Physical and biochemical factors in bone metabolism.
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Animals↗
Biomedical subjects
S Wallach
Publications and source records attributed to S Wallach.
Early clinical trials of calcitonin in North America.
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Bone Diseases↗
The role of calcitonin treatment in postmenopausal osteoporosis.
Synthetic salmon calcitonin (SCT) is a potent antiosteoclastic hormone with adjunctive stimulatory effects on osteoblastic function. It is capable of increasing or stabilizing bone mass in osteoporosis and thereby can lessen the risk of fractures. Treatment doses vary from 100 IU daily to 50 IU three times a week, and the duration of treatment is 2 to 5 years. SCT also exerts an analgesic effect on the skeleton that increases its beneficial effect. Side effects, which do not involve organ toxicity, are common but are usually mild and transient. More severe side effects can be managed by maneuvers such as bedtime dosing, premedication, and temporary dose reduction. Primary resistance occurs in approximately 25% of patients and secondary resistance, usually due to neutralizing antibody formation, in 10% to 20% of patients. SCT is indicated in both early and late osteoporosis and is the treatment of choice in the latter.
Antibody Formation↗
Paget's disease and fibrous dysplasia.
Many papers were published on both Paget's disease and fibrous dysplasia during the past year. In Paget's disease, evidence for a generalized, probably viral disorder of the skeleton has been adduced, although focal radiologic features dominate the clinical picture. Unusual clinical manifestations were highlighted in several clinical reports. A search for biochemical abnormalities other than increased serum alkaline phosphatase and urinary hydroxyproline levels yielded evidence for secondary hyperparathyroidism in many cases, and also, a confusing array of abnormalities in vitamin D metabolite levels. The application of newer imaging techniques such as computed tomography, MR imaging, bone marrow scintigraphy, and thermography was reported. The year's reports particularly highlighted new forms of effective therapy, including intranasal calcitonin, second- and third-generation bisphosphonates, and gallium nitrate. Finally, the feasibility of joint replacement in arthritic joints secondary to Paget's disease was again documented. Fibrous dysplasia continued to be an enigmatic disorder with no new insights as to etiology. Reports of unusual clinical features, imaging characteristics, bony distribution, and an array of endocrine linkages were prominent. A highlight of the year's reports was the discovery of an increased female sex steroid receptor number of dysplastic cells, and the possibility that sex steroids linked to their receptors may be responsible for the bony overgrowth. Concern was again expressed as to the possibility of malignant transformation of dysplastic lesions and the possible contribution of radiotherapy treatment to sarcoma development.
Calcitonin↗
Calcitonin, osteoclasts, and bone turnover.
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Animals↗
Effects of magnesium on skeletal metabolism.
Magnesium (Mg) makes up 0.5-1% of bone ash and is therefore not a trace element in the skeleton. Mg influences both mineral and matrix metabolism in bone by a combination of effects on hormones and other factors that regulate skeletal and mineral metabolism, and by direct effects on bone itself. The skeletal content of Mg is very variable both between and within species, and reported values range between 150 and 440 mmol/kg ash weight (AW). Dietary Mg has a direct influence and age an inverse influence on skeletal Mg content. It is unclear whether skeletal Mg content varies from region to region. In humans, reported values cluster around the 200 mmol/kg AW level, 30-40% lower than most rat data. Human iliac crest cortical bone has 10-20% less Mg per unit weight than iliac crest trabecular bone. Mg depletion adversely affects all phases of skeletal metabolism. In the rat, cessation of bone growth is noted with a decrease in both osteoblast and osteoblast activity, decreased bone formation, osteopenia, increased fragility and development of a form of 'aplastic bone disease'. The epiphyseal growth plate is thinned and the percent ash weight of the growth plate is increased, possibly due to enhanced crystallization of bone salt under conditions of Mg depletion. In contrast, in chicks and in rats with severe Mg deficiency, these 'antianabolic' effects are not observed but instead, predominant inhibition of bone resorption occurs with increased cortical thickness rather than osteopenia, and the occasional development of subperiosteal hyperplasia or of fibrous tumors of the periosteum. It is probable that this unusual response under conditions of severe Mg deficiency is in part an indirect effect secondary to a defect in secretion and/or skeletal responsiveness to parathyroid hormone (PTH) and vitamin D metabolites. Mg excess also has adverse biologic effects on bone. Crystallization of bone salt is severely impaired and an osteomalacia-like picture may be produced with decreased osteoblastic activity, widened growth plates, excessive osteoid seams and short, thickened bones. In some studies, especially in mice, Mg excess stimulates bone resorption, independently of PTH. The role of Mg deficiency and excess in human skeletal conditions requires more extensive investigation. Bone Mg is uniformly increased in renal insufficiency and may play a role in renal osteodystrophy since improvement has been noted in the osteomalacic component by normalizing the serum Mg. Decreased bone Mg has been reported in alcoholic patients, diabetes and in osteoporosis.(ABSTRACT TRUNCATED AT 400 WORDS)
Animals↗
Consistent N-myc copy number in simultaneous or consecutive neuroblastoma samples from sixty individual patients.
Amplification of the N-myc oncogene is detected in about 30% of untreated neuroblastomas. Amplification is associated with advanced stages of disease and rapid tumor progression. However, it was not known if the N-myc copy number was homogeneous in tumor tissue of an individual patient, or if it changed with time in vivo. Therefore, we have made 66 observations on multiple simultaneous or consecutive tumor samples from 60 patients with neuroblastoma. (a) Simultaneous samples were obtained from different areas of 31 tumor masses from 30 patients: a similar N-myc copy number (1-2, 3-10, or greater than 10) was found in all samples from each patient. (b) Simultaneous samples were obtained from different anatomical sites in ten patients. No difference in N-myc copy number was seen. (c) Finally, 25 patients had two or more tumor samples obtained over time. Thirteen patients had a single copy of N-myc in all samples, and 12 had consistent levels of amplification in all samples. Two of the latter cases had single copy of N-myc in a second-look surgery sample, but no tumor was evident histologically. This study demonstrates that the N-myc copy number in human neuroblastomas is usually consistent within a tumor, not only at different tumor sites, but also at different times in vivo. Overall, these findings suggest that N-myc amplification is an intrinsic biological property of a subset of neuroblastomas, and if amplification is going to occur, it is generally present at the time of diagnosis.
Child↗
Automated analysis of hydroxyproline with elimination of non-specific reacting substances.
A modified urinary hydroxyproline method is presented which utilizes an automated technique, Technicon instrumentation and Ehrlich's reagent. Acid hydrolysates are neutralized automatically. Non-specific reacting substances are determined simultaneously with each sample and subtracted as a blank. This method has been found to be superior to the use of charcoal-resin as an absorbent. After blank correction, the mean hydroxyproline excretion of normal and osteoporotic patients are similar. In all groups studied, including Paget's disease, the blanks reresent a significant fraction of total reacting substances and show wide variation between samples. Multiple samples from patients over a two year period show little variation in hydroxyproline excretion when corrected for non-specific reacting substances.
Autoanalysis↗
Effect of insulin on radiochromium distribution in diabetic rats.
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Animals↗
Radiochromium distribution in hypophysectomized and adrenalectomized rats.
The effects of hypophyseal and adrenal ablation (HYPOX, ADX) on trivalent radiochromium (51Cr) distribution and of GH and T4 replacement in HYPOX rats were determined. Hypophysectomy increased body retention of 51Cr by 20--35%, and hormonal replacement restored body retention to normal. Serum 51Cr was increased 300--800%, resulting in depressed tissue to serum 51Cr ratios. GH replacement partially restored the 51Cr distribution abnormalities in HYPOX rats to normal. The combination of T4 with GH enhanced the restoration of normal 51Cr distribution, and tissue to serum 51Cr ratios returned to baseline levels. ADX had no effect on body retention of 51Cr but had a small effect on increases in serum and tissue 51Cr levels. As a result, tissue to serum 51Cr ratios did not change. These data indicate that in the HYPOX state there is a marked disturbance in Cr metabolism which is due to deficiencies of both GH and T4. Whether or not adrenal hormones are envolved in 51Cr distribution will require further study.
Adrenalectomy↗
Neurologic disturbances in Paget disease of bone: response to calcitonin.
The neurologic manifestations of Paget disease and the therapeutic effect of calcitonin were studied in 49 patients. Twenty-four patients (49%) had neurologic disorders involving cranial nerves other than the auditory system, brainstem, spinal cord, or spinal roots and nerves. Eighteen of the 24 patients (75%) showed significant subjective or objective improvement after calcitonin treatment. The effect of calcitonin treatment on spinal cord compression was dramatic in three of six patients. The observations made of these patients support previous data suggesting that the neurologic signs and symptoms of Paget disease have their pathogenesis in both mechanical impingement and vascular distortion. The importance of early detection of neurologic signs and symptoms is emphasized, since prompt treatment with calcitonin may prevent severe complications.
Aged↗
Hormonal factors in osteoporosis.
Primary osteoporosis is a ubiquitous disease of unknown etiology. The condition undoubtedly has multiple causes and the metabolic pattern of bone loss may vary significantly from case to case. Five hormones, PTH, gonadal steroids, CT, T3 and T4, and glucocorticoids, and possibly a sixth, GH, have fundamental actions on bone metabolism and may therefore be causally involved in primary osteoporosis. A consideration of selected data on hormonal interactions culled from a much larger body of experimental and clinical data leads to the conclusion that in vitro studies, animal research, and data obtained in postmenopausal women with age-related bone atrophy, but not osteoporosis, have yielded considerable data relating to bone metabolism, but have failed to define the causes or treatment of primary osteoporosis. There has been excessive emphasis on hormonal reactions relating to bone metabolism and bone cell function, and too little concern for nonhormonal factors which might influence the kinetics of skeletal turnover through alterations in bone cell activity. A practical approach to the cause(s) and treatment in the only suitable model, the human with osteoporosis, is proposed with the expectation that a better insight into the pathogenesis of the condition will be achieved.
Adrenal Cortex Hormones↗
Management of osteoporosis.
Accelerated bone loss and diminished new bone formation in primary involutional osteoporosis far outstrip the rates seen in "normal aging." Their serious consequences can be mitigated with pharmacologic agents and adjunctive regimens.
Aged↗
Primary hyperparathyroidism and breast cancer.
Three cases demonstrating the coexistence of primary hyperparathyroidism and breast carcinoma with the disappearance of hypercalcemia following removal of parathyroid adenomas are presented. In these cases, the patients had the typical diagnostic findings of primary hyperparathyroidism. Reluctance to perform neck explorations in such patients does not appear warranted.
Adenoma↗
Paget's disease of the bone: observations after cessation of long-term synthetic salmon calcitonin treatment.
Thirteen patients with Paget's disease of the bone were treated with subcutaneous injections of synthetic salmon calcitonin (SCT) for a mean period of 22 months at doses of 50-100 MCR units daily or 3 times a week. They manifested symptomatic improvement and significant reductions in serum alkaline phosphatase and urinary hydroxyproline excretion during SCT administration. Following discontinuation of SCT, symptomatic improvement was maintained in 10 patients for up to one year, whereas a recurrence of symptoms was seen in only 3 patients. The serum alkaline phosphatase generally showed a return toward pretreatment values 6 months after discontinuation of SCT, whereas urinary hydroxyproline remained depressed for up to a year.
Aged↗
Effects of growth hormone in osteoporosis.
The effect of chronic administration of growth hormone (GH) to osteoporotic patients was studied using the techniques of total body neutron activation analysis, whole body counting, calcium tracer kinetics, photon absorptiometry, quantitative microradiography, and urinary hydroxyproline. Two dosage schedules were utilized for six months each: 2 units daily and 0.2 w3/4 units of GH daily (where W represents body weight expressed in kg). The lower dosage (2 units) did not produce any appreciable change in the indices studied. Following the higher dose, no evidence of any anabolic effect was apparent in most patients (i.e., no increase in total body levels of Ca, Na, K, P, or Cl). Increases were noted in the urinary calcium excretion rate and in the urinary hydroxyproline excretion. Bone mineral content decreased. The bone biopsies displayed an increase in bone formation and resorption surfaces in response to treatment, but these changes were not statistically significant. It may be concluded that under the conditions of this study, GH administration did not result in an increment in skeletal mass. Several side effects that are characteristic of acromegaly were observed, including hyperglycemia, hypertension, arthralgia, and the carpal tunnel syndrome. Because of the lack of demonstrated benefit and the associated complications of therapy, GH administration does not appear to be of value in the treatment of osteoporosis.
Bone and Bones↗
Paget's disease: New treatment for an old disease.
There are probably 2.5 million patients with Paget's disease in the U.S.; 125,000 of these have severe disease meriting specific treatment. While the diagnosis can often be made by inspection, or by measurement of the temperature of involved limbs, it is often missed. Nonspecific findings include pain, headaches, deafness, heart failure, neurologic deficits and renal stones. A specific diagnosis can usually be established by radiologic examination of the skeleton and measurement of the serum alkaline phosphatase level. Bone scans are often helpful. In moderate-to-severe symptomatic disease, calcitonin limits the unregulated chaotic bone resorption and exerts highly specific and effective suppressive activity.
Calcitonin↗