clinical investigation
http://www.kidney-international.org & 2014 International Society of Nephrology
The three-year incidence of fracture in chronic kidney disease Kyla L. Naylor1,2, Eric McArthur3, William D. Leslie4, Lisa-Ann Fraser5, Sophie A. Jamal6, Suzanne M. Cadarette3,7, Jennie G. Pouget8, Charmaine E. Lok9, Anthony B. Hodsman1, Jonathan D. Adachi10 and Amit X. Garg1,2,3 1
Division of Nephrology, Western University, London, Ontario, Canada; 2Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada; 3Institute for Clinical Evaluative Sciences (ICES), London, Ontario, Canada; 4Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; 5Division of Endocrinology, Western University, London, Ontario, Canada; 6Women’s College Hospital, Toronto, Ontario, Canada; 7Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; 8Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 9Division of Medicine, Toronto General Hospital, Toronto, Ontario, Canada and 10Division of Rheumatology, McMaster University, Hamilton, Ontario, Canada
Knowing a person’s fracture risk according to their kidney function, gender, and age may influence clinical management and decision-making. Using healthcare databases from Ontario, Canada, we conducted a cohort study of 679,114 adults of 40 years and over (mean age 62 years) stratified at cohort entry by estimated glomerular filtration rate ((eGFR) 60 and over, 45–59, 30–44, 15–29, and under 15 ml/min per 1.73 m2), gender, and age (40–65 and over 65 years). The primary outcome was the 3-year cumulative incidence of fracture (proportion of adults who fractured (hip, forearm, pelvis, or proximal humerus) at least once within 3-years of follow-up). Additional analyses examined the fracture incidence per 1000 person-years, hip fracture alone, stratification by prior fracture, stratification by eGFR and proteinuria, and 3-year cumulative incidence of falls with hospitalization. The 3-year cumulative incidence of fracture significantly increased in a graded manner in adults with a lower eGFR for both genders and both age groups. The 3-year cumulative incidence of fracture in women over 65 years of age across the 5 eGFR groups were 4.3%, 5.8%, 6.5%, 7.8%, and 9.6%, respectively. Corresponding estimates for men over 65 years were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. Similar graded relationships were found for falls with hospitalization and additional analyses. Thus, many adults with chronic kidney disease will fall and fracture. Results can be used for prognostication and guidance of sample size requirements for fracture prevention trials. Kidney International (2014) 86, 810–818; doi:10.1038/ki.2013.547; published online 15 January 2014 KEYWORDS: bone; chronic kidney disease; dialysis
Correspondence: Amit X. Garg, London Kidney Clinical Research Unit, London Health Sciences Centre, Room ELL-101, Westminster, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada. E-mail: [email protected] Received 2 August 2013; revised 12 October 2013; accepted 14 November 2013; published online 15 January 2014 810
The prevalence of chronic kidney disease (CKD) is increasing, with estimates ranging from 23% to 36% in older adults (X64 years).1 Bone fractures are an important outcome in adults with CKD and they can result in morbidity, high economic costs, and mortality.2–6 Bone changes that occur in CKD are well described and may increase fracture risk.7–12 In addition, many individuals with CKD are frail and prone to falling, which may also predispose them to suffer a fracture.13,14 It is well accepted that individuals with end-stage renal disease are at an increased fracture risk;15–17 therefore, more recent epidemiological studies have aimed to establish whether less severe forms of CKD are independently associated with a higher fracture risk.18,19 Compared with normal kidney function, moderate to severe decrements in kidney function (estimated glomerular filtration rate (eGFR) 15–60 ml/min per 1.73 m2) may be associated with a 1.5- to 3-fold higher risk of fracture, although this relationship has not been consistent in the literature.13,19–23 Although knowledge of whether CKD is independently associated with fracture is interesting from an epidemiological perspective, it is clinically important to know how likely a person is to suffer a fracture according to kidney function, sex, and age. This information is useful for clinical prognostication and to guide sample size requirements for future fracture prevention trials. A detailed review of bibliographic databases (PubMed and EMBASE) found limited studies that provided a reliable incidence of fracture according to these strata. One study did report the incidence of fracture stratified by kidney function, sex, and age; however, individuals with an eGFRo15 ml/min per 1.73 m2 were excluded, and the study defined CKD stage by a single eGFR measurement.18 We conducted this study to provide clinicians with estimates of fracture risk (hip, forearm, pelvis, or proximal humerus) and fall risk with hospitalization according to the level of kidney function, sex, and age, and we expressed the results in a manner that will help patients clearly understand their fracture risk. Kidney International (2014) 86, 810–818
clinical investigation
KL Naylor et al.: Fracture in chronic kidney disease
RESULTS Baseline characteristics
We included 679,114 Ontario residents in the primary cohort, who met the inclusion and exclusion criteria (Figure 1). Approximately 16% (n ¼ 107,641) of adults aged X40 years had an eGFRo60 ml/min per 1.73 m2 (Table 1). Of those with an eGFRo15 ml/min per 1.73 m2, 91.7% (n ¼ 10,181) were on dialysis. Individuals with an eGFRo60 versus X60 ml/min per 1.73 m2 were significantly older (75 vs. 60 years) but were not significantly more likely to be women (57% vs. 54%). With regard to comorbidities, those with an eGFRo60 versus X60 ml/min per 1.73 m2 were significantly more likely to have diabetes (38.7% vs. 28.4%) and hypertension (77.7% vs. 46.4%). Individuals with an eGFRo60 vs X60 ml/min per 1.73 m2 were significantly more likely to have a history of fracture (composite of proximal humerus, forearm, pelvis, and hip) in the 5 years before study entry (4.2% vs. 1.9%). Over 3 years, the total person-years of follow-up in those with an eGFRX60 ml/min per 1.73 m2 was 1,681,490 personyears, and in the remaining eGFR strata were 171,889 (45–59), 74,792 (30–44), 21,703 (15–29), and 24,864 (o15) person-years, respectively. Of the 679,114 adults who were followed up, 31,666 (4.7%) died (2.7% with an eGFRX60 ml/min per 1.73 m2, and 8.9%, 15.2%, 24.3%, and 39.7% with an eGFR of 45–59, 30–44, 15–29, and o15, respectively). A total of 13,551 (2.0%) individuals experienced a fracture event during the 3 years of follow-up. Primary results
The 3-year cumulative incidence of fracture (proximal humerus, forearm, pelvis, and hip) is presented in Figure 2 (proportion of adults who suffered a fracture at least once in 3 years, where patients who died without a defining fracture were retained in the analysis and assumed to remain fracture free). This incidence increased in a graded manner in groups of adults with a lower level of eGFR for both men and women for both age groups (P for trend o0.0001). For example, the 3-year cumulative incidence of fracture in women aged 465 years across the five eGFR groups were 4.3% (95% confidence interval (CI), 4.2–4.4), 5.8% (95% CI, 5.5–6.0), 6.5% (95% CI, 6.1–6.9), 7.8% (95% CI, 7.0–8.6), and 9.6% (95% CI, 8.6–10.7). Corresponding estimates for men aged 465 years were 1.6% (95% CI, 1.6–1.7), 2.0% (95% CI, 1.9–2.2), 2.7% (95% CI, 2.4–3.1), 3.8% (95% CI, 3.2–4.6), and 5.0% (95% CI, 4.4–5.7). Phrased another way, 1 in 10 women and 1 in 20 men who were 465 years with an eGFRo15 ml/min per 1.73 m2 experienced at least one fracture in the subsequent 3 years. Individuals aged 465 versus 40–65 years were significantly more likely to suffer a fracture across all eGFR groups (Po0.05). Additional analyses
The 3-year incidence rate of fracture per 1000 person-years stratified by kidney function, sex, and age is presented in Table 2. As with the 3-year cumulative incidence, the 3-year Kidney International (2014) 86, 810–818
798,969 Individuals with a stable estimated glomerular filtration rate or chronic dialysis 179 Individuals excluded due to invalid health identification number
798,790 Individuals with valid health identification number
119,676 Excluded: 111,890 65 Age 40–65
http://www.kidney-international.org & 2014 International Society of Nephrology
The three-year incidence of fracture in chronic kidney disease Kyla L. Naylor1,2, Eric McArthur3, William D. Leslie4, Lisa-Ann Fraser5, Sophie A. Jamal6, Suzanne M. Cadarette3,7, Jennie G. Pouget8, Charmaine E. Lok9, Anthony B. Hodsman1, Jonathan D. Adachi10 and Amit X. Garg1,2,3 1
Division of Nephrology, Western University, London, Ontario, Canada; 2Department of Epidemiology and Biostatistics, Western University, London, Ontario, Canada; 3Institute for Clinical Evaluative Sciences (ICES), London, Ontario, Canada; 4Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada; 5Division of Endocrinology, Western University, London, Ontario, Canada; 6Women’s College Hospital, Toronto, Ontario, Canada; 7Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada; 8Department of Medicine, University of Toronto, Toronto, Ontario, Canada; 9Division of Medicine, Toronto General Hospital, Toronto, Ontario, Canada and 10Division of Rheumatology, McMaster University, Hamilton, Ontario, Canada
Knowing a person’s fracture risk according to their kidney function, gender, and age may influence clinical management and decision-making. Using healthcare databases from Ontario, Canada, we conducted a cohort study of 679,114 adults of 40 years and over (mean age 62 years) stratified at cohort entry by estimated glomerular filtration rate ((eGFR) 60 and over, 45–59, 30–44, 15–29, and under 15 ml/min per 1.73 m2), gender, and age (40–65 and over 65 years). The primary outcome was the 3-year cumulative incidence of fracture (proportion of adults who fractured (hip, forearm, pelvis, or proximal humerus) at least once within 3-years of follow-up). Additional analyses examined the fracture incidence per 1000 person-years, hip fracture alone, stratification by prior fracture, stratification by eGFR and proteinuria, and 3-year cumulative incidence of falls with hospitalization. The 3-year cumulative incidence of fracture significantly increased in a graded manner in adults with a lower eGFR for both genders and both age groups. The 3-year cumulative incidence of fracture in women over 65 years of age across the 5 eGFR groups were 4.3%, 5.8%, 6.5%, 7.8%, and 9.6%, respectively. Corresponding estimates for men over 65 years were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. Similar graded relationships were found for falls with hospitalization and additional analyses. Thus, many adults with chronic kidney disease will fall and fracture. Results can be used for prognostication and guidance of sample size requirements for fracture prevention trials. Kidney International (2014) 86, 810–818; doi:10.1038/ki.2013.547; published online 15 January 2014 KEYWORDS: bone; chronic kidney disease; dialysis
Correspondence: Amit X. Garg, London Kidney Clinical Research Unit, London Health Sciences Centre, Room ELL-101, Westminster, 800 Commissioners Road East, London, Ontario N6A 4G5, Canada. E-mail: [email protected] Received 2 August 2013; revised 12 October 2013; accepted 14 November 2013; published online 15 January 2014 810
The prevalence of chronic kidney disease (CKD) is increasing, with estimates ranging from 23% to 36% in older adults (X64 years).1 Bone fractures are an important outcome in adults with CKD and they can result in morbidity, high economic costs, and mortality.2–6 Bone changes that occur in CKD are well described and may increase fracture risk.7–12 In addition, many individuals with CKD are frail and prone to falling, which may also predispose them to suffer a fracture.13,14 It is well accepted that individuals with end-stage renal disease are at an increased fracture risk;15–17 therefore, more recent epidemiological studies have aimed to establish whether less severe forms of CKD are independently associated with a higher fracture risk.18,19 Compared with normal kidney function, moderate to severe decrements in kidney function (estimated glomerular filtration rate (eGFR) 15–60 ml/min per 1.73 m2) may be associated with a 1.5- to 3-fold higher risk of fracture, although this relationship has not been consistent in the literature.13,19–23 Although knowledge of whether CKD is independently associated with fracture is interesting from an epidemiological perspective, it is clinically important to know how likely a person is to suffer a fracture according to kidney function, sex, and age. This information is useful for clinical prognostication and to guide sample size requirements for future fracture prevention trials. A detailed review of bibliographic databases (PubMed and EMBASE) found limited studies that provided a reliable incidence of fracture according to these strata. One study did report the incidence of fracture stratified by kidney function, sex, and age; however, individuals with an eGFRo15 ml/min per 1.73 m2 were excluded, and the study defined CKD stage by a single eGFR measurement.18 We conducted this study to provide clinicians with estimates of fracture risk (hip, forearm, pelvis, or proximal humerus) and fall risk with hospitalization according to the level of kidney function, sex, and age, and we expressed the results in a manner that will help patients clearly understand their fracture risk. Kidney International (2014) 86, 810–818
clinical investigation
KL Naylor et al.: Fracture in chronic kidney disease
RESULTS Baseline characteristics
We included 679,114 Ontario residents in the primary cohort, who met the inclusion and exclusion criteria (Figure 1). Approximately 16% (n ¼ 107,641) of adults aged X40 years had an eGFRo60 ml/min per 1.73 m2 (Table 1). Of those with an eGFRo15 ml/min per 1.73 m2, 91.7% (n ¼ 10,181) were on dialysis. Individuals with an eGFRo60 versus X60 ml/min per 1.73 m2 were significantly older (75 vs. 60 years) but were not significantly more likely to be women (57% vs. 54%). With regard to comorbidities, those with an eGFRo60 versus X60 ml/min per 1.73 m2 were significantly more likely to have diabetes (38.7% vs. 28.4%) and hypertension (77.7% vs. 46.4%). Individuals with an eGFRo60 vs X60 ml/min per 1.73 m2 were significantly more likely to have a history of fracture (composite of proximal humerus, forearm, pelvis, and hip) in the 5 years before study entry (4.2% vs. 1.9%). Over 3 years, the total person-years of follow-up in those with an eGFRX60 ml/min per 1.73 m2 was 1,681,490 personyears, and in the remaining eGFR strata were 171,889 (45–59), 74,792 (30–44), 21,703 (15–29), and 24,864 (o15) person-years, respectively. Of the 679,114 adults who were followed up, 31,666 (4.7%) died (2.7% with an eGFRX60 ml/min per 1.73 m2, and 8.9%, 15.2%, 24.3%, and 39.7% with an eGFR of 45–59, 30–44, 15–29, and o15, respectively). A total of 13,551 (2.0%) individuals experienced a fracture event during the 3 years of follow-up. Primary results
The 3-year cumulative incidence of fracture (proximal humerus, forearm, pelvis, and hip) is presented in Figure 2 (proportion of adults who suffered a fracture at least once in 3 years, where patients who died without a defining fracture were retained in the analysis and assumed to remain fracture free). This incidence increased in a graded manner in groups of adults with a lower level of eGFR for both men and women for both age groups (P for trend o0.0001). For example, the 3-year cumulative incidence of fracture in women aged 465 years across the five eGFR groups were 4.3% (95% confidence interval (CI), 4.2–4.4), 5.8% (95% CI, 5.5–6.0), 6.5% (95% CI, 6.1–6.9), 7.8% (95% CI, 7.0–8.6), and 9.6% (95% CI, 8.6–10.7). Corresponding estimates for men aged 465 years were 1.6% (95% CI, 1.6–1.7), 2.0% (95% CI, 1.9–2.2), 2.7% (95% CI, 2.4–3.1), 3.8% (95% CI, 3.2–4.6), and 5.0% (95% CI, 4.4–5.7). Phrased another way, 1 in 10 women and 1 in 20 men who were 465 years with an eGFRo15 ml/min per 1.73 m2 experienced at least one fracture in the subsequent 3 years. Individuals aged 465 versus 40–65 years were significantly more likely to suffer a fracture across all eGFR groups (Po0.05). Additional analyses
The 3-year incidence rate of fracture per 1000 person-years stratified by kidney function, sex, and age is presented in Table 2. As with the 3-year cumulative incidence, the 3-year Kidney International (2014) 86, 810–818
798,969 Individuals with a stable estimated glomerular filtration rate or chronic dialysis 179 Individuals excluded due to invalid health identification number
798,790 Individuals with valid health identification number
119,676 Excluded: 111,890 65 Age 40–65
