in the cytoplasm of parenchymal cells. One patient lacked detectable PTH in his tumor, yet showed regression of the hypercalcemia to normal values after removal of large masses of neoplastic tissue and recurrence of hypercalcemia when new growth occurred.Dilutional radioimmunoassay curves of nonparathyroid malignant tumors were in most cases different from those obtained with extracts of normal parathyroid glands and parathyroid adenomas. Although both nonparathyroid neoplasmas and parathyroid extracts demonstrated immunoheterogeneity by gel filtration, greater heterogeneity was found in nonparathyroid malignant tumors. In those tumors in which immunological cross-reactivity to PTH was detected, the capability of secreting PTH may be restricted to derepressed cell clones amidst other neoplastic cells, whereas the greater heterogeneity of ectopic PTH may reflect hormone cleavage by proteolytic enzymes in the tumor that is less specific than the Pro-PTH cleaving enzyme in the parathyroids.

Parathyroid ablation in dystrophic hamsters. Effects on Ca content and histology of heart, diaphragm, and rectus femoris.

Cumulative evidence indicates that there is an increased accumulation of calcium in dystrophic muscle and that this may have a pathophysiological role in the progression of the dystrophic process. The accumulation may be related to a defect of the plasma membrane. Because parathyroid hormone (PTH) stimulates calcium influx into the cytosol, the chronic effects of surgical ablation of the parathyroid glands on muscle Ca, Mg, protein synthesis, and histology, as well as plasma creatine phosphokinase (CPK), Ca, and Mg, were studied in normal and dystrophic (BIO 14.6) hamsters. Thyroparathyroidectomized (TPTX) hamsters receiving replacement doses of l-thyroxine were killed at age 90 d, 55 d after TPTX. In intact dystrophic hamsters, the Ca content in the heart was 20 times higher than in normal animals and was reduced by half in TPTX dystrophic hamsters. Similar results were observed in diaphragm and rectus femoris. No abnormalities in Mg content were observed in intact or TPTX dystrophic hamsters. Ether-extractable fat of the heart and diaphragm was reduced in dystrophic hamsters and was not modified by TPTX. Protein synthesis was enhanced in the diaphragm of dystrophic hamsters but was not changed by TPTX. The concentration of CPK in plasma was elevated in dystrophic hamsters and fell significantly after TPTX. In the latter animals, microscopic examination of the heart showed lesser signs of dystrophy, particularly in the degree of fibrosis. To determine the degree of dystrophy at the age when TPTX was performed, identical analyses were made in 35-d-old hamsters. Definitive histological signs of dystrophy were observed, and although the Ca content in heart, diaphragm, and rectus femoris was elevated, the values were lower than in 90-d-old intact and TPTX dystrophic hamsters. This indicates that chronic TPTX in dystrophic hamsters reduces, but does not arrest, the dystrophic process. In normal hamsters, a 50% reduction in plasma Ca concentration was observed 6 h after TPTX; 55 d after TPTX, however, plasma Ca was within normal limits in both normal and dystrophic hamsters. No parathyroid tissue was observed in serial sections of the trachea and adjacent tissues in TPTX animals. This suggests that in chronically TPTX hamsters fed a standard laboratory diet, plasma Ca can be maintained by mechanisms independent of parathyroid function. THE DATA INDICATE THAT IN DYSTROPHIC HAMSTERS TPTX CAUSES A MARKED REDUCTION IN: (a) muscle Ca accumulation, (b) levels of plasma CPK and, (c) intensity of histological changes in the heart. These changes were independent of the levels of plasma Ca and were not observed in normal hamsters. We conclude that PTH accentuates the dystrophic process, probably by enhancing the already increased Ca flux into muscle (apparently caused by defective sarcolemma). We postulate that normal secretion of PTH may have a deleterious effect in congenital or acquired conditions associated with altered plasma membranes.

Parathyroid storm.

Primary hyperparathyroidism frequently has a chronic and relatively benign course. Occasionally, however, it may have a stormy presentation requiring prompt adequate diagnosis and urgent surgical treatment. We describe a 71-year-old woman who had severe hypercalcemia, seizures, and coma refractory to treatment with anticonvulsant drugs, intravenous infusion of normal saline, furosemide, glucocorticoids, calcitonin, and hemodialysis. Bone roentgenograms were normal, but a strikingly positive bone scan that also showed marked soft-tissue uptake prompted the diagnosis of primary hyperparathyroidism and the successful surgical removal of a large parathyroid adenoma. This was followed by a remarkable recovery and marked reduction in soft-tissue radioactive uptake on bone scan. The association of hypercalcemia and seizures and the diagnostic value of bone scanning are discussed. An up-to-date review of the literature is presented. We proposed this condition to be named "parathyroid storm" on the basis of the rapid and lethal course unless surgery is performed without delay.

Pamidronate sodium and calcitonin-resistant Paget's disease. Immediate response in a patient.

One three-day course of intravenous pamidronate sodium (3-amino-1-hydroxypropylidene-1,1-bisphosphonate), 30 mg/d, in a patient with calcitonin-resistant Paget's disease resulted in the following: marked clinical improvement within two weeks; normalization of urinary hydroxyproline value; fall of serum alkaline phosphatase value (900 to 250 U/L); a rise in serum osteocalcin value by the tenth week that returned to pretreatment levels in the 16th week; transient hypocalcemia with elevation of parathyroid hormone value; reduction in urinary calcium excretion; and improvement in bone scans. No adverse reactions occurred, with the exception of mild and transient hyperpyrexia for 48 hours during pamidronate administration. White blood cell counts did not change and serum interleukin 1 was undetectable before and after treatment with pamidronate. Pamidronate seems to be highly effective in the treatment of Paget's disease of the bone, but its profound effects on mineral and bone metabolism require close monitoring during the short-term period of intravenous treatment.

Postabsorptive urinary hydroxyproline test in patients with metastatic bone disease from breast cancer.

Postabsorptive urine hydroxyproline (HYPRO) excretion ("spot" HYPRO test) was compared with the 24-hour urine excretion of HYPRO in 45 patients with breast cancer and nine normal subjects on a low-gelatin diet. A good correlation was observed between the results of these two tests in both groups. Patients with skeletal metastasis showed a higher spot HYPRO value than those without bone involvement and the number of lesions by bone scanning correlated with the values of spot HYPRO. In 20 of 22 patients with bone metastasis followed up for three to 19 months, spot HYPRO values correlated well with the evolution of bone disease. We conclude that the spot HYPRO test is a simple, inexpensive, and accurate method for the diagnosis and follow-up of patients with skeletal metastasis from breast cancer.

Total, dialyzable, and nondialyzable postabsorptive hydroxyproline. Values in patients with cancer.

The postabsorptive urinary total (T), dialyzable (D), and nondialyzable (ND) hydroxyproline (HYPRO) tests were evaluated to determine whether the patterns of excretion varied according to the predominance of osteoblastic v osteolytic bone involvement in 58 patients with neoplastic disease. In patients with osteolytic lesions from multiple myeloma, elevated T and D levels with normal ND HYPRO values were observed, along with elevated D/ND ratios. In prostate cancer, the T, D, and ND values were all elevated and the D/ND ratio was normal. Patients with Hodgkin's disease had elevated T, D, and ND HYPRO levels, and the D/ND ratio was in the range of patients with prostate cancer. The data suggest that these collagen markers may be useful in the long-term evaluation of these neoplasms in patients.

Hypercalcemic effect of insulin in the chick.

There are conflicting reports on the effect of insulin on plasma Ca concentration in rats. Low doses appear to decrease and higher doses to increase plasma Ca. Since birds are known to be very sensitive to parathyroid hormone and have resistance to the hypoglycemic effects of insulin, the effect of commercial and highly purified insulin on plasma Ca concentration was studied in 10-day-old chicks 60 min after the administration of the hormone. Both commerical bovine and purified porcine insulin provoked a dose-related elevation of plasma Ca. Although hypophosphatemia was observed with the highest dose of insulin used (0.4U), hypercalcemia was observed with 0.05 U insulin, a dose that did not modify plasma phosphate concentration. The slopes of the dose-response curves of insulin and parathyroid hormone were indistinguishable and different from that of 1 alpha-hydroxyvitamin D3. Neither propranolol nor deprivation of vitamin D altered the hypercalcemic response to insulin. Unexpectedly, propranolol (40 microgram/chick) provoked elevation of plasma Ca. It is concluded that insulin raises plasma Ca concentration in the chick by a mechanism(s) not yet elucidated.

Duchenne muscular dystrophy: normal ATP turnover in cultured cells.

We examined ATP metabolism in cultured muscle cells and fibroblasts from patients with Duchenne dystrophy. ATP and ADP levels were the same in cultured cells from normal subjects and patients, and there was no difference in ATP synthesis or degradation. Although there was a significant decrease in radioactively labeled ATP after incubation with deoxyglucose in Duchenne muscle cells, there was no difference in ATP concentration or ADP metabolism.

ATP degradation products after ischemic exercise: hereditary lack of phosphorylase or carnitine palmityltransferase.

We measured purine degradation products of ATP in plasma after ischemic exercise in eight normal subjects, one patient with myophosphorylase deficiency (McArdle's disease), and one with carnitine palmityltransferase deficiency. Normal subjects increase hypoxanthine and inosine, but not xanthine. Plasma purine levels were elevated above the normal range after ischemic exercise in McArdle's disease and in carnitine palmityltransferase deficiency after fasting. Those changes implied abnormally accelerated ATP degradation in these two myopathies.

Muscle calcium and magnesium content in Duchenne muscular dystrophy.

Calcium (Ca) and magnesium (Mg) content were determined in muscle of 27 patients with Duchenne muscular dystrophy, 36 with other neuromuscular diseases, and 22 whose muscle biopsy specimens were histochemically normal. Muscle Ca was significantly elevated in all diseases studied but was about 50% higher in Duchenne dystrophy patients (p less than 0.0001). Mg was decreased by 44% in Duchenne dystrophy, compared with less striking deficits in other diseases (p less than 0.005). In older, nonambulatory Duchenne dystrophy patients, Mg was significantly lower than in younger, ambulatory patients (p less than 0.001); muscle Ca was the same in both groups. On the basis of noncollagen nitrogen concentration, muscle MG depletion could not be attributed solely to reduced muscle mass. These findings strengthen arguments for a role of Ca in the pathogenesis of muscular dystrophy and may implicate Mg depletion as another pathogenetic factor.

Chronic allopurinol and adenine therapy in Duchenne muscular dystrophy: effects on muscle function, nucleotide degradation, and muscle ATP and ADP content.

Prompted by the controversy on the efficacy of allopurinol in Duchenne muscular dystrophy and by our observations of an abnormal adenine nucleotide turnover in this disease, we conducted an 18 month, double-blind clinical trial with allopurinol and adenine in 14 Duchenne boys paired according to age and functional activity. Detailed clinical evaluation was performed trimonthly. Muscle ATP and ADP content was measured before and after 1 year of treatment. The effect of therapy on adenine nucleotide turnover was determined. No significant difference was observed between the treated and placebo groups, but both showed a significant deterioration (p less than 0.05) in most clinical parameters. Muscle ATP was reduced in Duchenne dystrophy (p less than 0.02) but did not change with therapy, and no correction of the abnormal adenine nucleotide degradation was observed.

Effect of chronic treatment with the calcium antagonist diltiazem in Duchenne muscular dystrophy.

We conducted a double-blind trial with the calcium antagonist, diltiazem (8 mg/kg/d), for 24 to 32 months in 22 boys with Duchenne muscular dystrophy, who were paired by functional activity and age. No adverse clinical or ECG effects of diltiazem were detected. In eight matched pairs, completing 28 months, manual muscle testing scores fell somewhat less in the diltiazem group (from 5.5 to 4.6) than in the placebo group (from 5.3 to 4.2), although the difference between groups was not significant (p = 0.06). The 95% confidence interval for the difference in slopes of regression lines obtained from trimonthly manual muscle tests on all subjects was markedly asymmetric in favor of the diltiazem group, but this difference was also not significant. There was less deterioration of functional activity of lower extremities in the diltiazem-treated group, when beginning and end values were analyzed (p = 0.03). However, the difference in slopes of regression lines obtained from trimonthly determinations was nonsignificant. Similarly, the beginning versus end comparisons of systolic and diastolic blood pressure showed a significantly (p less than 0.05) smaller elevation of blood pressure in the diltiazem-treated group, but no difference was observed when the slopes of all values were analyzed. All other clinical and laboratory variables were unaffected by diltiazem treatment. The findings in manual muscle tests and functional activity suggest a beneficial trend with chronic diltiazem treatment in DMD.

Calcium and magnesium content in fetuses at risk and prenecrotic Duchenne muscular dystrophy.

We measured calcium (Ca) and magnesium (Mg) content in muscles of fetuses at risk of Duchenne muscular dystrophy (DMD) and in a premature infant who later developed typical DMD. There was a three- to six-fold increase in muscle Ca in the fetuses and in the premature infant. In contrast to our previous reports of reduced muscle Mg in DMD children, there was an 18 to 57% increase of Mg in the fetuses at risk. Opaque and Ca-positive fibers, rarely observed in normal fetuses, were numerous in fetuses at risk and in the premature infant. No necrotic fibers were detected in the fetuses or the premature infant. These findings suggest that excessive Ca accumulation precedes necrosis in DMD. Other factors related to growth and development that occur after birth may trigger the necrosis that follows muscle Ca accumulation.

Osteoporosis of pregnancy: long-term follow-up of patients and their offspring.

BACKGROUND: The usual course of osteoporosis of pregnancy is complete resolution without recurrence. We report the 10-year follow-up of two patients with osteoporosis of pregnancy and their offspring. CASES: A 30-year-old woman presented with right hip pain at 30 weeks' gestation. Single-photon absorptiometry of the distal radius showed osteopenia, which persisted on 10-year follow-up. A dual-energy x-ray absorptiometry performed on the 11-year-old daughter of this pregnancy showed osteopenia. A 26-year-old woman presented with left hip pain at 16 weeks' gestation. Single-photon absorptiometry of the distal radius showed osteopenia, which persisted on 10-year follow-up. Dual-energy x-ray absorptiometry performed on the 13-year-old daughter of this pregnancy showed osteopenia. CONCLUSION: Osteoporosis of the hip discovered during pregnancy may not be a transient process and should prompt a search for osteopenia in both mother and offspring.

Protrusio acetabuli in osteoporosis and osteomalacia.

Protrusio Acetabuli (PA) occurs in various rheumatic conditions and metabolic bone disorders as a result of bony remodeling in the pelvis. We sought evidence of early PA in patients with biopsy-proven postmenopausal osteoporosis and osteomalacia using a quantitative radiographic index of protrusion. The values in osteoporotic patients were not significantly different from those in controls and did not correlate with bone density measurements. In osteomalacia, the index was significantly increased relative both to the osteoporosis and control groups; early PA was found in 50% of patients with osteomalacia. This simple radiographic measurement may be useful in the differential diagnosis of osteopenia.

Oral propranolol in hypercalcemia associated with apathetic thyrotoxicosis.

A 68-year-old man with a history of organic heart disease and marked weight loss was found to have apathetic thyrotoxicosis and hypercalcemia. Oral propranolol, 20.0 mg four times a day, provoked a gradual fall in serum calcium and alkaline phosphatase. It is concluded that relatively small doses of oral propranolol may be effective in the management of hypercalcemia accompanying thyrotoxicosis and that beta-blocking agents may not only inhibit the enhanced bone resorption caused by thyroid hormones but also block the stimulated osteoblastic activity.

Oral calcium chloride in hypoparathyroidism refractory to massive doses of calcium carbonate and vitamin D.

Surgically induced hypoparathyroidism often responds satisfactorily to intravenous Ca administration, oral CaCO3 and vitamin D2. A 17-year-old girl developed hypoparathyroidism following partial thyroidectomy for thyrotoxicosis. Hypocalcemia was refractory to treatment with massive doses of vitamin D2, up to 150,000 U, 3-6 gm of oral Ca as CaCO3 and 2 micrograms of 1,25-dihydroxycholecalciferol per day. Intravenous Ca gluconate (360 mg of elemental Ca/d, in divided doses) was needed to correct tetany. After 25 days of unsuccessful therapy, oral administration of 30 ml of a 10% solution of CaCl2 (1.09 gm of elemental Ca) was followed by normalization of serum Ca (8.9 mg/dl) within 7 hours. This dose was repeated every 8 hours for 6 days and oral CaCO3 and IV Ca gluconate were discontinued. Serum Ca remained within normal range but hyperchloremic acidosis developed. This was corrected by providing, in addition to vitamin D, 2 g/d of Ca supplementation, 1 gm in the form of 10% CaCl2 solution and 1 gm as CaCO3 in two doses given simultaneously. During 12 months of observation, serum Ca, P and Cl have been consistently within normal limits. This patient was found to have achlorhydria, unresponsive to normalization of thyroid function and serum Ca. These findings indicate that refractoriness to oral CaCO3 and vitamin D may be caused by achlorhydria. Oral administration of CaCl2 solution can promptly correct this defect. Monitoring of serum Cl and CO2 is needed to avoid hyperchloremic acidosis.

Case report: long-term remission of parathyroid cancer: possible relation to vitamin D and calcitriol therapy.

Recurrence of surgically treated parathyroid cancer occurs in 30% to 65% of patients and has a poor prognosis; only 1 of 29 cases remained normocalcemic more than 2 years later. No medical attempts to prevent recurrence have been reported. A 24-year-old pregnant woman whose mother died of parathyroid cancer underwent apparently successful surgery for parathyroid cancer. Serum Ca and parathyroid hormone (PTH) returned to normal levels but 3 months after surgery, although normocalcemic, the serum PTH level was elevated. The administration of vitamin D 200,000 U/month or calcitriol 0.5 microgram daily and 1 g of Ca supplementation daily, resulted in the normalization of PTH during 81 months of follow-up. On three occasions, when vitamin D or calcitriol were omitted, serum intact, C-terminal, or mid-molecule PTH levels rose. Ionized and total serum Ca, creatinine, calcitriol and calcidiol levels were normal, and multiple ultrasounds of the neck remained negative after surgery. This observation suggests that serum PTH could be an early marker for the detection of recurrence in parathyroid cancer with normal serum Ca, and that suppression of PTH secretion by vitamin D or calcitriol could avert or delay the progression of recurrence. Additional trials with calcitriol in operated normocalcemic parathyroid cancer with an elevated serum PTH level is recommended.

Hypoparathyroidism counteracts risk factors for osteoporosis.

Although increased bone density has been reported in patients with hypoparathyroidism, it is not known whether hypoparathyroidism can overcome the influence of risk factors for osteoporosis and whether the increased bone density is uniform throughout the entire skeleton or greater in certain regions depending on the bone composition and location. In the current study, bone density was measured in patients with postsurgical hypoparathyroidism and risk factors for osteoporosis. Bone mineral density was determined in eight patients with postsurgical hypoparathyroidism, one with idiopathic hypoparathyroidism, and two with pseudohypoparathyroidism in eight different areas of the skeleton using well established methods: single photon absorptiometry of the radius, dual energy x-ray absorptiometry of the spine, hip, and the whole skeleton, and quantitative computed tomography of the spine. Risk factors for osteoporosis were documented in each subject. The data showed that despite the presence of 1-4 risk factors for osteoporosis, patients with postsurgical hypoparathyroidism had bone mineral density above the normal mean in most locations. The locations with the highest increment were the Ward's triangle and the trochanter area of the proximal femur (dual energy x-ray absorptiometry) (Ward's: Z score + 1.59 +/- 0.57, P < 0.03; trochanter 1.31 +/- 0.42, P < 0.02). The elevation of bone density was not observed in one patient with idiopathic hypoparathyroidism, and variable results were observed in two patients with pseudohypoparathyroidism. Based on these findings, in postsurgical hypoparathyroidism, the bone mineral density is above the normal mean despite the presence of risk factors for osteoporosis, and both cortical and trabecular bone are affected.

Effect of calcitriol and pamidronate in multiple myeloma.

Addition of bisphosphonates to standard treatment of multiple myeloma (MM) decreases bone pain and skeletal events without influencing bone healing. Calcitriol, besides its established effects on bone remodeling and calcium metabolism, has both immunoregulatory and cell differentiating effects in vitro and in vivo. Moreover, low serum calcitriol has been reported in MM. We tested the effects of supportive treatment with calcitriol and pamidronate on bone disease in two stage-III-B MM patients with diffuse bone involvement, normal serum calcium, and low serum calcitriol. Complete blood counts, serum calcium, creatinine, quantitative serum and urine immunoglobulins, and biochemical indices of bone turnover, serum calcidiol, calcitriol, parathyroid hormone, skeletal radiographs, and bone mineral density by dual x-ray absorbtiometry were measured every 1-6 months for 16 months in the first patient and 7 months in the second patient. Both patients showed a dramatic improvement of MM activity and in bone disease documented by serial radiographs in the first patient and by increased bone mineral density (approximately 15%) in the second. The reduced serum calcitriol in both patients and the elevated parathyroid hormone observed in the first patient before treatment returned to normal. Supportive treatment with pamidronate does not induce bone healing in MM. Therefore, the results observed with the addition of calcitriol suggest that this hormone may have contributed to the apparent arrest of the progression of MM and caused stimulation of bone healing.