Search

Osteoporosis is a highly prevalent condition, characterized by compromised bone strength and fragility fractures and with an important associated socio-economic burden. Bisphosphonates are well established as the first line treatment for osteoporosis. However, while randomized control trials have in general demonstrated reasonable anti-fracture efficacy at the spine, they have shown moderate reduction in fracture incidence for non-vertebral sites. Furthermore, oral bisphosphonates are commonly associated with adverse gastrointestinal effects and both oral and parenteral bisphosphonates have been linked with osteonecrosis of the jaw and atypical femoral fracture, two rare but debilitating side effects. In addition, bisphosphonates are not recommended in patients with GFR <35 ml/min/1.73 m(2). Hence, there is a clear requirement for newer agents, which are able to reduce fracture risk further, whilst overcoming the limitations of bisphosphonates. Over the past 20 years, knowledge and a deeper understanding of the various signalling pathways involved in bone remodelling has increased, enabling identification of additional targets for therapy. This review focuses on these newer therapies and includes anti-resorptive agents such as raloxifene and other selective oestrogen receptor modulators, the monoclonal antibody denosumab (which inhibits the RANKL pathway), odanacatib, a cathepsin K inhibitor and the anabolic agents, PTH analogue; PTH (1-34) and anti-sclerostin antibodies (activator of the Wnt pathway). Strontium ranelate will not be reviewed as recent reports highlight concerns surrounding its cardiovascular safety and together with an apparent increased risk of thrombosis, its future use remains uncertain. Some of these agents such as raloxifene, denosumab and teriparatide are already in clinical use whilst others are at varying stages of development. This review will provide an overview of the mechanisms of action of these therapeutic agents on the skeleton and assess their efficacy in osteoporosis and fracture prevention.

Unlabelled: We assessed the precision of lumbar spine (18)F-PET measurements based on 58 scans performed on 20 postmenopausal women. The percentage coefficient of variation (%CV) (95% confidence interval) was 9.2% (7.5-11.8) for standardised uptake values, 11.7% (9.5-14.9) for plasma clearance measurements using the Patlak method and 14.5% (11.7-18.5) for plasma clearance measurements using the Hawkins three-compartment model., Introduction: (18)F-Fluoride positron emission tomography ((18)F-PET) is a non-invasive technique that allows the assessment of regional bone turnover in patients with metabolic bone disease. Knowledge of the precision errors of (18)F-PET measurements is important for planning the number of subjects required for research studies., Methods: Twenty osteoporotic postmenopausal women had (18)F-PET scans of the lumbar spine at 0, 6 and 12 months after stopping long-term bisphosphonate treatment. No significant changes in the PET measurements were seen over the 12-month period, and the data were deemed suitable for a precision study. Precision errors were evaluated for standardised uptake values (SUVs) and for the fluoride plasma clearance to bone mineral (K (i)) determined using the Patlak and Hawkins methods. Precision errors were expressed as the %CV and were calculated for the mean L1-L4 region and for individual vertebrae., Results: %CV (95% confidence interval) for the L1-L4 region was 9.2% (7.5-11.8) for SUV, 11.7% (9.5-14.9) for K (i) measured using the Patlak method and 14.5% (11.7-18.5) for K (i) measured using the Hawkins method. There was no significant difference between precision errors obtained for the L1-L4 region and those obtained for a single vertebra., Conclusions: SUV measurements showed the smallest precision error followed by the Patlak method, while the Hawkins method gave the largest error. Measuring a smaller region of interest did not increase the precision error, suggesting that the factor determining the errors may be scanner calibration.

Unlabelled: The aim of this study was to examine the effects of bisphosphonate discontinuation on bone metabolism at the spine and hip measured using (18) F-fluoride PET. Bone metabolism at the spine remained stable following discontinuation of alendronate and risedronate at 1 year but increased in the hip in the alendronate group only., Introduction: Bisphosphonates such as alendronate (ALN) or risedronate (RIS) have persistent effects on spine BMD following discontinuation., Methods: Positron emission tomography (PET) was used to examine regional bone metabolism in 20 postmenopausal women treated with ALN (n = 11) or RIS (n = 9) for a minimum of 3 years at screening (range 3-9 years, mean 5 years for both groups). Subjects underwent a dynamic scan of the lumbar spine and a static scan of both hips at baseline and 6 and 12 months following treatment discontinuation. (18) F-fluoride plasma clearance (K(i)) at the spine was calculated using a three-compartment model. Standardised uptake values (SUV) were calculated for the spine, total hip, femoral neck and femoral shaft. Measurements of BMD and biochemical markers of bone turnover were also performed., Results: With the exception of a significant decrease in spine BMD in the ALN group, BMD remained stable. Bone turnover markers increased significantly from baseline by 12 months for both study groups. Measurements of K(i) and SUV at the spine and femoral neck did not change significantly in either group. SUV at the femoral shaft and total hip increased significantly but in the ALN group only, increasing by 33.8% (p = 0.028) and 24.0% (p = 0.013), respectively., Conclusions: Bone metabolism at the spine remained suppressed following treatment discontinuation. A significant increase in SUV at the femoral shaft and total hip after 12 months was observed but for the ALN group only. This study was small, and further clinical studies are required to fully evaluate the persistence of BP treatment.

Summary: We examined the effect of weight and weight change on the long-term precision of spine and hip bone mineral density (BMD) in a group of 64 postmenopausal women studied over a 10-year period. Long-term precision errors were 50% larger than short-term errors. Over the range 50-90-kg weight was associated with a statistically significantly larger precision error when precision was expressed in BMD units, but not when expressed as the coefficient of variation (CV). Weight changes up to 5 kg had little effect on precision., Introduction: Reliable knowledge of the precision of bone mineral density (BMD) measurements is important for the interpretation of follow-up dual-energy X-ray absorptiometry (DXA) scans. In this study, we examined the effect of body weight and change in weight on the long-term precision of spine and hip BMD., Methods: The study population was a group of 64 postmenopausal women enrolled in a 16-year trial of tibolone. We analyzed the spine, femoral neck, and total hip BMD data acquired over a 10-year period on a Hologic QDR4500A densitometer using linear regression to examine the trend of BMD with time for each subject. Precision was expressed in BMD units (g cm(-2)) (standard error of the estimate, SEE) and also as the coefficient of variation (CV)., Results: The long-term precision errors were in BMD (CV) units: 0.018 g cm(-2) (1.9%) for spine, 0.017 g cm(-2) (2.3%) for femoral neck, and 0.016 g cm(-2) (1.7%) for total hip BMD. An inverse relationship between CV and BMD was found for the spine (P = 0.003) and total hip (P = 0.043) sites, but none between SEE and BMD. For spine BMD, there were statistically significant correlations between SEE and weight (P = 0.025) and body thickness (P = 0.027). For femoral neck BMD, there were correlations between SEE and weight (P = 0.030), body mass index (BMI) (P = 0.023) and thickness (P = 0.021), but no correlations for total hip BMD or when precision was expressed as the CV. When study subjects were grouped in quartiles according to weight, the spine BMD SEE increased from 0.014 g cm(-2) for women in the lowest quartile (46-62 kg) to 0.018 g cm(-2) for women in the highest quartile (80-105 kg) (P = 0.008). There was a trend for SEE to be greater in individuals with larger weight changes, although these tended to be the heavier subjects., Conclusions: From the study, we were able to come up with the following conclusions: (1) long-term precision errors were 50% larger than short-term errors, (2) over the range 50 to 90 kg (BMI: 20-35 kg m(-2)), body weight had a small but statistically significant effect on precision expressed in BMD units, but not when expressed as the CV, and (3) weight changes up to 5 kg had little effect on precision. More studies of individuals >100 kg are required to fully investigate the dependence of DXA scan precision on weight.

Uncertainties exist regarding whether FGF-23 production is influenced by PTH and its involvement in bone formation. We evaluated FGF-23 response and its relation to changes in biomarkers of bone formation following intermittent PTH treatment. Twenty-seven women with a mean [SD] age of 75.8 [5.4] years with postmenopausal osteoporosis were treated with PTH(1-34) for 18 months. Bone mineral density (BMD) was measured at 6 and 18 months at the lumbar spine (LS) and total hip (TH). Blood samples were obtained at baseline, 1-3, 6-9, and 12-18 months. Serum calcium, phosphate, PTH, 25(OH)vitamin D, 1,25(OH)(2)vitamin D, markers of bone turnover, FGF-23, and sclerostin were measured. BMD increased at both the LS (11.6%, P < 0.001) and TH (2.5%, P < 0.01). The bone formation marker P1NP increased early (baseline mean [SD] 39.9 [24.4] μg/l, 1-3 months 88 [37.9] μg/l; P < 0.001) and remained higher than baseline throughout 18 months. FGF-23 also increased, with a peak response at 6-9 months (increase 65%, P = 0.002). Serum phosphate remained stable. A significant increase in 1.25(OH)(2)vitamin D (P = 0.02) was seen at 1-3 months only. A small but significant reduction in sclerostin was seen at 6-9 (P = 0.02) and 12-18 months (P = 0.06). There was a positive correlation between changes in P1NP and FGF-23 (6-9 months r = 0.78, P < 0.001). FGF-23 is increased by intermittent PTH(1-34). This is related to early changes in P1NP, suggesting that the skeletal effects of PTH may involve FGF-23. Further studies are required to elucidate this.

Teriparatide (TPTD) increases skeletal mass, bone turnover markers, and bone strength, but in vivo effects at individual skeletal sites have not been characterized. Quantitative radionuclide imaging studies reflect bone blood flow and osteoblast activity to assess regional changes in bone metabolism. Changes in bone plasma clearance using technetium-99m methylene diphosphonate ((99m)Tc-MDP) were quantified and correlated with changes in bone turnover markers in 10 postmenopausal women with osteoporosis. Subjects underwent bone scintigraphy at baseline and 3 and 18 months after initiating TPTD 20 microg/day subcutaneously. Subjects were injected with 600 MBq (99m)Tc-MDP, and whole-body bone scan images were acquired at 10 minutes and 1, 2, 3, and 4 hours. Multiple blood samples were taken between 5 minutes and 4 hours after treatment, and free (99m)Tc-MDP was measured using ultrafiltration. The Patlak plot method was used to evaluate whole-skeleton (99m)Tc-MDP plasma clearance (K(bone)) and derive regional bone clearance for the calvarium, mandible, spine, pelvis, and upper and lower extremities using gamma camera counts. Bone turnover markers were measured at baseline and 3, 12, and 18 months. Median increases from baseline in whole-skeleton K(bone) were 22.3% (p = .004) and 33.7% (p = .002) at 3 and 18 months, respectively. Regional K(bone) values were increased significantly in all six subregions at 3 months and in all subregions except the pelvis at 18 months. Bone markers were increased significantly from baseline at 3 and 18 months and correlated significantly with whole-skeleton K(bone). This is the first study showing a direct metabolic effect of TPTD at different skeletal sites in vivo, as measured by tracer kinetics., ((c) 2010 American Society for Bone and Mineral Research.)

Arterial calcification leading to increased arterial stiffness, a powerful risk factor for cardiovascular disease, may underlie the association of osteoporosis with cardiovascular disease in postmenopausal women. Osteoprotegerin (OPG), an indirect inhibitor of osteoclastogenesis, may be involved in arterial calcification. We examined relationships between calcification of subclinical atherosclerotic plaque and arterial stiffness with bone mineral density (BMD) and OPG in a group of 54 postmenopausal women referred for routine osteoporosis screening by dual-energy X-ray absorptiometric scanning of the lumbar spine and hip. Presence of calcified and noncalcified plaque in carotid and femoral arteries was examined using ultrasonography. Pulse wave velocity (PWV), a measure of arterial stiffness, was determined by sequential tonometry over the carotid and femoral region. Fifty-nine percent of osteoporotic women had calcified (echogenic) plaque at one or more sites compared with 42% and 20% for women with osteopenia and normal BMD, respectively (P = 0.04). There was a significant negative correlation between PWV and hip BMD (r = -0.35, P = 0.01), which remained significant when age, mean arterial pressure, and serum lipids were taken into account (P = 0.05). No significant relationships were observed between serum concentrations of OPG and lumbar spine or total hip BMD or with the number of arterial sites with calcified or noncalcified plaque. However, there was a strong correlation between OPG and PWV (r = 0.44, P = 0.001), which remained significant when adjusted for age (P = 0.01). These findings suggest that decreased BMD is associated with arterial calcification and stiffening and raise the possibility that OPG is a marker of arterial stiffening, independent of any association with BMD.

Treatment of postmenopausal osteoporosis (PMO) is based primarily on antiresorptive agents, including hormone replacement therapy (HT). To evaluate whether anabolic therapy together with HT provides additional benefits in the treatment of PMO, we evaluated the effects of parathyroid hormone (PTH) 1-84 in postmenopausal women with low bone mineral density (BMD) who were receiving chronic (> or =6 months) HT. Subjects were randomized to receive 100 microg PTH(1-84) or placebo injections daily for 24 months (n = 90/group). The primary efficacy outcome was change from baseline in lumbar spine BMD. Secondary end points included changes in hip and distal radius BMD, bone turnover markers, and fracture incidence. The study was terminated early following recommendations regarding HT for PMO. At 18 months, the mean increase in lumbar spine BMD was 7.9% for PTH(1-84) subjects vs. 1.5% for those receiving HT alone; between-group differences were significant at 6 months and persisted throughout the study. Lumbar spine BMD increased in 94% of women receiving PTH(1-84) compared to 59% for HT alone. Femoral neck BMD and bone turnover markers were significantly higher in PTH(1-84)-treated subjects, but the changes in total hip and distal radius BMD were not significant. PTH(1-84) treatment was generally well-tolerated, with hypercalciuria, hypercalcemia, nausea, vomiting, and dizziness reported more frequently in the HT + PTH(1-84) group. In conclusion, addition of PTH(1-84) to stable HT produced marked increases in lumbar spine BMD and may represent an additional approach to the treatment of PMO women receiving HT.

Unlabelled: Quantitative studies of bone using (99m)Tc-methylene diphosphonate ((99m)Tc-MDP) have a potentially valuable role in investigating the treatment of patients with metabolic bone disease. In this study we compared 3 different methods of measuring whole-skeleton (99m)Tc-MDP plasma clearance (K(bone)) in 12 osteoporotic postmenopausal women (mean age, 67.3 y) before participation in a clinical trial of an osteoporosis therapy. The aim was to compare the consistency and accuracy of the 3 methods before their use in evaluating the subjects' response to treatment., Methods: Subjects were injected with 600 MBq (99m)Tc-MDP and 3 MBq (51)Cr-ethylenediaminetetraacetic acid ((51)Cr-EDTA) and whole-body bone scan images were acquired at 10 min, 1, 2, 3, and 4 h. Two-minute static images of the thighs were acquired immediately after the 1- to 4-h whole-body scans. Six blood samples were taken between 5 min and 4 h, and free (99m)Tc-MDP was measured using ultrafiltration. The glomerular filtration rate (GFR) was estimated from the (51)Cr-EDTA plasma curve. The methods used to evaluate K(bone) were (a) the area-under-the-curve (AUC) method, in which the GFR measurement was subtracted from the total (bone plus renal) clearance (K(total)) measured from the free (99m)Tc-MDP plasma curve; (b) the modified Brenner method, in which (99m)Tc-MDP renal clearance estimated from the whole-body counts was subtracted from the total clearance measured from the rate of elimination of tracer from soft tissue; and (c) the Patlak plot method, which was also used to derive regional values of K(bone) for the skull, spine, pelvis, arms, and legs., Results: There was good agreement between the 3 methods of measuring K(bone). (mean K(bone) +/- SD: AUC method, 30.3 +/- 6.4 mL x min(-1); Brenner method, 31.1 +/- 5.8 mL x min(-1); Patlak method, 35.7 +/- 5.8 mL x min(-1)). The correlation coefficients between the methods varied from r = 0.767 (P = 0.004) to r = 0.805 (P = 0.002). Regional measurements of (99m)Tc-MDP clearance gave the following percentages of the whole-skeleton clearance: skull, 13.3%; spine, 16.6%; pelvis, 17.2%; arms, 11.1%; legs, 23.7%., Conclusion: The 3 methods gave consistent and accurate measurements of K(bone). The Patlak method can be used to study regional as well as total-skeleton values of K(bone).

Strontium ranelate is a new orally administered agent for the treatment of women with postmenopausal osteoporosis that reduces the risk of vertebral and nonvertebral fractures. This review article examines the evidence for the antifracture efficacy and safety of strontium ranelate treatment and discusses the effect of DXA scans, biochemical markers of bone turnover, and bone histology. In the SOTI trial, three years treatment with strontium ranelate led to a 41% reduction in vertebral fracture risk (relative risk [RR]=0.59; 95% CI: 0.48-0.73; p<0.001), while in the TROPOS study there was a 16% reduction in nonvertebral fractures (RR=0.84; 95% CI 0.702-0.995; p=0.04). Compared with alternative osteoporosis therapies, strontium ranelate treated patients show large increases in BMD coupled with comparatively modest changes in biochemical markers of bone turnover and bone histology. While the large BMD changes provide a useful way of monitoring patients' response to treatment, it is important to appreciate that much of the increase is a purely physical effect due to the increased attenuation of X-ray when some of the calcium in bone is replaced by strontium. Strontium ranelate is a useful addition to the range of antifracture treatments available for treating postmenopausal women with osteoporosis and is the only treatment proven to be effective at preventing both vertebral and nonvertebral fractures in women aged 80 yr and older.

The aim of this study was to determine whether forearm bone mineral density (BMD) measurements are affected by clinical risk factors for osteoporosis to the same extent as spine and hip BMD. The study population consisted of 1,009 female patients and volunteers, of whom 238 were premenopausal. Women were placed into seven groups according to which clinical risk factor they had (women could be placed in more than one group): (1) atraumatic fracture since the age of 25 years, (2) report of X-ray osteopenia, (3) predisposing medical condition or use of therapy known to affect bone metabolism, (4) premature menopause before the age of 45 years or a history of amenorrhea of longer than 6 months' duration, (5) family history of osteoporosis, (6) body mass index (BMI) <20 kg/m(2), and (7) current smoking habit. Forearm BMD was measured using an Osteometer DTX-200 peripheral dual-energy X-ray absorptiometry scanner, and spine and hip BMD measurements were obtained on a Hologic QDR-4500 scanner. Manufacturers' reference ranges were used to calculate Z scores for the spine and forearm, and the NHANES III reference range was used to calculate Z scores for the hip. Multivariate regression analysis was used to estimate the mean decrease in Z score associated with each clinical risk factor. The Z-score reductions associated with the seven risk factors were similar for forearm and central BMD measurements. For forearm measurements, Z-score decreases associated with a history of atraumatic fracture (-0.25), a medical condition or therapy known to affect bone metabolism (-0.26), premature menopause or history of amenorrhea (-0.30), and BMI <20 kg/m(2) (-0.82) were all statistically significantly different from zero (P < 0.05). With an increasing number of risk factors in each individual, the mean Z score at each measurement site became progressively more negative. In conclusion, clinical risk factors for low BMD affect forearm BMD measurements to a similar extent as central BMD.

Background: It is still unclear whether addition of calcium/vitamin D supplements leads to an incremental benefit in patients taking bisphosphonates and whether achievement of serum level of 25 (OH) vitamin D of at least 70 nmol/L has an impact on the skeletal response to bisphosphonates. Moreover the maintenance of BMD after bisphosphonates withdrawal with the continuation of calcium/vitamin D supplements only, remains uncertain. The aims were to assess the impact of vitamin D status on changes in bone mineral density (BMD) in firstly patients with post-menopausal osteoporosis on bisphosphonates and secondly following discontinuation of bisphosphonates after long-term use., Methods: Two patient groups were recruited. The first study population comprised of 112 women treated with a bisphosphonate. The second study population consisted of 35 women who had been on bisphosphonates for > 5 years in whom the treatment agent was discontinued. Baseline BMD, changes in BMD following treatment, duration of treatment, serum 25 (OH) vitamin D, parathyroid hormone (PTH), urine C-terminal telopeptides of type 1 collagen (CTX) were obtained on the study participants., Results: In the first study group, subjects with serum vitamin D concentrations (> 70 nmol/L) had a significantly lower serum PTH level (mean [SEM] 41 2 ng/L). PTH concentrations of 41 ng/L or less was associated with a significantly higher increase in BMD at the hip following treatment with bisphosphonates compared to patients with PTH > 41 ng/L (2.5% [0.9] v/s -0.2% [0.9], P = 0.04). In the second study group, discontinuation of bisphosphonate for 15 months after long-term treatment did not result in significant bone loss at the lumbar spine and total hip, although a trend towards gradual decline in BMD at the femoral neck was observed., Conclusion: the data suggest that optimal serum 25 (OH) vitamin D concentration may lead to further reduction in bone loss at the hip in patients on bisphosphonates. A prospective controlled trial is needed to evaluate whether the response to bisphosphonates is influenced by vitamin D status. BMD is preserved at the lumbar spine and total hip following discontinuation of bisphosphonate for a short period following long-term treatment, although a gradual loss occurs at the femoral neck.

Strontium ranelate is a new orally administered agent for the treatment of women with postmenopausal osteoporosis that reduces the risk of vertebral and hip fractures. Evidence for the safety and efficacy of strontium ranelate comes from two large multinational trials, the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of Postmenopausal Osteoporosis) studies. The SOTI study evaluated vertebral fracture prevention in 1649 postmenopausal women with a mean age of 69 y. The subjects all had at least one previous vertebral fracture and a low spine bone mineral density (BMD) (equivalent to a Hologic spine T-score below -1.9). The strontium ranelate group had a 41% lower risk of a new vertebral fracture than the placebo group over the three-year study period (relative risk [RR] = 0.59; 95% confidence interval [CI]: 0.48-0.73; p < 0.001). The TROPOS study evaluated non-vertebral fracture prevention in 5091 postmenopausal women with a mean age of 77 y. The subjects were aged 74 y and over (or 70-74 y with one additional risk factor) and a low femoral neck BMD (equivalent to an NHANES III [Third National Health and Nutrition Examination Survey] T-score below -2.2). Over the three-year study period there was a 16% reduction in all non-vertebral fractures (RR = 0.84; 95% CI 0.702-0.995; p = 0.04) and a 19% reduction at the principal sites for non-vertebral fractures. The TROPOS study was not powered to investigate hip fracture risk. However, in a high risk group of women aged 74 y and over and with an NHANES III femoral neck T-score less than -2.4 there was a 36% reduction in hip fracture risk (RR = 0.64; 95% CI: 0.412-0.997; p = 0.046). The overall incidence of adverse events did not differ significantly from placebo and were generally mild and transient, the most common being nausea and diarrhea. Strontium ranelate is a useful addition to the range of anti-fracture treatments available for treating postmenopausal women with osteoporosis and is the only treatment proven to be effective at preventing both vertebral and hip fractures in women aged 80 y and over.

A recent position statement issued by the UK National Osteoporosis Society recommends a triage approach to the use of peripheral dual-energy X-ray absorptiometry (pDXA) devices. Patients with a forearm T-score greater than -1 or less than -2.5 are regarded as normal or osteoporotic, respectively, while those with a T-score between -1 and -2.5 are sent for further assessment with spine and hip DXA. We have evaluated the NOS pDXA algorithm by comparing it with the alternative strategies of relying on forearm BMD alone, or performing spine and hip DXA in every patient. The evaluation was carried out using a mathematical model, and the predictions were compared with in vivo data obtained in patients referred for investigation by their general practitioner. In the model the population distribution of spine, hip, and forearm BMD was described by a trivariant Gaussian function. Relative risks of fracture were taken from a meta-analysis. The three strategies were compared using receiver operating characteristic (ROC) curves in which the percentage of future fracture cases identified was plotted against the percentage of the whole population found to have osteoporosis. ROC curves plotted for the discrimination of hip, vertebral, and Colles fracture risk and the risk of a fracture at any skeletal site were similar for all three strategies, with the curves for the NOS pDXA algorithm nearly identical to those for spine and hip DXA. For the case of hip fracture, vertebral fracture, or a fracture at any site, forearm BMD was slightly inferior to the NOS algorithm, but the reverse was true for Colles fracture. The small difference between the ROC curves suggests that forearm BMD used alone can reproduce clinical decision-making with the NOS pDXA algorithm provided that a T-score threshold of T=-2.1 is used for the diagnosis of osteoporosis, instead of the conventional figure of T=-2.5. Results from the in vivo study were in good agreement with the predictions of the model, although some differences were observed that were explained by inaccuracies in the forearm reference data. We conclude that use of forearm BMD alone with a modified T-score threshold of -2.1 would save the need for spine and hip DXA scans and identify only slightly fewer fracture cases for treatment.

Osteoporosis is a highly prevalent but preventable disease and, as such, it is important that there are appropriate diagnostic criteria to identify those at risk of low trauma fracture. In 1994 the World Health Organization (WHO) introduced definitions of osteoporosis and osteopenia using T-scores, which identified 30% of all Caucasian post-menopausal women as having osteoporosis. However, the use of the WHO T-score thresholds of -2.5 for osteoporosis and -1.0 for osteopenia may be inappropriate at skeletal sites other than the spine, hip and forearm or when other modalities, such as quantitative ultrasound (QUS) are used. The aim of this study was to evaluate the age-dependence of T-scores for speed of sound (SOS) measurements at the radius, tibia, phalanx and metatarsal by use of the Sunlight Omnisense, to evaluate the prevalence of osteoporosis and osteopenia at these sites by use of the WHO criteria, and calculate appropriate equivalent T-score thresholds. The study population consisted of 278 healthy pre-menopausal women, 194 healthy post-menopausal women and 115 women with atraumatic vertebral fractures. All women had SOS measurements at the radius, tibia, phalanx and metatarsal and bone mineral density (BMD) measurements at the lumbar spine and hip. A group of healthy pre-menopausal women aged 20-40 years from the pre-menopausal group were used to estimate the population mean and SD for each of the SOS and BMD measurement sites. Healthy post-menopausal women were classified into normal, osteopenic or osteoporotic, based upon the standard WHO definition of osteoporosis and expressed as a percentage. We investigated the age-related decline in T-scores from 20-79 by stratifying the healthy subjects into 10-year age groups and calculating the mean T-score for each of these groups. Finally, we estimated appropriate T-score thresholds, using five different approaches. The prevalence of osteoporosis in the post-menopausal women aged 50 years and over ranged from 1.4 to 12.7% for SOS and 1.3 to 5.2% for BMD. The age-related decline in T-scores ranged from -0.92 to -1.80 for SOS measurements in the 60 to 69-year age group and -0.60 to -1.19 for BMD measurements in the same age group. The WHO definition was not suitable for use with SOS measurements, and revised T-score thresholds for the diagnosis of osteoporosis of -2.6, -3.0, -3.0 and -2.2 and for osteopenia of -1.4, -1.6, -2.3, and -1.4, for the radius, tibia, phalanx and metatarsal, respectively, were recommended.

Malnutrition in elderly people contributes to osteoporosis and fracture. The aim of the study was to investigate the effects of nutritional improvement on bone metabolism in elderly community-dwelling women. A 12-month randomized controlled trial of 71 ambulant women aged > or =70 years with BMI < or =21 kg/m(2 )and osteoporosis at the hip was undertaken. They received either calcium (1 g) and vitamin D (800 units of cholecalciferol) only (group 1: n=35) or calcium/vitamin D and one or two cartons of a nutritional supplement drink which provided 300 Kcal, 12 g protein, 11.6 g fat and 36.8 g carbohydrate per carton (group 2: n=36). Body composition and bone mineral density (BMD) were assessed at baseline and 12 months. Biochemical markers of bone turnover were measured at baseline and at 1, 3, 6, 9 and 12 months. Group 2 gained significantly more weight [mean (SD) group 1: 0.15 (2.45), group 2:2.66 (2.8) kg P<0.001] and fat mass [group 1: -0.26 (1.8), group 2:1.9 (1.7) kg P<0.001]. BMD at the spine, femoral neck and total hip did not change significantly, although there was a positive trend at the total hip in group 2 [group 1: -0.5 (5.2), group 2:1.25 (3.3)%, P=0.13]. In a subgroup analysis, irrespective of their treatment group, there was a significant difference in changes in BMD at the lumbar spine and total hip in those who lost body weight (A) compared to those who had maintained or increased their weight (B), [mean (SD) % change in BMD lumbar spine; A: -1.64 (3.75), B: 0.96 (2.75) P=0.013, total hip A: -2.09 (6.0), B: 1.04 (3.3), P=0.05)] A significant reduction in serum CTX, a marker of bone resorption, was seen in group 2 [% decrease at 3 months, group 1: 1 (8.7), Group 2: 32 (5.8), P<0.01]. Serum osteoprotegerin (OPG) increased significantly in group 2 with a maximal increase (27%) observed at 6 ( P<0.01) and 9 months ( P<0.05). A small increase in bone-specific alkaline phosphatase was seen at 12 months in group 2 [% increase group 1:5 (5), group 2: 17 (6), P=0.05]. Serum osteocalcin increased at 12 months in group 2 ( P=0.01). Dietary improvement in elderly women with low BMI is associated with a reduction in bone resorption with a small but "net" positive effect on bone formation.

Quantitative studies of the kinetics of 99mTc-methylene diphosphonate (99mTc-MDP) in metabolic and metastatic bone disease require the measurement of free tracer in plasma to derive the input function. We describe a simple method of determination of free 99mTc-MDP in vivo based on measurements of the ratio of the renal plasma clearances of total 99mTc-MDP and 51Cr-ethylenediaminetetraacetic acid (51Cr-EDTA). The method is based on evidence that free MDP is cleared through the kidneys by glomerular filtration. Measurements of the fraction of free 99mTc-MDP were made between 0 and 4 h after injection in 70 postmenopausal women enrolled in a study of the effect of hormone replacement therapy on the whole-skeleton plasma clearance of 99mTc-MDP (K(bone)). The glomerular filtration rate (GFR) was measured simultaneously from the plasma clearance of 51Cr-EDTA. The mean fractions (and SD) of free MDP measured were 0.757 (0.050), 0.663 (0.062), 0.550 (0.052) and 0.472 (0.053), respectively, at 17, 90, 150 and 210 min after injection. The results agreed closely with data using protein precipitation with trichloroacetic acid. Between 2 and 4 h after injection, the biological half-life of free 99mTc-MDP in plasma was 92 min, compared with 540 min for bound MDP. Highly significant relationships were found between the fraction of free MDP measured in each patient at each of the four time points and the total plasma clearance of free 99mTc-MDP (K(total)=GFR+K(bone)), such that a larger value of K(total) was associated with a smaller fraction of free MDP. Multivariate regression analysis confirmed that this relationship held individually for both GFR and K(bone). A strong inverse relationship was found between K(total) and the plasma concentration of free 99mTc-MDP, but a much weaker relationship with the bound MDP concentration, a finding that is consistent with the slow re-equilibration of bound MDP in the circulation. The results confirm that the fraction of free 99mTc-MDP varies with time and shows significant differences between individuals, which are dependent on GFR and K(bone) amongst other factors.

Objectives: To assess the effects of tibolone 2.5 mg daily over a 10-year period on bone loss and other efficacy parameters in postmenopausal women, and to confirm its long-term safety and tolerability., Methods: A 10-year, open, non-randomized, prospective study was conducted in 110 postmenopausal women; 59 women received tibolone 2.5 mg daily and 51 were entered into an untreated control group. After 10 years, 31 women in the tibolone group (53%) and 26 (51%) in the control group remained in the study., Results: After 10 years, tibolone had significantly (p < 0.0001) increased the mean bone mineral density in the lumbar spine and femoral neck by 4.8% and 3.7%, respectively, compared with baseline. The corresponding changes in the control group were -8.5% and -8.9% (p < 0.0001 vs. baseline), respectively. The incidence and intensity of hot flushes were reduced in the tibolone group and there were improvements in vaginal cytology parameters. Tibolone was well tolerated., Conclusion: Tibolone 2.5 mg daily maintains its beneficial effects on bone loss over 10 years, while remaining well tolerated.

The aim of this study was to determine whether calcaneal quantitative ultrasound can discriminate between women with and those without fragility fracture at (1) the wrist or (2) at sites other than the spine, hip, or forearm, as well as axial DXA measurements of BMD can. The study population consisted of 342 postmenopausal Caucasian women who were placed into one of three groups: (1) healthy women with no clinical risk factors for osteoporosis (n = 240); (2) women with a history of atraumatic fracture at the wrist (n = 50); (3) women with a history of atraumatic fracture at a skeletal site other than the spine, hip, or wrist (n = 52). Subjects had DXA measurements of the lumbar spine (LS), femoral neck (FN), and total hip (THIP), and calcaneal broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements on the Hologic Sahara (s) and Osteometer DTUone (d). Z-scores were calculated using the mean and SD obtained from the healthy postmenopausal group. All the BMD and QUS variables were significantly reduced in women reporting a fracture of the wrist or at a site other than the spine, hip, or forearm. When the group of women with a history of wrist fracture were compared with the postmenopausal controls, age-adjusted logistic regression yielded odds ratios associated with a 1 SD decrease, that were significant for both BMD and QUS, averaging 2.2. The AUC values ranged from 0.65 for FN BMD to 0.75 for BUAd. BMD and QUS measurements were also significantly reduced in women reporting a skeletal fracture at a site other than the spine, hip, or wrist, and odds ratios for BMD and QUS were significant, averaging 1.7. BMD and QUS showed similar fracture discriminatory abilities that were not significantly different from one another. In conclusion, calcaneal QUS can discriminate between women with and those without fracture at the wrist or at sites other than the spine, hip, or forearm as well as axial DXA measurements of BMD can.

The lack of consensus of how the results of peripheral bone mineral density (BMD) measurements should be interpreted is proving a barrier to the wider use of these devices. One approach is to interpret peripheral measurements using thresholds (so-called equivalent T-scores) defined to have the same absolute fracture risk as a femoral neck T-score of -2.5. For this concept to be valid, the estimates of fracture risk for a population should be the same irrespective of the measurement technique used. We tested this prediction both theoretically and in vivo using data for 63 postmenopausal women with Colles fracture and 191 control subjects. The theoretical analysis showed that if the normal population has a Gaussian BMD distribution and fracture risk varies exponentially with Z-score as exp(-beta Z) then patients who experience a low-trauma fracture have a fracture risk that is larger by a factor exp(beta(2)) compared with the fracture risk of the whole population. Using data from the in vivo study, fracture risk predictions were compared for seven different types of measurement (lumbar spine; femoral neck; total hip BMD; and speed of sound [SOS] at the radius, tibia, phalanx, and metatarsal). When quantitative estimates of fracture risk were made for individual subjects, the average risk of fracture for the Colles group varied between 1.03 times larger (for tibial SOS) and 2.77 times larger (for total hip BMD) than the average fracture risk for the whole population. As predicted by the theoretical study, fracture risk varied according to the odds ratio determined by logistic regression analysis. Therefore, estimates of fracture risk derived for the same group of patients varied almost threefold according to the type of measurement. It was concluded that equating estimates of absolute fracture risk for different types of scan should not be used as the basis of deriving equivalent T-scores for interpreting peripheral measurements.

Unlabelled: Quantitative radionuclide studies of bone using the short-lived tracers (18)F-fluoride and (99m)Tc-methylene diphosphonate (MDP) are an alternative method to biochemical markers of bone turnover for investigating the dynamic state of the skeleton. In this study we evaluated their use to quantify bone turnover in women receiving antiresorptive therapy compared with that of untreated control subjects., Methods: The patients were 69 healthy postmenopausal women. Twenty-six women were receiving hormone replacement therapy (HRT) and 43 were untreated age-matched control subjects. After bolus injection of (18)F-fluoride (1 MBq), (99m)Tc-MDP (1 MBq), (51)Cr-ethylenediaminetetraacetic acid (3 MBq), and (125)I-labeled human serum albumin (0.25 MBq), multiple blood samples and urine collections were taken between 0 and 4 h. The clearance to bone mineral K(bone) was first evaluated using the area under the plasma concentration curve (AUC) on the assumption that the rate constant k(4) for the outflow of tracer from bone was negligibly small. AUC values of K(bone) were then compared with those found using a compartmental model method that allowed k(4) to be fitted as a free parameter., Results: Using the AUC method the mean plus minus SD for K(bone) for the 2 tracers were: (18)F-fluoride, 61.8 plus minus 12.0 mL center dot min(-1) (HRT group) versus 67.2 plus minus 12.6 mL center dot min(-1) (control group) (P = 0.045); and (99m)Tc-MDP, 40.3 plus minus 8.2 mL center dot min(-1) (HRT group) versus 44.2 plus minus 7.6 mL center dot min(-1) (control group) (P = 0.024). Values for the 2 tracers in individual patients were moderately well correlated (r = 0.76; P < 0.001). Using the compartmental model method, k(4) for (18)F-fluoride was shown to lie in the range 0--0.0025 min(-1) with a best-fit value of 0.0018 min(-1). Values of K(bone) determined using k(4) = 0.0018 min(-1) were highly correlated with the AUC values (r = 0.989; SEE = 2.05 mL center dot min(-1)) with numeric values that were larger by a factor of 1.53. Analysis of the (99m)Tc-MDP data was more difficult because of uncertainties in protein binding in the extracellular fluid compartment space. The best fit for k(4) was in the range 0.0010--0.0014 min(-1) with values of K(bone) similar to those found using the AUC method., Conclusion: Values of K(bone) determined using the AUC method were able to differentiate between HRT-treated women and postmenopausal women who were not treated and were highly correlated with those determined using a compartmental model method with nonzero values of k(4).

Risedronate treatment reduces the risk of vertebral fracture in women with existing vertebral fractures, but its efficacy in prevention of the first vertebral fracture in women with osteoporosis but without vertebral fractures has not been determined. We examined the risk of first vertebral fracture in postmenopausal women who were enrolled in four placebo-controlled clinical trials of risedronate and who had low lumbar spine bone mineral density (BMD) (mean T-score = -3.3) and no vertebral fractures at baseline. Subjects received risedronate 5 mg ( n = 328) or placebo ( n = 312) daily for up to 3 years; all subjects were given calcium (1000 mg daily), as well as vitamin D supplementation (up to 500 IU daily) if baseline serum 25-hydroxyvitamin D levels were low. The incidence of first vertebral fracture was 9.4% in the women treated with placebo and 2.6% in those treated with risedronate 5 mg (risk reduction of 75%, 95% confidence interval 37% to 90%; P = 0.002). The number of patients who would need to be treated to prevent one new vertebral fracture is 15. When subjects were stratified by age, similar significant reductions were observed in patients with a mean age of 64 years (risk reduction of 70%, 95% CI 8% to 90%; P = 0.030) and in those with a mean age of 76 years (risk reduction of 80%, 95% CI 7% to 96%; P = 0.024). Risedronate treatment therefore significantly reduces the risk of first vertebral fracture in postmenopausal women with osteoporosis, with a similar magnitude of effect early and late after the menopause.

In recent years, the range of treatments available for patients with osteoporosis has greatly increased. A decade ago, the only proven therapy was estrogen, but today the choices include bisphosphonates, selective estrogen-receptor modulators, calcitonin, and parathyroid hormone. Clinical trials involving bone mineral density (BMD) scans of the spine and femur have had an important role in the evaluation of these new therapies. In particular, the efficacy of treatments has now been verified in large studies powered to show reductions in fracture risk. In contrast with the use of BMD scans in research studies, their value for monitoring response to treatment in individual patients is less certain. In many cases, the increases in BMD are too small to reliably distinguish between true changes and measurement error. However, experience with estrogen and bisphosphonates suggests that these treatments have a beneficial effect on bone in most patients. Follow-up scans for patients taking these agents are therefore of limited value, apart from offering reassurance to the patient and the doctor. However, when new therapies are first introduced, follow-up scans have a useful role in building up the physician's experience and confidence.

Background: Risedronate increases bone mineral density in elderly women, but whether it prevents hip fracture is not known., Methods: We studied 5445 women 70 to 79 years old who had osteoporosis (indicated by a T score for bone mineral density at the femoral neck that was more than 4 SD below the mean peak value in young adults [-4] or lower than -3 plus a nonskeletal risk factor for hip fracture, such as poor gait or a propensity to fall) and 3886 women at least 80 years old who had at least one nonskeletal risk factor for hip fracture or low bone mineral density at the femoral neck (T score, lower than -4 or lower than -3 plus a hip-axis length of 11.1 cm or greater). The women were randomly assigned to receive treatment with oral risedronate (2.5 or 5.0 mg daily) or placebo for three years. The primary end point was the occurrence of hip fracture., Results: Overall, the incidence of hip fracture among all the women assigned to risedronate was 2.8 percent, as compared with 3.9 percent among those assigned to placebo (relative risk, 0.7; 95 percent confidence interval, 0.6 to 0.9; P=0.02). In the group of women with osteoporosis (those 70 to 79 years old), the incidence of hip fracture among those assigned to risedronate was 1.9 percent, as compared with 3.2 percent among those assigned to placebo (relative risk, 0.6; 95 percent confidence interval, 0.4 to 0.9; P=0.009). In the group of women selected primarily on the basis of nonskeletal risk factors (those at least 80 years of age), the incidence of hip fracture was 4.2 percent among those assigned to risedronate and 5.1 percent among those assigned to placebo (P=0.35)., Conclusions: Risedronate significantly reduces the risk of hip fracture among elderly women with confirmed osteoporosis but not among elderly women selected primarily on the basis of risk factors other than low bone mineral density.

The objective of this study was to assess the long-term effects of tibolone 2.5 mg daily (Livial; Organon) on bone mineral density in recently postmenopausal women. An 8-year, open, nonrandomized, prospective study was designed to compare the effects of tibolone 2.5 mg daily (n = 59) with an untreated control group (n = 51). The subjects of this study were 110 recently postmenopausal women (6-36 months since last menstrual period). The main outcome measures were bone mineral density of the spine and femur, measured by dual-energy X-ray absorptiometry, and assessment of biochemical markers of bone metabolism. After 8 years of tibolone use, the mean (+/- SEM) increase in bone mineral density compared with baseline was 4.1% +/- 0.8% (p<0.0001) in the spine and 4.6% +/- 1.8% (p = 0.015) in the femoral neck. Over the same period, bone mineral density in the control group decreased in the spine by -7.5% +/- 1.1%, (p<0.0001) and in the femur by -6.7% +/- 1.2% (p<0.0001). The bone resorption marker, calcium/creatinine ratio, decreased in the tibolone group but not in the control group. Serum bone formation markers decreased (alkaline phosphatase) or stayed approximately the same (osteocalcin) in the tibolone group. Adherence was high, with 58% (34 of 59) of the tibolone group continuing treatment for 8 years. We conclude that tibolone 2.5 mg daily prevents bone loss in the lumbar spine and femoral neck over 8 years and adherence to treatment is high. The greater bone density compared with untreated women would be expected to reduce the risk of bone fractures.

Vertebral morphometry, the quantification of vertebral body shape, has proved a useful tool in the identification and evaluation of osteoporotic vertebral deformities in both epidemiologic surveys and clinical trials. Although conventionally it has been performed on lateral radiographs of the thoracolumbar spine (morphometric radiography, MRX), it may now be accomplished on morphometric X-ray absorptiometry (MXA) scans, acquired on dual-energy X-ray absorptiometry (DXA) machines. In this study the long-term precision of vertebral height measurement using MXA and MRX was directly compared. Initially 24 postmenopausal women were recruited (mean age 67+/-5.8 years): 12 normal subjects (group 1) and 12 with osteoporosis and known vertebral deformities (group 2). Each subject attended for a baseline visit at which they had a MXA examination and lateral thoracic and lumbar radiographs. Twenty-one subjects then returned 1.7+/-0.4 years later (10 subjects from group 1 and 11 from group 2) for a follow-up visit to repeat both the MXA scans and conventional radiographs. The baseline MXA scans and conventional radiographs were each analyzed quantitatively by two observers in a masked fashion, using a standard six-point method. The follow-up images were then analyzed by the same observers. The MRX observers were masked to the baseline analyses, while the MXA observers utilized the manufacturer's 'compare' facility. On all scans and radiographs anterior (Ha), mid (Hm) and posterior (Hp) vertebral heights were measured and wedge (Ha/Hp) and mid-wedge (Hm/Hp) ratios calculated for each vertebral body, ideally from T4 to L4. MRX analyzed 129 of the 130 available vertebrae in group 1 at both visits and 141 of the 143 available in group 2, while MXA analyzed 124 vertebrae in group 1 at both visits and 127 in group 2. Intra- and inter-observer precision errors, particularly in terms of coefficient of variation (CV%), were larger for MXA than for MRX in both normal subjects and those with vertebral deformities. For example, intra-observer precision errors for vertebral height measurement were 0.62 mm (2.9%) for MXA compared with 0.63 mm (2.2%) for MRX in group 1 (normal) subjects and 0.82 mm (4.2%) for MXA compared with 0.85 mm (3.3%) for MRX for group 2 (osteoporosis and vertebral deformities) subjects. Both MXA and MRX inter-observer precision was clearly poorer than the intra-observer precision, a problem associated with any morphometric technique. This was particularly noticeable for MXA; for example, precision of vertebral height measurement in group 1 subjects was 0.62 mm (2.9%) for intra-observer compared with 0.99 mm (4.6%) for inter-observer analyses. MXA and MRX intra- and inter-observer precision was significantly poorer for subjects with vertebral deformities compared with those without, with the CV% for subjects with vertebral deformity approximately 50% greater than that of normal subjects. For example, MRX intra-observer precision for the midwedge ratio was 2.6% for group 1 subjects compared with 3.8% for group 2 subjects. The precision of vertebral height measurement on deformed vertebrae of group 2 subjects was poorer than that for normal vertebrae in the same subjects using both MXA and MRX, as a result of increased variability in point placement. For example, MXA intra-observer precision (RMS SD) for the wedge ratio precision was 0.037 (3.9%) for normal vertebrae compared with 0.060 (6.6%) for deformed vertebrae. We conclude that MXA precision was generally poorer than MRX, although both techniques were adversely affected by the presence of vertebral deformities and the use of more than one observer. Although precision errors for both techniques were substantially smaller than the 20-25% reduction in vertebral height frequently proposed to identify incident deformities, the poorer precision of MXA may lead to an increased risk of erroneous classification of vertebrae as normal or deformed.

From 1990 to 2000, several effective new treatments were introduced for the prevention of osteoporotic fractures; these treatments were proven effective in large, international, clinical trials. At the same time, there was rapid technologic innovation, with the introduction of new radiologic methods for the noninvasive assessment of patients' bone density status. These developments led to the publication of guidelines for the clinical use of bone densitometry that include criteria for the referral of patients for investigation as well as recommendations for intervention thresholds for the initiation of preventive treatment of osteoporosis. Dual-energy x-ray absorptiometry scanning of the spine and hip remains the technique of choice for bone densitometry studies, although there is now a wider appreciation of the need for smaller, cheaper devices for scanning the peripheral skeleton if the millions of women most at risk of a fragility fracture are to be identified and treated. This article reviews these developments, concentrating in particular on the advantages and disadvantages of the different types of equipment available for performing bone densitometry investigations, the guidelines for the referral of patients, and the principles for the interpretation of the scan findings.

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.

Our objective was to investigate the efficacy and tolerability of risedronate in postmenopausal women with low bone mass. Women with a mean lumbar spine T-score of -2 or less (n = 543) received 24 months of placebo or risedronate (2.5 or 5 mg/day). All received calcium (1 g/day). The principal outcome measures were bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter. At 24 months, lumbar spine BMD increased from baseline by 4% with 5 mg risedronate and 1.4% in the 2.5-mg group, compared with no change with placebo. Efficacy was similar in women who were less than 5 yr and more than 5 yr postmenopausal. At 24 months, risedronate (5 mg) had also increased BMD at the femoral neck and trochanter, whereas BMD decreased in the placebo group. BMD increases were seen at all three sites with risedronate (5 mg) after only 6 months of therapy. Risedronate was well tolerated; upper gastrointestinal adverse events were similar to placebo. We conclude that risedronate (5 mg) increases BMD rapidly and effectively and is well tolerated in postmenopausal women with low bone mass, regardless of time since menopause.

We studied the effect on bone mass of alendronate treatment for 5 yr and its withdrawal. Four hundred and forty-seven postmenopausal women with normal bone mass entered a 3-yr randomized trial followed by a 2-yr open label extension. Three hundred and eleven women completed the first 3 yr, and 263 consented to continue and completed the extension. We are reporting data from groups using the dose of alendronate currently approved for osteoporosis prevention (5 mg) or from the group in which alendronate treatment was withdrawn: 52 women received alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2 yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg) increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P < 0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs. baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine, hip, and total body in groups I and III. The 3-yr decrease in BMD after withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs. baseline) and similar to the 3-yr decrease in BMD in group II during the initial 3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal of alendronate (20 mg), bone loss resumed at the normal early postmenopausal rate.

Prevalent vertebral deformities are associated with a substantially increased risk of subsequent vertebral and nonvertebral fractures. Knowledge of vertebral fracture status is an important component in the prediction of further fractures in patients with osteoporosis. This study reports a comparison of the quantitative identification of vertebral deformities on morphometric X-ray absorptiometry (MXA) scans and conventional radiographs (MRX) in 161 postmenopausal women (mean age +/- SD, 64 +/- 7.1 years) recruited from patients referred by their family doctor for bone density measurement (n = 119) and osteoporotic subjects with known vertebral deformities attending an osteoporosis clinic (n = 42). Each subject had MXA scans and MRXs of the thoracolumbar spine, to image the vertebrae from T4-L4, at a single visit. The scans and radiographs were analyzed by two trained observers using six points to quantify the shape of each vertebral body. From these points, three vertebral heights were measured: anterior, middle, and posterior. Vertebral deformities were identified using the algorithms proposed by Eastell and by McCloskey. Generally good to excellent agreement (per vertebra, kappa = 0.87-0.93; per subject, kappa = 0.81-0.91) was observed between the two algorithms used for quantitative vertebral deformity identification using MXA or MRX. More moderate agreement (per vertebra, kappa = 0.70-0.79; per subject, kappa = 0.67-0.75) was seen when comparing the same algorithm between MXA and MRX. Agreement between MXA and MRX for the McCloskey algorithm was better than for the Eastell algorithm, largely because of the lower number of false positives produced by the McCloskey methodology. Deformity identification by MXA was limited because of poor image quality, primarily in the upper thoracic spine. One in six MRX deformities were missed by MXA as they occurred in vertebrae not visualized sufficiently for analysis on the MXA scans. Deformity identification was poorer in the upper thoracic spine in analyzable vertebrae with a sensitivity of 50.0% for MXA in terms of MRX using the Eastell algorithm for the vertebral levels T4-T7, compared with 80.6% for L1-L4A. MXA proved to be more effective at identifying moderate to severe MRX deformities producing a sensitivity of 22.0% for MXA in terms of identifying MRX grade 1 deformities using the Eastell algorithm, compared with 81.6% for grade 2 deformities. Although MXA image quality is inferior to that of conventional radiographs, MXA has distinct advantages such as a substantially reduced effective dose to the patient and acquisition of a single image of the spine. MXA is a potentially useful, relatively fast, low-radiation technique to identify prevalent vertebral deformities, particularly moderate to severe deformities in the middle/lower thoracic and lumbar spine, in conjunction with morphometric radiography in some patients.

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.

With the increasing number of quantitative ultrasound (QUS) devices in use worldwide it is important to develop strategies for the clinical use of QUS. The aims of this study were to examine the age-dependence of T-scores and the prevalence of osteoporosis using the World Health Organization Study Group criteria for diagnosing osteoporosis and to examine the T-score threshold that would be appropriate to identify women at risk of osteoporosis using QUS. Two groups of women were studied: (i) 420 healthy women aged 20-79 years with no known risk factors associated with osteoporosis; (ii) 97 postmenopausal women with vertebral fractures. All subjects had dual-energy X-ray absorptiometry (DXA) measurements of the spine and hip and QUS measurements on three calcaneal ultrasound devices (Hologic Sahara, Hologic UBA575+, Osteometer DTUone). A subgroup of 102 (76 on the DTUone) healthy women aged 20-40 years was used to estimate the young adult mean and SD for each QUS and DXA measurement parameter to calculate T-scores. The age-related decline in T-scores for QUS measurement parameters was half the rate observed for the bone mineral density (BMD) measurements. The average T-score for a woman aged 65 years was -1.2 for QUS measurements and -1.75 for the BMD measurements. When osteoporosis was defined by a T-score < or = -2.5 the prevalence of osteoporosis in healthy postmenopausal women was 17%, 16% and 12% for lumbar spine, femoral neck and total hip BMD respectively. When the same definition was used for QUS measurements the prevalence of osteoporosis ranged from 2% to 8% depending on which ultrasound device and measurement parameter was used. Four different approaches, based on DXA-equivalent prevalence rates of osteoporosis, were utilized to examine which T-score threshold would be appropriate for identifying postmenopausal women at risk of osteoporosis using QUS measurements. These ranged from -1.05 to -2.12 depending upon the approach used to estimate the threshold and on which QUS device the measurements were performed, but all were significantly lower than the threshold of -2.5 used for BMD measurements. In conclusion, the WHO threshold of T = -2.5 for diagnosing osteoporosis requires modification when using QUS to assess skeletal status. For the three QUS devices used in this study, a T-score threshold of -1.80 would result in the same percentage of postmenopausal women classified as osteoporotic as the WHO threshold for BMD measurements. Corresponding T-score thresholds for individual measurement parameters on the two commercially available devices were -1.61, -1.94 and -1.90 for Sahara BUA, SOS and estimated heel BMD respectively and -1.45 and -2.10 for DTU BUA and SOS respectively Additional studies are needed to determine suitable T-score thresholds for other commercial QUS devices.

The aim of this study was to assess a dry calcaneal quantitative ultrasound (QUS) device by examining: (i) short- and long-term precision; (ii) the ability of the ultrasound parameters to identify women with vertebral fractures; (iii) age- and menopause-related bone loss; (iv) applicability of the WHO criteria in scan interpretation. The study group consisted of 422 healthy women with no risk factors associated with osteoporosis (227 premenopausal and 195 postmenopausal) and 93 women with one or more vertebral fractures. All women had calcaneal QUS and bone mineral density (BMD) measurements of the lumbar spine and hip performed. Broadband ultrasound attenuation (BUA) and speed of sound (SOS) measurements in the heel were combined and expressed as estimated heel BMD. Short-term precision studies yielded coefficient of variations of 0. 3% for SOS, 4% for BUA and 3.3% for estimated heel BMD. Standardized short-term precision values were approximately 0.2 SD. Long-term standardized precision errors ranged from 0.17 to 0.38 SD. All the QUS and BMD measurement parameters showed significant negative relationships with age in the postmenopausal group. Annual losses were 0.35 dB/MHz per year for BUA, 0.56 m/s per year for SOS and 0. 002 g/cm(2) per year for estimated heel BMD. All the QUS and BMD parameters were able to discriminate between healthy postmenopausal women and women with vertebral fracture. Age-adjusted odds ratios for each SD decline in QUS measurements were 3.63, 5.25 and 4.79 for BUA, SOS and estimated heel BMD respectively. Corresponding odds ratios for BMD at the lumbar spine, femoral neck and total hip were 2.39, 2.51 and 2.95 respectively. When the QUS and BMD parameters were expressed as T-scores, estimated heel BMD showed the least age-related decline, while femoral neck BMD displayed the greatest decrease with age. The mean T-score and prevalence of osteoporosis (T<-2.5) for a Caucasian woman aged 60-65 years were -1.35 and 21% respectively for the lumbar spine compared with -0.59 and 2% for estimated heel BMD. In conclusion, this study revealed that contact ultrasound can detect age- and menopause-related influences on bone status and was able to discriminate between healthy individuals and women with vertebral fracture. However, the widely accepted threshold of a T-score of less than -2.5 for the definition of osteoporosis may need modifying for the interpretation of QUS scans.

Morphometric techniques, which use conventional lateral spine radiographs to quantify vertebral body shape (morphometric radiography, MRX), have proved a useful tool in the identification and evaluation of osteoporotic vertebral deformities. Recently a new method of acquiring the images required for vertebral morphometry using dual-energy X-ray absorptiometry scanners (morphometric X-ray absorptiometry, MXA) has been developed. In this study we compare repeat analysis precision of vertebral height measurement using MXA and MRX. Twenty-four postmenopausal women were recruited (mean age 67 +/- 5.8 years): 12 normal subjects and 12 with osteoporosis and vertebral deformities. Each subject had a MXA scan and lateral thoracic and lumbar radiographs at a single appointment, which were each analyzed quantitatively in a masked fashion, using a standard 6-point method, twice by one observer and once by a second observer. Anterior (Ha), mid (Hm) and posterior (Hp) vertebral heights were measured and wedge (Ha/Hp) and mid-wedge (Hm/Hp) ratios calculated for each vertebral body. Intra- and interobserver precision were consistently poorer in MXA compared with MRX in both normal subjects and those with vertebral deformities, with MXA CV% generally at least 50% higher than corresponding values for MRX. For both MXA and MRX interobserver precision was clearly poorer than intraobserver precision, a problem associated with any morphometric technique. MXA intra- and interobserver precision were significantly poorer for subjects with vertebral deformities compared with those without, with a CV% for deformity subjects up to twice that of normal subjects. Conversely, MRX showed little or no obvious worsening of intra- or interobserver precision for deformity subjects. Comparison of MXA precision in the normal and deformed vertebrae of the deformity subjects demonstrated that the poorer precision in these subjects compared with normal subjects was the result of increased variability in point placement on the deformed vertebrae themselves. However, the precision for normal vertebrae in these subjects was also somewhat poorer than the precision in normal subjects. We conclude that MXA precision is generally poorer than that of MRX and that the presence of vertebral deformities has a more pronounced effect on MXA precision than on MRX precision.

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.

Increased bone resorption following the menopause leads to accelerated bone loss and is a major contributory factor to subsequent osteoporosis. It is well recognised that an early menopause or prolonged amenorrhoea from whatever cause are also major risk factors for osteoporosis. The alterations in skeletal metabolism following oestrogen deficiency are inhibited by oestrogen replacement, and bone loss can be prevented. However, oestrogen therapy may often not be appropriate because of clinical contraindications, side effects or patient concerns regarding the risk of breast cancer. There is increasing evidence that bisphosphonates are effective in inhibiting bone resorption and these compounds are generally well tolerated. At the present time, for the prevention of bone loss related to hypo-oestrogenism, the main options for therapy are likely to be oestrogen replacement or treatment with bisphosphonates.

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.

A 2-year non-randomized prospective study was carried out in a teaching hospital menopause clinic to assess the effect on the skeleton of tibolone (Livial, Organon) 2.5 mg daily in recently postmenopausal women. One hundred women who were between 6 and 36 months since their last menstrual period and had raised gonadotrophin levels consistent with the menopause were allocated into two groups. One group received 2.5 mg tibolone daily and the other group no medication. Bone densitometry of the spine and femur was performed at 0, 6, 12 and 24 months and biochemical markers of bone metabolism were assessed at these points. Severity of hypo-oestrogenic symptoms was assessed at baseline and at 1 and 2 years. After 2 years there was a significant increase in bone mass as measured by dual energy X-ray absorptiometry (DXA) of 2.5% in the spine, and 3.5% in the neck of femur in the women who took tibolone (n = 46), whereas in the control group (n = 45) bone loss occurred (spine, 2.9%; femur, 3.7%). When these changes were compared they were significantly different for both sites (p < 0.001). In the treatment group the urinary hydroxyproline/creatinine and calcium/creatinine ratios fell from 0.014 (0.002-0.027) to 0.010 (0.000-0.111) (mol/l) (mmol/l) (p < 0.01) and 0.47 (0.08-0.96) to 0.33 (0.09-1.20) (mmol/l) (mmol/l) (p < 0.001) respectively, while the serum osteocalcin and alkaline phosphatase decreased from 1.90 (0.20-4.70) to 1.00 (0.00-3.00) mmol/l (p < 0.01) and 190 (92-301) to 138 (91-283) mmol/l (p < 0.001) respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

This study compared measurements of BMD using dual energy X-ray absorptiometry (DXA) at three sites in the nondominant forearm (ultradistal, distal one-third and a mid-region between these two), the lumbar spine (L1-L4) and the proximal femur (femoral neck, trochanter and Ward's triangle) for the evaluation of vertebral osteoporosis. Studies were performed on 100 normal women aged 29-69 yr (average 52 yr) and 63 osteoporotic women age 48-75 yr (average 66 yr) using the Hologic QDR-1000. Precision values of < 1% were obtained in both normal and osteoporotic women at both forearm and axial sites. Z-scores for the osteoporotics [Z = (mean BMD normal--mean abnormal)/S.D.] were--2.02 lumbar spine, -1.96 femoral neck, -1.79 ultradistal forearm, -1.73 mid region and -1.66 distal one-third forearm. Receiver operating characteristic curves showed that the lumbar spine and femoral neck equally discriminated between normals and osteoporotics with a 95% area under each curve, significantly greater values than those for the forearm which were 87% ultradistal, 89% mid forearm and 86% distal one-third forearm. Fracture thresholds, defined as the 90th centile of BMD for osteoporotic patients, were 1 S.D. below the normal mean for lumbar spine and femoral neck but equal to the mean for ultradistal, 0.6 S.D. below mean for mid region and 0.3 S.D. below mean for distal one-third region. We conclude that for the discrimination of normals and osteoporotic women the three forearm sites are comparable. However, both lumbar spine and proximal femur BMD are superior to all forearm sites.

Purpose: To determine the radiographic appearance of osteoporotic vertebral fracture., Materials and Methods: Lateral thoracic and lumbar spine radiographs were examined in 58 patients (812 vertebra) with osteoporosis and evidence of vertebral collapse at bone scintigraphy. Scintigraphic activity was graded as faint, moderate, or intense. Anterior, middle, and posterior heights of the T-4 to L-5 vertebrae were measured. The degree of vertebral deformity was derived by comparing a ratio of heights with the normal mean., Results: At radiography, 378 of the 812 vertebrae (47%) were normal, 434 (53%) had deformities that were more than two standard deviations (SDs) below the normal mean, 304 (37%) had deformities that were more than three SDs below the normal mean, and 222 (27%) had deformities that were more than four SDs below the normal mean. Of 86 vertebrae that showed moderate or intense radionuclide uptake at scintigraphy, all had deformities that were more than two SDs below the normal mean, and 80 (93%) had deformities that were more than three SDs below the normal mean., Conclusion: Only in vertebrae with deformities more than three SDs below the normal mean can fractures be confidently diagnosed.

This study investigated the pain and disability experienced by 85 consecutive postmenopausal Caucasian women, average age 64 years (range 50-82), with spinal osteoporosis, referred to a specialist bone clinic. Symptoms were related to the numbers and severity of vertebral deformities, and degree of kyphosis. Persistent back pain was experienced by 54 (63%) in the lumbar spine and 53 (62%) in the thoracic spine. The severity of thoracic but not lumbar back pain was significantly related by Kendall rank correlation to degree of kyphosis (R = 0.255, p < 0.01), numbers of collapsed vertebrae (R = 0.279, p < 0.01) and a summed score of the severity of collapse for all vertebrae (R = 0.253, p < 0.01). The severity and duration of thoracic back pain was also significantly related to numbers of collapsed vertebrae from T4-T8 alone. Sleep was disturbed in 60%, difficulty obtaining suitable clothes was found in 42% and difficulties with functional activities in 47%, although these were severe in only 10%. Significant associations were also found between scores of osteoporosis severity and sleep disturbance, difficulties with clothes and many functional activities. We conclude that in patients with spinal osteoporosis coming to medical attention, assessment and management of pain, disability, sleep pattern and difficulties with obtaining clothes are required for optimal care.

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)

Bone mineral density (BMD) at the lumbar spine, femoral neck, trochanteric region, and Ward's triangle was measured using dual-energy X-ray absorptiometry (DXA) in 118 women with osteoporotic vertebral collapse (average age 65 years), divided into four groups according to numbers and SD of vertebral deformation below norms: group 1: -3SD deformations only; group 2: one -4SD deformation; group 3: two-four -4SD deformations; and group 4: 5 or more -4SD deformations. There were no significant differences between the groups. Results were compared with those from 80 premenopausal (average age 32 years, range 20-40 years) and 109 postmenopausal normal women (average age 64, range 60-70 years). Mean BMD in osteoporotic group 1 was lower than premenopausal normal women by 32% at the lumbar spine, 31% femoral neck, 30% trochanteric region, and 44% at Ward's triangle, and postmenopausal controls by 17% lumbar spine, 16% femoral neck, 17% trochanter, and 14% Ward's triangle. There was a clear trend to reduction in mean BMD between osteoporotic groups 1 and 4 at all four measured sites with significant differences at the spine of 0.102 g/cm2 (P < 0.01) and Ward's triangle 0.059 g/cm2 (P < 0.01). When compared with premenopausal controls, there was a reduction in mean BMD between osteoporotic groups 1 and 4 of 10% at the lumbar spine, 7% femoral neck, 8% trochanteric region, and 13% Ward's triangle. Receiver operating characteristic analysis showed no significant differences in diagnostic sensitivities among the four measured sites for vertebral fractures. We conclude from this cross-sectional data that the majority of bone loss in spinal osteoporosis occurs before the onset of fractures.

The bone mineral densities of the lumbar spine and femoral neck were determined by dual energy chi ray absorptiometry in 110 women aged 40-82 years (average 65 years) with spinal osteoporosis who had had at least one atraumatic vertebral compression fracture and in 1026 normal women aged 40-79 years (average 52 years). The women with osteoporosis showed a significant decrease in bone mineral density (BMD) at the lumbar spine and femoral neck compared with age matched normal women (sixth decade of life -26% spine, -23% femoral neck; seventh decade -26% spine, -16% femoral neck). The fracture threshold, defined as the 90th centile of spinal BMD for women with osteoporosis, was 0.81 g/cm2 at the lumbar spine and 0.656 g/cm2 at the femoral neck. Five per cent of normal women aged 40-49 years, 20% aged 50-59 years, and 45% aged 60-69 years had a BMD below this threshold. To maintain the bones of women above the fracture threshold until the age of 70 years about 50% of postmenopausal women need hormone replacement therapy. However, if the BMD is to be kept above the fracture threshold for a women's lifetime, e.g. until the age of 80-90 years, then most women will need treatment, though for various lengths of time depending on their initial BMD. Measurements of BMD in postmenopausal women currently help in identifying the risk of osteoporotic fractures but in the lifetime assessment of risk in a single subject they may have a more important role in deciding the duration of hormone replacement therapy.

The osteoporosis epidemic will continue unabated unless the issue of prevention of bone loss is seriously addressed. While a continuing programme of education for both the medical profession and the general public is necessary, positive action is required. Women lose bone at an accelerated rate following the menopause and this seems to be the optimal time for intervention. Those women who enter the menopause with the lowest bone density are at greatest risk of subsequent fracture. An individual's bone density can be accurately measured and those women who have the lowest bone density should have hormone replacement therapy (HRT) recommended, but it is important to discuss fully the possible benefits and risks. It is probable that non-hormonal agents for prevention of bone loss will be available in the near future, and cyclical diphosphonate therapy appears particularly promising. However, at the present time, long-term HRT is the mainstay for the prevention of bone loss.