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Monitoring bone mineral density during antiresorptive
treatment for osteoporosis - Editorial
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Is potentially misleading and a misuse of healthcare resources
Juliet Compston, professor of bone medicine
1 University of Cambridge School of Clinical Medicine, Cambridge CB2 0SP
jec1001@cam.ac.uk
"the clear implication for clinical practice is that patients may be given inappropriate advice if changes in bone mineral density are used to monitor treatment."...."If true non-responders to antiresorptive treatment do exist they are rare, and most cases of non-response are caused by failure to persist with treatment."....."Routine monitoring of bone mineral density during the first few years of antiresorptive treatment cannot be justified because it may mislead patients, lead to inappropriate management decisions, and waste scarce healthcare resources."
Antiresorptive treatment for osteoporosis is usually prescribed for a minimum of five years. Although it reduces the risk of fracture, it does not relieve symptoms caused by existing fractures and may have side effects. Understandably, therefore, patients and their doctors seek reassurance that the treatment is working. The most common way to monitor response is repeated measurement of bone mineral density using dual energy x ray absorptiometry (DXA), an approach endorsed by recent guidelines.1 2 Routine monitoring is costly, however, and-if it does not reduce disease burden-may divert healthcare resources away from more deserving causes. In the linked study (doi:10.1136/bmj.b2266), Bell and colleagues assess the need to monitor the response to bisphosphonate treatment by estimating how much the effects of alendronate differ between individuals.3
Treatment 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 repeated measurement of bone mineral density to monitor treatment depends on two prerequisites. Firstly, the test used (DXA) should be able to detect a significant change in bone mineral density within a time scale that enables effective changes in management to occur, and, secondly, the change in bone mineral density must predict the reduction in fractures after treatment. If these criteria are not satisfied, patients may be misled and receive inappropriate advice.
To detect significant changes in bone mineral density, the rate of bone gain must be larger than the precision error of the DXA measurement. Although this may be achieved after five years of bisphosphonate or other antiresorptive drugs, the change in bone mineral density within the first one or two years (when monitoring is recommended by some guidelines) is generally too small to be detected. In everyday clinical practice, the precision of bone mineral density measurements is likely to be worse than in clinical trials, and even changes of 7% or more may not be reliably shown in individual patients.4 Not being able to detect a change until five years after the start of treatment is clearly not clinically useful; even one year is too long given the high rate of recurrent fractures in the first 12 months after an incident fracture.5
The study by Bell and colleagues analyses changes in bone mineral density during treatment with alendronate in a large randomised controlled trial, and it strengthens the case against routine monitoring during the first few years of treatment.3 Around 97.5% of women treated with alendronate showed an increase in hip bone mineral density of at least 0.019 g/cm2 after three years, and the variation in the effect of treatment between women was considerably less than the within person variation on treatment. In other words, although nearly all women gain bone mineral density during treatment, the large variability associated with the measurement of bone mineral density obscures the true treatment response in the individual, which makes monitoring of bone mineral density unnecessary and potentially misleading.
The final nail in the coffin for monitoring bone mineral density is the observation that only a small proportion of reduction in fractures attributable to treatment is explained by a change in bone mineral density. For example, only 16% and 4% of the decrease in the risk of fracture associated with treatment with alendronate or raloxifene, respectively, is attributable to an increase in bone mineral density.6 7 Furthermore, some studies have found similar reductions in fracture regardless of whether bone mineral density increased or decreased on treatment. In postmenopausal women treated with risedronate, the reduction in non-vertebral fractures after three years of treatment was similar in women who lost or gained bone mineral density.8 Similar findings have been reported for the reduction in vertebral fractures in women treated with alendronate.9 In the MORE study of raloxifene treatment, women in the treatment group with 4% bone loss in the hip had a lower risk of fracture than women in the placebo group who had a 4% gain in bone mineral density at this site.7 How much these findings reflect variation in the measurement of bone mineral density or a true lack of correlation between changes in bone mineral density and fracture reduction is uncertain, but the clear implication for clinical practice is that patients may be given inappropriate advice if changes in bone mineral density are used to monitor treatment.
Because adherence with treatment for osteoporosis is poor, it could be argued that monitoring bone mineral density is justified because it should improve adherence and thereby maximise efficacy. We have no evidence to support this, however, and it would be difficult to identify people who do not adhere with this test because of the large measurement variability. Because non-adherence occurs mostly within the first three months of starting treatment, early intervention would probably be more effective, and evidence exists that an interview with a healthcare professional a few months after starting treatment improves adherence.10 11 Biochemical markers of bone turnover could potentially be used for monitoring because they change rapidly in response to treatment and are more predictive of fracture reduction. However, at present within person variability and measurement variability are too great for these markers to be useful in clinical practice.12
If true non-responders to antiresorptive treatment do exist they are rare, and most cases of non-response are caused by failure to persist with treatment. This is best tackled by carefully explaining the treatment to patients before they start and follow-up after about three months to discuss problems related to treatment. Routine monitoring of bone mineral density during the first few years of antiresorptive treatment cannot be justified because it may mislead patients, lead to inappropriate management decisions, and waste scarce healthcare resources.
Cite this as: BMJ 2009;338:b1276
Juliet Compston, professor of bone medicine
1 University of Cambridge School of Clinical Medicine, Cambridge CB2 0SP
jec1001@cam.ac.uk
Research, doi:10.1136/bmj.b2266
Competing interests: None declared.
Provenance and peer review: Commissioned; not externally peer reviewed.
References
1. International Society for Clinical Densitometry (ISCD). Official positions 2007., www.iscd.org/Visitors/positions/OP-Index.cfm.
2. National Osteoporosis Foundation (NOF). New clinician's guide to prevention and treatment of osteoporosis. 2008. www.nof.org/professionals/Clinicians_Guide.htm.
3. Leslie WD. Factors affecting short-term bone density precision assessment and the effect on patient monitoring. J Bone Miner Res 2008;23:199-204.
4. Lindsay R, Pack S, Li Z. Longitudinal progression of fracture prevalence through a population of postmenopausal women with osteoporosis. Osteoporos Int 2005;16:306-12.
5. Bell KJL, Hayen A, Macaskill P, Irwig L, Craig JC, Ensrud K, et al. Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data BMJ 2009;338:b2266.
6. Cummings SR, Karpf DB, Harris F, Genant HK, Ensrud K, LaCroix AZ, et al. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am J Med 2002;112:281-9.
7. Sarkar S, Mitlak BH, Wong M, Stock JL, Black DM, Harper KD. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res 2002;17:1-10.
8. Watts NB, Geusens P, Barton IP, Felsenberg D. Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD. J Bone Miner Res 2005;20:2097-104.
9. Chapurlat RD, Palermo L, Ramsay P, Cummings SR. Risk of fracture among women who lose bone density during treatment with alendronate. The Fracture Intervention Trial. Osteoporos Int 2005;16:842-8.
10. Szulc P, Delmas PD. Biochemical markers of bone turnover: potential use in the investigation and management of osteoporosis. Osteoporos Int 2008;19:1683-704.
11. Compston J, Seeman E. Compliance with osteoporosis therapy is the weakest link. Lancet 2006;368:973-4.
12. Clowes JA, Peel NFA, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab 2004;89:1117-23.
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