Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial

CONTEXT: Alendronate sodium reduces fracture risk in postmenopausal women who have vertebral fractures, but its effects on fracture risk have not been studied for women without vertebral fractures. OBJECTIVE: To test the hypothesis that 4 years of alendronate would decrease the risk of clinical and vertebral fractures in women who have low bone mineral density (BMD) but no vertebral fractures. DESIGN: Randomized, blinded, placebo-controlled trial. SETTING: Eleven community-based clinical research centers. SUBJECTS: Women aged 54 to 81 years with a femoral neck BMD of 0.68 g/cm2 or less (Hologic Inc, Waltham, Mass) but no vertebral fracture; 4432 were randomized to alendronate or placebo and 4272 (96%) completed outcome measurements at the final visit (an average of 4.2 years later). INTERVENTION: All participants reporting calcium intakes of 1000 mg/d or less received a supplement containing 500 mg of calcium and 250 IU of cholecalciferol. Subjects were randomly assigned to either placebo or 5 mg/d of alendronate sodium for 2 years followed by 10 mg/d for the remainder of the trial. MAIN OUTCOME MEASURES: Clinical fractures confirmed by x-ray reports, new vertebral deformities detected by morphometric measurements on radiographs, and BMD measured by dual x-ray absorptiometry. RESULTS: Alendronate increased BMD at all sites studied (P<.001) and reduced clinical fractures from 312 in the placebo group to 272 in the intervention group, but not significantly so (14% reduction; relative hazard [RH], 0.86; 95% confidence interval [CI], 0.73-1.01). Alendronate reduced clinical fractures by 36% in women with baseline osteoporosis at the femoral neck (>2.5 SDs below the normal young adult mean; RH, 0.64; 95% CI, 0.50-0.82; treatment-control difference, 6.5%; number needed to treat [NNT], 15), but there was no significant reduction among those with higher BMD (RH, 1.08; 95% CI, 0.87-1.35). Alendronate decreased the risk of radiographic vertebral fractures by 44% overall (relative risk, 0.56; 95% CI, 0.39-0.80; treatment-control difference, 1.7%; NNT, 60). Alendronate did not increase the risk of gastrointestinal or other adverse effects. CONCLUSIONS: In women with low BMD but without vertebral fractures, 4 years of alendronate safely increased BMD and decreased the risk of first vertebral deformity. Alendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD.     

Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group

BACKGROUND: Previous studies have shown that alendronate can increase bone mineral density (BMD) and prevent radiographically defined (morphometric) vertebral fractures. The Fracture Intervention Trial aimed to investigate the effect of alendronate on the risk of morphometric as well as clinically evident fractures in postmenopausal women with low bone mass. METHODS: Women aged 55-81 with low femoral-neck BMD were enrolled in two study groups based on presence or absence of an existing vertebral fracture. Results for women with at least one vertebral fracture at baseline are reported here. 2027 women were randomly assigned placebo (1005) or alendronate (1022) and followed up for 36 months. The dose of alendronate (initially 5 mg daily) was increased (to 10 mg daily) at 24 months, with maintenance of the double blind. Lateral spine radiography was done at baseline and at 24 and 36 months. New vertebral fractures, the primary endpoint, were defined by morphometry as a decrease of 20% (and at least 4 mm) in at least one vertebral height between the baseline and latest follow-up radiograph. Non-spine clinical fractures were confirmed by radiographic reports. New symptomatic vertebral fractures were based on self-report and confirmed by radiography. FINDINGS: Follow-up radiographs were obtained for 1946 women (98% of surviving participants). 78 (8.0%) of women in the alendronate group had one or more new morphometric vertebral fractures compared with 145 (15.0%) in the placebo group (relative risk 0.53 [95% Cl 0.41-0.68]). For clinically apparent vertebral fractures, the corresponding numbers were 23 (2.3%) alendronate and 50 (5.0%) placebo (relative hazard 0.45 [0.27-0.72]). The risk of any clinical fracture, the main secondary endpoint, was lower in the alendronate than in the placebo group (139 [13.6%] vs 183 [18.2%]; relative hazard 0.72 [0.58-0.90]). The relative hazards for hip fracture and wrist fracture for alendronate versus placebo were 0.49 (0.23-0.99) and 0.52 (0.31-0.87). There was no significant difference between the groups in numbers of adverse experiences, including upper-gastrointestinal disorders. INTERPRETATION: We conclude that among women with low bone mass and existing vertebral fractures, alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebral fractures, as well as other clinical fractures.     

Osteoplastic frontal sinus flap. Study of 47 cases

Recent developments in computer-assisted radiographic absorptiometry (RA) and quantitative ultrasound techniques (QUS) provide readily accessible and relatively inexpensive methods for assessing bone mineral status. However, few population-based studies have investigated the ability of RA and ultrasound to predict fracture risk prospectively. We explored the ability of RA and QUS to predict fracture risk among 560 postmenopausal women from the Hawaii Osteoporosis Study; average follow-up was 2.7 years. An incident vertebral fracture was defined as a decrease of more than 15% in vertebral heights on subsequent films. Self-reported nonspine fractures were verified by medical records. The prospective associations of vertebral fractures, nonspine fractures, and any (spine or nonspine) fractures with bone measurements were examined using logistic regression, adjusting for age. Both phalangeal bone mineral density (BMD) and metacarpal BMD, measured using RA, predicted future fracture risk. The age-adjusted odds ratios (corresponding to 1 SD decrease in BMD) for vertebral fractures, nonspine fractures, and any fractures were 3.41, 1.50, and 1.91, respectively, for phalangeal BMD, and 1.71, 1.49, 1.55, respectively for metacarpal BMD. Calcaneal broadband ultrasound attenuation (BUA) also showed significant association with fracture risk, with age-adjusted odds ratios of 1.50, 1.89, and 1.72 for vertebral fractures, nonspine fractures, and any fractures, respectively. We conclude that hand RA and calcaneal BUA are significant predictors of nonspine fracture, vertebral fracture, and overall fracture risk. The attractive features of these techniques, such as portability, relatively low cost, and ease of use, make them promising alternatives to conventional bone measurement techniques used for the assessment of fracture risk.     

Trochanteric hip fracture: strong association with spinal trabecular bone mineral density measured with quantitative CT

PURPOSE: To determine the discriminatory capability for hip fracture of trabecular and integral bone mineral density (BMD) measured with quantitative computed tomography (CT) of the spine. MATERIALS AND METHODS: Fifty-six women who had sustained hip fractures and 59 control subjects underwent volumetric quantitative CT of L1 and L2 and dual x-ray absorptiometry of the hip. BMD was measured in vertebral regions of interest that encompassed trabecular, cortical, and integral bone. Logistic regression analysis was applied to each BMD measure to derive age-, weight-, and height-adjusted relative risk (RR) factors for overall hip fracture and for trochanteric fracture and cervical fracture separately. RESULTS: Spinal trabecular BMD was modestly related to overall hip fracture (RR, 1.4-1.7; P < .05) and strongly associated with trochanteric fracture (RR, 4.2-4.5; P < .005). Spinal integral BMD related similarly to overall hip fracture (RR, 1.7-1.8; P < .05) but more weakly to trochanteric fracture (RR, 2.3-3.2; P < .01). No spinal BMD measures were significantly related to cervical fracture. BMD at the hip was strongly related to overall hip fracture (RR, 3.3-4.3; P < .001), cervical fracture (RR, 2.7-5.3; P < .001), and trochanteric fracture (RR, 2.9-7.2; P < .001). CONCLUSION: Spinal trabecular BMD is strongly associated with both trochanteric and vertebral fractures.     

The combined use of ultrasound and densitometry in the prediction of vertebral fracture

Measurement of ultrasonographic parameters provides information concerning not only bone density but also bone architecture. We investigated the usefulness of ultrasonographic parameters and bone mineral density for evaluating the probability of vertebral fracture. 397 postmenopausal women (59.1 +/- 6.0 years) with (n = 178) or without (n = 219) atraumatic vertebral fractures were studied. In all women, bone mineral density (BMD) of the lumbar spine was evaluated by dual X-ray absorptiometry (DXA) and speed of sound (SOS); broadband ultrasound attenuation (BUA) and Stiffness in the calcaneus were evaluated by an Achilles unit (Lunar Corporation). Ultrasonographic parameters and BMD were compared by examining the magnitude of the odds ratios, to determine which produces the highest estimate of the probability of odds of fracture, and by examining widths of the respective confidence intervals (CI) to show which estimate of odd ratio is the most precise. The relative risk of vertebral fracture, after adjusting for potential confounders, was 3.5 (CI 2.6-4.8) for BUA; 4.5 (CI 3.2-6.2) for SOS; 5.8 (CI 4.0-8.4) for Stiffness and 7.5 (CI 4.8-11.5) for BMD. Ultrasound (US) parameters were still significant independent predictors of vertebral fracture, even after adjusting for BMD. The relative risk of fracture for a simultaneous decrease by 1 SD of BMD and by 1 SD of each ultrasound parameter was 17.3 (CI 9.4-39.6) for BMD and SOS; 18.3 (CI 8.4-30.6) for BMD and BUA and 22.1 (CI 8.9-52.7) for BMD and Stiffness. Our data suggest that US and BMD provide complementary information which can be combined to improve estimates of vertebral fracture risk.     

Insulin-dependent diabetes and psychiatric pathology: general clinical and epidemiologic review

The objective was to determine the diagnostic sensitivity of spinal and femoral dual x-ray absorptiometry (DXA) and to study whether a combination of both sites may enhance discriminatory capability in regard to the presence of vertebral fractures. Spinal and femoral DXA were obtained in 324 postmenopausal women, of whom 90 had at least one vertebral fracture. Age-adjusted logistic regression analyses, ROC analyses, and sensitivity-specificity statistics were used to assess the discriminatory ability of spinal and femoral bone density (BMD) alone and in combination. The age-adjusted odds ratios per standard deviation decrease in BMD (OR) for spinal and femoral measurements were comparable (Ward's triangle: OR = 1.62; femoral neck: OR = 1.51; total hip: OR = 1.47; spine: OR = 1.34). Combining spinal and femoral bone density measurements did not improve diagnostic sensitivity of DXA considerably as compared to using BMD of a single site and adjusting the "fracture threshold." The conclusion drawn is that spinal and femoral BMD measurements using DXA have a comparable diagnostic sensitivity for vertebral fracture discrimination. Different individuals at risk for osteoporosis may be identified using both methods. The clinical usefulness of a combination of two bone density measurements needs further study in a prospective setting.     

Fall-related factors and risk of hip fracture: the EPIDOS prospective study

BACKGROUND: Most hip fractures result from falls. However, the role of fall-related factors has seldom been examined. Comparison of the predictive value of these factors with that of bone mineral density (BMD) has important implications for the prevention of hip fractures. METHODS: We assessed femoral-neck BMD by dual-photon X-ray absorptiometry and potential fall-related risk factors, which included self-reported physical capacity, neuromuscular function, mobility, visual function, and use of medication in 7575 women, aged 75 years or older, with no history of hip fracture recruited at five centres in France. We followed up these women every 4 months to record incident hip fractures. During an average of 1.9 years of follow-up 154 women suffered a first hip fracture. FINDINGS: In age-adjusted multivariate analyses, we found four independent fall-related predictors of hip fracture: slower gait speed (relative risk = 1 . 4 for 1 SD decrease [95% Cl 1.1-1.6)]; difficulty in doing a tandem (heel-to-toe) walk (1.2 for 1 point on the difficulty score [1.0-1.5]); reduced visual acuity (2.0 for acuity < or = 2/10 [1.1-3.7]); and small calf circumference (1.5 [1.0-2.2]). After adjustment for femoral-neck BMD, neuromuscular impairment--gait speed, tandem walk--and poor vision remained significantly associated with an increased risk of subsequent hip fracture. With high risk defined as the top quartile of risk, the rate of hip fracture among women classified as high risk based on both a high fall-risk status and low BMD was 29 per 1000 women-years, compared with 11 per 1000 for women classified as high risk by either a high fall-risk status or low BMD; for women classified as low risk based on both criteria the rate was five per 1000. INTERPRETATION: We conclude that neuromuscular and visual impairments, as well as femoral-neck BMD, are significant and independent predictors of the risk of hip fracture in elderly mobile women, and that their combined assessment improves the prediction of hip fractures.     

Osteoporotic fracture rate, bone mineral density, and bone metabolism in Taiwan

Taiwanese people have spinal bone mineral density (BMD) values similar to those of Caucasians, whereas their hip BMD values are 10% to 15% lower. In 1992, the prevalence of vertebral fractures, diagnosed according to the -3 SD morphometric criteria, was 18% for women and 12% for men older than 65 years in the major cities of Taiwan. Despite this high prevalence of vertebral fractures, the incidence of hip fractures in the elderly of both sexes was only 203 per 100,000 in 1996, which was lower than in Caucasians and similar to that in mainland Chinese. Hip and vertebral fractures are both associated with lower BMD values. The risk factors for low BMD in Taiwan include a lighter body weight and aging in both sexes, and menopause for women. An increased bone turnover rate is associated with a lower BMD in both men and postmenopausal women, although the rate seems to increase in women but decrease in men with aging. In Taipei City, daily calcium intake is relatively low (mean intake +/- SD; 640 +/- 240 mg), but the vitamin D stores seem to be generally adequate for middle-aged and elderly women. There was a significant association between a higher daily calcium intake and a higher BMD/lower bone turnover rate for women in this age group. Vitamin D receptor allelic polymorphism was not an important factor in low BMD and rapid bone turnover.     

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.     

Markers of bone resorption predict hip fracture in elderly women: the EPIDOS Prospective Study

Increased bone turnover has been suggested as a potential risk factor for osteoporotic fractures. We investigated this hypothesis in a prospective cohort study performed on 7598 healthy women more than 75 years of age. One hundred and twenty-six women (mean years 82.5) who sustained a hip fracture during a mean 22-month follow-up were age-matched with three controls who did not fracture. Baseline samples were collected prior to fracture for the measurement of two markers of bone formation and three urinary markers of bone resorption: type I collagen cross-linked N- (NTX) or C-telopeptide (CTX) and free deoxypyridinoline (free D-Pyr). Elderly women had increased bone formation and resorption compared with healthy premenopausal women. Urinary excretion of CTX and free D-Pyr, but not other markers, was higher in patients with hip fracture than in age-matched controls (p = 0.02 and 0.005, respectively). CTX and free D-Pyr excretion above the upper limit of the premenopausal range was associated with an increased hip fracture risk with an odds ratio (95% confidence interval) of 2.2 (1.3-3.6) and 1.9 (1.1-3.2), respectively, while markers of formation were not. Increased bone resorption predicted hip fracture independently of bone mass, i.e., after adjustment for femoral neck bone mineral density (BMD) and independently of mobility status assessed by the gait speed. Women with both a femoral BMD value of 2.5 SD or more below the mean of young adults and either high CTX or high free D-Pyr levels were at greater risk of hip fracture, with an odds ratio of 4.8 and 4.1, respectively, than those with only low BMD or high bone resorption. Elderly women are characterized by increased bone turnover, and some markers of bone resorption predict the subsequent risk of hip fracture independently of hip BMD. Combining the measurement of BMD and bone resorption may be useful to improve the assessment of the risk of hip fracture in elderly women.     

Weight change between age 50 years and old age is associated with risk of hip fracture in white women aged 67 years and older

BACKGROUND: Although changes in body weight with aging are common, little is known about the effects of weight change on health in old age. OBJECTIVES: To study the effects of weight loss and weight gain from age 50 years to old age on the risk of hip fracture among postmenopausal white women aged 67 years and older and to determine if the level of weight at age 50 years modifies this risk. METHODS: The association between weight change and the risk of hip fracture was studied in 3683 community-dwelling white women aged 67 years and older from three sites of the Established Populations for Epidemiologic Studies of the Elderly. RESULTS: Extreme weight loss (10% or more) beginning at age 50 years was associated in a proportional hazards model with increased risk of hip fracture (relative risk [RR], 2.9; 95% confidence interval [CI], 2.0-4.1). This risk was greatest among women in the lowest (RR, 2.3; CI, 1.1-4.8) and middle (RR, 2.8; CI, 1.5-5.3) tertiles of body mass index at age 50 years. Among the thinnest women, even more modest weight loss (5% to < 10%) was associated with increased risk of hip fracture (RR, 2.3; CI, 1.0-5.2). Weight gain of 10% or more beginning at age 50 years provided borderline protection against the risk of hip fracture (RR, 0.7; CI, 0.4-1.0). The RRs for weight gain of 10% or more were protective only among women in the middle and high tertiles of body mass index at age 50 years and were not significant (middle tertile RR, 0.8; CI, 0.3-1.8; high tertile RR, 0.6; CI, 0.2-1.9). CONCLUSIONS: Weight history is an important determinant of the risk of hip fracture. Weight loss beginning at age 50 years increases the risk of hip fracture in older white women, especially among those who are thin at age 50 years; weight gain of 10% or more decreases the risk of hip fracture. Physicians should include weight history in their assessment of postmenopausal older women for risk of hip fracture.     

Effectiveness of screening for osteoporosis by bone density measurement for the prevention of fractures: a review of the evidence]

To review evidence on the benefits of screening women and men for osteoporosis, a Pub Med search was performed in English papers published between 1990 and 2002. We used data from a cohort study to estimate risk of fracture from bone mineral density. Bone mineral density measured by dual X-ray absorptiometry (DXA) can predict bone fracture among elderly women, peri- and early post-menopausal women, and elderly men. It is recommended that all white women older than 65 years be screened routinely for osteoporosis. We suggest that Japanese elderly women should receive BMD measurements as a screening, but we have still issues to be solved including age from when the screening should be started, methods, and how to treat the women found to have osteoporosis at the screening. For peri- and postmenopausal women and elderly men, it might be beneficial to measure BMD as a screening and start treatment for those patients found to have osteoporosis. However, incidence of fractures for these people is lower than that for elderly women. One bone mass measurement can predict bone fracture risk for as long as over 10 years or more, but predictive ability of BMD decreases with time. Therefore, cost effectiveness needs to be reviewed to determine the benefits of screening among peri-menopausal women and men. Although bone assessment by quantitative ultra sound (QUS) method by ultrasound can also predict future fractures, only a relatively small number of longitudinal studies have been conducted in the Western countries, and there is no established evidence by means of longitudinal studies among Japanese. It is necessary in Japan to seek such evidence, however, since this method is widely used for an osteoporosis examinations.     

Ultrasound transmission speed and ultrasound bone profile score (UBPS) of the phalanges in normal women and women with osteoporosis

The distal metaphysis of the first phalanx of the fingers II-V is, like the vertebral body, a useful site for the measurement of mineralisation and structure of the bone because of the simultaneous presence of compact and trabecular bone. With an ultrasound device (DBM sonic 1200, IGEA, Italy), we measured the adSOS (the amplitude dependent speed of sound) and the UBPS (ultrasound bone profile score), a score which is calculated from the graphic traces of the receiving probe with an expert system which uses fuzzy-logic at phalanges II-IV, as well as bone mineral density (BMD) at lumbar spine using dual X-ray absorptiometry (DXA). Precision of the measurements was as follows: adSOS: short-time-CV% = 0.576, long-time-CV% = 1.1, SCV% = 5.9, RMSSD% = 1.825. UBPS: short-time CV% = 5.95. There was no correlation between adSOS or UBPS and lumbar BMD (DXA). There was a significant positive correlation between adSOS and UBPS, r = 0.804 (p<0.00001). The validity of adSOS and UBPS was examined in 25 young and healthy women (mean age: 33.4 year), 15 postmenopausal healthy women (mean age: 58.5 years), 17 women with osteopenia, (mean age: 52.4 years), as defined by a t-score between -1 to -2.5 SD as lumbar BMD (DXA), and 20 women with osteoporosis and vertebral fractures (mean age: 61.4 years). We compared the healthy postmenopausal women and the women with osteoporotic vertebral fractures, the z-score of the adSOS was below minus 1.5 SD and UBPS was below 40, sensitivity was 0.7 for adSOS, and 0.85 for UBPS, with a specificity 0.97 for adSOS, and of 0.93 for UBPS; positive predictive value: adSOS: 0.93, UBPS: 0.85. AdSOS declined with age (r= 0.694, p=0.021); the UBPS was not age dependent (r=-0.15, p = n.s.). The ROC-curve shows a value of 0.96 for adSOS and 0.94 for UBPS. AdSOS and UBPS could discriminate well between the healthy controls and the women with osteopenia or vertebral fractures (p<0.00001). These results show that adSOS and UBPS are precise parameters to be measured at the phalanges. The detection level of pathological changes in osteoporosis are similar between adSOS and lumbar BMD (DXA) and improved by using the UBPS. This might be explained by the influence of structural changes in bone on UBPS, rather than change in bone mineral alone. Prospective studies have to clarify the role of adSOS and UBPS in fracture prediction.     

Advantages of peripheral radiogrametry over dual-photon absorptiometry of the spine in the assessment of prevalence of osteoporotic vertebral fractures in women

Since osteoporosis develops in most postmenopausal women and is probably the most important single factor in the pathogenesis of osteoporotic fractures of the spine, hip, and wrist (and at other sites), methods suitable for mass screening should be developed. In this study of 97 women aged 24-79, measurements of the lumbar spine mineral content by dual-photon absorptiometry (DPA) were compared with the summed combined cortical thickness measurements from radiographs of the radius and metacarpal II (MR). There was good correlation between the two methods (r = 0.90). The correlation of age with MR was higher than with DPA. The correlation of years postmenopause was significant with MR but not with DPA. Taking the -2 SD level of the premenopausal means to be previously established vertebral fracture thresholds, 24% of the DPA measurements, but no MR measurements in patients with vertebral compressions, were above the fracture threshold. Since MR measurement requires taking only two small plain radiographs using ordinary x-ray equipment, it is concluded that this less expensive method is better suited to screening for osteoporotic vertebral fracture risk in postmenopausal women than DPA.     

Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial

Although the antiresorptive agent alendronate has been shown to increase bone mineral density (BMD) at the hip and spine and decrease the incidence of osteoporotic fractures in older women, few data are available regarding early prediction of long-term response to therapy, particularly with regard to increases in hip BMD. Examining short-term changes in biochemical markers incorporates physiologic response with therapeutic compliance and should provide useful prognostic information for patients. The objective of this study was to examine whether early changes in biochemical markers of bone turnover predict long-term changes in hip BMD in elderly women. The study was a double-blind, placebo-controlled, randomized clinical trial which took place in a community-based academic hospital. One hundred and twenty community-dwelling, ambulatory women 65 years of age and older participated in the study. Intervention consisted of alendronate versus placebo for 2.5 years. All patients received appropriate calcium and vitamin D supplementation. The principal outcome measures included BMD of the hip (total hip, femoral neck, trochanter, and intertrochanter), spine (posteroanterior [PA] and lateral), total body, and radius. Biochemical markers of bone resorption included urinary N-telopeptide cross-linked collagen type I and free deoxypyridinoline; markers of bone formation included serum osteocalcin and bone-specific alkaline phosphatase. Long-term alendronate therapy was associated with increased BMD at the total hip (4.0%), femoral neck (3.1%), trochanter (5.5%), intertrochanter (3.8%), PA spine (7.8%), lateral spine (10.6%), total body (2.2%), and one-third distal radius (1.3%) in elderly women (all p < 0.01). In the placebo group, bone density increased 1.9-2.1% at the spine (p < 0.05) and remained stable at all other sites. At 6 months, there were significant decreases in all markers of bone turnover (-10% to -53%, p < 0.01) in women on alendronate. The changes in urinary cross-linked collagen at 6 months correlated with long-term bone density changes at the hip (r = -0.35, p < 0.01), trochanter (r = -0.36, p < 0.01), PA spine (r = -0.41, p < 0.01), and total body (r = -0.34, p < 0.05). At 6 months, patients with the greatest drop in urinary cross-linked collagen (65% or more) demonstrated the greatest gains in total hip, trochanteric, and vertebral bone density (all p < 0.05). A 30% decrease in urinary cross-linked collagen at 6 months predicted a bone density increase of 2.8-4.1% for the hip regions and 5.8-6.9% for the spine views at the 2.5-year time point (p < 0.05). There were no substantive associations between changes in biochemical markers and bone density in the placebo group. Alendronate therapy was associated with significant long-term gains in BMD at all clinically relevant sites, including the hip, in elderly women. Moreover, these improvements were associated with early decreases in biochemical markers of bone turnover. Early dynamic decreases in urinary cross-linked collagen can be used to monitor and predict long-term response to bisphosphonate therapy in elderly women. Future studies are needed to determine if early assessment improves long-term patient compliance or uncovers poor compliance, thereby aiding the physician in maximizing the benefits of therapy.     

Calcitonin receptor polymorphism is associated with a decreased fracture risk in post-menopausal women

High bone resorption by the osteoclast results in osteoporosis, a disease affecting 40% of women after the menopause. Calcitonin, used to treat osteoporosis, inhibits bone resorption via receptors located on the osteoclasts. Two alleles of the calcitonin receptor gene ( CTR ) exist: a base mutation T-->C in the third intracellular C-terminal domain changes a proline (CCG) at position 447 to a leucine (CTG). We therefore studied the distribution of these alleles in a cohort of 215 post-menopausal Caucasian women suffering or not from osteoporotic fractures. The region of interest within the point mutation was amplified by PCR and screened for single strand conformation polymorphism. This work was followed by DNA sequencing of the fragments amplified. We found that bone mineral density (BMD) at the femoral neck was significantly higher in heterozygous subjects with the Rr genotype compared with the homozygous leucine (RR) and homozygous proline (rr) genotypes. Also, a decreased fracture risk was observed in heterozygote subjects. In conclusion, our results suggest that polymorphism of CTR could be associated with osteoporotic fractures and BMD in a population of post-menopausal women. CTR heterozygotes could produce both alleles of the receptor. The heterozygous advantage effect of Rr subjects could explain their protection against osteoporosis: higher bone density and decreased fracture risk. Establishing the genotype of the CTR gene in post-menopausal women could be of value in evaluating their risk of developing fractures.     

Epilepsy--a time for change?

OBJECTIVE: To examine the association between postmenopausal hormone use and cholecystectomy. METHODS: A prospective cohort study was performed, with follow-up every 2 years. Participants were 54,845 postmenopausal United States nurses, who reported both hormone use and cholecystectomy on mailed questionnaires. RESULTS: Cholecystectomy was reported by 1750 women during 8 years of follow-up. After adjusting for confounding factors, women currently using postmenopausal hormones were at an increased risk of cholecystectomy (relative risk [RR] 2.1, 95% confidence interval [CI] 1.9-2.4) compared to never-users. For current users, the risk of cholecystectomy increased with increasing duration of hormone use (RR 2.6, 95% CI 2.2-3.1 for 10 years or more) and higher doses of estrogen (RR 2.4, 95% CI 2.0-2.9 for users of 1.25 mg or more). Although the risk for past hormone users decreased substantially in women who had discontinued use 1-2.9 years ago (RR 1.6, 95% CI 1.2-2.0), a small risk persisted for women who had stopped taking hormones 5 or more years previously (RR 1.3, 95% CI 1.1-1.6). However, after controlling for time since last use, duration of past use had little or no effect on the risk of cholecystectomy (RR 1.4 and RR 1.7 for past users of less than 2 years and 10 or more years' duration, respectively). CONCLUSION: Women using postmenopausal hormones are at an increased risk of cholecystectomy. Women and their physicians should consider the spectrum of risks and benefits when deciding whether to take hormones.     

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.     

Prediction of low bone mineral density in postmenopausal women by artificial neural network model compared to logistic regression model

Measuring bone mineral density (BMD) is currently the best modality to diagnose osteoporosis and predict future fractures. The use of risk factors to predict BMD and fracture risk has been considered to be inadequate for precise diagnostic purpose, but it may be helpful as a screening tool to determine who actually needs BMD assessment. Recently, artificial neural network (ANN), a nonlinear computational model, has been used in clinical diagnosis and classification. In the present study, we evaluated the risk factors associated with low BMD in Thai postmenopausal women and assessed the prediction of low BMD using an ANN model compared to a logistic regression model. The subjects consisted of 129 Thai postmenopausal women divided into 2 groups, 100 subjects in the training set and the remaining 29 subjects in the validation set. The subjects were classified as having either low BMD or normal BMD by using BMD value 1 SD lower than the mean value of young adults as the cutoff point. Decreased body weight, decreased hip circumference and increased years since menopause were found to be associated with low BMD at the lumbar spine by logistic regression. For the femoral neck, increased age and decreased urinary calcium were associated with low BMD. The models had a sensitivity of 85.0 per cent, a specificity of 11.1 per cent and an accuracy of 62.0 per cent for the diagnosis of low BMD at the lumbar spine when tested in the validation group. For the femoral neck, the sensitivity, specificity and accuracy were 90.5 per cent, 12.5 per cent, and 69.0 per cent, respectively. Models based on ANN correctly classified 65.5 per cent of the subjects in the validation group according to BMD at the lumbar spine with a sensitivity of 80.0 per cent and a specificity of 33.3 per cent while it correctly classified 58.6 per cent of the subjects at the femoral neck with a sensitivity of 76.2 per cent and a specificity of 12.5 per cent. There was no significant difference in terms of accuracy, sensitivity and specificity in the prediction of low BMD at the lumbar spine or the femoral neck between ANN model and logistic regression model. We concluded that ANN does not perform better than convention statistical methods in the prediction of low BMD. The less than perfect performance of the prediction rules used in the prediction of low BMD may be due to the lack of adequate association between the commonly used risk factors and BMD rather than the nature of the computational models.     

Hip fracture prediction in elderly men and women: validation in the Rotterdam study

The aim of our study was to validate a hip fracture risk function, composed of age and femoral neck bone mineral density (BMD). This estimate of the 1-year cumulative risk was previously developed on the basis of Dutch hip fracture incidence data and BMD in men and women. A cohort of 7046 persons (2778 men) aged 55 years and over was followed for an average of 3.8 years. The 1-year hip fracture risk estimate was calculated for each participant according to the risk function and categorized as low (<0.1%), moderate (0.1 to < 1%), or high (> or =1%). Observed first hip fracture incidence was then analyzed for each of these risk categories by age and gender. Additionally, we calculated the relative risk per standard deviation (SD) decrease in femoral neck BMD in this population. At baseline, 2360 individuals were categorized as low risk, 2567 as moderate risk, and 378 as high risk During follow-up, 110 first hip fractures were observed corresponding to an incidence rate of 4.1/1000 person-years (pyrs) (95% confidence interval 3.4-5.0). The observed incidence rate in the low risk group was 0.2/1000 pyrs (0.1-0.9), 2.7/1000 pyrs (1.8-3.9) in the moderate risk group, and 18.4/1000 pyrs (12.4-27.2) in the high risk group. Below the age of 70 years, incidence was low in all categories, and very few individuals were considered at high risk Above the age of 70 years, the observed incidence was high in the high risk group, while in the low and moderate risk groups, the incidence remained low even over 80 years of age. In women, the age-adjusted relative risk for hip fractures was 2.5 per SD decrease in femoral neck BMD (1.8-3.6), while in men this relative risk was 3.0 per SD (1.7-5.4). In conclusion, we observed a similar relation of hip fracture with femoral neck BMD in men and women and were able to predict accurately hip fracture rates over a period of almost 4 years.