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.

We conclude that the use of clinical risk factors can identify elderly women at high fracture risk and that such patients have a low average BMD. BMD testing is required, however, in a minority of women--a fraction that depends on the probabilities accepted for classification and the thresholds of risk chosen. These findings need to be validated in other cohorts at different ages and from different regions of the world.

The estimation of an individual's 10-year probability of fracture by the FRAX algorithm identifies patients at high risk of fracture who will respond to bisphosphonate therapy.

The efficacy of oral clodronate 800 mg daily to reduce vertebral fractures was studied in 593 women with postmenopausal or secondary osteoporosis. The incidence of vertebral fractures was significantly reduced by 46%. The effect was not modified by the underlying cause of osteoporosis or other baseline factors including bone mineral density, QUS, weight, and smoking.Introduction: This study aimed to determine if the bisphosphonate, clodronate (Bonefos), reduced the incidence of vertebral fractures in osteoporotic women. Materials and Methods: Women fulfilling the WHO criteria for osteoporosis at the lumbar spine (T-score Յ Ϫ2.5) and/or with at least one prevalent vertebral fracture were recruited to a 3-year double-blind, placebo-controlled study. A total of 593 patients were randomized to two strata comprised of women with postmenopausal osteoporosis (I, n ϭ 483) and secondary osteoporosis (II, n ϭ 110). They received either clodronate 800 mg daily orally (n ϭ 292) or an identical placebo (n ϭ 301). All patients received a calcium supplement of 500 mg daily. BMD was measured at 6, 12, 24, and 36 months, and lateral spine radiographs were obtained at baseline and annually thereafter for vertebral morphometry. Results: Treatment with clodronate was associated with a significant increase in mean spine BMD over 3 years (percent change from baseline, 4.35 Ϯ 6.34% versus 0.64 Ϯ 6.02% in the placebo group, p Ͻ 0.0001). At the hip, clodronate maintained total BMD, whereas a significant decrease was observed in the placebo group (percent change from baseline 0.70 Ϯ 5.67% versus Ϫ3.03 Ϯ 6.32% in the placebo group, p Ͻ 0.0001). The changes at the spine and hip were similar in both strata. Incident vertebral fractures at 3 years were observed in 63 women in the placebo group and 33 patients receiving clodronate (relative risk, 0.54; 95% CI, 0.37-0.80; p ϭ 0.001). Clodronate significantly reduced vertebral fracture risk in both strata and in women with or without prior vertebral fracture at baseline. Nonvertebral osteoporosisassociated fractures occurred in 21 women in the placebo group and in 14 women treated with clodronate. Treatment was well tolerated, with no significant difference in adverse event rates, including esophagitis, during clodronate treatment. Conclusion:We conclude that clodronate 800 mg daily is a safe and effective treatment to reduce fracture risk in women with osteoporosis, regardless of causation.

Previous studies have demonstrated that an Sp1 binding site polymorphism in the collagen type I gene (COLIA1) is related to reduced bone mineral density (BMD) and osteoporotic fractures in certain populations, particularly in the elderly. We have examined the relationship among these COLIA1 Sp1 alleles, BMD, quantitative ultrasound properties of bone, and fractures in a population-based cohort of elderly women from the UK. The study group comprised 314 women aged 75 years and over who agreed to participate in a clinical study of bisphosphonate therapy in preventing bone loss at the hip. Women were enrolled regardless of the presence or absence of osteoporosis, but those with other diseases that might affect skeletal metabolism were excluded. The genotype distribution for the Sp1 polymorphism was in Hardy-Weinberg equilibrium (SS - 78%; Ss - 20%; ss - 2%) but the proportion of individuals who carried the "s" allele (22%) was significantly lower than previously observed in another study of the UK population (37.1%) (P < 0.001). There were no significant associations between COLIA1 genotypes and metacarpal cortical index, BMD of the forearm, tibial SOS, calcaneal SOS, or calcaneal BUA. While there was a trend towards lower BMD values at the hip in patients with Ss and ss genotypes, this was not statistically significant (SS = 0.721 +/- 0.14; Ss = 0.704 +/- 0.13; ss = 0.683 +/- 0.20 P = 0.6). Prevalent vertebral fractures occurred in 22% of subjects and prior fractures of the wrist, ankle, and hip were reported by 20%, but there was no significant difference in COLIA1 genotype distribution between fracture patients and controls. We conclude that COLIA1 Sp1 alleles are not significantly associated with BMD, ultrasound properties of bone, or fractures in this population-based sample of elderly women.