Can fall risk be incorporated into fracture risk assessment algorithms: a pilot study of responsiveness to clodronate.

SUMMARY: Fall risk does not significantly impact on the efficacy of the bisphosphonate clodronate in reducing the incidence of fracture. INTRODUCTION: The debate about the efficacy of skeletal therapies on fracture risk in women at increased risk of falling continues. We determined whether fall risk impeded the efficacy of clodronate to reduce osteoporotic fracture incidence. METHODS: This is a post hoc analysis of a 3-year placebo-controlled study of bisphosphonate clodronate involving 5,212 women aged 75 years or more. At entry, self-reported multiple falls in the previous month and ability to rise from a chair were documented. Their interaction with treatment efficacy was examined using Poisson regression. RESULTS: Oral doses of clodronate at 800 mg daily reduced osteoporotic fracture incidence by 24% (hazard ration (HR) 0.76, 95% confidence interval 0.63-0.93). The efficacy was similar in women with recent multiple falls compared to those without (HR 0.61 vs. 0.77, p value for interaction >0.30) or impaired ability in rising compared to those with no impairment (HR 0.79 vs. 0.74, respectively; p value > 0.30). CONCLUSION: Fall risk does not significantly impact on the anti-fracture efficacy of clodronate. If confirmed with other agents, fall risk may be incorporated into risk assessment tools designed to target skeletal therapies.

Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis.

Postmenopausal women with established vertebral osteoporosis were studied for 2 years to determine the terminal elimination half-life and the duration of response to treatment with intravenous alendronate (30 mg) given over 4 days. The urinary excretion of alendronate followed a multiexponential decline. Approximately 50% of the total dose was excreted over the first 5 days, and a further 17% was excreted in the succeeding 6 months. Thereafter, there was a much slower elimination phase with an estimated mean terminal half-life of greater than 10 years (n = 11). Urinary excretion of hydroxyproline and calcium decreased significantly from pretreatment values by day 3, reaching a nadir by 1 week (40% and 67% decrease, respectively). Thereafter, hydroxyproline remained suppressed for the following 2 years. In contrast, urinary calcium excretion returned gradually toward pretreatment values over the first year and during the second year was comparable to pretreatment values. Serum activity of alkaline phosphatase activity decreased over 3 months (23% reduction), increased gradually thereafter, and returned to pretreatment values at month 24. Bone mineral density measured at the spine increased by approximately 5% during the first year and remained significantly higher than pretreatment values at 2 years. We conclude that a short course of high doses of intravenous alendronate is associated with a prolonged skeletal retention of the agent. This open study also suggests that this regimen has a sustained effect on bone turnover persisting for at least 1 year.

Alendronate in the treatment of Paget's disease of bone.

We studied four treatment regimens of oral alendronate in 60 patients with active Paget's disease. Two groups received an oral daily dose of either 40 or 80 mg of alendronate for 3 months, followed by placebo for a further 3 months: the other two groups received treatment with 40 or 80 mg per day for 6 months. Activity of alkaline phosphatase and urinary hydroxyproline excretion were measured before, during, and after treatment, at intervals for a total follow-up of 1 year. A transiliac bone biopsy was performed in 24 patients before and after the treatment. An additional 16 patients had a third biopsy more than a year after stopping treatment. Alendronate induced a marked suppression in the urinary excretion of hydroxyproline within 2 weeks (p < 0.01) followed by a fall in serum activity of alkaline phosphatase at 1 month (p < 0.01) in all treatment groups. Nine months after the start of treatment patients treated with 80 mg for 6 months had a significantly lower mean alkaline phosphatase activity compared to the other treatment groups (p < 0.02), which persisted at 1 year (p < 0.05). Alkaline phosphatase decreased to within the laboratory reference range in all patients given 80 mg for 6 months. In contrast, alkaline phosphatase decreased to within the laboratory reference range in 73-83% of patients given 80 mg for 3 months and the 40 mg dose. Histomorphometric assessment showed a decrease in indices of bone turnover in the pagetic biopsies. None of the biopsies taken after treatment showed evidence of impaired mineralization of bone. Gastrointestinal side effects occurred in 25% of patients of whom two withdrew from treatment. We conclude that oral alendronate is an effective agent for the treatment of Paget's disease of bone.

Comparison of three intravenous regimens of clodronate in Paget disease of bone.

We compared the effects of three different regimens of intravenous clodronate in a retrospective study of 60 patients with Paget disease. A total dose of 1500 mg of clodronate was given as 300 mg for 5 consecutive days (n = 20), 1500 mg as a single infusion (n = 20), or 300 mg as a single infusion for 5 consecutive months (n = 20). The response to treatment and the duration of the effect were assessed from sequential changes in the activity of serum alkaline phosphatase. Treatment with clodronate induced a significant response in 85% of patients. The response rate was comparable in patients treated with 5 daily infusions (90%), with a single infusion (75%), and with 5 monthly infusions (90%). The median duration of response from the start of treatment was 11 months for those treated with five daily infusions and 12 months for the other two regimens. At one year, 22, 40, and 44% of patients had maintained their response in the daily, single, and monthly infusion regimen, respectively (NS). Six patients (32%) treated with 5 daily infusions achieved a remission (complete response) compared with 3 patients treated with a single infusion and 5 monthly infusions, respectively (16 and 15% respectively, NS). Patients attaining a complete response had a significantly longer duration of response compared with partial responders (median time 15.0 versus 11.5 months, respectively, p < 0.05). We conclude that intravenous clodronate (total dose 1500 mg) suppresses disease activity in the majority of patients with Paget disease of bone. The degree and duration of response were similar for the three regimens. Thus, in the treatment of Paget disease, the choice of regimen is a matter of convenience.

Duration of response with oral clodronate in Paget's disease of bone.

We studied retrospectively 51 patients with Paget's disease of bone treated with oral clodronate, 1600 mg daily given for 1 (n = 23), 3 (n = 13), or 6 months (n = 15), to compare the effect of a variable length of treatment on the response rate to treatment and the duration of disease suppression. Activity of alkaline phosphatase and urinary hydroxyproline excretion were measured before treatment at monthly intervals for a year and every 3 months thereafter until biochemical relapse. Before treatment, patients given the three regimens had similar disease activity as judged by serum alkaline phosphatase and urinary hydroxyproline values. There was no significant difference in the time to response between groups (median = 2 months). The proportion of patients attaining normal values of alkaline phosphatase activity was significantly higher in patients treated for 6 months (71%, p < 0.03) compared with those treated for 1 or 3 months (23% and 39%, respectively). The time to relapse from the start of treatment was significantly shorter in patients treated for 1 month compared with those treated for 3 or 6 months (median = 11, 18, and 23 months, respectively). Thus, at 2 years all patients treated for 1 month had relapsed, whereas 31% and 40% were still relapse-free in patients receiving treatment for 3 and 6 months, respectively. The length of treatment was the only variable identified by stepwise linear regression that significantly affected the duration of response. We conclude that oral clodronate (1600 mg daily) suppresses disease activity in the vast majority of patients with Paget's disease of bone. The magnitude of the response and its duration depend on the duration of treatment or the total dose administered, so that several months of treatment with oral clodronate are required when a durable response is desired.

A precise method for the assessment of tibial ultrasound velocity.

We assessed a method for the measurement of ultrasound velocity in cortical bone of the human tibia using a probe designed to minimize the effects of surrounding soft tissues. Of four different measurement values, the maximum velocity (average of the five highest readings) gave the lowest errors of reproducibility in relation to the population variance (standardized coefficient of variation = 1.8%). The maximum velocity varied according to the tibial site measured and for practical reasons the mid-tibial site was chosen for further study. The short-term intra- and inter-observer reproducibilities (coefficients of variation) were 0.35% (n = 22) and 0.50% (n = 27) respectively. Long-term reproducibility over 4 months in 31 subjects was 0.68%. There was no significant difference in maximum ultrasound velocity between the dominant and nondominant tibia in 78 women (3764 +/- 209 vs 3763 +/- 199 m/s). Tibial ultrasound velocity was significantly higher in 73 premenopausal women (3999 +/- 102 m/s) than in 129 women referred for assessment of postmenopausal osteoporosis (3780 +/- 168 m/s), 26 women with steroid-induced osteoporosis (3790 +/- 188 m/s) and 4 women with hyperparathyroidism (3575 +/- 261 m/s). In premenopausal women, ultrasound velocity did not correlate significantly with age, height, weight or body mass index. In women with postmenopausal osteoporosis, ultrasound velocity decreased with age after the menopause (r = -0.47, p < 0.0001) and body weight exerted a weaker protective effect. The apparent annual decrease in velocity with age in postmenopausal osteoporosis (8.5 m/s) was comparable to the error of reproducibility. We conclude that the technique for measuring tibial ultrasound velocity is highly reproducible in relation to the distribution of values in the population and is sensitive to age- and osteoporosis-induced changes in bone. Further studies are required to examine its relationship to other indices of skeletal status to determine the biological and clinical relevance of the technique.