Arch Osteoporos (2014) 8:169 DOI 10.1007/s11657-013-0169-5
ORIGINAL ARTICLE
Glucocorticoids predict 10-year fragility fracture risk in a population-based ambulatory cohort of men and women: Canadian Multicentre Osteoporosis Study (CaMos) George Ioannidis & Shelley Pallan & Alexandra Papaioannou & Manisha Mulgund & Lorena Rios & Jinhui Ma & Lehana Thabane & Kenneth S. Davison & Robert G. Josse & Christopher S. Kovacs & Nancy Kreiger & Wojciech P. Olszynski & Jerilynn C. Prior & Tanveer Towheed & Jonathan D. Adachi & CaMos Research Group
Received: 1 August 2013 / Accepted: 16 December 2013 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary We determined the prospective 10-year association among incident fragility fractures and four glucocorticoid (GC) treatment groups (Never GC, Prior GC, Baseline GC, and Ever GC). Results showed that GC treatment is associated with increased 10-year incident fracture risk in ambulatory men and women across Canada. Purpose Using the Canadian Multicentre Osteoporosis Study dataset, we determined the prospective 10-year association between incident fragility fractures and GC treatment.
Methods We conducted a 10-year prospective observational cohort study at nine sites across Canada. A total of 9,263 ambulatory men and women 25 years of age and older were included in the analysis. Multivariable Cox proportional hazards analyses were conducted to determine the relationship among GC treatment groups in four levels that included Never GC, Prior GC, Baseline GC, and Ever GC (combined baseline and prior groups) and time to fracture. Results In each of the Never GC, Prior GC, Baseline GC, and Ever GC treatment groups, the number of participants
G. Ioannidis (*) : A. Papaioannou : J. D. Adachi Faculty of Medicine, McMaster University, Hamilton, ON, Canada e-mail: [email protected]
K. S. Davison University of Victoria, Victoria, BC, Canada
J. D. Adachi e-mail: [email protected]
R. G. Josse Department of Medicine, University of Toronto, Toronto, ON, Canada
S. Pallan Department of Medicine, McMaster University, Hamilton, ON, Canada M. Mulgund Department of Rheumatology, McMaster University, Hamilton, ON, Canada L. Rios Medicina Interna, Hospital Clinico FUSAT, Rancagua, VI Region, Chile J. Ma Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada L. Thabane Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
C. S. Kovacs Faculty of Medicine- Endocrinology, Memorial University, St. John’s, Newfoundland and Labrador, Canada N. Kreiger Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada W. P. Olszynski Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada J. C. Prior Department of Medicine/Endocrinology, University of British Columbia, British Columbia, Canada T. Towheed Department of Medicine, Queen’s University, Kingston, ON, Canada
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were 8,832 (95.4 %), 303 (3.3 %), 128 (1.4 %), and 431 (4.7 %), respectively. Of the 9,263 individuals enrolled, incident fragility non-spine, hip, spine, and any fractures were experienced by a total of 896 (9.67 %), 157 (1.69 %), 130 (1.40 %), and 1,102 (11.90 %) over 10-years, respectively. For men and women combined, prior GC treatment was associated with a higher hazard ratio (HR) for time to incident non-vertebral (HR=1.5, 95 % confidence interval [CI]=1.1, 2.0), hip (HR=2.1, 95 % CI=1.1, 4.0), and any fracture (HR=1.4, 95 % CI=1.0, 1.8) compared with never GC treatment. Conclusions GC treatment is associated with increased 10-year incident fracture risk; this highlights the importance of considering therapy to prevent GC-induced fractures for patients who are using GC for various medical conditions. Keywords Fracture risk . Fragility fractures . Glucocorticoids
Introduction Glucocorticoids (GC) are prescribed for a variety of inflammatory disorders including chronic obstructive pulmonary disease, rheumatologic and skin conditions [1], as well as for transplantation and some infectious diseases. GC therapy suppresses osteoblast function, increases bone resorption, decreases calcium gut absorption, and suppresses endogenous gonadal steroids, all of which lead to increased bone loss [2, 3]. Major adverse effects of prolonged GC use are decreased bone mineral density and increased fracture risk [4]. There is evidence that after GC initiation, bone loss occurs quickly within the first 3 to 12 months of beginning therapy and that the risk of GC-induced osteoporosis increases as the dose increases [4, 5]. However, low doses of GC (3 drinks/day), age (years), femoral neck bone mineral density T score, number of co-morbid conditions (including coronary artery disease or acute myocardial infarction, stroke, chronic obstructive lung disease, rheumatoid arthritis, liver disease, diabetes, kidney disease, breast cancer, uterine cancer, prostate cancer, and inflammatory bowel disease), and body mass index (kilogram per square meter). The covariates were selected a priori for their potential association with fractures and GC use. To assess the impact of individuals who were lost to follow-up prior to the 10-year follow-up period on the GC variables (Baseline GC, Prior GC, and Never GC), a sensitivity analysis was conducted for individuals who were followed for the entire 10-year period. The proportionality assumption was assessed using martingale residuals. All statistical analyses were performed using the SAS/STAT (version 9.2; SAS Institute, Cary, NC, USA) software package running on Windows XP Professional. The criterion for statistical significance was set at α=0.05.
Results A total of 9,263 participants, 2,819 men and 6,444 women ages 25 and older, participated in this 10-year prospective study (Fig. 1). Most of the participants in the study (>95 %) had never used GC at baseline. Only 0.2 % of the men and 25 % of the women were on some form of antiresorptive therapy at the start of the study. Baseline participant characteristics are shown in detail in Table 1. During the 10-year study period, more fractures occurred in those who reported treatment with GC as compared with the Never GC group. Fractures occurred for a total of 896 (9.67 %) of the cohort including non-vertebral fracture in 157 (1.69 %), hip fractures in 130 (1.40 %), and the total for any fractures was 1,102 (11.90 %) during the 10-year study period. The absolute fracture rate, for any fracture, was approximately 21 and 23 % of participants (men and women combined) for the Prior GC and Baseline GC groups compared with a rate of approximately 11 % in the Never GC group (Table 2).
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Arch Osteoporos (2014) 8:169 CaMos participants N=9423 Participants without a follow-up visit N=160 Participants with at least one year of follow-up N=9263
Men N=2819
Women N=6444
Sensitivity Analysis
Sensitivity Analysis
Men who completed 10 years of follow-up N=1778
Women who completed 10 years of follow-up N=4469
Fig. 1 Participants selection process of Canadian Multicentre Osteoporosis Study participants 25 years and older
Table 3 summarizes the multivariable Cox proportional hazards analyses expressed as adjusted hazard ratios and 95 % confidence intervals among those reporting Baseline GC, Prior GC, and never treatment with GC. Results showed that prior use of GC was associated with a higher hazard ratio for time to new fragility fracture at the non-spine, hip, and any fracture region compared with those who had never taken GC. Inconclusive results were found for Baseline GC users (all three groups and all fracture types) versus never GC users.
Table 1 Characteristics at baseline for community-dwelling randomly selected Canadian Multicentre Osteoporosis Study participants (age 25 and older) by categories of glucocorticoid (GC) therapy
a
See text for explanation
The sensitivity analysis including only participants that completed all 10 years of follow-up showed similar results for the combined and men alone analyses. However, for women, prior use of GC was associated with a higher hazard ratio for time to new fragility fracture at the hip compared with those who had never taken GC (HR 2.95; 95 % CI: 1.31, 6.67). In our primary analysis (Table 3), the results were inconclusive for this comparison (HR=1.91; 95 % CI: 0.91, 3.99). Figure 2a, b, and c display the adjusted hazard ratio and 95 % confidence interval among GC status (two levels: Ever GC and Never GC) and time to each fracture type for the whole adult cohort, men and women, respectively. The ever GC group showed a higher rate of non-spine fracture and any fracture in the whole group (Fig. 1a). Inconclusive results were obtained for the hip and spine fractures in the combined group. In the analysis of men and women separately, significantly more non-spine fractures occurred in the Ever GC group as compared with the Never GC group (Fig. 2b and c).
Discussion Our study is the first prospective population-based cohort study to examine the persistent effects of baseline or prior to baseline GC therapy on fracture risk. These data show that over 10 years, prior use of GC for a month or more significantly increased the risk of incident fragility fractures including those at the hip and at any site. This clinically meaningful increase in fracture risk in those who had previously been treated with GC (Prior GC) may indicate that an elevated fracture risk persists, although at a lower level, even after the discontinuation of GC. Although the exact determinants of elevated fracture risk in the prior GC group could not be
Never GC N=8,832 Number (%) Participants Men Women Antiresportive medicationsa Prevalent fragility fractures Smoking status Alcohol≥3 drinks/day Mean (SD) Age (years) T score femoral neck Number of other disease conditions Height (cm) Weight (kg) Body mass index (kg/m2)
Prior GC N=303
Baseline GC N=128
2,734 (31.0) 6,098 (69.0) 1,508 (17.1) 1,825 (20.7) 1,431 (16.2) 232 (2.6)
51 (16.8) 252 (83.2) 73 (24.1) 86 (28.4) 27 (8.9) 5 (1.7)
34 (26.6) 94 (73.4) 24 (26.6) 51 (39.8) 14 (10.9) 0 (0.0)
61.8 (13.4) −0.93 (1.08)
64.5 (11.6) −1.27 (1.0)
69.7 (10.4) −1.59 (1.07)
0.4 (0.7) 164.0 (9.3) 72.7 (15.2) 27.0 (4.8)
0.9 (1.0) 161.3 (8.3) 71.6 (15.2) 27.5 (5.4)
1.1 (1.1) 162.4 (8.8) 69.0 (15.6) 26.2 (5.5)
Arch Osteoporos (2014) 8:169
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Table 2 Absolute 10-year incident clinical fragility fractures (Fx) rates in the adult Canadian Multicentre Osteoporosis Study cohort by categories of glucocorticoid (GC) therapy Never GC N (%)
Prior GC N (%)
Baseline GC N (%)
Combined (men, women) Incident non-spine Fx Incident hip Fx Incident spine Fx Any Fx Men Incident non-spine Fx Incident hip Fx Incident spine Fx
8,832 817 (9.3) 140 (1.6) 117 (1.3) 1,009 (11.4) 2,734 136 (5.0) 29 (1.1) 13 (0.5)
303 55 (18.2) 14 (4.6) 6 (2.0) 64 (21.1) 51 9 (17.7) 3 (5.9) 2 (3.9)
128 24 (18.8) 3 (2.3) 7 (5.5) 29 (22.7) 34 2 (5.9) 0 (0.0) 0 (0.0)
Any Fx Women Incident non-spine Fx Incident hip Fx Incident spine Fx Any Fx
170 (6.2) 6,098 681 (11.2) 111 (1.8) 104 (1.7) 839 (13.8)
10 (19.6) 252 46 (18.3) 11 (4.4) 4 (1.6) 54 (21.4)
2 (5.9) 94 22 (23.4) 3 (3.2) 7 (7.5) 27 (28.7)
P values Never vs. Prior/Baseline GCa
P values Prior vs. Baseline GCa
ORIGINAL ARTICLE
Glucocorticoids predict 10-year fragility fracture risk in a population-based ambulatory cohort of men and women: Canadian Multicentre Osteoporosis Study (CaMos) George Ioannidis & Shelley Pallan & Alexandra Papaioannou & Manisha Mulgund & Lorena Rios & Jinhui Ma & Lehana Thabane & Kenneth S. Davison & Robert G. Josse & Christopher S. Kovacs & Nancy Kreiger & Wojciech P. Olszynski & Jerilynn C. Prior & Tanveer Towheed & Jonathan D. Adachi & CaMos Research Group
Received: 1 August 2013 / Accepted: 16 December 2013 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary We determined the prospective 10-year association among incident fragility fractures and four glucocorticoid (GC) treatment groups (Never GC, Prior GC, Baseline GC, and Ever GC). Results showed that GC treatment is associated with increased 10-year incident fracture risk in ambulatory men and women across Canada. Purpose Using the Canadian Multicentre Osteoporosis Study dataset, we determined the prospective 10-year association between incident fragility fractures and GC treatment.
Methods We conducted a 10-year prospective observational cohort study at nine sites across Canada. A total of 9,263 ambulatory men and women 25 years of age and older were included in the analysis. Multivariable Cox proportional hazards analyses were conducted to determine the relationship among GC treatment groups in four levels that included Never GC, Prior GC, Baseline GC, and Ever GC (combined baseline and prior groups) and time to fracture. Results In each of the Never GC, Prior GC, Baseline GC, and Ever GC treatment groups, the number of participants
G. Ioannidis (*) : A. Papaioannou : J. D. Adachi Faculty of Medicine, McMaster University, Hamilton, ON, Canada e-mail: [email protected]
K. S. Davison University of Victoria, Victoria, BC, Canada
J. D. Adachi e-mail: [email protected]
R. G. Josse Department of Medicine, University of Toronto, Toronto, ON, Canada
S. Pallan Department of Medicine, McMaster University, Hamilton, ON, Canada M. Mulgund Department of Rheumatology, McMaster University, Hamilton, ON, Canada L. Rios Medicina Interna, Hospital Clinico FUSAT, Rancagua, VI Region, Chile J. Ma Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada L. Thabane Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada
C. S. Kovacs Faculty of Medicine- Endocrinology, Memorial University, St. John’s, Newfoundland and Labrador, Canada N. Kreiger Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada W. P. Olszynski Department of Medicine, University of Saskatchewan, Saskatoon, SK, Canada J. C. Prior Department of Medicine/Endocrinology, University of British Columbia, British Columbia, Canada T. Towheed Department of Medicine, Queen’s University, Kingston, ON, Canada
169, Page 2 of 8
were 8,832 (95.4 %), 303 (3.3 %), 128 (1.4 %), and 431 (4.7 %), respectively. Of the 9,263 individuals enrolled, incident fragility non-spine, hip, spine, and any fractures were experienced by a total of 896 (9.67 %), 157 (1.69 %), 130 (1.40 %), and 1,102 (11.90 %) over 10-years, respectively. For men and women combined, prior GC treatment was associated with a higher hazard ratio (HR) for time to incident non-vertebral (HR=1.5, 95 % confidence interval [CI]=1.1, 2.0), hip (HR=2.1, 95 % CI=1.1, 4.0), and any fracture (HR=1.4, 95 % CI=1.0, 1.8) compared with never GC treatment. Conclusions GC treatment is associated with increased 10-year incident fracture risk; this highlights the importance of considering therapy to prevent GC-induced fractures for patients who are using GC for various medical conditions. Keywords Fracture risk . Fragility fractures . Glucocorticoids
Introduction Glucocorticoids (GC) are prescribed for a variety of inflammatory disorders including chronic obstructive pulmonary disease, rheumatologic and skin conditions [1], as well as for transplantation and some infectious diseases. GC therapy suppresses osteoblast function, increases bone resorption, decreases calcium gut absorption, and suppresses endogenous gonadal steroids, all of which lead to increased bone loss [2, 3]. Major adverse effects of prolonged GC use are decreased bone mineral density and increased fracture risk [4]. There is evidence that after GC initiation, bone loss occurs quickly within the first 3 to 12 months of beginning therapy and that the risk of GC-induced osteoporosis increases as the dose increases [4, 5]. However, low doses of GC (3 drinks/day), age (years), femoral neck bone mineral density T score, number of co-morbid conditions (including coronary artery disease or acute myocardial infarction, stroke, chronic obstructive lung disease, rheumatoid arthritis, liver disease, diabetes, kidney disease, breast cancer, uterine cancer, prostate cancer, and inflammatory bowel disease), and body mass index (kilogram per square meter). The covariates were selected a priori for their potential association with fractures and GC use. To assess the impact of individuals who were lost to follow-up prior to the 10-year follow-up period on the GC variables (Baseline GC, Prior GC, and Never GC), a sensitivity analysis was conducted for individuals who were followed for the entire 10-year period. The proportionality assumption was assessed using martingale residuals. All statistical analyses were performed using the SAS/STAT (version 9.2; SAS Institute, Cary, NC, USA) software package running on Windows XP Professional. The criterion for statistical significance was set at α=0.05.
Results A total of 9,263 participants, 2,819 men and 6,444 women ages 25 and older, participated in this 10-year prospective study (Fig. 1). Most of the participants in the study (>95 %) had never used GC at baseline. Only 0.2 % of the men and 25 % of the women were on some form of antiresorptive therapy at the start of the study. Baseline participant characteristics are shown in detail in Table 1. During the 10-year study period, more fractures occurred in those who reported treatment with GC as compared with the Never GC group. Fractures occurred for a total of 896 (9.67 %) of the cohort including non-vertebral fracture in 157 (1.69 %), hip fractures in 130 (1.40 %), and the total for any fractures was 1,102 (11.90 %) during the 10-year study period. The absolute fracture rate, for any fracture, was approximately 21 and 23 % of participants (men and women combined) for the Prior GC and Baseline GC groups compared with a rate of approximately 11 % in the Never GC group (Table 2).
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Arch Osteoporos (2014) 8:169 CaMos participants N=9423 Participants without a follow-up visit N=160 Participants with at least one year of follow-up N=9263
Men N=2819
Women N=6444
Sensitivity Analysis
Sensitivity Analysis
Men who completed 10 years of follow-up N=1778
Women who completed 10 years of follow-up N=4469
Fig. 1 Participants selection process of Canadian Multicentre Osteoporosis Study participants 25 years and older
Table 3 summarizes the multivariable Cox proportional hazards analyses expressed as adjusted hazard ratios and 95 % confidence intervals among those reporting Baseline GC, Prior GC, and never treatment with GC. Results showed that prior use of GC was associated with a higher hazard ratio for time to new fragility fracture at the non-spine, hip, and any fracture region compared with those who had never taken GC. Inconclusive results were found for Baseline GC users (all three groups and all fracture types) versus never GC users.
Table 1 Characteristics at baseline for community-dwelling randomly selected Canadian Multicentre Osteoporosis Study participants (age 25 and older) by categories of glucocorticoid (GC) therapy
a
See text for explanation
The sensitivity analysis including only participants that completed all 10 years of follow-up showed similar results for the combined and men alone analyses. However, for women, prior use of GC was associated with a higher hazard ratio for time to new fragility fracture at the hip compared with those who had never taken GC (HR 2.95; 95 % CI: 1.31, 6.67). In our primary analysis (Table 3), the results were inconclusive for this comparison (HR=1.91; 95 % CI: 0.91, 3.99). Figure 2a, b, and c display the adjusted hazard ratio and 95 % confidence interval among GC status (two levels: Ever GC and Never GC) and time to each fracture type for the whole adult cohort, men and women, respectively. The ever GC group showed a higher rate of non-spine fracture and any fracture in the whole group (Fig. 1a). Inconclusive results were obtained for the hip and spine fractures in the combined group. In the analysis of men and women separately, significantly more non-spine fractures occurred in the Ever GC group as compared with the Never GC group (Fig. 2b and c).
Discussion Our study is the first prospective population-based cohort study to examine the persistent effects of baseline or prior to baseline GC therapy on fracture risk. These data show that over 10 years, prior use of GC for a month or more significantly increased the risk of incident fragility fractures including those at the hip and at any site. This clinically meaningful increase in fracture risk in those who had previously been treated with GC (Prior GC) may indicate that an elevated fracture risk persists, although at a lower level, even after the discontinuation of GC. Although the exact determinants of elevated fracture risk in the prior GC group could not be
Never GC N=8,832 Number (%) Participants Men Women Antiresportive medicationsa Prevalent fragility fractures Smoking status Alcohol≥3 drinks/day Mean (SD) Age (years) T score femoral neck Number of other disease conditions Height (cm) Weight (kg) Body mass index (kg/m2)
Prior GC N=303
Baseline GC N=128
2,734 (31.0) 6,098 (69.0) 1,508 (17.1) 1,825 (20.7) 1,431 (16.2) 232 (2.6)
51 (16.8) 252 (83.2) 73 (24.1) 86 (28.4) 27 (8.9) 5 (1.7)
34 (26.6) 94 (73.4) 24 (26.6) 51 (39.8) 14 (10.9) 0 (0.0)
61.8 (13.4) −0.93 (1.08)
64.5 (11.6) −1.27 (1.0)
69.7 (10.4) −1.59 (1.07)
0.4 (0.7) 164.0 (9.3) 72.7 (15.2) 27.0 (4.8)
0.9 (1.0) 161.3 (8.3) 71.6 (15.2) 27.5 (5.4)
1.1 (1.1) 162.4 (8.8) 69.0 (15.6) 26.2 (5.5)
Arch Osteoporos (2014) 8:169
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Table 2 Absolute 10-year incident clinical fragility fractures (Fx) rates in the adult Canadian Multicentre Osteoporosis Study cohort by categories of glucocorticoid (GC) therapy Never GC N (%)
Prior GC N (%)
Baseline GC N (%)
Combined (men, women) Incident non-spine Fx Incident hip Fx Incident spine Fx Any Fx Men Incident non-spine Fx Incident hip Fx Incident spine Fx
8,832 817 (9.3) 140 (1.6) 117 (1.3) 1,009 (11.4) 2,734 136 (5.0) 29 (1.1) 13 (0.5)
303 55 (18.2) 14 (4.6) 6 (2.0) 64 (21.1) 51 9 (17.7) 3 (5.9) 2 (3.9)
128 24 (18.8) 3 (2.3) 7 (5.5) 29 (22.7) 34 2 (5.9) 0 (0.0) 0 (0.0)
Any Fx Women Incident non-spine Fx Incident hip Fx Incident spine Fx Any Fx
170 (6.2) 6,098 681 (11.2) 111 (1.8) 104 (1.7) 839 (13.8)
10 (19.6) 252 46 (18.3) 11 (4.4) 4 (1.6) 54 (21.4)
2 (5.9) 94 22 (23.4) 3 (3.2) 7 (7.5) 27 (28.7)
P values Never vs. Prior/Baseline GCa
P values Prior vs. Baseline GCa
