Search PubMed⌕ Search

Biomedical subjects

R M Neer

Publications and source records attributed to R M Neer.

At least 55 records · Page 3Linked to original sources
PubMed1986

Inhibition of the in vivo parathyroid hormone-mediated calcemic response in rats by a synthetic hormone antagonist.

The parathyroid hormone (PTH) analog, [Tyr34]bovine PTH-(7-34)-amide, can inhibit the PTH-mediated elevation of plasma calcium in thyroparathyroidectomized rats in vivo. The analog is devoid of PTH-like agonist activity in this system. Repeated doses of analog inhibit the animal's calcemic response to PTH. The elevation in serum calcium levels mediated by PTH in this assay reflects PTH action (calcium mobilization) on bone. Earlier studies demonstrated antagonist properties of the analog in a renal-based assay; PTH-stimulated increases in urinary phosphate and cyclic AMP excretion were completely inhibited by the synthetic analog. Along with previous studies, this report indicates that [Tyr34]bovine PTH-(7-34)-amide is an effective in vivo antagonist for several major parameters of PTH action in both kidney and bone.

Animals↗
PubMed1986

Osteoporosis in men with hyperprolactinemic hypogonadism.

To ascertain the effects of chronic hyperprolactinemia and testosterone deficiency on skeletal integrity in men, we measured forearm bone density and hormone concentrations in 18 men aged 30 to 79 who had prolactin-secreting pituitary tumors. We also measured vertebral bone density in 12 of the men. Patients with hyperprolactinemia had significant decreases in both forearm (p less than 0.001) and vertebral bone density (p = 0.003) compared with age-matched controls. Cortical osteopenia was significantly related to the duration of hyperprolactinemia (p less than 0.01) but not to the absolute levels of prolactin or androgens. Seven patients had longitudinal follow-up measurements of forearm bone density. Normalization of serum levels of prolactin or testosterone was associated with an increase in forearm bone density (p less than 0.05). These data show that chronic hyperprolactinemia and testosterone deficiency in men have deleterious and previously unrecognized extragonadal effects that may be alleviated after normalization of hormone concentrations.

Adenoma↗
PubMed1984

Osteoporosis in women with anorexia nervosa.

Because estrogen deficiency predisposes to osteoporosis, we assessed the skeletal mass of women with anorexia nervosa, using direct photon absorptiometry to measure radial bone density in 18 anorectic women and 28 normal controls. The patients with anorexia had significantly reduced mean bone density as compared with the controls (0.64 +/- 0.06 vs. 0.72 +/- 0.04 g per square centimeter, P less than 0.001). Vertebral compression fractures developed in two patients, and bone biopsy in one of them demonstrated osteoporosis. Bone density in the patients was not related to the estradiol level (r = 0.02). Levels of parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D were normal despite low calcium intakes. The patients with anorexia who reported a high physical activity level had a greater bone density than the patients who were less active (P less than 0.001); this difference could not be accounted for by differences in age, relative weight, duration of illness, or serum estradiol levels. The bone density of physically active patients did not differ from that of active or sedentary controls. We conclude that women with anorexia nervosa have a reduced bone mass due to osteoporosis, but that a high level of physical activity may protect their skeletons.

Adult↗
PubMed1984

Impaired osteoblast function in osteoporosis: comparison between calcium balance and dynamic histomorphometry.

Osteoblast function was investigated in 27 patients with idiopathic osteoporosis. Transiliac bone biopsy specimens were taken after double labelling with tetracycline, and metabolic calcium balance was studied almost simultaneously. Many of the patients showed poor double labelling of their otherwise unremarkable trabecular osteoid, suggesting impaired formation of bone at many of these surfaces. This phenomenon was not accompanied by increased width of osteoid seams (as seen in osteomalacia), indicating that formation of the matrix and its mineralisation were in equilibrium. For the first time, highly significant positive correlations (p less than 0.01) were found between indices of bone formation, determined by labelling with tetracycline, and calcium balance. Thus some patients with osteoporosis who are rapidly losing bone have low rates of formation of trabecular bone both by individual osteoblasts and in relation to available bone surfaces. As histological indices of bone resorption also independently correlated strongly and inversely (p less than 0.01) with calcium balance the rate of initiation of new basic multicellular units by osteoclastic resorption of trabecular surfaces (or the depth of resorption at these surfaces) also appears to be an important determinant of mineral balance. The mechanisms that regulate the effective life span of mature osteoblasts require further investigation, particularly as some promising treatments that can increase trabecular bone volume in osteoporosis, such as parathyroid peptide hPTH (1-34) and sodium fluoride, must work through a reversal of osteoblastic depression.

Aged↗
PubMed1984

Renal 1,25-dihydroxyvitamin D, phosphaturic, and cyclic-AMP responses to intravenous synthetic human parathyroid hormone-(1-34) administration in normal subjects.

The exogenous administration of bovine parathyroid hormone or parathyroid extract has been used to differentiate states of parathyroid hormone resistance and parathyroid gland secretory failure, and in recent years to test renal 1,25-dihydroxyvitamin D (1,25-(OH)2-D) secretion. We evaluated the effect of synthetic human parathyroid hormone (hPTH-(1-34] administration on the renal 1,25-(OH)2-D, phosphaturic and cyclic-AMP responses in eleven normal young adults. The intravenous administration of 200 units of hPTH-(1-34) over 10 min produced a 1.3-5.4 fold increase (P less than 0.01) in renal phosphate clearance and a 19-75 fold increase (P less than 0.0001) in urinary cyclic-AMP excretion. Serum 1,25-(OH)2-D levels showed a small and insignificant change at 2.5 h and a significant (P less than 0.05) but small (21 +/- 24 pmol/l) increase at 7 h after the first injection. In eight subjects a second injection of hPTH-(1-34) was given at 7 h. In these individuals serum 1,25-(OH)2-D levels at 24 h were 40 +/- 14 pmol/l (44%) higher than baseline (P less than 0.01), but were variable over the 24 h period. The present study shows that hPTH-(1-34) produces renal phosphaturic and cyclic-AMP responses in normals similar to those produced by bovine PTH preparations. However, the serum 1,25-(OH)2-D response to one or two intravenous injections of hPTH-(1-34) is small, variable, and inconsistent and, therefore, will not provide a consistent way of stimulating renal 1,25-(OH)2-D secretion.

Adult↗
PubMed1984

Clinical evaluation of bone turnover by serum osteocalcin measurements in a hospital setting.

Serum levels of osteocalcin, the major noncollagenous bone protein, are elevated in patients with certain metabolic bone diseases, but the effects of other illnesses on serum osteocalcin levels are not known. We measured serum osteocalcin concentrations in 250 patients in a rehabilitation hospital who suffered from various illnesses. Mean serum osteocalcin levels were elevated in patients with 1) recent hip fracture who required open reduction and pin insertion (mean +/- SE, 19.0 +/- 3.2 ng/ml), 2) primary (22.0 +/- 4.9 ng/ml) or secondary hyperparathyroidism (51.6 +/- 9.9 ng/ml), 3) Paget's disease of bone (22.7 +/- 6.1 ng/ml), or 4) metastatic skeletal disease who had not received therapy (37.5 +/- 11.3). Mean serum osteocalcin levels were normal in patients who had received 1) a hip prosthesis for a recent fracture or for severe degenerative joint disease of the hip (6.4 +/- 0.9 ng/ml), 2) recent chemotherapy or irradiation for bone metastases (6.1 +/- 1.3 ng/ml), or 3) a variety of medical problems not related to bone disease (5.2 +/- 0.3 ng/ml). Serum osteocalcin and alkaline phosphatase values did not correlate. This study demonstrates that serum osteocalcin levels are normal in disorders not involving bone, can be used in a general-hospital setting, where concomitant illnesses are present, and may provide additional information for the clinical evaluation of metabolic bone disease.

Adult↗
PubMed1984

Father to son transmission of decreased Ns activity in pseudohypoparathyroidism type Ia.

We found both renal resistance to endogenous and exogenous PTH and reduced activity of the stimulatory guanine nucleotide-binding regulatory protein (Ns) of adenylate cyclase in a man with clinical signs of pseudohypoparathyroidism type Ia (PHP-Ia). Both of his children also had reduced Ns levels and short stature. The girl, 11 yr old, had evidence of partial resistance to PTH, while the son, age 7 yr, had no apparent abnormalities in calcium metabolism or response to administered PTH. Variable expression of the metabolic abnormalities of PHP during childhood has been previously described. The occurrence of reduced Ns activity in father and son is consistent with autosomal dominant inheritance for the primary biochemical defect of PHP-Ia in this family.

Adult↗
PubMed1982

Gut-mediated hypercalcemia in rabbits bearing VX2 carcinoma: new mechanism for tumor-induced hypercalcemia.

The VX2 carcinoma-bearing rabbit is an animal model for tumor-induced hypercalcemia, thought to be due to increased bone destruction effected by prostaglandin E2. The present experiments suggest that the pathophysiology of the hypercalcemia differs from that previously proposed. Tumor was transplanted intramuscularly into 2.5- to 3-kg male New Zealand White rabbits, which were conditioned to a 1.5% calcium diet and treated with daily subcutaneous injections of dichloromethane diphosphonate (10 mg . kg-1 . day-1), a potent inhibitor of bone resorption, or 0.9% NaCl (2 ml . kg-1 . day -1). The diphosphonate had no significant effect on plasma Ca2+ in either group. After day 31, half the animals of each group were fed a calcium-free diet. This normalized the plasma Ca2+ in each VX2-bearing rabbit within 3 to 4 days but had little effect in control rabbits. In a second series of experiments, VX2-bearing rabbits maintained on standard rabbit chow were treated for 11 days with parenteral indomethacin (30--60 mg/day) or 0.9% NaCl. Although indomethacin normalized the markedly elevated urinary excretion of prostaglandin E2, both treatment groups became severely hypercalcemic. Dietary calcium restriction promptly restored to normal the plasma Ca2+ concentration. In a third series of experiments, rabbits were fed standard rabbit chow and treated with oral indomethacin (40 mg/day) while control-rabbits were pair fed in identical chow. Transplantation of VX2 tumor into both groups caused hypercalcemia. We conclude that the hypercalcemia produced by this tumor strain is indomethacin resistant and dependent on an increase in gastrointestinal calcium absorption, not on skeletal calcium mobilization.

Animals↗
PubMed1982

Secondary hyperparathyroidism associated with dichloromethane diphosphonate treatment of Paget's disease.

Six patients with extensive polyostotic Paget's disease were treated for 3 months with dichloromethane diphosphonate (CL2MDP; 1600 mg/day, orally). Serum alkaline phosphatase and urinary hydroxyproline excretion decreased 60-80% in each patient. Blood ionized calcium (ca++) and immunoreactive PTH (iPTH) were measured weekly during the first month of therapy and monthly thereafter. As an index of parathyroid function, PTH secretory reserve was assessed by EDTA infusions before treatment, at the end of treatment, and 3 months after Cl2 MDP therapy was stopped. Before therapy, iPTH and Ca++ were normal in all patients. During treatment, Ca++ decreased and iPTH increased in all patients; mean iPTH approximately doubled (95% confidence limits, 1.5- to 2.7-fold increase). At the end of 3 months of treatment, EDTA infusion raised iPTH in each patient to a level higher than that in the control infusion, indicating augmented PTH secretory reserve. Ca++, iPTH, and the iPTH response to EDTA-induced hypocalcemia returned toward baseline by 3 months after the end of CL2MDP treatment. The results indicate that secondary hyperparathyroidism developed as a result of Cl2MDP therapy. The cause of the parathyroid-gland adaptation is not known; the hyperparathyroidism is, however, at least partly reversible. Cl2MDP inhibits bone resorption while allowing bone mineralization to continue; this differential effect could lead to the hypocalcemia and parathyroid hyperfunction.

Aged↗
PubMed1982

Osteoporosis in primary biliary cirrhosis: effects of 25-hydroxyvitamin D3 treatment.

Bone histology, bone mineral content, and calcium absorption were evaluated in 10 patients with primary biliary cirrhosis and osteopenia, before and after 1 yr of treatment with oral 25-hydroxycholecalciferol. Before treatment, quantitative histomorphometric analysis of full-thickness iliac crest bone biopsy specimens with double-tetracycline labeling demonstrated that 9 of 10 patients had osteoporosis. None had osteomalacia. Fasting intestinal calcium absorption correlated well with trabecular bone volume (r = 0.85). Bone mineral content measured by 125I-photon absorption was low in 6 of 10 patients, and it correlated poorly with iliac crest trabecular bone volume. After 1 yr of treatment with oral 25-hydroxyvitamin D3, bone mineral content fell in all 8 patients who were restudied. Iliac crest trabecular bone volume increased in 3 patients, 2 of whom had the greatest pretreatment impairment in calcium absorption, but fell in 5. Bone fractures continued to occur in 3 of 5 patients who were alive after 1 yr and developed for the first time in a sixth patient. We conclude that 25-hydroxyvitamin D3 is ineffective in reversing the bone thinning in the majority of primary biliary cirrhosis patients, but it may be helpful in a few selected patients.

Adult↗
PubMed1981

Deficient production of 1,25-dihydroxyvitamin D in elderly osteoporotic patients.

There is uncertainty about the adequacy of renal secretion of 1,25-dihydroxyvitamin D(1,25-(OH)2-D) in elderly patients with osteoporosis. To investigate this uncertainty, we stimulated secretion of 1,25-(OH)2-D with a 24-hour intravenous infusion of synthetic human parathyroid hormone fragment 1-34 and compared the results in normal young adults and elderly patients with untreated osteoporosis. Serum levels of 1,25-(OH)2-D were similar in both groups (49 +/- 10 and 42 +/- 9 pg per milliliter [116 +/- 24 and 99 +/- 21 pmol per liter]) before the infusion. However, during the 24-hour infusion, serum levels nearly doubled (P less than 0.01) in the normal volunteers but did not change significantly in the patients. Serum ionized calcium increased and serum inorganic phosphate decreased similarly in both groups during the infusion (P less than 0.05). Although the present study does not establish whether deficient 1,25-(OH)2-D secretory reserve is an effect of age or of osteoporosis, it is possible that such a deficiency will explain the inability of elderly osteoporotic patients to adapt to the low-calcium diets common in this age group. If so, this phenomenon may play a part in the pathogenesis of age-related osteoporosis.

Age Factors↗
PubMed1981

Short-term effects of synthetic human parathyroid hormone-(1--34) administration on bone mineral metabolism in osteoporotic patients.

Since studies in animals and humans have shown that parathyroid hormone can stimulate bone formation and increase trabecular bone, and patients with primary and secondary hyperparathyroidism may exhibit osteosclerosis, we evaluated the effect of short-term administration of human parathyroid hormone, hPTH-(1--34), in patients with osteoporosis. Six patients with osteoporosis underwent detailed studies including blood and urinary measurements of calcium, phosphate, and magnesium; 47Ca kinetic studies; and 18-d balance studies before and during the short-term administration (3--4 wk) of a daily subcutaneous injection of hPTH fragment 1--34 given as 450 or 750 U/dose. The mean fasting plasma calcium values rose slightly after hPTH-(1--34) administration, primarily in the high-dose group. There was no difference in the mean fasting plasma inorganic phosphate levels. The mean daily urinary excretion of calcium and phosphate was significantly increased in patients given the higher dose. In patients given 750 U, net intestinal calcium absorption increased, phosphate absorption increased, calcium balance improved, and phosphate balance improved. In patients given 450 U, calcium balance and phosphate balance worsened. 47Ca kinetic studies showed a minimal increase in bone accretion rate, a decrease in the mean transit time of calcium in the exchangeable pools, and a decrease in the exchangeable-pool size. In all six patients there was an increased renal clearance of 47Ca as a result of hPTH-(1--34) administration. These studies indicate that low doses of parathyroid hormone may promote bone formation, whereas higher doses clearly have an adverse effect on the skeleton.

Aged↗
PubMed1981

Effect of 25-hydroxyvitamin D3 on vitamin D metabolites in primary biliary cirrhosis.

The osteopenic bone disease associated with primary biliary cirrhosis is thought to be de to a deficiency in vitamin D or its metabolites. However, this has never been proven. Therefore, we measured serum levels of 25-hydroxyvitamin D3 (25-OHD3), 1,25-dihydroxyvitamin D (1,25(OD)2D), and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3), before and after a 1 yr treatment with oral 25,OHD3, in 10 patients with primary biliary cirrhosis selected because of documented osteopenic bone disease. Only in 1 patient was the pretreatment serum 25-OHD3 level below normal, less than 4.4 ng/ml. In 8 patients the serum 25,OHD3 level was in the low normal range and in one, was above normal. Serum levels of 1,25(OH)2D, the vitamin D metabolite with the greatest stimulatory effect on intestinal calcium absorption, were normal in 9 patients and elevated in 1. In contrast, serum levels of 24,25-(OH)2D3, a metabolite whose function is not known with certainty, were undetectable in 8 patients, low normal in a ninth, and normal in 1 patient who had been on large amounts of vitamin D2 (50,000 U b.i.w.,) before the start of the study. After 1 yr of treatment with oral 25-OHD3, serum 25-OHD3 rose to above normal in 9 patients. Serum 1,25-(OH)2D levels did not change significantly, while 24,25-(OH)2D3 rose to normal levels or higher in 9 of 10 patients. The bone disease of primary biliary cirrhosis is not due to 25-hydroxyvitamin D deficiency alone and is certainly not due to a deficiency of 1,25-(OH)2D as has been postulated. It may be related to low blood levels of 24,25-(OH)2D3 or to other as yet undefined factors.

24,25-Dihydroxyvitamin D 3↗