UK NICE multimorbidity guidance will increase osteoporosis treatment gap

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While supporting the general sentiment of the NICE guidance, IOF statement strongly refutes the bisphosphonate specific recommendations which, if followed, are likely to further increase the treatment gap in osteoporosis.

Below is a Statement issued by IOF to the BMJ in response to: Clinical assessment and management of multimorbidity: summary of NICE guidance. Farmer et al, BMJ 2016; 354: i4843

UK NICE multimorbidity guidance will increase osteoporosis treatment gap

Nicholas C Harvey1,2, Eugene McCloskey3,4, John A Kanis3,5, Cyrus Cooper1,2,6

1MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; 2NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Tremona Road, Southampton, UK; 3Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK; 4Centre for Integrated research in Musculoskeletal Ageing (CIMA), Mellanby Centre for Bone Research, University of Sheffield, Sheffield, UK; 5Institute for Health and Ageing, Catholic University of Australia, Melbourne; 6NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK

The recent NICE guidance on assessment and management of multimorbidity, summarised by Farmer et al. in the BMJ[1], offers much laudable advice to the clinician caring for elderly patients. The scenario of ever increasing medication load, some of which is instituted to counter side-effects of other medications, is unfortunately common, and few would argue with the overall NICE approach, aiming to actively evaluate and optimise prescription lists. Such a complex document necessitates review of numerous disease areas, with the implication that similar evidential criteria will have been applied across all sections. Sadly, we would contend that the requisite uniformity of approach is absent from the section entitled “Review medicines and other treatments”, specifically in the recommendations pertaining to bisphosphonates.

The requirements of drug development and registration ensure that all drugs currently prescribed have been trialled over a finite length of time (usually relatively short compared with durations of use for chronic conditions commonly encountered in clinical practice).  Further, for regulatory purposes across all specialties, the majority of pivotal randomised controlled trials have focused on initiating rather than stopping treatment. The evidence for long-term benefits is frequently assumed and the risks of stopping therapy under-studied.  Given the perhaps unique ability of bisphosphonates to persist within the skeleton, several studies have examined the effects of withdrawing these agents. Although there is variation in endpoints, statistical power and approaches to controls across these investigations, the recommendation by NICE that bisphosphonates should be reviewed at 3 years, with the strong implication that treatment is discontinued in all patients, fails to appreciate the harms that will clearly ensue in patients at higher risk of fracture. The flaws of this recommendation, which ignores evidence for efficacy of bisphosphonates beyond 3 years[2-7] and for the increased risk of vertebral fractures following discontinuation of treatment[7, 8], were drawn to the attention of NICE during the consultation process, but apparently ignored [https://www.nice.org.uk/guidance/NG56/documents/consultation-comments-and-responses]). Since then the BMJ itself has published data, not based on RCTs but on well-powered population cohort studies, showing a favourable effect of long-term bisphosphonate use on fracture risk and a very favourable risk-benefit ratio for prevention of outcomes such as hip fractures compared to potential iatrogenic femoral shaft fractures[9].

Whilst the emphasis on bisphosphonates is perhaps not surprising, it highlights the dearth of data on other therapies and demonstrates an obvious imbalance in the criteria applied across diseases (https://www.nice.org.uk/guidance/ng56/evidence/full-guideline-2615543101).  For example, the Guideline Development Group identified only one non-blinded trial of cessation of statin therapy containing only 381 individuals, which the group graded as low quality (p263). Similarly, evidence from the 3 trials of antihypertensive cessation was graded as very low quality, other than for an increase in blood pressure (p249). For both these interventions, the recommendation is further research; for bisphosphonates, with arguably a stronger evidence base supporting longer term treatment, the recommendation is clinical review, and suggested cessation of treatment, at 3 years. This clearly does not represent an entirely equitable approach across the entirety of the NICE guidance.

When viewed from a global perspective, it is clear that bisphosphonates, and treatments for osteoporosis in general, are vastly under-prescribed relative to the burden of osteoporotic fractures[10-13]. A further danger introduced by this guidance is that the bisphosphonate recommendations, inappropriate even in their current context, may be misinterpreted as applicable to all osteoporosis therapies. Such an inference would clearly be misplaced for medications such as raloxifene, denosumab and teriparatide, which have substantially shorter durations of action than do bisphosphonates. Major osteoporotic fractures reduce survival by around 20%, increase morbidity, dependence on care and cause a huge economic impact, for example €39 billion per year across Europe[11, 14]. Whilst supporting the general sentiment of the NICE guidance, we strongly refute the bisphosphonate specific recommendations, which if followed are likely to further increase the treatment gap in osteoporosis, ironically making a substantial contribution to the multimorbidity that NICE is attempting to address.

References
1. Farmer C, Fenu E, O'Flynn N, et al. Clinical assessment and management of multimorbidity: summary of NICE guidance. BMJ 2016;354:i4843. doi: 10.1136/bmj.i4843 [published Online First: 2016/09/23]
2. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial [see comments]. JAMA 1998;280(24):2077-82.
3. Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone 2003;32(2):120-6. [published Online First: 2003/03/14]
4. Ensrud KE, Barrett-Connor EL, Schwartz A, et al. Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from the Fracture Intervention Trial long-term extension. J Bone Miner Res 2004;19(8):1259-69. doi: 10.1359/jbmr.040326 [published Online First: 2004/07/03]
5. 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(24):2927-38. doi: 10.1001/jama.296.24.2927 [published Online First: 2006/12/28]
6. Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res 2010;25(5):976-82. doi: 10.1002/jbmr.11 [published Online First: 2010/03/05]
7. 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(2):243-54. doi: 10.1002/jbmr.1494 [published Online First: 2011/12/14]
8. Strom O, Landfeldt E, Garellick G. Residual effect after oral bisphosphonate treatment and healthy adherer effects--the Swedish Adherence Register Analysis (SARA). Osteoporos Int 2015;26(1):315-25. doi: 10.1007/s00198-014-2900-5 [published Online First: 2014/10/10]
9. Abrahamsen B, Eiken P, Prieto-Alhambra D, et al. Risk of hip, subtrochanteric, and femoral shaft fractures among mid and long term users of alendronate: nationwide cohort and nested case-control study. Bmj 2016;353:i3365. doi: 10.1136/bmj.i3365 [published Online First: 2016/06/30]
10. Kanis JA, Svedbom A, Harvey N, et al. The osteoporosis treatment gap. J Bone Miner Res 2014;29(9):1926-8. doi: 10.1002/jbmr.2301 [published Online First: 2014/06/24]
11. Svedbom A, Hernlund E, Ivergard M, et al. Osteoporosis in the European Union: a compendium of country-specific reports. Archives of osteoporosis 2013;8(1-2):137. doi: 10.1007/s11657-013-0137-0 [published Online First: 2013/10/12]
12. Klop C, Gibson-Smith D, Elders PJ, et al. Anti-osteoporosis drug prescribing after hip fracture in the UK: 2000-2010. Osteoporos Int 2015;26(7):1919-28. doi: 10.1007/s00198-015-3098-x [published Online First: 2015/05/13]
13. Kanis JA, Borgstrom F, Compston J, et al. SCOPE: a scorecard for osteoporosis in Europe. Archives of osteoporosis 2013;8:144. doi: 10.1007/s11657-013-0144-1 [published Online First: 2013/09/14]
14. Harvey N, Dennison E, Cooper C. Osteoporosis: impact on health and economics. Nat Rev Rheumatol 2010;6(2):99-105.

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