A 3-year prospective, randomized, placebo-controlled trial of oral clodronate 800 mg showed that the incidence of clinical fractures was decreased by 20% in 5596 elderly women unselected for osteoporosis. The effect occurred in the absence of systematic calcium and vitamin D supplementation and was observed across a wide range of BMDs.Introduction: To date, most studies with bisphosphonates have reported on their use in individuals selected to be at high risk for fracture usually by the presence of low BMD or a prior fragility fracture, usually of the spine. We wished to determine the effect of the bisphosphonate, clodronate, on the rate of fractures in women Ն75 years of age living in the community. Materials and Methods: Women Ն75 years of age living in the general community in South Yorkshire and North Derbyshire, identified from general practice registers, were recruited by letter of invitation to a randomized, double-blind, controlled trial of 800 mg oral clodronate (Bonefos) or matching placebo daily over 3 years. The main outcomes were the incidences of hip and any clinical fracture. Results: Of the 5579 elderly women included in the intention-to-treat analysis of efficacy, 114 had a new hip fracture during the 3-year treatment phase: 56 (2.0%) women in the clodronate group and 58 (2.1%) women in the placebo group (hazard ration [HR], 1.02; 95% CI, 0.71-1.47). Clodronate did, however, decrease the incidence of any clinical fracture by 20% (264 women [9.5%] versus 337 [12.1%] in the placebo group; HR, 0.80; 95% CI, 0.68-0.94). The incidence of osteoporosis-associated nonhip fractures was also significantly decreased by 29% (5.2% versus 7.4%; HR, 0.71; 95% CI, 0.57-0.87). The ability of clodronate to reduce the risk of osteoporotic fracture was independent of baseline BMD, but the number needed-to-treat was lower in the presence of osteoporosis. Conclusions: Oral daily clodronate can prevent fractures without significant adverse effects in elderly women living in the general community. The effect on hip fracture risk is not significant, but an effect similar to that at other nonvertebral sites cannot be excluded. This study suggests that antiresorptive therapies can reduce fracture incidence in high-risk individuals even in the presence of a normal or osteopenic BMD.

There is debate about the possible deleterious effect of excessive vitamin A exposure on fracture risk. In this nested case control study in older women (312 cases and 934 controls), serum retinol, retinyl palmitate, and ␤-carotene were not associated with fracture risk, and there was no evidence of excess risk with multivitamin or cod liver oil supplementation.Introduction: Recent studies have suggested that higher vitamin A intake may account for a component of fracture risk within the general population and that supplemental vitamin A may be harmful even within recommended limits. No studies have examined the relationship between biochemical retinol status and fracture in older women. Materials and Methods:We examined serum retinol, retinyl palmitate, and ␤-carotene as predictors of incident hip and other fractures in a large prospective study of British women over the age of 75 years (n ‫ס‬ 2606, 312 incident osteoporotic fractures, 92 incident hip fractures; mean follow-up duration, 3.7 years). Fasting blood samples (9:00-11:00 a.m.) were collected at baseline. Using a case-control design (three controls per case), serum retinol, retinyl palmitate, and ␤-carotene were assessed as univariate predictors of incident osteoporotic fracture or hip fracture. Baseline BMD at the total hip, age, 25(OH)D, serum ␤ Crosslaps, bone-specific alkaline phosphatase, weight, height, and smoking were considered as covariates in a multivariate model. Results: Serum retinol, retinyl palmitate, and ␤-carotene were not significant univariate predictors of either hip fracture or any fracture (all p > 0.05; Cox proportional hazards regression). For all osteoporotic fractures, the hazard ratio (HR) was 0.92 (95% CI, 0.81-1.05) per 1 SD increase in serum retinol. Risk of any osteoporotic fracture was slightly less in the highest quartile of serum retinol compared with the lowest quartile (HR, 0.85; 95% CI, 0.69-1.05; p ‫ס‬ 0.132) There was a tendency for increased serum retinol to predict benefit rather than harm in terms of BMD (r ‫ס‬ 0.09, p ‫ס‬ 0.002). Multivitamin or cod liver oil supplementation was associated with a significantly lower risk of any fracture (HR, 0.76; 95% CI, 0.60-0.96; p ‫ס‬ 0.021). In multivariate analysis, only age, total hip BMD, and weight were associated with fracture risk (p < 0.05). Conclusions:We found no evidence to support any skeletal harm associated with increased serum indices of retinol exposure or modest retinol supplementation in this population.

Low radiation dose imaging of the lateral spine acquired with a bone densitometer for vertebral fracture assessment (VFA) has great potential for clinical use. We have undertaken an evaluation of VFA in a prospective population cohort of elderly women to examine the prevalence of vertebral fractures, their ability to predict incident fractures, and their use in targeting therapy. Women (n ‫ס‬ 5157) Ն75 yr of age living in the general community in the United Kingdom underwent posteroanterior and lateral imaging of the spine (T 4 -L 4 ) with a densitometer (Hologic QDR4500A) at entry to a randomized, double-blind, controlled trial of 800 mg oral clodronate (Bonefos) or matching placebo daily over 3 yr. The women were identified from general practice registers and recruited by letter of invitation regardless of skeletal status. The proportion of vertebrae interpretable varied from 98.2% at T 12 to 57.1% at T 4 , with >92% interpretable at levels between T 8 and L 3 . As judged by BMD at the total hip, 19.6% of the women had osteoporosis, and the prevalence of vertebral fracture was 14.5%. Women with one or more vertebral fractures had a relative risk (RR) for incident osteoporotic fractures of 2.01 (95% CI, 1.64-2.47). The RR for hip fractures was 2.29 (95% CI, 1.63-3.21). After adjustment for age, femoral neck BMD, weight, and treatment, the RR was 1.50 (95% CI, 1.21-1.86) for osteoporotic fractures, with similar results for hip fractures (RR, 1.41; 95% CI, 0.99-2.02). For women with two or more vertebral fractures, the adjusted RRs were 1.97 (95% CI, 1.24-2.72) and 1.86 (95% CI, 1.14-3.03) for osteoporotic and hip fractures, respectively. We conclude that VFA can frequently detect vertebral fractures in a population cohort of elderly women. These fractures, like radiographic fractures, predict future clinical fractures independent of age, weight, and BMD. Having multiple vertebral fractures was associated with greater risk of incident osteoporotic fractures and hip fractures.

1. We have examined the relationship between broadband ultrasound attenuation in the os calcis and measurements of bone mineral in the distal forearm and lumbar spine of normal and postmenopausal osteoporotic women. 2. Values of broadband ultrasound attenuation in postmenopausal women with vertebral osteoporotic fractures were significantly lower (35%) than in normal pre- and peri-menopausal women (55.4 +/- 3.8 and 79.6 +/- 0.8 dB/MHz, respectively). 3. Broadband ultrasound attenuation correlated significantly with bone mineral content measured in the distal forearm by single-photon absorptiometry (r = 0.77, P less than 0.0001) and with bone mineral content (r = 0.66, P less than 0.0001) and bone mineral density (r = 0.72, P less than 0.0001) measured in the lumbar spine by dual-photon absorptiometry. 4. Although significant, these correlations are not sufficiently close to be predictive. However, the accuracy of broadband ultrasound attenuation in discriminating between normal subjects and patients with vertebral fracture compared very favourably with direct measurements in the spine by dual-photon absorptiometry. 5. Broadband ultrasound attenuation, but not the other measurements, correlated significantly with age in the osteoporotic patients (r = 0.50, P less than 0.05). 6. These findings may reflect the partial dependence of broadband ultrasound attenuation on the intrinsic trabecular architecture of cancellous bone, the disruption of which contributes to an increase in fracture risk.

1. We have examined the relationship between the attenuation of broadband ultrasound in the os calcis in vitro and its bone mineral density measured by quantitative computed tomography and by physical density. 2. Broadband ultrasound attenuation was found to correlate closely with physical density (r = 0.85, P less than 0.0001), but the correlation was less than that observed between quantitative computed tomography and physical density (r = 0.92, P less than 0.0001). Measurements of broadband ultrasound attenuation and quantitative computed tomography were significantly correlated (r = 0.80, P less than 0.0001). 3. Partial correlation analysis showed a significant relationship between broadband ultrasound attenuation and bone density, but when the effect of physical density was taken into account no significant correlation was found between broadband ultrasound attenuation and quantitative computed tomography (r = 0.08, not significant). 4. Broadband ultrasound attenuation in three prospective amputees showed a high degree of concordance between measurements in vivo and in vitro, with no interference by surrounding soft tissues. 5. The correlation between physical density and broadband ultrasound attenuation was independent of quantitative computed tomography, suggesting that the technique measures aspects of density which differ from its mineral density. Broadband ultrasound attenuation holds promise as a reproducible, rapid, radiation-free assessment of skeletal status.