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Biomedical subjects

I R Reid

Publications and source records attributed to I R Reid.

At least 55 records · Page 3Linked to original sources
PubMed1999

Bone mineral density in patients with treated Addison's disease.

Some studies have reported low bone mineral density (BMD) in patients with Addison's disease, whereas others have found BMD to be normal. It is possible that over-replacement of corticosteroids and adrenal androgen deficiency may contribute to a reduction in BMD in these patients. The aims of this study were to examine BMD using dual-energy X-ray absorptiometry in patients with treated Addison's disease at multiple skeletal sites and to investigate the relationships between these measurements and corticosteroid dose. Nineteen men, 3 premenopausal and 7 postmenopausal women with Addison's disease were studied and data from these patients were analyzed separately and as a group. The mean SEM age and duration of Addison's disease of the men were 44 +/- 3.8 years and 15 +/- 2.2 years, in the premenopausal women 40 +/- 2 years and 5 +/- 2.4 years, and in the postmenopausal women 68 +/- 4 years and 20 +/- 5 years, respectively. Eight men were unexpectedly hypogonadal (serum testosterone <13 nmol/l). BMD was expressed as a percent of values in normal controls (n = 418) adjusted for age, sex, ethnic origin, menopausal status and body weight. In the whole group (n = 29), mean BMD of the patients with Addison's disease was not different from normal at any site [mean (+/- SEM) lumbar spine 99.5% +/- 2.9%; femoral neck 99.3% +/- 2.5%; Ward's triangle 96.2% +/- 3.5%; trochanter 99.2% +/- 2.9%; radius 99.8% +/- 2.1%; total body 98.5% +/- 1.4%]. However, there was a wide range of bone densities, with some patients having a low BMD at multiple sites. Bone density was negatively correlated with current and cumulative corticosteroid dose per kilogram body weight and duration of Addison's disease. In conclusion, BMD in patients with Addison's disease is little different from normal, but may be lower in patients with disease of long duration and a high cumulative corticosteroid dose. Unexpected hypogonadism in men with Addison's disease is common.

Absorptiometry, Photon↗
PubMed1999

Residential status and risk of hip fracture.

OBJECTIVE: to examine the association between residential status and risk of hip fracture in older people. DESIGN: population-based case-control study. SETTING: Auckland, New Zealand. SUBJECTS: a random sample of all individuals > or = 60 years, hospitalized with a fracture of the proximal femur between July 1991 and February 1994. Controls were age and gender frequency-matched to the cases, randomly selected from a random sample of general practitioners. MAIN OUTCOME MEASURES: radiographically-confirmed fracture of the proximal femur. Fractures sustained as a result of major trauma, such as in a motor vehicle crash, and those associated with pre-existing pathological conditions were excluded. RESULTS: individuals living in institutions were almost four times more likely to sustain a hip fracture [age- and gender-adjusted odds ratio (OR)=3.8; 95% confidence interval (CI): 3.0-4.8] than those living in private homes. After adjustment for potential confounding factors, the risk of hip fracture associated with living in an institution remained significantly increased (P< 0.0001), although the magnitude of the risk was somewhat diminished (OR=2.2; 95% (CI: 1.5-3.5). CONCLUSIONS: living in an institution is associated with an increased risk of hip fracture in older people. Specific factors that place these individuals at increased risk need to be identified, in order to develop intervention strategies.

Aged↗
PubMed1999

Trifluoroacetate, a contaminant in purified proteins, inhibits proliferation of osteoblasts and chondrocytes.

Peptides purified by HPLC are often in the form of a trifluoroacetate (TFA) salt, because trifluoroacetic acid is used as a solvent in reversed-phase HPLC separation. However, the potential effects of this contaminant in culture systems have not been addressed previously. TFA (10(-8) to 10(-7) M) reduced cell numbers and thymidine incorporation into fetal rat osteoblast cultures after 24 h. Similar effects were found in cultures of articular chondrocytes and neonatal mouse calvariae, indicating that the effect is not specific to one cell type or to one species of origin. When the activities of the TFA and hydrochloride salts of amylin, amylin-(1-8), and calcitonin were compared in osteoblasts, cell proliferation was consistently less with the TFA salts of these peptides, resulting in failure to detect a proliferative effect or wrongly attributing an antiproliferative effect. This finding is likely to be relevant to all studies of purified peptides in concentrations above 10(-9) M in whatever cell or tissue type. Such peptides should be converted to a hydrochloride or biologically equivalent salt before assessment of their biological effects is undertaken.

Amyloid↗
PubMed1999

Hormone replacement therapy causes a respiratory alkalosis in normal postmenopausal women.

Menopause is associated with an increase in venous bicarbonate concentrations that is reversible with hormone replacement therapy (HRT). However, the mechanism underlying this effect is not known. To address this question, we studied the changes in acid-base indexes in the arterialized venous blood of normal postmenopausal women commencing conjugated equine estrogen (0.625 mg/day), medroxyprogesterone acetate (MPA; 5 mg/day), their combination, or placebo, in a double blind randomized controlled study over 3 months. Serum bicarbonate concentrations decreased significantly in the groups receiving either MPA or estrogen plus MPA (P = 0.008). This trend was apparent as early as 2 days and reached 2.7 and 2.3 mmol/L in the respective groups by 3 months. Similar changes were seen with partial pressure of carbon dioxide (P = 0.04); a change of -0.7 kPa occurred in the estrogen plus MPA group at 3 months. There were no changes in bicarbonate concentrations or partial pressure of carbon dioxide in those receiving estrogen alone or placebo. Accompanying changes in blood pH were apparent in the estrogen plus MPA group, where there was an upward trend at 1 week (P = 0.056) and a significant change from baseline (+0.013) at 3 months (P = 0.03). In the whole group, the changes in pH were inversely correlated with those in urinary excretion of hydroxyproline (r = -0.44; P = 0.01). We conclude that HRT using conjugated estrogens and MPA produces small, but sustained, changes in acid-base status. These may contribute to the effects of HRT and menopause on many tissues and disease processes, including the development of osteoporosis.

Acid-Base Equilibrium↗
PubMed1999

Stimulation of osteoblast proliferation by C-terminal fragments of parathyroid hormone-related protein.

Parathyroid hormone (PTH)-related protein (107-139) (PTHrP(107-139)) and PTHrP(107-111) have been reported to be potent inhibitors of isolated osteoclast activity, and inhibition of bone resorption by PTHrP(107-139) occurs in vivo. However, the actions of C-terminal PTHrP on osteoblast activity has not been studied much. The present study addresses this issue by examining the effect of PTHrP(107-139), PTHrP(107-119), PTHrP(120-139), and PTHrP(107-111) on the proliferation of fetal rat osteoblasts. Treatment with PTHrP(107-139) for 24 h caused a dose-dependent increase in cell number, [3H]thymidine and [3H]phenylalanine incorporation in cultured osteoblasts. The effect was apparent at concentrations of 10-10 M and greater and was sustained over time. PTHrP(107-119) and PTHrP(107-111) had effects on cell number, DNA, and protein synthesis which were comparable to those of PTHrP(107-139), whereas PTHrP(120-139) was without effect. Retroverted PTHrP(107-111) also stimulated all three activities but was only one tenth as potent as PTHrP(107-139). PTHrP(107-139) had no effect on osteoblast apoptosis. It is concluded that PTHrP(107-139) is not only an inhibitor of osteoclastic bone resorption but that it also stimulates osteoblast growth. This activity resides within the pentapeptide fragment PTHrP(107-111). These findings support a possible role for C-terminal fragments of PTHrP in the normal regulation of bone cell function and, possibly, bone mass.

Animals↗
PubMed1999

Comparison of the effects of calcitonin gene-related peptide and amylin on osteoblasts.

Calcitonin gene-related peptide (CGRP) and amylin are homologous 37-amino-acid peptides which have been demonstrated to have anabolic effects on bone. It is not clear whether these effects are mediated by a common receptor, nor is it known which ligand is the more potent. These questions are addressed in the present study using cultures of fetal rat osteoblasts. CGRP increased cell number when present in a concentration >/=10-9 M, but 10-8 M CGRP was required to stimulate thymidine and phenylalanine incorporation. Amylin was effective on these indices at 100-fold lower concentrations, and its maximal effects were about twice as great as those of CGRP. ED50's for the effects of amylin and CGRP on cell number were 10-12 M and 10-10 M, respectively. There was no additivity between maximal doses of the peptides on these indices. The effects of specific receptor blockers on the maximal stimulation of cell number by these peptides were also studied. The CGRP receptor-blocker, CGRP-(8-37), completely blocked the effect of CGRP at blocker concentrations >/=10-9 M. In contrast, the amylin receptor blocker, amylin-(8-37), completely blocked the effects of CGRP when the blocker was present in concentrations as low as 10-11 M. The KI of CGRP-(8-37) was 2 x 10-10 M and that of amylin-(8-37) was 7 x 10-12 M. In converse experiments studying the blockade of maximal doses of amylin, amylin-(8-37) 10-10 M was effective (KI 1 x 10-10 M), whereas a 100-fold greater concentration of CGRP-(8-37) was necessary to achieve the same effect (KI 6 x 10-9 M). It is concluded that amylin and CGRP probably act through a common receptor to stimulate osteoblast growth, and that this receptor has a higher affinity for amylin than for CGRP.

Amyloid↗
PubMed1999

Pharmacological management of osteoporosis in postmenopausal women: a comparative review.

Optimising lifestyle and diet are important in the management of osteoporosis, however, they cannot completely prevent postmenopausal bone loss. Calcium supplementation significantly retards but does not completely arrest bone loss, but several small controlled studies suggest that it reduces fracture incidence. Thiazide diuretics slow bone loss similarly but their effects on fracture incidence remain to be determined. Hormone replacement therapy (HRT) increases or maintains bone density, prevents height loss and prevents vertebral fractures. There is observational evidence that HRT decreases cardiovascular disease and increases the risks of thromboembolic disease and breast cancer. The selective estrogen receptor modulator (SERM) raloxifene also slows postmenopausal bone loss although it is less effective that HRT. It also increases the risk of thromboembolic disease but is associated with a significantly reduced risk of breast cancer. The bisphosphonates are of comparable efficacy to HRT in the prevention of bone loss and have been shown to halve the risk of fractures of the vertebrae, forearm and hip. The maintenance of normal vitamin D (colecalciferol) status is important, particularly in the elderly. HRT, the bisphosphonates and raloxifene are all suitable for use in the prevention of postmenopausal bone loss, but the former 2 are to be preferred in the treatment of established disease. The most comprehensive long term safety data are available for HRT. Clinical trials are underway at present with more potent bisphosphonates which may make possible longer dose intervals and alternative routes of administration. There is a need for an effective bone anabolic factor but those which have been trialled to date have not proceeded because of significant adverse effects.

Benzothiadiazines↗
PubMed1999

Alendronate in the treatment of Paget's disease of bone.

This review reports the results of 2 recently completed long-term, randomised, double-blind, multicentre, controlled studies in which men and women with moderate to severe Paget's disease received oral alendronate 40 mg daily for 6 months One study conducted in the United States, compared the effects of alendronate 60 mg/day (n=41) with those of oral etidronate 400 mg/day (n=47); the other, conducted in the United Kingdom, Australia, and New Zealand, compared the effects of alendronate (n=27) with those of placebo (n=28). In both studies alendronate significantly reduced serum concentrations of alkaline phosphatase by more than 70%, which was significant in comparison with baseline (P < 0.001) and the comparator regimens (P < 0.001). Response to treatment (i.e. a > 60% decrease in or normalisation of serum alkaline phosphatase) was seen in more than three-quarters of patients treated with alendronate in both trials, compared with less than one-third of patients treated with etidronate and no patients treated with placebo. Radiologic scores, reflecting the status of osteolytic lesions, improved in a greater proportion of patients receiving alendronate than in those receiving etidronate or placebo. Histomorphometric analysis performed at 6 months showed that bone formed during alendronate treatment was of normal quality, without evidence of impaired mineralisation or other abnormalities. Alendronate was well tolerated, with an adverse event profile comparable with those of etidronate and placebo. These studies therefore showed that 6 months of treatment with oral alendronate suppresses disease activity in patients with Paget's disease of bone, with beneficial effects on biochemical, radiologic, and histomorphometric indices superior to those of etidronate and placebo.

Alendronate↗
PubMed1998

Spinal bone density in women using depot medroxyprogesterone contraception.

OBJECTIVE: To determine factors possibly associated with reduced bone density in women using the injectable contraceptive depot medroxyprogesterone acetate. METHODS: In a cross-sectional study, bone mineral density of the lumbar spine was measured by dual energy x-ray absorptiometry in 200 current users of depot medroxyprogesterone acetate who had used this method of contraception for 2-26 years and compared with 350 control subjects. Bone density results are expressed as standard deviation scores (z score). RESULTS: The bone density was significantly lower in depot medroxyprogesterone acetate users (mean z score: -0.65, 95% confidence intervals [CI] -0.80, -0.49, P < .001). Bone density was significantly reduced in nonsmokers and smokers, and there was no significant difference in mean z score between smokers and nonsmokers (mean -0.75 versus -0.58, P=.30). Women who had started depot medroxyprogesterone acetate after the age of 20 years and who had used it for 15 or fewer years had a significantly higher bone density than the remainder of the cohort (mean -0.45 [95% CI -0.62, -0.27] versus -1.02 [95% CI -1.32, -0.73], P < .005). Bone density in depot medroxyprogesterone acetate users was not related to current age, parity, body mass index, calcium intake, or exercise. CONCLUSION: Depot medroxyprogesterone acetate use is associated with a significant reduction in bone density, and although a high proportion of depot medroxyprogesterone users do smoke, the reduction in bone density cannot be explained by smoking. Women who use it for a long time and those who start it before peak bone mass is attained may be at highest risk.

Adolescent↗
PubMed1998

The roles of calcium and vitamin D in the prevention of osteoporosis.

Calcium supplementation produces small beneficial effects on bone mass throughout postmenopausal life and may reduce fracture rates by more than this change would predict--possibly by as much as 50%. There is little reason to use vitamin D in young populations that are replete in this compound, but in the elderly at risk of vitamin D deficiency, there is now evidence of significant reductions in nonvertebral fracture rates from physiologic replacement regimens. Some of the most substantial reductions in fracture rates have been found with combined therapy with calcium and vitamin D, and in these protocols it is not clear which is the principal active agent or whether, in fact, the combination is necessary for optimal antifracture efficacy.

Bone Density↗
PubMed1998

The effect of past use of the injectable contraceptive depot medroxyprogesterone acetate on bone mineral density in normal post-menopausal women.

OBJECTIVE: Depot medroxyprogesterone acetate (DMPA), an injectable progestogen, is a widely used contraceptive acting primarily by inhibiting secretion of pituitary gonadotrophins, thus producing oestrogen deficiency. Cross-sectional and prospective studies in pre-menopausal women have shown DMPA use to be associated with reduced bone density, but bone density increases following discontinuation of the drug. Because fracture rates are low in pre-menopausal women, the principal concern arising from the effects of DMPA on bone is that there may be residual osteopenia in former users such that their post-menopausal fracture risk is increased. The present study addresses this question. DESIGN: Cross-sectional study of bone density in post-menopausal former users of DPMA and controls. SUBJECTS: Three hundred and forty-six normal post-menopausal women, of whom 34 had previously used DMPA. The median age at which DMPA use began was 41 years and the median duration of use was 3.0 years. MEASUREMENTS: Bone density was measured in the spine, proximal femur and total body by dual-energy, X-ray absorptiometry. RESULTS: There were no significant differences in bone density at any site between the women who had previously used DMPA and the others in the cohort. However, in those who had used DMPA for > 2 years there was a trend towards bone densities being lower in the former users, the differences from non-users being 1.6% in the lumbar spine (P = 0.6), 3.1% in the femoral neck (P = 0.4) and 0.5% in the total body (P = 0.8). There was no correlation between bone densities and the duration of DMPA use, the age at discontinuation of DMPA, or the time between DMPA discontinuation and the menopause. CONCLUSIONS: Any residual effects of depot medroxyprogesterone acetate use on post-menopausal bone density are small and therefore unlikely to have a substantial impact on fracture risk in the post-menopausal years.

Bone Density↗
PubMed1998

Dissociation of the effects of amylin on osteoblast proliferation and bone resorption.

This study assesses the structure-activity relationships of the actions of amylin on bone. In fetal rat osteoblasts, only intact amylin and amylin-(1-8) stimulated cell proliferation (half-maximal concentrations 2.0 x 10(-11) and 2.4 x 10(-10) M, respectively). Amylin-(8-37), COOH terminally deamidated amylin, reduced amylin, and reduced amylin-(1-8) (reduction results in cleavage of the disulfide bond) were without agonist effect but acted as antagonists to the effects of both amylin and amylin-(1-8). Calcitonin gene-related peptide-(8-37) also antagonized the effects of amylin and amylin-(1-8) on osteoblasts but was substantially less potent in this regard than amylin-(8-37). In contrast, inhibition of bone resorption in neonatal mouse calvariae only occurred with the intact amylin molecule and was not antagonized by any of these peptides. The rate of catabolism of the peptides in calvarial cultures was not accelerated in comparison with that of intact amylin. This dissociation of the actions of amylin suggests that it acts through two separate receptors, one on the osteoclast (possibly the calcitonin receptor) and a second on the osteoblast.

Amyloid↗
PubMed1998

Systemic administration of amylin increases bone mass, linear growth, and adiposity in adult male mice.

Amylin is a peptide hormone cosecreted with insulin from the pancreatic beta-cells that can act as an osteoblast mitogen and as an inhibitor of bone resorption. The effects on bone of its systemic administration are uncertain. The present study addresses this question in adult male mice that were given daily subcutaneous injections of amylin (10.5 microgram) or vehicle (n = 20 in each group) for 4 wk. Histomorphometric indices of bone formation increased 30-100% in the amylin-treated group, whereas resorption indices were reduced by approximately 70% (P < 0.005 for all indices). Total bone volume in the proximal tibia was 13.5 +/- 1.4% in control animals and 23.0 +/- 2.0% in those receiving amylin (P = 0.0005). Cortical width, tibial growth plate width, tibial length, body weight, and fat mass were all increased in the amylin-treated group. It is concluded that systemic administration of amylin increases skeletal mass and linear bone growth. This peptide has potential as a therapy for osteoporosis if its bone effects can be dissociated from those on soft tissue mass.

Adipose Tissue↗
PubMed1998

Glucocorticoid-induced osteoporosis: assessment and treatment.

Supraphysiologic levels of glucocorticoids result in substantial bone loss, particularly at sites rich in trabecular bone. This results in fractures, typically in the vertebrae and ribs, in up to one third of long-term steroid users. Patients requiring long-term steroid treatment or with incurable Cushing's syndrome should have a bone density measurement, preferably at the spine. They should be offered specific prophylaxis against bone loss if their bone density is in the lower part of the young normal range, or below. Treatment should consist of sex hormone replacement in hypogonadal subjects, a bisphosphonate, or possibly a vitamin D metabolite. These medications can be used in combination. Correction of vitamin D deficiency, provision of calcium supplementation, cessation of smoking, and the provision of adequate exercise are sensible adjunctive interventions. Attention to the issue of steroid osteoporosis before fractures occur will substantially reduce the skeletal morbidity attendant upon the use of these lifesaving medications.

Journal Article↗
PubMed1997

Differences in hip axis and femoral neck length in premenopausal women of Polynesian, Asian and European origin.

There are substantial inter-racial differences in hip fracture incidence. Studies in several different ethnic groups have suggested that differences in the length of the femoral neck may contribute to these. The present study assesses femoral neck and hip axis lengths in three ethnic groups in which it has not been documented previously (Chinese, Indians and Polynesians) and compares these values with those in Europeans. Lengths were measured from dual-energy X-ray absorptiometry scans of the proximal femur in normal premenopausal women (n = 225). The Polynesian (1.65 m) and European (1.64 m) women were significantly taller than the two Asian groups (mean height in each, 1.58 m). There were also differences in mean body weight, the Polynesians being the heaviest (76 kg) and the Chinese the lightest (53 kg). Femoral neck lengths were (mean +/- SD) Chinese 61.5 +/- 4.4 mm, Indian 61.5 +/- 5.1 mm, Polynesian 68.2 +/- 4.3 mm and Europeans 66.0 +/- 4.8 mm. Hip axis lengths were Chinese 98.0 +/- 5.6 mm, Indian 94.5 +/- 5.2 mm, Polynesian 106.4 +/- 5.3 mm and European 102.3 +/- 5.3 mm. Each of the other groups were significantly different from the Europeans for both variables and, in general, this remained so after height adjustment. These data suggest that shorter femoral necks are common to the major Asian racial groups. However, in contrast to all other ethnic groups studied, Polynesians have longer femoral necks than Europeans and their low incidence of hip fracture is not explicable, therefore, in terms of their femoral neck length. This suggests that either higher bone density or other more subtle differences in proximal femoral geometry must account for the low hip fracture incidence in Polynesians.

Absorptiometry, Photon↗