1. Epidemiology and Global Health
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Epidemiological transition to mortality and refracture following an initial fracture

  1. Thao Phuong Ho-Le  Is a corresponding author
  2. Thach S Tran
  3. Dana Bliuc
  4. Hanh M Pham
  5. Steven A Frost
  6. Jacqueline R Center
  7. John A Eisman
  8. Tuan V Nguyen  Is a corresponding author
  1. Healthy Ageing Theme, Garvan Institute of Medical Research, Australia
  2. Swinburne University of Technology, Australia
  3. Faculty of Engineering and Information Technology, Hatinh University, Viet Nam
  4. St Vincent Clinical School, UNSW Sydney, Australia
  5. Fertility Department, Andrology and Fertility Hospital of Hanoi, Viet Nam
  6. School of Medicine Sydney, University of Notre Dame Australia, Australia
  7. School of Biomedical Engineering, University of Technology, Australia
Research Article
Cite this article as: eLife 2021;10:e61142 doi: 10.7554/eLife.61142
4 figures, 7 tables and 4 additional files

Figures

Flowchart of recruitment and follow-up.
Predictors of transition to fracture/refracture (Panel A) and predictors of transition to death (Panel B): hazard ratio and 95% confidence interval from the multistate model, adjusting for age, femoral neck BMD, BMI, history of fall within 12 months, prior fracture, and other comorbidities (cardiovascular disease, cancer, type 2 diabetes, neuromuscular, rheumatoid arthritis, and chronic obstructive pulmonary disease).

Fx, fracture. FNBMD, femoral neck bone mineral density. COPD, chronic obstructive pulmonary disease. Symbol * indicates statistical significance at level of 5% (p<0.05).

Figure 3 with 2 supplements
Adjusted cumulative probability of mortality in women (left panel) and men (right panel) who had stayed in different states of bone health.

There were four potential bone heath states before transiting to state 5 (i.e., mortality): state 1: no fracture (green blue colour area) if the individual entered the study without any osteoporotic fracture; state 2: initial fracture (light blue area) if an individual had sustained a fracture after study entry; state 3: second fracture (purple-orange area) if an individual had suffered a second fracture; and state 4: third and further fractures (red area) if an individual had suffered two or more subsequent fractures during the follow-up period. Risk was estimated for women and men with different BMD profiles (i.e., −1.5 vs −2.5), at the event age of 70 and 80, having all other factors set to the population mean, that is, body mass index = 26.6 kg/m2, no history of fall at baseline, no prior fracture and no comorbidities.

Figure 3—source data 1

Adjusted cumulative probability of mortality in women and men, who had stayed in different states of bone health.

Risk was estimated for women and men with different BMD profiles (i.e.,−1.5 vs −2.5), at the event age of 70 and 80, having all other factors set to the population mean, that is, body massindex = 26.6 kg/m2, no history of fall at baseline, no prior fracture and no comorbidities.

https://cdn.elifesciences.org/articles/61142/elife-61142-fig3-data1-v2.xlsx
Figure 3—figure supplement 1
Adjusted cumulative mortality probability in women (left panel) and men (right panel) by bone health state.

An individual could stay in a state (state 1 to state 4) before transiting to state 5 (i.e., mortality): state 1: no fracture (blue area) if an individual entered the study without any osteoporotic fracture; state 2: initial fracture (light blue area) if an individual had sustained a fracture after study entry; state 3: second fracture (orange area) if an individual had suffered a second fracture; and state 4: third and further fractures (red area) if an individual had suffered two or more subsequent fractures during the follow-up period. Risk was estimated for women and men with different BMD profiles (i.e., T-score = 0, –1.5, and −2.5), at different event ages (60, 70, and 80), with all other factors being at the sample mean, that is, body mass index = 26.6 kg/m2 (equal to mean), no history of fall at baseline, no prior fracture and no comorbidities.

Figure 3—figure supplement 1—source data 1

Adjusted cumulative mortality probability in women and men by bone health state.

Risk was estimated for women and men with different BMD profiles (i.e., T-score = 0, –1.5, and −2.5), at different event ages (60, 70, and 80), with all other factors being at the sample mean, that is, body massindex = 26.6 kg/m2 (equal to mean), no history of fall at baseline, no prior fracture and no comorbidities.

https://cdn.elifesciences.org/articles/61142/elife-61142-fig3-figsupp1-data1-v2.xlsx
Figure 3—figure supplement 2
Assessment of goodness-of-fit of the analysis model for each of five heath states: alive and free of fracture, initial fracture, second fracture, third and further fracture, and death.

Grey curve shows the observed prevalence of each heath state while the expected values are shown in dashed black curve with 95% confident interval (dotted grey curves).

Figure 3—figure supplement 2—source data 1

Assessment of goodness-of-fit of the analysis model: Observed and expected prevalences of each heath state.

https://cdn.elifesciences.org/articles/61142/elife-61142-fig3-figsupp2-data1-v2.xlsx
Markovian model of transition between five heath states (e.g., alive without a fracture, initial fracture, second fracture, third and further fractures, and death).

The transition between state r to state s is 'governed' by the instantaneous risk of transition (i.e., intensity) qrs, where r and s represent each of the five health states. At a given time point, for example, a fracture-free individual (state 1) had an instantaneous risk of staying at that state 1 (q11), an instantaneous risks of suffering an initial fracture (q12), and an instantaneous risk of death (q15).

Tables

Table 1
Baseline characteristics and incident illnesses of 2046 women and 1205 men in the Dubbo Osteoporosis Epidemiology Study.
WomenMenP-value
Number of participants20461205
BMI (kg/m2)26.5 (5.1)26.8 (3.9)0.035
FNBMD (g/cm2)0.81 (0.14)0.92 (0.15)<0.001
FNBMD T-score−1.62 (–1.15)−0.99 (–1.22)<0.001
Osteoporosis (n; %)458 (22.4)111 (9.2)<0.001
History of falls (n; %)776 (37.9)317 (26.3)<0.001
Prior fracture since age 50 (n; %)357 (17.5)139 (11.5)<0.001
Cardiovascular disease (n; %)632 (30.9)470 (39.0)<0.001
Bone-unrelated cancer (n; %)174 (8.5)108 (9.0)0.654
Neurological disease (n; %)142 (6.9)69 (5.7)0.175
Rheumatoid arthritis (n; %)84 (4.1)25 (2.1)0.002
Respiratory disease (n; %)221 (10.8)141 (11.7)0.431
Type 2 diabetes (n; %)219 (10.7)158 (13.1)0.038
  1. Notes: Values shown are mean and standard deviation (in brackets), unless otherwise specified. P-values were derived from t-test for continuous variables and from chi-squared test for binary variables. FNBMD, femoral neck bone mineral density.

Table 2
Instantaneous risk of transition between states of bone health for women and men.
Transitional stateWomen: risk (95% CI)Men: risk (95% CI)Hazard ratio for men vs women
(95% CI)
 No Fx → Initial Fx2.7 (2.4–3.0)1.7 (1.4–2.0)0.63 (0.53–0.75)
 Initial Fx → Second Fx4.8 (3.8–6.3)4.1 (2.8–5.9)0.85 (0.61–1.19)
 Second Fx → Third+ Fx6.3 (3.7–10.9)13.3 (6.7–26.1)2.11 (1.13–3.95)
 No Fx → Death1.8 (1.5–2.0)3.2 (2.8–3.7)1.81 (1.55–2.10)
 Initial Fx → Death2.1 (1.5–2.9)5.0 (3.5–7.4)2.40 (1.79–3.21)
 Second Fx → Death2.2 (1.1–4.4)16.5 (8.8–32.9)7.52 (4.33–13.07)
 Third+ Fx → Death12.9 (5.8–28.9)33.9 (11.8–86.2)2.62 (1.17–5.87)
  1. Note: ‘Fx’, fracture. CI, confidence interval. BMD, bone mineral density. BMI, body mass index. See Data Analysis for the definition of ‘instantaneous risk’ (hazard). Risk was estimated for a ‘typical’ man or woman having average BMD, characterized by mean values of predictors as follows: age at event = 70 years, femoral neck bone mineral density T-score = −1.5 (equal to mean), BMI = 26.6 kg/m2 (equal to mean), no history of falls, no prior fracture, no comorbidities. Hazard ratio and 95% confidence interval were derived from the multistate model, adjusting for age, femoral neck BMD, BMI, history of a fall within 12 months, prior fracture, and other comorbidities (cardiovascular disease, cancer, type 2 diabetes, neuromuscular, rheumatoid arthritis, and chronic obstructive pulmonary disease). Bold-face values indicate a statistically significant difference between men and women. In each cell, values are percentage of risk and 95% confident interval (in the brackets).

Table 3
Sojourn time (in years) of women/men with different bone health*.
TransitionT-score = 0T-score = −1.5T-score = −2.5
Women
 No Fx.32.1 (28.2–36.6)22.4 (20.4–24.6)16.9 (15.2–18.7)
 Initial Fx.21.9 (16.7–28.8)14.5 (11.8–17.7)10.1 (8.8–13.4)
 Second Fx.18.5 (10.1–34.0)11.8 (7.6–18.1)8.7 (5.7–13.1)
 Third+ Fx.5.2 (1.7–15.9)7.7 (3.4–17.7)10.0 (4.7–21.5)
Men
 No Fx.25.5 (22.5–28.9)20.4 (18.3–22.8)16.9 (14.8–19.3)
 Initial Fx.15.5 (11.5–20.9)11.0 (8.5–14.3)08.7 (6.6–11.4)
 Second Fx.5.4 (3.0–9.9)3.3 (2.2–5.4)2.4 (1.5–3.9)
 Third+ Fx.2.0 (0.6–7.2)3.0 (1.1–8.2)3.8 (1.5–9.9)
  1. *Time was estimated for women or men with different BMD profiles (i.e., 0, –1.5 vs −2.5), at the age of 70, with BMI of 26.6 kg/m2 (equal to mean), with no history of falls, no prior fracture and no comorbidities. Sojourn time is defined as the predicted time an individual stays in one state before moving to the next state. Fx, fracture. In each cell, values are number of years and 95% confident interval (in the brackets).

Table 4
Five-year probability of transition between states of bone health for women and men.
Women
FromTo
No fracture1st fracture2nd fracture3rd fractureDeath
No fracture80.0
(78.2–81.4)
10.1
(9.1–11.3)
1.2
(0.9–1.5)
0.1
(0.1–0.2)
8.6
(7.6–9.7)
1st fracture70.8
(65.3–75.4)
16.5
(12.9–20.6)
2.4
(1.4–3.9)
10.4
(7.9–14.0)
2nd fracture65.3
(51.4–75.5)
18.5
(10.2–28.9)
16.2
(10.0–26.4)
3rd fracture52.4
(22.9–75.0)
47.6
(25.0–77.1)
Men
FromTo
No fracture1st fracture2nd fracture3rd fractureDeath
No fracture78.3
(76.1–80.3)
6.0
(5.0–7.0)
0.4
(0.3–0.6)
0.1
(0.0–0.2)
15.3
(13.6–17.2)
1st fracture63.5
(54.9–70.2)
8.1
(4.9–12.1)
2.1
(0.8–4.3)
26.3
(20.0–34.3)
2nd fracture22.4
(8.4–38.4)
13.6
(3.7–29.7)
64.0
(44.5–82.5)
3rd fracture18.4
(0.8–53.8)
81.6
(46.2–99.2)
  1. Note: Risk was estimated for a ‘typical’ man or woman having a risk profile characterized by mean values of predictors as follows: age at event = 70 years, femoral neck bone mineral density T-score of −1.5, BMI = 26.6 kg/m2, no history of falls, no prior fracture, no comorbidities. In each cell, values are percentage of risk and 95% confident interval (in the brackets).

Key resources table
Reagent type (species) or resourceDesignationSource or referenceIdentifiersAdditional information
Software, algorithmR Project for Statistical ComputingR Project for Statistical ComputingRRID:SCR_001905
Software, algorithmAlgorithm SAS programStatistical Analysis SystemRRID:SCR_008567
Author response table 1
Event age (years)
60-6970-79≥80Total
Baseline age (years)60-6915820968435
70-79-115171286
≥80--9595
Total158324334816
Author response table 2
Fracture typeWomenMenTotal
Hip fracture8729116
Vertebral fracture24080320
Non-hip non-vertebral fracture30575380
Total632184816

Additional files

Supplementary file 1

Age at study entry, initial fracture, second fracture, third fracture, and death in women and men.

Values shown are mean and standard deviation (in brackets).

https://cdn.elifesciences.org/articles/61142/elife-61142-supp1-v2.docx
Supplementary file 2

Transition between health states during the study period: actual number of individuals and probability for 2046 women and 1205 men.

Data shown are the number of individuals (percentage in brackets). The sign ‘–’ in a state indicates that the transition to the state is shown in the next row.

https://cdn.elifesciences.org/articles/61142/elife-61142-supp2-v2.docx
Supplementary file 3

Five-year probability of transition between states of bone health for women and men with femoral neck BMD T-score of 0 (normal) and −2.5 (osteoporosis).

Risk was estimated for a man or woman characterized as follows: age = 70 years, BMI = 26.6 kg/m2 (equal to mean), no history of falls, no prior fracture, no comorbidities. Bold values indicate transition probability for initial and subsequent fractures significantly different between an individual with a BMD T-score of 0 (normal) and one with a BMD T-score of −2.5 (osteoporosis). In each cell, values are percentages of risks for T-score = 0 and T-score = −2.5, separated by a slash sign.

https://cdn.elifesciences.org/articles/61142/elife-61142-supp3-v2.docx
Transparent reporting form
https://cdn.elifesciences.org/articles/61142/elife-61142-transrepform-v2.docx

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