International Journal of Rheumatic Diseases 2016; 19: 521–528
ORIGINAL ARTICLE
Prevalence and associated factors of reduced bone mineral density in patients with idiopathic inflammatory myopathies Ho SO, Man Lung YIP and Andrew Kui Man WONG Department of Medicine and Geriatrics, Kwong Wah Hospital, Kowloon, Hong Kong
Abstract Aim: To determine the prevalence and identify the associated factors of reduced bone mineral density (BMD) in patients with idiopathic inflammatory myopathies (IIMs). Method: Existing patients diagnosed to have IIMs were recruited for measurement of BMD by dual energy X-ray absorptiometry. Demographic, clinical and treatment variables of these patients were recorded. The prevalence of osteopenia and osteoporosis were calculated. Using multivariate analysis, the independent associated factors for reduced BMD were evaluated. Results: Thirty-eight patients with IIMs completed the study with 32 (84.2%) being female. The mean age of the patients was 52.8 13.0 years. Nine (23.7%) patients had osteoporosis and 18 (47.4%) had osteopenia. Multivariate analysis revealed female gender and low serum albumin levels at onset were associated with lower spinal BMD. For femoral neck, the factors associated with lower BMD were high Myositis Disease Activity Assessment Visual Analogue Scales (MYOACT) score and high cumulative prednisolone dose. Conclusions: Reduced BMD is prevalent in patients with IIMs. Female gender, low serum albumin level at onset, high disease activity and high cumulative corticosteroid dose appeared to be the independent associated factors. Regular assessment of BMD is advisable. The use of anti-osteoporotic and steroid-sparing agents should be encouraged. Key words: idiopathic inflammatory myopathies, osteopenia, osteoporosis, reduced bone mineral density.
INTRODUCTION The last two decades have seen major advances in the treatment of rheumatic diseases, resulting in a significant improvement in patient survival. Emphasis started to be put on prevention of long-term problems and medication side-effects such as osteoporosis. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and susceptibility to fracture.1 In the United States, 1 year after hip fracture, 40% of the patients aged 50 and above were unable to walk
Correspondence: Dr Ho So, Kwong Wah Hospital, 25 Waterloo Road, Kowloon, Hong Kong. Email: [email protected]
independently and 60% required assistance with at least 1 activity of daily living.2 Fractures were also associated with excess mortality. The 5-year survival for male patients with vertebral fractures was 72% and that for women was 84%.3 Further, the annual cost to the healthcare system from osteoporotic fractures has been estimated at 17.9 billion US dollars in the United States.4 Nevertheless, reduced bone mineral density (BMD) and the consequent fragility fractures are treatable and more importantly preventable. Many studies have shown that reduced BMD is prevalent in inflammatory musculoskeletal conditions.5–10 Osteoporosis occurred in up to 40% of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).5,6 The potential mechanisms of bone loss in rheumatic diseases include induction of the
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
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bone-resorbing cytokines as a result of systemic inflammation, reduced mobility and the use of systemic corticosteroids for treatment.5,11–13 Idiopathic inflammatory myopathies (IIMs), including dermatomyositis (DM) and polymyositis (PM), are characterized by chronic inflammation of muscle that results in skeletal muscle weakness. Therefore, patients with IIMs may be physically more disabled than SLE patients. At the same time, systemic corticosteroid is the mainstay of treatment for IIMs. Thus, IIM patients usually require higher corticosteroid doses than RA patients. As a result, they may be at particularly high risk for bone loss. However, the data regarding reduced BMD in patients with IIMs are scanty. On the other hand, there are still controversies concerning the predictors of bone loss in patients with inflammatory musculoskeletal conditions, especially corticosteroid use. In this cross-sectional study, we aimed to assess the prevalence of reduced BMD in our patients with IIMs. We further intended to study its association with various demographic, disease and treatment variables.
MATERIALS AND METHODS Patients Existing patients with IIMs followed up in the rheumatology clinics in Kwong Wah Hospital and Queen Mary Hospital in Hong Kong were invited to participate in the study during the clinic visits from September 2010 to March 2011. Patients with DM and PM had to fulfill the Bohan-Peter criteria.14 Patients with amyopathic dermatomyositis (ADM) who had the typical Gottron’s rash or heliotrope rash as determined by rheumatologists or dermatologists but with no symptoms or signs of muscle involvement were also included.15 Pregnant patients or patients who had juvenile onset disease (< 18 years old), non-Asian ethnicity or documented metabolic bone disorders were excluded from the study.
Data collection Participants of the study were interviewed and examined during the clinic visits. Their clinical records were also reviewed. For each patient, demographic data, including current age, sex, body mass index (BMI), menopausal status, personal history of smoking and drinking and family history of low-impact fracture were collected. Significant smoking and drinking history was defined as daily use of tobacco and alcohol for at least 3 years. Low impact fracture was defined as a fracture resulting from a fall of standing height or less.
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The disease characteristics including the type of myositis, presence of concomitant connective tissue diseases and duration of disease were obtained. Details of the treatment regimens, including the duration of corticosteroid use, peak corticosteroid dose, high-dose corticosteroids ever, cumulative corticosteroid dose, current corticosteroid dose, use of other immunosuppressants and use of anti-osteoporotic drugs were also recorded. High-dose corticosteroid use was defined as oral prednisolone more than 0.5 mg/kg body weight per day for more than 6 weeks. The activity of the myositis was evaluated using the tools developed by the International Myositis and Clinical Studies Group (IMACS).16 They included physician global activity – visual analogue scale (VAS), patient global activity – VAS, Manual Muscle Testing 8 (MMT8) and Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT). Maximal and latest levels of muscle enzymes, including creatinine kinase (CK) and lactate dehydrogenase (LDH) were collected. Biochemical markers of inflammation, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum albumin level at disease onset and 1 month within the assessment were also recorded. Physical disability of the patients was assessed by the self-administered Health Assessment Questionnaire Disability Index (HAQDI). The disease damage was evaluated using physician global damage – VAS and patient global damage – VAS. They are also tools endorsed by the IMACS and form part of the IMACS core set disease damage measures.16 Complications related to IIMs or its treatments which included interstitial lung disease, dysphagia, malignancy and avascular necrosis were also documented. Bone mineral density was measured by dual energy X-ray absorptiometry (DEXA) which was performed within 3 months of the assessment.
BMD measurement Bone mineral density of the lumbar spine (L1–L4) and left hip (femoral neck and total hip) was measured by DEXA using a Discovery SL densitometer with software version 12.3 (Hologic, Bedford, MA, USA) in the Kwong Wah Hospital Well Women Clinic for female patients and an Explorer densitometer with software version 12.5.2 (Hologic) in a private radiology center for male patients whenever possible. The machines were calibrated and measurements were assessed according to standard procedures. The precision of either machine calculated as a coefficient of variation was < 1.0%. The reference population used for female
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Reduced bone mineral density in myositis
patients was the machine manufacturer’s database of Japanese women. For male patients, the reference was derived from the National Health and Nutrition Examination Survey (NHANES) database.17 All BMD results were expressed in absolute values (g/ cm2) and as the number of standard deviations (SD) above or below the mean results of young adults, the Tscore, as well as the mean results of the age matched population, the Z-score. Osteoporosis was defined using the 1994 World Health Organization (WHO)18 Classification as a T-score equal or less than 2.5, and osteopenia between 1 and 2.5.
Statistical analysis Descriptive statistics were presented for demographic and clinical data. Values were expressed as mean SD if they were normally distributed. Otherwise, they were expressed as median and range. Independent Student’s t-test was used for analyzing continuous variables with normal distribution and Mann–Whitney U-test for nonparametric continuous variables. Kruskal–Wallis test was used to compare means when there are more than two groups due to the small sample size. The associations between the continuous variables and BMD were assessed by Pearson’s correlation test or Spearman’s rank correlation test where appropriate. Probable associated factors identified in the univariate analysis were then entered into the multiple linear regression model to identify the independent variables for BMD. A P-value of < 0.05 was considered as statistically significant. SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA) was used as a means of statistical analysis.
Ethics This study was approved by the local ethics committees (Kowloon West Cluster Ethical Committee and Hong Kong West Cluster Ethical Committee). It was conducted in full compliance with the Helsinki Declaration. All patients gave informed consent prior to participation.
Table 1 Demographic and clinical data of the 38 idiopathic inflammatory myopathy patients (values represent n [%] unless otherwise specified) Age (years) Gender Female (%) Menopausal (%) BMI (kg/m2) Smoking (%) Drinking (%) Underweight (BMI < 18.5 kg/m2) (%) Family history of fragility (%) Type (%) Dermatomyositis Polymyositis Amyopathic dermatomyositis Concomitant connective tissue disease (%) Rheumatoid arthritis (%) Mixed connective tissue disease (%) Systemic lupus erythematosus (%) Vasculitis (%) Scleroderma (%) Duration of disease (months) Complications (%) Interstitial lung disease (%) Dysphagia (%) Malignancy (%) Avascular necrosis (%) Health assessment questionnaire disability index (HAQDI) (%) HAQDI = 0 0 < HAQDI < 1 1 ≤ HAQDI < 2 HAQDI ≥ 2 Manual muscle testing 8 Myositis disease activity assessment visual analogue scale
Mean 52.8 (SD 13.0) 32 (84.2) 19/32 (59.4) Mean 23.8 (SD 3.94) 8 (21.1) 1 (2.6) 4 (10.5) 0 (0) 17 (44.7) 15 (39.5) 6 (15.8) 15 (39.5) 5/15 (33.3) 4/15 (26.7) 3/15 (20.0) 2/15 (13.3) 1/15 (6.7) Median 56.5 (range: 3–432) 23 (60.5) 21 (55.3) 5 (13.2) 2 (5.3) 2 (5.3)
3 (7.9) 23 (60.5) 8 (21.1) 4 (10.5) Median 75 (range: 66–80) Median 1.04 (range: 0–3.33)
BMI, body mass index.
RESULTS Demographic and disease-related variables Forty-seven patients were invited to participate in the study. Eight patients did not want to take part and one was lost to follow-up during the study period. At the end, 38 patients completed the study. The demographic and clinical characteristics of the participants are shown in Table 1. All patients were ethnic Chinese and their mean age was 52.8 13.0 years.
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There were 32 (84.2%) female patients with 19 (59.4%) of them being post-menopausal. Eight (21.1%) patients were smokers and one (2.6%) was a drinker. Four (10.5%) patients were underweight as defined by BMI < 18.5 kg/m2.19 None of the patients reported any family history of low-impact fracture. Seventeen (44.7%) patients had PM, 15 (39.5%) had DM and six (15.8%) had ADM. Fifteen (39.5%) patients had other concomitant connective tissue
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diseases. These included RA, mixed connective tissue disease, SLE, vasculitis and scleroderma, in descending order of frequency. The median duration of disease was 56.5 months (range: 3–432). Twenty-one (55.3%) patients were complicated by interstitial lung disease, five (13.2%) by dysphagia and two (5.3%) by avascular necrosis of hip. At disease onset, the median ESR was 45 mm/h (range: 7–120), the median CRP was 9.8 mg/ L (range: 0.6–173) and the mean serum albumin was 33.1 6.6 g/L. The latest median ESR was 32 mm/h (range: 2–119), the median CRP was 4.3 mg/L (range: 0.4–115) and the mean serum albumin was 38.2 3.8 g/L. When patients with ADM were excluded, the median maximal CK was 1493 IU/L (range: 62–47199) and the median latest CK was 138 IU/L (range: 26–3272). According to the HAQDI scores, eight (21.1%) were moderately disabled (1 ≤ HAQDI < 2) and four (10.5%) were severely disabled (HAQDI ≥ 2). Only three (7.9%) patients had no disability (HAQDI = 0). The treatment characteristics are shown in Table 2. All patients had been treated with systemic corticosteroids, Table 2 Treatment data of the 38 idiopathic inflammatory myopathy patients (values represent n [%] unless otherwise specified) Ever use of systemic steroid (%) Ever use of high dose steroid (%) Duration of steroid use (months) Cumulative prednisolone dose (g) Average prednisolone dose (mg/day) Peak prednisolone dose (mg/day) Ever use of (%) Immunosuppressants Azathioprine Hydroxychloroquine Methotrexate Cyclosporin A Cyclophosphamide Mycophenolate mofetil Sulphasalazine Intravenous immunoglobulin Plasmaphoresis Use of (%) Calcium Vitamin D Bisphosphonates Strontium
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38 (100) 31 (81.6) Median 53 (range: 2–199) Median 14.3 (range: 1.02–62.8) Median 9.8 (range: 0.49–31.9) Median 50.0 (range: 10–80) 36 (94.7) 28 (73.7) 11 (28.9) 10 (26.3) 9 (23.7) 6 (15.8) 5 (13.2) 2 (5.3) 2 (5.3) 1 (2.6) 30 (78.9) 20 (52.6) 4 (10.5) 1 (2.6)
predominantly prednisolone. Thirty-one (81.6%) patients had been exposed to high-dose prednisolone. The median duration of corticosteroid use was 53 months (range: 2–199) and the median cumulative prednisolone dose was 14.3 g (range: 1.02–62.8). Corticosteroid could be weaned off only in six (15.8%) patients. The great majority (94.7%) of patients had been put on additional immunosuppressants, with azathioprine and methotrexate being the most common. Thirty (78.9%) patients were on calcium supplements and 20 (52.6%) of them were also on vitamin D. Bisphosphonates were given to four (10.5%) patients.
BMD results All BMD measurements of the 38 IIM patients were obtained by the two previously mentioned machines, except four patients who had recent DEXA done in other centers. One patient only had spinal results due to bilateral total hip replacement as a consequence of avascular necrosis. The mean lumbar spine BMD was 0.89 0.15 g/cm2 and that of the femoral neck was 0.66 0.13 g/cm2. Nine (23.7%) patients had osteoporosis and 18 (47.4%) patients had osteopenia in one of the body parts, making the number of patients who had either osteoporosis or osteopenia 27 (71.1%).
Associated factors of reduced BMD The potential determinants of lumbar spine and hip BMD are listed in Table 3. Univariate analysis showed that MMT8 score, serum albumin level at onset and latest serum albumin level were positively associated with the lumbar spine BMD. On the other hand, female gender, HAQDI score, physician global damage score and MYOACT score were negatively associated with spine BMD. For the hip, MMT8 score and the latest serum albumin levels were associated with higher BMD. Female gender, high HAQ score, high physician and patient global damage scores, high MYOACT score and increased cumulative corticosteroid dosage were associated with lower hip BMD. All variables significantly correlated with BMD in the univariate analysis were put into the multiple linear regression model. Female gender and lower serum albumin level at onset were found to be unfavorably associated with spinal BMD, while for the hip, the risk factors for lower BMD were high MYOACT score and increased cumulative corticosteroid dose. Some conventional risk factors such as smoking and drinking were not found to be associated with reduced BMD in this study. At the same time, the type of IIM, the duration of disease and the presence or absence of
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International Journal of Rheumatic Diseases 2016; 19: 521–528 0.14 0.081 0.35 0.326
Maximal CK Latest CK Albumin at onset
Latest albumin Complication Yes No Cumulative prednisolone dose (g) 0.87 0.93 0.19
0.27
0.20
0.046
0.41 0.63 0.034
0.68 0.005 0.023 0.042 0.092 0.042
0.92
0.89 0.90 0.87 0.07 0.45 0.37 0.33 0.28 0.33
0.16
0.70 0.90
0.053 0.88 0.41
0.32 0.025
0.037
P
0.93 0.88
1.02 0.87
Sex Male Female Age BMI Smoking Yes No Drinking Yes No Type of myositis DM PM ADM Duration of disease MMT8 HAQDI Physician damage score Patient damage score MYOACT
BMD (g/cm ) (mean) r
Univariate 2
Multivariate
0.009 (0.002, 0.016)
0.16 (0.039, 0.278)
Unstandar-dized b (95% CI)
Lumbar spine
Table 3 Potential determinants of spine and hip bone mineral density
0.01
0.011
P
0.65 0.68
0.64 0.67 0.71
0.62 0.66
0.72 0.64
0.64 0.76
0.47
0.51
0.049 0.76 0.24
0.21 0.57 0.33 0.40 0.51 0.57
0.23 0.06
r
Univariate BMD (g/cm ) (mean)
2
0.004
0.25
0.001
0.77 0.66 0.16
0.22 < 0.001 0.049 0.014 0.001 < 0.001
0.58
0.81
0.15
0.18 0.73
0.035
P
Multivariate
0.040)
2.87 3 10 6 ( 5.21 3 10 6, 5.25 3 10 7)
0.08 ( 0.121,
Unstandar-dized b (95% CI)
Femoral neck
0.018
< 0.001
P
Reduced bone mineral density in myositis
525
0.65 0.71
P
0.61
0.51 0.11
r BMD (g/cm ) (mean)
Average prednisolone dose Ever high-dose steroid Yes No
0.88 0.93
2
Univariate
P
Unstandar-dized b (95% CI)
Multivariate Lumbar spine Table 3 (continued)
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r2 = 0.361 for lumbar spine model; 0.426 for femoral neck model. BMI, body mass index; DM, dermatomyositis; PM, polymyositis; ADM, amyopathic dermatomyositis; MMT8, Manual Muscle Testing 8; HAQDI, Health Assessment Questionnaire Disability Index; MYOACT, Myositis Disease Activity Assessment Visual Analogue Scale; CK, creatinine kinase. Statistically significant values are in bold.
0.31
0.11
0.53
Unstandar-dized b (95% CI) r BMD (g/cm ) (mean)
2
Univariate
P
Femoral neck
Multivariate
P
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complications were not shown to affect BMD. Muscle enzyme levels also did not correlate with BMD, even after excluding patients with ADM in subgroup analyses.
DISCUSSION In this study, we found a high prevalence of osteoporosis (23.7%) and osteopenia (47.4%). In a study by Ponyi et al.20 on functional outcome and quality of life in adult IIM patients, 22 (25%) were labeled as having corticosteroid-induced osteoporosis on the basis of evaluating the clinical records. In a Russian study, the prevalence of osteoporosis was found to be 31% in a cohort of 42 female IIM patients.21 In another study on concomitant diseases in 55 patients with IIMs, 30.9% of the patients were found to have either osteoporosis or osteopenia, again from retrospective review of medical records.22 Apparently, the results of these studies should not be directly compared with those of the current one due to the vast differences in the patient population and methodology. However, they all pointed out that reduced BMD was prevalent in patients with IIMs. There are several possible explanations for the high prevalence of reduced BMD in patients with IIMs. First, previous studies suggested that disability and reduced mobility are important determinants of bone loss in different rheumatic diseases.5 Patients with IIMs were known to have significant disability. In the study by Ponyi et al.20 mentioned earlier, the majority of patients were mildly to moderately disabled according to the HAQDI scores: 12.5% of the patients were severely disabled, while only 17.5% had no disability. Our patients with IIMs had a similar level of disability with 81.6% being mildly or moderately disabled and 10.5% being severely disabled. Second, it was found that uncontrolled disease activity and systemic inflammation had detrimental effects on bone density.5,12 Chronic inflammation of the muscle, and skin in cases of DM, are the hallmarks of IIMs. In our study, the significant inflammatory burden may be reflected by high ESR, high CRP and low serum albumin at disease onset. Lastly, pharmacological agents, most importantly systemic corticosteroids, can adversely affect bone density.5,12 Corticosteroid has been the cornerstone of treatment and a high dose is employed typically at least initially in patients with IIMs.23 This is exemplified in our cohort that all patients have been put on systemic corticosteroids and the majority (81.6%) had exposure to high doses.
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High cumulative doses of corticosteroid were found to be independently associated with lower hip BMD in our study. As mentioned earlier, it has been well studied that corticosteroids have detrimental effects on bone health. Corticosteroids adversely affect the bone by decreasing osteoblast function, increasing osteoblast and osteocyte apoptosis and impairing preosteoblast formation.24 Our result is in agreement with the data from a meta-analysis on the skeletal effect of corticosteroids that found strong correlations between cumulative doses of oral corticosteroids and loss of BMD independent of underlying disease.25 However, the association of corticosteroids with low BMD in rheumatic diseases was inconsistent in the literature. A large study of osteoporosis in SLE patients by Petri found a strong association of BMD with cumulative prednisolone doses.12 On the other hand, four studies failed to identify any dependency of low bone mass in patients who had SLE and were taking corticosteroids.26–29 In RA, a crosssectional study on 925 patients found that the use of corticosteroids was an independent predictor of reduced BMD.13 Conversely, a cross-sectional study on 146 female RA patients concluded that long disease duration, severity of disease and decreased lean body mass, but not corticosteroids, were associated with generalized osteoporosis.30 It was postulated that the adverse effect of corticosteroids on bone may be outweighed by the benefit of suppression of uncontrolled disease activity and inflammation.31 There was evidence in our study that active disease could adversely affect bone. Low MMT8 score, high MYOACT score and low serum albumin levels were found to be correlated with a lower spine or hip BMD in univariate analysis. Low serum albumin at onset, which was postulated to reflect significant systemic inflammation, and high MYOACT score were unfavorable factors in the regression models of spine and hip BMD, respectively. Bone resorption has been found to be increased by systemic inflammation as a result of increased number of various cytokines.31 In RA, it has also been found that a persistently elevated CRP, another marker of inflammation, was the single best predictor of BMD and suppression of disease activity stabilized bone loss,32 while in SLE, a study demonstrated a lower BMD as compared with controls in patients who had never been treated with corticosteroids, which indicates that the disease activity, per se, may induce bone loss.33 IIMs are characterized by inflammation of the muscles or skin with increased expression of many types of cytokines in immunohistochemistry studies.34 Further studies are necessary to
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evaluate the effect of these molecules on bone health in patients with IIMs. As this study is of a cross-sectional design, BMD of the patients were measured at different moments in their disease. It also does not allow accurate evaluation of some risk factors for low BMD, such as disease activity, which may change over time. A prospective cohort study may provide better information about the timevariant factors that influence bone mass. The lack of a control group is another major limitation. A further case control study, using normal subjects or patients with other rheumatic diseases as controls, will help to prove if IIM patients are truly at greater risk of reduced BMD. In conclusion, our study is one of the few which focuses on BMD in patients with IIMs. It demonstrated a high prevalence of reduced BMD (71.1%). There was evidence in this study that large corticosteroid dose and certain indicators of high disease activity were associated with bone loss. More liberal assessment of BMD and use of anti-osteoporotic drugs are advisable. At the same time, early use of steroid-sparing agents to minimize steroid exposure and to obtain a prompt and stable disease control may be helpful. Early intensive rehabilitation for patients with significant disability would also be equally important.
REFERENCES 1 Consensus Development Conference (1991) Prophylaxis and treatment of osteoporosis. Osteoporos Int 1, 114–7. 2 Office of Technology Assessment, Congress of the United States (1993) Hip Fracture Outcomes in People Aged Fifty and Over: Mortality, Service Use, Expenditures, and Long-term Functional Impairment. Office of Technology Assessment, Congress of the United States, Washington, DC. US Department of Commerce Publication NTIS PB94107653. 3 Falch J, Aho H, Berglund K et al. (1995) Hip fractures in Nordic cities: difference in incidence. Ann Chir Gynaecol 84, 286–90. 4 Dennison E, Mohamed MA, Cooper C (2006) Epidemiology of osteoporosis. Rheum Dis Clin North Am 32, 617–29. 5 Luigi S, Massimo V, Giuseppe G (2006) Epidemiology of osteoporosis in rheumatic disease. Clin Exp Rheuamtol 32, 631–58. 6 Mok CC, Ying S, To CH, Ma KM (2008) Bone mineral density and body composition in men with systemic lupus erythermatosus: a case control study. Bone 43, 327– 31. 7 Bilboe IM, Kvien TK, Haugeberg G (2000) Bone mineral density in systemic lupus erythematosus: comparison with rheumatoid arthritis and healthy controls. Ann Rheum Dis 59, 110–5.
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8 Yee CS, Crabtree N, Skan J et al. (2005) Prevalence and predictors of fragility fractures in systemic lupus erythermatosus. Ann Rheum Dis 64, 111–3. 9 Mok CC, Mak A, Ma KM (2005) Bone mineral density in postmenopausal Chinese patients with systemic lupus erythermatosus. Lupus 14, 106–12. 10 Almehed K, Forsblad H, Kvist G, Ohlsson C, Carlsten H (2007) Prevalence and risk factors of osteoporosis in female SLE patients – extended report. Rheumatology (Oxford) 46, 1185–90. 11 Lee C, Ramsey-Goldman R (2005) Osteoporosis in systemic lupus erythermatosus mechanisms. Rheum Dis Clin North Am 31, 363–85. 12 Petri M (1995) Musculoskeletal complications of systemic lupus erythermatosus in the Hopkins Lupus Cohort: an update. Arthritis Care Res 8, 137–45. 13 Sinigaglia L, Nervetti A, Mela Q et al. (2000) A multi-center cross-sectional study on bone mineral density in rheumatoid arthritis. J Rheumatol 27, 2582–9. 14 Bohan A, Peter JB (1995) Polymyositis and dermatomyositis. N Engl J Med 292, 344–7 403–7. 15 Sontheimer RD (1999) Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis. Curr Opin Rheumatol 11, 475–82. 16 Isenberg DA, Allen E, Farewell V et al. (2004) International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis and damage indices in patients with adult onset disease. Rheumatology (Oxford) 43, 49–54. 17 Looker AC, Wahner HW, Dunn WL et al. (1998) Updated data on proximal femur bone mineral levels of US adults. Osteoporos Int 8, 468–89. 18 World Health Organization (1994) Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis. WHO Technical Report Series 843. WHO, Geneva. 19 World Health Organization (1995) Physical Status: The Use and Interpretation of Anthropometry. Report of a WHO Expert Committee. WHO Technical Report Series 854. WHO, Geneva. 20 Ponyi A, Borgulya G, Constantin T, Vancsa A, Gergely L, Danko K (2005) Functional outcome and quality of life in adult patients with idiopathic inflammatory myositis. Rheumatology (Oxford) 44, 83–8. 21 Antelava OA, Smirnov AV, Demin NV, Khitrov AN, Benevolenskaia LI, Nasonov EL (2003) Bone mineral density in
528
22
23
24 25
26
27
28
29
30
31
32
33
34
idiopathic inflammatory myopathies. Klin Med (Mosk) 81 (8), 57–61. Ng KP, Ramos F, Sultan SM, Isenberg DA (2009) Concomitant diseases in a cohort of patients with idiopathic myositis during long-term follow-up. Clin Rheumatol 28, 947–53. Dalakas MC (2006) Therapeutic targets in patients with inflammatory myopathies: present approaches and a look to the future. Neuromuscul Disord 16, 223–36. Dore RK (2010) How to prevent glucocorticoid-induced osteoporosis. Cleve Clin J Med 77, 529–36. Van Staa TP, Leufkens HGM, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a metaanalysis. Osteoporos Int 13, 777–87. Kalla AA, Fataar AB, Jessop SJ, Bewerunge L (1993) Loss of trabecular bone mineral density in systemic lupus erythematosus. Arthritis Rheum 12, 1726–34. Formiga F, Moga I, Nolla JM, Pac M, Mitjavila F, RoigEscofet D (1995) Loss of bone mineral density in premenopausal women with systemic lupus erythematosus. Ann Rheum Dis 54, 274–6. Li EK, Tam LS, Young RP, Ko GT, Li M, Lau EM (1998) Loss of bone mineral density in Chinese premenopausal women with systemic lupus erythematosus treated with corticosteroids. Br J Rheumatol 37, 405–10. Pineau CA, Urowitz MB, Fortin D, Ibanez D, Gladman DD (2004) Osteoporosis in systemic lupus erythematosus: factors associated with referral for bone mineral density studies, prevalence of osteoporosis and factors associated with reduced bone density. Lupus 13, 436–41. Shibuya K, Hagino H, Morio Y, Teshima R (2002) Crosssectional and longitudinal study of osteoporosis in patients with rheumatoid arthritis. Clin Rheumatol 21, 150–8. Schett G, Saag KG, Bijlsma J (2010) From bone biology to clinical outcome: state of the art and future perspectives. Ann Rheum Dis 69, 1415–9. Cough AKS, Lilley J, Eyre S (1994) Generalized bone loss in patients with early rheumatoid arthritis. Lancet 344, 23– 7. Houssiau FA, Lefebvre C, Depresseux G, Lambert M, Devogelaer JP, Nagant-de-Deuxchaisnes C (1996) Trabecular and cortical bone loss in systemic lupus erythematosus. Br J Rheumatol 35, 244–7. Wortmann R (2008). Idiopathic inflammatory myopathies. In: Klippel J, Stone J, White P (eds) Primer on the Rheumatic Diseases, pp 353–80. Springer, New York.
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ORIGINAL ARTICLE
Prevalence and associated factors of reduced bone mineral density in patients with idiopathic inflammatory myopathies Ho SO, Man Lung YIP and Andrew Kui Man WONG Department of Medicine and Geriatrics, Kwong Wah Hospital, Kowloon, Hong Kong
Abstract Aim: To determine the prevalence and identify the associated factors of reduced bone mineral density (BMD) in patients with idiopathic inflammatory myopathies (IIMs). Method: Existing patients diagnosed to have IIMs were recruited for measurement of BMD by dual energy X-ray absorptiometry. Demographic, clinical and treatment variables of these patients were recorded. The prevalence of osteopenia and osteoporosis were calculated. Using multivariate analysis, the independent associated factors for reduced BMD were evaluated. Results: Thirty-eight patients with IIMs completed the study with 32 (84.2%) being female. The mean age of the patients was 52.8 13.0 years. Nine (23.7%) patients had osteoporosis and 18 (47.4%) had osteopenia. Multivariate analysis revealed female gender and low serum albumin levels at onset were associated with lower spinal BMD. For femoral neck, the factors associated with lower BMD were high Myositis Disease Activity Assessment Visual Analogue Scales (MYOACT) score and high cumulative prednisolone dose. Conclusions: Reduced BMD is prevalent in patients with IIMs. Female gender, low serum albumin level at onset, high disease activity and high cumulative corticosteroid dose appeared to be the independent associated factors. Regular assessment of BMD is advisable. The use of anti-osteoporotic and steroid-sparing agents should be encouraged. Key words: idiopathic inflammatory myopathies, osteopenia, osteoporosis, reduced bone mineral density.
INTRODUCTION The last two decades have seen major advances in the treatment of rheumatic diseases, resulting in a significant improvement in patient survival. Emphasis started to be put on prevention of long-term problems and medication side-effects such as osteoporosis. Osteoporosis is characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in increased bone fragility and susceptibility to fracture.1 In the United States, 1 year after hip fracture, 40% of the patients aged 50 and above were unable to walk
Correspondence: Dr Ho So, Kwong Wah Hospital, 25 Waterloo Road, Kowloon, Hong Kong. Email: [email protected]
independently and 60% required assistance with at least 1 activity of daily living.2 Fractures were also associated with excess mortality. The 5-year survival for male patients with vertebral fractures was 72% and that for women was 84%.3 Further, the annual cost to the healthcare system from osteoporotic fractures has been estimated at 17.9 billion US dollars in the United States.4 Nevertheless, reduced bone mineral density (BMD) and the consequent fragility fractures are treatable and more importantly preventable. Many studies have shown that reduced BMD is prevalent in inflammatory musculoskeletal conditions.5–10 Osteoporosis occurred in up to 40% of patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE).5,6 The potential mechanisms of bone loss in rheumatic diseases include induction of the
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
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bone-resorbing cytokines as a result of systemic inflammation, reduced mobility and the use of systemic corticosteroids for treatment.5,11–13 Idiopathic inflammatory myopathies (IIMs), including dermatomyositis (DM) and polymyositis (PM), are characterized by chronic inflammation of muscle that results in skeletal muscle weakness. Therefore, patients with IIMs may be physically more disabled than SLE patients. At the same time, systemic corticosteroid is the mainstay of treatment for IIMs. Thus, IIM patients usually require higher corticosteroid doses than RA patients. As a result, they may be at particularly high risk for bone loss. However, the data regarding reduced BMD in patients with IIMs are scanty. On the other hand, there are still controversies concerning the predictors of bone loss in patients with inflammatory musculoskeletal conditions, especially corticosteroid use. In this cross-sectional study, we aimed to assess the prevalence of reduced BMD in our patients with IIMs. We further intended to study its association with various demographic, disease and treatment variables.
MATERIALS AND METHODS Patients Existing patients with IIMs followed up in the rheumatology clinics in Kwong Wah Hospital and Queen Mary Hospital in Hong Kong were invited to participate in the study during the clinic visits from September 2010 to March 2011. Patients with DM and PM had to fulfill the Bohan-Peter criteria.14 Patients with amyopathic dermatomyositis (ADM) who had the typical Gottron’s rash or heliotrope rash as determined by rheumatologists or dermatologists but with no symptoms or signs of muscle involvement were also included.15 Pregnant patients or patients who had juvenile onset disease (< 18 years old), non-Asian ethnicity or documented metabolic bone disorders were excluded from the study.
Data collection Participants of the study were interviewed and examined during the clinic visits. Their clinical records were also reviewed. For each patient, demographic data, including current age, sex, body mass index (BMI), menopausal status, personal history of smoking and drinking and family history of low-impact fracture were collected. Significant smoking and drinking history was defined as daily use of tobacco and alcohol for at least 3 years. Low impact fracture was defined as a fracture resulting from a fall of standing height or less.
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The disease characteristics including the type of myositis, presence of concomitant connective tissue diseases and duration of disease were obtained. Details of the treatment regimens, including the duration of corticosteroid use, peak corticosteroid dose, high-dose corticosteroids ever, cumulative corticosteroid dose, current corticosteroid dose, use of other immunosuppressants and use of anti-osteoporotic drugs were also recorded. High-dose corticosteroid use was defined as oral prednisolone more than 0.5 mg/kg body weight per day for more than 6 weeks. The activity of the myositis was evaluated using the tools developed by the International Myositis and Clinical Studies Group (IMACS).16 They included physician global activity – visual analogue scale (VAS), patient global activity – VAS, Manual Muscle Testing 8 (MMT8) and Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT). Maximal and latest levels of muscle enzymes, including creatinine kinase (CK) and lactate dehydrogenase (LDH) were collected. Biochemical markers of inflammation, including erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and serum albumin level at disease onset and 1 month within the assessment were also recorded. Physical disability of the patients was assessed by the self-administered Health Assessment Questionnaire Disability Index (HAQDI). The disease damage was evaluated using physician global damage – VAS and patient global damage – VAS. They are also tools endorsed by the IMACS and form part of the IMACS core set disease damage measures.16 Complications related to IIMs or its treatments which included interstitial lung disease, dysphagia, malignancy and avascular necrosis were also documented. Bone mineral density was measured by dual energy X-ray absorptiometry (DEXA) which was performed within 3 months of the assessment.
BMD measurement Bone mineral density of the lumbar spine (L1–L4) and left hip (femoral neck and total hip) was measured by DEXA using a Discovery SL densitometer with software version 12.3 (Hologic, Bedford, MA, USA) in the Kwong Wah Hospital Well Women Clinic for female patients and an Explorer densitometer with software version 12.5.2 (Hologic) in a private radiology center for male patients whenever possible. The machines were calibrated and measurements were assessed according to standard procedures. The precision of either machine calculated as a coefficient of variation was < 1.0%. The reference population used for female
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patients was the machine manufacturer’s database of Japanese women. For male patients, the reference was derived from the National Health and Nutrition Examination Survey (NHANES) database.17 All BMD results were expressed in absolute values (g/ cm2) and as the number of standard deviations (SD) above or below the mean results of young adults, the Tscore, as well as the mean results of the age matched population, the Z-score. Osteoporosis was defined using the 1994 World Health Organization (WHO)18 Classification as a T-score equal or less than 2.5, and osteopenia between 1 and 2.5.
Statistical analysis Descriptive statistics were presented for demographic and clinical data. Values were expressed as mean SD if they were normally distributed. Otherwise, they were expressed as median and range. Independent Student’s t-test was used for analyzing continuous variables with normal distribution and Mann–Whitney U-test for nonparametric continuous variables. Kruskal–Wallis test was used to compare means when there are more than two groups due to the small sample size. The associations between the continuous variables and BMD were assessed by Pearson’s correlation test or Spearman’s rank correlation test where appropriate. Probable associated factors identified in the univariate analysis were then entered into the multiple linear regression model to identify the independent variables for BMD. A P-value of < 0.05 was considered as statistically significant. SPSS 20.0 for Windows (SPSS Inc., Chicago, IL, USA) was used as a means of statistical analysis.
Ethics This study was approved by the local ethics committees (Kowloon West Cluster Ethical Committee and Hong Kong West Cluster Ethical Committee). It was conducted in full compliance with the Helsinki Declaration. All patients gave informed consent prior to participation.
Table 1 Demographic and clinical data of the 38 idiopathic inflammatory myopathy patients (values represent n [%] unless otherwise specified) Age (years) Gender Female (%) Menopausal (%) BMI (kg/m2) Smoking (%) Drinking (%) Underweight (BMI < 18.5 kg/m2) (%) Family history of fragility (%) Type (%) Dermatomyositis Polymyositis Amyopathic dermatomyositis Concomitant connective tissue disease (%) Rheumatoid arthritis (%) Mixed connective tissue disease (%) Systemic lupus erythematosus (%) Vasculitis (%) Scleroderma (%) Duration of disease (months) Complications (%) Interstitial lung disease (%) Dysphagia (%) Malignancy (%) Avascular necrosis (%) Health assessment questionnaire disability index (HAQDI) (%) HAQDI = 0 0 < HAQDI < 1 1 ≤ HAQDI < 2 HAQDI ≥ 2 Manual muscle testing 8 Myositis disease activity assessment visual analogue scale
Mean 52.8 (SD 13.0) 32 (84.2) 19/32 (59.4) Mean 23.8 (SD 3.94) 8 (21.1) 1 (2.6) 4 (10.5) 0 (0) 17 (44.7) 15 (39.5) 6 (15.8) 15 (39.5) 5/15 (33.3) 4/15 (26.7) 3/15 (20.0) 2/15 (13.3) 1/15 (6.7) Median 56.5 (range: 3–432) 23 (60.5) 21 (55.3) 5 (13.2) 2 (5.3) 2 (5.3)
3 (7.9) 23 (60.5) 8 (21.1) 4 (10.5) Median 75 (range: 66–80) Median 1.04 (range: 0–3.33)
BMI, body mass index.
RESULTS Demographic and disease-related variables Forty-seven patients were invited to participate in the study. Eight patients did not want to take part and one was lost to follow-up during the study period. At the end, 38 patients completed the study. The demographic and clinical characteristics of the participants are shown in Table 1. All patients were ethnic Chinese and their mean age was 52.8 13.0 years.
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There were 32 (84.2%) female patients with 19 (59.4%) of them being post-menopausal. Eight (21.1%) patients were smokers and one (2.6%) was a drinker. Four (10.5%) patients were underweight as defined by BMI < 18.5 kg/m2.19 None of the patients reported any family history of low-impact fracture. Seventeen (44.7%) patients had PM, 15 (39.5%) had DM and six (15.8%) had ADM. Fifteen (39.5%) patients had other concomitant connective tissue
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diseases. These included RA, mixed connective tissue disease, SLE, vasculitis and scleroderma, in descending order of frequency. The median duration of disease was 56.5 months (range: 3–432). Twenty-one (55.3%) patients were complicated by interstitial lung disease, five (13.2%) by dysphagia and two (5.3%) by avascular necrosis of hip. At disease onset, the median ESR was 45 mm/h (range: 7–120), the median CRP was 9.8 mg/ L (range: 0.6–173) and the mean serum albumin was 33.1 6.6 g/L. The latest median ESR was 32 mm/h (range: 2–119), the median CRP was 4.3 mg/L (range: 0.4–115) and the mean serum albumin was 38.2 3.8 g/L. When patients with ADM were excluded, the median maximal CK was 1493 IU/L (range: 62–47199) and the median latest CK was 138 IU/L (range: 26–3272). According to the HAQDI scores, eight (21.1%) were moderately disabled (1 ≤ HAQDI < 2) and four (10.5%) were severely disabled (HAQDI ≥ 2). Only three (7.9%) patients had no disability (HAQDI = 0). The treatment characteristics are shown in Table 2. All patients had been treated with systemic corticosteroids, Table 2 Treatment data of the 38 idiopathic inflammatory myopathy patients (values represent n [%] unless otherwise specified) Ever use of systemic steroid (%) Ever use of high dose steroid (%) Duration of steroid use (months) Cumulative prednisolone dose (g) Average prednisolone dose (mg/day) Peak prednisolone dose (mg/day) Ever use of (%) Immunosuppressants Azathioprine Hydroxychloroquine Methotrexate Cyclosporin A Cyclophosphamide Mycophenolate mofetil Sulphasalazine Intravenous immunoglobulin Plasmaphoresis Use of (%) Calcium Vitamin D Bisphosphonates Strontium
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38 (100) 31 (81.6) Median 53 (range: 2–199) Median 14.3 (range: 1.02–62.8) Median 9.8 (range: 0.49–31.9) Median 50.0 (range: 10–80) 36 (94.7) 28 (73.7) 11 (28.9) 10 (26.3) 9 (23.7) 6 (15.8) 5 (13.2) 2 (5.3) 2 (5.3) 1 (2.6) 30 (78.9) 20 (52.6) 4 (10.5) 1 (2.6)
predominantly prednisolone. Thirty-one (81.6%) patients had been exposed to high-dose prednisolone. The median duration of corticosteroid use was 53 months (range: 2–199) and the median cumulative prednisolone dose was 14.3 g (range: 1.02–62.8). Corticosteroid could be weaned off only in six (15.8%) patients. The great majority (94.7%) of patients had been put on additional immunosuppressants, with azathioprine and methotrexate being the most common. Thirty (78.9%) patients were on calcium supplements and 20 (52.6%) of them were also on vitamin D. Bisphosphonates were given to four (10.5%) patients.
BMD results All BMD measurements of the 38 IIM patients were obtained by the two previously mentioned machines, except four patients who had recent DEXA done in other centers. One patient only had spinal results due to bilateral total hip replacement as a consequence of avascular necrosis. The mean lumbar spine BMD was 0.89 0.15 g/cm2 and that of the femoral neck was 0.66 0.13 g/cm2. Nine (23.7%) patients had osteoporosis and 18 (47.4%) patients had osteopenia in one of the body parts, making the number of patients who had either osteoporosis or osteopenia 27 (71.1%).
Associated factors of reduced BMD The potential determinants of lumbar spine and hip BMD are listed in Table 3. Univariate analysis showed that MMT8 score, serum albumin level at onset and latest serum albumin level were positively associated with the lumbar spine BMD. On the other hand, female gender, HAQDI score, physician global damage score and MYOACT score were negatively associated with spine BMD. For the hip, MMT8 score and the latest serum albumin levels were associated with higher BMD. Female gender, high HAQ score, high physician and patient global damage scores, high MYOACT score and increased cumulative corticosteroid dosage were associated with lower hip BMD. All variables significantly correlated with BMD in the univariate analysis were put into the multiple linear regression model. Female gender and lower serum albumin level at onset were found to be unfavorably associated with spinal BMD, while for the hip, the risk factors for lower BMD were high MYOACT score and increased cumulative corticosteroid dose. Some conventional risk factors such as smoking and drinking were not found to be associated with reduced BMD in this study. At the same time, the type of IIM, the duration of disease and the presence or absence of
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International Journal of Rheumatic Diseases 2016; 19: 521–528 0.14 0.081 0.35 0.326
Maximal CK Latest CK Albumin at onset
Latest albumin Complication Yes No Cumulative prednisolone dose (g) 0.87 0.93 0.19
0.27
0.20
0.046
0.41 0.63 0.034
0.68 0.005 0.023 0.042 0.092 0.042
0.92
0.89 0.90 0.87 0.07 0.45 0.37 0.33 0.28 0.33
0.16
0.70 0.90
0.053 0.88 0.41
0.32 0.025
0.037
P
0.93 0.88
1.02 0.87
Sex Male Female Age BMI Smoking Yes No Drinking Yes No Type of myositis DM PM ADM Duration of disease MMT8 HAQDI Physician damage score Patient damage score MYOACT
BMD (g/cm ) (mean) r
Univariate 2
Multivariate
0.009 (0.002, 0.016)
0.16 (0.039, 0.278)
Unstandar-dized b (95% CI)
Lumbar spine
Table 3 Potential determinants of spine and hip bone mineral density
0.01
0.011
P
0.65 0.68
0.64 0.67 0.71
0.62 0.66
0.72 0.64
0.64 0.76
0.47
0.51
0.049 0.76 0.24
0.21 0.57 0.33 0.40 0.51 0.57
0.23 0.06
r
Univariate BMD (g/cm ) (mean)
2
0.004
0.25
0.001
0.77 0.66 0.16
0.22 < 0.001 0.049 0.014 0.001 < 0.001
0.58
0.81
0.15
0.18 0.73
0.035
P
Multivariate
0.040)
2.87 3 10 6 ( 5.21 3 10 6, 5.25 3 10 7)
0.08 ( 0.121,
Unstandar-dized b (95% CI)
Femoral neck
0.018
< 0.001
P
Reduced bone mineral density in myositis
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0.65 0.71
P
0.61
0.51 0.11
r BMD (g/cm ) (mean)
Average prednisolone dose Ever high-dose steroid Yes No
0.88 0.93
2
Univariate
P
Unstandar-dized b (95% CI)
Multivariate Lumbar spine Table 3 (continued)
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r2 = 0.361 for lumbar spine model; 0.426 for femoral neck model. BMI, body mass index; DM, dermatomyositis; PM, polymyositis; ADM, amyopathic dermatomyositis; MMT8, Manual Muscle Testing 8; HAQDI, Health Assessment Questionnaire Disability Index; MYOACT, Myositis Disease Activity Assessment Visual Analogue Scale; CK, creatinine kinase. Statistically significant values are in bold.
0.31
0.11
0.53
Unstandar-dized b (95% CI) r BMD (g/cm ) (mean)
2
Univariate
P
Femoral neck
Multivariate
P
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complications were not shown to affect BMD. Muscle enzyme levels also did not correlate with BMD, even after excluding patients with ADM in subgroup analyses.
DISCUSSION In this study, we found a high prevalence of osteoporosis (23.7%) and osteopenia (47.4%). In a study by Ponyi et al.20 on functional outcome and quality of life in adult IIM patients, 22 (25%) were labeled as having corticosteroid-induced osteoporosis on the basis of evaluating the clinical records. In a Russian study, the prevalence of osteoporosis was found to be 31% in a cohort of 42 female IIM patients.21 In another study on concomitant diseases in 55 patients with IIMs, 30.9% of the patients were found to have either osteoporosis or osteopenia, again from retrospective review of medical records.22 Apparently, the results of these studies should not be directly compared with those of the current one due to the vast differences in the patient population and methodology. However, they all pointed out that reduced BMD was prevalent in patients with IIMs. There are several possible explanations for the high prevalence of reduced BMD in patients with IIMs. First, previous studies suggested that disability and reduced mobility are important determinants of bone loss in different rheumatic diseases.5 Patients with IIMs were known to have significant disability. In the study by Ponyi et al.20 mentioned earlier, the majority of patients were mildly to moderately disabled according to the HAQDI scores: 12.5% of the patients were severely disabled, while only 17.5% had no disability. Our patients with IIMs had a similar level of disability with 81.6% being mildly or moderately disabled and 10.5% being severely disabled. Second, it was found that uncontrolled disease activity and systemic inflammation had detrimental effects on bone density.5,12 Chronic inflammation of the muscle, and skin in cases of DM, are the hallmarks of IIMs. In our study, the significant inflammatory burden may be reflected by high ESR, high CRP and low serum albumin at disease onset. Lastly, pharmacological agents, most importantly systemic corticosteroids, can adversely affect bone density.5,12 Corticosteroid has been the cornerstone of treatment and a high dose is employed typically at least initially in patients with IIMs.23 This is exemplified in our cohort that all patients have been put on systemic corticosteroids and the majority (81.6%) had exposure to high doses.
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High cumulative doses of corticosteroid were found to be independently associated with lower hip BMD in our study. As mentioned earlier, it has been well studied that corticosteroids have detrimental effects on bone health. Corticosteroids adversely affect the bone by decreasing osteoblast function, increasing osteoblast and osteocyte apoptosis and impairing preosteoblast formation.24 Our result is in agreement with the data from a meta-analysis on the skeletal effect of corticosteroids that found strong correlations between cumulative doses of oral corticosteroids and loss of BMD independent of underlying disease.25 However, the association of corticosteroids with low BMD in rheumatic diseases was inconsistent in the literature. A large study of osteoporosis in SLE patients by Petri found a strong association of BMD with cumulative prednisolone doses.12 On the other hand, four studies failed to identify any dependency of low bone mass in patients who had SLE and were taking corticosteroids.26–29 In RA, a crosssectional study on 925 patients found that the use of corticosteroids was an independent predictor of reduced BMD.13 Conversely, a cross-sectional study on 146 female RA patients concluded that long disease duration, severity of disease and decreased lean body mass, but not corticosteroids, were associated with generalized osteoporosis.30 It was postulated that the adverse effect of corticosteroids on bone may be outweighed by the benefit of suppression of uncontrolled disease activity and inflammation.31 There was evidence in our study that active disease could adversely affect bone. Low MMT8 score, high MYOACT score and low serum albumin levels were found to be correlated with a lower spine or hip BMD in univariate analysis. Low serum albumin at onset, which was postulated to reflect significant systemic inflammation, and high MYOACT score were unfavorable factors in the regression models of spine and hip BMD, respectively. Bone resorption has been found to be increased by systemic inflammation as a result of increased number of various cytokines.31 In RA, it has also been found that a persistently elevated CRP, another marker of inflammation, was the single best predictor of BMD and suppression of disease activity stabilized bone loss,32 while in SLE, a study demonstrated a lower BMD as compared with controls in patients who had never been treated with corticosteroids, which indicates that the disease activity, per se, may induce bone loss.33 IIMs are characterized by inflammation of the muscles or skin with increased expression of many types of cytokines in immunohistochemistry studies.34 Further studies are necessary to
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evaluate the effect of these molecules on bone health in patients with IIMs. As this study is of a cross-sectional design, BMD of the patients were measured at different moments in their disease. It also does not allow accurate evaluation of some risk factors for low BMD, such as disease activity, which may change over time. A prospective cohort study may provide better information about the timevariant factors that influence bone mass. The lack of a control group is another major limitation. A further case control study, using normal subjects or patients with other rheumatic diseases as controls, will help to prove if IIM patients are truly at greater risk of reduced BMD. In conclusion, our study is one of the few which focuses on BMD in patients with IIMs. It demonstrated a high prevalence of reduced BMD (71.1%). There was evidence in this study that large corticosteroid dose and certain indicators of high disease activity were associated with bone loss. More liberal assessment of BMD and use of anti-osteoporotic drugs are advisable. At the same time, early use of steroid-sparing agents to minimize steroid exposure and to obtain a prompt and stable disease control may be helpful. Early intensive rehabilitation for patients with significant disability would also be equally important.
REFERENCES 1 Consensus Development Conference (1991) Prophylaxis and treatment of osteoporosis. Osteoporos Int 1, 114–7. 2 Office of Technology Assessment, Congress of the United States (1993) Hip Fracture Outcomes in People Aged Fifty and Over: Mortality, Service Use, Expenditures, and Long-term Functional Impairment. Office of Technology Assessment, Congress of the United States, Washington, DC. US Department of Commerce Publication NTIS PB94107653. 3 Falch J, Aho H, Berglund K et al. (1995) Hip fractures in Nordic cities: difference in incidence. Ann Chir Gynaecol 84, 286–90. 4 Dennison E, Mohamed MA, Cooper C (2006) Epidemiology of osteoporosis. Rheum Dis Clin North Am 32, 617–29. 5 Luigi S, Massimo V, Giuseppe G (2006) Epidemiology of osteoporosis in rheumatic disease. Clin Exp Rheuamtol 32, 631–58. 6 Mok CC, Ying S, To CH, Ma KM (2008) Bone mineral density and body composition in men with systemic lupus erythermatosus: a case control study. Bone 43, 327– 31. 7 Bilboe IM, Kvien TK, Haugeberg G (2000) Bone mineral density in systemic lupus erythematosus: comparison with rheumatoid arthritis and healthy controls. Ann Rheum Dis 59, 110–5.
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8 Yee CS, Crabtree N, Skan J et al. (2005) Prevalence and predictors of fragility fractures in systemic lupus erythermatosus. Ann Rheum Dis 64, 111–3. 9 Mok CC, Mak A, Ma KM (2005) Bone mineral density in postmenopausal Chinese patients with systemic lupus erythermatosus. Lupus 14, 106–12. 10 Almehed K, Forsblad H, Kvist G, Ohlsson C, Carlsten H (2007) Prevalence and risk factors of osteoporosis in female SLE patients – extended report. Rheumatology (Oxford) 46, 1185–90. 11 Lee C, Ramsey-Goldman R (2005) Osteoporosis in systemic lupus erythermatosus mechanisms. Rheum Dis Clin North Am 31, 363–85. 12 Petri M (1995) Musculoskeletal complications of systemic lupus erythermatosus in the Hopkins Lupus Cohort: an update. Arthritis Care Res 8, 137–45. 13 Sinigaglia L, Nervetti A, Mela Q et al. (2000) A multi-center cross-sectional study on bone mineral density in rheumatoid arthritis. J Rheumatol 27, 2582–9. 14 Bohan A, Peter JB (1995) Polymyositis and dermatomyositis. N Engl J Med 292, 344–7 403–7. 15 Sontheimer RD (1999) Cutaneous features of classic dermatomyositis and amyopathic dermatomyositis. Curr Opin Rheumatol 11, 475–82. 16 Isenberg DA, Allen E, Farewell V et al. (2004) International consensus outcome measures for patients with idiopathic inflammatory myopathies. Development and initial validation of myositis and damage indices in patients with adult onset disease. Rheumatology (Oxford) 43, 49–54. 17 Looker AC, Wahner HW, Dunn WL et al. (1998) Updated data on proximal femur bone mineral levels of US adults. Osteoporos Int 8, 468–89. 18 World Health Organization (1994) Assessment of Fracture Risk and Its Application to Screening for Postmenopausal Osteoporosis. WHO Technical Report Series 843. WHO, Geneva. 19 World Health Organization (1995) Physical Status: The Use and Interpretation of Anthropometry. Report of a WHO Expert Committee. WHO Technical Report Series 854. WHO, Geneva. 20 Ponyi A, Borgulya G, Constantin T, Vancsa A, Gergely L, Danko K (2005) Functional outcome and quality of life in adult patients with idiopathic inflammatory myositis. Rheumatology (Oxford) 44, 83–8. 21 Antelava OA, Smirnov AV, Demin NV, Khitrov AN, Benevolenskaia LI, Nasonov EL (2003) Bone mineral density in
528
22
23
24 25
26
27
28
29
30
31
32
33
34
idiopathic inflammatory myopathies. Klin Med (Mosk) 81 (8), 57–61. Ng KP, Ramos F, Sultan SM, Isenberg DA (2009) Concomitant diseases in a cohort of patients with idiopathic myositis during long-term follow-up. Clin Rheumatol 28, 947–53. Dalakas MC (2006) Therapeutic targets in patients with inflammatory myopathies: present approaches and a look to the future. Neuromuscul Disord 16, 223–36. Dore RK (2010) How to prevent glucocorticoid-induced osteoporosis. Cleve Clin J Med 77, 529–36. Van Staa TP, Leufkens HGM, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a metaanalysis. Osteoporos Int 13, 777–87. Kalla AA, Fataar AB, Jessop SJ, Bewerunge L (1993) Loss of trabecular bone mineral density in systemic lupus erythematosus. Arthritis Rheum 12, 1726–34. Formiga F, Moga I, Nolla JM, Pac M, Mitjavila F, RoigEscofet D (1995) Loss of bone mineral density in premenopausal women with systemic lupus erythematosus. Ann Rheum Dis 54, 274–6. Li EK, Tam LS, Young RP, Ko GT, Li M, Lau EM (1998) Loss of bone mineral density in Chinese premenopausal women with systemic lupus erythematosus treated with corticosteroids. Br J Rheumatol 37, 405–10. Pineau CA, Urowitz MB, Fortin D, Ibanez D, Gladman DD (2004) Osteoporosis in systemic lupus erythematosus: factors associated with referral for bone mineral density studies, prevalence of osteoporosis and factors associated with reduced bone density. Lupus 13, 436–41. Shibuya K, Hagino H, Morio Y, Teshima R (2002) Crosssectional and longitudinal study of osteoporosis in patients with rheumatoid arthritis. Clin Rheumatol 21, 150–8. Schett G, Saag KG, Bijlsma J (2010) From bone biology to clinical outcome: state of the art and future perspectives. Ann Rheum Dis 69, 1415–9. Cough AKS, Lilley J, Eyre S (1994) Generalized bone loss in patients with early rheumatoid arthritis. Lancet 344, 23– 7. Houssiau FA, Lefebvre C, Depresseux G, Lambert M, Devogelaer JP, Nagant-de-Deuxchaisnes C (1996) Trabecular and cortical bone loss in systemic lupus erythematosus. Br J Rheumatol 35, 244–7. Wortmann R (2008). Idiopathic inflammatory myopathies. In: Klippel J, Stone J, White P (eds) Primer on the Rheumatic Diseases, pp 353–80. Springer, New York.
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