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.     

The predictive value of biochemical markers of bone turnover for bone mineral density in early postmenopausal women treated with hormone replacement or calcium supplementation

To compare the relative sensitivity and specificity of bone turnover indexes for bone loss or gain in early postmenopausal women, we performed a multicenter trial in 236 menopausal women (mean age, 51 yr), who were randomized to hormone replacement therapy (HRT) or calcium supplementation (CS; 500 mg/day) for 1 yr. Two markers of bone formation, osteocalcin (OC) and bone alkaline phosphatase (BSAP), and two markers of bone resorption, urinary N-telopeptide (NTx) and urinary free deoxypyridinoline (fDpd), as well as spine and femoral neck bone mineral density (BMD) were measured at baseline and 3, 6, and 12 months after treatment. Women receiving HRT (n = 105) showed a significant increase in spine BMD (+2.5%; P < 0.0001) and hip BMD (+1.0%; P = 0.02) compared to women receiving CS, who showed a decline at both sites (-1.1%; P < 0.01). All four markers showed time-dependent decreases in women receiving HRT (P < 0.001) and no change in women receiving CS alone. When baseline indexes of turnover were stratified by quartile, there was a significantly greater increase in BMD among those with the highest NTx, OC, and BSAP levels compared to that in those with the lowest NTx, OC, and BSAP levels (P < 0.05). The highest quartile for percent change from baseline to 6 months in fDpd, BSAP, and NTx was also associated with the greatest change in spine BMD at 1 yr. Receiver operator characteristic curves for percent change from baseline to 6 months in an individual marker to 1 yr change in BMD during HRT revealed that the percent change in NTx provided the greatest discrimination between gain and loss of BMD. When subjects receiving HRT were compared by their positive or negative skeletal response at 1 yr and their baseline turnover marker, initial NTx values were significantly higher in those that gained bone than in those that lost bone (P = 0.0002). CS women in the highest quartile for NTx at baseline had significantly greater decreases in spine BMD than subjects with the lowest NTx values (P < 0.005), although this was not true for fDpd (P < 0.20). In conclusion, for early postmenopausal women there are differential responses of biochemical markers to HRT and CS. Baseline urinary NTx and serum OC were the most sensitive predictors of change in spine BMD after 1 yr of either HRT or CS. Similarly, the percent change in NTx and OC from baseline to 6 months best predicted bone gain or loss. We conclude that markers of bone formation and resorption can be used clinically to predict future BMD in early postmenopausal women.     

Recruitment strategies in the women's health trial: feasibility study in minority populations. WHT:FSMP Investigators Group. Women's Health Trial:Feasibility Study in Minority Populations

The Women's Health Trial:Feasibility Study in Minority Populations (WHT:FSMP) examined the feasibility of recruiting postmenopausal women from a broad range of racial and socioeconomic backgrounds into a primary prevention trial requiring marked reductions in dietary fat. Postmenopausal women aged 50-79 yr who had no history of cardiovascular disease or cancer and who consumed 36% or more total energy from fat qualified to participate. We randomized the women into dietary intervention (60%) or control (40%) groups; we aimed to randomize 750 women in 18 months in each of the three clinical centers. All centers achieved goals for randomization based on ethnicity, and two centers exceeded overall recruitment goals. The greatest source of randomized participants was mass mailing, followed by items in the media, referrals, and community outreach. Recruitment yields were generally similar for the ethnic groups but lower for less-educated participants. The experience of WHT:FSMP indicates that postmenopausal women from the African-American, Hispanic, and non-Hispanic white communities can be recruited into dietary intervention studies for the prevention of disease.     

Cyclosporine combined with methylprednisolone or methotrexate in prophylaxis of moderate to severe acute graft-versus-host disease

BP and urinary sodium and potassium were assessed in 183 African-American, 113 US white and 72 Nigerian college students. SBP was higher in African-American males compared with Nigerian and US white males (123.1, 117.6 and 115.7 mmHg, respectively, P < 0.05). There were no significant differences observed between African-American and white male students in overnight urinary excretion rates of sodium and potassium. In contrast, African-American females excreted more sodium (41.0 vs. 31.3 mEq per 8 hours, P < 0.01) and potassium (12.0 vs. 8.9 mEq per 8 hours, P < 0.05) compared with white females. Only among the white students was a significant sex difference observed in urinary electrolyte excretion rates, where males excreted at higher rates than females. Multiple regression models for the African-Americans revealed that potassium explained only 4% of the SBP variance. Among the US whites and Nigerians, sodium explained 4.9% and 6.8%, respectively, of the DBP variance.     

Prevention of bone loss induced by thyroxine suppressive therapy in postmenopausal women: the effect of calcium and calcitonin

Although controversies exist on the possible adverse effect of T4 on bone mass, most studies reported bone loss in estrogen-deprived postmenopausal women taking suppressive doses of T4. We prospectively studied 46 postmenopausal women with carcinoma of thyroid for 2 yr to evaluate the rate of bone loss and assess whether calcium supplementation with or without intranasal calcitonin was able to decrease the rate of bone loss. All patients were receiving a stable dose of L-T4 (170 +/- 60 micrograms/day or 3.0 +/- 1.4 micrograms/kg.day) for more than 1 yr. All had TSH levels of 0.03 mIU/L or less and an elevated free T4 (FT4) index, but normal T3 levels. The calcium intake was low and averaged 507 +/- 384 g/day as assessed by dietary recall. The subjects were randomized into three groups: 1) intranasal calcitonin (200 IU daily) for 5 days/week plus 1000 mg calcium daily, 2) calcium alone, or 3) placebo. Total body and regional bone mineral density were measured by a dual energy x-ray absorptiometry bone densitometer at 6-month intervals. The results showed that both groups 1 and 2 had stable bone mass, whereas patients in groups 3 showed significant bone loss at the end of 2 yr (lumbar spine, 5.0%, hip, 6.7%, trochanter, 4.7%; Ward's triangle, 8.8%; P < 0.05), with bone mineral densities at all four regions lower than those in the other two groups (P < 0.05). There were no differences between groups 1 and 2. All three groups had elevated osteocalcin levels compared with age-matched reference controls. At 1 yr, the osteocalcin level decreased in groups 1 and 2, but remained significantly raised in group 3. No significant changes were detected in the bone-specific alkaline phosphatase levels. Urinary hydroxyproline excretion increased in group 3 at the end of 2 yr, but remained the same in groups 1 and 2. In conclusion, T4-suppressive therapy was associated with bone loss in postmenopausal women, which could be prevented by either calcium supplementation or intranasal calcitonin, although the latter did not provide additional benefit compared to calcium alone. However, careful titration of T4 dosage to maintain biochemical euthyroidism is a better way to avoid the adverse effect of T4 on bone.     

Lens epithelial proliferation cataract in segmental trisomy involving mouse Chromosomes 4 and 17

To determine whether vitamin D receptor (VDR) gene polymorphisms are associated with bone mineral density (BMD) and bone loss in the Japanese population, VDR BsmI RFLPs were analyzed in 191 postmenopausal Japanese women by comparing B allele and b allele DNA sequences, and a point mutation was confirmed. We examined VDR BsmI restriction fragment length polymorphism (RFLP) with an amplification refractory mutation system (ARMS) using this point of mutation. The frequency of VDR BsmI alleles in the Japanese population was significantly different from that in whites. The bb genotype was identified in 79.6%, of the subjects, the Bb genotype in 19.3%, and the BB genotype was in only 1.1%. We find no significant differences in lumbar spine baseline BMD between the bb genotype and the Bb genotype. In both early and late postmenopausal periods, serial measurements of vertebral BMD revealed that subjects with the Bb genotype lost BMD faster than those with the bb genotype (P = 0.001). We conclude that there is a significant relationship between RFLPs of BsmI VDR and the annual rates of bone loss during early and late postmenopausal periods in the Japanese population.     

Comparison of the sedative and amnesic effects of midazolam and propofol

OBJECTIVE: To determine normal serum bone-related biochemical variables in older African-Americans. DESIGN: A convenience sample of older African-Americans who had a health screening and blood testing for calciotropic hormones was compared with white Americans who were recruited at the end of the Systolic Hypertension in the Elderly Program (SHEP) study and were not on a thiazide diuretic. SETTING: Community-dwelling African-Americans who participated in SHEP or who attended one of two mass health screenings. PARTICIPANTS: Thirty-two African-Americans aged 68-93 years and 43 white Americans aged 70-89 years. MEASUREMENTS: Twenty-five hydroxyvitamin D (25OHD), parathyroid hormone, osteocalcin, and calcitonin. RESULTS: Serum 25OHD levels in 38% of the African-American men and 38% of African-American women were less than 8 ng/mL compared with 22% of Caucasian men and 40% of Caucasian women. Serum parathyroid hormone (PTH) was above the normal range in 25% of men and 33% of women of African-American descent and 14% of Caucasian men and 30% of Caucasian women. Serum 25OHD was lower (P < 0.05) in individuals with a previous history of fracture. Serum albumin (P < 0.05), calcitonin (P < 0.05), and osteocalcin (P < 0.05), but not 25OHD, were lower in African-Americans (men and women) when compared with Caucasians (P < 0.05). Serum calcium corrected for albumin was higher in the African-Americans than in the Caucasians (P < 0.05). As previously reported in Caucasians, PTH was inversely related to log 25OHD in African-Americans. Serum osteocalcin was positively correlated to PTH in African-Americans, as previously reported in Caucasians. Log 25OHD correlated inversely with osteocalcin in African-Americans, but this was not seen in Caucasians. CONCLUSIONS: In this limited sample, hypovitaminosis D (as assessed by 25OHD level) with secondary hyperparathyroidism occurred frequently in elderly African-Americans. Osteocalcin, a measure of osteoblast activity, correlated with 25OHD and parathyroid hormone. Osteocalcin serum levels were lower in African-Americans than Caucasians, but serum calcium corrected for albumin was higher in the former compared to the latter.     

Density functional studies on herpes simplex virus type 1 thymidine kinase-substrate interactions: the role of Tyr-172 and Met-128 in thymine fixation

It has been well documented that the prevalence of certain electrocardiographic (ECG) findings among individuals free of coronary heart disease (CHD) differs by race. However, it is not known whether these differences exist independently of CHD risk factors (e.g., hypertension). We examined the ECG tracings of 2,686 apparently healthy, middle-aged African-American and white men and women who participated in the Atherosclerosis Risk in Communities Study and were at low risk of CHD. Using the Minnesota Code, among men, 46% of African-Americans, but only 25% of whites, had a minor ECG finding (p < 0.001). In women, 32% of African-Americans and 23% of whites had a minor ECG finding (p < 0.01). Specifically, the age-adjusted prevalences of high-amplitude R wave, ST elevation, T-wave findings, and prolonged P-R interval were statistically significantly higher in African-Americans. As for continuous ECG measurements, the R wave in leads V5 and V6, the S wave in V1, the J-point amplitude in leads V2 and V5, the P-R interval, and the Cornell voltage (?S V3? + R aVL) for left ventricular hypertrophy were all significantly greater in African-Americans than in whites. However, in both men and women, the heart rate corrected QT interval was shorter in African-Americans than in whites. All of these findings remained statistically significant after further adjustment for traditional CHD risk factors. These results suggest that racial differences in electrocardiograms may not be explained entirely by differences in established CHD risk factors, and because current diagnostic ECG criteria are largely based on data from middle-aged white men and women, race should be considered in the interpretation of ECG findings.     

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.     

The effect on bone mass and bone markers of different doses of ibandronate: a new bisphosphonate for prevention and treatment of postmenopausal osteoporosis: a 1-year, randomized, double-blind, placebo-controlled dose-finding study

The present article describes the results from a phase II dose finding study of the effect of ibandronate, a new, third generation bisphosphonate, in postmenopausal osteoporosis. One hundred and eighty postmenopausal, white women, at least 10 years past a natural menopause, with osteopenia defined as a bone mineral density (BMD) in the distal forearm at least 1.5 SD below the premenopausal mean, entered and 141 (78%) completed a 12 months randomized, double-blind, placebo-controlled study. The women received 0.25, 0.5, 1.0, 2.5, or 5.0 mg ibandronate daily or placebo. All women received a daily calcium supplementation of 1000 mg Ca2+. Bone mass and biochemical markers of bone turnover were measured every 3 months throughout the study period. The average changes in bone mass showed positive outcome in all regions in the groups receiving ibandronate 2.5 and 5.0 mg. The responses in the two groups were not significantly different, although there was a tendency toward a higher response in bone mass in the group receiving ibandronate 2.5 mg, where the increase in BMD was 4.6 +/- 3.1% (SD) in the spine (p < 0.001), 1.3 +/- 3.0% (SD) to 3.5 +/- 5.3% (SD) in the different regions of the proximal femur (p < 0.03 to p < 0.002), and 2.0 +/- 1.9% (SD) in total body bone mineral content (BMC) (p < 0.001). There was no significant changes in bone mass in the group receiving calcium (placebo) and ibandronate 0.25 mg. Dose-related responses were found in all biochemical markers of bone turnover. In average, serum osteocalcin decreased 13 +/- 14% (SD) (placebo) and 35 +/- 14% (SD) (5.0 mg). Urinary excretions of breakdown products of type I collagen decreased 35 +/- 21% (SD) (placebo) and 78 +/- 28% (SD) (5.0 mg), p < 0.001 in all groups. In conclusion, the results suggest that ibandronate treatment increases bone mass in all skeletal regions in a dose dependent manner with 2.5 mg being the most effective dose. Ibandronate treatment reduces bone turnover to premenopausal levels and is well tolerated.     

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.     

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.     

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.     

Spinal and femoral bone mass accumulation during normal adolescence: comparison with female patients with sexual precocity and with hypogonadism

Since the attainment of higher bone mineral density (BMD) is a crucial strategy in preventing age-related bone loss and consequent fracture, we determined when bone mass of the lumbar spine (L2-L4) (g/cm2) and femoral neck (g/cm2) reaches its peak in healthy Japanese subjects and examined the influence of early exposure to estrogen and estrogen deficiency on BMD. We also determined the volumetric BMD, termed bone mineral apparent density (BMAD), of the lumbar spine and femoral neck. Using dual-energy x-ray absorptiometry (DXA) (Hologic QDR-1000), we measured BMD of both the lumbar spine and the femoral neck in 31 healthy children aged 2-11 yr, 269 children (138 males and 131 females) aged 13-19 yr, 12 men and 12 women aged 20-34 yr as adult controls, 11 patients with female central sexual precocity, and 3 patients with female primary hypogonadism. Because the densitometric data obtained from DXA are strongly influenced by the size of the bone in growing subjects, the volumetric BMAD (g/cm3) of the vertebral cube (L2-L4) and femoral neck were determined: BMAD (g/cm3) = BMD (g/cm2)/square root of scanned area (cm2) for the lumbar spine and by BMAD = BMD/width for the femoral neck. The BMD, both lumbar spine and femoral neck, nearly reached its peak at age 14.5-15 yr in girls and 16.5-17 yr in boys when compared with adult normal values. The difference in this age between sexes is identical to the difference in age at sexual maturation. BMD in patients with sexual precocity was high compared to age-matched controls, whereas patients with primary hypogonadism showed lower lumbar apparent BMD, and the increase in lumbar BMAD (g/cm3) was noted after the progression of puberty in healthy children, probably suggesting the importance of sex steroids in the increase of BMD and lumbar BMAD in both sexes. The girls with earlier menarche showed higher lumbar BMD at age 18 and 19 yr. For the femoral BMAD, there was no significant relationship between this value and age in girls. We conclude that peak bone mass is mainly achieved by late adolescence in Japanese as in Caucasians and that pubertal progression and probably estrogen itself play a crucial role in accumulation of bone mass in females.     

Peripheral monocyte culture supernatants of menopausal women can induce bone resorption: involvement of cytokines

Increased bone resorption is a mechanism contributing to bone loss in the postmenopausal period. Cytokines are involved in osteoclastic differentiation and, therefore, may play a role in the regulation of bone resorption. Several previous works showed the implication of interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF alpha) in the modulation of bone remodeling. This study determines the concomitant production of the three cytokines and tests the bone-resorbing activity of peripheral monocyte supernatants. Four groups of women were studied: premenopausal women (n = 13; mean age, 47 +/- 0.9 yr), untreated postmenopausal women (n = 21; mean age, 52 +/- 0.6 yr), postmenopausal women treated with estrogens (n = 14; mean age, 54.2 +/- 1.1 yr), or postmenopausal women treated with ethanehydroxydiphosphonate (n = 12; mean age, 53.2 +/- 2 yr). Assignment to clinical groups was verified by plasma FSH and estradiol determinations. Lumbar spine bone mineral density was significantly higher in the premenopausal women group than in the three postmenopausal groups. Peripheral blood monocytes were cultured for 48 h with 20% autologous plasma, and after stimulation with lipopolysaccharides. IL-1, IL-6, and TNF alpha levels were measured by RIA in the monocyte surpernatants. The three cytokines were highly correlated to each other, IL-1 with IL-6 (r = 0.76; P < 0.001), IL-1 with TNF alpha (r = 0.89; P < 0.001), and IL-6 with TNF alpha (r = 0.89; P < 0.001). The mean levels of the three cytokines could not be compared because of the variations in the values. However, a trend toward lower levels in the three cytokines was noted in estrogen-treated women compared to the untreated postmenopausals. The bone-resorbing activity of monocyte supernatants, assessed by fetal long bone-resorbing assay, increased in untreated postmenopausal compared to that in premenopausal women (1.22 +/- 0.08 vs. 0.87 +/- 0.11; P < 0.05). In estrogen-treated patients, this activity decreased to premenopausal levels (0.89 +/- 0.04 vs. 0.87 +/- 0.11; P = NS). The resorbing activity was correlated to IL-1 (r = 0.28; P = 0.03), IL-6 (r = 0.52; P < 0.01), and TNF alpha (r = 0.48; P < 0.01). The addition of cytokine inhibitors and IL-1 receptor antagonist and TNF alpha antibodies to the supernatant bone culture medium induced a significant decrease in the calcium release. Those data show the involvement of several cytokines in the bone resorption process after estrogen deficiency.     

Effects of methyl ethyl ketone, acetone, or toluene coadministration on 2,5-hexanedione concentration in the sciatic nerve, serum, and urine of rats

PURPOSE: The aim of this study was to examine the associations among fasting insulin, adiposity, waist girth, and blood pressure among a nondiabetic multiethnic population. METHODS: A cross-sectional study was performed among 25-44-year-old African-Americans (n = 159), Cuban-Americans (n = 128), and non-Hispanic whites (n = 207) selected from Dade County, Florida. Fasting insulin levels were correlated with resting blood pressure level within each ethnic group. The separate effects of percentage body fat and waist girth on the association between blood pressure and insulin were analyzed in multiple linear regression and analysis of covariance. RESULTS: Fasting insulin was positively associated with systolic (r = 0.26-0.39; P < 0.01) and diastolic blood pressure (r = 0.19-0.30; P = 0.10 to P < 0.001) among women of all ethnic groups and among non-Hispanic white men (r = 0.27; P < 0.05). Stepwise linear regression analyses revealed statistically significant associations between systolic and diastolic blood pressure and fasting insulin level in non-Hispanic whites independent of other covariates, including sex and percentage body fat (P < 0.001). Fasting insulin was also independently and significantly related to systolic blood pressure among African-Americans (P = 0.02). Among Cuban-Americans, sex and percentage body fat were the main correlates of blood pressure level. Analysis of covariance revealed a relationship between insulin and blood pressure that was independent of waist girth among men and women. CONCLUSIONS: Fasting insulin level and blood pressure were positively associated among African-Americans and non-Hispanic whites. This association was not entirely due to the common association with percentage body fat or waist girth.     

NIDDM incidence in a tri-ethnic population of diagnosed hypertensives

OBJECTIVE: Significant racial/ethnic differences exist in the prevalence of hypertension (HTN) and non-insulin dependent diabetes mellitus (NIDDM). The purpose of this study was to determine if ethnicity (African-American, Hispanic and non-Hispanic white) was related to NIDDM incidence over a maximum follow-up period of 10 years. DESIGN: Retrospective cohort study. SETTING: A large, urban public health care system serving over 200,000 predominantly minority persons. The system includes nine primary care health centers. PATIENTS: African-American, Hispanic and non-Hispanic white patients with diagnosed hypertension who received primary care in the study setting. METHODS: Medical records of 2,941 hypertensives free of NIDDM at their baseline visit were reviewed to document incident NIDDM during follow-up. Sociodemographic characteristics and physiologic covariates consistently available in the medical record (blood pressure, height, weight, and blood glucose) were also abstracted. RESULTS: The mean age of patients at the baseline visit was 56 years; 67% were female, 63% were African-American. 17% Hispanic, and 20% non-Hispanic white. Two hundred thirty-six incident cases of NIDDM were identified in the cohort. In Cox proportional hazards analysis, the risk of developing NIDDM was not related to ethnicity either in univariate analysis or after adjusting for age, baseline blood glucose, and body mass index (adjusted RR for African Americans compared with whites = .82, 95% CI = .57-1.18; adjusted RR for Hispanics compared with whites = .84, 95% CI = .51-1.38). CONCLUSION: The lack of association between ethnicity and NIDDM risk among hypertensives is unexpected, and may indicate differences in the pathogenetic mechanisms that underlie the development of hypertension and NIDDM in these three ethnic groups.     

Comprehensive analysis of risk factors for acquisition of Pseudomonas aeruginosa in young children with cystic fibrosis

Racial differences in insulin secretion and insulin sensitivity in healthy children were studied by administering a 2-hour hyperglycemic clamp (225 mg/dL) to 14 black and 16 white healthy adolescents (Tanner II-V), and 12 black and 11 white prepubertal children, matched for age, body mass index, and Tanner I pubertal development. In prepubertal children, fasting and first-phase insulin concentrations were higher in blacks compared with whites (14.7+/-1.3 vs 10.4+/-1.2, P=0.02, and 76.9+/-6.8 vs 52.1+/-6.4 microu/mL, P=0.016). There were no differences in second-phase insulin levels and insulin sensitivity index. In pubertal adolescents, first-phase and second-phase insulin concentrations were higher in blacks compared with whites (first-phase: 157.3+/-18.3 vs 77.0+/-8.7 microu/mL, P=0.0003; second-phase: 175.0+/-24.3 vs 108.7+/-8.8 microu/mL, P=0.012). Insulin sensitivity index was 35% lower in black adolescents compared with whites (P=0.02). These findings indicate that significant differences in insulin secretion and sensitivity are detectable early in childhood in healthy African-American vs American whites. However, genetic (race) vs environmental factors (physical activity/fitness, energy balance) should be carefully scrutinized as potential factors responsible for such differences.     

Increased bone resorbing activity of peripheral monocyte culture supernatants in elderly women

Accelerated bone loss occurs in the years after menopause, and is an ongoing phenomenon in elderly women. The role of cytokines in bone loss after estrogen deficiency has been shown in ovariectomized rat and mice models. In humans, the involvement of bone resorbing cytokines is now well established. In the early years after menopause, monocyte activation leads to increased cytokine production. We have previously shown that the bone resorbing activity (BRA) of peripheral blood monocyte culture supernatants from postmenopausal women is higher than in premenopausal (Pre-M) women. This increased activity was related to interleukin (IL)-1, IL-6, and tumor necrosis factor-alpha levels. We here investigate whether monocyte activation still occurs in older women and whether this relates to bone resorption. We studied 19 healthy Pre-M, and 24 early (E-Post-M, menopause < 10 yr) and 24 late (L-Post-M, menopause > 10 yr) postmenopausal women. Peripheral blood monocytes were cultured for 48 h with 20% autologous plasma. BRA of monocyte supernatants (expressed as the ratio of monocyte supernatant over control bones supernatant) was assessed using fetal long-bone resorbing assays. Bone resorption was determined by urinary total pyridinoline excretion. BRA was significantly increased in E-Post-M and L-Post-M, compared with Pre-M subjects (1.20 +/- 0.10 and 1.15 +/- 0.20 vs. 0.73 +/- 0.10, respectively, both P < 0.05). Moreover, BRA of bones cultured with the supernatant of Pre-M was lower than BRA of control bones. BRA was significantly correlated with levels of IL-1, IL-6, and tumor necrosis factor-alpha in supernatant. Supernatant IL-1 levels were increased in E-Post-M, compared with Pre-M women (506 +/- 180 vs. 122 +/- 30, P < 0.05). Similarly, pyridinoline levels were increased in E-Post-M and L-Post-M, compared with Pre-M subjects (8.8 +/- 1 and 10.5 +/- 0.9 vs. 5.8 +/- 0.5, respectively, both P < 0.05). BRA was significantly correlated to pyridinoline levels. These data indicate the presence of monocyte activation in L-Post-M, which may be responsible for the increased bone resorption and bone loss observed in this elderly population.     

Changes in bone mass and serum markers of bone metabolism after parathyroidectomy

BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with an increased bone turnover. The simultaneous use of biochemical and bone mass measurements before and after parathyroidectomy is sparsely reported. This study was carried out to evaluate changes in bone mass and markers of bone metabolism in postmenopausal women with PHPT after parathyroidectomy. METHODS: Twelve women, mean age of 63 years, were investigated. Measurements of bone mineral density (total body, spine, hip, and forearm bone mineral density) with dual-energy x-ray absorptiometry were performed before operation and at follow-up at a median of 23 months. Concomitantly, changes in serum intact parathyroid hormone, bone-specific alkaline phosphatase (B-ALP), osteocalcin, carboxyterminal propeptide of type I procollagen, and the immunoactive carboxyterminal telopeptide of type I collagen were recorded. RESULTS: At follow-up a significant increase in bone mineral density of the spine (p < 0.05), femoral neck (p < 0.05), Ward's triangle (p < 0.05), and trochanter (p < 0.01) was observed. No significant changes in the forearm were registered. Levels of parathyroid hormone, B-ALP, and osteocalcin were elevated and intercorrelated before operation. The serum levels of these parameters decreased significantly after operation. Serum levels of carboxyterminal propeptide of type I procollagen and the immunoactive carboxyterminal telopeptide of type I collagen did not significantly differ from a reference population, and no major changes were observed at follow-up. CONCLUSIONS: Bone mineral density in the spine and hip is improved after parathyroidectomy in postmenopausal women with primary hyperparathyrodism. Serum levels of B-ALP and osteocalcin are elevated in PHPT and decrease after operation. The clinical usefulness of serum markers of collagen metabolism in investigating bone metabolism in PHPT seems limited.