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.     

Uteroplacental vascular involvement in recurrent spontaneous abortion

In the present study, we assessed the ability of increasing doses of intranasal calcitonin to suppress urinary deoxypyridinoline cross-link (DPD), a specific biochemical marker of bone resorption, in early postmenopausal women. Subjects consisted of 30 healthy Thai women within 5 years of postmenopause, randomly assigned to 50, 100, or 200 IU of intranasal calcitonin 5 days/week for 3 months. Calcium supplementation by calcium carbonate capsules at 750 mg of elemental calcium per day was given to all subjects. Twenty four-hour urine for DPD and creatinine assays was collected at baseline, 1 month, and 3 months after treatment. All DPD values were corrected with urinary creatinine before analyses. Data were expressed as mean +/- SEM. DPD decreased significantly 1 month after intranasal calcitonin treatment (P < 0.01). However, at 3 months, DPD increased when compared with the values at 1 month (P < 0.01), suggesting that there may be a reduction in the suppression of bone resorption after prolonged calcitonin therapy. Using a stepwise multiple regression model to address whether dosage and DPD at baseline influence the response to intranasal calcitonin, it was found that DPD suppression after intranasal calcitonin was not related to dosage but was strongly associated with baseline DPD (P < 0.0001). Suppression of bone resorption in early postmenopausal women by intranasal calcitonin is determined more by the state of bone turnover at baseline than the dosage of calcitonin.     

Calcium supplementation prevents seasonal bone loss and changes in biochemical markers of bone turnover in elderly New England women: a randomized placebo-controlled trial

Elderly women are at increased risk for bone loss and fractures. In previous cross-sectional and longitudinal studies of women residing in northern latitudes, bone loss was most pronounced during winter months and in those consuming less than 1 g calcium per day. In this study we sought to test the hypothesis that calcium supplementation by either calcium carbonate or dietary means would prevent seasonal bone loss and preserve bone mass. Sixty older postmenopausal women without osteoporosis were randomized to one of three treatment arms: Dietary milk supplementation (D-4 glasses of milk/day), Calcium carbonate (CaCO3-1000 mg/day in two divided doses), or placebo (P). After 2 yr, placebo-treated women consumed a mean of 683 mg/day of calcium and lost 3.0% of their greater trochanteric (GT) bone mineral density (BMD) (P < 0.03 vs. baseline); Dietary supplemented women averaged a calcium intake of 1028 mg/day and sustained minimal loss from the GT (-1.5%; P = 0.30), whereas CaCO3-treated women (total Ca intake, 1633 mg/day) suffered no bone loss from the GT and showed a significant increase in spinal and femoral neck BMD (P < 0.05). Femoral bone loss occurred exclusively during the two winters of the study (i.e. total loss, -3.2%; P < 0.02 in placebo-treated women) with virtually no change in GT BMD during summer. Serum 25-OH vitamin D declined by more than 20% (P < 0.001) in all groups during the winter months but returned to baseline in summer; PTH levels rose approximately 20% (P < 0.001) during winter but did not return to baseline during the summers. Urine N-telopeptide and osteocalcin levels increased significantly but only in the P-treated women and only during winter. Serum insulin growth factor binding protein 4, an inhibitory insulin growth factor binding protein, rose 15% (P < 0.03) from summer to winter, but this increase was significant only in those women consuming <1000 mg/day of calcium. By multivariate analysis, total calcium intake was the strongest predictor of bone loss from the hip. Urinary N-telopeptide also closely correlated with GT BMD but only during winter (P = 0.003). We conclude that calcium supplementation prevents bone loss in elderly women by suppressing bone turnover during the winter when serum 25-OH vitamin D declines and serum PTH increases. The precise amount of calcium necessary to preserve BMD in elderly women requires further studies, although in this study, at least 1000 mg/day of supplemental calcium was adequate prophylaxis against femoral bone loss.     

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.     

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.     

Vitamin D receptor gene polymorphism is associated with urinary calcium excretion but not with bone mineral density in postmenopausal women

Polymorphism of vitamin D receptor (VDR) gene has been found to be associated with serum osteocalcin (OC) levels and bone mineral density (BMD) in Caucasian identical twins and unrelated postmenopausal women. Being ethnically different and living in a geographic area with adequate vitamin D status due to abundant sunshine exposure, it is unclear whether VDR gene polymorphism will affect bone mass in Thai population. In the present study, we investigated the association between VDR gene polymorphism and bone metabolism in Thai postmenopausal women. Subjects consisted of 84 postmenopausal women. Bsm I, Taq I and Apa I polymorphisms of VDR gene were determined by PCR-RFLP. B, T and A represent the absence of the corresponding restriction sites while b, t and a indicate the presence of the restriction sites. Data were expressed as mean +/- SE. Sixty-six subjects (78.6%) had bb genotype while 18 (21.4%) had Bb genotype. None of the subjects was found to have BB genotype. Taq I restriction site was in linkage disequilibrium to the Bsm I site. For Apa I polymorphism, 33 (39.3%), 42 (50.0%) and 9 (10.7%) of the subjects had aa, Aa and AA genotypes, respectively. There was no significant difference in serum intact OC levels and BMD at various skeletal sites among subjects with different genotypes. Despite the lack of difference in BMD and intact OC levels, subjects with bb genotype had higher 24-hour urinary calcium excretion than those with Bb genotype (bb, 6.1 +/- 0.3 mmol/day; Bb, 4.4 +/- 0.6 mmol/day; p < 0.05). The effect of Bsm I VDR genotype was still significant (p < 0.05) after dietary calcium intake was controlled using analysis of covariance. Despite the difference in urinary calcium levels, there was no significant difference in fractional excretion of calcium among subjects with different Bsm I-related genotypes, suggesting that the effect of the VDR gene polymorphism on urinary calcium excretion is more likely due to the effect on intestinal calcium absorption rather than renal tubular calcium reabsorption. We conclude that VDR genotype distributions in Thai postmenopausal women are different from those reported in Caucasians. VDR gene polymorphism does not appear to be associated with BMD or bone turnover in Thai postmenopausal women. However, Bsm I VDR polymorphism may have physiologic role in calcium homeostatasis by modulating intestinal calcium absorption.     

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.     

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.     

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.     

The effects of the aminobisphosphonate alendronate on thyroid hormone-induced osteopenia in rats

Hyperthyroidism, either endogenous or iatrogenic, leads to increased bone turnover and osteopenia. This study was conducted to examine (1) whether thyroid hormone excess in rats causes bone changes similar to those seen in patients with hyperthyroidism, and (2) the effects of the aminobisphosphonate alendronate on the thyroid hormone-induced bone changes. Sprague-Dawley male rats, divided into four groups, received L-thyroxine (T4) 250 micrograms/kg/day (+T4) or vehicle (-T4) subcutaneously six times per week and alendronate 1.75 mg/kg (+ALN) or vehicle (-ALN) orally twice a week. Rats were sacrificed after 3 weeks of treatment, blood samples were analyzed for serum T4, triiodo-L-thyronine (T3), and osteocalcin, and the proximal tibiae were processed for histomorphometric analysis. Serum T4 and T3 levels measured 20-24 hours after the last injection were 2 to 2.5-fold higher in +T4 groups than in -T4 groups. Serum osteocalcin was significantly (P < 0.05) higher in +T4/-ALN group than in the other groups, which were not statistically different from each other. T4 treatment (+T4/-ALN) significantly decreased the amount of cancellous bone volume (-45%) and increased osteoid surface (+254%), osteoblast surface (+111%), and osteoclast surface (+176%) relative to control values. Alendronate increased the bone volume above control values in both T4-treated (+T4/+ALN) and untreated (-T4/+ALN) rats, and prevented the T4-induced increase in bone turnover in +T4/+ALN rats. It is concluded that (1) excess thyroid hormone induces cancellous bone loss associated with high bone turnover in the rat, and (2) this bone loss can be prevented by alendronate through the inhibition of osteoclastic activity.     

Biochemical markers of calcium and bone metabolism during 18 months of lactation in Gambian women accustomed to a low calcium intake and in those consuming a calcium supplement

The effect of 18 months of lactation on indexes of calcium and bone metabolism was studied in 60 Gambian women accustomed to a very low calcium intake. Half the women consumed a calcium supplement from 10 days postpartum for 52 weeks (supplement, 714 mg Ca/day; total Ca intake, 992 +/- 114 mg/day), and half consumed placebo (total Ca intake, 288 +/- 128 mg/day). Fasting blood and 24-h urine samples were collected at 1.5, 13, 52, and 78 weeks of lactation and analyzed for calciotropic hormones (intact PTH, 1,25-dihydroxyvitamin D, and calcitonin), bone turnover markers (osteocalcin, bone alkaline phosphatase, and urinary deoxypyridinoline), and plasma minerals (calcium and phosphate). The first months of lactation were associated with increased bone turnover and plasma phosphate, and decreased PTH and 1,25-dihydroxyvitamin D. These effects diminished by 52 weeks, although breast milk volumes remained high. The Gambians had higher PTH, 1,25-dihydroxyvitamin D, and bone formation than British women with a greater customary calcium intake. None of the biochemical indexes was affected by calcium supplementation, with the possible exception of bone alkaline phosphatase (-29% at 52 weeks; P = 0.015). These data demonstrate that lactation-associated changes in calcium and bone metabolism are physiological and are independent of dietary calcium supply in women with very low calcium intakes.     

Abnormalities of calcium, phosphorous and vitamin D metabolism with proximal renal tubular dysfunction in subjects environmentally exposed to cadmium

Calcium, phosphorus and vitamin D metabolism were examined in 21 male and 13 female subjects with renal tubular dysfunction in the cadmium-polluted Jinzu River basin in Toyama prefecture, Japan. Multiple proximal renal tubular dysfunction was detected in all subjects showing increased FE beta 2-m and FFua, generalized aminoaciduria and renal glucosuria. Reduced ability of tubular reabsorption of phosphate resulted in hypophosphatemia in 31% of the women. Despite decreased tubular reabsorption of calcium, the level of serum calcium remained normal in all subjects. Serum 1,25-dihydroxyvitamin-D [1,25(OH)2D], which is produced in the proximal tubules through 1 alpha-hydroxylation from 25-hydroxyvitamin-D [25OHD], was normal or increased to more than 60pg/ml. The serum level of 1,25(OH)2D was inversely related to creatinine clearance in both the men (p < 0.05) and women (p < 0.01). Serum iPTH was slightly increased to more than 0.9 mg/ml, whereas the levels of other hormones, including 25OHD, calcitonin, thyroxine (T4) and triiodothyronine (T3) were normal. The serum alkaline phosphatase activity and serum osteocalcin concentration were significantly increased compared to those of controls in both sexes. Bone loss detected by the measurement of bone density was prominent in female subjects. These results support the hypothesis that the serum phosphate concentration is more important than the serum concentration of 1,25(OH)2D for abnormalities of bone metabolism in cadmium-induced renal tubular dysfunction.     

The hamstring index

Hyperthyroidism is characterized by increased bone turnover and resorptive activity. Similar changes in remodeling are seen in osteoporosis. To study the pathogenetic role of thyroid hormone in osteoporosis, we measured concentrations of free and total thyroid hormones and investigated the sensitivity of the skeleton toward thyroid hormones in 14 osteoporotic, 16 estrogen-treated, and 15 normal postmenopausal women with comparable thyroid status. Triiodothyronine (T3, 60 microg/day for 7 days) was administered to the three groups. The skeletal response was assessed by monitoring bone alkaline phosphatase (BAP), osteocalcin (BGP), and pyridinium cross-linked telopeptide domain of type I collagen (ICTP) in serum and urinary excretion of hydroxyproline (OHP), pyridinoline (PYR), and deoxypyridinoline (DPR) at days 0, 8, 15, and 57. Women on estrogen replacement therapy exhibited lower bone turnover than the normal postmenopausal women. Markers of bone formation were reduced by 19-43% and markers of resorption by 22-48%. The osteoporotic women displayed lower bone mass at the lumbar spine and the distal forearm (p < 0.01-0.001), but the levels of biochemical markers of bone formation and resorption were comparable to values obtained in the normal postmenopausal women. T3 stimulation caused significant increases (p values ranging between 0.05-0.001) in all three groups of the resorptive markers: ICTP (47%, 47%, 45%), OHP (29%, 30%, 33%), PYR (43%, 27%, 51%), and DPR (42%, 24%, 59%). Of the formative markers, only BGP increased significantly (32%, 40%, 47%) (p < 0.001). At day 57, however, all three formative markers increased compared with day 15 (p < 0.05-0.001). No significant differences in bone markers were demonstrated between groups. In the osteoporotic group, as the only group, serum calcium increased (p < 0.05) and serum PTH fell (p < 0.05). In conclusion, osteoporosis and estrogen substitution are not characterized by altered concentrations of thyroid hormones or responsiveness to thyroid hormones at the level of individual bone cells; however, altered responses pertaining to PTH and calcium were detected.     

Dietary caffeine intake and bone status of postmenopausal women

Dietary caffeine intake has been suggested as a risk factor for bone loss in postmenopausal women. We measured the bone density of both hips and the total body in 138 healthy, postmenopausal women aged 55-70 y who had either never used hormone replacement therapy (HRT) or had used HRT for < 1 y. In this cross-sectional study, participants were stratified according to their reported current and long-time caffeinated beverage use into one of three groups: low [0-2 cups (180 mL, or 6 oz per cup) caffeinated coffee per day], moderate (3-4 cups caffeinated coffee per day), or high (> or = 5 cups caffeinated coffee per day). Caffeine intake was measured from diet records and by gas chromatography of each subject's brewed, caffeinated beverages. No association between caffeine intake and any bone measurement was observed. The anthropometric and nutrient intakes of the three groups were similar. Compared with caffeine intake based on chemical analysis of brewed beverages, 3-d prospective food records and computer-assisted analysis overestimated caffeine intake by nearly two-thirds. In conclusion, the habitual dietary caffeine intake of this cohort of 138 postmenopausal women ranged from 0-1400 mg/d and was not associated with total body or hip bone mineral density measurements. This study does not support the notion that caffeine is a risk factor for bone loss in healthy postmenopausal women.     

Advice for the ''90s traveler

There are controversial reports on the potential role of L-thyroxine administration as a risk factor for osteoporosis. We studied bone mass and metabolism in a homogeneous series of 50 Caucasian women, 25 premenopausal and 25 postmenopausal, having nontoxic goitre treated with slightly suppressive L-thyroxine doses (50-200 micrograms/day) with subnormal serum TSH and normal thyroid hormone levels. These patients were matched with 50 controls for age, sex, body mass index, menopausal and thyroid disease. Patients and controls were also investigated for minor determinants of bone loss, such as hereditary and life-style factors. Patients and controls filled in a questionnaire and underwent physical examination, routine laboratory tests and calciotropic and thyroid hormone assay. Bone mineral turnover was evaluated by determining serum osteocalcin, alkaline phosphatase, tartrate-resistant acid phosphatase, calcium, phosphate, urine hydroxyproline/creatinine and calcium/ creatinine ratio. Bone mineral density was measured by dual-energy X-ray absorptiometry at the lumbar spine, femoral neck, trochanter and Ward's triangle. No difference in bone mineral density or biochemical markers was found between patients and controls; bone density and turnover were significantly affected by menopausal status. No relationship between bone density or turnover values and L-thyroxine administration was found. A significant positive correlation was found between osteocalcin and the hydroxyproline/creatinine ratio in premenopausal and postmenopausal patients, but not in controls. Our study suggests that slightly suppressive L-thyroxine administration in nontoxic goitre can activate bone turnover but constitutes neither an actual risk factor for bone loss nor, consequently, for osteoporotic fractures.     

Serum N-terminal osteocalcin is a good indicator for estimating responders to hormone replacement therapy in postmenopausal women

To estimate the response to hormone replacement therapy (HRT) by bone metabolic markers, 36 patients with postmenopausal osteoporosis or osteopenia were studied to assess the correlation between percent baseline changes in lumbar bone mineral density (BMD) after 12 months and those in various bone metabolic markers after 3, 6, and 12 months of HRT. All the patients were treated with 0.625 mg of conjugated estrogen and 2.5 mg of medroxyprogesterone per day and continued for 12 months. BMD was significantly increased up to 4.19 +/- 0.87% after 6 months and 4.93 +/- 1.27% after 12 months of HRT (p = 0.0001 by analysis of variance). In accordance with this, changes in the levels of osteocalcin (p = 0.041), alkaline phosphatase (p = 0.0001), N-terminal osteocalcin (p = 0.0001), urinary excretion of pyridinoline/Cr (p = 0.0001), and deoxypyridinoline/Cr (p = 0.0001) were significantly decreased, respectively. Among these bone metabolic markers, only the change in the serum N-terminal osteocalcin at 3 months (r = 0.557, p = 0.0022), at 6 months (r = 0.470, p = 0.0184), and at 12 months (r = 0.545, p = 0.0061) significantly correlated with the change in BMD 12 months after HRT. The elution profiles of immunoreactive osteocalcin-related molecules in serum fractionated by reverse-phase high performance liquid chromatography revealed that the N-terminal fragment as well as the intact osteocalcin molecule decreased after 3 months of HRT. These results demonstrate that N-terminal osteocalcin is a suitable predictor for estimating good responders to HRT in postmenopausal women.     

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.     

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.     

Long-term efficacy of cyclical etidronate therapy in postmenopausal osteoporosis

Sixty-two women (mean age 68.7 +/- 0.9 yr) with postmenopausal spinal osteoporosis were treated with cyclical etidronate therapy (400 mg for 2 weeks alternating with 12 weeks of 1 gm elemental calcium and 400 IU Vitamin D3) for a minimum of 2 yr. Bone mineral density (BMD) of the lumbar spine (g/cm2) increased significantly (p < 0.0001) after yr 1 (4.1 +/- 0.5 per cent) and yr 2 compared with yr 1 (2.2 +/- 0.5 per cent). The response rate was 89 per cent after yr 1 and 84 per cent after yr 2. BMD of the hip (30 patients) increased by 1.5 +/- 0.9 per cent after yr 1 and 5.5 +/- 1.1 per cent (p < 0.0001) after yr 2 when compared with baseline. The response rate was 63 per cent after yr 1 and 80 per cent after yr 2. Smaller numbers of patients continued with treatment up to 4 yr with no adverse long-term effects.     

Risedronate

Risedronate is a pyridinyl bisphosphonate that can be administered orally in lower dosages than other antiresorptive bisphosphonates. Like others of its class risedronate inhibits osteoclast-mediated bone resorption. In experimental models of osteoporosis, risedronate inhibited bone loss and improved trabecular architecture. In patients with Paget's disease, pain diminished or disappeared and serum alkaline phosphatase levels decreased after treatment with oral risedronate 30 mg/day for < or = 3 months. Risedronate 30 mg/day orally for 2 months significantly reduced pain, whereas etidronate 400 mg/day orally for 6 months tended to reduce pain, in a randomised double-blind trial of patients with Paget's disease. Oral risedronate 5 mg/day for < or = 2 years increased bone mass in postmenopausal women with low or normal bone mass. Risedronate 2.5 mg/day prevented bone loss in postmenopausal women treated with glucocorticoids for rheumatoid arthritis. The incidence of gastrointestinal or other adverse events was similar in patients treated with risedronate or placebo in clinical trials.