Dear Editor,
We read with interest the paper by Modi and colleaguesCitation1. The authors evaluated the effect of non-compliance with osteoporosis treatment on fracture risk and medical costs.
Non-compliance, which was quite high (59.5%), was associated with a 20% higher risk for any fracture, 46% for vertebral fracture and 51% for hip fracture. It was also associated with higher utilization of inpatient services and higher medical costs, which outweigh the all-cause pharmacy costs in non-compliant patients.
A few comments may be of interest. Compliance with osteoporosis medications seems to be a fundamental issue determining efficacy of treatment. It appears quite low with oral medications. In general, 40–50% of patients on oral bisphosphonates (mainly alendronate and risedronate)Citation2 or raloxifeneCitation3 remain on treatment at 12 or 24 months. The magnitude of the effect of non-compliance on the increase in fracture risk can be further realized if one takes into account that it is comparable to the effect of osteoporosis medication on fracture risk reductionCitation4. A meta-analysis showed that the absolute frequency of fracture in non-compliant patients was 6–38% and the relative risk was 30% higher than in compliant patients. The relative risk was also 30–40% higher with non-persistenceCitation5. Surprisingly, no difference in persistence has been reported between a weekly and a monthly dosing schedule of bisphosphonates, although a weekly regimen is associated with 76% more persistence than a daily regimen. Moreover, persistence seems to decrease in younger patients (<50 years)Citation6.
However, this is not the case with zoledronic acid (intravenously once annually) or denosumab (subcutaneously every 6 months). It must be underlined that the vast majority of patients (>85%) included in the study by Modi et al.Citation1 had been treated with oral bisphosphonates (mainly alendronate and risedronate) and raloxifene, which perhaps did not permit direct comparisons between different regimens. Denosumab has been associated with less non-compliance, non-persistence and non-adherence to treatment in comparison with oral bisphosphonates (i.e. weekly alendronate) at 12 and 24 monthsCitation7. It is more cost-effective compared with weekly or daily regimens, with a high impact on fracture preventionCitation8. The superiority in terms of cost-effectiveness over oral bisphosphonates has been also shown for zoledronic acid (once annually)Citation9. Although comparative data regarding compliance or persistence between oral bisphosphonates and zoledronic acid are not currently available, a general patient preference exists for annual infusions of zoledronic acid over weekly bisphosphonates. In general, drug effectiveness, side effects and route of administration appear to be more important than frequencyCitation10. The new forthcoming anti-osteoporosis medications, such as anti-sclerostin antibodies (administered subcutaneously monthly or every 3 months) may also increase compliance, which along with their promising beneficial effects on bone mineral density, may further contribute to greater anti-fracture efficacyCitation11. This may also be seen with weekly teriparatideCitation12.
In this new era of osteoporosis management, it seems prudent to take compliance into account prior to initiation or during medical treatment, as well as other parameters that may preclude anti-fracture efficacy and adherence to treatment, such as polypharmacy and drug–drug interactions. Thus, interventions to improve compliance and persistence are suggested. One of them is to switch to medications taken once or twice annually, such as zoledronic acid or denosumab, respectively. Aside from compliance, adherence to and persistence with treatment should also be taken into account. Furthermore, assessment of markers of bone turnover during therapy, such as C-telopeptide of type 1 collagen and procollagen type 1 amino-terminal propeptide are useful tools in monitoring complianceCitation13.
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Declaration of funding
This letter was not funded. The authors did not receive financial or professional help with the preparation of the manuscript.
Declaration of financial/other relationships
P.A. and S.N.K. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.
References
- Modi A, Siris ES, Tang J, Sen S. Cost and consequences of noncompliance with osteoporosis treatment among women initiating therapy. Curr Med Res Opin 2015 Feb 23:1-9 . [Epub ahead of print]
- Ziller V, Kostev K, Kyvernitakis I, et al. Persistence and compliance of medications used in the treatment of osteoporosis – analysis using a large scale, representative, longitudinal German database. Int J Clin Pharmacol Ther 2012;50:315-22
- Ziller V, Wetzel K, Kyvernitakis I, et al. Adherence and persistence in patients with postmenopausal osteoporosis treated with raloxifene. Climacteric 2011;14:228-35
- Freemantle N, Cooper C, Diez-Perez A, et al. Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis. Osteoporos Int 2013;24:209-17
- Ross S, Samuels E, Gairy K, et al. A meta-analysis of osteoporotic fracture risk with medication nonadherence. Value Health 2011;14:571-8
- van Boven JF, de Boer PT, Postma MJ, Vegter S. Persistence with osteoporosis medication among newly-treated osteoporotic patients. J Bone Miner Metab 2013;31:562-70
- Freemantle N, Satram-Hoang S, Tang ET, et al. Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women. Osteoporos Int 2012;23:317-26
- Jönsson B, Ström O, Eisman JA, et al. Cost-effectiveness of denosumab for the treatment of postmenopausal osteoporosis. Osteoporos Int 2011;22:967-82
- Chávez-Valencia V, Arce-Salinas CA, Espinosa-Ortega F. Cost-minimization study comparing annual infusion of zoledronic acid or weekly oral alendronate in women with low bone mineral density. J Clin Densitom 2014;17:484-9
- Lee S, Glendenning P, Inderjeeth CA. Efficacy, side effects and route of administration are more important than frequency of dosing of anti-osteoporosis treatments in determining patient adherence: a critical review of published articles from 1970 to 2009. Osteoporos Int 2001;22:741-53
- McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med 2014;370:412-20
- Anagnostis P, Karras SN, Goulis DG. Monitoring the efficacy of once-weekly teriparatide. Are bone turnover markers useful in predicting fracture risk? Curr Med Res Opin 2014;30:1177-8
- Diez-Perez A, Adachi JD, Agnusdei D, et al. Treatment failure in osteoporosis. Osteoporos Int 2012;23:2769-74