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Date of release: 12 September, 2016

Does long-term bisphosphonate treatment increase fracture risk?

The latest report from the Women’s Health Initiative (WHI) study combines results from the two randomized, controlled trials and the observational study [1]. The aim of the study was to examine the association of long-term oral bisphosphonate use, compared with short-term use, with clinical fracture risk among postmenopausal women with breast cancer. Participants were 887 postmenopausal women who were enrolled to the WHI from 1993 to 1998, diagnosed with breast cancer after enrollment, and who reported current oral bisphosphonate use of 2 years or more on a medication inventory administered in 2008–2009. The outcome of any clinical fracture was ascertained by self-report on an annual study form; a subset of fractures was confirmed with medical records. Women were followed from completion of the medication inventory until 2014. The association between duration of bisphosphonate use reported on the medication inventory and fracture was estimated using multivariate Cox proportional hazards survival models that compared 4–7 years and 8 or more years of bisphosphonate use with 2–3 years of use.

There were 142 clinical fractures reported. In the multivariate-adjusted analysis for fracture risk factors, 8 or more years of bisphosphonate use was associated with higher risk of fracture compared with 2–3 years of use (hazard ratio 1.67; 95% confidence interval 1.06–2.62). There was no significant association of 4–7 years of use with fracture. It was concluded that bisphosphonate use of 8 or more years was associated with higher risk of any clinical fracture compared with 2–3 years of use. The authors raise concern about potential harm or decreased effectiveness of long-term bisphosphonate use on fracture risk. They caution, though, that the findings warrant confirmatory studies.

Comment

The question of how long to treat with bisphosphonates to prevent osteoporosis-related fractures remains unanswered because of present lack of data and the poor prospect of future data. The two main concerns regarding long-term use of bisphosphonates are: (1) Decreasing efficacy of fracture prevention over time. The inhibition of the osteoclast is over time balanced out by inhibition of the osteoblast with the potential of poor bone strength; (2) Increased incidence of atypical (femur shaft) fractures over time.

This study adds to our knowledge of long-term use of bisphosphonates but, as pointed out by the authors, the results should be treated with caution. Breast cancer patients with fractures are a very selective group compared to patients without breast cancer, mostly because of the effects of adjuvant therapy.

My greatest disappointment with the study is the lack of description of the type of fractures that were encountered, especially the disregard of atypical fractures in both the results and the discussion.

The limitations of the study are well pointed out by the authors. These are self -reporting of fractures (possible underestimation of fractures) and self-reporting of medication, as well as no distinction between different bisphosphonates and mode of delivery (oral or intravenous).

So for how long should we treat with bisphosphonates? This question remains unanswered but best practice based on the limited evidence available suggests that, after 5 years of oral alendronate therapy [2] and 3 years of zoledronic acid intravenous treatment [3], the need for further treatment or interruption of therapy should be individually reassessed based on response to treatment and remaining risk of fracture. In patients at high risk of fracture, a change in therapeutic agent can be considered or, if the bisphosphonate is continued, the patient should be informed about the risk of atypical fractures. The length of drug holiday should be individually determined. In cases of breast cancer, bisphosphonates also add another dimension of anti-cancer treatment, but, for most of the time, bisphosphonates are used to counter the risk of fracture induced by aromatase inhibitors (AI). Previously, AI therapy was limited to 5 years in total but longer periods are presently advocated [4]. It is an option after 5 years to change from bisphosphonates to denosumab or, when available, odanacatib (cathepsin K inhibitor).

Tobie J. de Villiers


Department of Gynaecology, Stellenbosch University, South Africa



    References

  1. Drieling RL, LaCroix AZ, Beresford SA, et al. Long-term oral bisphosphonate use in relation to fracture risk in postmenopausal women with breast cancer: findings from the Women’s Health Initiative. Menopause 2016 July 18. Epub ahead of print


    http://www.ncbi.nlm.nih.gov/pubmed/27433859

  2. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA 2006;296:2927-38


    http://www.ncbi.nlm.nih.gov/pubmed/17190893

  3. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the Horizon-pivotal Fracture Trial (PFT). J Bone Miner Res 2012;27:243-54


    http://www.ncbi.nlm.nih.gov/pubmed/22161728

  4. Goss PE, Ingle JN, Pritchard KI, et al. Extending aromatase-inhibitor adjuvant therapy to 10 years. N Engl J Med 2016; 375:209-19


    http://www.ncbi.nlm.nih.gov/pubmed/27264120