Rheumatol Int DOI 10.1007/s00296-011-1821-2
ORIGINAL ARTICLE
High frequency of osteoporosis and fractures in women with dermatomyositis/polymyositis Danieli Castro Oliveira de Andrade • Sonia Cristina de Magalha˜es Souza • Joze´lio Freire de Carvalho • Liliam Takayama • Claudia Teresa Lobato Borges Jose´ Mendes Aldrighi • Rosa Maria Rodrigues Pereira
•
Received: 2 October 2010 / Accepted: 30 January 2011 Ó Springer-Verlag 2011
Abstract Bone mass was only previously studied in juvenile dermatomyositis/polymyositis (DM/PM) patients. Therefore, the objective this study was to evaluate the prevalence of osteoporosis and fractures in adult DM/PM. Forty female DM/PM and 78 age-, gender-, and BMImatched healthy controls were studied. Medical charts and clinical interviews of all patients were evaluated for demographic and clinical data, including disease activity, cumulative doses of glucocorticoid, menarche and menopause age, and fractures. Bone mineral density (BMD) using dual X-ray absorptiometry (DXA) were measured at lumbar spine (L1–L4) and hip. A decreased BMD in lumbar spine [0.902 (0.136) vs. 0.965 (0.141) g/cm2, P = 0.022] and femoral neck [0.729 (0.12) vs. 0.784 (0.127) g/cm2, P = 0.027] was observed in patients compared to controls. In addition, osteoporosis was more frequent in patients than in controls in both lumbar spine (20 vs. 3.8%, P = 0.007) and the femoral neck (27.5 vs. 10.3%, P = 0.016). Moreover, a high prevalence of fractures was found in patients in comparison to healthy subjects (17.9 vs. 5.1%, P = 0.040; OR = 3.92; CI 95%:1.07–14.33). Comparing DM/PM patients with (n = 17) and without (n = 23) osteoporosis/fractures, significant differences were observed regarding age [56.8
D. C. O. de Andrade S. C. de Magalha˜es Souza J. F. de Carvalho L. Takayama C. T. L. Borges R. M. R. Pereira (&) Division of Rheumatology, Faculdade de Medicina da Universidade de Sa˜o Paulo, Av. Dr. Arnaldo, 455–3° andar– Reumatologia, sala 3105, Sa˜o Paulo, SP 01246-903, Brazil e-mail:
[email protected] J. M. Aldrighi Faculdade de Sau´de Pu´blica da Universidade de Sa˜o Paulo, Sa˜o Paulo, Brazil
(11.9) vs. 48.3 (13.2) years, P = 0.042], weight [62.05 (13.56) vs. 71.51 (11.46) kg, P = 0.022] and frequency of post menopausal women (94.1 vs. 65.2%, P = 0.0002). No differences were observed concerning height, lean mass, total fat mass, disease activity, mean value of creatine kinase, cumulative glucocorticoid dose, or bisphosphonate use. Logistic regression analysis revealed a negative association between the presence of osteoporosis/fractures and weight (OR: 0.92, 95% CI: 0.85–0.98; P = 0.016). This is the first study that analyzed bone mass in adult DM/ PM patients and it demonstrated that about one quarter of these patients have osteoporosis/fracture. Keywords Idiopathic myositis Osteoporosis Fractures Bone mineral density Weight
Introduction Patients with rheumatic diseases could have an elevated susceptibility to osteoporosis and fractures [1–4]. This complication, besides the traditional risk factors for osteoporosis, may be secondary to the disease’s chronic inflammatory response, immobilization, weight, therapeutic approach (glucocorticoid and immunosuppressive drugs) and menopausal status [5–8]. Dermatomyositis and polymyositis are uncommon idiopathic inflammatory myopathies clinically characterized by proximal symmetric muscle weakness, rashes and fatigue [9]. The prognosis of dermatomyositis and polymyositis (DM/PM) has improved due to the introduction and increasing availability of glucocorticoids, although the morbidity remains poor [9]. A previous prospective study demonstrated that disease course and iatrogenic factors, represented mainly by vertebral compression
123
Rheumatol Int
fracture, were related to functional disability in this disease [10]. Regarding bone mineral density and fractures, we and other authors have analyzed these issues solely in children and adolescents with idiopathic inflammatory myositis [4, 11–13]. Most of them found low bone mineral density in these patients, even when the disease was inactive, with or without the use of glucocorticoids [4, 11–13]. The objective of this study was therefore to evaluate bone mineral density, biochemical markers, frequencies of osteoporosis and fractures, as well as the osteoporosis- and disease-related factors to these bone alterations in adult DM/PM women.
Subjects and methods Forty female patients with definitive dermatomyositis/ polymyositis according to Bohan and Peter’s criteria [14] were enrolled. All patients were followed in the Myopathy Outpatient Clinic (Rheumatology Division) at our University. Seventy-eight age-, race- and BMI-matched healthy females were included as control group. The control group was selected from a primary health care centre, the Public Health School, Sa˜o Paulo. This group consisted of healthy women who went annually to the center for gynaecological routinely evaluation. Medical records were extensively reviewed and patients were interviewed about menarche onset age, menopause onset age, hormone replacement therapy (HRT), smoking habits, disease features (activity, duration of disease, and remission), cumulative and current glucocorticoid dose, drugs that potentially affect bone metabolism and self reported fractures. Disease activity was defined based upon the following criteria: (1) constant or progressive reduction in muscle strength at clinical evaluation, (2) elevation of serum creatinine kinase (CK), and (3) the presence of the characteristic rash in patients with dermatomyositis. Remission was defined by the following events: (1) stable improvement or normalization of muscle strength at clinical evaluation, (2) normalization of serum CK, and (3) improvement in cutaneous activity [15]. By definition, patients were in the inactive phase of the disease when remission was achieved. In some patients, moderate and stable doses of immunosuppressive drugs were used to maintain remission. Laboratory parameters performed in patients included serum calcium, phosphorus, alkaline phosphatase and 24-h urinary calcium. Erythrocyte sedimentation rate (ESR) measured by modified Westergren and C-reactive protein (CRP) by nephelometry were the inflammatory markers analyzed.
123
Bone mineral density (BMD) was measured in patients and healthy controls by dual X-ray absorptiometry (DXA) using Hologic densitometry equipment (QDR 2000 densitometry) at the lumbar spine and the femoral neck. All BMD measurements were performed by the same experienced technologist. Precision error for BMD measurements was determined based on standard International Society for Clinical Densitometry (ISCD) protocols [16]. All patients and controls were specifically asked about fragility fractures, the year they occurred, and the way they happened. While attending the clinical examination, all patients received a detailed questionnaire, including questions on fractures. Participants were specifically asked about fractures of the wrist, humerus, ankle, tibia, hip and spine. All fractures due to trauma and those that occurred before the disease were excluded. All patients and controls gave their written informed consent and the study was approved by the Ethics Committee of the University Hospital. Statistical analysis Results are presented as the mean (standard deviations) or percentage. Data were compared by t Student, Mann– Whitney, or Fisher’s exact tests to evaluate differences between patients and controls. The disease activity and levels of CK and drug (glucocorticoid and bisphosphonate) use were also compared in patients with and without osteoporosis/fractures. Logistic regression analyses were performed for all subjects (patients and controls) using osteoporosis/fracture as the dependent variables and the parameter that was significant in the univariate analysis as the independent variables. Values of P \ 0.05 were considered statistically significant.
Results Demographical, anthropometrical features and gonadal status of DM/PM patients and controls are shown in Table 1. There was no difference between patients and controls in relation to age, Caucasian race, weight, height, BMI, menarche onset age, and menopause onset age (P [ 0.05). The frequency of postmenopausal women was higher in DM/PM patients than in controls (77.5 vs. 56.4%, P = 0.024). Dermatomyositis/polymyositis patients had a mean disease duration of 9.62 ± 9.18 years and 17.5% of patients had an active disease at the time of the study. More than half of these patients (60%) were using glucocorticoids with a cumulative dose of 33.61 (SD: 31.94) g. Three patients were under bisphosphonates.
Rheumatol Int Table 1 Demographic and anthropometric data and gonadal status of women with dermatomyositis/polymyositis (DM/PM) and healthy controls
DM/PM n = 40
Healthy controls n = 78
P value
Age, (years)
51.93 (13.23)
52.67 (12.34)
0.76
Caucasian (race), %
60
76.9
0.084
Weight, (kg)
67.49 (13.11)
66.65 (14.43)
0.758
Height, (m)
1.56 (0.06)
1.55 (0.06)
0.478
BMI, (kg/m2)
27.76 (4.57)
27.67 (5.72)
0.933
BMI body mass index, kg kilograms
Menarche age, (years)
13.55 (1.60)
12.96 (1.62)
0.067
Menopause age, (years)
43.77 (7.80)
46.62 (4.65)
0.089
Data are expressed in mean (SD) or percentage
Postmenopausal women, (%)
77.5
56.4
0.024
Lower bone mineral density in the lumbar spine (L1– L4) (P = 0.022) and the femoral neck (P = 0.027) was observed in DM/PM patients when compared to controls. Osteoporosis in the lumbar spine (T B 2.5 SD) was observed in 20% of DM/PM patients, compared to 3.8% of the controls (OR = 6.25, 95% CI: 1.55–25.10; P = 0.007). In the femoral neck, it was observed in 25% of myositis patients compared to 10.2% of healthy controls (P = 0.055). Fractures after the diagnosis of DM/PM were related by 17.5% of DM/PM patients compared to 3.85% of controls (OR = 3.03, 95% CI: 1.29–21.79; P = 0.031) (Table 2). Serum calcium [9.36 (SD: 0.63) mg/dL], alkaline phosphatase [74.67 (SD: 32.15) U/L], and 24-h urinary calcium [115.49 (SD: 85.64) mg/day] were all within the normal range. Fractures were related in seven (17.5%) patients in the following locations: ribs (n = 1), distal forearm (n = 1), femoral neck (n = 1), humerus (n = 2) and foot (n = 2). These fractures occurred after a median time of 11.28 years of DM/PM diagnosis. In controls, they occurred in 3 (5.13%) subjects after menopause, at humerus and ribs (n = 1), shoulder (n = 1), and humerus and fibula (n = 1) sites. No patient or control subjects had clinical history of vertebral fracture.
Table 2 Bone mineral density (BMD), osteoporosis (T-score T B -2.5 SD) in lumbar spine (L1–L4) and femoral neck and selfreported fractures in women with dermatomyositis/polymyositis (DM/PM) and healthy controls DM/PM n = 40
Healthy controls n = 78
P value
BMD L1–L4, (g/cm2)
0.902 (0.136) 0.965 (0.141) 0.022
T B -2.5 SD L1–L4, (%)
20
3.8
0.007
BMD femoral neck, (g/cm2) 0.729 (0.12)
0.784 (0.127) 0.027
T B -2.5 SD femoral neck, (%)
25
10.2
0.055
Fractures, (%)
17.5
3.85
0.031
Data are expressed in mean (SD) or percentage
Analysis of DM/PM patients with (n = 17) and without (n = 23) osteoporosis/fractures showed significant differences regarding age [56.8 (SD: 11.9) vs. 48.3 (SD: 13.2) years, P = 0.042], weight [62.05 (SD: 13.56) vs. 71.51 (SD: 11.46) kg, P = 0.022] and frequency of post menopausal women (94.1 vs. 65.2%, P = 0.0002). No differences were observed concerning height, disease duration and activity, mean values of creatine kinase, ESR or CRP, cumulative glucocorticoid dose or bisphosphonate use (P [ 0.05) (Table 3). Logistic regression analysis of all patients, using the variables that were significant in the univariate analysis, revealed a negative association between the presence of osteoporosis/fractures and weight (OR: 0.92, 95% CI: 0.85–0.98; P = 0.016).
Discussion This is the first study that analyzed bone mass in adult DM/ PM patients and it demonstrated that about one quarter of these patients have osteoporosis/fracture. This bone alteration was associated to lower weight. One advantage of this work was the presence of healthy controls matched to the patients’ age, race, and BMI, since it is well known that these factors influence bone metabolism [17, 18]. Furthermore, the inclusion of only female subjects allowed a homogeneous group, since osteoporosis, fractures and DM/PM disease are found more frequently in this gender [18]. The analysis of the disease-related factors that could influence the bone metabolism such as disease activity, mean levels of creatine kinase and cumulative glucocorticoid dose did not distinguish patients with and without osteoporosis/fractures. In agreement with these findings, other studies on juvenile DM/PM have also failed to demonstrate an association between low bone mass and disease activity [4, 13], and also glucocorticoid use [13]. One possible explanation for this result may be due to the limited number of patients, since myositis is a rare disease. The main finding of this study that demonstrated lower weight in myositis patients with osteoporosis/factures is
123
Rheumatol Int Table 3 Demographic and anthropometric data and gonadal status of dermatomyositis/polymyositis (DM/PM) patients with and without osteoporosis/fractures (OP/fractures) DM/PM with OP/fracture n = 17
DM/PM without OP/fractures n = 23
P value
Age, (years)
56.8 (11.9)
48.3 (13.2)
0.042
Caucasian race, (%)
52.9
52.2
1.00
Weight, (kg)
62.05 (13.56)
71.51 (11.46)
0.022
Height, (m)
1.55 (0.08)
1.57 (0.04)
0.300
Postmenopausal women, (%)
94.1
Disease duration, (years)
12.12 (11.85)
8.07 (6.08)
0.166
23.1 145.08 (155.90)
31.6 167.62 (164.0)
0.705 0.694
20.24 (20.01)
18.43 (22.89)
0.796
5.14 (7.11)
6.46 (15.80)
0.750
41.16 (39.52)
28.59 (23.51)
0.281
Current disease activity, (%) Creatine kinase, (U/L) Erythrocyte sedimentation rate, (mm/1st h) C-reactive protein, (mg/L) Cumulative glucocorticoid dose, (g)
65.2
0.0002
BMI body mass index, kg kilograms Data are expressed in mean (SD) or percentage
corroborated by several studies in normal population. In fact, low weight may predict osteoporosis and it is associated with increased fracture risk in healthy women from 40 to 59 years, similar to the patients herein studied [19]. Moreover, this negative association was also found in other rheumatic diseases such as systemic lupus erythematosus [20] and rheumatoid arthritis [21]. One possible hypothesis to explain the inferior weight in DM/PM subjects with bone involvement may be the result of a chronic disease even in the absence of elevated inflammatory serum markers. Indeed, this relationship was demonstrated in chronic obstructive pulmonary disease [22], a well known condition without increased of biomarkers of inflammation. Although patients and controls were matched by age, a greater percentage of DM/PM patients were postmenopausal. In fact, an increased bone turnover in perimenopausal women is correlated with decreased estrogen and elevated FSH serum levels. Estrogen deficiency induces production of bone-resorbing cytokines such as interleukin (IL)-1, IL-6, tumor necrosis factor (TNF)-a, macrophage colony stimulating factor (M-CSF), prostaglandins and RANKL. However, in the present study the multiple regression did not show menopause as an independent factor for osteoporosis/fractures in DM/PM patients [23]. In the present study, lower BMD and the frequency of osteoporosis were observed in DM/PM, compromising the trabecular and cortical bone, in comparison to controls. In fact, the site of fractures observed herein in DM/PM patients after a long disease duration involved both bone types. This study also showed a higher frequency of low traumatic fractures in adult DM/PM patients. In the
123
literature, there is only one report of a juvenile DM patient that had severe vertebral fracture [24]. In other rheumatic autoimmune diseases, fragility fractures have been described. In this way, lupus patients demonstrate bone alteration that varies from 5.0 to 26.1% [25–29]. Furthermore, in a large rheumatoid arthritis study, the authors found an increase in hip fractures, and this alteration was associated with longer disease duration, presence of at least one deformed joint, lower age and weight, and BMD [30]. This study demonstrated that osteoporosis/fractures are a common bone involvement in adult DM/PM patients and that these bone disorders are associated with lower weight. Our results recommend periodic bone evaluations, including BMD and fracture screening, for myositis patients. Acknowledgments We are grateful to Conselho Nacional de Desenvolvimento Cientı´fico e Tecnolo´gico (CNPQ) # 300559/2009-7 (to RMRP) and #300665/2009-1 (to JFC), Wilhelm Agricola Federico Foundation Grant (to RMRP and JFC).
References 1. Yeap S, Fauzi A, Kong N et al (2009) Influences on bone mineral density in Malaysian premenopausal systemic lupus erythematosus patients on corticosteroids. Lupus 18:178–181 2. Book C, Karlsson M, Akesson K et al (2008) Disease activity and disability but probably not glucocorticoid treatment predicts loss in bone mineral density in women with early rheumatoid arthritis. Scand J Rheumatol 37:248–254 3. Souza RB, Borges CT, Takayama L et al (2006) Systemic sclerosis and bone loss: the role of the disease and body composition. Scand J Rheumatol 35:384–387 4. Santiago RA, Silva CA, Caparbo VF et al (2008) Bone mineral apparent density in juvenile dermatomyositis: the role of lean body mass and glucocorticoid use. Scand J Rheumatol 37:40–47 5. Michel BA, Bloch DA, Fries JF (1991) Predictors of fractures in early rheumatoid arthritis. J Rheum 18:804–808
Rheumatol Int 6. Adinoff AD, Hollister JR (1983) Steroid-induced fractures and bone loss in patients with asthma. N Engl J Med 309:265–268 7. Van Staa TP, Leufkens HGM, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int 13:777–787 8. Mazess RB, Whedon GD (1983) Immobilization and bone (editorial). Calcif Tissue Int 35:265–267 9. Wortmann RL (2001) Inflammatory and metabolic disease of muscle. In: Klipple JH, Crofford LJ, Stone JH, Weyand CM (ed) Primer on the rheumatic disease. Arthritis Foundation, Atlanta pp 369–376 10. Clarke AE, Bloch DA, Medsger TA Jr et al (1995) A longitudinal study of functional disability in a national cohort of patients with polymyositis/dermatomyositis. Arthritis Rheum 38:1218–1224 11. Stewart WA, Acott PD, Salisbury SR et al (2003) Bone mineral density in juvenile dermatomyositis. Arthritis Rheum 48:2294–2298 12. Alsufyani KA, Ortiz-Alvarez O, Cabral DA et al (2005) Bone mineral density in children and adolescents with systemic lupus erythematosus, juvenile dermatomyositis and systemic vasculitis: relationship to disease duration, cumulative corticosteroid dose, calcium intake and exercise. J Rheumatol 32:729–733 13. Castro TC, Terreri MT, Szejnfeld VL et al (2005) Bone mineral density of Brazilian girls with juvenile dermatomyositis. Braz J Med Biol Res 38:309–313 14. Bohan A, Peter JB (1975) Polymyositis and dermatomyositis (first of two parts). N Eng J Med 292:344–347 15. Ponyi A, Borgulya G, Constantin T et al (2005) Functional outcome and quality of life in adlt patients with idiopathic inflammatory myositis. Rheumatology 44:83–88 16. Lewiecki EM, Baim S, Binkley N et al (2008) Report of the international society for clinical densitometry 2007 adult position development conference and official positions. South Med J 101:735–739 17. van Geel TA, van den Bergh JP, Dinant GJ et al (2010) Individualizing fracture risk prediction. Maturitas 65:143–814 18. Kanis A, Oden A, Johansson H et al (2009) FRAX(R) and its applications to clinical practice. Bone 44:734–743
19. Morin S, Tsang JF, Leslie WD (2009) Weight and body mass index predict bone mineral density and fractures in women aged 40 to 59 years. Osteoporos Int 20:363–370 20. Almehed K, Forsblad d’Elia H, Kvist G, Ohlsson C, Carlsten H (2007) Prevalence and risk factors of osteoporosis in female SLE patients-extended report. Rheumatology (Oxford) 46:1185–1190 21. El Maghraoui A, Rezqi A, Mounach A, Achemlal L, Bezza A, Ghozlani I (2010) Prevalence and risk factors of vertebral fractures in women with rheumatoid arthritis using vertebral fracture assessment. Rheumatology (Oxford) 49:1303–1310 22. Gan WQ, Man SF, Senthilselvan A, Sin DD (2004) Association between chronic obstructive pulmonary disease and systemic inflammation: a systematic review and a meta-analysis. Thorax 59:574–580 23. Clarke BL, Khosla S (2010) Female reproductive system and bone. Arch Biochem Biophys 503:118–128 24. Tau C, Russo R (2007) Severe osteoporosis with vertebral crushes in juvenile dermatomyositis. Effect of oral alendronate therapy. Medicina (B Aires) 67:53–56 25. Mok CC, Cheung MY, Ho LY et al (2008) Risk and predictors of work disability in Chinese patients with systemic lupus erythematosus. Lupus 17:1103–1107 26. Yee CS, Crabtree N, Skan J et al (2005) Prevalence and predictors of fragility fractures in systemic lupus erythematosus. Ann Rheum Dis 64:111–113 27. Li EK, Tam LS, Griffith JF et al (2009) High prevalence of asymptomatic vertebral fractures in Chinese women with systemic lupus erythematosus. J Rheumatol 36:1646–1652 28. Mendoza-Pinto C, Garcı´a-Carrasco M, Sandoval-Cruz H et al (2009) Risk factors of vertebral fractures in women with systemic lupus erythematosus. Clin Rheumatol 28:579–585 29. Borba VZ, Matos PG, da Silva Viana PR et al (2005) High prevalence of vertebral deformity in premenopausal systemic lupus erythematosus patients. Lupus 14:529–533 30. Ørstavik RE, Haugeberg G, Uhlig T et al (2004) Self reported non-vertebral fractures in rheumatoid arthritis and population based controls: incidence and relationship with bone mineral density and clinical variables. Ann Rheum Dis 63:177–182
123
