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Date of release: 15 July, 2009

Randomized, controlled trials vs. observational studies on bisphosphonate therapy to reduce fracture risk in osteoporotic postmenopausal women


Among the methodological questions raised following the Women’s Health Initiative trial was the alleged disparity between the results of randomized, controlled trials (RCTs) and observational studies on hormone replacement therapy. A similar argument could be posed in regard to treatment of postmenopausal osteoporosis by bisphosphonates: are the results of RCTs in line with ‘real world’ populations? Do the selective cohorts in the RCTs represent women in the routine clinical scenario? Wilkes and co-investigators [1] have looked into this issue by mapping all studies published until 2008, and selecting the largest RCTs on the one hand, as well as observational studies which compared high- with low-compliant patients on the other hand. Data were extracted from 20 RCTs (44,878 postmenopausal women, mean age 68 years) and 11 retrospective, observational studies (331,256 postmenopausal women, median age 68 years). The duration of the majority of the studies was 2–3 years. Highly compliant patients were defined as those who took at least 80% of study medications. Only clinical fractures were assessed, ignoring any vertebral morphometric changes. A 23.8% decreased risk for total fractures was recorded in RCTs when active treatment was compared to placebo, whereas a similar figure of a 20.3% reduction was obtained in highly compliant/persistent bisphosphonate users in observational studies of large databases from routine practices.

Comment

Clinicians are often faced with a dilemma when trying to evaluate potential efficacy of any bone-protective medication in a certain individual. The main tool at hand is bone mineral density, which may not be an accurate measure because of technical drawbacks. Nevertheless, RCTs clearly demonstrate the osteoprotective characteristics of the various drugs in the market, which increase both bone mineral density and reduce fracture risk. A recent post-hoc analysis of the FIT trial data concluded that monitoring bone mineral density in postmenopausal women in the first 3 years after starting treatment with a potent bisphosphonate is unnecessary and may be misleading [2]. Compliance of patients to therapy is another major factor which may determine effectiveness. According to a US study, 45% of patients were not continuing to fill prescriptions 1 year after initiation of osteoporosis therapy [3]. In RCTs, surveillance is stricter and therefore compliance tends to be better than in routine practice. However, the definition of a compliant patient in the RCTs varied between at least 70% to at least 80% of study medications taken. Is it possible to extrapolate from the RCT results to real life? Indeed, the analysis of Wilkes and colleagues shows that one could expect the same anti-fracture effect of bisphosphonates in a highly compliant patient as in the RCTs. Clinicians should be aware of this fact and must do their utmost to increase compliance by actively monitoring the intake of medications and by initiating discussions with their patients on the importance of a continuous and orderly use as a key to successful treatment.

Comentario

Amos Pines
Department of Medicine T, Ichilov Hospital, Tel-Aviv, Israel

    References

  1. Wilkes MM, Navickis RJ, Chan WW, Lewiecki EM. Bisphosphonates and osteoporotic fractures: a cross-design synthesis of results among compliant/persistent postmenopausal women in clinical practice versus randomized controlled trials. Osteoporos Int 2009; July 2 (Epub ahead of print).
    http://www.ncbi.nlm.nih.gov/pubmed/19572092

  2. Bell KJ, Hayen A, Macaskill P, et al. Value of routine monitoring of bone mineral density after starting bisphosphonate treatment: secondary analysis of trial data. BMJ 2009;338:b2266.
    http://www.ncbi.nlm.nih.gov/pubmed/19549996

  3. Solomon DH, Avorn J, Katz JN, et al. Compliance with osteoporosis medications. Arch Intern Med 2005;165:2414-19.
    http://www.ncbi.nlm.nih.gov/pubmed/16287772