The risk of fracture and prevalence of osteoporosis is elevated in patients with idiopathic inflammatory myopathies: data from a single Hungarian center

Background: The prevalence of osteoporosis and risk of fractures is elevated in rheumatoid arthritis, but we have little information about the bone mineral density and fracture risk in patients with inflammatory myopathies. We intended to ascertain and compare fracture risk, bone mineral density (BMD) and the prevalence of vertebral fractures in patients with inflammatory myositis and rheumatoid arthritis (RA) and to assess the effect of prevalent fractures on the quality of life and functional capacity. Methods: Fifty-two patients with myositis and 43 patients with rheumatoid arthritis were included in the study. Fracture Risk was determined using FRAX® Calculation Tool developed by the University of Sheffield. Dual energy X-ray absorptiometry and bidirectional thoracolumbar radiographs were performed to assess BMD and vertebral fractures. Quality of life was measured with Short Form-36 (SF-36) and physical function assessment was performed using Health Assessment Questionnaire (HAQ). Results: We found a significantly elevated fracture risk in RA compared to myositis patients if the risk assessment was performed without the application of the BMD results. If BMD results and glucocorticoid dose adjustment were taken into account, the differences in fracture risk were no longer significant. The prevalence of osteoporosis was found to be significantly higher in the myositis group (7% vs. 13.5%, p: 0,045), but the fracture prevalence was similar in the two groups (75% vs. 68%). The fractures rates were associated with age in both groups, but not with cumulative dose of steroid and BMD results correlated with fracture prevalence only in the RA patients. The number of prevalent fractures was significantly correlated to poorer physical function in both groups, and poorer health status in the myositis group, but not in the RA group. Conclusions: Our findings suggest that inflammatory myopathies carry significantly elevated risk for osteoporosis and fractures. This higher risk is comparable to one detected with RA in studies and strongly affects the physical function and quality of life of patients. Therefore further efforts are required to make the fracture risk assessment reliable and to facilitate the use early preventive treatments. 1. What is the prevalence of low BMD, vertebral fracture and high fracture risk in our patients with inflammatory myositis and RA? 2. Which factors are associated with fracture rates in myositis and RA patients? 3. How do the vertebral fractures influence the physical function and quality of life of patients? markers (BTM): (parathyroid hormone, osteocalcin /OC/, beta-crosslaps / C-terminal telopeptides of type-I collagen:CTX-I/) levels. Blood sampling was done after overnight fasting to measure levels of PTH, OC and CTX-I. Plasma 25-OH-D3 level was analyzed by high pressure liquid chromatography (HPLC) using

gender-matched population [10,13]. The Fracture Risk Assessment Tool (FRAX ® ) developed and validated by Kanis et al, more than 10 years ago, is the most widely accepted and used method in clinical practice to estimate the 10-year probability of osteoporotic fractures [14]. FRAX score takes into account the relevant risk factors for a bone fracture, e.g., the presence of RA, but not myositis.
Our present work is a cross-sectional observational study, whereby we intended to answer the following questions: 1. What is the prevalence of low BMD, vertebral fracture and high fracture risk in Helsinki. The inclusion criteria were the diagnosis of probable, or definitive idiopathic inflammatory myopathy (IIM) based on the Bohan and Peter criteria [15], and rheumatoid arthritis according to the 2010 American College of Rheumatology-European League Against Rheumatism (ACR-EULAR) classification criteria [16]. The patients with confounders of bone health were excluded from the study: if the patient took any drug affecting bone mineral density (including bisphosphonates, thiazide diuretics, anticoagulants, anticonvulsants, glitazones, etc.) except for vitamin D3 and Ca; secondary osteoporosis and those patients suffering from malignancies.
We measured the BMD of the lumbar spine (L 1-4 vertebrae) and the left femoral neck by AP-DXA. The scan was performed with a DPX Pro bone densitometer (GE-Lunar Radiation Corporation, Madison, WI, USA), according to the manufacturer's protocol. In patients with a history of a previous hip fracture, hip replacement surgery, or severe joint destruction, we measured bone mineral density in the right femoral neck. Osteoporosis was diagnosed according to the criteria proposed by the World Health Organization Study Group, when the BMD was 2.5 or more standard deviations below the young-adult mean, and osteopenia was diagnosed when the BMD was between -1 and -2. To assess the prevalence of vertebral fractures 40 myositis patients and 35 RA patients underwent a bidirectional (anteroposterior and lateral) X-ray imaging of the thoracic (Th) and lumbar (L) spine on separate cassettes for each picture. The Genant's semi-quantitative assessment on standard radiographs was used to evaluate vertebral fractures [21]. Vertebral shape (wedge, concave, or The fracture risk assessment was calculated first without applying the BMD values. Regarding the other major and femoral neck fractures the fracture risk in RA patients was significantly higher than in myositis patients (15.58% vs. 9.68% and 6.23% vs 3.06%; p = 0.008 and p = 0.022). As a second step, the fracture risk calculation was repeated, and this time with the BMD values taken into account, with the earlier significant difference in the fracture probability disappearing (13.25% vs. 9.44% and 3.57% vs. 2.77%; p = 0.053 and p = 0.811). During third step, the fracture risk assessment was performed after adjustment to the dose of glucocorticoids according to Kanis et al [22]. With this correction the magnitude of the difference further decreased: the risk of major osteoporotic and hip fracture were found to be 9.96% vs 9.54% (p = 0.884) and 2.  Table 2). Overall 194 vertebral fractures were discovered in 54 patients (115 fractures in 30 myositis and 79 fractures in 24 RA patients), with these patients representing75% of the myositis group and 68% the RA group, and the difference was not statistically significant ( Table   2). As a next step the myositis and RA patients were divided into two groups according to the presence of vertebral fractures. The mean age of the fractured patients was significantly higher in  (Table 3, Table 4).
Finally we investigated the influence of vertebral fractures on the patients' physical function and quality of life using HAQ and SF-36 questionnaires (Figure 2a-b). It was found that the decrease in

Discussion
To our knowledge this study is the first, which investigates and compares bone fracture risks in IIM and RA, and the first work which correlates BMD, FRAX and vertebral fracture data of myositis patients with rheumatoid arthritis patients. Data from a recent population based study from Taiwan also showed a higher osteoporosis prevalence rate among patients with DM/PM. The increased osteoporosis risk was independent of the corticosteroids and immunosuppressant treatment [9].

Gupta et al recently published a study about prevalence of vertebral deformities in patients with
inflammatory myositis and found a high prevalence of asymptomatic vertebral fractures, but they did not examine the fracture risk and the consequences of fracture on physical function and quality of life [23]. Basically, fracture risk assessed without taking BMD into consideration showed greater risk of fracture in patients with rheumatoid arthritis than in myositis patients. If the BMD data were applied as well, there was no longer any significant differences between the values of the two groups. This might support the argument that for the lower BMD-which is more frequent in patients with myositis -counterbalanced the "confounding" effect of RA as a risk factor. With an adjustment of FRAX according to the dose of glucocorticoids, the remaining non-significant differences further decreased.
Taking into account the high prevalence of osteoporosis/osteopenia in the myositis group, it seems logical to consider incorporating a factor that modifies the FRAX tool and allows for a more reliable risk calculation in patients with myositis. Of course, this requires studies with larger patient population and with bone fracture endpoints. In addition, it would generate a necessity for multiple, disease dependent modifying factor development according to other systemic musculoskeletal diseases (lupus, Sjögren's syndrome, vasculitis, etc). We showed, that the fractured patients were significantly older in both groups, and had higher -CTx levels in RA. The occurrence of vertebral fractures in both myositis and rheumatoid arthritis were very common and seriously affected the patients' physical function and quality of life, especially in those with multiple fractures. It was interesting to observe that this effect was more pronounced in myositis patients with regard to the HAQ results, and surprisingly, the fractures did not modify significantly the health status of the RA patients. This latter phenomenon could be explained by the frequent joint damage and secondary fibromyalgia seen in RA, which might bias the results of the questionnaire. We found a similar high prevalence rate of vertebral fracture as Gupta et al [22], but in their myositis population the median age and disease duration were shorter than in our population and only patients with myositis were investigated. Despite the longer duration of the disease in our population the prevalence of fractures were not materially more frequent, therefore it is imperative to speculate that the majority of fractures occur in the early phase of the disease, when the administration of higher corticosteroid doses is more frequent. Based on the results of our study, a national patient educational material, a patient warning card has been constructed, which we use regularly to increase the patients' awareness and adherence to preventive pharmacological and non-pharmacological antiporotic treatments.
The possible limitations of this study should be acknowledged. This work was a single institution study from a national myositis center in Hungary, the number of participants in the study was relatively low and due to the cross sectional nature of the investigation the calculated and the real fracture risk were not comparable.

Conclusions
It can be concluded that osteoporosis and consequential fractures in myositis are common and probably underestimated and that their examination is often neglected. Therefore it would be important to pay greater attention to the recognition of the low BMD and high fracture risk and the use of preventive measures. Our results showed a good agreement with data of groups from other    Figure 1 Fracture risk in patients with myositis and rheumatoid arthritis