15 September 2009
This analysis of data from the FIT study found that measuring bone mineral density in postmenopausal women taking alendronate produces unreliable results. Early routine monitoring should be avoided because it has the potential to mislead.
Level of evidence:
Level 3 (other evidence) according to the SORT criteria.
Monitoring bone mineral density (BMD) in the first three years of bisphosphonate treatment is generally unnecessary because BMD will increase in the vast majority of women and, in the short-term, measurements are unreliable and may be misleading.
What is the background to this?
NICE recommends alendronate as first choice for the initiation of therapy for secondary prevention of osteoporotic fragility fractures in postmenopausal women with confirmed osteoporosis. Alendronate is also first line for primary prevention in postmenopausal women who meet certain criteria based on a combination of T-score, age and number of independent clinical risk factors.
It is unclear how a woman’s response to treatment should be measured. One option is to monitor BMD to estimate a woman’s response to bisphosphonate therapy for osteoporosis. However, there is no evidence that such monitoring is of clinical benefit and routine monitoring is costly. In addition, the observed response to bisphosphonate therapy may not reflect the true response because of measurement variability.
This study analysed data from the Fracture Intervention Trial, which was a randomised controlled trial that compared the effects of alendronate with placebo in 6,459 postmenopausal women with low BMD. BMD was measured annually for three years. This analysis looked at the changes in BMD during treatment, between different women and within individual women, to determine whether BMD should be used for monitoring treatment effects on an individual, rather than population level.
What does this study claim?
Three years treatment with alendronate increased hip BMD by a mean of 0.030g/cm2, compared with a decrease of 0.012g/cm2 with placebo. 97.5% of women treated with alendronate had an increase in BMD of at least 0.019g/cm2 after three years. This increase is generally considered sufficient to continue therapy. There was some between-person (treatment related) variation in the effects of alendronate, but this was small in size compared with the within-person (measurement related) variation.
As an accompanying editorial points out, treatment with bisphosphonates aims to reduce the rate of fractures. Therefore, monitoring should detect whether treatment will reduce the risk of fracture in individual patients. The effectiveness of monitoring using repeated BMD measurements depends on whether the test used can detect a significant change in BMD within a time scale that enables effective changes in management to occur. Also, the change in BMD must predict the reduction in fractures after treatment.
In this study, the BMD measurements varied over time within patients, which suggests that test results are unreliable and routine monitoring may be misleading. Over three years, treatment with alendronate increased hip BMD and was beneficial for the vast majority of patients. The variation in the effect of treatment between patients was small. This suggests that the response to alendronate is similar in all women and monitoring for individual response is unnecessary.
Bisphosphonates, or indeed any intervention, can only reduce the risk of fracture: they cannot abolish it. This means that all patients, even if they adhere strictly to their prescribed regimen and also change their lifestyle (e.g. ensuring adequate calcium and vitamin D intake, stopping smoking, moderating alcohol intake, remaining physically active, action taken to reduce the risk of falls) will still have a residual risk of fracture. If a fracture occurs this does not necessarily mean the drug is ineffective.
NICE technology appraisals on the use of drugs for the primary and secondary prevention of osteoporotic fragility fractures in postmenopausal women define an unsatisfactory response to treatment as occurring when a woman has another fragility fracture despite adhering fully to treatment for one year, and when there is evidence of a decline in BMD below her pre-treatment baseline. This can present a number of practical problems, especially when no pre-treatment BMD is available; therefore the initial decision not to scan before initiating treatment, which is an option for patients aged over 75 years, must be taken carefully. Rather than measuring BMD on a routine, population level, the decision to repeat BMD measurement should be made on an individual patient level, using clinical judgement. In addition, the limitations of treatment and monitoring should be discussed with the patient.
NICE is developing a clinical guideline on ‘Osteoporosis: assessment of fracture risk and the prevention of osteoporotic fractures in individuals at high risk’. The development of this is currently being reviewed following the publication of the two technology appraisals. In addition, a NICE clinical guideline has been published on the assessment and prevention of falls in older people.
Design: Secondary analysis of trial data from the Fracture Intervention Trial that compared the effects of alendronate and placebo.
Patients: 6,459 postmenopausal women with low BMD recruited between May 1992 and May 1993. Hip and spine BMD measurements were obtained at baseline and one, two, and three years after randomisation.
Outcomes: Between-person (treatment related) variation and within-person (measurement related) variation in hip and spine bone mineral density.
Results: The mean effect of three years’ treatment with alendronate was to increase hip bone mineral density by 0.030 g/cm2. There was some between-person variation in the effects of alendronate, but this was small in size compared with within-person variation. Alendronate treatment was estimated to result in increases in hip bone density 0.019 g/cm2 in 97.5% of patients.
Sponsorship: The Australian National Health and Medical Research Council. The Fracture Intervention Trial was sponsored by Merck Research Laboratories.
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