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Context: Denosumab and zoledronic acid (ZOL) are parenteral treatments for patients with osteoporosis., Objective: The objective of the study was to compare the effect of transitioning from oral bisphosphonates to denosumab or ZOL on bone mineral density (BMD) and bone turnover., Design and Setting: This was an international, multicenter, randomized, double-blind trial., Participants: A total of 643 postmenopausal women with osteoporosis previously treated with oral bisphosphonates participated in the study., Interventions: Subjects were randomized 1:1 to sc denosumab 60 mg every 6 months plus iv placebo once or ZOL 5 mg iv once plus sc placebo every 6 months for 12 months., Main Outcome Measures: Changes in BMD and bone turnover markers were measured., Results: BMD change from baseline at month 12 was significantly greater with denosumab compared with ZOL at the lumbar spine (primary end point; 3.2% vs 1.1%; P < .0001), total hip (1.9% vs 0.6%; P < .0001), femoral neck (1.2% vs -0.1%; P < .0001), and one-third radius (0.6% vs 0.0%; P < .05). The median decrease from baseline was greater with denosumab than ZOL for serum C-telopeptide of type 1 collagen at all time points after day 10 and for serum procollagen type 1 N-terminal propeptide at month 1 and at all time points after month 3 (all P < .05). Median percentage changes from baseline in serum intact PTH were significantly greater at months 3 and 9 with denosumab compared with ZOL (all P < .05). Adverse events were similar between groups. Three events consistent with the definition of atypical femoral fracture were observed (two denosumab and one ZOL)., Conclusions: In postmenopausal women with osteoporosis previously treated with oral bisphosphonates, denosumab was associated with greater BMD increases at all measured skeletal sites and greater inhibition of bone remodeling compared with ZOL.

We report here the second 2-yr extension of a clinical trial among postmenopausal women; 235 women continued blinded treatment with 5 or 10 mg alendronate daily, and 115 women who had been treated with alendronate for 5 yr were switched to blinded placebo. Continuous treatment with alendronate (10 mg daily) for 7 yr increased lumbar spine bone mineral density (BMD) by 11.4% compared to baseline. After the initial 18 months, each additional year of treatment through yr 7 increased spine BMD by 0.8% for the 10-mg dose and 0.6% for the 5-mg dose, with significant increases during yr 6-7. Previously reported increases in BMD at other skeletal sites and decreases in biochemical markers of bone turnover remained stable during yr 6-7. Among women previously taking alendronate for 5 yr who were switched to placebo, there was no significant decline in BMD at the spine or hip, whereas small, but significant, decreases in BMD at the forearm and total body and small increases in biochemical markers were observed. The safety and tolerability profiles were similar to those of placebo. This is the largest published long-term study of antiresorptive therapy. Our findings indicate that long-term alendronate treatment is well tolerated and effective for 7 yr. Increases in spinal BMD continue for at least 7 yr, and other skeletal benefits are maintained. Discontinuation does not lead to accelerated bone loss, but continuous treatment yields better skeletal benefits than shorter treatment.

The bisphosphonate alendronate and conjugated equine estrogens are both widely used for the treatment of postmenopausal osteoporosis. Acting by different mechanisms, these two agents decrease bone resorption and thereby increase or preserve bone mineral density (BMD). The comparative and combined effects of these medications have not been rigorously studied. This prospective, double blind, placebo-controlled, randomized clinical trial examined the effects of oral alendronate and conjugated estrogen, in combination and separately, on BMD, biochemical markers of bone turnover, safety, and tolerability in 425 hysterectomized postmenopausal women with low bone mass. In addition, bone biopsy with histomorphometry was performed in a subset of subjects. Treatment included placebo, alendronate (10 mg daily), conjugated equine estrogen (CEE; 0.625 mg daily), or alendronate (10 mg daily) plus CEE (0.625 mg daily) for 2 yr. All of the women received a supplement of 500 mg calcium daily. At 2 yr, placebo-treated patients showed a mean 0.6% loss in lumbar spine BMD, compared with mean increases in women receiving alendronate, CEE, and alendronate plus CEE of 6.0% (P < 0.001 vs. placebo), 6.0% (P < 0.001 vs. placebo), and 8.3% (P < 0.001 vs. placebo and CEE; P = 0.022 vs. alendronate), respectively. The corresponding changes in total proximal femur bone mineral density were +4.0%, +3.4%, +4.7%, and +0.3% for the alendronate, estrogen, alendronate plus estrogen, and placebo groups, respectively. Both alendronate and CEE significantly decreased biochemical markers of bone turnover, specifically urinary N-telopeptide of type I collagen and serum bone-specific alkaline phosphatase. The alendronate plus CEE combination produced slightly greater decreases in these markers than either treatment alone, but the mean absolute values remained within the normal premenopausal range. Alendronate, alone or in combination with CEE, was well tolerated. In the subset of patients who underwent bone biopsies, histomorphometry showed normal bone histology with the expected decrease in bone turnover, which was somewhat more pronounced in the combination group. Thus, alendronate and estrogen produced favorable effects on BMD. Combined use of alendronate and estrogen produced somewhat larger increases in BMD than either agent alone and was well tolerated.

There is little debate about the primacy of surgery in the management of classical PHPT. Rather, the question has been what to do about the many patients with nonclassical disease. A 1990 NIH consensus conference (55) clearly recommended surgery for patients with significant adverse effects of PHPT, for patients with complicating coexistent illnesses, for younger patients, and for those in whom consistent long-term follow-up could not be assured. It allowed that conscientious surveillance may be justified in patients with minimal hypercalcemia and no adverse effects, but it recognized that for many patients, the time and expense involved in rigorous follow-up would outweigh the burden of surgery. Nine years later, the demonstrated prevalence of nonclassical symptoms and their reversibility, the evidence of "asymptomatic" but harmful effects reversible by surgery, and the accumulating evidence for surgical reduction of increased long-term mortality risk substantially strengthen the argument for surgery in such patients. For these reasons, parathyroidectomy should generally be recommended for patients with a secure diagnosis of PHPT, even in the absence of classical symptoms.

Alendronate (ALN) is an aminobisphosphonate employed as an antiresorptive agent in the treatment of osteoporosis. The present study was carried out to determine dose-response relationships, particularly the effects of relatively low doses of ALN, on bone mineral density (BMD), biochemical indexes of bone and mineral metabolism, and bone histology, with particular attention to effects in elderly women. This prospective, randomized, double blind, 2-yr multicenter study compared the effects of placebo with those of 1.0, 2.5, or 5.0 mg ALN daily. All subjects received supplemental calcium (500 mg daily) as the carbonate. We studied 359 women with lumbar spine BMD at least 2.0 SD below the peak young adult mean. Subjects were stratified by age, with 135 aged 60-69 yr and 224 aged 70-85 yr. Histomorphometry was performed on transiliac bone biopsies obtained from 104 subjects after 1 yr and from 83 subjects after 2 yr. This study elucidated the previously uninvestigated lower region of the dose-response curve for ALN in osteoporosis. Over 2 yr, treatment with 1.0, 2.5, or 5.0 mg/day increased lumbar spine BMD, on the average, by 0.65%, 3.54%, and 5.67%, respectively, compared with that in the placebo group (P < 0.001 vs. placebo for the 2.5 and 5 mg groups). Significant dose-related increases were also seen in BMD at appendicular sites and in total body BMD. Dose-dependent reductions in bone turnover to new steady states were indicated by serum and urine biochemical markers as well as by histomorphometry. There was also a dose-related reduction in the proportion of subjects suffering nonvertebral fractures (P < 0.05). Safety profiles were similar for the ALN and placebo groups and for both age strata. Efficacy was similar for both age strata. There was no evidence of impaired mineralization or other histological abnormalities due to ALN treatment. We conclude that treatment with ALN over a period of 2 yr was well tolerated and produced dose-dependent increases in BMD without evidence of a plateau over the dose range of 1.0-5.0 mg daily. One milligram daily did not result in a significant effect on BMD, and 5.0 mg daily produced favorable effects at all sites measured. Other studies have demonstrated somewhat greater effects on 10 mg daily. ALN, was equally effective and well tolerated in osteoporotic women over 70 yr old as in younger women with the same condition.

Gorham-Stout disease (GSD) or massive osteolysis, is an extremely rare osteolytic condition that involves extensive locally aggressive resorption of bone. The etiology and pathophysiology are unknown, and the role of the osteoclast in GSD is unclear. We studied a patient with GSD who had massive resorption of his mandible, which extended to his maxilla, zygoma, right parietal region, and cranium. To investigate the cause of the extensive resorption, we tested the effects of the patient's serum, sampled early in the course of treatment and later after the osteolysis was stabilized, on the formation of osteoclast-like multinucleated cells (MNC) in cultures of normal human marrow. GSD serum (10%, vol/vol) markedly increased the number of MNC formed in these cultures compared to that in normal serum as well as stimulated the formation of resorption pits by these MNC on dentine slices. GSD serum, collected after further therapy, did not enhance the number of MNC formed in marrow cultures compared to that in normal serum. Elevated levels of interleukin-6 (IL-6) were detected in the earlier GSD serum that were 7 times the upper limit of the normal range, and after further treatment, IL-6 levels fell to one quarter the pretreatment value. The levels of IL-1 beta, tumor necrosis factor-alpha, transforming growth factor-alpha, PTH, and PTH-related peptide in pretreatment GSD serum were not increased. Moreover, the addition of neutralizing antibodies to IL-6 to the normal human bone marrow cultures effectively blocked the increase in MNC formation induced by active GSD serum. These data suggest that bone resorption in GSD patients is due to enhanced osteoclast activity, and that IL-6 may play a role in the increased bone resorption in GSD.

A series of 59 thyroidal C cell neoplasms was studied by immunoperoxidase histology. These neoplasms included human medullary thyroid carcinoma and C cell hyperplasia and rat medullary thyroid carcinoma. In addition to calcitonin, the tumors were studied by immunohistology for the presence of beta-endorphin, ACTH, and somatostain. All but one of the neoplasms were positive for calcitonin, 25 of 31 were positive for beta-endorphin, 12 of 18 were positive for ACTH, and 9 of 19 were positive for somatostatin immunoreactivity. Many tissues contained all 4 peptides, and in some sections these peptide immunoreactivities seemed to be present in the same cells. These studies suggest that there is a relationship in these tumors among the 4 peptides studied, but the basis of this relationship is not clear.

Serum concentration of 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] and intestinal absorption were measured before and after parathyroidectomy in 11 patients with primary hyperparathyroidism. Serum 1,25(OH)2D was high preoperatively (P less than 0.001) and normal postoperatively. Ca absorption was elevated preoperatively (P less than 0.001) and decreased significantly after parathyroidectomy (P less than 0.001). However, 5 of 11 patients had a persistent hyperabsorption of Ca postoperatively, despite normal serum 1,25(OH)2D. The results suggest that factors other than 1,25(OH)2D contribute to the maintenance of high intestinal Ca absorption in hyperparathyroid patients in the postoperative state.

We have demonstrated by a specific immunoperoxidase procedure the presence of calcitonin-containing cells in the rat pituitary gland. These cells are widely distributed throughout the anterior lobe and seem to constitute the entire population of cells of the intermediate lobe. No such cells were seen in the posterior lobe. The presence of calcitonin-containing cells in the pituitary provides novel implications about the physiological significance of this hormone.