Osteoporos Int DOI 10.1007/s00198-015-3405-6
LETTER
The real enemy is fragility fracture, not osteoporosis C. E. Uzoigwe 1
Received: 24 August 2015 / Accepted: 4 November 2015 # International Osteoporosis Foundation and National Osteoporosis Foundation 2015
Professor Compston writes a robust, persuasive and, in parts, irrefragable riposte to the work published in the British Medical Journal by Jarvinen et al. [1, 2]. While FRAX and bisphosphonates have revolutionised our management of fragility fractures, neither is a panacea nor are they beyond criticism. There is room for a much greater sophistication in our management of fragility fractures both pathophysiologically and at the level of public health. In this regard, some of Jarvinen’s comments merit more detailed consideration. Treatment of fragility fracture risk predicated on bone mineral density (BMD) falls prey to the BGeoffrey Rose prevention paradox^ of public health [3]. This posits that most adverse events occur in the majority at low risk rather than the minority at very high risk. FRAX has allowed a transition from the Bhigh-risk^ BMD-based strategy to a populationcentred prevention paradigm. This in effect reduces the population burden of disease and has a greater societal benefit. However, the great strength of FRAX is also its greatest weakness. Professor Compston recognises that the vast majority of fragility fractures occur in those who are not osteoporotic. The evidence for this is incontrovertible [4–7]. The National Osteoporosis Guideline Group (NOGG) advocates treatment for patients with previous fragility fracture or those whose 10year FRAX-determined risk exceeds a certain threshold without reference to BMD. A significant proportion of these may not have osteoporosis. The evidence that bisphosphonates are effective in those who are not osteoporotic is far from A response to these comments can be found at doi: 10.1007/s00198-0153406-5. * C. E. Uzoigwe [email protected] 1
Harcourt House, Sheffield, UK
conclusive. Cummings et al. reporting their 4200-patient strong work in the Journal of the American Medical Association (JAMA) found that Balendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD^ [8]. Similarly, Donaldson et al. used in excess of 6200 patients from the Fracture Intervention Trial (FIT) [9]. They found that alendronate only significantly reduced the risk of nonvertebral fractures in the osteoporotic but not in those with a higher bone mineral density. They further divided the patients into tertiles of fracture risk as determined by FRAX with BMD, for none of the tertiles (even the highest risk) was alendronate associated with a risk reduction of non-vertebral fractures. Fragility fractures are distinct from osteoporotic fractures. Osteoporosis is not the sole and possibly not even the most important factor for fragility fracture [10, 11]. FRAX determines fragility fracture risk. Bisphosphonates protect against osteoporotic fractures. Hence, Jarvinen et al. pose a valid question: In those who breach the treatment threshold, on the basis of FRAX 10-year fragility fracture risk, but who are not osteoporotic, do bisphosphonates reduce the risk of fragility fracture? One could even pose a more radical question: Given that FRAX determines fragility fracture risk and bisphosphonates appear to be most effective in instances of osteoporotic fracture, can FRAX (with or without BMD) be used to determine if treatment with bisphosphonates is indicated? McCloskey et al. found that FRAX-determined fracture risk correlated with the efficacy of clodronate at preventing
Osteoporos Int
fragility fracture, only when FRAX was used without BMD. Even under these circumstances, FRAX only predicted the efficacy of clodronate where the FRAX 10-year fracture risk exceeded 24 %. Now the NOGG 10-year fracture risk treatment threshold is less than 24 % for all patients, excepting those over 80 years old. Hence, according to McCloskey’s findings, for example, for a 60-year-old whose fracture risk is 20 %, hence exceeding the NOGG treatment threshold, the use of bisphosphonates may not reduce fracture risk. While on an individual level osteoporosis is important, at a population level, it may be less significant, given that most cases of fragility fracture occur in those who are not osteoporotic. The population attributable risk of osteoporosis with regard to fragility fracture refers to the number of fragility fractures in the population due to osteoporosis. Stone et al., cited by both Jarvinen and Professor Compston, in their 9700-patient strong prospective cohort study, found that only 15 % of fragility and 28 % of hip fractures were due to osteoporosis [12]. Marsahall et al. in their meta-analysis estimate that in patients with a 30 % lifetime risk of fracture, even if all those with a BMD of less than 1 standard deviation below the young mean had this normalised, this would only eliminate 20 % of hip fracture cases [13]. One may pose the question whether the amount of energy channelled into the promotion of bisphosphonates is commensurate with the population attributable effect of osteoporosis, a fortiori given that this class of drug protects against osteoporotic but not necessarily fragility fractures. A number of authors have highlighted a cohort of high-risk elderly patients for whom bisphosphonates appear not to be protective against fragility hip fracture [14–16]. Professor Compston correctly identifies that the work of Greenspan was underpowered. However, the same cannot be said of that of Lyles whose study involved in excess of 2100 patients. Similarly, Boonen involved in excess of 3800 participants. Both failed to show a preventative effect of bisphosphonates with regard to hip fracture. Perhaps a different model is required for hip fracture, more sophisticated than the mere reduction in bone density. It is well established that the precipitous increase in hip fracture seen with senescence cannot be explained by loss in bone mineral density alone [17]. Writing in The Lancet, Mayhew et al. showed that ageing had differing effects on the thickness of various parts of the femoral neck cortex, which are not reflected by bone densitometry. They reported that senescence was associated with significant thinning of the supero-lateral cortex but thickening of the inferior cortex of the femoral neck. This was due to the unloading of the supero-lateral cortex but loading of the inferior cortex with weightbearing. Hence, following a fall, the superior cortex buckles and the femoral neck breaks. This effect was independent of osteoporosis [17]. The group advocated the evaluation of various techniques that could preferentially load and thus strengthen the supero-lateral cortex. They highlight the fact that in populations where this
occurs due cultural practices such as squatting and kneeling, the incidence of hip fracture is low, notwithstanding low BMD. As unpalatable as the views of Jarvinen et al. may be, I do not share any laudable but quixotic notion that primary care physicians need protecting from such publications. The BMJ is designed for a medical readership. General practitioners are just as capable at evaluating evidence presented to them as members of any discipline. The real enemy is fragility fracture, not osteoporosis per se. We are becoming increasingly able at treating the latter while the former remains a formidable foe. Even Osteoporosis International notwithstanding its title has championed the protection of those at risk of fragility fracture and the elucidation of means of preserving their health, not exclusively the osteoporotic. Compliance with ethical standards Conflict of interest None.
References 1. 2.
3. 4.
5.
6. 7.
8.
9.
10.
Compston J (2015) Overdiagnosis of osteoporosis: fact or fallacy? Osteoporos Int 26:2051–2054. doi:10.1007/s00198-015-3220-0 Järvinen TL, Michaëlsson K, Jokihaara J, Collins GS, Perry TL, Mintzes B, Musini V, Erviti J, Gorricho J, Wright JM, Sievänen H (2015) Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 350:h208 Hunt K, Emslie C (2001) Commentary: the prevention paradox in lay epidemiology—Rose revisited. Int J Epidemiol 30(3):442–446 Sanders KM, Nicholson GC, Watts JJ et al (2006) Half the burden of fragility fractures in the community occur in women without osteoporosis: when is fracture prevention cost-effective? Bone 38: 694–700 Siris ES, Chen YT, Abbott TA et al (2004) Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108–1112 Adami S (2009) Bone health in diabetes: considerations for clinical management. Curr Med Res Opin 25:1057–1072 Bliuc D, Alarkawi D, Nguyen TV, Eisman JA, Center JR (2015) Risk of subsequent fractures and mortality in elderly women and men with fragility fractures with and without osteoporotic bone density: the Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res 30:637–646 Cummings SR, Black DM, Thompson DE, Applegate WB, BarrettConnor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082 Donaldson MG, Palermo L, Ensrud KE, Hochberg MC, Schousboe JT, Cummings SR (2012) Effect of alendronate for reducing fracture by FRAX score and femoral neck bone mineral density: the Fracture Intervention Trial. J Bone Miner Res 27:1804–1810 Uitterlinden AG, Burger H, Huang Q, Yue F, McGuigan FE, Grant SF, Hofman A, van Leeuwen JP, Pols HA, Ralston SH (1998) Relation of alleles of the collagen type Ialpha1 gene to bone density
Osteoporos Int
11.
12.
13.
and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 338:1016–1021 Barrett‐Connor E, Siris ES, Wehren LE, Miller PD, Abbott TA, Berger ML, Santora AC, Sherwood LM (2005) Osteoporosis and fracture risk in women of different ethnic groups. J Bone Miner Res 20:185–194 Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner WS, Nevitt MC, Cummings SR, Osteoporotic Fractures Research Group (2003) BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 18:1947–1954 Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254–1259
14.
Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM (2015) Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA Intern Med 15. Boonen S, Black DM, Colon-Emeric CS et al (2010) 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 58:292–299 16. Lyles KW, Colon-Emeric CS, Magaziner JS et al (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809 17. Mayhew PM, Thomas CD, Clement JG, Loveridge N, Beck TJ, Bonfield W, Burgoyne CJ, Reeve J (2005) Relation between age, femoral neck cortical stability, and hip fracture risk. Lancet 366:129–135
LETTER
The real enemy is fragility fracture, not osteoporosis C. E. Uzoigwe 1
Received: 24 August 2015 / Accepted: 4 November 2015 # International Osteoporosis Foundation and National Osteoporosis Foundation 2015
Professor Compston writes a robust, persuasive and, in parts, irrefragable riposte to the work published in the British Medical Journal by Jarvinen et al. [1, 2]. While FRAX and bisphosphonates have revolutionised our management of fragility fractures, neither is a panacea nor are they beyond criticism. There is room for a much greater sophistication in our management of fragility fractures both pathophysiologically and at the level of public health. In this regard, some of Jarvinen’s comments merit more detailed consideration. Treatment of fragility fracture risk predicated on bone mineral density (BMD) falls prey to the BGeoffrey Rose prevention paradox^ of public health [3]. This posits that most adverse events occur in the majority at low risk rather than the minority at very high risk. FRAX has allowed a transition from the Bhigh-risk^ BMD-based strategy to a populationcentred prevention paradigm. This in effect reduces the population burden of disease and has a greater societal benefit. However, the great strength of FRAX is also its greatest weakness. Professor Compston recognises that the vast majority of fragility fractures occur in those who are not osteoporotic. The evidence for this is incontrovertible [4–7]. The National Osteoporosis Guideline Group (NOGG) advocates treatment for patients with previous fragility fracture or those whose 10year FRAX-determined risk exceeds a certain threshold without reference to BMD. A significant proportion of these may not have osteoporosis. The evidence that bisphosphonates are effective in those who are not osteoporotic is far from A response to these comments can be found at doi: 10.1007/s00198-0153406-5. * C. E. Uzoigwe [email protected] 1
Harcourt House, Sheffield, UK
conclusive. Cummings et al. reporting their 4200-patient strong work in the Journal of the American Medical Association (JAMA) found that Balendronate significantly reduced the risk of clinical fractures among women with osteoporosis but not among women with higher BMD^ [8]. Similarly, Donaldson et al. used in excess of 6200 patients from the Fracture Intervention Trial (FIT) [9]. They found that alendronate only significantly reduced the risk of nonvertebral fractures in the osteoporotic but not in those with a higher bone mineral density. They further divided the patients into tertiles of fracture risk as determined by FRAX with BMD, for none of the tertiles (even the highest risk) was alendronate associated with a risk reduction of non-vertebral fractures. Fragility fractures are distinct from osteoporotic fractures. Osteoporosis is not the sole and possibly not even the most important factor for fragility fracture [10, 11]. FRAX determines fragility fracture risk. Bisphosphonates protect against osteoporotic fractures. Hence, Jarvinen et al. pose a valid question: In those who breach the treatment threshold, on the basis of FRAX 10-year fragility fracture risk, but who are not osteoporotic, do bisphosphonates reduce the risk of fragility fracture? One could even pose a more radical question: Given that FRAX determines fragility fracture risk and bisphosphonates appear to be most effective in instances of osteoporotic fracture, can FRAX (with or without BMD) be used to determine if treatment with bisphosphonates is indicated? McCloskey et al. found that FRAX-determined fracture risk correlated with the efficacy of clodronate at preventing
Osteoporos Int
fragility fracture, only when FRAX was used without BMD. Even under these circumstances, FRAX only predicted the efficacy of clodronate where the FRAX 10-year fracture risk exceeded 24 %. Now the NOGG 10-year fracture risk treatment threshold is less than 24 % for all patients, excepting those over 80 years old. Hence, according to McCloskey’s findings, for example, for a 60-year-old whose fracture risk is 20 %, hence exceeding the NOGG treatment threshold, the use of bisphosphonates may not reduce fracture risk. While on an individual level osteoporosis is important, at a population level, it may be less significant, given that most cases of fragility fracture occur in those who are not osteoporotic. The population attributable risk of osteoporosis with regard to fragility fracture refers to the number of fragility fractures in the population due to osteoporosis. Stone et al., cited by both Jarvinen and Professor Compston, in their 9700-patient strong prospective cohort study, found that only 15 % of fragility and 28 % of hip fractures were due to osteoporosis [12]. Marsahall et al. in their meta-analysis estimate that in patients with a 30 % lifetime risk of fracture, even if all those with a BMD of less than 1 standard deviation below the young mean had this normalised, this would only eliminate 20 % of hip fracture cases [13]. One may pose the question whether the amount of energy channelled into the promotion of bisphosphonates is commensurate with the population attributable effect of osteoporosis, a fortiori given that this class of drug protects against osteoporotic but not necessarily fragility fractures. A number of authors have highlighted a cohort of high-risk elderly patients for whom bisphosphonates appear not to be protective against fragility hip fracture [14–16]. Professor Compston correctly identifies that the work of Greenspan was underpowered. However, the same cannot be said of that of Lyles whose study involved in excess of 2100 patients. Similarly, Boonen involved in excess of 3800 participants. Both failed to show a preventative effect of bisphosphonates with regard to hip fracture. Perhaps a different model is required for hip fracture, more sophisticated than the mere reduction in bone density. It is well established that the precipitous increase in hip fracture seen with senescence cannot be explained by loss in bone mineral density alone [17]. Writing in The Lancet, Mayhew et al. showed that ageing had differing effects on the thickness of various parts of the femoral neck cortex, which are not reflected by bone densitometry. They reported that senescence was associated with significant thinning of the supero-lateral cortex but thickening of the inferior cortex of the femoral neck. This was due to the unloading of the supero-lateral cortex but loading of the inferior cortex with weightbearing. Hence, following a fall, the superior cortex buckles and the femoral neck breaks. This effect was independent of osteoporosis [17]. The group advocated the evaluation of various techniques that could preferentially load and thus strengthen the supero-lateral cortex. They highlight the fact that in populations where this
occurs due cultural practices such as squatting and kneeling, the incidence of hip fracture is low, notwithstanding low BMD. As unpalatable as the views of Jarvinen et al. may be, I do not share any laudable but quixotic notion that primary care physicians need protecting from such publications. The BMJ is designed for a medical readership. General practitioners are just as capable at evaluating evidence presented to them as members of any discipline. The real enemy is fragility fracture, not osteoporosis per se. We are becoming increasingly able at treating the latter while the former remains a formidable foe. Even Osteoporosis International notwithstanding its title has championed the protection of those at risk of fragility fracture and the elucidation of means of preserving their health, not exclusively the osteoporotic. Compliance with ethical standards Conflict of interest None.
References 1. 2.
3. 4.
5.
6. 7.
8.
9.
10.
Compston J (2015) Overdiagnosis of osteoporosis: fact or fallacy? Osteoporos Int 26:2051–2054. doi:10.1007/s00198-015-3220-0 Järvinen TL, Michaëlsson K, Jokihaara J, Collins GS, Perry TL, Mintzes B, Musini V, Erviti J, Gorricho J, Wright JM, Sievänen H (2015) Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 350:h208 Hunt K, Emslie C (2001) Commentary: the prevention paradox in lay epidemiology—Rose revisited. Int J Epidemiol 30(3):442–446 Sanders KM, Nicholson GC, Watts JJ et al (2006) Half the burden of fragility fractures in the community occur in women without osteoporosis: when is fracture prevention cost-effective? Bone 38: 694–700 Siris ES, Chen YT, Abbott TA et al (2004) Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med 164:1108–1112 Adami S (2009) Bone health in diabetes: considerations for clinical management. Curr Med Res Opin 25:1057–1072 Bliuc D, Alarkawi D, Nguyen TV, Eisman JA, Center JR (2015) Risk of subsequent fractures and mortality in elderly women and men with fragility fractures with and without osteoporotic bone density: the Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res 30:637–646 Cummings SR, Black DM, Thompson DE, Applegate WB, BarrettConnor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 280:2077–2082 Donaldson MG, Palermo L, Ensrud KE, Hochberg MC, Schousboe JT, Cummings SR (2012) Effect of alendronate for reducing fracture by FRAX score and femoral neck bone mineral density: the Fracture Intervention Trial. J Bone Miner Res 27:1804–1810 Uitterlinden AG, Burger H, Huang Q, Yue F, McGuigan FE, Grant SF, Hofman A, van Leeuwen JP, Pols HA, Ralston SH (1998) Relation of alleles of the collagen type Ialpha1 gene to bone density
Osteoporos Int
11.
12.
13.
and the risk of osteoporotic fractures in postmenopausal women. N Engl J Med 338:1016–1021 Barrett‐Connor E, Siris ES, Wehren LE, Miller PD, Abbott TA, Berger ML, Santora AC, Sherwood LM (2005) Osteoporosis and fracture risk in women of different ethnic groups. J Bone Miner Res 20:185–194 Stone KL, Seeley DG, Lui LY, Cauley JA, Ensrud K, Browner WS, Nevitt MC, Cummings SR, Osteoporotic Fractures Research Group (2003) BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures. J Bone Miner Res 18:1947–1954 Marshall D, Johnell O, Wedel H (1996) Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254–1259
14.
Greenspan SL, Perera S, Ferchak MA, Nace DA, Resnick NM (2015) Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA Intern Med 15. Boonen S, Black DM, Colon-Emeric CS et al (2010) 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 58:292–299 16. Lyles KW, Colon-Emeric CS, Magaziner JS et al (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809 17. Mayhew PM, Thomas CD, Clement JG, Loveridge N, Beck TJ, Bonfield W, Burgoyne CJ, Reeve J (2005) Relation between age, femoral neck cortical stability, and hip fracture risk. Lancet 366:129–135
