Bone loss and depot medroxyprogesterone.
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Endometriosis↗
Biomedical subjects
I R Reid
Publications and source records attributed to I R Reid.
Racial effects on body composition: it's not all black and white.
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Black People↗
The management of osteoporosis.
The management of osteoporosis used to centre upon investigation and treatment of patients with fracture. The spectrum has now widened to include the detection of patients at high risk of fracture before a fracture occurs. This is best achieved by consideration of clinical risk factors and the selective use of bone densitometry. The frequency of osteoporotic fractures in elderly women is such that detailed investigation of such patients is often not necessary unless the patient's bone density is outside the normal range for age. When bone density is inexplicably low, secondary causes of osteoporosis should be sought by appropriate investigations. Fracture prevention involves a correction of lifestyle factors (stopping smoking, moderating alcohol intake etc.) and achieving a total calcium intake of 1-1.5 g/day. The first line for pharmacological intervention is hormone replacement therapy because of its proven efficacy and the extensive data available documenting its safety. The bisphosphonates have comparable effects on bone density and fractures in studies extending for up to 3 years, and are increasingly used, particularly in older patients and those reluctant to take hormone replacement therapy. Other available agents have significant drawbacks, either with respect to side-effects or inconsistent documentation of efficacy and should be used only in special circumstances.
Female↗
Leukemia inhibitory factor is mitogenic to osteoblasts.
Leukemia inhibitory factor (LIF) regulates cell growth and is produced by a variety of tissues, including bone. Previously we have shown that recombinant human LIF induced an increase in osteoclast number, bone formation, and DNA synthesis. In the present study, we have defined the cells in intact bone at which the proliferative effects of LIF occur, using simultaneous enzyme histochemistry and autoradiographic techniques. The area of alkaline phosphatase-positive staining was increased twofold (p = 0.0008) and the number of [3H]thymidine-positive cells was increased twofold (p = 0.0024) in LIF-treated bones. The radiolabeled cells either colocalized with alkaline phosphatase or were in the osteoprogenitor region. They were not found in the acid phosphatase-positive staining osteoclasts. These results indicate that cells which have a mitogenic response to LIF are bone-forming rather than bone-resorbing cells.
Acid Phosphatase↗
Effects of prolonged bisphosphonate therapy and its discontinuation on bone mineral density in post-menopausal osteoporosis.
OBJECTIVE: The bisphosphonates have proven efficacy in the management of post-menopausal osteoporosis. However, the benefits of prolonged (> 2 years) administration and the effects of discontinuation of bisphosphonate treatment are not clear. DESIGN: We have previously reported a 2-year, randomized, double-blind, placebo-controlled trial of pamidronate therapy (150 mg/day) in women with established post-menopausal osteoporosis. We now report the bone mineral density (BMD) changes in those women who continued for a third year of active treatment and were then observed off therapy for a further 12 months. PATIENTS: Twenty-two women (mean age 66 years) continued on pamidronate in year 3, and in 16 of these the effects of subsequent discontinuation of therapy for 12 months were studied. MEASUREMENTS: BMD was measured in the total body, lumbar spine and proximal femur using a Lunar DPX-L dual-energy, X-ray absorptiometer. RESULTS: The third year of therapy with pamidronate was associated with a significant further gain in BMD only at the lumbar spine (2.1 +/- 0.6%, P = 0.003), resulting in a total gain of 9.5 +/- 1.0% at that site over 3 years of treatment. In the total body, BMD tended to decline (-0.6 +/- 0.3%) in year 3. One year after discontinuation of pamidronate, there were significant losses of BMD in the total body (-1.9 +/- 0.3%, P < 0.0001) and femoral trochanter (-2.7 +/- 0.9%, P = 0.01), and non-significant changes at the lumbar spine (-0.9 +/- 0.8%), femoral neck (-0.5 +/- 1.6%), and Ward's triangle (-2.9 +/- 3.7%). By the end of one year off therapy, BMD was greater than baseline only in the lumbar spine (7.1 +/- 1.1%, P < 0.0001) and femoral trochanter (4.5 +/- 1.88%, P < 0.03). In the total body, BMD was 0.3 +/- 0.7% below the values at the trial's inception (P = 0.7). CONCLUSIONS: These data demonstrate that the rate of bone gain associated with bisphosphonate use slows over time, and that significant bone loss follows withdrawal of these agents. These findings have important implications for the duration of use of these novel drugs in the therapy of osteoporosis and suggest a need for close observation following their discontinuation.
Aged↗
The anti-oestrogen tamoxifen produces haemodilution in normal postmenopausal women.
OBJECTIVES: To report the effects of the anti-oestrogen tamoxifen on biochemical and haematological parameters. DESIGN: Randomized, double-blind comparison of tamoxifen 20 mg per day and placebo, over two years. SETTING: A university hospital. SUBJECTS: Forty-six healthy late-postmenopausal women (mean, SD time since menopause; 11, seven years). MAIN OUTCOME MEASURES: Blood specimens were drawn in the fasting state at baseline, six months and two years for measurement of haemoglobin, haematocrit, erythrocyte mean cell volume, mean erythrocyte haemoglobin, leucocyte count, platelet count, urea, electrolytes, creatinine and albumin. RESULTS: There was a significant decline in the haemoglobin concentration in the tamoxifen group (-4.4, 1.2 g/L; mean, SE) and its levels were lower in this group than in those receiving placebo (P = 0.004). Similarly, haematocrit, erythrocyte count and total leucocyte count were lower in those on placebo (P = 0.002, P = 0.01 and P = 0.01, respectively) and platelet count showed a similar trend (P = 0.08). In the tamoxifen group, the level of serum albumin fell significantly (-2.2, 0.4 g/L) and was lower throughout the study than that in the placebo group (P = 0.006). That of serum urea tended to fall (-0.4, 0.2 mmol L) but the between-groups comparison was not significant (P = 0.18). CONCLUSIONS: These data suggest that tamoxifen exerts a haemodilutory effect in normal postmenopausal women. Since a similar effect has been reported in response to postmenopausal oestrogen therapy, it is likely that the observed changes represent another oestrogenic effect of tamoxifen in postmenopausal women. Haemodilution may contribute to the reduced incidence of cardiovascular disease reported in tamoxifen-treated women, and, therefore, its assessment in the new oestrogen agonists/antagonists being developed for cardiovascular disease prevention may be important.
Antineoplastic Agents, Hormonal↗
Osteoporosis--emerging consensus.
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Aged↗
Adrenomedullin is a potent stimulator of osteoblastic activity in vitro and in vivo.
Adrenomedullin is a 52-amino acid vasodilator peptide produced in many tissues, including bone. It has 20% sequence identity with amylin, a regulator of osteoblast growth, and circulates in picomolar concentrations. The present study assesses whether adrenomedullin also acts on osteoblasts. At concentrations of 10(-12) M and greater, adrenomedullin produced a dose-dependent increase in cell number and [3H]thymidine incorporation in cultures of fetal rat osteoblasts. This effect was also seen with adrenomedullin-(15-52), -(22-52), and -(27-52), but adrenomedullin-(40-52) was inactive. These effects were lost in the presence of amylin blockers, suggesting they were mediated by the amylin receptor. Adrenomedullin also increased [3H]thymidine incorporation into cultured neonatal mouse calvaria but, unlike amylin, did not reduce bone resorption in this model. Adrenomedullin stimulated phenylalanine incorporation into both isolated osteoblasts and calvaria. When injected daily for 5 days over the calvariae of adult mice, it increased indexes of bone formation two- to threefold (P < 0.0001) and increased mineralized bone area by 14% (P = 0.004). It is concluded that adrenomedullin regulates osteoblast function and that it increases bone mass in vivo. The potential of this family of peptides in the therapy of osteoporosis should be further evaluated.
Adrenomedullin↗
Parathyroid hormone-related protein-(107-139) inhibits bone resorption in vivo.
PTH-related protein-(107-139) [PTHrP-(107-139)] has been reported previously to be a potent inhibitor of osteoclast activity. However, this finding has not been reproduced in other in vitro models. We have now examined the effects of this peptide in an in vivo model, employing intact adult mice. Four groups of eight male mice were given injections of either vehicle or one of three doses of PTHrP-(107-139) (4 x 10(-13), 4 x 10(-11), or 4 x 10(-9) mol) over the periosteum of the right hemicalvaria for 5 consecutive days. The animals were killed 1 week after the last injection. There were significant decreases in bone resorption indexes after all doses of PTHrP-(107-139), with a 70% decrease in osteoclast number (P < 0.001), a 70% decrease in osteoclast perimeter (P = 0.004) and a 50% decrease in eroded perimeter (P = 0.001). In addition, some indexes of bone formation were significantly decreased, with 40% decreases in both osteoblast number (P = 0.05) and osteoblast perimeter (P = 0.02), but no significant change in osteoid area. There was a dose-related upward trend in mineralized bone area, reaching 12% at the highest dose, but this was not statistically significant. It is concluded that PTHrP-(107-139) is a potent inhibitor of bone resorption in vivo. As this model is very dissimilar to that of isolated osteoclasts, in which this peptide is also active, the present findings suggest that osteoclast inhibition is an authentic action of the C-terminus of PTHrP, which may, therefore, play a role in the regulation of bone turnover in vivo.
Animals↗
Premature hair graying and bone mineral density.
In a recent case-control study, premature hair graying was found to be associated with osteopenia, suggesting that this might be a clinically useful risk factor for osteoporosis. We report a reexamination of this possibility in 293 healthy postmenopausal women. Subjects experiencing onset of hair graying in their 20s tended to have lower bone mineral density throughout the skeleton (adjusted for age and weight) than those with onset of graying later in life. The same was true for those in whom the majority of their hair was gray by the age of 40 yr (n = 16), in whom bone density was reduced by 7% in the femoral neck, 8% in the femoral trochanter, and 4% in the total body (P < 0.05) when compared with those not prematurely gray. Bone density at the lumbar spine and Ward's triangle showed similar trends that were not significant. However, premature hair graying explained only 0.6-1.3% of the variance in bone mineral density within the population. We conclude that premature hair graying is associated with low bone density, but that its infrequency in the normal postmenopausal population leads to its accounting for only a tiny fraction of the variance of bone density.
Aged↗
Glucocorticoid osteoporosis--mechanisms and management.
Glucocorticoids are potent osteopenic agents, producing negative calcium and bone balance via actions at many sites. The most significant adverse effects of glucocorticoid drugs on the skeleton are probably a direct inhibition of matrix synthesis by the osteoblast, reductions in calcium absorption in both the gut and the renal tubule, and the production of hypogonadism, particularly in men. Reductions in bone density of 10-40% result, the loss being more marked in trabecular bone and in patients receiving a high cumulative dose of the steroid. Fractures occur in about 30% of individuals who take these drugs for an average of 5 years. Bone loss is reversible when glucocorticoid treatment is withdrawn. Bone density can also be increased by sex hormone replacement in those with demonstrable deficiency, by bisphosphonates, and possibly by vitamin D metabolites. All patients treated with glucocorticoids for more than 6 months should be considered for bone densitometry and be offered appropriate drug treatment if values are towards the lower end of the young normal range or if there is already evidence of fractures occurring after minimal trauma. With this approach, the significant morbidity associated with steroid osteoporosis might be substantially avoided.
Animals↗
Establishing healthy bones in the young.
Osteoporosis is uncommon in young adults and is usually attributable to underlying medical conditions. Doctors caring for patients with these conditions should assess bone mass and provide prophylaxis against bone loss where indicated. There are also identifiable risk factors for low bone mass in this age group which uncommonly lead to fractures in the short term but more importantly may predispose to fractures later in life. These include low body weight, amenorrhoea and smoking. Doctors should detect these problems in the course of routine patient care and provide appropriate advice.
Absorptiometry, Photon↗
Has improved nutrition contributed to the hip fracture epidemic?
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Hip Fractures↗
Effect of hormone replacement therapy on bone mineral density in postmenopausal women with mild primary hyperparathyroidism. A randomized, controlled trial.
BACKGROUND: Most patients with primary hyperparathyroidism are postmenopausal women. The presence of osteopenia in persons with mild primary hyperparathyroidism is considered an indication for parathyroidectomy. No prospective, controlled trials have assessed medical therapies for osteopenia in primary hyperparathyroidism. OBJECTIVE: To examine the effects of estrogen-progestin therapy (hormone replacement therapy) on bone mineral density and biochemical indices in postmenopausal women with mild primary hyperparathyroidism. DESIGN: Double-blind, randomized, placebo-controlled trial. SETTING: University teaching hospital. PATIENTS: 42 postmenopausal women with mild primary hyperparathyroidism. INTERVENTION: Patients were randomly assigned to receive either conjugated estrogens, 0.625 mg/d, and medroxyprogesterone, 5 mg/d, or placebo. MEASUREMENTS: Bone mineral densities of the total body, lumbar spine, proximal femur (femoral neck, Ward triangle, trochanter), and proximal forearm were measured every 6 months using dual-energy x-ray absorptiometry. Biochemical indices of bone turnover and calcium metabolism were measured at baseline, 6 months, and 2 years. RESULTS: In the placebo group, bone mineral densities of the total body and the proximal forearm decreased significantly from baseline (mean +/- SE, -2.3% +/- 0.7% [p = 0.005] and -3.5% +/- 1.2% [p = 0.01], respectively). At the other sites, bone mineral density also tended to decline. In the hormone replacement therapy group, bone mineral density increased from baseline in the total body (1.3% +/- 0.4%; P = 0.004), lumbar spine (5.2% +/- 1.4%; p = 0.002), and femoral neck (3.4% +/- 1.5%; p = 0.05). The between-group differences in bone mineral density at the end of the study ranged from 3.6% to 6.6% and were significant at all sites (P > 0.001 and P < 0.05) except for the Ward triangle (p = 0.06). In the hormone replacement therapy group, serum alkaline phosphatase levels decreased by 22% (p = 0.0004 compared with baseline), urinary hydroxyproline excretion decreased by 42% (p = 0.0004), urinary N-telopeptide excretion decreased by 54% (p = 0.001), and urinary calcium excretion decreased by 45% (p = 0.007). Hormone replacement therapy did not change levels of serum ionized calcium or intact parathyroid hormone. CONCLUSIONS: Although hormone replacement therapy has little effect on serum calcium levels, it suppresses bone turnover, reduces urinary calcium excretion, and increase bone mineral density throughout the skeleton in postmenopausal women with mild primary hyperparathyroidism. This therapy is thus an important management option for these patients.
Aged↗
Longer femoral necks in the young: a predictor of further increases in hip fracture incidence?
AIMS: To determine whether femoral neck length, a risk factor for hip fracture, is likely to increase in the coming decades in normal elderly New Zealand women. METHODS: Femoral neck length was measured from dual-energy x-ray absorptiometry scans of the proximal femur in white women aged 19-88 years (n = 211). Since this length remains constant throughout adult life, it is possible to predict future trends in this index in the elderly, from its measurement at the present time in younger adults. RESULTS: Femoral neck length was inversely related to age (p = 0.018) such that a 3.7 mm (5.7%) difference occurred over the age-range of this sample. CONCLUSIONS: Femoral neck length in elderly New Zealand women is likely to increase in the coming decades. As a result of the dependence of hip fracture risk on femoral neck length, future age-adjusted hip fracture incidence will increase by about 50% over the next 50 years unless significant public health initiatives are taken, either to increase bone density or to reduce fall frequency.
Absorptiometry, Photon↗
Testosterone therapy in glucocorticoid-treated men.
BACKGROUND: Treatment with glucocorticoid drugs is a valuable therapy, but the use of these drugs is associated with major side effects, including osteoporosis, muscle wasting, and obesity. In men who take glucocorticoids, circulating testosterone concentrations are reduced, and this might contribute to the changes in bone and soft-tissue mass. OBJECTIVE: To asses the effect of testosterone replacement on these above-mentioned parameters in glucocorticoid-treated men. METHODS: Fifteen asthmatic men who were receiving long-term glucocorticoid treatment were randomly allocated to receive therapy with testosterone esters (30 mg of proprionate, 60 mg of phenylprionate, 60 mg of isocaproate, and 100 mg of decanoate [Sustanon]) (250-mg/mo intramuscular depot injection) or to act as control subjects during 12 months. After a washout period for those men who were receiving testosterone, the groups were then crossed over and studied for a further 12 months. Bone density and body composition were assessed by dual-energy, x-ray absorptiometry. Paired or unpaired 2-tailed t tested were calculated. Unless otherwise stated, all values are given as mean +/- SEM. RESULTS: Bone density in the lumbar spine increased 5.0% +/- 1.4% (mean +/- SEM) (P = .005) during testosterone supplementation, but it did not change during the control period (between-groups difference, P = .05). These changes were accompanied by a decrease in the indexes of bone turnover. There was a gain in body fat mass (2.1 +/- 0.06 kg, P = .01) and a loss of lean body mass (1.4 +/- 0.5 kg, P = .02) during the control period, with both changes being reversed by testosterone treatment (P < .03). CONCLUSION: Testosterone treatment reverses the deleterious effects glucocorticoid drugs on skeletal and soft tissues in men.
Aged↗
Effects of vertical-banded gastroplasty on bone and mineral metabolism in obese patients.
The surgical treatment of obesity can have adverse effects on bone, but there are few published data on the effects of vertical-banded gastroplasty. Serial measurements of bone mineral density at the lumbar spine and three upper femoral sites, using dual-energy X-ray absorptiometry, and also of biochemical indices of bone and mineral metabolism at intervals up to 2 years after operation were performed in 18 patients with morbid obesity who had vertical-banded gastroplasty. Bone mineral density measurements were also made in age- and sex-matched non-obese controls. Bone density before operation was significantly greater in the obese than in the controls (P < 0.02 at all sites). The obese patients lost weight rapidly after vertical-banded gastroplasty (mean weight loss 29 kg at 1 year, P < 0.001). This was accompanied by a measurable loss of bone density from the trochanter and Ward's triangle sites in the upper femur (P < 0.05), but not from the lumbar spine. Bone density values remained stable over 14 months in the controls. Hydroxyproline excretion increased significantly (P < 0.005), indicating an increase in bone resorption. Alkaline phosphatase levels decreased significantly (P < 0.001), but this probably represents the reversal of hepatic steatosis. There was no evidence of hyperparathyroidism or vitamin D deficiency. In conclusion, vertical-banded gastroplasty causes modest bone density loss from femoral sites, but not the lumbar spine. The difficulties of assessing bone density changes in the obese are discussed.
Adult↗
Insulin increases histomorphometric indices of bone formation In vivo.
Recent clinical studies have established that bone density is related to both fat mass and circulating insulin levels. A direct action of insulin on the osteoblast may contribute to these relationships. Osteoblast-like cells have insulin receptors, and insulin has been shown to stimulate proliferation of these cells in vitro. However, it has not been possible to study the effects of insulin administration on bone in vivo because of the metabolic effects of insulin, particularly hypoglycemia. A model involving the local injection of insulin over one hemicalvaria of an adult mouse overcomes these difficulties and permits the histomorphometric study of insulin's action on bone. Insulin or vehicle was injected daily for 5 days over the right hemicalvariae of adult mice, and the animals were sacrificed 1 week later. All indices of bone formation were significantly increased in insulin-treated hemicalvariae compared with the noninjected hemicalvariae. There was a 2.73 +/- 0. 50-fold increase in osteoid area (P = 0.005), a 2.20 +/- 0.37-fold increase in osteoblast surface (P = 0.021) and a 2.04 +/- 0.29-fold increase in osteoblast number (P = 0.012). Indices of bone resorption tended to decline and mineralized bone area tended to increase in insulin-treated animals. The direct action of insulin on bone may contribute to the increased bone density seen in obesity and to the osteopenia of type I diabetes, conditions associated with insulin excess and deficiency, respectively.
Animals↗