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Genetic factors are important in the pathogenesis of osteoporosis but less is known about their possible role in predicting response to anti-osteoporotic therapy. Previous studies have shown that a polymorphic Sp1 binding site in the collagen type 1 alpha 1 gene (COLIA1) is associated with bone mineral density (BMD) and osteoporotic vertebral fracture. In this study we sought to determine if the COLIA1 Sp1 polymorphism might also act as a predictor of the response to treatment of osteoporosis with bisphosphonate therapy. The study group comprised 108 perimenopausal women with osteopenia who had been randomized to receive cyclical etidronate therapy for 2 years with a 1-year treatment-free follow-up as part of a randomized placebo controlled trial. Bone mineral density was measured at the lumbar spine and femoral neck by dual X-ray absorptiometry and genotyping performed on DNA extracted from peripheral blood leukocytes using standard techniques. The distribution of COLIA1 genotypes was similar to that previously reported in Caucasians with 69 (63.9%) "SS" homozygotes, 38 (35.2%) "Ss" heterozygotes, and 1 (0.9%) "ss" homozygote. There was no association between COLIA1 genotype and response of lumbar spine BMD during etidronate treatment or the follow-up phase. The response of femoral neck (FN) BMD, however, differed significantly between the genotype groups throughout the study period, such that FN BMD increased by 0.56%, 2.36%, 1.82%, and 1.32 % after 1, 2, 2.5, and 3 years, respectively in the "SS" genotype group, compared with -1.56%, -0.62%, -0.37%, and -0.66% in the "Ss/ss" genotype groups (P = 0.002). The data presented here show that site-specific heterogeneity exists in the response of BMD to cyclical etidronate therapy, which is related to COLIA1 genotype. Our data raise the possibility that COLIA1 genotyping could be used to target etidronate therapy to those most likely to respond in terms of FN BMD, with potential benefits in terms of economic cost and clinical outcome.

In the past it was usual to interpret bone mineral density (BMD) scans of the femur using the femoral neck, trochanter, or Ward's triangle sites. Recently, a study by the International Committee for Standards in Bone Measurement recommended that the total hip should be the preferred site for the interpretation of femur BMD, and another study described a new central hip site that may offer improved precision. This article compares the longitudinal sensitivities of the different femur BMD sites for monitoring patient response to treatment. The study population was 152 postmenopausal women enrolled in a trial of a bisphosphonate therapy. Spine and hip BMD scans were performed at 0, 1, and 2 yr. The mean percentage change at 2 yr was calculated for six sites in the hip, and the spine was also included for comparison. Treatment effect was defined as the difference in the BMD change between the treated and placebo groups. Although the data analysis incorporated a term for a calibration change caused by a repair of the dual X-ray absorptiometry scanner, the effect of this event on the estimation of treatment effect was negligible. Longitudinal sensitivity was derived by dividing the treatment effect by the root mean square error (RMSE) of the statistical model. Results (and standard errors) normalized to the ratio of treatment effect: RMSE for femoral neck BMD were as follows: femoral neck: 1.00; trochanter: 1.33 (0.38); intertrochanteric: 0.84 (0.41); total hip: 1.20 (0.38); Ward's triangle: 1.03 (0.27); central hip: 1.09 (0.30); spine: 2.08 (0. 45). At none of the femur sites was the change in BMD large enough to allow monitoring of response to treatment in individual patients. However, for studies involving the follow-up of a group of subjects, the longitudinal sensitivities of the different femur sites were equal within the statistical errors of the study. In particular, total hip BMD appears to be as effective as femoral neck BMD for detecting response to treatment in the femur in the setting of a clinical trial or similar research study.

The objective of this study was to evaluate whether the pharmacological activity of cyclical etidronate therapy is sustained beyond the dosing period. A group of 121 postmenopausal women who had completed a 2-year, double-blind, placebo-controlled parallel study with etidronate or placebo (400 mg/day for 14 days every 3 months) and calcium agreed to participate in a 1-year open-label follow-up study to evaluate the effect of discontinuing etidronate treatment. Fifty-nine subjects in the former etidronate group and 62 in the placebo group received 500 mg/day of elemental calcium; 54/59 and 58/62 subjects, respectively, completed the study. Outcomes of the study were bone mineral density (BMD), measured by dual energy X-ray absorptiometry (DXA), and biochemical markers of bone turnover (urinary deoxypyridinoline/creatinine and serum osteocalcin). To determine whether there was a residual effect of previous therapy we compared mean percentage changes from baseline (year 0) to year 3 for both spinal and femoral neck BMD and markers of bone turnover in the former cyclical etidronate and placebo groups. To evaluate the carryover effect of treatment we compared the percent change from year 2 to year 3 for the same variables. Mean percentage change (SEM) from year 2 to year 3 for spinal BMD in the former cyclical etidronate group was -2.87% (0.48%) versus -0.99% (0.36%) in the placebo group (P = 0.0022). In the femoral neck, the BMD changes were -0.86% (0.42%) versus -1.01% (0.41%) (NS). Biochemical markers increased within 6 months toward baseline levels. Mean percentage changes from baseline (year 0) in both spinal and femoral neck BMD were significantly different between groups 1 year after treatment discontinuation. No differences between groups were maintained in deoxypyridinoline and osteocalcin. It is concluded that following withdrawal of cyclical etidronate therapy bone loss resumes at a normal and moderately accelerated rate in the proximal femur and lumbar spine, respectively. A positive effect on BMD at both cortical and trabecular sites is maintained for 1 year after treatment withdrawal.

In the past decade dual-energy X-ray absorptiometry (DXA) scanning has assumed an important role in the evaluation of new treatments for osteoporosis. Although the spine and hip are the sites usually chosen for monitoring bone mineral density (BMD) changes, total body DXA is also of interest because of the comprehensive view it gives of the whole skeleton. However, recent studies have reported anomalies in total body DXA in subjects undergoing weight change, suggesting that the technique may not be valid in this circumstance. The present study evaluated total body DXA in a trial of cyclical etidronate therapy in which many subjects underwent significant weight change. The study population was 152 postmenopausal women who had spine, hip and total body DXA scans performed at baseline, 1 and 2 years. The total body scans were analyzed using two software options referred to as 'standard' and 'enhanced'. The following variables were studied: total body BMD, total body bone mineral content (BMC), and subregional BMD values for the following seven sites: lumbar spine, thoracic spine, pelvis, head, ribs, arms and legs. The percentage change from baseline was analyzed in a multivariate regression analysis to derive the treatment effect (defined as the difference in changes between the etidronate and placebo groups) and a coefficient that described the effect of weight change on the total body DXA variable. Mean weight change after 2 years was +1.1 kg (range -9.3 to +16.8 kg). Results for the weight change coefficient were significantly different from zero for five of nine total body variables using the standard analysis and seven of nine for the enhanced analysis with values (and standard errors) that varied from +0.67 (0.04)%/kg for standard total body BMC to -0.32 (0.11)%/kg for enhanced arm BMD. Results for the treatment effect at 2 years were significantly different from zero for total body BMD, total body BMC and for the lumbar spine, thoracic spine and pelvis BMD subregions, but were not significant for head, rib, arm or leg BMD. Findings for the standard and enhanced analyses agreed closely and the size of the treatment effect was related to the proportion of trabecular bone at the measurement site. We conclude that in a randomized study the effects of weight change can be corrected and total body DXA can give useful information about the response to treatment across the whole skeleton.

Since its commercial introduction a decade ago, the technique of dual-energy X-ray absorptiometry (DXA) has been widely recognized as a useful and sensitive method of measuring changes in bone mineral density (BMD) at selected sites in the skeleton such as the spine and proximal femur. Because of their high precision and stable calibration, DXA scanners are frequently used in clinical trials to evaluate new treatments for osteoporosis. Quality assurance procedures based on regular scanning of phantoms are widely adopted in such trials, and continuity of the phantom BMD measurements is generally believed to ensure continuity in the in-vivo calibration. We report a change in calibration of a DXA scanner that occurred during a clinical trial where the calibration shift was different for the spine and femur sites and was not predicted or explained by the standard quality control procedures using phantoms. However, we show that provided patients enrolled in studies are thoroughly randomized and the statistical analysis is confined to the differences between the treated and control groups, then the effects of such calibration shifts on conclusions regarding the efficacy of treatment are considerably smaller than the random statistical errors.

Variation in soft tissue composition is a potential cause of error in dual X-ray absorptiometry (DXA) measurements of bone mineral density (BMD). We investigated the effect of patients' change of weight on DXA scans in 152 women enrolled in a 2-year trial of cyclical etidronate therapy. Scans of the spine, hip, and total body were performed at baseline, 1 and 2 years on a Hologic QDR-2000. The study was completed by 135 subjects (64 on etidronate, 71 on placebo). Results were expressed as the percentage change in BMD (spine, femoral neck, total body) or bone mineral content (BMC)(total body only) at 2 years. Total body scans were analyzed using the manufacturer's 'standard' and 'enhanced' algorithms. Analysis was performed using multivariate regression with percentage change in BMD or BMC as the dependent variable, and treatment group and percentage change in weight as the independent variables. Weight change varied between -14.4% and +16.7%. All DXA variables showed a statistically significant treatment effect. Standard total body BMD and BMC and enhanced total body BMC all showed a significant dependence on weight change (P < 0.01, P < 0.001 and P < 0.01, respectively). No effect of weight change was seen on spine, femoral neck, or enhanced total body BMD. In order to investigate the effects of weight on long-term precision, patients were allocated to two groups according to baseline body mass index (BMI < 25 and > 25 kg/m2, respectively). For femoral neck BMD the root mean square (RMS) residual percentage change was statistically significantly larger in the high BMI group (P < 0.05) but all other bone density variables showed no significant difference. With patients allocated to two groups according to their absolute percentage change in weight (< 5% and > 5%, respectively) the RMS residual percentage changes in the bone density variables were statistically significantly larger in the large weight change group for femoral neck BMD (P < 0.05) and for standard and enhanced total body BMC (P < 0.01 and P < 0.05, respectively). With the exception of the standard total body algorithm, weight change in a longitudinal study of postmenopausal women was not found to cause systematic errors in the results of DXA studies but may adversely affect precision.

Purpose: To determine whether intermittent cyclical etidronate therapy can prevent early postmenopausal bone loss., Patients and Method: This was a 2-year outpatient, randomized, double-blind, placebo-controlled clinical trial. The subjects were 152 women within 1 to 10 years of the onset of menopause and bone mineral density (BMD) between 0 and -2 SD of normal values for a 50 year old woman. The women were stratified according to years since the menopause (1 to 3 years: n = 43; 4 to 6 years: n = 53; 7 to 10 years: n = 56). Measurements of lumbar spine, proximal femur and total body BMD were performed at baseline, 12 and 24 months by dual x-ray absorptiometry. Biochemical markers of bone resorption and bone formation were measured on the same visits., Results: One hundred thirty-five subjects completed the study. Mean percentage change in lumbar spine BMD (and SEM) at 2 years was +2.14 (0.47)% in the etidronate group and -1.72 (0.41)% in the placebo group. Results for lumbar spine BMD in the treated and control groups stratified according to years since the menopause were: 1 to 3 years: +1.73 (0.84)% and -3.30 (0.70)%; 4 to 6 years: +1.37 (0.88)% and -1.80 (0.61)%; 7 to 10 years: +3.42 (0.61)% and -0.38 (0.70)%. The effect of both treatment group and menopausal stratum were highly statistically significant for lumbar spine and total body BMD. Treatment group, but not stratum, was significant for BMD in the proximal femur. Markers of bone resorption and bone formation were significantly decreased by etidronate therapy., Conclusions: Cyclical etidronate prevents bone loss in the total skeleton and at the clinically relevant sites (spine and proximal femur) even in the early postmenopausal years. Hence, it appears to be an effective and safe nonhormonal therapy in postmenopausal women with normal or low BMD.

We report a study to assess whether supine lateral dual-energy X-ray absorptiometry (DXA) scans of the lumbar spine provide better data for monitoring response to treatment than alternative measurement sites such as the posteroanterior (PA) spine, hip and total body. The study population was 152 women enrolled in a placebo-controlled clinical trial of cyclical etidronate therapy. All subjects were 1-10 years after the menopause with bone mineral density (BMD) between 0 and -2 SD of age-matched normal women. Paired PA and lateral spine, left hip and total-body DXA scans were performed at baseline, 1 year and 2 years on a Hologic QDR-2000. One hundred and thirty-one subjects completed the study. Mean percentage change from baseline at 2 years in the treated (n = 61) and control (n = 70) groups was calculated for vertebral body, width-adjusted (WA) vertebral body, mid-vertebral body and WA mid-vertebral body BMD measurement on the lateral scans and compared with the percentage changes in PA spine, femoral neck, trochanter, Ward's triangle and total-body BMD. The long-term precision for each BMD measurement site was obtained by linear regression analysis in subjects taking placebo. Overall treatment effect, defined as the difference in the percentage change in BMD in the two treatment groups at 2 years, was divided by long-term precision to give an index of the ability of each site to monitor response to treatment. Results (and standard errors) normalized to the ratio of treatment effect/ precision for PA spine BMD were as follows: PA spine, 1.00; vertebral body, 0.89 (0.14); WA vertebral body, 0.78 (0.14); mid-vertebral body, 0.65 (0.14); WA mid-vertebral body, 0.60 (0.13); femoral neck, 0.35 (0.15); trochanter, 0.45 (0.15); Ward's triangle, 0.59 (0.22); total body, 0.52 (0.19). Although treatment effect was larger for lateral than for PA spine BMD, this advantage was offset by the greater precision errors. PA spine BMD remains the optimum measurement for longitudinal studies in recently postmenopausal women.

Broadband ultrasonic attenuation (BUA) is a measure of ultrasound transmission through the calcaneus that is dependent on bone thickness as well as the density of scattering centres. This report examines whether the normalization of BUA (units dB MHz-1) for calcaneal width (nBUA: units dB MHz-1mm-1) improves the discrimination of clinical studies. BUA and calcaneal width were measured in 200 women using a contact ultrasound (CUBA-Research) system and nBUA evaluated by dividing BUA by bone width. 150 subjects were early post-menopausal and the remaining 50 were osteoporotic women with confirmed vertebral crush fracture. The ability of BUA and nBUA to differentiate between the two groups of subjects was compared using receiver operating characteristic (ROC) analysis. The areas (and standard errors) under the ROC curves were 0.878 (0.033) for BUA and 0.910 (0.028) for nBUA. The difference (and standard error) between the areas under the ROC curves was 0.033 (0.026) and was not statistically significant.

Supine lateral dual X-ray absorptiometry (DXA) has the potential to provide a sensitive and precise method of measuring changes in trabecular bone mass in the lumbar vertebral bodies. An important reason for the improvement in precision compared with the earlier decubitus lateral technique is the use of baseline compensation, an algorithm which computes the changes in lateral bone mineral density (BMD) using data from both anteroposterior (AP) and lateral scans. This report examines the precision of supine lateral DXA based on scans of 12 female volunteers (age range 21-56 years). Five AP/lateral scan pairs were performed on each subject and precision expressed by the coefficient of variation (CV). For the AP scan the CV for both L1-L4 and L2-L4 BMD was 0.8%. Precision of the L2-L4 lateral vertebral body, mid-vertebral and volumetric BMD parameters with (without) the baseline compensation correction were 1.2% (2.1%), 2.4% (3.0%) and 1.5% (2.5%), respectively. Two methods of performing baseline compensation, referred to as the multiplicative and additive algorithms, were compared and the former shown to give significantly better precision. The precisions of different combinations of lumbar vertebrae for the measurement of lateral vertebral body BMD were compared and the precision for L2-L4 shown to be significantly better than for L3-L4. When individual vertebrae were examined L3 had the best precision although the differences with L2 and L4 were not significant. The study confirmed that supine lateral measurements of vertebral body BMD with baseline compensation give better precision than the decubitus method. The improvement makes it feasible to follow patients longitudinally and may allow the sensitivity of the lateral scan to supersede that of AP measurements.

Dual X-ray absorptiometry (DXA) studies of bone mineral density (BMD) of the lumbar spine and femoral neck were compared with measurements of broadband ultrasonic attenuation (BUA) and velocity of ultrasound (VOS) in the calcaneus in 300 pre- and postmenopausal women (mean age 53 years). The women were referred for evaluation of possible osteopenia as defined by DXA. The ability of ultrasound measurements to predict osteopenia in women was compared with the ability of lumbar spine and femoral neck DXA scans to predict osteopenia in the hip and spine. A new ultrasound parameter obtained by combining BUA and VOS (combined attenuation and velocity (CAV)) was also evaluated. Linear regression analysis of the three ultrasound parameters and lumbar spine and femoral neck BMD gave weak but statistically significant correlations (r = 0.45-0.54). The correlation between spine and femoral neck BMD was statistically significantly better (r = 0.72). Receiver-operating characteristic (ROC) analysis was used to investigate the sensitivity and specificity of ultrasound measurements in predicting patients with osteopenia. The areas under the ROC curves ranged from 0.64 to 0.75 and ultrasound parameters were shown to be poor at predicting osteopenia as defined by DXA. The ability of lumbar spine and femoral neck DXA measurement to predict osteopenia in the hip and spine, respectively, was statistically significantly better than any of the ultrasound parameters. Ultrasound measurements in the calcaneus did not appear to identify accurately patients with osteopenia defined by DXA measurements of bone density in the axial and appendicular skeleton.

Measurements of broadband ultrasonic attenuation (BUA) and velocity of ultrasound through the heel (heel velocity, HV) were performed with a Contact Ultrasonic Bone Analyzer (CUBA-Research model) in 229 women. The subjects consisted of 16 healthy young volunteers (Group 1, mean age 26 years), 170 healthy pre- and postmenopausal women (Group 2, mean age 53 years), and 43 osteoporotic women with radiographically defined vertebral crush fracture (Group 3, mean age 66 years). Subjects in Group 1 had 10 repeated measurements in a study of short-term precision. Women in Groups 2 and 3 also had dual X-ray absorptiometry (DXA) scans to measure lumbar spine and femoral neck bone mineral density (BMD). The BUA and HV measurements for all 229 women showed a significant correlation (r = 0.75, P < 0.001). The precision study on the subjects in Group 1 gave a root mean square coefficient of variation of 6.3% for BUA and 1.04% for HV. Linear regression analysis gave the following relationship between BUA and age for the 170 normal women in Group 2: BUA = 83.6-0.86 (age 40) dB/MHz (r = -0.31, P < 0.001, SEE = 16.3 dB/MHz). The relationship between HV and age was as follows: HV = 1614-2:3 (age 40) m/s (r = -0.33, P < 0.001, SEE = 42 m/s). Multivariate regression analysis showed that in addition to age, years since the menopause was also a significant factor in determining both BUA and HV.(ABSTRACT TRUNCATED AT 250 WORDS)

We report dual energy X-ray absorptiometry (DXA) studies of total body bone mineral and body composition performed in 111 normal caucasian women (aged 42-61). Conventional DXA scans of the lumbar spine and femoral neck were also obtained and each woman completed a detailed questionnaire. Significant correlations were found between total body BMD and BMD in the lumbar spine (r = 0.76) and femoral neck (r = 0.72). We present reference range data for BMD in the total body and in seven subregions of the skeleton. Multiple linear regressions of total body BMD and BMC on weight, height and age showed that the inclusion of height compared with weight and age alone was not statistically significant. The dependence of total body BMD on weight and age was: total body BMD (g cm-2) = 1.043 + 0.0042 x weight (kg) - 0.0039 x age (years) (R = 0.46, SEE = 0.074 g cm2). Body mass derived from DXA scans correlated well with weight measured on scales (r = 0.996, SEE = 0.77 kg). Body composition measurements agreed closely with % body fat estimated from skinfold measurements (r = 0.93), body fat mass estimated from a predictive equation based on weight, height and age (r = 0.91) and % body fat estimated from a predictive equation based on body mass index (r = 0.76). Study precision gave coefficients of variation of 0.6% for total body BMD and 0.7% for % body fat.

The assessment of skeletal integrity by the measurement of ultrasonic velocity through the calcaneus has only recently become widely available and is usually made in conjunction with the measurement of broadband ultrasonic attenuation. Using data obtained with a contact ultrasonic bone analyser (CUBA) system, this report examines whether ultrasonic studies of the heel require the measurement of true velocity of sound in the calcaneus (Vbone), or whether heel velocity (Vheel, defined as the mean velocity through bone and soft tissue) or time of flight velocity (Vtof, defined as the mean velocity between the two transducers) are adequate surrogates. The populations selected for study were 15 healthy young women (group 1, mean age 26 years), 231 healthy peri- and postmenopausal women (group 2, mean age 52 years) and 33 osteoporotic women with confirmed vertebral fracture (group 3, mean age 66 years). Precision was studied by performing 10 repeated scans on the subjects in group 1 and duplicate scans on 144 women randomly selected in groups 2 and 3. Precision was expressed as the percentage coefficient of variation (CV). Both precision studies yielded similar results. The precisions (and 5% to 95% ranges) for all groups combined were: Vbone 2.71% (1465-1809 m/s); Vheel, 1.10% (1511-1646 m/s): Vtof, 0.70% (1349-1425 m/s). Although the precision data suggest Vtof should be preferred, when the range of clinical values is taken into account the smaller CV is exactly cancelled by the narrower range.(ABSTRACT TRUNCATED AT 250 WORDS)

The results of a pilot investigation are presented. The study aimed to show that the presence of radioactive strontium-90 in human bone could be used as evidence of active uptake during life. In this way the time since death of the individual could be identified as occurring before or after the date when atmospheric levels of radioactive strontium were at a peak in the early 1960s. The results of this initial investigation were encouraging but further detailed analysis is required on a substantially larger sample of material spanning a more controlled time period.

We report a study of broadband ultrasonic attenuation (BUA) in the calcaneus in 248 women. Measurements were performed with a Walker-Sonix UBA-575 ultrasonic bone analyser. The populations studied were 15 healthy young volunteers (group 1, mean age 26 years), 200 healthy pre- and postmenopausal women (group 2, mean age 53 years) and 33 osteoporotic women with vertebral crush fractures (group 3, mean age 66 years). Subjects in group 1 each had 10 repeated measurements of their right heel. Duplicate BUA measurements in the right heel were performed in 96 subjects and bilateral scans in a further 87 women in group 2. The remaining 17 subjects in group 2 and those in group 3 had a single scan of the right heel. All women in groups 2 and 3 had dual X-ray absorptiometry (DXA) scans of the lumbar spine and femoral neck. The precision study on the women in group 1 gave a root mean square (RMS) coefficient of variation (CV) of 4.2%. Individual CV results showed statistically significant differences (range 1.3%-7.6%). Duplicate scans in subjects in group 2 gave a RMS CV of 4.6% while the bilateral measurements showed no significant difference between the two heels. Linear regression analysis gave the following relationship between BUA and age: BUA = 87.1 - 0.76 (Age - 40) dB/MHz (r = -0.31, p less than 0.001, SEE = 14.0 dB/MHz). Multivariate regression analysis showed that, in addition to age, years since the menopause was also a significant factor in predicting BUA.(ABSTRACT TRUNCATED AT 250 WORDS)