Overdiagnosis of bone fragility in the quest to prevent hip fracture
BMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2088 (Published 26 May 2015) Cite this as: BMJ 2015;350:h2088
All rapid responses
A clinical trial testing the utility of applying the WHO FRAX tool (and DXA, if subsequently indicated) in a real-world community setting of at-risk individuals might bring clarity here, alongside a carefully selected intervention threshold for offering treatment. Whether such an approach will lead to reductions in hip and other fractures, improvement in quality of life or indeed psychological or therapeutic harms are pertinent questions to ask, and it is hoped that SCOOP, the large multi-centre trial evaluating precisely those outcomes will provide answers. That carefully planned study involving almost 12000 women is now in its 6th year [1,2] supported by the Medical Research Council and Arthritis Research UK- and one hopes is close to finding some answers. A similarly powered trial evaluating the efficacy, plausibility and harms of the lifestyle/exercise measures lauded by Jarvinnen and colleagues would also be most welcome.
Until then, those of us looking after people suffering from, and at risk of vertebral fragility fractures might find it safest to make clinical decisions by following peer-reviewed, published RCT's and meta-analyses, rather than 'opinion piece' journalism. The old Welsh proverb that 'bad news goes around in clogs, good news in stockinged feet', seems apt here, and clinicians who do value an unbiased clinical effectiveness systematic review of osteoporosis therapy might wish to read the summary of the new draft NICE report, which covers both a primary and secondary indication for bisphosphonate therapy [3]. The authors of that report seem to be without major conflicts of interest. (https://www.nice.org.uk/guidance/GID-TAG462/documents/osteoporosis-preve...)
[1] http://public.ukcrn.org.uk/search/StudyDetail.aspx?StudyID=2490
[2] Shepstone L, Fordham R, Lenaghan E, Harvey I, Cooper C, Gittoes N, Heawood A, Peters T, O'Neill T, Torgerson D, Holland, R, Howe A, Marshall T, Kanis J, McCloskey E. A pragmatic randomised controlled trial of the effectiveness and cost-effectiveness of screening older women for the prevention of fractures: rationale, design and methods for the SCOOP study. Osteoporos Int. 2012 Oct;23(10):2507-15.
[3] Davis S, Martyn-St James M, Sanderson J, Stevens J, Goka E, Rawdin A, Sadler S, Wong R, Campbell, F, Stevenson M, Strong M, Selby P, Gittoes N. Bisphosphonates for preventing osteoporotic fragility fractures (including a partial update of NICE technology appraisal guidance 160 and 161). Technology Assessment Report: Final report to the National Institute for Health and Care Excellence, 2015. https://www.nice.org.uk/guidance/GID-TAG462/documents/osteoporosis-preve...
Competing interests: Pharmaceutical advisory and lecturing roles for Amgen, Lilly and UCB Celltech via Cambridge Enterprise, the commercial arm of the University of Cambridge on a charity fee-donation basis (http://www.enterprise.cam.ac.uk/our-services/industry-government-and-non-profits/find-a-consultant/). I am not involved in the SCOOP study, or the NICE clinical effectiveness systematic review.
The debate following the recent article by Jarvinen and colleagues illustrates the difficulties in devising strategies to prevent fractures. 1 Jarvinen and colleagues highlight that most fractures occur in patients who do not have low bone density, and that the thresholds of fracture risk at which current fracture prevention strategies recommend pharmacological treatments mean that very large numbers of older people are recommended for treatment, but the majority of those treated do not benefit. On the other hand, correspondents from advocacy groups and specialist societies focus on the societal burden of fractures and the relative underuse of pharmacological treatments in patients who have had fractures, and contend that osteoporosis is underdiagnosed. Since pharmacological treatments and the measurement of risk factors for fracture (such as bone density or vitamin D levels) are both profitable and central to the debate, conflicts of interest are highly relevant.
None of the correspondents representing advocacy organisations (the International Osteoporosis Foundation, the National Bone Health Alliance) or specialist societies (the American Society for Bone and Mineral Research, the European Calcified Tissue Society, the International Society for Clinical Densitometry) declared conflicts of interest for the organisation. However, each organisation has corporate sponsors with vested interests in the diagnosis and/or management of osteoporosis. On their respective websites, the International Osteoporosis Foundation lists 20 corporate sponsors (http://www.iofbonehealth.org/about-us/global-structure/committee-corpora...), the National Bone Health Alliance 13 corporate sponsors (http://www.nbha.org/members), the American Society for Bone and Mineral Research 4 corporate sponsors (http://www.asbmr.org/TopicalMeetings/Sponsorship.aspx), the European Calcified Tissue Society 4 corporate sponsors (http://www.ectsoc.org/corpmem.htm) and the International Society for Clinical Densitometry 10 corporate sponsors (http://www.iscd.org/membership/corporate-membership/corporate-membership...). The International Osteoporosis Foundation acknowledges that its existence depends on commercial sponsorship (http://www.iofbonehealth.org/news/iof-response-recent-report-questioning...). Relationships with corporate sponsors may influence the advice offered by osteoporosis advocacy groups.2 Publications, position statements and correspondence from organisations that are supported by companies with vested interests in the subject should be accompanied by a declaration of financial conflicts of interest.
References
1. Järvinen TLN, Michaëlsson K, Jokihaara J, Collins GS, Perry TL, Mintzes B, et al. Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 2015;350:h2088.
2. Grey A, Bolland M. Web of industry, advocacy, and academia in the management of osteoporosis. BMJ 2015;351:h3170.
Competing interests: Andrew Grey is a shareholder in Auckland Bone Density, a company that provides bone densitometry services. Mark Bolland has no conflict of interest.
As noted in my previous rapid response (1) to the paper of Järvinen and colleagues (2), hip fracture should be the main target of the fracture prevention in older adults. Later on, prof. Sugiyama wrote that both falling and bone fragility should be the main focus of this task (3). This is easy to agree.
Concerning falls prevention, it is evidence-based that regular strength and balance training can reduce the risk of falling in community-dwelling older adults (4). However, it is not well proven that this benefit translates into fracture reduction, although a recent meta-analysis points to that direction (5). Also, without further evidence, extrapolation of these promising results to frail elderly adults at risk of hip fracture can be misleading.
Concerning prevention and treatment of bone fragility in a clinical setting, the situation is not better. As pointed out in several previous responses to Järvinen et al., Cochrane and other reviews have summarized that bisphosphonates (BIS) have very limited value in primary prevention of (hip) fractures. For this reason, the focus and hope have turned towards secondary prevention, in many of the above noted responses, via Fracture Liaison Services (FLS) (6-9). But, as noted in my previous rapid response (1), there seems to be no randomised, controlled study to show that FLS works – let alone its cost-effectiveness. Despite this major gap, patients, health officers and tax payers would be most keen to know the costs needed to prevent one hip fracture via FLS.
FLS have been developed and implemented to identify, evaluate and treat older patients with a recent fracture, the treatment clearly having the main focus in the treatment of osteoporosis by BIS, calcium and vitamin D (6-9). However, a recent analysis, again in the prestigious BMJ, showed that calcium and vitamin D supplementation have no sufficient and reasonable effect on osteoporosis, falls and fractures of older adults (10). Thus, the entire FLS system seem to rely on BIS only - an approach which has the known evidence gap in prevention of hip fractures (2).
Altogether, prevention of hip fracture is very difficult, especially if the goal is to do it cost-effectively in real life. However, this difficulty should not mean that we are allowed to advocate ineffective and often costly surrogate methods. I see that this approach is the gold standard for all preventive work in medicine.
Pekka Kannus, MD,PhD
UKK Institute, Tampere, Finland
References
1. Kannus P. Hip fracture is the main target of fracture prevention, but where is RCT-proof that Fracture Liaison Services work? BMJ 2015;350:h2088. Rapid response June 23, 2015.
2. Järvinen TL, Michaelsson K, Jokihaara J et al. Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 2015;350:h2088.
3. Sugiyama T. Both falling and bone fragility should be targeted: the limited effectiveness of exercise on fall prevention. BMJ 2015;350:h2088. Rapid response July 25, 2015.
4. Gillespie LD, Robertson MC, Gillespie WJ et al. Interventions for preventing falls in older people living in the community. Cochrane Database Syst Rev 2012;9:CD007146.
5. El-Khoury F, Cassou B, Charles M-A et al. The effect of fall prevention exercise programmes on fall induced injuries in community-dwelling older adults: systematic review and meta-analysis of randomized controlled trials. BMJ 2013;347:f6234.
6. McLellan AR, Wolowacz SE, Zimovetz EA et al. Fracture liaison services for the evaluation and management of patients with osteoporotic fracture: a cost-effectiveness evaluation based on data collected over 8 years of service provision. Osteoporos Int 2011;22:2083-2098.
7. Lih A, Nandapalan H, Kim M et al. Targeted intervention reduces refracture rates in patients with incident non-vertebral osteoporotic fractures: a 4-year prospective controlled study. Osteoporos Int 2011;22:849-858.
8. Huntjens KBM, van Geel TACM, van den Bergh JPW et al. Fracture liaison service: impact on subsequent nonvertebral fracture incidence and mortality. J Bone Joint Surg (Am) 2014;96:e29(1-8).
9. Nakayama A, Major G, Bogduk N. Comparative refracture rates in hospitals with and without a fracture liaison service: a 6 month historical cohort study. Intern Med J 2015;45(Suppl.2):3.
10. Grey A, Bolland M. Analysis.Web of industry, advocacy, and academia in the management of osteoporosis. BMJ 2015;351:h3170.
Competing interests: No competing interests
6 August 2015
Pekka A Kannus
Chief Physician
Injury & Osteoporosis Research Center, UKK Institute for Health Promotion Research
P.O. Box 30, FIN-33501 Tampere, Finland
Competing interests: No competing interests
The decision of the BMJ to embrace a theme of over-diagnosis and over-treatment may be built on worthy foundations but the success of such an approach requires the application of the same rigour and standards to submitted articles that would be applied to any research manuscript. Chasing headlines and controversy might bring short term publicity but the strategy is fraught with problems. The line between being a responsible widely-read, scientific journal and one that has a reputation for notoriety and inaccuracy can be precariously thin.
Failing to distinguish between personal opinions, that often fail to stand up to scientific scrutiny, and scientifically founded reviews is one fault, but then headlining these hints at a worrying lowering of editorial standards. The latter is reflected even more worryingly in the concerns raised about the review process prior to publication. The request by Dr Javaid and others for the reviewers’ comments to be shared is an important one to be addressed to maintain the integrity of the journal and its editorial processes. I was pleased to note that the BMJ is seeking permission from the reviewers to enable them to do this and would seek to know when this might occur; personally, I cannot see how these comments could not be published anonymously even if permission is withheld.
There are many topics that deserve discussion and scrutiny within the field of medicine. The integrity of processes within our scientific journals needs to be held in the highest regard. We will all lose if a journalistic theme, no matter how noble, is pursued at the cost of eroding this integrity.
Competing interests: Prof. McCloskey has contributed to the development of the FRAX® tool in collaboration with the World Health Organization. He has been or is in receipt of research funding, speaker fees and/or consultancy fees from the following: ActiveSignal, Amgen, Arthritis Research UK, Consilient Health, GSK, GE Lunar, Hologic, Internis, Lilly, MRC, MSD, NIHR, Novartis, Ono, Pfizer, Roche, Servier, Synexus, Tethys, Unilever and Wyeth.
Anyone who finds the arguments advanced by Jarvinen et al even slightly persuasive should first read the rebuttal published in Osteoporosis International (July 2015) by Dr Juliet Compston (Cambridge) before forming a personal view of the validity of Jarvinen et al's arguments.
Competing interests: I was previously in the same University Department as Dr Compston
Dear Editor,
We agree with the authors that falling should be targeted to prevent hip fracture (1). As pointed out in our previous rapid response (2), however, it would not be easy to effectively and continuously reduce fall risk in older adults over 75. Here we can confirm the situation by the latest well conducted randomised controlled trial (3), though there is no doubt regarding the importance of physical activity for health (4).
In women aged 75-85, living in community and at risk of falling, two-year balance training programme did not significantly reduce serious falls associated with fractures (hazard ratio 0.83, confidence interval 0.60 to 1.16) (3). The result might be due to lack of power (352 in the intervention group and 354 in the control group), but notably the effectiveness of this kind of exercise was limited (fall prevention by less than 20%). More importantly, the motivation in this age group was very low; indeed, less than 10% of the invited women agreed to participate the study and more than 25% of the participants stopped the training programme during the first month.
It is also important to note that skeletal fragility is determined not only by areal bone mineral density (BMD) but also by other factors including collagen-related bone quality (5). Bone fragility is associated with hip fracture, whereas the authors used two different terms, osteoporosis (defined by areal BMD) and bone fragility, interchangeably (6). Thus, it is reasonable to conclude that both falling and bone fragility should be targeted to prevent hip fracture in older adults (7).
Toshihiro Sugiyama, Yoon Taek Kim and Hiromi Oda
Department of Orthopaedic Surgery, Saitama Medical University, Saitama, Japan
1 Jarvinen TL, Michaelsson K, Jokihaara J, et al. Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 2015;350:h2088. (26 May.)
2 Sugiyama T, Kim YT, Oda H. Both falling and bone fragility should be targeted. www.bmj.com/content/350/bmj.h2088/rr-4. (2 June.)
3 El-Khoury F, Cassou B, Latouche A, et al. Effectiveness of two year balance training programme on prevention of fall induced injuries in at risk women aged 75-85 living in community: Ossebo randomised controlled trial. BMJ 2015;351:h3830. (22 July.)
4 Lee LM, Shiroma EJ, Lobelo F, et al. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 2012;380:219-29.
5 Seeman E, Delmas PD. Bone quality: the material and structural basis of bone strength and fragility. N Engl J Med 2006;354:2250-61.
6 Compston J. Overdiagnosis of osteoporosis: fact or fallacy? Osteoporos Int 2015;26:2051-4.
7 Sugiyama T, Torio T, Miyajima T, Kim YT, Oda H. Romosozumab and blosozumab: alternative drugs of mechanical strain-related stimulus toward a cure for osteoporosis. Front Endocrinol 2015;6:54.
Competing interests: No competing interests
The International Society for Clinical Densitometry (ISCD) is a multidisciplinary, nonprofit organization whose mission is to advance excellence in the assessment of skeletal health. The ISCD wishes to support the comments from the National Bone Health Alliance (NBHA), International Osteoporosis Foundation (IOF), American Society for Bone Mineral Research (ASBMR) and others who have objected to the tone and content of the article. In their provocative article, Teppo Järvinen and colleagues have distorted and misrepresented the osteoporosis burden. The following simple statements of fact are supported by high-level scientific evidence and commonsense:
• Osteoporosis is a disease with major health consequences that include death,
• Osteoporosis remains severely underdiagnosed and undertreated,
• DXA and FRAX are able to identify those at high fracture risk,
• Approved treatments for osteoporosis are effective, safe and additive to non-pharmacological interventions (diet, exercise and fall prevention).
William D. Leslie, MD, MSc, FRCPC, CCD
ISCD President
Competing interests: Speaker fees and/or research grants (all paid to facility): Amgen, Eli Lilly, Novartis, Genzyme.
Dear Editor,
As President of the International Osteoporosis Foundation (IOF) and Editor-in-Chief of the journal Osteoporosis International (OI), I fully support Dr Javaid’s call for the BMJ to be transparent about their review process for the article by Järvinen and colleagues.
I am certain that not only I but also many of my peers, who responded to this article, would welcome the move suggested by Dr Javaid for you to share the reviewers’ comments. I am pleased to note that the BMJ is seeking permission from the reviewers to enable them to do this. Since publication of the article, IOF and many other likeminded organizations around the world have been actively involved in damage control exercises to ensure that the misconceptions published in this paper do not have a negative impact on the heath of those people we are trying to protect.
I posted a rapid response on behalf of IOF and its leadership on June 1 when the paper first came to light. Further to this I would like to draw attention to an editorial authored by Prof. Juliet Compston, Chair of the National Osteoporosis Guideline Group that has just been published in OI, which provides comprehensive arguments against a number of points raised in the original paper: http://link.springer.com/article/10.1007/s00198-015-3220-0/fulltext.html
I would appreciate you informing us by when you anticipate receiving approval from the reviewers to share their comments? Also, if this approval is not obtained how will you address the concerns raised by Dr Javaid and assure your readership that all articles do undergo a robust review process?
Prof. John A. Kanis,
President, International Osteoporosis Foundation and Editor-in-Chief, Osteoporosis International
www.iofbonehealth.org
Competing interests: Prof. John A. Kanis developed the FRAX® tool in collaboration with the World Health Organization.
We thank Dr Javaid for his rapid response.
We are seeking permission from the reviewers to share their reviews. Unlike for research articles, for Analysis articles we do not routinely ask for permission from reviewers and therefore had not sought it from them at the outset.
Competing interests: No competing interests
'What can lie behind an osteoporosis diagnosis'?
Quite apart from whether osteoporosis is over- or under-diagnosed, there is another pertinent question. How often is the underlying cause of osteoporosis in the individual patient investigated?
My own experience suggests, “Not often enough.” I was diagnosed with osteopenia (BUA 63.9) in 2000, after suffering an agonising fracture through falling in the night on the way to the toilet. I was 57.
There were in fact four possible underlying causes for this.
First, I had been exposed to the organophosphate Malathion in my twenties.
Secondly, although I did not know it then, I had a parathyroid tumour which had been growing for at least six years.
Thirdly, although again, I did not know it at the time, I was almost certainly suffering from testosterone and growth hormone deficiency resulting from a bad head injury I sustained when I was 31.
Finally, I was in all probability B12 deficient for hereditary reasons.
I would now like to expand on these four factors and their relationship with osteoporosis.
Malathion exposure
A 1999 paper by Compston points out “Emerging evidence of premature osteoporotic change in people exposed to organophosphates means that a referral for bone density studies would seem to be an ethical part of any management plan, if these have not already been carried out. “ [1] No management plan I had ever included this.
Parathyroid tumour
I was eventually diagnosed with a parathyroid tumour in 2006, that is, a full six years after my osteopenia diagnosis, by which time the tumour was at least twelve years old. The effect of a parathyroid tumour is to leach calcium from the bones. [2]
Head injury
Severe traumatic brain injury very commonly results in hypopituitarism. [3] I was diagnosed as hypothyroid early on, but did not receive a diagnosis of growth hormone and testosterone deficiency until 2014. It is likely that I had been deficient in the latter two hormones throughout the twenty-six years since my head injury (1974), and both deficiencies are well documented to cause osteoporosis [4,5].
B12 deficiency
My mother was B12-deficient, so there was an inherent possibility that I might be too. Yet I was not diagnosed with this until 2005. This too has an association with osteoporosis. [6]
In short, my osteoporosis was a warning signal which could have led to the prompt diagnosis of the B12 deficiency, the hyperparathyroidism, and the hypopituitarism which had been undermining my health for so many years. Instead, I had to wait four, six and fourteen more years respectively for these diagnoses, years which were dogged by depression, weakness, weight gain and fatigue. What a wasted chance. Forty-one years is a long time to suffer from undiagnosed hypopituitarism.
I am 72 now, and at last receiving some benefit from replacement growth hormone and testosterone. I hope my story will help to save others from the catastrophic delay I suffered.
[1] Compston JE et al, reduced bone formation after exposure to organophosphates, Lancet 1999 Nov 20;354(9192):1791-2 http://www.ncbi.nlm.nih.gov/pubmed/10577647
[2] Editorials, Male Osteoporosis, Rheumatology 2000 39 1055-1059
http://rheumatology.oxfordjournals.org/content/39/10/1055.full.pdf+html
“Any underlying secondary cause of osteoporosis should be treated if possible, as specific treatment of underlying conditions such as hyperthyroidism, hypogonadism and hyperparathyroidism may increase bone density by 10–20%.”
[3] Schneider HJ et al, Hypothalamopituitary Dysfunction following Traumatic Brain Injury and Aneurysmal Subarachnoid Haemorrage. A Systematic Review, 2007 JAMA http://jama.jamanetwork.com/article.aspx?articleid=208915
[4] Dupree K et al, Osteopenia and male hypogonadism, Rev Urol. 2004; 6(Suppl 6): S30–S34.
“Male hypogonadism is an important and treatable cause of osteoporosis. One of the primary treatment regimens for hypogonadism is testosterone replacement therapy, which helps not only to ameliorate the symptoms of hypogonadism, but to increase bone mineral density (BMD) as well.” http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1472878/
[5] Society for Endocrinology, You and your hormones http://www.yourhormones.info/endocrine_conditions/adult_growth_hormone_d...
[6] Tucker K et al, Low Plasma Vitamin B12 is Associated With Lower BMD: The Framingham Osteoporosis Study, 2005, Journal of Bone and Mineral Research Vol 20, 152-158,
Competing interests: No competing interests