29 July, 2013

Although oral bisphosphonates are highly effective in preventing fractures, some patients will still suffer a fracture while on treatment. In fact, it is important to explain to the patient that any anti-fracture treatment is indeed capable of reducing, but not aborting the risk for fractures. The following study from Spain quantified the remaining risk of fracture while on bisphosphonate therapy [1].

The SIDIAP database was searched to identify new users of oral bisphosphonates in 2006–2007. SIDIAP includes pharmacy invoice data and primary-care electronic medical records for a representative 5 million people in Catalonia (Spain). Exclusion criteria were: Paget disease, < 40 years of age, and any anti-osteoporosis treatment in the previous year. A priori defined risk factors included age, gender, body mass index, vitamin D deficiency, smoking, alcohol drinking, pre-existing co-morbidities, and medications. Fractures were considered if they appeared after at least 6 months after treatment initiation. Fractures while on treatment were defined as those occurring among participants persisting for at least 6 months and with an overall high compliance (medication possession ratio ≥ 80%). Only 7449/21,385 (34.8%) participants completed > 6 months of therapy. Incidence of 'fracture while on treatment' was 3.4/100 person-years (95% confidence interval (CI) 3.1–3.7). Predictors of these among patients persisting and adhering to treatment included: older age (sub-hazard ratio (SHR) for 60 to < 80 years 2.18; 95% CI 1.70–2.80; for ≥ 80 years, SHR 2.5; 95% CI 1.82–3.43), previous fracture (SHR 1.75; 95% CI 1.39–2.20 and SHR 2.49; 95% CI 1.98–3.13 in the last 6 months and longer, respectively), underweight (SHR 2.11; 95% CI 1.14–3.92), inflammatory arthritis (SHR 1.46; 95% CI 1.02–2.10), use of proton pump inhibitors (SHR 1.22; 95% CI 1.02–1.46), and vitamin D deficiency (SHR 2.69; 95% CI 1.27–5.72). Thus, even among high compliers, 3.4% of oral bisphosphonate users will fracture every year. Older age, underweight, vitamin D deficiency, proton pump inhibitor use, previous fracture and inflammatory arthritides are associated with increased fracture risk.

Comment

This recent study from Spain produced data on the incidence of any fracture in a cohort of bisphosphonate users [1]. The investigators claimed that we should expect around 3.5 new fractures among 100 treated persons per year. In the first alendronate randomized, placebo-controlled study of postmenopausal women with osteoporosis (n = 881, mean age 64 years, alendronate at 5, 10, 20 mg daily, 3-year follow-up), a significant decrease in vertebral fractures was recorded in the active group versus placebo, but no difference was observed for the non-vertebral fractures [2]. A meta-analysis of six randomized, placebo-controlled trials (n = 9023 women with T-score < 2 SD) demonstrated a benefit for the alendronate users, who had a hip fracture rate of 28 cases per 10,000 person-years, compared with a rate of 49 cases per 10,000 person-years in the controls [3]. These data support the widespread use of bisphosphonates for prevention and treatment of osteoporosis, and there seems to be no debate about treatment efficacy. However, a recent publication challenges this clinical practice [4]: Erviti and colleagues from Spain summarized their study on postmenopausal women, which included 2009 women with incident hip fractures and 10,045 matched controls (age above 65), as follows: hip-fracture risk did not differ between bisphosphonate users and never-users (adjusted odds ratio 1.09; 95% CI 0.94–1.27). No association was observed between hip fracture risk and cumulative duration of bisphosphonate treatment. Moreover, when treatment duration was analyzed as time since first prescription, a statistically significant increased risk for hip fracture was observed in patients exposed to bisphosphonates over 3 years when compared to never-users. Still, for every study with a negative message, several new positive databases are published. In a post-hoc analysis of studies on 2-year duration of alendronate and risendronate use, it was found that, although at year 1 alendronate did not change the risk for hip fracture, both risedronate and alendronate were effective at reducing the risk of hip and non-vertebral fracture at the end of the study period [5]. The intriguing question, whether all bisphosphonates or other anti-fracture therapies are similar in regard to bone protection, received a lot of attention in the literature and results seem to vary, pending not only on the specific medicines, but also on the characteristics of the cohorts, the duration of therapy, adherence to therapy and the potential fracture sites tested. As examples, a survey from the USA (n = 45,939) showed that 'Absolute unadjusted rates of fracture were small and did not significantly differ among agents, but, after controlling for differences in member characteristics, the risk of fracture was 12% lower for alendronate users than for ibandronate users' [6]; another study from Switzerland (n ~ 120,000 persons) concluded that 'In poorly adherent patients, neither drug decreased hip fracture risk. Risedronate treatment in adherent patients rapidly decreased the risk of hip fractures, whereas raloxifene treatment did not' [7]. Olsen and colleagues provided data from Denmark (n  =  54,876, 87% women) which pointed at lower risk reduction with etidronate compared to alendronate, stressing the fact that poor refill compliance is not unusual in patients on oral bisphosphonates, and that this was accompanied by excess major osteoporotic fractures and health-care costs at the societal level [8]. The issue of secondary prevention of hip fracture was addressed in a study from South Korea on 59,782 patients with first hip fracture. It was found that compliant and persistent use of bisphosphonates decreased the risk of second hip fracture by at least 40% [9].

To conclude, the available anti-fracture medications are efficacious in reducing fracture risk, mainly at vertebral sites, but also, although to a lesser extent, at non-vertebral sites and at the hip/femur. Using the mixed treatment comparison meta-analysis technique allows the prescribing physician to compare the different medications and make better individualized decisions [10]. A major contributing factor is adequate compliance, yet, even under the most ideal settings, people using the medicines appropriately still may fracture. The newer drugs that are given non-orally, such as intravenous zoledronic acid or subcutaneous denozumab are potent therapies which are associated with higher compliance because of their route of administration.

Amos Pines
Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel

References

1. Prieto-Alhambra D, Pagès-Castellà A, Wallace G, et al. Predictors of fracture while on treatment with oral bisphosphonates: A population-based cohort study. J Bone Miner Res 2013 Jun 12. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/23761350 
2. Liberman UA, Weiss SR, Bröll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 1995;333:1437-43.
http://www.ncbi.nlm.nih.gov/pubmed/7477143 
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http://www.ncbi.nlm.nih.gov/pubmed/1544898 5
4. Erviti J, Alonso A, Gorricho J, López A.Oral bisphosphonates may not decrease hip fracture risk in elderly Spanish women: a nested case–control study. BMJ Open 2013;3:e002084. Published online 2013 February 20.
http://www.ncbi.nlm.nih.gov/pubmed/23430594 
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http://www.ncbi.nlm.nih.gov/pubmed/21942301
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8. Olsen KR, Hansen C, Abrahamsen B. Association between refill compliance to oral bisphosphonate treatment, incident fractures, and health care costs-an analysis using national health databases. Osteoporos Int 2013 Apr 20. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/23604250 
9. Lee YK, Ha YC, Choi HJ, et al. Bisphosphonate use and subsequent hip fracture in South Korea. Osteoporos Int 2013 May 17.
http://www.ncbi.nlm.nih.gov/pubmed/23681088 
10. Migliore A, Broccoli S, Massafra U, Cassol M, Frediani B. Ranking antireabsorptive agents to prevent vertebral fractures in postmenopausal osteoporosis by mixed treatment comparison meta-analysis. Eur Rev Med Pharmacol Sci 2013;17:658-67.
http://www.ncbi.nlm.nih.gov/pubmed/23543450