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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.

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.

We have designed a cyclic regimen for the treatment of osteoporosis based on the activate, depress, free, and repeat (ADFR) concept. Osteoclastic bone resorption is activated by 7 days of oral neutral phosphate and inhibited with a brief pulse (5 days) of etidronate disodium at a high dose (20 mg/kg body weight). Patients next take calcium supplements for 48 days before resuming phosphate to enter the next cycle. Osteoporotic women increased the bone mineral density of the lumbar spine at 6 months by 7.2 +/- 5.2% (mean +/- SD, N = 14) and at 12 months by 8.2 +/- 4.0% (N = 8). Control observations in regularly exercising postmenopausal women (N = 30) showed no significant change in spine mineral density after 20 months (0.5 +/- 3.2%), confirming the stability of the measurement technique. The two patients who responded poorly to the cyclic regimen each showed a blunted rise in serum PTH during oral phosphate administration, suggesting that the rise in PTH induced by oral phosphate may be an important component of this cyclic regimen. This preliminary study does not identify which component or components of the regimen are responsible for the increase in bone mass but provides positive encouragement for randomized studies designed to determine the optimum dosage, duration, and timing of each component of the regimen.

A patient with early Paget's disease of bone was treated for 12 months with calcitonin and 10 months with etidronate. During this time the cortex of each diseased bone showed a progressive 2- to 3-fold increase in thickness. Lytic areas regressed and the new bone appeared radiographically very compact. No bowing deformity developed in 3 years of observation. This form of morphologic evolution differs markedly from those previously reported during treatment. For this patient, treatment was instituted very early during the course of the disease and moderately high doses of vitamin D were given during part of the treatment course. Observation of a larger number of patients will be needed to determine whether these factors actually modified the treatment outcome.

Serum autoantibodies directed toward antigenic determinants on the surface of human parathyroid cells (PTAb-CS) have been demonstrated in a subset (8 of 23) of adult patients with idiopathic hypoparathyroidism (IHP). In sera from 3 of 8 patients with PTAb-CS, binding of these autoantibodies to their respective parathyroid cell surface antigen(s) resulted in marked inhibition of parathyroid hormone (PTH) secretion in an in vitro dispersed human parathyroid cell (dPTC) system. In 1 subject evaluated longitudinally, circulating levels of PTAb-CS, and the magnitude of the inhibitory effect on PTH secretion, temporally correlated with the clinical course of the hypoparathyroidism. These findings suggest a causative role for antibodies directed against cell surface antigens in parathyroid dysfunction in some cases of "autoimmune" hypoparathyroidism.

Autogenous parathyroid grafts are used in the treatment of primary and secondary parathyroid hyperplasia and for salvaging normal parathyroid glands removed during thyroid surgery. Placement of the autogenous grafts in the forearm may allow assessment of graft function by comparing the patient's background level of immunoreactive parathyroid hormone (iPTH) with the iPTH value in the antecubital vein above the parathyroid graft. Among patients who on clinical grounds seem to have functioning parathyroid tissue, significant iPTH gradients can be demonstrated in only approximately 80%. Several technical and clinical factors can prevent demonstration of an iPTH gradient in patients who in fact do have functioning parathyroid grafts. Hypercalcemia may suppress iPTH secretion. PTH secretion may be intermittent. High background levels of iPTH due to renal failure may transform a significant numerical gradient for iPTH into an insignificant percentage change in iPTH. It may be technically difficult to obtain blood from the particular vein bearing effluent from the parathyroid graft. The regional specificity of the iPTH assay employed may have an important influence on the magnitude of the apparent iPTH gradient. Knowledge of these factors should maximize the chance of documenting parathyroid graft function.