‘Skeletal Age’ for mapping the impact of fracture on mortality

  1. Thach Tran
  2. Thao Ho-Le
  3. Dana Bliuc
  4. Bo Abrahamsen
  5. Louise Hansen
  6. Peter Vestergaard
  7. Jacqueline R Center
  8. Tuan V Nguyen

  • Curated by eLife

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    This important study presents the idea of "Skeletal Age", defined as the age of one's skeleton as a consequence of fragility fracture, as a potential new tool to raise awareness about the increased risk of mortality following a fracture (particularly hip fractures) and thus improve the medical management of osteoporosis. The evidence is convincing and is derived from a very large database from the Danish National Hospital Discharge Registry. The proposed approach might represent a starting point for making doctor-patient communication about the health risks of an osteoporotic fracture more intuitive and possibly more effective.

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Abstract

Fragility fracture is associated with an increased risk of mortality, but mortality is not part of doctor-patient communication. Here, we introduce a new concept called ‘Skeletal Age’ as the age of an individual’s skeleton resulting from a fragility fracture to convey the combined risk of fracture and fracture-associated mortality for an individual.

Methods:

We used the Danish National Hospital Discharge Register which includes the whole-country data of 1,667,339 adults in Denmark born on or before January 1, 1950, who were followed up to December 31, 2016 for incident low-trauma fracture and mortality. Skeletal age is defined as the sum of chronological age and the number of years of life lost (YLL) associated with a fracture. Cox’s proportional hazards model was employed to determine the hazard of mortality associated with a specific fracture for a given risk profile, and the hazard was then transformed into YLL using the Gompertz law of mortality.

Results:

During the median follow-up period of 16 years, there had been 307,870 fractures and 122,744 post-fracture deaths. A fracture was associated with between 1 and 7 years of life lost, with the loss being greater in men than women. Hip fractures incurred the greatest loss of life years. For instance, a 60-year-old individual with a hip fracture is estimated to have a skeletal age of 66 for men and 65 for women. Skeletal Age was estimated for each age and fracture site stratified by gender.

Conclusions:

We propose ‘Skeletal Age’ as a new metric to assess the impact of a fragility fracture on an individual’s life expectancy. This approach will enhance doctor-patient risk communication about the risks associated with osteoporosis.

Funding:

National Health and Medical Research Council in Australia and Amgen Competitive Grant Program 2019.

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  1. Version published to 10.7554/elife.83888 on eLife
  2. eLife

    Author Response

    Reviewer #1 (Public Review):

    The authors developed a new concept: Skeletal age, which is chronological age + years lost due to suffering a low-energy fracture. There seem to be conceptual problems with this concept: It is not known if the years lost are lost due to the fracture or co-morbidities.

    The Reviewer raises an important point, and we are happy to discuss it as follows. While it is not possible to show the causal relationship between a fragility fracture and excess mortality, it has been shown repeatedly that a fracture is associated with an increased risk of pre-mature mortality after accounting for comorbidities and frailty. Indeed, we and others have found that comorbidities contribute little to the increased risk10,11. Moreover, in a previous study using the ‘relative survival analysis’ technique12, we have shown that hip and proximal fractures were associated with reduced life expectancy after accounting for time-related changes in background mortality in the population, suggesting that hip and proximal fractures are an independent clinical risk factor for mortality.

    In this study, we used a multivariable Cox’s proportional hazards model to adjust for confounding effects of age and severity of comorbidities, and our result clearly indicated that a fracture is associated with years of life lost. Moreover, comorbidities were considered a factor in an individual's risk profile for estimating skeletal age. As a result, skeletal age reflects the common real-world scenario that the combination of comorbidities and proximal or lower leg fractures compounded post-fracture excess mortality, much greater than each alone13.

    Technically, there are two steps to individualise skeletal age for each individual with a specific risk profile. First, we used the statistical approach recommended for the individualisation of survival time prediction using statistical models14 to individualise specific mortality risk for each participant with a specific risk profile. Specifically, we calculated the prognostic risk index as a single-number summary of the combined effects of his/her specific risk profile of a specific fracture site and the severity of comorbidity. His/her individualised fracture-mortality association was then computed as the difference between his/her prognostic index and the mean prognostic index of “typical” people in the general population. In the second step, we used the Gompertz law of mortality and the Danish national lifetable data to transform the individualised association into life expectancy loss as a result of a fracture15.

    We have modified part of the description of the methodology as follows:

    “For the second aim, we determined skeletal age for individual based on the individual’s specific risk profile. First, we calculated the prognostic risk index as a single-number summary of the combined effects of his/her specific fracture site and the severity of comorbidity51. The prognostic index is a linear combination of the risk factors with weights derived from the regression coefficients. The individualised fracture-mortality association for an individual with a specific risk profile is then the difference between the individual's prognostic index and the mean prognostic index of 'typical' people in the general population51. In the second step, we used the Gompertz law of mortality and the Danish national lifetable data to transform the excess mortality into life expectancy loss as a result of a fracture49.”.

    In addition, with the possible exception of zoledronate after hip fracture, we have no evidence that this increased risk of mortality can be changed with interventions.

    We agree that there is a lack of strong evidence from randomised controlled trials supporting the benefit of anti-resorptive therapy on post-fracture survival. As mentioned above, the mention of zoledronic acid was simply for illustrating the use of skeletal age to convey a treatment benefit. We have decided to remove the section related to the benefit of pharmacological treatment on post-fracture mortality.

    Furthermore, it is not clear why the authors think that patients and doctors will better understand the implications of older "skeletal age", on future fracture risk and the need for prevention, for example, the 10-year risk of MOF? Knowing that my bones are older than me, could make a patient feel even more fragile and afraid of being physically active. The treatment will reduce the risk of future fractures, but this study provides no information about the effect on mortality of preventing the subsequent fracture or the risk of mortality associated with recurrent fractures.

    The risk of fracture is typically conveyed to patients and the public in terms of absolute risk metric (e.g., probability) or relative risk metrics (e.g., risk ratio). However, patients and doctors often struggle to comprehend probabilistic statements such as 'Your risk of death over the next 10 years is 5% if you have suffered from a bone fracture'. The underappreciation of post-fracture mortality's gravity has caused patients to be hesitant towards treatment and prevention, contributing to the current crisis of osteoporosis treatment.

    We consider that skeletal age will make doctor-patient risk communication more intuitive and probably more effective. For example, for the same 2-fold increased mortality risk of hip fracture, telling a 60-year man with a hip fracture that his skeletal age would be 66 years old, equivalent to a 6-year loss of life is much more intuitive. The patient might be thus more likely to accept the recommended pharmacological treatment, ultimately improving health benefits. However, we have not had RCT evidence for the effectiveness of skeletal age, and this will be one of our future research focus. We would like to point out that there is RCT evidence that effective age (such as 'Heart Age', 'Lung Age') could improve the uptake of preventive actions. For example, informing patients about their heart age, as shown by Lopez-Gonzalez et al16 was found to better improve their cardiovascular risk compared to informing the Framingham probabilistic risk score.

    Introduction:

    The statement that treatment reduces the risk of dying, needs modification as the majority of clinical trials have not demonstrated reduced mortality with treatment.

    We have modified the statement as follows: “In randomised controlled trials, treating high-risk individuals with bisphosphonates or denosumab reduces the risk of fracture4, though whether the reduction translates into reduced mortality risk remains contentious5, 6.”

    It is not clear how the skeletal age captures the risk of a future fracture. The other difference between the idea of "skeletal age" and for example "heart age" is that there are treatments available for heart disease that reduce the risk of mortality, as mentioned above this has not been shown consistently in clinical trials in osteoporosis.

    We take the Reviewer's point, but we would like to point out that there are at least two RCTs on zoledronic acid showing that treating patients with a fragility fracture reduces their risk of mortality17,18.

    Because the risk profile that is associated with a post-fracture mortality is also associated with the risk of fracture, skeletal age can be seen as a measure of the decline of the skeleton due to a fracture or exposure to risk factors that raise the risk of fracture. Thus, a 60-year-old with a skeletal age of 66 is in the same risk category as a 66-year-old with 'favourable risk factors' or at least the ones that are potentially modifiable. Hence, an older skeletal age means a greater risk of fracture.

    Neither the “Skeletal Age” nor the “Heart Age”16,19,20 has the treatment intervention incorporated into its calculator. We have added details to explain how the assessment of skeletal age would provide the conceptual risk of both fracture and post-fracture mortality as follows:

    “Unlike the current fracture risk assessment tools17 which estimate the probability of fracture over a period of time using probability-based metrics, such as relative risk and absolute risk, skeletal age quantifies the consequence of a fracture using a natural frequency metric. A natural frequency metric has been consistently shown to be easier and more friendly to doctors and patients than the probability-based metrics9 11 30. It is not straightforward to appreciate the importance of the two-fold increased risk of death (i.e., relative risk = 2.0) without knowing the background risk (i.e., 2 folds of 1% would remarkably differ from 2 folds of 10%). By contrast, for the same 2-fold mortality risk of hip fracture, telling a 60-year man with a hip fracture that his skeletal age would be 66 years old, equivalent to a 6-year loss of life, is more intuitive. The skeletal age can also be interpreted as the individual being in the same risk category as a 66-year-old with 'favorable risk factors' or at least the ones that are potentially modifiable. Hence, an older skeletal age means a greater risk of fracture.”.

    Discussion:

    The prevalent comorbidities; cardiovascular diseases, cancer, and diabetes, suggest that fracture patients die from their comorbidities and not their fractures.

    Please refer to the above response for more detail. Briefly, the multivariable Cox’s proportional hazards regression adjusted for the confounding effect of age and the severity of comorbidities, indicating the association between fracture and mortality was independent of aging and comorbidity severity. On the other hand, skeletal age is a measure of excess mortality related to either fracture or co-morbidities or both.

    The discussion should be more balanced as there is a number of clinical trials demonstrating reductions in vertebral and non-vertebral fractures without effect on mortality. There may be specific effects of zoledronate on mortality, but that has not been shown for the vast majority of treatments.

    Please refer to the above response for more detail. Specifically, as the study primarily aimed at introducing skeletal age as a new metric for risk communication, we have decided to omit the paragraph discussing the potential benefit of zoledronic acid on post-fracture mortality risk in order to maintain the clarity and focus of the study.

    It is not correct that FRAX does not take mortality into account? It does not tell you specifically how high the risk of dying and how high the risk of a fracture is but integrates the two. "Skeletal age" does not provide either information, it just tells you that your skeleton is older than your chronological age - most patients and doctors will not associate that with an increased risk of dying - only of frailty.

    Although it is commonly believed that FRAX accounts for competing risk of death, it does not provide the risk of post-fracture mortality. Indeed, none of the current fracture risk assessment tools was designed to provide post-fracture mortality risk5. Skeletal age fills the gap by providing the excess mortality following a fracture for an individual with specific risk profile.

    The statement that zoledronate reduces the "skeletal age" by 3 years, has not been demonstrated and it is not clear how this can be demonstrated by the analysis reported here. As the reduced mortality has only been shown for the Horizon RFT, this cannot be inferred for other treatments and other fracture types. The information provided by the "skeletal age" is only that the fracture you already had took x years of your remaining lifetime. With the exception of perhaps zoledronate after hip fracture, we have no indication from clinical trials that the treatment of osteoporosis will change this.

    The current study was not designed to examine the effectiveness of an intervention. The statement related to the survival benefit of zoledronate is used to illustrate how skeletal age is used to convey the treatment benefit in real-world doctor-patient risk communication. Given the hazard ratio of 0.72 for zoledronate-mortality association17, a patient might find the statement “Zoledronic acid treatment helps a patient with a hip fracture gain (back) 3 years of life” much easier to understand and probably more persuasive than the traditional statement of “Zoledronic acid treatment reduced the risk of death by 28%”.

    Reviewer #2 (Public Review):

    The paper of Tran et al. introduces the concept of 'skeletal age' as a means of conveying the combined risk of fracture and fracture-associated mortality for an individual. Skeletal age is defined as the sum of chronological age and the number of years of life lost associated with a fracture. Using the very comprehensive Danish national registry and employing Cox's proportional hazards model they estimated the hazard of mortality associated with a fracture. Skeletal age was estimated for each age and fracture site stratified by gender. The authors propose to replace the fracture probability with skeletal age for individualized fracture risk assessment.

    Strengths of the study lie in the novelty of the concept of 'skeletal age' as an informative metric to internalize the combined risks of fracture and mortality, the very large and well-described Danish National Hospital Discharge Registry, the sophisticated statistical analysis and the clear messages presented in the manuscript. The limitations of the study are acknowledged by the authors.

    We appreciate your positive remark that captures the essence of our work.

    References:

    1. Lujic S, Simpson JM, Zwar N, Hosseinzadeh H, Jorm L. Multimorbidity in Australia: Comparing estimates derived using administrative data sources and survey data. PloS one 2017; 12(8): e0183817.
    2. Andersen TF, Madsen M, Jorgensen J, Mellemkjoer L, Olsen JH. The Danish National Hospital Register. A valuable source of data for modern health sciences. Dan Med Bull 1999; 46(3): 263-8.
    3. Vestergaard P, Mosekilde L. Fracture risk in patients with celiac Disease, Crohn's disease, and ulcerative colitis: a nationwide follow-up study of 16,416 patients in Denmark. Am J Epidemiol 2002; 156(1): 1-10.
    4. Hundrup YA, Hoidrup S, Obel EB, Rasmussen NK. The validity of self-reported fractures among Danish female nurses: comparison with fractures registered in the Danish National Hospital Register. Scand J Public Health 2004; 32(2): 136-43.
    5. Beaudoin C, Moore L, Gagne M, et al. Performance of predictive tools to identify individuals at risk of non-traumatic fracture: a systematic review, meta-analysis, and meta-regression. Osteoporos Int 2019; 30(4): 721-40.
    6. Spiegelhalter D. How old are you, really? Communicating chronic risk through 'effective age' of your body and organs. BMC Med Inform Decis Mak 2016; 16: 104.
    7. Vestergaard P, Rejnmark L, Mosekilde L. Osteoporosis is markedly underdiagnosed: a nationwide study from Denmark. Osteoporos Int 2005; 16(2): 134-41.
    8. Roerholt C, Eiken P, Abrahamsen B. Initiation of anti-osteoporotic therapy in patients with recent fractures: a nationwide analysis of prescription rates and persistence. Osteoporos Int 2009; 20(2): 299-307.
    9. Cummings SR, Lui LY, Eastell R, Allen IE. Association Between Drug Treatments for Patients With Osteoporosis and Overall Mortality Rates: A Meta-analysis. JAMA Int Med 2019; 179(11): 1491-500.
    10. Chen W, Simpson JM, March LM, et al. Comorbidities Only Account for a Small Proportion of Excess Mortality After Fracture: A Record Linkage Study of Individual Fracture Types. J Bone Miner Res 2018; 33(5):795-802
    11. Vestergaard P, Rejnmark L, Mosekilde L. Increased mortality in patients with a hip fracture-effect of pre-morbid conditions and post-fracture complications. Osteoporos Int 2007; 18(12): 1583-93.
    12. Tran T, Bliuc D, Hansen L, et al. Persistence of Excess Mortality Following Individual Nonhip Fractures: A Relative Survival Analysis. J Clin Endocrinol Metab 2018; 103(9): 3205-14.
    13. Tran T, Bliuc D, Ho-Le T, et al. Association of Multimorbidity and Excess Mortality After Fractures Among Danish Adults. JAMA Netw Open 2022; 5(10): e2235856.
    14. Henderson R, Keiding N. Individual survival time prediction using statistical models. J Med Ethics 2005; 31(12): 703-6.
    15. Kulinskaya E, Gitsels LA, Bakbergenuly I, Wright N. Calculation of changes in life expectancy based on proportional hazards model of an intervention. Insur Math Econ 2020; 93: 27-35. 16 Lopez-Gonzalez AA, Aguilo A, Frontera M, et al. Effectiveness of the Heart Age tool for improving modifiable cardiovascular risk factors in a Southern European population: a randomized trial. Eur J Prev Cardiol 2015; 22(3): 389-96.
    16. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007; 357(18): 1799-809.
    17. Reid IR, Horne AM, Mihov B, et al. Fracture Prevention with Zoledronate in Older Women with Osteopenia. N Engl J Med 2018; 379(25): 2407-16.
    18. Bonner C, Batcup C, Cornell S, et al. Interventions Using Heart Age for Cardiovascular Disease Risk Communication: Systematic Review of Psychological, Behavioral, and Clinical Effects. JMIR Cardio 2021; 5(2): e31056.
    19. Svendsen K, Jacobs DR, Morch-Reiersen LT, et al. Evaluating the use of the heart age tool in community pharmacies: a 4-week cluster-randomized controlled trial. Eur J Public Health 2020; 30(6): 1139-45.
    20. Suissa S. Immortal time bias in pharmaco-epidemiology. Am J Epidemiol 2008; 167(4): 492-9.
  3. eLife

    eLife assessment

    This important study presents the idea of "Skeletal Age", defined as the age of one's skeleton as a consequence of fragility fracture, as a potential new tool to raise awareness about the increased risk of mortality following a fracture (particularly hip fractures) and thus improve the medical management of osteoporosis. The evidence is convincing and is derived from a very large database from the Danish National Hospital Discharge Registry. The proposed approach might represent a starting point for making doctor-patient communication about the health risks of an osteoporotic fracture more intuitive and possibly more effective.

  4. eLife

    Reviewer #1 (Public Review):

    The authors developed a new concept: Skeletal age, which is chronological age + years lost due to suffering a low-energy fracture.
    There seem to be conceptual problems with this concept: It is not known if the years lost are lost due to the fracture or co-morbidities. In addition, with the possible exception of zoledronate after hip fracture, we have no evidence that this increased risk of mortality can be changed with interventions. Furthermore, it is not clear why the authors think that patients and doctors will better understand the implications of older "skeletal age", on future fracture risk and the need for prevention, for example, the 10-year risk of MOF? Knowing that my bones are older than me, could make a patient feel even more fragile and afraid of being physically active. The treatment will reduce the risk of future fractures, but this study provides no information about the effect on mortality of preventing the subsequent fracture or the risk of mortality associated with recurrent fractures.

    Introduction:
    The statement that treatment reduces the risk of dying, needs modification as the majority of clinical trials have not demonstrated reduced mortality with treatment.
    It is not clear how the skeletal age captures the risk of a future fracture. The other difference between the idea of "skeletal age" and for example "heart age" is that there are treatments available for heart disease that reduce the risk of mortality, as mentioned above this has not been shown consistently in clinical trials in osteoporosis.

    Discussion:
    The prevalent comorbidities; cardiovascular diseases, cancer, and diabetes, suggest that fracture patients die from their comorbidities and not their fractures.
    The discussion should be more balanced as there is a number of clinical trials demonstrating reductions in vertebral and non-vertebral fractures without effect on mortality. There may be specific effects of zoledronate on mortality, but that has not been shown for the vast majority of treatments.
    It is not correct that FRAX does not take mortality into account? It does not tell you specifically how high the risk of dying and how high the risk of a fracture is but integrates the two. "Skeletal age" does not provide either information, it just tells you that your skeleton is older than your chronological age - most patients and doctors will not associate that with an increased risk of dying - only of frailty.
    The statement that zoledronate reduces the "skeletal age" by 3 years, has not been demonstrated and it is not clear how this can be demonstrated by the analysis reported here. As the reduced mortality has only been shown for the Horizon RFT, this cannot be inferred for other treatments and other fracture types.
    The information provided by the "skeletal age" is only that the fracture you already had took x years of your remaining lifetime. With the exception of perhaps zoledronate after hip fracture, we have no indication from clinical trials that the treatment of osteoporosis will change this.

  5. eLife

    Reviewer #2 (Public Review):

    The paper of Tran et al. introduces the concept of 'skeletal age' as a means of conveying the combined risk of fracture and fracture-associated mortality for an individual. Skeletal age is defined as the sum of chronological age and the number of years of life lost associated with a fracture. Using the very comprehensive Danish national registry and employing Cox's proportional hazards model they estimated the hazard of mortality associated with a fracture. Skeletal age was estimated for each age and fracture site stratified by gender. The authors propose to replace the fracture probability with skeletal age for individualized fracture risk assessment.

    Strengths of the study lie in the novelty of the concept of 'skeletal age' as an informative metric to internalize the combined risks of fracture and mortality, the very large and well-described Danish National Hospital Discharge Registry, the sophisticated statistical analysis and the clear messages presented in the manuscript. The limitations of the study are acknowledged by the authors.

  6. Version published to 10.1101/2022.09.09.22279789v1 on medRxiv