Risedronate in the treatment of Paget's disease of bone: an open label, multicenter study.

An open-label, multicenter study was conducted to determine the efficacy and safety of oral risedronate (a pyridinyl bisphosphonate) in 162 patients (102 men, 60 postmenopausal women; mean age, 68 years) with moderate to severe Paget's disease of bone (mean serum alkaline phosphatase [ALP] approximately seven times the upper limit of normal). Patients were treated with oral risedronate, 30 mg/day for 84 days, followed by 112 days without treatment. This 196-day cycle was repeated once if serum ALP did not normalize or increased from the nadir value by > or = 25%. At the end of the first and second cycles, the mean percentage decreases for serum ALP were 65.7% and 69.1%, and for urinary hydroxyproline/creatinine 50.4% and 66.9%, respectively. The decreases from baseline in ALP and urinary hydroxyproline/creatinine were significant (p < 0.001). Normalization of serum ALP was observed in 86 patients (53.8%): 53 during the first treatment cycle and 33 during the second. There was a significant proportion of patients reporting a decrease in the pagetic bone pain at days 84 and 196 (p < 0.001). Overall, risedronate was well tolerated. Five patients withdrew due to adverse events, none of which were considered to be drug related. In conclusion, 30 mg of oral risedronate administered daily for 84 days significantly reduced the biochemical indices of disease activity and was associated with pain reduction in patients with moderate to severe Paget's disease of bone. Normalization of ALP was observed in the majority of patients. Repeated administration of risedronate was shown to be beneficial. In general, risedronate was well tolerated and demonstrated a good safety profile.

Case report: vitamin D-mediated hypercalcemia in fungal infections.

Hypercalcemia has been well described in a variety of neoplastic and granulomatous diseases. One mechanism for this hypercalcemia is via the excess production of 1,25-dihydroxyvitamin D from extra-renal sources. The authors describe an AIDS patient infected with Cryptococcus neoformans who had suggestive evidence of vitamin D-mediated hypercalcemia. He had an elevated serum 1,25-dihydroxyvitamin D value, a normal 25-hydroxyvitamin D value, and low values for parathyroid hormone and parathyroid hormone-related peptide. Most previously reported cases of hypercalcemia associated with fungal infections did not include sufficient evidence to implicate a role for excess 1,25-dihydroxyvitamin D production, except for two case reports involving patients with hypercalcemia with infections due to Pneumocystis carinii and Candida albicans. The authors' patient's hypercalcemia resolved during treatment of his underlying infection. Patients with hypercalcemia or in whom hypercalcemia develops during a disseminated fungal infection should have vitamin D metabolites measured as part of their work-up.

Hereditary hyperparathyroidism-jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to chromosome 1q21-q31.

The syndrome of hereditary hyperparathyroidism and jaw tumors (HPT-JT) is characterized by inheritance, in an autosomal dominant pattern, of recurrent parathyroid adenomas, fibro-osseous tumors of the mandible and/or maxilla, Wilms tumor, and parathyroid carcinoma. This syndrome is clinically and genetically distinct from other endocrine neoplasia syndromes and appears to result from mutation of an endocrine tumor gene designated "HRPT2." We studied five HPT-JT families (59 persons, 20 affected); using PCR-based markers, we instituted a genomewide linkage search after excluding several candidate genes. Lod scores were calculated at various recombination fractions (theta), penetrance 90%. We mapped HRPT2 to the long arm of chromosome 1 (1q21-q31). The maximal lod score was 6.10 at theta = .0 with marker D1S212, or > 10(6) odds in favor of linkage. In six hereditary Wilms tumor families (96 persons, 29 affected), we found no linkage to 1q markers closely linked with HRPT2 (lod scores -15.6 [D1S191] and -17.8 [D1S196], theta = .001). Nine parathyroid adenomas and one Wilms tumor from nine members of three HPT-JT families were examined for loss of heterozygosity at linked loci. The parathyroid adenomas and Wilms tumor showed no loss of heterozygosity for these DNA markers. Our data establish that HRPT2, an endocrine tumor gene on the long arm of chromosome 1, is responsible for the HPT-JT syndrome but not for the classical hereditary Wilms tumor syndrome.

Management of hyperparathyroidism in the multiple endocrine neoplasia syndromes and other familial endocrinopathies.

Generalized parathyroid hyperplasia with superimposed clonal tumor growth is the most frequent expression of the MEN 1 trait and must be corrected surgically. The Zollinger-Ellison syndrome is an indication for early and aggressive control of hypercalcemia. If gastrin secretion is normal, early parathyroid surgery is usually not required; and to delay the operation will facilitate location of all parathyroid glands, a requisite for successful surgery. The best surgical approach is an extensive primary dissection including thymectomy, followed by total parathyroidectomy with autogenous parathyroid grafting. Parathyroid disease in MEN 2 is less frequent and of later onset. It usually takes secondary consideration to the cure of the C-cell neoplasm. Several other less common hereditary syndromes with parathyroid involvement are reviewed.

Single-dose intravenous therapy with pamidronate for the treatment of hypercalcemia of malignancy: comparison of 30-, 60-, and 90-mg dosages.

PURPOSE: To determine the efficacy, dose-response relationship, and safety of 30, 60, and 90 mg of a single intravenous dose of an aminobisphosphonate, pamidronate (APD), for the treatment of moderate to severe hypercalcemia of malignancy. PATIENTS AND METHODS: Patients with histologically proven cancer and a corrected serum calcium level of at least 12.0 mg/dL after 48 hours of normal saline hydration were enrolled in a double-blind, multicenter, randomized clinical trial. Pamidronate in 30-, 60-, or 90-mg doses was administered as a single 24-hour infusion. Serum calcium corrected for albumin, urine hydroxyproline, and calcium excretion, and serum parathyroid hormone (PTH) (1-84) were determined before and after pamidronate therapy. RESULTS: Thirty-two men and 18 women entered the study. A dose-response relationship for normalization of corrected serum calcium was seen after pamidronate administration. Corrected serum calcium normalized in 40% of patients who received 30 mg, in 61% of patients who received 60 mg, and in 100% of patients who received 90 mg of pamidronate. The decline in the serum calcium level was associated with decreased osteoclastic skeletal resorption evidenced by a decrease in urine calcium and hydroxyproline excretion. Among those with a normalized corrected serum calcium level, the mean (median) duration of normalization of the corrected serum calcium value was 9.2 (4), 13.3 (5), and 10.8 (6) days in the 30-, 60-, and 90-mg treatment groups, respectively. The response of hypercalcemia to pamidronate was not significantly influenced by the presence of skeletal metastases. PTH 1-84, suppressed in patients on entry into this study, increased to a greater extent in those patients with osteolytic skeletal metastases compared with those with humoral hypercalcemia of malignancy. Clinical improvement, including improved mental status and decreased anorexia, accompanied the decline in the corrected serum calcium level in all three treatment groups. Side effects included low-grade fever, asymptomatic hypocalcemia, hypomagnesemia, and hypophosphatemia. CONCLUSIONS: A single-dose infusion of 60 to 90 mg of pamidronate was highly effective and well tolerated and normalized corrected serum calcium in nearly all patients (61% to 100%) with hypercalcemia of malignancy.

Dominant familial syndromes with endocrine hyperfunction: an additional syndrome?

At least 8 separate dominant syndromes have been described which have hyperfunctioning endocrine tumors as an important component. Scattered reports in the literature suggest that there may be an additional syndrome, in which extra-adrenal paragangliomas (often multiple), pituitary adenomas, and parathyroid hyperplasia coexist. Of 3 such cases described to date, 2 have included information about the family history, which in each case suggested dominant inheritance. This would presumably be a less common syndrome than the others recognized previously, so that full evaluation of endocrine findings and family history in future cases will be important for developing our understanding of the syndrome.

Case report: hypoparathyroidism with menses-associated hypocalcemia.

For 18 years, a patient with idiopathic hypoparathyroidism has experienced stiffness or tetany chiefly at the time of menses. A significant decline (0.2 mmol/L) in her serum total and ionized calcium values was observed after the withdrawal of oral contraceptive and after spontaneous onset of menses. No increase in urinary calcium excretion or decline in serum magnesium or calcitriol occurred to explain the fall in serum calcium. In two hypoparathyroid women without the history of menses-associated tetany, serum calcium remained stable after withdrawal of oral contraceptive or conjugated estrogen. Serum calcitriol levels unexpectedly increased in these controls, possibly helping sustain serum calcium. The author concludes the following: (1) some hypoparathyroid women show a significant and symptomatic decline in serum calcium at the time of menses; (2) serum calcium values obtained at the time of menses may not be a reliable guide to adjusting medication dosage for hypoparathyroidism; and (3) further investigation will be needed to determine the mechanism of the decline in serum calcium values and whether the effect of estrogens on serum calcitriol might be altered in the absence of the parathyroid glands.

T-lymphocyte activation in adult-onset idiopathic hypoparathyroidism.

PURPOSE: Patients with adult-onset idiopathic hypoparathyroidism (AOIH) often have antibodies against the parathyroid glands and other tissues, suggestive of immune activation. The purpose of this study was to determine whether T-cell activation is also a component of the endocrine disease. PATIENTS AND METHODS: We identified eight patients with idiopathic hypoparathyroidism diagnosed after the age of 30 years at two tertiary care centers and evaluated peripheral blood lymphocyte subset phenotype frequencies using monoclonal antibodies and flow cytometry. Control subjects were 13 patients with Graves' disease (five thyrotoxic and eight euthyroid) and 110 healthy volunteers. In two of the patients with AOIH, we also determined the mitogenic response to parathyroid cell membranes in peripheral lymphocytes. RESULTS: Patients with AOIH had higher than normal frequencies of the following phenotypes (p less than 0.05 versus controls, one-way analysis of variance): CD4, helper T cells; CD29/CD4, inducer of helper T cells; CD16 and CD56, natural killer cells; and CD3/DR, activated T cells coexpressing DR. Patients with Graves' disease had significantly higher than control frequencies of CD25 (T cells bearing the interleukin-2 receptor), CD3/DR, and CD26 (also a marker of T-cell activation); whereas the frequency of CD29/CD4 was significantly less than the control frequency. Neither of the two AOIH patients tested showed lymphocyte proliferation in response to parathyroid or thyroid cell membrane fractions. CONCLUSIONS: Generalized T-cell activation represents a novel feature associated with AOIH. Although we could not demonstrate parathyroid-specific lymphocyte clonal expansion, these data are suggestive of a generalized immune disturbance possibly related to autoimmunity, in which one of the manifestations is hypoparathyroidism.

The modulation of circulating parathyroid hormone immunoheterogeneity in man by ionized calcium concentration.

Twenty normal individuals received 2-h iv infusions of CaCl2 and Na2 ethylenediamine tetra-acetate, with sampling every 15 min. PTH was measured by means of an intact hormone assay (I) and two carboxylterminal assays structured to react mostly with mid (M) or late (L) carboxylterminal fragments. A mathematical model was used to fit the sigmoidal relationship between ionized calcium (CA++) and PTH values. The influence of Ca++ on circulating PTH immunoheterogeneity was assessed via changes in L/I, M/I, and M/L ratios. Results are reported as means +/- SD. Response to hypocalcemia was highest with M (57.8 +/- 26.4 pmol/L, P less than 0.005 vs. L or I) and higher with L (20.1 +/- 5.6 pmol/L; P less than 0.0005 vs. I) than with I (14.1 +/- 6.4 pmol/L). L/I, M/I, and M/L decreased from 2.43 +/- 0.56 to 1.54 +/- 0.19 (P less than 0.0005), 8.44 +/- 2.38 to 4.36 +/- 4.07 (P less than 0.0005), and 3.49 +/- 0.71 to 2.86 +/- 0.76 (P less than 0.005), respectively, during Na2 ethylenediamine tetra-acetate infusion. Nonsuppressible PTH was again higher with M (13.7 +/- 4.8 pmol/L; P less than 0.0005 vs. L or I) and higher with L (2.8 +/- 0.7 pmol/L, P less than 0.0005 vs. I) than with I (0.5 +/- 0.3 pmol/L). L/I, M/I, and M/L ratios increased from 2.47 +/- 0.97 to 5.35 +/- 2.09 (P less than 0.0005), 8.90 +/- 3.10 to 29.56 +/- 14.89 (P less than 0.0005), and 3.62 +/- 0.90 to 5.30 +/- 1.91 (P less than 0.005) during CaCl2 infusion. The set-point for PTH stimulation by calcium was similar for M (1.15 +/- 0.035 mmol/L) and L (1.175 +/- 0.041 mmol/L) but significantly higher with the I assay (1.184 +/- 0.31 mmol/L; P less than 0.0005 vs. M). The M/I, L/I, and M/L ratio set-points were similar at 1.28 +/- 0.01, 1.27 +/- 0.01, and 1.29 +/- 0.02 mmol/L. Thus, even if proportionately more intact PTH and less carboxylterminal fragments are produced and secreted during hypocalcemia, the latter still predominate in the circulation. Furthermore, at high calcium values, secretion of fragments is less well inhibited than that of intact hormone. The lower secretion and higher ratio set-points suggest that the secretion and intracellular degradation of PTH have different sensitivities to inhibition by calcium.

Comparative study of pamidronate disodium and etidronate disodium in the treatment of cancer-related hypercalcemia.

PURPOSE: This multicenter, double-blind, randomized trial was performed to determine the efficacy and safety of pamidronate disodium (APD) in comparison to etidronate disodium (EHDP) in the treatment of cancer-related hypercalcemia. PATIENTS AND METHODS: Sixty-five male and female adult patients with cancer and corrected calcium levels of greater than or equal to 12.0 mg/dL after 24 hours of hydration were randomized to receive either 60 mg APD given as a single 24-hour infusion or 7.5 mg/kg EHDP given as a 2-hour infusion daily for 3 days. RESULTS: APD normalized corrected calcium levels in 70% (21 of 30) of patients, whereas EHDP did so in 41% (14 of 34) of patients (P = .026). The mean corrected serum calcium level decreased from 14.6 to 10.5 mg/dL in the APD-treated group and from 13.8 to 11.6 mg/dL in the EHDP-treated group within the first week of treatment. There was no difference in response to APD in patients without versus those with bone metastases (78% v 67%). Both drugs were well tolerated. CONCLUSION: This study demonstrated that a single 60-mg infusion of APD is safe and more effective than EHDP given at the dose of 7.5 mg/kg for 3 days in the treatment of cancer-related hypercalcemia.

Malignancy hypercalcemia: evaluation of parathyroid function and response to treatment.

In 53 patients with malignancy-associated hypercalcemia, we measured serum parathyroid hormone (PTH) with an immunoradiometric assay (IRMA) for intact PTH and a midregion-specific radioimmunoassay (RIA). Values were measured at baseline to detect clinically unrecognized hyperparathyroidism and after treatment with intravenous bisphosphonate to test for a parathyroid response. One patient probably had primary hyperparathyroidism, since his serum PTH values were not appropriately suppressed at baseline and increased markedly during treatment before normocalcemia was achieved. In each of the 51 other evaluable cases, the intact PTH value was suppressed below 25 pg/ml (normal range 10-55 pg/ml), confirming a nonparathyroid hypercalcemia. Midregion PTH values were less fully suppressed but supported the diagnosis in 44 out of 49 cases. The five patients with high midregion PTH values each had renal insufficiency but in four, the intact PTH values were also the highest we observed in these patients. This suggests either a poorly suppressible intact PTH secretion or prolongation of intact PTH half-life by the renal insufficiency. Overall, midregion and intact PTH values were highly correlated (p less than 0.001). Restoration of normocalcemia increased PTH in both assays into or within the normal range, and when posttreatment hypocalcemia occurred, PTH values became elevated in both assays. We conclude the following: (1) both assays are useful for detecting parathyroid hyperfunction but the intact PTH assay is the better diagnostic tool when renal insufficiency is present, (2) hypercalcemia seems to suppress intact PTH secretion more fully than secretion of PTH fragments, and (3) parathyroid glands chronically suppressed by hypercalcemia can increase PTH secretion within 1 or 2 days after the hypercalcemia is corrected.

Ten weeks of intermittent hypocalcemic stimulation does not produce functional parathyroid hyperplasia.

Hypocalcemia is a major stimulus for parathyroid hormone secretion and presumably the major cause of parathyroid hyperplasia in chronic hypocalcemic syndromes. We could find no data to indicate what degree, duration, or frequency of hypocalcemia is needed to produce parathyroid hyperplasia in humans. We have monitored the effects of thrice weekly hypocalcemic parathyroid stimulation for 10 weeks. Measurements were made during a study designed to test the feasibility of carrying out a randomized, blinded trial of "chelation therapy," a widely used but unproven method to treat atherosclerotic symptoms. Eight patients received infusions of disodium ethylenediaminetetraacetic acid (EDTA) and six received placebo infusions thrice weekly for ten weeks. The EDTA infusions (50 mg/kg over three hours) lowered serum ionized calcium at two hours by an average of 0.20 mmol/L and trebled the immunoreactive parathyroid hormone (iPTH) value. Basal serum iPTH, ionized calcium and 1,25-dihydroxyvitamin D values, measured just before the infusion, did not change significantly after 10 weeks of treatment with either EDTA or placebo. The increment in serum iPTH produced by the EDTA-induced hypocalcemia was also unchanged. Lowering ionized serum calcium to values below the normal range three times a week for 10 weeks is not a sufficient stimulus to cause a detectable increase in basal or stimulated parathyroid function.

Hereditary hyperparathyroidism and multiple ossifying jaw fibromas: a clinically and genetically distinct syndrome.

A large previously reported family with hyperparathyroidism has been reinvestigated recently because of the occurrence of multiple ossifying jaw fibromas in two affected members of the third generation similar to the jaw tumors of four of five affected members of the first generation. These maxillary and mandibular tumors can be differentiated from the "brown tumors" of hyperparathyroidism because they can appear and enlarge even though the hypercalcemia is surgically corrected. These tumors are histologically distinct fibroosseous lesions without the giant cells seen in "brown tumors." The parathyroid enlargement was mostly uniglandular, with multiple tumors found occasionally. Studies in DNA linkage were performed within this large family and a similar family in Houston to determine if the gene for this syndrome, termed HRPT2, is linked to DNA markers on chromosome 11, to which the gene for multiple endocrine neoplasia (MEN) type 1 has been linked. (This linkage is supported by our findings in one family with MEN 1 reported here.) Linkage studies were also performed with markers on chromosome 10, to which the genes for MEN 2A and MEN 2B have been linked. Evidence against close linkage with chromosome 10 and chromosome 11 markers suggests that this clinically distinct syndrome is also genetically distinct.

Successful treatment of resistant Paget's disease of bone with pamidronate.

Several agents are available for treatment of Paget's disease of bone, but their long-term use may be limited by resistance or adverse effects. I have treated two patients with exceptionally severe polyostotic Paget's disease (serum alkaline phosphatase values 25- to 30-fold above normal), in whom salmon calcitonin, sodium etidronate, and plicamycin each had become ineffective or could not be used. Pamidronate (3-amino-1-hydroxypropylidene-1,1-bisphosphonate) decreased serum alkaline phosphatase to normal or near-normal values and almost completely relieved symptoms, without recognizable adverse effects, except for transient mild hypocalcemia. The symptomatic and biochemical responses were maintained through 2 years of treatment and for more than 6 months after the treatment was discontinued. Thus, pamidronate can be very effective in severe, resistant cases of Paget's disease. Further study of this potent agent is needed to define the optimum regimen for maximum effectiveness and minimal long-term toxicity.