Overdiagnosis of bone fragility in the quest to prevent hip fractureBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h2088 (Published 26 May 2015) Cite this as: BMJ 2015;350:h2088
All rapid responses
I value the BMJ as a providing a forum for high-level intellectual debate. It is read by both experts and more importantly non-experts in the field. However, this comes with responsibility that what is published represents the high standard of scholarship. However, I wish to question the editorial process that is essential for any high impact journal.
I was asked to review this paper some months ago and had thought I had rejected it as in my opinion the data presented and conclusions drawn were false and would mislead patients, clinicians and academics. The subsequent responses from others in the field have eloquently detailed the same and additional errors in the paper.
Given the BMJ admirable drive for transparency, I would clearly be interested in the other reviewers' comments.
Email maybe fallible and I apologise if I missed both BMJ response to the reviewers comments and authors comments but I do not recall receiving them.
I suggest the BMJ share not only my review but those of other reviewers, who must have clearly accepted the paper without changes as the published paper bears a striking resemblance to the one I reviewed and rejected so clearly. I am also keen to understand the editorial trail including responsible officers from receiving the reviews to the acceptance of the paper.
Dr MK Javaid
Competing interests: In last fives years received honoraria, travel and/or subsistence expenses from: Amgen, Eli Lilly, Medtronic, Norvartis, Proctor and Gamble, Servier, Shire, Internis, Consilient Health and Jarrow Formula Member of IOF Fracture Working Group Member of NOS FLS implementation group and CSC Clinical Lead for RCP CEEU FFFAP FLS-DB
As the world’s leading scientific organization for bone health research, the American Society for Bone and Mineral Research (ASBMR) is dedicated to making ground-breaking discoveries, translating these into effective therapies for osteoporosis and other bone diseases, and educating patients and clinicians about appropriate osteoporosis care and treatment. As scientific researchers, physicians and other healthcare practitioners, we are greatly concerned that the recent paper by Järvinen et al. in the British Medical Journal will confuse and mislead the public and the medical community with inaccurate and harmful conclusions about the treatment of osteoporosis.
We believe that the authors have selectively chosen data to support their conclusions that “The dominant approach to hip fracture prevention is neither viable as a public health strategy nor cost effective.” This conclusion is wrong. As scientists and clinicians, we can say without equivocation that for many people with osteoporosis, current drug treatments prevent fractures, which allows them to remain independent and free of suffering. Ultimately, these treatments save lives (20% of elder individuals with femoral neck fractures die within a year).1
Overwhelming evidence clearly shows that osteoporosis is a significant and costly public health problem that continues to grow with the aging of our population. Contrary to the contention that osteoporosis is overtreated, those that suffer with osteoporosis are vastly undertreated due to lack of awareness and confusion regarding the benefits of, and the need for, treatment, which these articles will increase even further. Even in those who suffer the most devastating of fractures, a hip fracture, only about 20% are treated to reduce the risk of a subsequent fracture.2 Osteoporosis is the underlying cause of millions of wrist, vertebral compression and hip fractures that all too often lead to pain, loss of independence and mortality. Despite this, fewer than 10% of older women with fragility fractures receive any osteoporosis therapy.3
More effectively preventing falls, one of the evidence-based approaches the authors of this study prescribe, is not enough to reduce the risk of fracture because it does not address the underlying bone fragility. Many fracture spontaneously without a fall or precipitating trauma. While adequate intake of calcium and vitamin D, and participation in exercise and fall prevention programs, are important components of treatment, they are insufficient and unable to significantly reduce the risk of fracture and prevent future fractures.4,5
Treating high-risk patients with drug therapy is highly effective in preventing fractures. As little as three years of pharmacotherapy can achieve a 30-50% reduction in fracture incidence6 and reduce mortality in those with hip fracture.7 Current recommendations for osteoporosis drug therapy target high risk individuals who may have already suffered from an osteoporotic fracture and are at great risk of a future fracture. Fracture Liaison Services (FLS), programs to coordinate the diagnosis and treatment of patients over 50 years old suffering fractures, effectively improve treatment rates, save hospital costs by preventing future fractures and save lives.8
The benefits of osteoporosis drug treatment in high risk individuals are clear; yet, Järvinen et al. have inflated the danger of extremely rare side effects of some osteoporosis therapies. We, as bone experts, are concerned about these rare side effects and are working to understand their causes, but we strive to provide evidence and guidance for clinicians so that high risk individuals are treated for an appropriate interval and low risk individuals are not unnecessarily treated. This summer, the ASBMR Task Force on Long-Term Bisphosphonate Use will release its recommendations offering more specific clinical guidance for practitioners treating patients who are at risk for fractures.
Ongoing research is the best way to improve prevention, detection and treatment of bone diseases like osteoporosis to rein in costs and alleviate suffering. ASBMR urges BMJ to join the experts in the field in accurately informing the public and the medical community with the most comprehensive and current research on the critical need to identify and treat patients at risk for fractures from osteoporosis. To do less than this or worse, to do nothing, as the article suggests, is irresponsible and a disservice to our patients.
1. Liebson CL, Tosteson AN, Gabriel SE, Ransom JE, Melton LJ. Mortality, disability, and nursing home use for persons with and without hip fracture: a population-based study. Journal of the American Geriatric Society 2002; 50(10):1644-50.
2. Solomon DH, Johnson SS, Boytsov NN, McMorrow D, Lane JM, Krohn KD. Osteoporosis medication use after hip fracture in US patients 2002 and 2011. Journal of Bone and Mineral Research 2014; 29(9): 1929-1937.
3. Kanis JA, Svedbom A, Harvey N, McCloskey EV. The Osteoporosis Treatment Gap. Journal of Bone and Mineral Research 2014; 29(9): 1926-1928.
4. Bischoff-Ferarri HA, Dawson-Hughes B, Baron JA et al. Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. Am J Clin Nutr 2007; 86(6): 1780-1790.
5. Tang BM, Eslick GC, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people 50 years and older: A meta-analysis 2007; Lancet 370 (9588):657-666.
6. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, Cosman F, Lakatos P, Leung PC, Man Z, Mautalen C, Mesenbrink P, Hu H, Caminis J, Tong K, Rosario-Jansen T, Krasnow J, Hue TF, Sellmeyer D, Eriksen EF, Cummings SR; HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007 May 3;356(18):1809-22.
7. Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S. HORIZON Pivotal Fracture Trial. Zoledronic acid and clinical fracture and mortality after hip fracture. N Engl J Med. 2007; 357(18):1799–809.
8. Eisman JA Bogoch ER, Dell R,Harrington JT, McKinney RE, McLellan A, Mitchell PJ, Silverman S, Singleton R, Siris E. Making the First Fracture the Last Fracture: ASBMR Task Force Report on Secondary Fracture Prevention. For the American Society for Bone and Mineral Research Task Force on Secondary Fracture Prevention. Journal of Bone and Mineral Research 2012; 27(9): 1-8.
Competing interests: No competing interests
Hip fracture is the main target of fracture prevention, but where is RCT-proof that Fracture Liaison Services work?
As Järvinen and colleagues (1) point out hip fractures should be the main target of the fracture prevention in older adults since the consequences of hip fractures, both individually and financially, clearly exceed those of all other age-related fractures combined (2). In other words, any prevention method, whether pharmacological or nonpharmacological, should show its ability to prevent hip fractures to deserve large scale implementation. If this condition is not fulfilled, the method in question is likely to have limited value in ordinary health care settings. Thus, ability to prevent other fractures is of secondary importance, but naturally a welcome additional benefit if there.
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). 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 (3-6).
So far so good, but a more detailed evaluation of the study reports (3-6) on FLS effectiveness in fracture prevention reveals a major gap in evidence. Surprisingly, none of the studies was a randomized controlled trial (RCT) thus leaving lots of space for all the well-known biases in the observational non-randomized studies. Most likely, this was the main reason for the huge differences in the results of preventing refractures, from a nonsignificant effect ( 5) to significant, unbelievably high 80% effect (4). This type of results emphasize the urgent need for high-quality RCTs for FLS, especially when IOF and other related organizations are already now, without real evidence base, strongly advocating for worldwide implementation of the FLS.
Pekka Kannus, MD,PhD
1. Järvinen TL, Michaelsson K, Jokihaara J et al. Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 2015;350:h2088.
2. Kanis J, Oden A, Johnell O et al. The burden of osteoporotic fractures: a method for setting intervention thresholds. Osteoporos Int 2001;12:417-427.
3. 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.
4. 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.
5. 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).
6. 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.
Competing interests: No competing interests
Question: When is a person's idea of primary prevention the other person's secondary prevention?
Answer: I don't know, unless the authors are on the same page as the readers.
Järvinen TLN et al (ref 1) (through citing Musini V et al in Appendix 2 http://www.bmj.com/highwire/filestream/897049/field_highwire_adjunct_fil...) (post-menopausal women):
Primary prevention is defined as women without prior fragility fractures or vertebral compression; secondary prevention, women with prior fragility fractures or prior vertebral compression.
“primary prevention refers to opportunistic identification, during visits to a healthcare professional for any reason, of postmenopausal women who are at risk of osteoporotic fragility fractures and who could benefit from drug treatment. It does not imply a dedicated screening programme.” (Ref 2)
“secondary prevention of fragility fractures in postmenopausal women who have osteoporosis and have sustained a clinically apparent osteoporotic fragility fracture. Osteoporosis is defined by a T-score of −2.5 standard deviations (SD) or below on dual-energy X-ray absorptiometry (DXA) scanning. However, the diagnosis may be assumed in women aged 75 years or older if the responsible clinician considers a DXA scan to be clinically inappropriate or unfeasible.” (Ref 3)
Cochrane (for post-menopausal women):
“That is, if the inclusion criteria restricted the population to women whose bone density was at least 2 SD values below the peak bone mass, or the inclusion criteria restricted the population to women who had experienced previous vertebral compression fractures, then the trial was considered a secondary prevention study. If such inclusion criteria were not provided, then the baseline statistics were considered as follows: (a) we considered the trial as primary prevention if the average T-score (and SD) was such that it included women whose bone density was within 2 SD of the mean, or if the prevalence of vertebral fracture at baseline was less than 20%; and (b) when these data were not available, we considered a trial as secondary prevention if the average age was above 62 years.” (ref 4)
Fragility fracture in absence of WHO 2010 definition of osteoporosis by BMD estimation does not simply point to the possibility that osteoporosis does not account for all fragility fractures as the authors seem to suggest; it is also possible that that the BMD cut-off for osteoporosis suitable for treatment (as defined by WHO) may in fact be too conservative, that some BMD values classified as osteopaenia may in fact predispose patients to fragility fracture.
Question: When is "vertebral compression" not a vertebral fracture?
Answer: I didn't know there was a difference. Can someone else explain that to me because
1. Järvinen TLN et al. Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 2015;350:h2088
2. NICE technology appraisal guidance [TA160] Alendronate, etidronate, risedronate, raloxifene and strontium ranelate for the primary prevention of osteoporotic fragility fractures in postmenopausal women (amended) 2008
3. NICE technology appraisal guidance [TA161] Alendronate, etidronate, risedronate, raloxifene, strontium ranelate and teriparatide for the secondary prevention of osteoporotic fragility fractures in postmenopausal women (amended) 2008
4. Wells GA et al. (2008) Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane Database Syst Rev: (1) CD001155.
Competing interests: I look after patients with hip fractures and get paid for it
We thank our colleagues for insightful comments on our Too much medicine –analysis entitled ‘Overdiagnosis of bone fragility in the quest to prevent hip fracture’ 1. A number of correspondents understood the key message of our article that fractures in the elderly are caused mostly by falling - rather than osteoporosis, and that marginal evidence supports pharmacological prevention of hip fractures. These facts remain poorly recognised.
However, as some rapid responses included misunderstandings and untenable inferences, we welcome the opportunity to clarify some key issues here.
Many responses construe our Analysis as “focusing on hip fractures to the exclusion of other clinically important fractures”, while some argue that “fragility fractures cause excess mortality that can be remedied through bone-targeted pharmacotherapy”, “anti-fracture efficacy of bone-targeted pharmacotherapy is enhanced in secondary prevention and/or by treating those at high risk of fractures”, “moving from conventional BMD-based screening to the concept of fracture risk enhances screening/treatment efficacy”, and that “fracture liaison services are the new panacea for fracture epidemic”.
As intuitively rational as such assertions may seem, the arguments supporting them and the purported flaws in our paper do not stand up to scrutiny. We share our colleagues’ views that fractures are a serious health concern, and are aware that a multiple risk factor approach is commonly used in most non-communicable diseases. However, if such an approach has not been shown to reduce morbidity or mortality from serious fractures, reference to analogous practice in other fields of medicine is not rational. We reprimand children when they justify misbehaviours because their peers behaved similarly. Should we accept a lower ethical standard for our own work?
One repeated assertion was that our analysis focused on hip fractures to the exclusion of other clinically important fractures. The rationale is the importance of hip fractures to health, as stated in the opening paragraph of our paper: “hip fractures constitute a minority of fractures linked to osteoporosis, their consequences exceed those of all other fragility fractures combined.2 Vertebral fractures, recognised only by radiography, are of much less clinical concern (see appendix 1 on thebmj.com).3 4”.
A link to the “appendix 1”:
Vertebral fractures are often considered equivalent in importance to those of the hip. However, the diagnosis of vertebral fracture is notoriously arbitrary. Depending on criteria used to classify a change in an x-ray image as a fracture, the prevalence of vertebral fractures in an elderly population can vary from 3% to 90%. Referring to a “vertebral fracture epidemic” without clarifying the arbitrary nature of the definition of “fracture”, the fact that these are measures of the degree of vertebral compression rather than an actual break in the bone, and the asymptomatic nature of most “vertebral fractures” is analogous to raising alarm that the prevalence of prostate cancer in elderly men approaches 100%.
The arbitrary and inconsistent way that vertebral fractures have been defined affects the distinction between “primary” and “secondary” prevention trials of pharmacotherapy, as well as guidelines promoting a different treatment strategy for people with “existing/prevalent fractures”. Most of these prevalent fractures are deformations of the vertebrae, only visible on X-ray, with differing diagnostic thresholds affecting who is defined as a primary prevention or a secondary prevention patient.
Moreover, a symptomatic vertebral fracture is rarely “spontaneous” or purely osteoporotic; at least 50% are trauma-induced, particularly due to falling on the buttocks or lifting an object with straight knees 2-4. In a recent survey of vertebral fracture-related emergency department visits and hospitalizations in the older Dutch population, 83% of vertebral fractures were caused by a low-energy fall5. Seemingly benign activities such as bending or lifting light objects produce large loads on the spinal column (up to 10 times higher than with perfect posture) and are capable of fracturing a vertebra 4 6. Only one-third of the x-ray compressions, wrongly termed vertebral fractures, are symptomatic, and the occurrence of these vertebral compressions rather poorly predicts either the existence of back pain or functional status of the spine7.
Many rapid responses argue that “fragility fractures” cause excess mortality and that bone-targeted pharmacotherapy improves survival. While it is true that “fragility fractures” are associated with increased short and medium term mortality, this is also true for almost every illness of older adults. This association does not imply that the fractures caused the additional deaths; an elderly frail person is at higher risk both of fragility fractures, and of illness and death than a younger and less frail person. The relevant question is how much the increased morbidity and mortality linked to “fragility fractures” can be reduced by pharmacotherapy.
A recent study8 estimated the effect of hip fracture on excess mortality by following identical twin pairs discordant for hip fracture. In younger men and in women of any age, the excess risk of mortality lasted only one year after hip fracture. Only in men older than 75 did hip fracture affect mortality beyond the first year. This is a strong indication that previous studies overrated the excess mortality after a hip fracture in women, including the duration of the excess risk 9.
Rapid responses arguing for a mortality benefit of bone-targeted pharmacotherapy reference the “secondary prevention arm” of the HORIZON trial10 (HORIZON also had a “primary prevention arm” 11) but neglect its recognized flaws and questions about its results.12 In fact, immediately after publication of this “secondary prevention arm” of the HORIZON trial10, concern was expressed regarding the alleged mortality benefit (http://www.nejm.org/doi/full/10.1056/NEJMc073292). The authors responded (http://www.nejm.org/doi/pdf/10.1056/NEJMc073292) by stating that “the time-to-death analysis was a prespecified safety analysis that was described in both the protocol and the statistical-analysis plan (provided in the online Supplementary Appendix to our article)”. However, this statement might not be entirely accurate.
First, time to death was not a prespecified primary or secondary outcome nor a prespecified safety analysis as described in the primary study protocol (http://www.nejm.org/doi/suppl/10.1056/NEJMoa074941/suppl_file/nejmoa0749...) or in the updated protocol (http://www.nejm.org/doi/suppl/10.1056/NEJMoa074941/suppl_file/nejmoa0749...). The first mention we have found of a time to death analysis was in the statistical analysis plan (first release date June 5th 2006 and last revised March 28th, 2007). This was shortly before manuscript submission and after the HORIZON trial was completed.
Second, mortality was never listed in the Clinicaltrials.gov database as any kind of outcome. Of most concern, according to the history of changes to the HORIZON trial registration (https://clinicaltrials.gov/archive/NCT00046254/2006_05_31/changes), even the primary outcomes were added only on May 31, 2006, that is, four months after patient recruitment was completed.
Third, a total of 242 deaths were included in the analysis of the HORIZON secondary prevention trial 10 and the analysis rendered a hazard ratio of 0.72 (95% CI 0.56-0.93) for death in those allocated to zoledronic acid. While subsequent fractures were associated with death, they explained only 8% of the zoledronic acid effect on mortality13 12. In the HORIZON primary prevention trial11, an identical number of deaths occurred (n=242) but the relative risk of death in the zoledronic acid treatment arm was 1.16 (95% CI 0.91-1.49). The HORIZON trialists claimed that the difference in estimates was due to limited study power in the primary prevention trial14 but given the similar number of outcomes this is not a likely explanation. A further puzzling finding is the protective effect against fatal arrhythmias apparent in the “secondary prevention arm” of the HORIZON trial 10, whereas in the “primary prevention arm” of the HORIZON trial 11, the incidence of arrhythmias was paradoxically increased among the zoledronic acid treated group.
The proposed mechanism for zoledronic acid to reduce the risk of lethal infectious and cardiovascular diseases is by modifying the pro-inflammatory and immunologic effects of hip fracture 12. However, elevated serum markers of inflammation return to normal levels within the first month after the fracture in most patients.13 15 16 Infusion of zoledronic acid within the first month after the fracture did not reduce mortality rates 14, although this was the period with postulated highest efficacy. On the contrary, the statistically significant difference was observed with infusion more than 12 weeks after the fracture 14. This seems incompatible with the proposed pathogenetic mechanism for the mortality reduction benefit 12. Interestingly, the trial was initially designed to include patients within a week after hip fracture, but was later modified to include patients for up to 12 weeks. Mortality survival curves started to diverge only after 16 months of follow-up (median follow-up 23 months).10 12
Another possible explanation is differences in loss to follow-up. While incomplete follow-up was a minor problem in the primary prevention trial11, in the secondary prevention trial, 155 participants withdrew consent or were lost to follow-up (out of a total of 295 subjects who did not complete follow-up) in the zoledronate arm and 137 in the placebo arm (out of 316 who did not complete follow-up)10. These numbers correspond to a relative risk of consent withdrawal or loss to follow-up in zoledronic acid users of 1.21 (95% CI 1.03-1-43; p=0.02) compared with those on placebo. Consent withdrawal or loss to follow-up are likely to be related to higher rate of disability and death.17-19 The trial was also stopped early, following an additional unplanned interim analysis. Early termination of trials has been shown to overestimate reported benefits, with a ratio of relative risks versus non-truncated trials of 0.71 (95% CI 0.65-0.77), regardless of whether statistical stopping rules are used20. This bias is thought to be due to random fluctuations that occur during the conduct of a trial.
Deviation from intention to treat analyses inflates treatment effect estimates21, and this seems to hold true here, too: after exclusion of the “secondary prevention arm” of the HORIZON trial10 from a meta-analysis9, the alleged mortality benefit of osteoporosis therapy vanished (RR 0.94 with 95% CI 0.84-1.06; p=0.31).
Until other randomized controlled trials designed a priori to assess mortality replicate the results of the secondary prevention HORIZON trial, we recommend caution in interpreting these results.
Regarding the general anti-fracture efficacy of bone-targeted pharmacotherapy, many responses referred to drug-specific Cochrane systematic reviews published in 2008 22-24, but none disputed the findings of our more recent and comprehensive systematic review (Figure 3).
Dr. Treadwell highlights the fundamental difference between primary and secondary prevention. As he notes, some correspondents infer that secondary prevention could represent a more productive opportunity for pharmacotherapy. As intuitively obvious as this seems, what truly is the evidence? Our systematic review attempted to discriminate trials of primary prevention (enrolment based on low BMD alone) from secondary prevention (prior vertebral fractures only). This proved very challenging, notably because of the variable definitions of “vertebral fractures”. Additionally, our exploratory subgroup analysis of trial results for populations that have been defined as primary versus secondary (based on the presence of previous vertebral fractures) failed to reveal a significant interaction effect. This finding not only supports the decision to report the results of all trials as a single estimate only, but also questions the conventional wisdom that drugs are more potent in secondary prevention.
The only “true” secondary prevention trial is the “secondary prevention arm” of HORIZON10, for which patients were randomized to intravenous zoledronic acid or placebo after having sustained a hip fracture. We have addressed above some concerns about the execution of the trial, including early termination, outcome reporting, and loss to follow-up, but it is also worth reviewing the effectiveness evidence. With a median follow-up of nearly two years, hip fracture rates did not differ significantly between zoledronic acid and placebo: 2.0% on zoledronic acid vs. 3.5% on placebo, NS. There were fewer clinical non-vertebral fractures, 7.6% vs. 10.7% (an absolute risk reduction (ARR) of 3.1% and and a relative risk reduction (RRR) of 27%, p=0.03), and fewer clinical vertebral fracture, 1.7% in the zoledronic acid group vs. 3.8% in the placebo group (ARR 2.1% and RRR 55%, p=0.02). Effects of pharmacotherapy remained modest even in this secondary prevention population. The great majority of patients do not benefit.
Many authors question the validity of providing a single NNT, 175 over three years of bisphosphonate treatment to prevent one hip fracture,, as the estimate is only for one fracture type, albeit the most devastating. We similarly restricted our estimate of the potential harms of treatment to a single, most devastating one – atypical fracture of the femur (NNH of 300 for a three-year treatment period25 26). Accordingly, we feel that a trade-off of 175 to gain vs. 300 to be harmed is a relatively fair comparison, except that the former comes from “unrealistic” efficacy studies whereas the latter is derived from ordinary healthcare settings (real life).
Several rapid responses also note that the field is moving from conventional BMD-based screening to the concept of “fracture risk” (identification of those at highest risk of fractures). As already briefly discussed above, this is another intuitively rational strategy that lacks proper evidence.
Dr. Chika E Uzoigwe notes possible biases in studies that failed to show anti-fracture efficacy in people with higher risk of fracture, but does not provide any evidence that pharmacotherapy is effective in this population.
It has become common for doctors to feel driven to deliver any and all available treatments to their patients, even when there is little hope of a benefit and real potential for harm. Many rapid responses postulated the existence of a treatment or care gap affecting individuals who have suffered a fracture but are left “untreated”. Naturally we agree that society should seek to prevent fractures in the elderly. Those who have already suffered a fracture represent a logical target for intervention. However noble the intentions, they do not eliminate the responsibility to abstain from interventions that have not been proven to be effective, for which there is a poor ratio of potential benefit versus potential harm, or whose cost precludes more effective alternative strategies.
Several responses also suggest using various non-BMD-based approaches to decide whom to treat. Although such approaches are tempting, there is still no reliable evidence that they are effective.
Many correspondents argued that fracture liaison services (FLS), programs “to identify and treat osteoporosis in high risk individuals” are the panacea for a future fracture epidemic. However, the scientific basis/rationale rests either on low-quality (observational, non-RCT) evidence or modeling-type cost-effectiveness extrapolations, the validity of which we have questioned previously27. As appealing as such programs appear, their effectiveness can only be proven by appropriately designed comparative-effectiveness RCTs which take account of overall costs as well as clinical outcomes.
To be treated or not: who should make the decision? Advocates of more aggressive intervention do not seem to endorse shared-decision making28. Whilst many of the organisations criticizing our paper advocate a 3% 10-year risk of hip fracture (or 20% risk of ‘major osteoporotic fracture’) as being high enough to justify drug therapy, patients consider the appropriate threshold of 10-year risk to be 50% (sic!)29. Patients may not – when fully informed – want pharmacological fracture prevention.
Competing interest: BMJ asks authors of all contributions in The BMJ (including rapid responses) to declare their competing interests. Some authors of rapid responses with obvious conflicts have chosen not to do so. We share BMJ’s stance on competing interest: “A competing interest—often called a conflict of interest—exists when professional judgment concerning a primary interest (such as patients' welfare or the validity of research) may be influenced by a secondary interest (such as financial gain or personal rivalry). It may arise for the authors of an article in The BMJ when they have a financial interest that may influence, probably without their knowing, their interpretation of their results or those of others.”
We are convinced that open and unemotive discussion of the current scientific evidence on how best to reduce the fracture burden can benefit patients in the long run. Orthodoxy, inattention to methodological issues in RCTs, and lack of transparency concerning competing interests are barriers to achieving the best and most cost-effective results.30-33
1. Jarvinen TL, Michaelsson K, Jokihaara J, et al. Overdiagnosis of bone fragility in the quest to prevent hip fracture. Bmj 2015;350:h2088.
2. Cooper C, Atkinson EJ, Kotowicz M, et al. Secular trends in the incidence of postmenopausal vertebral fractures. Calcified tissue international 1992;51(2):100-4.
3. Cooper C, Atkinson EJ, O'Fallon WM, et al. Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985-1989. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 1992;7(2):221-7.
4. Myers ER, Wilson SE. Biomechanics of osteoporosis and vertebral fracture. Spine (Phila Pa 1976) 1997;22(24 Suppl):25S-31S.
5. Oudshoorn C, Hartholt KA, Zillikens MC, et al. Emergency department visits due to vertebral fractures in the Netherlands, 1986-2008: steep increase in the oldest old, strong association with falls. Injury 2012;43(4):458-61.
6. Duan Y, Seeman E, Turner CH. The biomechanical basis of vertebral body fragility in men and women. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2001;16(12):2276-83.
7. O'Neill TW, Cockerill W, Matthis C, et al. Back pain, disability, and radiographic vertebral fracture in European women: a prospective study. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2004;15(9):760-5.
8. Michaelsson K, Nordstrom P, Nordstrom A, et al. Impact of hip fracture on mortality: a cohort study in hip fracture discordant identical twins. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2014;29(2):424-31.
9. Haentjens P, Magaziner J, Colon-Emeric CS, et al. Meta-analysis: excess mortality after hip fracture among older women and men. Annals of internal medicine 2010;152(6):380-90.
10. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. The New England journal of medicine 2007;357(18):1799-809.
11. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. The New England journal of medicine 2007;356(18):1809-22.
12. Colon-Emeric CS, Mesenbrink P, Lyles KW, et al. Potential mediators of the mortality reduction with zoledronic acid after hip fracture. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2010;25(1):91-7.
13. Sedlar M, Kudrnova Z, Erhart D, et al. Older age and type of surgery predict the early inflammatory response to hip trauma mediated by interleukin-6 (IL-6). Archives of gerontology and geriatrics 2010;51(1):e1-6.
14. Eriksen EF, Lyles KW, Colon-Emeric CS, et al. Antifracture efficacy and reduction of mortality in relation to timing of the first dose of zoledronic acid after hip fracture. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2009;24(7):1308-13.
15. Beloosesky Y, Hendel D, Weiss A, et al. Cytokines and C-reactive protein production in hip-fracture-operated elderly patients. The journals of gerontology Series A, Biological sciences and medical sciences 2007;62(4):420-6.
16. Baehl S, Garneau H, Le Page A, et al. Altered neutrophil functions in elderly patients during a 6-month follow-up period after a hip fracture. Experimental gerontology 2015;65:58-68.
17. May GS, DeMets DL, Friedman LM, et al. The randomized clinical trial: bias in analysis. Circulation 1981;64(4):669-73.
18. Juni P, Altman DG, Egger M. Systematic reviews in health care: Assessing the quality of controlled clinical trials. Bmj 2001;323(7303):42-6.
19. Moher D, Hopewell S, Schulz KF, et al. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. Bmj 2010;340:c869.
20. Bassler D, Briel M, Montori VM, et al. Stopping randomized trials early for benefit and estimation of treatment effects: systematic review and meta-regression analysis. JAMA : the journal of the American Medical Association 2010;303(12):1180-7.
21. Abraha I, Cherubini A, Cozzolino F, et al. Deviation from intention to treat analysis in randomised trials and treatment effect estimates: meta-epidemiological study. Bmj 2015;350:h2445.
22. Wells G, Cranney A, Peterson J, et al. Risedronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane database of systematic reviews 2008(1):CD004523.
23. Wells GA, Cranney A, Peterson J, et al. Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane database of systematic reviews 2008(1):CD001155.
24. Wells GA, Cranney A, Peterson J, et al. Etidronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women. Cochrane database of systematic reviews 2008(1):CD003376.
25. Schilcher J, Koeppen V, Aspenberg P, et al. Risk of atypical femoral fracture during and after bisphosphonate use. N Engl J Med 2014;371(10):974-6.
26. Schilcher J, Koeppen V, Aspenberg P, et al. Risk of atypical femoral fracture during and after bisphosphonate use. Acta Orthop 2015;86(1):100-7.
27. Jarvinen TL, Sievanen H, Kannus P, et al. The true cost of pharmacological disease prevention. Bmj 2011;342:d2175.
28. Stiggelbout AM, Van der Weijden T, De Wit MP, et al. Shared decision making: really putting patients at the centre of healthcare. Bmj 2012;344:e256.
29. Douglas F, Petrie KJ, Cundy T, et al. Differing perceptions of intervention thresholds for fracture risk: a survey of patients and doctors. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2012;23(8):2135-40.
30. Jarvinen TL, Jokihaara J, Guy P, et al. Conflicts at the heart of the FRAX tool. CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne 2013.
31. Collins GS, Michaelsson K. Fracture risk assessment: state of the art, methodologically unsound, or poorly reported? Current osteoporosis reports 2012;10(3):199-207.
32. Bolland MJ, Grey A, Gamble G, et al. Comment on Kanis et al.: Pitfalls in the external validation of FRAX. Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2013;24(1):389-90.
33. Collins GS, Mallett S, Altman DG. Predicting risk of osteoporotic and hip fracture in the United Kingdom: prospective independent and external validation of QFractureScores. Bmj 2011;342:d3651.
Competing interests: TLNJ is he Jane and Aatos Erkko foundation clinical professor of Orthopedics and Traumatology at the University of Helsinki and is supported by unrestricted academic grants from the Academy of Finland and the Sigrid Juselius Foundation.
The European Calcified Tissue Society (ECTS) has issued a statement in response to the recent paper by Järvinen et al. in the BMJ (1). As a scientific organization promoting research to improve bone health, we wish to make the following comments to this paper, which we find just adds to the confusion amongst patients with biased citations and unsubstantiated statements.
The authors are of the opinion that stopping smoking, eating healthy food and exercising will take care of the problem more effectively, but fail to produce the evidence that such public health approaches really have shown superiority over pharmacological therapy in the long term. Where is the evidence that such measures would be more cost-effective, and what would be the long-term adherence to such measures among elderly frail individuals?
The authors also ignore that a hip fracture is the last stage in a cascade involving forearm fractures and vertebral fractures, where the latter also has shown significant mortality of some 30% within one year. With the most effective antiresorptive drugs the number needed to treat to avoid one vertebral fracture employing the commonly agreed criteria for identification of individuals at risk is 9. This is much lower than numbers for interventions like antihypertensives to prevent an ischemic stroke. By looking at hip fractures in isolation the authors leave out the effect of treatment on other important consequences of osteoporosis; for example vertebral fractures, pelvic fractures and forearm fractures. This corresponds to only considering the effect of antihypertensives on myocardial infarction, without acknowledging additional beneficial effects on, for example, strokes and peripheral arteriosclerosis.
The authors state that prevention of falls is not employed to avoid hip fracture. All osteoporosis guidelines worldwide emphasize prevention of falls and “fall clinics” are widespread. But this does not rule out to further reduce risk by strengthening bone in individuals at risk. Ignoring pharmacotherapy would be analogous to withholding statins in individuals at risk for CV disease, where weight loss and smoking cessation are important non-pharmacologic measures. The authors use the study by Greenspan et al. (2) to prove that drug treatment of hip fractures is ineffective, but this study, comprising only 181 women, was severely underpowered to look at fractures.
The cost effectiveness of pharmacological interventions in patients at risk of hip fracture has clearly been demonstrated in analyses of fracture liaison approaches to treatment of osteoporosis. Moreover, most countries are employing cost effectiveness analyses to determine whether new drugs should be approved. In this context, hip fractures have the biggest impact due to their severe economic consequences.
The authors cite atypical femoral fractures (AFF) after antiresorptive drug treatment as a major concern, despite the fact that numerous analyses have demonstrated that the risk benefit ratio vs. number of hip fractures prevented is still way in favor of continued antiresorptive treatment. The 3 studies on AFF where X-ray based diagnosis was performed cite incidence rates between 0,3-5/10,000 (3). The risk of GI bleeds associated with NSAIDS is 100 fold higher (4).
The authors do not mention at all that osteoporosis treatment after hip fracture reduces all cause mortality by around 30%. This should be taken into account when considering the risk to benefit ratio of osteoporosis treatment.
While we agree with Järvinen et al. that other preventive measures apart from drug treatment should be employed when treating hip fractures, we strongly regret the potential negative impact of this manuscript on effective prevention of osteoporotic fractures and the well-demonstrated effects of such treatments on morbidity, mortality and health care costs.
1. Jarvinen TL, Michaelsson 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. Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM. Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial. . JAMA internal medicine. 2015;ePub.
3. Schilcher J, Michaelsson K, Aspenberg P. Bisphosphonate use and atypical fractures of the femoral shaft. NEnglJMed. 2011;364(18):1728-37.
4. Hernandez-Diaz S, Garcia-Rodriguez LA. Epidemiologic assessment of the safety of conventional nonsteroidal anti-inflammatory drugs. The American journal of medicine. 2001;110 Suppl 3A:20S-7S.
Competing interests: No competing interests
Jarvinen and colleagues question the value of focusing on osteoporosis as the best means of dealing with the increasing personal and public health burden of fragility fractures. They site a NNT (number neededto treat) of 175 to prevent one new hip fracture, to support their argument for a reorientation in management away from osteoporosis (1). This argument however is contingent on the make up of the target population and in fact highlights the importance of focusing on the most appropriate patient group. Recognition that patients who sustain a minimal trauma fracture are self-identifying as being at high risk of further fractures has been the basis of calls by organisations such as the International Osteoporosis Foundation (IOF) for the establishment of fracture liaison services (FLS), as the best way of bridging the lamentabkle gap in service delivery, whereby only 10-20% of patients with minimal trauma fractures go onto treatment (2,3)
While to date, confirmation of their effctiveness has been lagely indirect and based on projected benefits, there is now accumulating direct evidence of their effectiveness in reducing the risk of further fractures.
The gains are significant. In a recent analysis we demonstrated a ~40% reduction in the risk of having a further major fracture in patients attending a large trauma hospital with a FLS compared to a similar institution without a FLS. The NNT to prevent a new fracture over a 3 year follow up was 20. (4) As a comparison the NNT to prevent a cardiovascular event over 5 years is 55.
Though FLS use a multipronged approach to management, treatment of the osteoporosis is a crucial element and any "refocusing" away from it would neuter a demonstrably effective programme
1 Jarvinen T ,Michaelsson K, Jokihaara J et al. Overdiagnosis of bone fragility in the quest to prevent hip fractures BMJ 2015 doi:10.1136/bmj.h2008
2 Akesson K, Marsh D, Mitchell PJ, et al. Capture the fracture: A bestpractice framework and global campaign to break the fragility fracture cycle. Osteoporosis Int. 2013;24:2135-2152
3 Kanis JA, Svedbom A,, HarveyN, McCloskey EV. The osteoporosis treatment gap. JBMR 2014;9:1926-1928
4 Nakayama A, Major G, Bogduk N, Comperative refracture rates inhospitals with and without a fracture liaison service: A 6 month historical cohort study. Inter Med J 2015; 45:(S2) 3
Competing interests: No competing interests
We are writing on behalf of the United States National Bone Health Alliance (www.nbha.org), a public-private partnership of 48 organizations and 5 U.S. federal government agency liaisons, co-chaired by the American Society for Bone and Mineral Research (ASBMR) and the National Osteoporosis Foundation (NOF). The NBHA goal is to enact the recommendations outlined in the 2004 Bone Health and Osteoporosis: A Report of the United States Surgeon General to reduce osteoporosis-related fractures.
Although we agree with the authors that osteoporosis and the resulting fractures are a terrible problem worldwide and responsible for high morbidity, mortality and loss of independence, we disagree with their basic premise – that treatment of osteoporosis is futile. NBHA and its partners are focused on identifying those individuals at greatest risk for a second fracture: those who have already suffered from a previous osteoporotic fracture, through the widespread implementation of fracture liaison service (FLS) programs, whose goal is to identify and treat osteoporosis in high risk individuals (1). There is abundant evidence that treatment of individuals who have already fractured is effective and prevents secondary spine and hip fractures (2).
This approach is being successfully implemented in the United Kingdom; in the United States, the Affordable Care Act is helping to drive a coordinated FLS approach by focusing on physician payment for quality outcomes (prevention of second fractures) rather than fee-for-service approaches (payment for repair of the fracture).
Our goal is to raise the percentage of post-fracture patients (those over 50 years of age with wrist, humerus, spine or hip fractures) from the 25-30% who currently receive evaluation and treatment for osteoporosis after a fracture(3) to a figure of 80% or greater. There is now abundant evidence that this approach will lower fracture incidence and costs in this group of patients (4-7). Although adequate calcium, vitamin D and lifestyle changes (including falls prevention) are important components of this program, alone they are inadequate to stem bone loss and prevent future fractures. Pharmacotherapy has proven its efficacy to reduce the incidence of future fractures as documented in multiple studies (8-10).
If we are going to have any chance of stemming this epidemic of unnecessary fractures, we consider it essential to identify and treat patients at highest risk through the FLS model.
We fear that an unintended consequence of Dr. Järvinen and colleagues’ manuscript is that individuals currently treated for osteoporosis may stop therapy and suffer a preventable osteoporotic fracture. This is antithetical to a clearly defined strategy for reducing osteoporotic fractures.
We would welcome the opportunity to provide a more extensive rebuttal to this paper at your invitation. Thank you.
Robert A. Adler, MD (ASBMR Co-Chair)
Robert F. Gagel, MD (NOF Co-Chair)
National Bone Health Alliance
Washington, DC USA
(1) Eisman JA Bogoch ER, Dell R,Harrington JT, McKinney RE, McLellan A, Mitchell PJ, Silverman S, Singleton R, Siris E. Making the First Fracture the Last Fracture: ASBMR Task Force Report on Secondary Fracture Prevention. For the American Society for Bone and Mineral Research Task Force on Secondary Fracture Prevention. Journal of Bone and Mineral Research 2012; 27(9): 1-8.
(2) Lyles KW, Colon-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, Hyldstrup L, Recknor C, Nordsletten L, Moore KA, Lavecchia C, Zhang J, Mesenbrink P, Hodgson PK, Abrams K, Orloff JJ, Horowitz Z, Eriksen EF, Boonen S. HORIZON Pivotal Fracture Trial. Zoledronic acid and clinical fracture and mortality after hip fracture. N Engl J Med. 2007; 357(18):1799–809.
(3) National Committee on Quality Assurance. The State of Health Care Quality 2014. 2014: 90-91.
(4) Newman ED, Ayoub WT, Starkey RH, Diehl JM, Wood GC. Osteoporosis disease management in a rural health care population: hip fracture reduction and reduced costs in postmenopausal women after 5 years. Osteoporosis International 2003; 14(2): 146‐51.
(5) Dell R, Greene D, Schelkun SR, Williams K. Osteoporosis disease management: the role of the orthopaedic surgeon. Journal of Bone and Joint Surgery 2008; 90 Supplement 4: 188‐194.
(6) Cooper MS, Palmer AJ, Seibel MJ. Cost‐effectiveness of the Concord Minimal Trauma Fracture Liaison service, a prospective, controlled fracture prevention study. Osteoporosis International 2012; 23(1): 97‐107.
(7) McLellan AR, Gallacher SJ, Fraser M, McQuillian C. The fracture liaison service: success of a program for the evaluation and management of patients with osteoporotic fracture. Osteoporosis International 2003; 14(12): 1028‐34.
(8) Black DM, Cummings SR, Karpf DB, Cauley JA, Thompson DE, Nevitt MC, Bauer DC, Genant HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group. Lancet 1996 Dec 7; 348 (9041): 1535-41.
(9) Lonnroos E, Kautiainen H, Karppi P, Hartikainen S, Kiviranta I, Sulkava R. Incidence of second hip fractures. A population-based study. Osteoporosis International 2007; 18(9): 1279–85.
(10) Nymark T, Lauritsen JM, Ovesen O, Rock ND, Jeune B. Short timeframe from first to second hip fracture in the Funen County Hip Fracture Study. Osteoporosis International 2006;17(9):1353–7.
Competing interests: No competing interests
Jarvinen et al report a number of apparent paradoxes in studies exploring the efficacy of bisphosphonates on fragility fracture prevention in the over-75s(1). They seem to suggest that those most at risk of fragility fracture enjoy the least benefit. However caution is required before these observations are treated as evidence of ineffectiveness of bisphosphonates in this cohort. The well-characterised but infrequently appreciated “collider stratification bias” (also termed index event bias) may be operative(2). It is a form of selection bias. The studies cited by Jarvinen et al include a significant proportion of patients already on bisphosphonates and/or anti-resorptives who suffer a fragility fracture. The studies then look to see if bisphosphonates prevent recurrence. Those who suffer fragility fracture, while medicated on bisphosphonates, have already demonstrated a proclivity to fracture due to a cluster of risk factors not controlled by bisphosphonates. Hence an evaluation of this cohort with regard to recurrence is likely to show that bisphosphonates are ineffective or weakly protective. This is “collider stratification” or “index event” bias. It can lead to counter-intuitive results. Index event bias occurs when the occurrence of a particular event is required for inclusion in a study. The study then explores the effect of risk factors or an intervention on recurrence. It explains a number of apparent paradoxes. It accounts for the antithetical observation that prior use of aspirin reduces the risk of primary MI but increases the risk of recurrent MI (the aspirin paradox)(3). Those who do not take aspirin and suffer MI tend will have a lower incidence of other risk factors compared to patients who suffered MI with aspirin. Thrombolphilias are a risk factor for a first deep venous thrombosis (DVT) but not for recurrent episodes (the thrombophilia paradox)(4). Obesity is a recognised risk factor for coronary artery disease, yet it appears to protect against recurrent coronary events (the obesity paradox)(5).
If we explore the studies included by Jarvinen, Lyles et al included both those with previous hip fracture and those previously medicated with bisphosphonate or anti-resorptive (6). They then went on to evaluate the effect of zolendronate on recurrent fragility fracture. Their post hoc study had a similar methodology(7). Intriguingly both studies reported a reduction in clinical vertebral and non-vertebral fractures but not hip fractures. Greenspan et al. prospectively evaluated the efficacy of zolendronic acid(8). They also included patients with previous fragility fractures and indeed used this as one of the diagnostic criteria for osteoporosis. The group allowed bisphosphonate and
/or alternative bisphosphonate therapy coincident with the time of original fragility fracture. Patients were only excluded if currently medicated on bisphosphonate at the time of recruitment or if they had been compliant with bisphosphonate treatment for over a year within the last two years of recruitment. The group then went on to see if zolendronate prevented recurrence or new fragility fracture. Unsurprisingly they found zolendronic not to be protective against fragility hip fracture in this group in this context. However, their mode of selection inadvertently concentrates their population with “bisphosphonate and/or antiresorptive resistant fragility fractures”. This weakens the apparent efficacy of bisphosphonates. This is index event bias and explains the observed anomalies. Those who suffer hip fracture while on bisphosphonate or anti-resorptive treatment are likely to find a substitute or new concurrent bisphosphonate ineffective or weakly protective. To truly evaluate the effect of bisphosphonates in the elderly or those most at risk; the fracture incidence in a group of bisphosphonate-naïve osteoporotic septua/octo/nona-genarians or institutionalised elderly patients must be compared with that of a similar cohort medicated on bisphosphonate. However in the current climate is very unlikely for individuals to reach this level of maturity without receiving anti-osteoporosis treatment. Hence studies evaluating anti-resorptives in this group will almost invariably involve those already or previously medicated on bisphosphonates and assess some degree of recurrence, thus allowing collider bias.
1.Järvinen TL, Michaëlsson K, Jokihaara J, Collins GS, Perry TL, Mintzes B, Musini V, Erviti J, Gorricho J, Wright JM, Sievänen H.Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ. 2015 May 26;350:h2088
2.Dahabreh IJ, Kent DM. Index event bias as an explanation for the paradoxes of recurrence risk research. JAMA. 2011; 305:822-3
3.Rich JD, Cannon CP, Murphy SA, Qin J, Giugliano RP, Braunwald E. Prior aspirin use and outcomes in acute coronary syndromes. J Am Coll Cardiol. 2010; 56:1376–1385.
4.Baglin T. Unraveling the thrombophilia paradox: from hypercoagulability to the prothrombotic state. J Thromb Haemost. 2010; 8:228–233.
5.Gruberg L, Weissman NJ, Waksman R, et al. The impact of obesity on the short-term and long-term outcomes after percutaneous coronary intervention: the obesity paradox? J Am Coll Cardiol. 2002;39:578–584.
6.Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fracturesand mortality after hip fracture. N Engl J Med 2007;357:1799-809.
7.Boonen S, Black DM, Colon-Emeric CS, et al. Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older. J Am Geriatr Soc 2010;58:292-9.
8.Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM. Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA Intern Med 2015 Apr 13.
Competing interests: No competing interests
Re: Overdiagnosis of bone fragility in the quest to prevent hip fracture- before we reach breaking point
Further to the recent publication on over-prediction of hip fracture risk and ensuing challenges (1), current data highlight the limitations of Dual-Energy-X-ray-Absorptiometry scans (DEXA). In this context, at best, DEXA scans (which measure bone mineral density (BMD)) can account for no greater than 50% of overall bone strength (defined as the ability to resist fracture). This is because the resulting images are two-dimensional (2D) and therefore unable to capture skeletal micro-architecture, which also contributes to bone strength (2).
Clearly, better clinical measures of overall bone strength that more accurately reflect the ability of that bone to resist fracture represent an unmet need and are urgently required. Recent evidence suggests that micro-Computed Tomography (CT) scans, which enable 3D imaging, might provide a solution but use so far has necessarily been limited to ex vivo assessment owing to radiation hazards as well as technical and accessibility issues (3, 4). However micro-CT images have identified bone volume fraction (BVF, the volumetric distribution of bone mass) as a strong determinant of bone strength (r2 > 0.8) (5,6).
Other potential tools, alone or in combination with imaging may also play a role. For example serum biomarkers of bone metabolism (7,8) along with other imaging modalities such as magnetic resonance imaging could capture the complex factors that make up bone strength (9). Input of such data into pre-existing algorithms like the FRAX (a Fracture Risk Assessment tool calculator) (10) might help reduce the over-prediction issue currently faced.
Clinical trials of medications for non-bone disease, that nonetheless may also have the unwanted effect of inducing rapid changes to bone strength, could offer opportunities for accelerating the assessment of currently developing fracture prediction tools. An example is a sub-study of PATCH, (Prostate Adenocarcinoma TransCutaneous Hormones (MRC PR09)), an ongoing National Phase III randomized clinical trial (ClinicalTrials.gov number NCT00303784) comparing efficacy and toxicity of LHRHa (lutenising hormone releasing hormone analogues) and oestradiol transdermal patches in suppressing testosterone to castrate levels (androgen deprivation therapy (ADT)). LHRHa delivers this through suppression of (initially) testosterone (by about 95%), and then oestradiol (by about 80%; oestradiol is synthesized in men from testeosterone through aromatase). Lack of these sex hormones rapidly alters the balance of activity between osteoblasts and osteoclasts resulting in a loss of up to 10% BMD in the first year of ADT and 2-4% annually thereafter (11) and so development of osteoporosis. Conversely, whilst transdermal oestradiol patches (EP) also lead to suppression of testosterone, the ‘lost’ endogenous oestradiol is replaced by the exogenous oestradiol patches, resulting overall in a gain of BMD (12,13).
In light of the above and the pressing need to resolve the problems identified by Järvinen et al, it would appear prudent to invest in further studies to determine the extent and management of this issue now, before the NHS itself becomes fractured, having reached a breaking point in the face of an ever-ageing population.
1. Järvinen TL. Overdiagnosis of bone fragility in the quest to prevent
hip fracture. BMJ. 2015. 2015;350:h2088
2. Greenspan SL, Wagner J, Nelson JB, Perera S, Britton C, Resnick NM. Vertebral fractures and trabecular microstructure in men with prostate cancer on androgen deprivation therapy. J Bone Miner Res. 2013;28:325–32.
3. Genant HK, Engelke K, Prevrhal S. Advanced CT bone imaging in osteoporosis. Rheumatology. 2008;47:suppl 4:9-16
4. Cooper D, Turinsky A, Sensen C, Hallgrimsson B. Effect of voxel size on 3D micro-CT analysis of cortical bone porosity. Calcified Tissue Int. 2007;80(3):211-9.
5. Nazarian A, von Stechow D, Zurakowski D, Muller R, Snyder BD. Bone volume fraction explains the variation in strength and stiffness of cancellous bone affected by metastatic cancer and osteoporosis. Calcified Tissue Int. 2008;83(6):368-79.
6. Van Hemelrijck M, Garmo H, Michaelsson K, Thorstenson A, Akre O, Stattin P, et al. Mortality following hip fracture in men with prostate cancer. PloS one. 2013;8(9):e74492.
7. Wilson HCP, Shah SIA, Abel, PD, Price P, Honeyfield L,Edwards S, Abel RL. Contemporary hormone therapy with LHRH agonists for prostate cancer: avoiding osteoporosis and fracture. Central European Journal of Urology. 2015 (In press)
8. Dabaja A, Bryson C, Schlegel P, Paduch D. The effect of hypogonadism and testosterone-enhancing therapy on alkaline-phosphatase and bone mineral density. BJU Int 2015; 115: 3
9. Kröger H, Vainio P, Nieminen J, Kotaniemi A. Comparison of different models for interpreting bone mineral density measurements using DXA and MRI technology. Bone.1995. 17: 157-5
11. Shahinian VB, Kuo YF, Freeman JL, Goodwin JS. Risk of fracture after androgen deprivation for prostate cancer.NEJM. 2005;352(2):154-64
12. Langley RE, Cafferty FH, Alhasso AA, et al. Cardiovascular outcomes in patients with locally advanced and metastatic prostate cancer treated with luteinising-hormone-releasing-hormone agonists or transdermal oestrogen: the randomised, phase 2 MRC PATCH trial (PR09). The Lancet Oncology 2013;14:306-16
13. Langley, R.E., Duong T., Jovic G. et al., Bone density in men receiving androgen deprivation therapy for prostate cancer: a randomized comparison between transdermal estrogen and luteinising hormone-releasing hormone agonists. Journal of Clinical Oncology. 2014, 32, suppl; abstr 5067
Competing interests: No competing interests