Abstract
Background
We investigated the association between cardiovascular disease (CVD) and the risk of major osteoporotic fracture in Taiwan.
Methods
Using the Taiwan National Health Insurance Database for the period 2000–2007, we classified 43 874 patients aged 50 years or older with newly diagnosed CVD (coronary artery disease, heart failure, cerebrovascular disease, or peripheral atherosclerosis) as the CVD group and 43 874 subjects without CVD (frequency-matched by sex, age, and date selected) as the non-CVD group. Incidence and hazard ratios (HRs) for major osteoporotic fracture of the spine, hip, humerus, and forearm/wrist were estimated for the period until the end of 2010.
Results
After adjustment for confounders, the overall HRs for major osteoporotic fracture were 1.24 (95% CI = 1.13, 1.36) in men with CVD and 1.18 (95% CI = 1.11, 1.25) in women with CVD, as compared with the non-CVD group. As compared with the non-CVD group, the adjusted HR for major osteoporotic fracture was highest among subjects with cerebrovascular disease (HR 1.31; 95% CI 1.23, 1.39), followed by those with heart failure (HR 1.18; 95% CI 1.11, 1.27), peripheral atherosclerosis (HR 1.12; 95% CI 1.04, 1.20), and coronary artery disease (HR 1.07; 95% CI 1.01, 1.12).
Conclusions
CVD is associated with risk of major osteoporotic fracture in men and women in Taiwan.
Key words: atherosclerosis, cardiovascular disease, cerebrovascular disease, fracture, heart failure
INTRODUCTION
Cardiovascular disease (CVD) and osteoporosis are major diseases that cause marked morbidity, disability, and mortality, and a very large socioeconomic burden worldwide.1–3 In their review, Deaton et al noted that CVD accounts for about one-third of all deaths in the world.1 Another review showed that osteoporosis is responsible for fractures in about 2 million people in the United States annually.2 Recently, accumulating evidence shows a robust association between CVD and osteoporosis/osteoporotic fracture, which share risk factors and pathophysiologic pathways.4–9 Aging, menopause, and chronic inflammation may partially explain this association.6,7 A study in Australia by Chen et al found that fracture was 1.23 times (95% CI = 1.13–1.35) as likely among women with CVD than among those without CVD.8 Gerber et al reported that US patients had a 1.32-fold risk of fracture (95% CI = 1.12–1.56) after myocardial infarction.9
In 2010, CVD was the second leading cause of death in Taiwan, accounting for 10.8% of all deaths.10 In a study using data from the Taiwan National Health Insurance database, Yang et al estimated that the average prevalence of osteoporosis in 1999–2001 was 11.4% in women, and 1.6% in men, aged 50 years or older.11 To date, most studies of the association between CVD and osteoporosis/osteoporotic fracture were limited to white populations, and little evidence is available in Taiwan. Identifying risk factors for fracture is important in preventing development of fractures and improving outcomes. In this population-based cohort study, we used claims data from the National Health Insurance program in Taiwan to investigate the association between CVD and risk of major osteoporotic fracture.
METHODS
Data sources
This study used claims data from the National Health Insurance program in Taiwan, which has been described in detail in previous studies.12–16 In brief, the National Health Research Institute in Taiwan has used insurance claims data to establish several longitudinal data files on medical services provided to inpatients and outpatients. All data files were linked with scrambled identifiers to protect patient privacy. Disease diagnoses were coded according to the International Classification of Diseases 9th Revision-Clinical Modification (ICD-9-CM). In addition, the A-code was used to define diseases, because its use predated adoption of ICD-9 coding in Taiwan.
Design
We used claims data covering 1 million insured persons and established 2 study groups. The CVD group included patients who received new diagnoses during 2000–2007 of coronary artery disease (ICD-9 410–414; A-code A270, A279), heart failure (ICD-9 428), cerebrovascular disease (ICD-9 430–438; A-code A290–A294, A299), or peripheral atherosclerosis (ICD-9 440–448; A-code A300). All people younger than 50 years on the day of diagnosis were excluded. For each selected CVD patient, 1 adult without medical claims for CVD was randomly selected for the non-CVD group, after frequency-matching for sex, age (every 5-year span), and index data. The index date was defined as the date of diagnosis for CVD patients and as the middle date of the same index month as their matched CVD patients for non-CVD subjects. To decrease confounding effects, subjects previously diagnosed with fracture at any site (ICD-9 800–829, E887, and A-code A470–A476, A479) before the index date were excluded from the study. Diagnosis of a major osteoporotic fracture, including fracture of the spine (ICD-9 805 and 806), hip (ICD-9 820), humerus (ICD-9 812), and forearm (ICD-9 813)/wrist (ICD-9 814), were used as the study end-point. These fracture sites have been defined by the World Health Organization fracture risk assessment tool, FRAX.17 Both the CVD and non-CVD groups were followed up to determine fracture incidence until a subject received a fracture diagnosis, death, withdrawal from the insurance program, loss to follow-up, or December 31, 2010.
Comorbidities potentially associated with major osteoporotic fracture before the index date were hypertension, arrhythmia, hyperlipidemia, obesity, diabetes mellitus, dementia, Parkinson’s disease, depression, chronic kidney disease, osteoporosis, menopause, cancer, thyrotoxicosis, tobacco use, and alcoholism. All were diagnosed by using ICD-9 code and A-code.
Definition of exposure
Medical therapy for osteoporosis was defined as at least 1 recorded prescription for bisphosphonate, calcitonin, estrogen, or raloxifene before the index date. Use of other bone-related medications was defined as at least 1 prescription for thiazolidinedione, proton-pump inhibitor, glucocorticoid, statin, warfarin, or heparin before the index date.
Statistical analysis
Demographic status, comorbidities, and medications were compared between the CVD and non-CVD groups among men and women separately. The chi-square test and Student t test were used to compare differences between the CVD and non-CVD groups in sociodemographic characteristics, comorbidities, and medications. The incidence rate of fracture was calculated as number of fracture cases identified during follow-up divided by total person-years for each group. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% CIs for sex-specific risk of hip fracture and major osteoporotic fracture in association with CVD. Subanalysis evaluated whether different types of CVD were associated with risk of major osteoporotic fracture. All analyses were performed using SAS software version 9.1 (SAS Institute Inc., Cary, NC, USA), and the statistical significance level was defined as a 2-sided P value less than 0.05.
RESULTS
Baseline characteristics of the study population
Analysis of claims data from 2000–2007 revealed 43 874 patients with CVD (CVD group) and 43 874 subjects free from disease (non-CVD group) who met the eligibility criteria. Men in the CVD group had a significantly shorter mean duration of follow-up than did men in the non-CVD group (6.03 vs 6.44 years, P < 0.0001; Table 1). Comorbidities and medications were more frequent in the CVD group than in the non-CVD group, with the exception of obesity, cancer, and use of bisphosphonate and raloxifene. Women in the CVD group had a significantly shorter mean duration of follow-up than did women in the non-CVD group (6.25 vs 6.64 years, P < 0.0001; Table 1). As with men, most comorbidities and medications were more frequent in the CVD group than in the non-CVD group, with the exception of obesity, cancer, tobacco use, alcoholism, and use of bisphosphonate and raloxifene. There was no significant difference in medical therapy for osteoporosis between the CVD group and non-CVD group in either sex (data not shown).
Table 1. Baseline characteristics of subjects with and without cardiovascular disease.
| Men | Women | |||||||||
| Cardiovascular disease | Cardiovascular disease | |||||||||
| No | Yes | No | Yes | |||||||
| N = 23 161 | N = 23 161 | N = 20 713 | N = 20 713 | |||||||
| n | % | n | % | P value | n | % | n | % | P value | |
| Age group (years) | ||||||||||
| 50–64 | 10 017 | 43.3 | 9849 | 42.5 | 0.11 | 9785 | 47.2 | 9495 | 45.8 | 0.004 |
| 65–84 | 13 144 | 56.8 | 13 312 | 57.5 | 10 928 | 52.8 | 11 218 | 54.2 | ||
| Mean (SD) (years)a | 65.8 | 9.14 | 66 | 9.13 | 0.08 | 65 | 8.91 | 65.2 | 8.9 | 0.028 |
| Follow-up years, mean (SD) | 6.44 | 2.79 | 6.03 | 3.01 | <0.0001 | 6.64 | 2.78 | 6.25 | 2.97 | <0.0001 |
| Comorbidities before index date | ||||||||||
| Hypertension | 7818 | 33.8 | 16 655 | 71.9 | <0.0001 | 8050 | 38.9 | 15 344 | 74.1 | <0.0001 |
| Arrhythmia | 1063 | 4.59 | 3747 | 16.2 | <0.0001 | 1259 | 6.08 | 3921 | 18.9 | <0.0001 |
| Hyperlipidemia | 1815 | 7.84 | 4232 | 18.3 | <0.0001 | 2539 | 12.3 | 4888 | 23.6 | <0.0001 |
| Obesity | 11 | 0.05 | 19 | 0.08 | 0.14 | 18 | 0.09 | 29 | 0.14 | 0.11 |
| Diabetes mellitus | 3213 | 13.9 | 6461 | 27.9 | <0.0001 | 3233 | 15.6 | 6529 | 31.5 | <0.0001 |
| Dementia | 179 | 0.77 | 377 | 1.63 | <0.0001 | 140 | 0.68 | 292 | 1.41 | <0.0001 |
| Parkinson’s disease | 246 | 1.06 | 465 | 2.01 | <0.0001 | 194 | 0.94 | 358 | 1.73 | <0.0001 |
| Depression | 558 | 2.41 | 862 | 3.72 | <0.0001 | 734 | 3.54 | 1269 | 6.13 | <0.0001 |
| Chronic kidney disease | 432 | 1.87 | 972 | 4.2 | <0.0001 | 252 | 1.22 | 772 | 3.73 | <0.0001 |
| Osteoporosis | 390 | 1.68 | 628 | 2.71 | <0.0001 | 2804 | 13.5 | 3850 | 18.6 | <0.0001 |
| Menopause | — | — | — | — | — | 3905 | 18.9 | 4992 | 24.1 | <0.0001 |
| Cancers | 894 | 3.86 | 785 | 3.39 | 0.007 | 829 | 4 | 719 | 3.47 | 0.004 |
| Thyrotoxicosis | 94 | 0.41 | 123 | 0.53 | 0.049 | 267 | 1.29 | 382 | 1.84 | <0.0001 |
| Tobacco use | 39 | 0.17 | 80 | 0.35 | 0.0002 | 4 | 0.02 | 6 | 0.03 | 0.53 |
| Alcoholism | 55 | 0.24 | 107 | 0.46 | <0.0001 | 3 | 0.01 | 6 | 0.03 | 0.32 |
| Ever use of medications | ||||||||||
| Thiazolidinedione | 260 | 1.12 | 564 | 2.44 | <0.0001 | 216 | 1.04 | 623 | 3.01 | <0.0001 |
| Proton-pump inhibitor | 999 | 4.31 | 1746 | 7.54 | <0.0001 | 569 | 2.75 | 1087 | 5.25 | <0.0001 |
| Glucocorticoid | 3509 | 37.6 | 19 652 | 53.1 | <0.0001 | 2043 | 35.4 | 18 670 | 52.4 | <0.0001 |
| Statin | 1031 | 4.45 | 3006 | 13 | <0.0001 | 1533 | 7.4 | 3407 | 16.5 | <0.0001 |
| Warfarin | 87 | 0.38 | 551 | 2.38 | <0.0001 | 55 | 0.27 | 374 | 1.81 | <0.0001 |
| Heparin | 209 | 0.9 | 1454 | 6.28 | <0.0001 | 166 | 0.8 | 718 | 3.47 | <0.0001 |
| Bisphosphonate | 13 | 0.06 | 17 | 0.07 | 0.47 | 109 | 0.53 | 119 | 0.57 | 0.51 |
| Calcitonin | 30 | 0.13 | 62 | 0.27 | 0.0008 | 153 | 0.74 | 224 | 1.08 | 0.0002 |
| Estrogen | — | — | — | — | — | 1652 | 7.98 | 2051 | 9.9 | <0.0001 |
| Raloxifene | 1 | 0 | 0 | 0 | 0.99 | 25 | 0.12 | 25 | 0.12 | 0.99 |
The chi-square test and at-test were used to compare subjects with and without cardiovascular disease.
Association between CVD and hip fracture
Table 2 shows the sex-specific risk of hip fracture by duration of follow-up for the CVD and non-CVD groups. The incidence of hip fracture was highest among women with CVD (4.27 per 1000 person-years), followed by women without CVD, men with CVD, and men without CVD (1.96 per 1000 person-years). Multivariate Cox regression analysis revealed that the HR for hip fracture associated with CVD was not significant (HR, 1.02; 95% CI = 0.92, 1.13).
Table 2. Incidence and hazard ratios (HRs) for hip fracture among subjects with and without cardiovascular disease (CVD), by sex and duration of follow-up.
| Non-CVD | CVD | Crude HR (95% CI) |
Adjusted HR (95% CI) |
|||||
| Events | Person-years | Incidence ratea |
Events | Person-years | Incidence ratea |
|||
| Men | 298 | 151 808 | 1.96 | 399 | 142 873 | 2.79 | 1.43 (1.23, 1.66) | 0.93 (0.79, 1.10) |
| Follow-up years | ||||||||
| ≤1 | 32 | 22 793 | 1.40 | 46 | 22 186 | 2.07 | 1.47 (0.94, 2.32) | 0.77 (0.45, 1.32) |
| >1 | 266 | 129 016 | 2.06 | 353 | 120 686 | 2.92 | 1.42 (1.21, 1.67) | 0.95 (0.79, 1.13) |
| Women | 422 | 145 104 | 2.91 | 591 | 138 555 | 4.27 | 1.47 (1.30, 1.67) | 1.11 (0.97, 1.27) |
| Follow-up years | ||||||||
| ≤1 | 36 | 20 528 | 1.75 | 76 | 20 146 | 3.77 | 2.15 (1.45, 3.20) | 0.96 (0.63, 1.45) |
| >1 | 386 | 124 577 | 3.10 | 515 | 118 409 | 4.35 | 1.41 (1.24, 1.61) | 1.13 (0.98, 1.30) |
| Overall | 720 | 296 913 | 2.42 | 990 | 281 428 | 3.52 | 1.46 (1.32, 1.60) | 1.02 (0.92, 1.13) |
| Follow-up years | ||||||||
| ≤1 | 68 | 43 320 | 1.57 | 122 | 42 333 | 2.88 | 1.84 (1.36, 2.47) | 0.87 (0.63, 1.21) |
| >1 | 652 | 253 592 | 2.57 | 868 | 239 096 | 3.63 | 1.42 (1.28, 1.57) | 1.03 (0.93, 1.16) |
Adjusted HR in men: adjusted for age, hypertension, arrhythmia, diabetes mellitus, dementia, Parkinson’s disease, depression, chronic kidney disease, osteoporosis, alcoholism, proton-pump inhibitor, glucocorticoid, and calcitonin.
Adjusted HR in women: adjusted for age, hypertension, arrhythmia, hyperlipidemia, diabetes mellitus, dementia, Parkinson’s disease, chronic kidney disease, osteoporosis, menopause, thiazolidinedione, glucocorticoid, bisphosphonate, calcitonin, estrogen, and raloxifene.
Adjusted overall HR: adjusted for age, diabetes mellitus, hyperlipidemia, Parkinson’s disease, osteoporosis, glucocorticoid, bisphosphonate, calcitonin, and estrogen.
aIncidence rate: per 1000 person-years.
Association between CVD and major osteoporotic fractures
Table 3 shows the sex-specific risk of major osteoporotic fracture by duration of follow-up among adults with and without CVD. The incidence of fracture was highest among women with CVD (21.5 per 1000 person-years), followed by women without CVD, men with CVD, and men without CVD (7.02 per 1000 person-years). Multivariate Cox regression analysis revealed that the HR for major osteoporotic fracture associated with CVD was 1.16 (95% CI 1.10, 1.22). The sex-specific HRs were similar for men and women (HR, 1.24 vs 1.18). The risk of fracture declined slightly after 1 year of follow-up.
Table 3. Incidence and hazard ratios (HRs) for major osteoporotic fractures among subjects with and without cardiovascular disease (CVD), by sex and duration of follow-up.
| Non-CVD | CVD | Crude HR (95% CI) |
Adjusted HR (95% CI) |
|||||
| Events | Person-years | Incidence ratea |
Events | Person-years | Incidence ratea |
|||
| Men | 1047 | 149 200 | 7.02 | 1276 | 139 562 | 9.14 | 1.31 (1.20, 1.42) | 1.24 (1.13, 1.36) |
| Follow-up years | ||||||||
| ≤1 | 128 | 22 747 | 5.63 | 195 | 22 109 | 8.82 | 1.57 (1.25, 1.96) | 1.47 (1.15, 1.88) |
| >1 | 919 | 126 453 | 7.27 | 1081 | 117 453 | 9.20 | 1.27 (1.16, 1.39) | 1.21 (1.09, 1.33) |
| Women | 2324 | 137 578 | 16.9 | 2786 | 129 484 | 21.5 | 1.28 (1.21, 1.35) | 1.18 (1.11, 1.25) |
| Follow-up years | ||||||||
| ≤1 | 296 | 20 404 | 14.5 | 412 | 19 972 | 20.6 | 1.42 (1.23, 1.65) | 1.32 (1.12, 1.55) |
| >1 | 2028 | 117 174 | 17.3 | 2374 | 109 512 | 21.7 | 1.26 (1.18, 1.33) | 1.16 (1.08, 1.23) |
| Overall | 3371 | 286 778 | 11.8 | 4062 | 269 047 | 15.1 | 1.29 (1.23, 1.35) | 1.16 (1.10, 1.22) |
| Follow-up years | ||||||||
| ≤1 | 424 | 43 152 | 9.83 | 607 | 42 081 | 14.4 | 1.47 (1.30, 1.66) | 1.33 (1.16, 1.52) |
| >1 | 2947 | 243 627 | 12.1 | 3455 | 226 965 | 15.2 | 1.26 (1.20, 1.32) | 1.14 (1.08, 1.20) |
Adjusted HR in men: adjusted for age, hypertension, arrhythmia, diabetes mellitus, dementia, Parkinson’s disease, depression, chronic kidney disease, osteoporosis, alcoholism, proton-pump inhibitor, glucocorticoid, and calcitonin.
Adjusted HR in women: adjusted for age, hypertension, arrhythmia, hyperlipidemia, diabetes mellitus, dementia, Parkinson’s disease, chronic kidney disease, osteoporosis, menopause, thiazolidinedione, glucocorticoid, bisphosphonate, calcitonin, estrogen, and raloxifene.
Adjusted overall HR: adjusted for age, diabetes mellitus, hyperlipidemia, Parkinson’s disease, osteoporosis, glucocorticoid, bisphosphonate, calcitonin, and estrogen.
aIncidence rate: per 1000 person-years.
Subanalysis of the association between type of CVD and major osteoporotic fracture
The association between type of CVD and risk of major osteoporotic fracture was also analyzed (Table 4). As compared with the non-CVD group, the adjusted HR of major osteoporotic fracture was highest among patients with cerebrovascular disease (HR 1.31, 95% CI 1.23, 1.39), followed by those with heart failure (1.18; 1.11, 1.27), peripheral atherosclerosis (1.12; 1.04, 1.20), and coronary artery disease (1.07; 1.01, 1.12).
Table 4. Hazard ratios (HRs) and 95% CIs for major osteoporotic fracture associated with 4 types of cardiovascular disease (CVD).
| Crude HR (95% CI) | Adjusted HR (95% CI) | |
| Men | ||
| Non-CVD (reference) | 1.00 (Reference) | 1.00 (Reference) |
| Coronary artery disease | 1.09 (1.00, 1.18) | 1.05 (0.96, 1.15) |
| Heart failure | 1.58 (1.41, 1.78) | 1.29 (1.14, 1.45) |
| Cerebrovascular disease | 1.71 (1.55, 1.89) | 1.47 (1.33, 1.63) |
| Peripheral atherosclerosis | 1.32 (1.16, 1.50) | 1.21 (1.06, 1.37) |
| Women | ||
| Non-CVD (reference) | 1.00 (Reference) | 1.00 (Reference) |
| Coronary artery disease | 1.16 (1.10, 1.23) | 1.12 (1.05, 1.18) |
| Heart failure | 1.45 (1.34, 1.58) | 1.12 (1.03, 1.22) |
| Cerebrovascular disease | 1.67 (1.55, 1.80) | 1.32 (1.23, 1.43) |
| Peripheral atherosclerosis | 1.16 (1.06, 1.26) | 1.10 (1.01, 1.20) |
| Overall | ||
| Non-CVD (reference) | 1.00 (Reference) | 1.00 (Reference) |
| Coronary artery disease | 1.15 (1.10, 1.20) | 1.07 (1.01, 1.12) |
| Heart failure | 1.50 (1.40, 1.60) | 1.18 (1.11, 1.27) |
| Cerebrovascular disease | 1.57 (1.48, 1.66) | 1.31 (1.23, 1.39) |
| Peripheral atherosclerosis | 1.23 (1.15, 1.32) | 1.12 (1.04, 1.20) |
Adjusted HR in men: adjusted for age, hypertension, arrhythmia, diabetes mellitus, dementia, Parkinson’s disease, depression, chronic kidney disease, osteoporosis, alcoholism, proton-pump inhibitor, glucocorticoid, and calcitonin.
Adjusted HR in women: adjusted for age, hypertension, arrhythmia, hyperlipidemia, diabetes mellitus, dementia, Parkinson’s disease, chronic kidney disease, osteoporosis, menopause, thiazolidinedione, glucocorticoid, bisphosphonate, calcitonin, estrogen, and raloxifene.
Adjusted overall HR: adjusted for age, diabetes mellitus, hyperlipidemia, Parkinson’s disease, osteoporosis, glucocorticoid, bisphosphonate, calcitonin, and estrogen.
DISCUSSION
Although this study is not novel, it is to our knowledge the first population-based cohort study to examine the association between CVD and risk of major osteoporotic fracture in Taiwan. We selected only adults aged 50 years or older, and the prevalences of most comorbidities and medications were therefore greater among the CVD group than among the non-CVD group. The incidence of major osteoporotic fracture among women was more than 2-fold that among men, regardless of CVD status. Our finding of a risk of major osteoporotic fracture was somewhat comparable to the results of previous studies (risk rates, 1.2 to 1.5).7–9 The present study found that the overall risk of fracture in the CVD group was approximately 1.2-fold that of the non-CVD group. However, there were variations in men and women with regard to duration of follow-up and interaction between comorbidities.
Additional analysis by CVD type showed that cerebrovascular disease (HR 1.31), heart failure (HR 1.18), peripheral atherosclerosis group (HR 1.12), and coronary artery disease (HR 1.07) were substantially associated with increased risk of major osteoporotic fracture. Two studies by Sennerby et al showed that Swedish patients with cerebrovascular disease had higher fracture risk (OR = 2.76 and HR = 5.09),4,5 and our findings are similar. The authors suggested that the increased likelihood of falling after cerebrovascular disease partially explained this trend.4,5
Variation in fracture risk during follow-up is important in preventive care. Though the absolute incidence rate of major osteoporotic fracture was higher after 1 year of follow-up, the hazard was lower during subsequent follow-up. In contrast, Sennerby et al found a higher risk of hip fracture within the first year after a CVD diagnosis in Sweden.4,5 In the present study, the absolute incidence rate of hip fracture was higher among the CVD group, but the HR was not statistically significant (HR 1.02, 95% CI 0.92, 1.13). Although the time-course effect differed between previous studies and the present study, we believe that clinicians should be mindful of the risk of major osteoporotic fracture even at 1 year after a CVD diagnosis, as risk did not substantially vary during the follow-up period.
Some limitations should be addressed. First, because claims data were used, some CVD diagnoses might not fulfill all criteria for each disease. Also, instances of fracture at hip or major skeletal sites could not be diagnosed as fragility fracture. This limitation may have led to underestimation of fracture risk. Second, because claims data did not provide information on bone mineral density (BMD), we were unable to evaluate fracture risk in relation to presence of osteoporosis, osteopenia, or normal BMD. Therefore, we were unable to examine the relation between CVD and BMD. Third, although there was no record of body mass index (BMI) in the claims data, we were able to include information on obesity (ie, ICD-9 278.00 and 278.01 and A-code A183) as a comorbidity in the analysis.
Conclusion
After careful adjustment for covariates and consideration of duration of follow-up, CVD was associated with increased risk of major osteoporotic fracture in both sexes, although the incidence of such fractures was higher among women than among men.
ACKNOWLEDGMENTS
The authors thank the National Health Research Institute in Taiwan for providing the insurance claims data. This study was supported in part by grants from Taiwan Department of Health Clinical Trial and Research Center of Excellence (DOH101-TD-B-111-004), the Cancer Research Center of Excellence (DOH 101-TD-C-111-005), and the National Science Council (NSC 100-2621-M-039-001). The funding agencies did not influence the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Specific author contributions: Shih-Wei Lai (1) substantially contributed to the conception of this article, (2) planned and conducted the study, and (3) drafted and critically revised the article. Kuan-Fu Liao, Hsueh-Chou Lai, and Pei-Chun Chen (1) participated in data interpretation and (2) critically revised the article. Pang-Yao Tsai and Cheng-Li Lin (1) conducted data analyses and (2) critically revised the article. Fung-Chang Sung (1) conducted study design and data analysis and participated in data interpretation and (2) critically revised the article.
Conflicts of interest: None declared.
REFERENCES
- 1.Deaton C, Froelicher ES, Wu LH, Ho C, Shishani K, Jaarsma T. The global burden of cardiovascular disease. J Cardiovasc Nurs. 2011;26(4Suppl):S5–14 10.1016/S1474-5151(11)00111-3 [DOI] [PubMed] [Google Scholar]
- 2.Dempster DW Osteoporosis and the burden of osteoporosis-related fractures. Am J Manag Care. 2011;17Suppl 6:S164–9 [PubMed] [Google Scholar]
- 3.Sasser AC, Rousculp MD, Birnbaum HG, Oster EF, Lufkin E, Mallet D. Economic burden of osteoporosis, breast cancer, and cardiovascular disease among postmenopausal women in an employed population. Womens Health Issues. 2005;15(3):97–108 10.1016/j.whi.2004.11.006 [DOI] [PubMed] [Google Scholar]
- 4.Sennerby U, Farahmand B, Ahlbom A, Ljunghall S, Michaëlsson K. Cardiovascular diseases and future risk of hip fracture in women. Osteoporos Int. 2007;18(10):1355–62 10.1007/s00198-007-0386-0 [DOI] [PubMed] [Google Scholar]
- 5.Sennerby U, Melhus H, Gedeborg R, Byberg L, Garmo H, Ahlbom A, et al. Cardiovascular diseases and risk of hip fracture. JAMA. 2009;302(15):1666–73 10.1001/jama.2009.1463 [DOI] [PubMed] [Google Scholar]
- 6.Crepaldi G, Maggi S. Epidemiologic link between osteoporosis and cardiovascular disease. J Endocrinol Invest. 2009;32(4Suppl):2–5 [PubMed] [Google Scholar]
- 7.den Uyl D, Nurmohamed MT, van Tuyl LH, Raterman HG, Lems WF. (Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; a systematic review of the association between cardiovascular disease and osteoporosis. Arthritis Res Ther. 2011;13(1):R5 10.1186/ar3224 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Chen JS, Hogan C, Lyubomirsky G, Sambrook PN. Women with cardiovascular disease have increased risk of osteoporotic fracture. Calcif Tissue Int. 2011;88(1):9–15 10.1007/s00223-010-9431-7 [DOI] [PubMed] [Google Scholar]
- 9.Gerber Y, Melton LJ 3rd, Weston SA, Roger VL. Association between myocardial infarction and fractures: an emerging phenomenon. Circulation. 2011;124(3):297–303 10.1161/CIRCULATIONAHA.110.007195 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Department of Health. Taiwan: Main Causes of Death in 2010. http://www.doh.gov.tw [cited November 7, 2011].
- 11.Yang NP, Deng CY, Chou YJ, Chen PQ, Lin CH, Chou P, et al. Estimated prevalence of osteoporosis from a Nationwide Health Insurance database in Taiwan. Health Policy. 2006;75(3):329–37 10.1016/j.healthpol.2005.04.009 [DOI] [PubMed] [Google Scholar]
- 12.Lai SW, Liao KF, Liao CC, Muo CH, Liu CS, Sung FC. Polypharmacy correlates with increased risk for hip fracture in the elderly: a population-based study. Medicine (Baltimore). 2010;89(5):295–9 10.1097/MD.0b013e3181f15efc [DOI] [PubMed] [Google Scholar]
- 13.Lai SW, Su LT, Lin CH, Tsai CH, Sung FC, Hsieh DP. Polypharmacy increases the risk of Parkinson’s disease in older people in Taiwan: a population-based study. Psychogeriatrics. 2011;11(3):150–6 10.1111/j.1479-8301.2011.00369.x [DOI] [PubMed] [Google Scholar]
- 14.Lai SW, Muo CH, Liao KF, Sung FC, Chen PC. Risk of acute pancreatitis in type 2 diabetes and risk reduction on anti-diabetic drugs: a population-based cohort study in Taiwan. Am J Gastroenterol. 2011;106(9):1697–704 10.1038/ajg.2011.155 [DOI] [PubMed] [Google Scholar]
- 15.Liao KF, Lai SW, Li CI, Chen WC. Diabetes mellitus correlates with increased risk of pancreatic cancer: a population-based cohort study in Taiwan. J Gastroenterol Hepatol. 2012;27(4):709–13 10.1111/j.1440-1746.2011.06938.x [DOI] [PubMed] [Google Scholar]
- 16.Lai SW, Lin CH, Liao KF, Su LT, Sung FC, Lin CC. Association between polypharmacy and dementia in older people: a population-based case-control study in Taiwan. Geriatr Gerontol Int. 2012;12(3):491–8 10.1111/j.1447-0594.2011.00800.x [DOI] [PubMed] [Google Scholar]
- 17.Kanis JA, Hans D, Cooper C, Baim S, Bilezikian JP, Binkley N, et al. Task Force of the FRAX Initiative. Interpretation and use of FRAX in clinical practice. Osteoporos Int. 2011;22(9):2395–411 10.1007/s00198-011-1713-z [DOI] [PubMed] [Google Scholar]