Aspirin therapy for cardiovascular disease

Bone densitometry has become a major tool for osteoporosis risk assessment. The traditional dual-energy X-ray absorptiometry (DXA) methods are able to evaluate the bone mineral content (BMC; mg/cm) and the areal density (BMD; mg/cm2), but only quantitative computed tomography (QCT) has the potential to measure the true volumetric bone density in the sense of mass per unit volume (mg/cm3). Peripheral QCT (pQCT) measurements were carried out at the nondominant radius using a Stratec XCT 960 (Unitrem, Roma) in 241 postmenopausal and 29 premenopausal women. The sites of evaluation were both the ultradistal and the proximal radius. The technique used has a coefficient of variation of 2% and it allows separation of the bone section into trabecular and cortical bone on the basis of density threshold. Bone mass of radius, hip and spine was also evaluated by DXA procedures. The bone density data obtained by pQCT were significantly correlated with all DXA measurements. The correlation coefficients between their respective BMD values ranged from 0.48 to 0.75, but for the BMC values of the radius the correlation coefficients ranged from 0.82 to 0.93. The BMD values measured by DXA, but not by pQCT, were positively related with patient heights. All pQCT density measurements, including those obtained at the proximal radius and containing exclusively cortical bone, where negatively related with age and years since menopause. A partial volume effect, which is increasingly relevant the thinner are the bone cortices, might explain that. However, by applying increasing density thresholds, cortical bone density seems to decrease with age as a consequence of a gradual density diminution from the inner part of the bone cortex outwards. Trabecular bone density decreases with aging, but its overall mass does not change as a consequence of an age-related enlargement of trabecular area. Thus, the proportion of trabecular bone over total bone rises, and this might be relevant for our understanding of the age-related changes in bone turnover and rate of bone loss.     

Effect of menopause on femoral and vertebral bone loss

The aim of this study was to investigate the effect of menopause on bone loss in the proximal femur and the lumbar spine. The rates of change in bone mineral density (BMD) were measured longitudinally by dual X-ray absorptiometry (DXA) at the femoral neck (FN), Ward's triangle (WT), and trochanter (TR) together with the lumbar spine in 81 healthy postmenopausal women (45-65 years of age) who had passed a natural menopause, 6 months to 12 years before. A significant correlation between the rate of change and interval since menopause was evidenced. The best fit of the data was a binomial function of interval since menopause at the spine, FN, and WT and a simple linear regression at TR level. At each skeletal site, the rate of bone loss (mean +/- SD) was significantly different (p<0.05) and twice as high in women who were between 6 months and 2 years postmenopausal at enrollment (FN, -1.82 +/- 1.1%; WT, -2.43 +/- 1.7%; TR, -1.12 +/- 1.7%) than in those who were beyond 5 years of menopause (FN, -0.48 +/- 0.8%; WT, -0.68 +/- 2.1% TR, 0.41 +/- 1.2%). A poor correlation (r = 0.39 - 0.42, p<0.001) was found between the rate of vertebral and that of femoral postmenopausal bone loss. This study demonstrates that menopause is associated with a rapid and transient bone loss in BMD of the proximal femur, which declines with time after 3 years. These data suggest that therapy should be initiated as early as possible after menopause to prevent bone loss.     

Association of bone mineral density with vitamin D receptor gene polymorphism--changes in radial bone mineral density with long-term follow-up: longitudinal study

Recent studies have shown that genetic effects on bone mineral density (BMD) and bone turnover are related to vitamin D receptor (VDR) gene polymorphism. However, discordant studies have been published and it is still not clear whether VDR genotypes influence bone mass accretion and/or postmenopausal bone loss. To assess allelic influence of the VDR gene on BMD, we determined changes in 1/6-radial-BMD by several repeat measurements in the same subjects for about ten years and analyzed VDR polymorphism of BsmI restriction enzyme in 53 normal healthy Japanese women (age: 50.3 +/- 4.7 years, mean +/- SD). Twenty-seven (age: 53.2 +/- 4.7 years) of the subjects were post-menopausal (POST group). Among these 53 subjects, the distribution of bb, Bb and BB genotypes was 64.2%, 34% and 1.9%, respectively. The genotype frequencies in this study were very similar to those in previous reports concerning other Japanese women. There was no difference between the b group (women with bb genotype) and B group (women with BB or Bb genotype) in age, body weight, height, body mass index (BMI), years since menopause, serum osteocalcin and serum alkaline phosphatase values. In the POST group, BMD of the B group at menopause was lower than that of the b group (p < 0.05). About ten years after menopause, BMD did not differ significantly between these groups because the decrease in BMD in the b group was larger than that in the B group. Regarding changes in BMD in the POST group for four years after menopause, BMD of the b group was significantly decreased compared with the B group (p < 0.01). Our findings suggest that the differences in BMD by VDR genotype were larger among pre- and pri-menopausal women and seemed to decrease with years after menopause. It is suggested that there are other factors influencing BMD and postmenopausal bone loss in elderly women.     

Co-purification of a ribonuclease and human chorionic gonadotrophin beta-core protein from human urine and displacement of 125I-human luteinizing hormone from Candida albicans binding sites by ribonucleases

OBJECTIVE: To re-examine the minimal effective dose of conjugated estrogen (CEE)-progestin hormone replacement on postmenopausal bone loss. DESIGN: A 2-year, prospective, open label, randomized study. SETTING: Department of Obstetrics and Gynecology of a university hospital. PARTICIPANTS: Fifty-two postmenopausal or oophorectomized women. INTERVENTION: One of the following regimens was continuously administered for 2 years: (1) CEE 0.625 mg/day, (2) CEE 0.625 mg + medroxyprogesterone (MPA) 2.5 mg/day, (3) CEE 0.31 mg + MPA 2.5 mg/day and (4) control. MEASUREMENTS: Lumbar spine and femoral BMD by dual energy X-ray absorptiometry (DXA), a monthly based incidence of bleeding, serum lipids, PTH, calcitonin. A1-p, and osteocalcin. RESULTS: Of the 52 patients enrolled in this study, 49 patients completed the 1 year of therapy and 36 completed the 2- year study. The control group showed a significant decrease in lumbar BMD over the 2 years (P < 0.05). The % changes in lumbar BMD at 2 years of CEE alone, CEE 0.625 + MPA and CEE 0.31 + MPA were 8.52% (95% confidence intervals; 4.61 approximately 12.4%), 7.4% (0.60 approximately 14.2%) and 3.20% (0.61 approximately 5.84%), respectively, and were significantly higher than pretreatment values. The incidence of bleeding was significantly lower in women taking CEE 0.31 mg + MPA. HDL cholesterol increased in women taking CEE 0.625 mg alone or with MPA. No significant changes in lipid profiles were seen in the control or in the group of women taking CEE 0.31 mg + MPA. CONCLUSIONS: Continuous hormone replacement therapy (HRT) using 0.31 mg of CEE and 2.5 mg of MPA is effective in increasing lumbar BMD in postmenopausal or oophorectomized women and can be an appropriate option for women with a normal lipid profile or those women wishing to eliminate unscheduled bleeding.     

Is there a means for cost reduction in intensive care fluid therapy without a loss of quality?

The objective of this study was to examine the value of NTx, a urinary cross-linked N-telopeptides of type I collagen, as a marker of bone resorption. We assessed changes in pre- and postmenopausal bone resorption by evaluating the correlation of NTx with L2-4 bone mineral density (BMD) in a total of 1100 Japanese women, aged 19-80 years [272 premenopausal (45.2 +/- 6.2 years) and 828 postmenopausal (59.5 +/- 6.2 years)]. Postmenopausal women were divided into three groups based on the range of BMD (normal, osteopenic, and osteoporotic). Within each group, subjects were further segregated according to years since menopause (YSM). NTx values were then evaluated for each group. Our results showed that BMD was significantly decreased (P < 0.05) and NTx was significantly increased (P < 0.01) after menopause in age-matched analysis. Consistent with a previous report, NTx was inversely correlated with BMD for the entire cohort of study subjects (r = -0.299), although NTx correlated better with premenopausal than postmenopausal BMD (r = -0.240 versus r = -0.086). This may have been due to the fact that elevated values of NTx were exhibited over the entire range of BMD present in the postmenopausal women, suggesting that NTx might respond faster to the estrogen withdrawal than BMD. In all postmenopausal women, regardless of the range of BMD, the increase in NTx reached a peak within 5 YSM. After 11 YSM, however, NTx remained elevated in the osteoporotic group but it decreased in the osteopenic group, and showed no significant change in the group of postmenopausal women with normal BMD. These findings suggest that bone resorption is dramatically increased within 5 years after menopause but remains increased only in osteoporotic women.     

Approximating dipoles from human EEG activity: the effect of dipole source configuration on dipolarity using single dipole models

Long-term daily administration of oral bisphosphonates has been effective in the treatment of postmenopausal osteoporosis, but the duration, mode and cost of the therapy may sometimes affect patient compliance. In Italy, the bisphosphonate clodronate is also available via the intramuscular (i.m.) route of administration, and the present study was performed to test its efficacy in postmenopausal osteoporosis. Ninety osteoporotic postmenopausal women were enrolled in a randomized, controlled 3 year study. The diet of all patients was adjusted to provide 1200-1300 mg of calcium daily, eventually by administration of supplements. Patients were randomly assigned to no therapy (30 patients) or to receive clodronate 100 mg i.m. either every 2 weeks (30 patients) or 1 week (30 patients). The i.m. injection caused substantial pain at the site of injection, which led to treatment withdrawal in almost 50% of the patients receiving weekly dosing. In control patients, a progressive, slow decline in spine and femoral bone mineral density (BMD), which became statistically significant at the end of the second year of observation, was observed. In the patients given weekly i.m. clodronate, spinal BMD rose by 3.8% (+/-7.3 SD) within 6 months. A slight, nonsignificant increase was observed thereafter, such that, at the completion of 3 years of observation, the mean gain was 4.5% (+/-6.3). In the patients treated with injections of 100 mg of clodronate every two weeks the increase in BMD was somewhat lower and slower, becoming significant only at month 24 (2.9+/-4.6%). In none of the two active groups was the femoral neck BMD changed significantly during the 3 years of the study. A significant increase in trochanter and Ward's triangle BMD was observed at month 12 only in the patients on the highest dose of clodronate. In both groups treated, the hip BMD changes were significantly different from those observed in control patients. The biochemical markers of bone turnover were suppressed in both clodronate groups. These results indicate that intermittent i.m. clodronate administration can provide clinically relevant benefits to skeletal bone density in osteoporotic postmenopausal women, but the in situ pain may limit its extensive use.     

The use of antibiotic-impregnated cement in infected reconstructions after resection for bone tumours

Bone mobilization, lowering of bone mineral density (BMD), and osteoporotic fractures are recognized in postmenopausal women with weight loss. Because a high-calcium intake suppresses bone loss in peri- and postmenopausal women, the present randomized, double-blind, placebo-controlled study was designed to test the hypothesis that calcium supplementation prevents net bone mobilization and consequent bone mineral loss during voluntary weight reduction in obese postmenopausal women. Subjects were placed on a moderate energy-restricted diet and either calcium supplementation (1 g/day) or placebo for 6 months. Body weight, bone turnover markers (pyridinium cross-links), osteocalcin, and parathyroid hormone (PTH) were measured at treatment weeks 1-5, 7, 10, 13, 16, 20, and 25. Total body BMD, insulin-like growth factor, 25-hydroxyvitamin D, and sex hormone binding globulin (SHBG) were measured at baseline and week 25. The calcium supplemented (n = 15; age 60.9 +/- 9.4 years, body mass index [BMI] 33.2 +/- 4.6 kg/m2) and placebo (n = 16; age 55.8 +/- 8.3 years, BMI 32.9 +/- 4.5 kg/m2) groups lost similar amounts of weight over the study interval (10.2 +/- 5.3% vs. 10.0 +/- 5.2%) and both groups increased SHBG (p < 0.001). There was a statistical effect of calcium supplementation during weight loss to suppress pyridinium cross-links, osteocalcin, and PTH (p < 0.05, < 0.01, and < 0.05, respectively). Loss of BMD tended to be greater in the placebo group by 1.4% (p < 0.08) after weight loss. One gram per day calcium supplementation normalizes the increased calcium-PTH axis activity and the elevated bone turnover rate observed during moderate voluntary energy restriction in postmenopausal women.     

Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up

This double-blind, placebo-controlled study was undertaken to determine 1) the efficacy of oral risedronate for prevention of bone loss in healthy, early postmenopausal patients with normal bone mass, 2) the effect on bone mass when treatment was stopped, and 3) the safety and tolerance of risedronate in this population. A group of 111 patients were randomized to oral placebo, risedronate 5 mg daily, or risedronate 5 mg cyclically, for 2 yr followed by 1 yr off treatment. Measurements included percentage change from baseline in lumbar spine bone mineral density (BMD) at 24 months; percentage change from baseline in BMD of the femoral neck, trochanteric region, and Ward's triangle region of the proximal femur; and changes in biochemical markers of bone turnover. After 2 yr, there was a mean increase in BMD of the lumbar spine of 1.4% from baseline and of 5.7% vs. placebo in the risedronate 5 mg daily group. There were decreases from baseline in BMD of 1.6% and 4.3% in the risedronate 5 mg cyclic and placebo groups, respectively. By the end of 24 months, trochanteric bone mass at the hip increased by 5.4% in the risedronate 5 mg daily group and by 3.3% in the risedronate 5 mg cyclic group vs. placebo. Bone mass was maintained at the femoral neck in the 2 active-treatment groups vs. a 2.4% mean loss with placebo. During the treatment-free follow-up, bone turnover increased toward baseline in both risedronate groups. By the end of that year, lumbar spine bone mass in all 3 groups was lower than at baseline. Oral risedronate was well tolerated. We conclude that risedronate (5 mg daily) increases bone mass and risedronate (5 mg cyclic) appears to prevent bone loss in early postmenopausal women with normal BMD.     

A prospective study of bone loss in African-American and white women--a clinical research center study

Although bone loss occurs universally with age, the incidence of age-related osteoporotic fractures varies widely among ethnic groups. In the U.S., age-adjusted hip fracture incidence is 50% lower in African-American than in white women. Adult African-American women also have higher bone mass, but it is not known whether this difference is entirely due to higher peak bone mass or also results from slower rates of bone loss. Rates of bone loss were measured prospectively in 122 white and 121 African-American healthy, nonobese, pre- and postmenopausal women. Bone density was measured at 6-month intervals over a mean of 3-4 yr using single and dual photon absorptiometry of the forearm (cortical bone) and spine (trabecular bone). Similar rates of premenopausal bone loss were documented in both white and African-American women. However, in early menopause, bone loss was faster in the white women in the forearm (-2.4%/yr in whites vs. -1.2%/yr in African-Americans; P = 0.045), with a similar trend in the spine (-2.2%/yr in whites vs. -1.3/yr in African-Americans; P = 0.27). In women more than 5 yr postmenopause, the rates of bone loss did not differ by ethnic group. Our results indicate that the higher bone mass in African-American women is largely due to the attainment of a greater peak bone mass by early adulthood. However, slower rates of bone loss in the early postmenopausal period may also contribute to the higher bone density of older African-American women. Although bone loss occurs in both groups, there are ethnic differences in bone loss rates which indicate that data derived from white women cannot be simply extrapolated to nonwhite populations. Ethnic group-specific data on the determinants of bone homeostasis are needed.     

Bone mass improves in alcoholics after 2 years of abstinence

To evaluate the effect of abstinence on bone mass and bone mineral metabolism in chronic alcoholics, a 2 year longitudinal follow-up study was carried out in a group of 30 chronic alcoholic males who started a rehabilitation program. Lumbar and femoral bone mineral density (BMD) and serum levels of osteocalcin and 25-hydroxyvitamin D were measured at entry and after 1 and 2 years in all patients. Circulating cortisol and parathyroid hormone were measured in 14 and 6 patients, respectively, at entry and every year. Testosterone was measured in 18 patients at entry and after 1 year. At entry, lumbar BMD was significantly lower in alcoholics (1.06 +/- 0.03 g/cm2) than in age-matched healthy men (1.22 +/- 0.03 g/cm2; p < 0.001). Circulating osteocalcin and vitamin D levels were also significantly lower in alcoholics than in controls. Lumbar and femoral neck BMD increased in alcoholics after 2 years of abstinence (lumbar BMD, mean +/- SEM, 1.06 +/- 0.03 to 1.10 +/- 0.04 g/cm2, p < 0.05; femoral BMD, 0.82 +/- 0.02 to 0.84 +/- 0.02 g/cm2; p < 0.02). Moreover, lumbar BMD increased in alcoholics (2.9 +/- 1.4%) and decreased in controls (-1.1 +/- 0.2%; p < 0.02). Femoral BMD also increased in alcoholics (2.8 +/- 1.0%) but the expected mean decrease of -0.92% was found in healthy age-matched males. Baseline low osteocalcin levels (5.1 +/- 0.6 ng/ml) increased after 1 year (8.6 +/- 0.5 ng/ml, p < 0.001) and 2 years of abstinence (9.5 +/- 0.7 ng/ml, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)     

Bone loss associated with a high fibre weight reduction diet in postmenopausal women

OBJECTIVE: To examine the effect of high fibre weight reduction on bone density in postmenopausal women. DESIGN: Case-control study. SETTING: Hospital outpatient dietetic clinic and Osteoporosis Screening Unit. SUBJECTS AND INTERVENTIONS: Sixteen overweight volunteers who followed a high fibre reducing diet for 6 months, to lose 20% of excess body weight (above body mass index 25 kg/m2), and returned to their starting weight by the end of a further 6 months. Forty-six non-dieting controls, matched for age and years postmenopause, selected from screening unit volunteer register. RESULTS: Annual percentage changes in lumbar spine bone mineral density, measured by dual energy X-ray absorptiometry were: controls -2.5% (SE 0.5), dieters -4.8% (0.9), 95% confidence interval of difference between groups -0.2 to -4.3% (P = 0.03); femoral neck bone density controls -2.5% (0.5), dieters -2.1% (0.9), 95% confidence interval of difference -1.7 to 2.5% (P = 0.69). CONCLUSIONS: High fibre weight reduction in postmenopausal women significantly increased annual bone loss from the lumbar spine. This loss was not reversed by weight regain in the second 6 months. Repeated cycles of high fibre weight loss and weight gain may increase the risk of spinal osteoporosis.     

Monophosphoryl lipid A induces delayed preconditioning against cardiac ischemia-reperfusion injury

Quantitative ultrasound (QUS) bone measurement is a promising, relatively new technique for the diagnosis of osteoporosis. Unlike to the more established method of bone densitometry [measurement of bone mineral density (BMD) e.g. using dual X-ray absorptiometry (DEXA)], QUS does not use ionizing radiation. It is cheaper, takes up less space and is easier to use than densitometry techniques. The two QUS parameters currently measured are broadband ultrasound attenuation (BUA) and speed of sound (SOS). The reported age-related changes for healthy women range from -0.27% to -1.62% per year for BUA and from -0.06% to -0.19% per year for SOS. Precision ranges from 1.0 to 3.8% (CV) for BUA and from 0.19 to 0.30% (CV) for SOS. The new method of imaging ultrasound has improved the precision of QUS measurements. QUS is significantly correlated with BMD. Studies with the latest equipment have shown r-values between 0.6 and 0.9 in site-specific measurements, and QUS is thus believed to reflect mainly BMD. However, other studies indicate that QUS measures something other than the actual mineral content of bone, namely bone quality, e.g. in vitro studies have shown that QUS reflects trabecular orientation independently of BMD. In both cross-sectional and prospective studies, QUS seems to be as good a predictor of osteoporotic fractures as BMD. In two large prospective studies, QUS also predicted fracture risk independently of BMD. QUS has just begun to be used systematically for monitoring the response to anti-osteoporotic treatments in prospective trials. In the studies performed, QUS has been found to be useful in the follow-up of patients. QUS is thus a promising new technique for bone assessment.     

Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial

Raloxifene is a selective estrogen receptor modulator that in experimental animals acts as an estrogen receptor antagonist in breast and endometrium but as an estrogen receptor agonist in the skeletal and cardiovascular systems. We conducted a 1-year prospective, randomized, double-blind trial in 143 postmenopausal osteoporotic women (mean +/- SD age, 68.4+/-5.0 years) with at least one prevalent vertebral fractures and low bone mineral density (BMD), comparing groups receiving raloxifene at 60 mg/day (RLX60) or 120 mg/day (RLX120) and a control group receiving supplements of 750 mg/day of calcium and 400 IU/day of vitamin D. There were no differences among groups in the occurrence of uterine bleeding, thrombophlebitis, breast abnormalities, or increased endometrial thickness (assessed by ultrasonography). As compared with controls, the changes in values over 1 year for RLX60 and RLX120, respectively, were significant for serum bone alkaline phosphatase (-14.9%, -8.87%), serum osteocalcin (-20.7%, -17.0%), and urinary C-telopeptide fragment of type I collagen/creatinine (-24.9%, -30.8%), markers of bone turnover; for serum total cholesterol (-7.0% for RLX60) and low density lipoprotein cholesterol (LDL) (-11.4% for RLX60) and for the LDL/HDL cholesterol ratio (-13.2%, -8.3%). BMD increased significantly in the total hip (1.66% for RLX60) and ultradistal radius (2.92%, 2.50%). There were nonsignificant trends toward increases over controls in BMD for lumbar spine, total body, and total hip (for RLX120). Using a >15% cutoff definition, raloxifene had no effect on incident fractures, but using a >30% cutoff, there was a dose-related reduction (p = 0.047). We conclude that raloxifene therapy is well tolerated, reduces serum lipids, and does not stimulate the uterus or breasts. It has beneficial effects on bone, although, under the conditions of this study, these appear to be of a smaller magnitude than have been reported with estrogen therapy.     

Bisphosphonate risedronate prevents bone loss in women with artificial menopause due to chemotherapy of breast cancer: a double-blind, placebo-controlled study

PURPOSE: To determine the effectiveness and safety of the bisphosphonate risedronate in preventing bone loss in young women with breast cancer and early menopause induced by chemotherapy who are at major risk for the development of postmenopausal osteoporosis. PATIENTS AND METHODS: Fifty-three white women, aged 36 to 55 years, with breast cancer and artificially induced menopause were stratified according to prior tamoxifen use. Thirty-six patients received tamoxifen (20 mg/d). Within each stratum, patients were randomly assigned to receive risedronate (n = 27) or placebo (n = 26). Treatment consisted of eight cycles oral risedronate 30 mg/d or placebo daily for 2 weeks followed by 10 weeks of no drug (12 weeks per cycle). Patients were monitored for a third year without treatment. RESULTS: Main outcomes of the study were changes in lumbar spine and proximal femur (femoral neck, trochanter, and Ward's triangle) bone mineral density (BMD), and biochemical markers of bone turnover. In contrast to a significant decrease of BMD at the lumbar spine and hip in the placebo group, there was an increase in BMD in the risedronate group. On treatment withdrawal, bone loss ensued, which suggests that treatment needs to be continuous to maintain a protective effect on bone mass. At 2 years, the mean difference (+/- SEM) between groups was 2.5% +/- 1.2%, (95% confidence interval [CI], 0.2 to 4.9) at the lumbar spine (P = .041) and 2.6% +/- 1.1%, (95% CI, 0.3 to 4.8) at the femoral neck (P = .029). Similar results were observed at the hip trochanter. Results by stratum indicate a beneficial, although partial, effect of tamoxifen in reducing bone loss. Risedronate was well tolerated and showed a good safety profile, with no evidence of laboratory abnormalities. CONCLUSION: Risedronate appears to be a safe treatment that prevents both trabecular and cortical bone loss in women with menopause induced by chemotherapy for breast cancer.     

Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after seven years of treatment

PURPOSE: To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy. PATIENTS AND METHODS: Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs. RESULTS: The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P < 0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P < 0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures. CONCLUSIONS: Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy.     

Differential presentation of cortical and trabecular peripheral bone mineral density in acromegaly

Growth hormone (GH) has been suggested as a therapeutic tool for the treatment of osteopenia. To assess the differential influence of growth hormone on cortical and trabecular bone, bone mineral densities (BMD) of the ultradistal radius were determined in 18 men and 19 women with clinically and biochemically confirmed acromegaly using peripheral computed tomography and a specialized scanner (Stratec XCT 900). The results were expressed in equivalents to hydroxyl-apatite (mg/ccm) and compared with the BMD of healthy controls (17 men, 34 women). Cortical bone mineral density was significantly higher in acromegalic women (295.2 +/- 18.4, X +/- SEM) and men (339.4 +/- 21.2) compared to healthy women (243.0 +/- 12.8) and men (272.2 +/- 15.9). In contrast, trabecular BMD did not differ between acromegalic patients (men: 161.0 +/- 16.1; women: 116.5 +/- 10.5) and controls (men: 158.0 +/- 12.2; women: 134.1 +/- 6.3). Acromegalic women showed a significant correlation between insulin-like growth factor (IGF-I) expression and cortical BMD, whereas in acromegalic men GH levels correlated significantly with cortical BMD. Greatly increased serum osteocalcin levels in both, acromegalic men (15.5 +/- 3.3 ng/ml) and women (12.9 +/- 1.8) compared to controls (men: 6.7 +/- 1.7; women: 7.7 +/- 1.0) indicates the activation of osteoblastic bone formation. This study revealed an increase in cortical BMD at the forearm; in acromegalic patients; though trabecular BMD did not differ from controls. The differential mineralization of cortical and trabecular bone in acromegaly may be indicative of the detrimental effect accompanying pituitary insufficiency can have on trabecular bone, despite substitution therapy, but could also be due to different reactivity of cortical and trabecular bone to GH and/or IGF I. The observable increase of bone mineral density in acromegaly suggests a potential use for GH in treating osteoporosis.     

Comparison of the T cell-independent antibody response of mice and rats exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin

In a prospective population-based cohort study, we assessed whether bone mineral density (BMD) measurements of perimenopausal women and other risk factors for osteoporosis are predictive of subsequent fracture. Women aged 47-51 years chosen randomly from a population register who underwent a bone density measurement 2 years previously were followed up by questionnaire to assess the 2-year incidence of any self-reported fractures. We found that 44 women, out of 1857 who completed the questionnaire, sustained at least one fracture within a 2-year follow-up period. After adjustment for covariates, the odds ratio of sustaining a fracture was 1.6 (95% confidence interval [CI] 1.16-2.34) for every standard deviation reduction in BMD at the spine, for women with a prior history of fracture the odds ratio of a subsequent fracture was approximately 2 (95% CI 1.31-3.03), a family history of hip fracture (maternal grandmother) carried an odds ratio of 3.7 (95% CI 1.55-8.85), while being postmenopausal or having a hysterectomy resulted in an odds ratio of 1.98 (1.02-3.56). This study has shown that BMD measurements at the hip and spine and other risk factors predict any nonhip and nonspine perimenopausal fractures. Further follow-up is required to assess the predictive performance of BMD measurements and other risk factors for hip and spine fractures.     

Evidence that increased calcium intake does not prevent early postmenopausal bone loss

Calcium's ability to prevent bone loss in early postmenopausal women is controversial. We used data on 394 women from the placebo group of the Early Postmenopausal Interventional Cohort study, a clinical trial of alendronate, to investigate the relation of calcium intake to bone loss. Calcium intake was recorded, and bone mineral density (BMD) (in the lumbar spine, total body, forearm, and hip) and biochemical markers of bone turnover (serum total alkaline phosphatase, serum osteocalcin, and urinary N-telopeptide crosslink levels) were measured at baseline and annually thereafter. Women whose baseline calcium intake was <500 mg/d were advised to increase their calcium intake. Mean (+/- SE) BMD decreased by 1.9% +/- 0.16% at the lumbar spine and 1.6% +/- 0.14% at the hip over the 24-month period. Despite wide variations in baseline calcium intake and changes in calcium intake, these measures were not significantly associated with changes in BMD or bone turnover. Even women whose total calcium intake was >1333 mg/d (the highest tertile of total calcium intake) showed a decline in BMD of almost 2%, similar to declines in the lower two tertiles of total calcium intake (<869 and 869-1333 mg/d, respectively). Increased calcium intake resulted in modest mean increases of approximately 200 mg/d. We were unable to demonstrate that increases of this magnitude or much greater (1 g/d) were protective against declines in BMD at any site, even in women who had the lowest calcium intake at baseline. In addition to adequate calcium intake, more effective therapy appears to be required when the therapeutic goal is to increase or maintain BMD.     

Maintenance of bone mass in patients receiving dialytic therapy

To determine what factors contribute to and change bone mineral density (BMD) in dialysis patients, serial lumbar spine dual x-ray absorptiometry studies were analyzed by stepwise regression analysis in 67 black dialysis patients. The patients were 50.5 +/- 2.0 years of age (mean +/- SE) and 49% were men; the patients had received dialytic therapy for 3.7 +/- 0.5 years. The mean initial BMD z-score was 0.147 +/- 0.182. By cross-sectional analysis, the BMD increased in the male and premenopausal female patients but decreased in the postmenopausal female patients by 2.5% g/cm2/decade of life, less than that observed in black patients with normal renal function. Univariate analysis and stepwise regression analysis demonstrated radiographic evidence of osteopenia (beta-coefficient = -0.180 +/- 0.050; P = 0.001) and prior parathyroidectomy (beta-coefficient = 0.133 +/- 0.070; P = 0.054) as the only variables significantly correlated to the BMD. The effects of biochemical variables and different treatments on the delta BMD, calculated as the difference between each patient's first and second BMDs divided by the interval in years, were evaluated by stepwise regression analysis in 41 patients. The mean interval between the two BMDs was 18.4 +/- 1.02 months (range, 5 to 34 months) and the delta BMD was 0.025 +/- 0.018 g/cm2/yr, increasing in 65% of the patients. By univariate and stepwise regression analysis, the mean monthly serum total alkaline phosphatase concentration was the only variable that correlated with the delta BMD (beta-coefficient = 0.0001; P = 0.030).(ABSTRACT TRUNCATED AT 250 WORDS)     

Association of bone mineral density with apolipoprotein E phenotype

The phenotypes of apolipoprotein E (Apo E) and their relationship with the bone mineral density (BMD) were examined in 284 unrelated postmenopausal Japanese women aged 47-82 years (64.0 +/- 1.0 years, mean +/- SE). The Apo E phenotype was analyzed by the isoelectric focusing method, followed by immunoblotting. The relationship between the Apo E phenotype and the vitamin D receptor (VDR) gene or estrogen receptor (ER) gene genotypes was also studied in the same population. The Apo E phenotypic frequencies in our population were 9.9% for E3/2, 66.5% for E3/3, 1.8% for E4/2, 19.7% for E4/3, and 2.1% for E4/4. We classified these phenotypes into three categories: Apo E4-/- (E3/2 and E3/3, n = 217, Apo E4 +/- (E4/3 and E4/2, n = 61), and Apo E4+/+ (E4/4, n = 6). The age, body weight, body height, and years since menopause were not significantly different among these three categories. The lumbar BMD values in these three groups were significantly different in the order of E4-/- (0.91 +/- 0.01 g/cm2), E4 +/- (0.85 +/- 0.02 g/cm2), and E4+/+ (0.83 +/- 0.06 g/cm2) (p = 0.031). The same trend was also observed for the Z score of the total BMD (p = 0.022). The serum level of intact osteocalcin in E4+/+ (15.2 +/- 5.7 ng/ml) was higher than in E4-/- (7.7 +/- 0.3 ng/ml) or E4 +/- (7.7 +/- 0.7 ng/ml) (p = 0.004 by analysis of variance). However, there were no other significant differences in the serum or urinary levels of bone turnover markers. Serum cholesterol in the E4+/+ group tended to be higher than in the other two groups (p = 0.05). There were no significant associations of the VDR and ER genotypes with the Apo E4 phenotype. A multivariate linear regression analysis revealed Apo E4 to be a significant, independent predictor of the Z score of the lumbar BMD. The effect of the Apo E4 allele on the Z score of the lumbar BMD (-0.493 +/- 0.152) was not significantly different from that in the AAB of VDR (-0.616 +/- 0.225) or PPxx of ER (-0.785 +/- 0.314). In conclusion, the Apo E4 allele is associated with a low bone mass in postmenopausal Japanese.