INTRODUCTION
The prevalence of osteoporosis and osteoporotic fractures, which are common metabolic conditions associated with aging, is dramatically increasing due to rapidly aging populations in most developing and developed countries. Since osteoporotic fractures not only reduce quality-of-life but also increase medical and health care expenses, this condition imposes a significant healthcare and financial burden [
1,
2].
Systemic lupus erythematosus (SLE) is predominant among African Americans, Native Americans, Hispanics, and Asians, and both the prevalence and incidence of SLE are increasing in the Korean population [
3]. In Korea, the prevalence and incidence of SLE between 2006 and 2010 was 20.6 to 26.5 (per 100,000 person) and over 2.5 (per 100,000 person), respectively [
4]. SLE is a chronic systemic autoimmune disorder that commonly affects bone homeostasis, which is associated with increased serum levels of various inflammatory cytokines, premature menopause, and maintaining glucocorticoids therapy [
5-
11]. Recently, a population-based study showed that the incidence ratios for cervical hip fractures in SLE patients were about 3-time higher than those in age- and sex-matched healthy subjects [
8]. Moreover, the incidence of fragility fractures in SLE patients increases in younger-aged patients compared to the general population [
6,
12]. However, limited data are available on the incidence, as well as the risk factors, of osteoporotic fractures in Korean patients with SLE.
The aim of the present study was to determine the incidence rate (IR) of osteoporotic fractures between SLE patients and age- and sex-matched controls, as well as to determine the risk factors for osteoporotic fractures among SLE patients, using nationwide population-based data in Korea.
DISCUSSION
In this study that analyzed nationwide, population-based data, we found that patients with SLE may have a higher osteoporotic fracture risk than age- and sex-matched control cohorts. There was no significant difference in the osteoporotic fracture risk of SLE patients, with regard to either having a low income level, or a previous history of diabetes, hypertension, dyslipidemia, COPD, ESRD, or congestive heart failure, compared to SLE patients without such characteristics. However, male or younger-aged SLE patients as well as those not having a previous history of either ischemic heart disease, stroke, or cancer showed a higher relative osteoporotic fracture risk among SLE patients.
Although SLE patients have been shown to be at a higher risk of symptomatic vertebral fracture in several small cross-sectional studies [
17-
20], the association between osteoporotic fracture and SLE in a population-based cohort has not been well characterized. An early retrospective cohort study of 702 female SLE patients found a nearly 5-fold increase in fracture incidence compared with the general United States female population [
7]. In a recent large population-based study from Taiwan, there was an approximately 3.2-fold higher incidence of cervical hip fractures in 14,544 SLE patients than in age- and sex-matched controls, and that fracture risk was elevated starting at a younger age than the general population [
8]. Another population-based study in the United Kingdom analyzed a total of 4,343 SLE patients, as well as 21,780 age- and sex-matched controls. This study showed a 1.2-fold increase in the risk of clinical fracture for SLE patients, when compared to controls, using a mean follow-up period of 6.4 years [
10]. In line with previous studies, after adjustment for confounding variables, our results showed that SLE patients had a 2.96-fold increase in the risk of osteoporotic fracture, when compared to age- and sex-matched non-SLE controls, which was similar to above study from Taiwan. The reason for the differences in relative risk of fracture between previous population-based studies may be due to racial disparities and disease severities between the different study populations.
Mechanistically, SLE is a chronic inflammatory state that contributes to bone loss by increasing osteoclast activity, while reducing activity of osteoblasts [
21]. This appeared to be mediated by the elevated expression of receptor activator of nuclear factor-κB ligand (RANKL), tumor necrosis factor, and interleukin-1 and -6 [
5,
22]. Of note, increased oxidized low-density lipoprotein correlated negatively with low bone-mineral density of the lumbar spine and total hip in SLE patients, which may attenuate osteoblast maturation and increase the expression of RANKL, which may eventually induce osteoporosis [
23]. Moreover, SLE patients may have lower vitamin D levels as a result of the avoidance of sun exposure, decreased renal function, and the use of glucocorticoids, anticonvulsants, hydroxychloroquine, and calcineurin inhibitors. Low levels of vitamin D is also associated with disease severity via inappropriate immune response and has been shown to be correlated with osteoporosis in SLE patients [
21,
24].
Notwithstanding the fact that men comprised 10% of the study cohort, which is similar to previous SLE cohort studies [
8,
10,
25], our results identified male SLE patients have a high risk of osteoporotic fracture in the SLE cohort according to subgroup analysis. Similar to our findings, a study from United Kingdom showed a higher relative risk of clinical fracture in male SLE patients than in female SLE patients (adjusted relative risk, 1.91 vs. 1.18), although statistical significance was not found [
10]. Furthermore, SLE patients aged 40 to 65 years were at an increased relative risk of osteoporotic fracture when compared to SLE patients older than 65 years. This finding was consistent with a previous study from Taiwan that found the incidence of hip fracture was higher in SLE patients younger than 50 years than in those aged ≥ 50 years [
8]. Although the IR of osteoporotic fracture increases with age among the SLE cohort (aged 40 to 65 years, 7.4 cases per 1,000 person-years; aged ≥ 65 years, 32.6 cases per 1,000 person-years), the relative risk was higher for younger SLE patients than for older SLE patients when compared with matched controls. In other words, despite the incidence of osteoporotic fracture is low in male and young general population, male or younger SLE patients had a relatively higher fracture risk than female or older SLE patients, which suggested that SLE is associated with the risk of osteoporotic fracture. One possible explanation is that SLE patients have a higher rate of premature menopause and the use of glucocorticoid at a younger age.
The findings of the present study provide the first evidence of an independent association between SLE and the risk of osteoporotic fracture using a larger, nationwide population-based cohort from Korea. Consequently, we believe that our findings could be used as a fundamental data for treatment and future prevention of osteoporotic fracture in Korean SLE patients by understanding of risk factors for osteoporotic fracture. However, there are several limitations to this study. First, our data did not identify the use of drugs such as glucocorticoids, anticonvulsants, hydroxychloroquine, calcineurin inhibitors, vitamin D supplements, and bisphosphonates, which could affect the risk of osteoporotic fracture. Second, we did not evaluate the association of osteoporotic fracture risk with SLE patients according to other sites, such as the vertebrae, hip, ankle, or wrist. Future studies are required to determine the influence of drug use and fracture site on the risk of osteoporotic fractures.
In this large population-based cohort study, we found that there was an approximately 3-fold increased risk of osteoporotic fracture in SLE patients, when compared to age- and sex-matched non-SLE controls. Male or middle-aged SLE patients had a relatively higher fracture risk among SLE patients. Therefore, strategies to prevent osteoporotic fracture, including the treatment of osteoporosis in SLE patients, should be examined in the future, especially in both male and younger patients.