Calcitriol or calcium for postmenopausal osteoporosis.
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Calcitriol↗
Biomedical subjects
R M Neer
Publications and source records attributed to R M Neer.
Osteopenia in men with a history of delayed puberty.
BACKGROUND AND METHODS: The effect of delayed puberty on peak bone mineral density in men is unknown. To determine whether such a delay reduces normal peak bone density and leads to osteopenia during adulthood, we measured radial bone mineral density by single-photon absorptiometry and spinal bone mineral density by dual-energy x-ray absorptiometry in 23 men who had a history of constitutionally delayed puberty and 21 men who underwent normal puberty. Their mean ages were 26 and 24 years, respectively. The groups were matched for other factors known to affect bone mass. RESULTS: The mean (+/- SD) radial bone mineral density was significantly lower in the men with a history of delayed puberty than in the normal men (0.73 +/- 0.07 vs. 0.80 +/- 0.05 g per square centimeter; P less than 0.0002). Spinal bone mineral density was also significantly lower in the men with delayed puberty than in the normal men (1.03 +/- 0.10 vs. 1.13 +/- 0.11 g per square centimeter; P less than 0.003). Radial bone density was at least 1 SD below the mean value for the normal men in 15 of the 23 men with a history of delayed puberty, and spinal bone density was similarly decreased in 10 of the 23. CONCLUSIONS: Adult men with a history of constitutionally delayed puberty have decreased radial and spinal bone mineral density. These findings suggest that the timing of puberty is an important determinant of peak bone density in men. Because the peak bone mineral density achieved during young adulthood is a major determinant of bone density in later life, men in whom puberty was delayed may be at increased risk for osteoporotic fractures when they are older.
Absorptiometry, Photon↗
Intermittent administration of bovine PTH-(1-34) increases serum 1,25-dihydroxyvitamin D concentrations and spinal bone density in senile (23 month) rats.
We examined the effect of intermittent administration of bovine parathyroid hormone (1-34) (bPTH) on spinal bone mineral content (BMC) and bone mineral density (BMD), serum 1,25-dihydroxyvitamin D concentrations, and serum markers of osteoblast function in senile male and female rats (23 and 24 months of age, respectively). Sexually mature young (3 month) male rats were similarly treated for comparison. bPTH administration increased serum osteocalcin concentrations without changing serum inorganic phosphate or calcium concentrations in either group of old animals. In young animals, PTH administration increased the serum calcium and inorganic phosphate concentrations significantly (p less than 0.05), although values remained within the normal range. In the vehicle-treated male rats, serum 1,25-dihydroxyvitamin D concentrations were lower in the senile than in the young animals (18 +/- 5 versus 47 +/- 6 pg/ml, p less than 0.05). PTH administration resulted in significantly increased serum 1,25-dihydroxyvitamin D concentrations in the senile and young male animals (both, p less than 0.05) and the final mean serum 1,25-dihydroxyvitamin D concentrations were not statistically different (68 +/- 9 versus 85 +/- 6 pg/ml respectively; p = NS). Serum 1,25-dihydroxyvitamin D concentrations were significantly (p less than 0.05) higher in the PTH-treated senile female rats than the sex-matched, vehicle-treated controls. The pretreatment spinal BMC and BMD as assessed by dual-energy x-ray absorptiometry (DEXA) were significantly higher in the senile male animals than in the young animals. Spinal BMC and BMD decreased in the vehicle-treated senile male rats (p less than 0.05) over the 3 weeks of the study despite a gain in weight.(ABSTRACT TRUNCATED AT 250 WORDS)
Aging↗
The utility of single-photon absorptiometry and dual-energy x-ray absorptiometry.
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Absorptiometry, Photon↗
The clinical course of osteoporosis in anorexia nervosa. A longitudinal study of cortical bone mass.
Women with anorexia nervosa have reduced bone mass and may develop fractures. Neither the pathophysiology of this osteoporosis nor its natural history is known. To study the clinical course of osteoporosis, we followed up 27 women with anorexia nervosa for a median of 25 months (range, 9 to 53 months). At study entry, cortical bone density, measured by single-photon absorptiometry of the radial shaft, was low (mean +/- SD, 0.63 +/- 0.07 g/cm2) and inversely related to the duration of amenorrhea (r = -0.49). During follow-up, most patients gained weight (n = 19), took calcium supplements (n = 16), and exercised regularly (n = 22), but fewer than half reached 80% or more of ideal body weight (n = 11), resumed menses (n = 6), or received estrogen (n = 4). Cortical bone density was stable during follow-up for the group as a whole; the mean annual change (+/- SD) was +0.005 (+/- .015) g/cm2 (95% confidence interval, -0.0009 to +0.0109). There was no significant difference in the mean change in bone density between women who attained 80% of ideal weight and those who did not or between groups who did or did not regain menses, take estrogen or calcium, or exercise vigorously. Four fractures were clinically observed in three women during follow-up. The rate of 0.05 nonspine fractures per person-year (95% confidence interval, 0.02 to 0.13) exceeds that of normal women in this age range (relative risk, 7.1; 95% confidence interval, 3.2 to 18.5). We conclude that reductions in cortical bone density appear not to be rapidly reversed by recovery from anorexia nervosa and that anorectic women may have an increased risk of fracture.
Adult↗
Pamidronate reduces PTH-mediated bone loss in a gene transfer model of hyperparathyroidism in rats.
We evaluated spinal and femoral bone mass and density utilizing dual-energy x-ray absorptiometry (DEXA) in rats in which severe hyperparathyroidism was produced by the expression of the gene for human PTH-(1-84) (hPTH). This gene was incorporated into a retroviral vector that was transfected into fibroblasts which were subsequently injected into their peritoneal cavities. Further, we examined the effect of the administration of pamidronate on bone mass and density in the presence of extremely high concentrations of hPTH. Three groups of rats were studied. Groups 1 and 2 receive the hPTH-secreting fibroblasts; group 2 subsequently received pamidronate (2.5 mg/kg IV) 18 and 27 days after receiving the fibroblasts. These animals developed levels of hPTH greater than 1.0 microgram/liter and became hypercalcemia within 20 days. These animals became lethargic and were significantly lower in weight than age-matched controls (group 3, p less than 0.05). After accounting for the animal weight there was a further significant decrease in bone mineral content and density (BMC and BMD) on day 29 attributable to hPTH-mediated bone loss. Treatment with pamidronate resulted in a higher BMC of the lumbar spine than in the untreated animals, with elevated concentrations of hPTH. The BMD was significantly higher at both the lumbar spine and femur in the pamidronate-treated animals (p less than 0.05). The CV of paired measurements of BMD was 2.7% at the spine and 1.5% of a femur, respectively. The BMC of the lumbar spine and femur was closely correlated with the ashed weight of the same bones (r = 0.92 and 0.85, respectively).
Absorptiometry, Photon↗
Asymptomatic primary hyperparathyroidism.
Of 118 consecutive white patients referred for asymptomatic primary hyperparathyroidism, the diagnosis was clinically confirmed in 100, of whom 85 adults had a serum calcium less than 3.0 mM (12 mg/dl) and no skeletal, rheumatic, or significant neuropsychiatric symptoms, azotemia, or other significant illnesses. Among these 85, 68 had both asymptomatic and medically uncomplicated hyperparathyroidism, whereas 17 had historical, radiographic, or ultrasonic evidence of renal stone disease. The 20% with past or present renal calculi concentrated their urine significantly better than the 68 others (p = 0.05), but these two groups were otherwise not distinguished by the tests we performed, so all 85 patients were analyzed together. Systolic and diastolic blood pressures were normal, but premature osteopenia and/or impaired renal function were present in 29-36% of the patients. Micrometer measurements of metacarpal radiographs and 125I photon absorptiometry at the shaft of the radius revealed cortical osteopenia. Osteopenia was equally significant in the distal radius (cortical plus trabecular bone). These quantitative measurements were superior to routine bone radiography, and ROC analysis showed that 125I absorptiometry at either site was superior (p less than 0.01) to metacarpal cortex measurements for detecting premature osteopenia, which was present in more than a third of these patients. Creatinine clearances (24 h) and maximum urine concentrating capacity (overnight dehydration plus the synthetic vasopressin analog DDAVP) were each significantly reduced, despite all patients' normal BUN and serum creatinine levels. Sequential performance of a 24 h creatinine clearance and a urine concentration test revealed abnormalities in the renal function of 27 of 74 patients (36%), with a specificity of 95% and a higher sensitivity than either test alone (27-29%).(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗
Parathyroid function in normocalcemic renal transplant recipients: evaluation by calcium infusion.
The extent to which secondary hyperparathyroidism may involute remains poorly defined. Renal transplantation offers a clinical situation in which metabolic stimuli for hyperparathyroidism are removed. To examine whether hyperparathyroidism resolves after transplantation, we evaluated 11 renal transplant recipients who had been normocalcemic 6 or more months after transplantation using a sensitive 2-site immunoradiometric assay for intact serum PTH. Nine of the 11 had PTH concentrations within the normal range. Of these 9, 6 were found to have abnormal parathyroid function when challenged with an iv calcium infusion. The other 2 patients demonstrated significantly elevated basal PTH concentrations and elevated ionized calcium despite normal total serum calcium and albumin concentrations. In both, the PTH response to infused calcium was markedly abnormal, confirming hyperparathyroidism. The estimated renal threshold phosphate concentration was low in 4 of 9 patients with normal basal PTH concentrations and in both with elevated basal PTH. Bone mineral density, measured at the radius by single photon absorptiometry and at the spine by dual energy x-ray absorptiometry, was normal in 8 of the 9 transplant recipients who had normal basal PTH concentrations.
Adult↗
Lack of evidence for estrogen receptors in human and bovine parathyroid tissue.
It has been hypothesized that estrogen may have a direct effect to reduce the set-point for PTH secretion which may be implicated in its hypocalcemic action. If this is so, estrogen receptors should be demonstrable within parathyroid tissue. Seven human parathyroid adenomas and five samples of normal bovine parathyroid tissue were examined using classical hormone-binding techniques. In no case was there evidence of displaceable estrogen binding of high affinity and low capacity. To exclude the presence of receptors within a small subset of the cells, five of the human adenomas were further studied by immunohistochemistry using a monoclonal antibody to the human estrogen receptor. In no case was there evidence of estrogen receptors. We conclude that the hypocalcemic action of estrogen replacement is unlikely to be mediated via a classical estrogen receptor within the parathyroid, although normal parathyroid tissue was not studied.
Adenoma↗
Effect of season on activity and bone mineral density.
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Absorptiometry, Photon↗
Effects of transdermal estrogen replacement on parathyroid hormone secretion.
The effect of transdermal 17 beta-estradiol replacement on ionized calcium and PTH levels was examined in 15 postmenopausal women. After baseline studies in the fasting state, the effect of a calcium infusion on PTH levels was studied. Estrogen replacement resulted in a fall in fasting resting ionized calcium and a rise in PTH levels. After calcium infusion there was no change in the shape of the relationship between plasma calcium and PTH. The level of nonsuppressible PTH secretion was not altered. Transdermal estrogen did not alter basal vitamin D-binding protein levels, 25-hydroxyvitamin D levels, or calcitriol levels. We conclude that the effect of transdermal estrogen replacement on PTH secretion is completely explained by the lowering of ionized calcium, causing a rise in PTH secretion. Thus, with this route of estrogen replacement, there is no necessity to postulate a direct effect of 17 beta-estradiol on the parathyroid gland.
Administration, Cutaneous↗
Age and bone mass in premenopausal women.
It is important to determine the bone mass in normal premenopausal women because increasing numbers of conditions have been identified that result in premenopausal osteoporosis. The relationship between age and bone density was evaluated in 57 carefully characterized normal, premenopausal women using both single energy quantitative computed tomography (SEQCT) and dual energy (DEQCT). The mean bone density measurements were 172 mg/ml K2HPO4 SEQCT and 185 DEQCT. Bone density showed no statistically significant decline between age 18 and age 44. Single- and dual-energy data were highly correlated with each other (r = 0.89), and dual energy appeared to confer no advantage. There was an inverse relation between density and age of menarche. Bone density did not correlate with ideal body weight, percentage fat, or subcutaneous fat area.
Adolescent↗
Calibration and standardization of bone mineral densitometers.
Measurements of bone mineral density (BMD) by four 153Gd and two x-ray bone densitometers were compared utilizing spine phantoms that simulated the human lumbar spine. The six instruments provided BMD values that differed by as much as 16%, due to differences as large as 8% in bone mineral content and as large as 7% in bone area. Instrument calibration curves, determined by measuring thin, medium, and thick hydroxyapatite blocks, were linear (r = 0.99) but had different (p less than 0.0001) slopes and intercepts. Serial measurements of spine and total body phantoms were employed to evaluate the long-term stability of 153Gd bone densitometry. These measurements of spine phantom BMD increased 1.0-2.6% (p less than 0.0001) following a software change, and measurements of total body bone density increased 4-6% after 153Gd source replacement. The changes occurred at a time when serial measurements of cylindrical calibration standards were stable, indicating that such simple standards are unable to detect and correct for changes in instrumental response. We conclude that investigators, manufacturers, and government regulatory agencies must develop and implement the following: (1) effective calibration procedures that would assure comparability among instruments, and (2) appropriate quality control phantoms that would allow the confident interpretation of serial patient measurements.
Analysis of Variance↗
Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism.
To assess the effects of gonadal steroid replacement on bone density in men with osteoporosis due to severe hypogonadism, we measured cortical bone density in the distal radius by 125I photon absorptiometry and trabecular bone density in the lumbar spine by quantitative computed tomography in 21 men with isolated GnRH deficiency while serum testosterone levels were maintained in the normal adult male range for 12-31 months (mean +/- SE, 23.7 +/- 1.1). In men who initially had fused epiphyses (n = 15), cortical bone density increased from 0.71 +/- 0.02 to 0.74 +/- 0.01 g/cm2 (P less than 0.01), while trabecular bone density did not change (116 +/- 9 compared with 119 +/- 7 mg/cm3). In men who initially had open epiphyses (n = 6), cortical bone density increased from 0.62 +/- 0.01 to 0.70 +/- 0.03 g/cm2 (P less than 0.01), while trabecular bone density increased from 96 +/- 13 to 109 +/- 12 mg/cm3 (P less than 0.01). Cortical bone density increased 0.03 +/- 0.01 g/cm2 in men with fused epiphyses and 0.08 +/- 0.02 g/cm2 in men with open epiphyses (P less than 0.05). Despite these increases, neither cortical nor trabecular bone density returned to normal levels. Histomorphometric analyses of iliac crest bone biopsies demonstrated that most of the men had low turnover osteoporosis, although some men had normal to high turnover osteoporosis. We conclude that bone density increases during gonadal steroid replacement of GnRH-deficient men, particularly in men who are skeletally immature.
Adult↗
Changes in serum levels of type I and III procollagen extension peptides during infusion of human parathyroid hormone fragment (1-34).
Parathyroid hormone (PTH) inhibits collagen synthesis in vitro, in organ or cell culture and cell-free translation systems. We have designed studies to measure the effects of PTH on collagen synthesis in vivo in humans, utilizing measurements of the serum levels of procollagen extension peptides during and after infusion of synthetic human PTH (hPTH) fragment (1-34). Radioimmunoassays for the carboxy-terminal peptide of type I procollagen (pColl-C) and the amino-terminal peptide of type III procollagen (pColl-III-N) were used to measure acute changes in serum during and after hPTH(1-34). In all six osteoporotic subjects and two normal individuals, serum levels of pColl-I-C were decreased by 16 hr of infusion and returned towards normal 14 hr after the infusion was discontinued; serum levels of pColl-III-N did not change significantly during the infusion, but were increased at 14 hr after the infusion was discontinued. The PTH-induced decrease in levels of pColl-I-C correlated with an increase in blood levels of ionized calcium. In all but two subjects the serum levels of 1,25-dihydroxy vitamin D [1,25(OH)2D] were also increased during the period when serum levels of pColl-I-C were decreased. These results are compatible with the conclusion that infusion of PTH acutely inhibits type I (bone) collagen synthesis, but not type III collagen synthesis. These effects could be direct or indirect, related in part to PTH-induced increased 1-alpha-hydroxylation of 25-(OH) vitamin D and the resultant increased serum levels of 1,25(OH)2D.
Adult↗
Quantitative digital radiography versus dual photon absorptiometry of the lumbar spine.
Lumbar spine bone mineral density (BMD) was measured by quantitative digital radiography, a new dual energy x-ray technique, and by 153Gd dual photon absorptiometry (DPA) in 85 patients. Each patient was measured twice by the new method and once by DPA on the same day, with repositioning between measurements. Serial measurements were made on an hydroxyapatite spine phantom embedded in tissue-equivalent plastic to evaluate the long term reproducibility of each instrument. The spinal BMD measurements with the 2 techniques were linearly related and highly correlated (r = 0.98) over a range from severely osteopenic to high normal. This correlation was not affected by the age, weight, or BMD of the patient measured. Quantitative digital radiography's long-term reproducibility using the spine phantom was stable for 180 days (coefficient of variation, 0.23%); DPA values were 3 times as variable for 170 days (coefficient of variation 0.73%) and increased 1.0% (P less than 0.0001) after a software change. The short term reproducibility of quantitative digital radiography, estimated from paired patient measurements, was 2-fold better than reported values for DPA and was independent of the patient's age, weight, or BMD. Measurement time by quantitative digital radiography was 5-8 min, with a maximum radiation exposure of 3 mrem, significantly lower than the corresponding DPA values. Quantitative digital radiography's image resolution was superior to that of DPA, enabling it to measure more bones. These advantages along with the elimination of 153Gd source changes and Nuclear Regulatory Commission licensing requirements indicate that quantitative digital radiography is the superior method for spinal BMD measurements.
Adult↗
Monoclonal antibodies to bovine parathyroid hormone: production and characterization.
1. This paper describes the production and characterization of monoclonal antibodies against bovine parathyroid hormone (bPTH)-(1-84). 2. Spleen cells from A/J mice successfully immunized with bPTH-(1-84) were fused with SP2/O myeloma cells using PEG 4000 as fusogen. The screening method employed microtiter plates coated with sheep antimouse IgG and the presence of specific monoclonal antibodies was demonstrated by the binding of 125I-bPTH-(1-84). 3. A detailed study of the specificity of the three viable monoclonals with highest affinity showed that two (6FH6 and 6CD4) were amino-terminal specific and the other (5BG9) carboxyl-terminal specific. The two amino-terminal monoclonal antibodies appear to recognize the same antigenic site. 4. The monoclonal antibodies produced are potentially useful reagents for the development of new methods for the measurement of PTH in biological fluids, studies on the interaction of PTH with its receptor, as well as localization of PTH producing cells.
Animals↗
Subclinical hyperthyroidism and reduced bone density as a possible result of prolonged suppression of the pituitary-thyroid axis with L-thyroxine.
Spontaneous hyperthyroidism and that due to excessive administration of thyroid hormone result in osteopenia. Bone density was measured in 28 white premenopausal female patients who were taking commonly prescribed suppressive doses of L-thyroxine (mean dose 0.171 +/- 0.035 g) for five or more years. The thyroxine level was 13.5 +/- 2.6 micrograms/dl (normal 8.0 +/- 2.4 micrograms/dl), the free thyroxine index was 4.4 +/- 1.0 (normal 2.4 +/- 0.8), and the triiodothyronine value was 154 +/- 26 ng/dl (normal 132 +/- 32 ng/dl). Basal thyrotropin was undetectable (less than 0.08 microIU/ml) in 23 patients, and thyrotropin measured 20 minutes after thyrotropin-releasing hormone administration was not demonstrable in 13 patients and subnormal in 10 patients. Women who had taken L-thyroxine for 10 or more years (n = 12, age 37 +/- 4 years) had a 9 percent reduction in bone density (0.667 +/- 0.044 g/cm2, p less than 0.01) compared with normal premenopausal age-matched control subjects (n = 56, age 35 +/- 6 years, bone density 0.733 +/- 0.055 g/cm2). It is concluded that prolonged suppressive L-thyroxine treatment may result in mild subclinical hyperthyroidism with adverse effects on bone. Patients requiring suppression of the pituitary-thyroid axis should be given the smallest dose of L-thyroxine necessary to achieve a satisfactory clinical response.
Adult↗