Methotrexate in the treatment of rheumatoid arthritis. II. In vivo effects on bone mineral density

OBJECTIVE: To determine the effect of methotrexate (MTX) on bone mineral density (BMD) in rheumatoid arthritis (RA). METHODS: One hundred and sixteen non-steroid-treated RA subjects (90 women) were studied in a prospective, longitudinal, non-randomized study. Subjects started MTX (n=36) or sulphasalazine (n=23) or continued long-term (>5 yr) treatment with MTX (n=28) or other disease-modifying anti-rheumatic drugs (n=29). BMD was estimated at entry and after 1 yr. Markers of bone turnover were measured at entry and at 1 yr, and additionally at 3 and 6 months in those starting treatment. Bone biopsies were taken before and after MTX treatment in four subjects. The primary outcome was change in BMD Z score and secondary outcomes were changes in bone turnover markers and bone formation by histomorphometry. RESULTS: Univariate analysis of covariance found that MTX at baseline was associated with reduced BMD at the femoral neck. However, femoral neck BMD was also associated with radiological damage score for the hand. Multivariate analysis and discriminant analysis of the subset of post-menopausal women showed that reduced bone density associated with MTX was due to confounders such as disease activity. There was no adverse effect of MTX on bone turnover markers or on measures of bone formation in biopsies. CONCLUSIONS: No adverse effect of low-dose MTX (mean 10 mg/week) on bone formation in RA was found.     

类风湿关节炎患者骨质疏松与骨侵蚀关系的研究

目的 探讨类风湿关节炎(RA)患者骨质疏松的发生情况及其与关节骨侵蚀及其他临床指标的相关性.方法 采用双能X线骨密度仪.测量111例RA患者和30名健康人腰椎和股骨区的骨密度(BMD),并同时测定手关节X线分期及其他各临床指标.结果 RA患者的骨量丢失较对照组明显,骨质疏松的患病率更高(P＜0.05),随关节骨侵蚀加重,各测定部位的BMD呈下降趋势,手关节病变Ⅲ期、Ⅳ组的BMD均明显低于对照组(P＜0.05).RA患者中骨质疏松组较非骨质疏松组病程更长(P＜0.05),手关节骨侵蚀更重(P＜0.05),关节功能更差(P＜0.05).服用糖皮质激素比例更高(P＜0.05).Logistic回归分析显示手关节骨侵蚀(OR=0.636,0.424～0.954,P=0.029)和糖皮质激素服用情况(OR=2.696,1.026～7.083,P=0.044)是与RA患者骨质疏松发生有显著相关的因素.结论 随手关节骨侵蚀加蕈RA患者BMD呈下降趋势,RA患者骨质疏松的发生是多因素的,主要与关节骨侵蚀和是否服用糖皮质激素等有关.     

类风湿性关节炎患者骨密度变化的临床研究

目的　探讨类风湿性关节炎 (RA)患者骨密度 (BMD)的变化和骨质疏松 (OP)的发生情况及其与临床指标的相关性。方法　采用双能X线骨密度仪 ,测量 5 3例RA患者和 63名正常人的前臂、腰椎和股骨区的BMD ,并同时测定各临床指标。结果　RA患者的骨量丢失较对照组明显(P <0 .0 5 ) ,除股骨颈外 ,各测定部位的BMD均明显低于对照组 (P <0 .0 5～ 0 .0 1)。RA患者中发生OP组较非OP组年龄更大 (P <0 .0 0 1) ,关节功能更差 (P <0 .0 0 1) ,健康评估表积分更高 (P <0 .0 1) ,握力更低 (P <0 .0 5 )。 2 8例服用糖皮质激素的RA患者中有 13例 ( 4 6.4% )发生OP ,明显高于未服用糖皮质激素组的 5 /2 5 ( 2 0 .0 % ) ( χ2 =4.113 ,P =0 .0 5 ) ,服用激素组腰椎 3 (L3 )的BMD明显低于未服用激素组 (t =2 .163 ,P =0 .0 5 )。LogisticRegression分析显示年龄 (OR =1.10 3 ,P =0 .0 1)和关节功能 (OR =5 .689,P =0 .0 1)为RA患者OP发生的相关因素。结论　RA患者多部位的BMD均显著降低。其BMD的降低和OP的发生是多因素的 ,与年龄、关节炎的严重程度和是否服用糖皮质激素等有关     

Relationship between bone mineral density and duration of rheumatoid arthritis

BackgroundLonger disease duration is believed to be associated with more pronounced bone loss in rheumatoid arthritis (RA). This study was designed to assess bone mineral density (BMD) status in RA compared with age-matched control in relation to disease duration.MethodsThis study included 177 RA and 283 age-matched non-RA controls. BMD at the femoral neck and lumbar spine was assessed by Dual Energy X-ray Absorptiometry Osteoporosis was diagnosed according to WHO criteria. We divided patients with RA into groups based on disease duration of <2, 2–5, 5–10, and >10 years and compared them with controls. The relationship between disease duration and BMD was investigated by chi square and Spearman test.ResultsMean age of patients and control subjects was 51.2 ± 12.5 and 52.2 ± 6.7 years, respectively and mean disease duration was 86.5 ± 73.3 months. Osteoporosis at the femoral neck and lumbar spine in patients with RA was significantly higher than in controls. Femoral neck BMD in RA was negatively correlated with disease duration and 4.5% variations of femoral neck BMD was explained by disease duration (r² = 0.045, P = 0.005). Odds Ratio (OR) for osteoporosis in RA patients as compared to controls was increased by prolongation of disease duration from 2.38 (0.38–14.7) in patients with disease duration <2 years to 12.56 (2.24–70.2) in patients with disease duration >10 years. For patients treated with methotrexate compared to those who had never received methotrexate the odds ratio for femoral neck osteoporosis reduced by 64% (OR = 0.36, 95% CI, 0.15–0.91).ConclusionThere is a significant negative relationship between femoral neck BMD and disease duration in RA. The value of OR increases proportionately with lengthening of disease duration which can be reduced significantly by methotrexate therapy.     

Calcaneus bone mineral density in Japanese women with rheumatoid arthritis

Objectives The aim of this study was to investigate the relationships among bone mineral densities (BMD) in the calcaneus and leg activity of daily living (L-ADL) in rheumatoid arthritis (RA) patients.Methods We measured and compared calcaneus BMD using single X-ray absorptiometry and lumbar spine and femoral neck BMD using dual X-ray absorptiometry in 158 Japanese female outpatients with RA and 358 normal controls (NC).Results Regardless of whether the women were premenopausal or postmenopausal, calcaneus and femoral neck BMDs in the RA group were significantly lower than in the NC group. Calcaneus BMD correlated with the modified health assessment questionnaire, L-ADL score, and 10-m walking time, regardless of whether the patients were premenopausal or postmenopausal (P<0.01).Conclusions We conclude that calcaneus BMD reflects the L-ADL of RA patients very well and allows us to perform the same level of BMD evaluation as that with current BMD measurement methods.     

Androgen deficiency and bone mineral density in men with rheumatoid arthritis

OBJECTIVE: To investigate the prevalence of osteopenia/osteoporosis in a group of men with rheumatoid arthritis (RA); and to analyze the relationship between sex hormone status and bone mineral density (BMD), taking into account disease activity, disease duration, and corticosteroid intake. METHODS: Clinical and demographic details were collected on 50 consecutive men with RA. BMD at the lumbar spine and femoral neck were measured, together with plasma concentrations of testosterone, sex hormone binding globulin, and luteinizing hormone. RESULTS: The median age of patients was 67 years, with median disease duration 20 years. Fourteen patients had never been treated with oral corticosteroids, the remaining 36 received a range of prednisone doses over prolonged periods. Plasma testosterone concentration was moderately reduced in 40% (< 10 nmol/l) and severely reduced in 6% of men (< 8 nmol/l), but androgen deficiency was not related to bone density or fractures. Spinal and femoral neck BMD was reduced in 38 and 71% of the men, respectively. Femoral neck BMD was related to age, weight, disability status, and specific disease activity scores. The only predictors of spinal BMD were pack-years of smoking and physician global assessment. CONCLUSION: Reduced BMD is common among men with RA. The predictors for spine and femoral neck BMD bear little direct relationship to blood testosterone concentrations despite the relatively high prevalence of low testosterone concentrations in this population. These findings are more consistent with the possibility that low testosterone concentrations in men with RA are a bystander effect of systemic inflammatory disease.     

Bone mineral density in patients with rheumatoid arthritis: relation between disease severity and low bone mineral density

OBJECTIVE: To examine variables associated with bone mineral density (BMD) in patients with rheumatoid arthritis (RA). METHODS: We investigated 373 patients with low to moderately active RA. Patients with low disease activity were recruited from a cohort of patients in clinical remission. Patients with moderately active disease were included in a trial comparing the effects of long term high intensity exercise programme and conventional physical therapy. Demographic and clinical data were collected. Bone mineral density (BMD) was measured by means of dual x ray absorptiometry (DXA). Associations between demographic and clinical measurements on the one hand and BMD on the other were investigated in regression analyses. RESULTS: The patient group consisted of middle aged, mainly female, patients. The median (interquartile range) disease duration was 7 (4 to 13) years, the mean disease activity score (standard deviation) was 3.2 (1.4). Of the group, 66% was rheumatoid factor positive, and 83% (n = 304) had never used corticosteroids. The median Larsen score of hands and feet was 27 (5 to 61). Greater age and low body mass index were related to low BMD at the hip and spine. High Larsen score for hands and feet was significantly associated with low BMD at the hip. The use of corticosteroids was not independently associated with BMD. The results of the multiple regression analyses also applied to the subgroup of corticosteroid naive patients. CONCLUSION: BMD data of patients with low to moderately active RA demonstrated an association between high radiological RA damage and low BMD at the hip, which suggests an association between the severity of RA and the risk of generalised bone loss, which also occurred in corticosteroid naive patients.     

Adjuvant oestrogen treatment increases bone mineral density in postmenopausal women with rheumatoid arthritis.

OBJECTIVES--The beneficial effect of oestrogens on bone mineral density in women with osteoporosis is well known. Patients with rheumatoid arthritis (RA) are at risk for osteoporosis. A study was therefore set up to investigate the effects of adjuvant oestrogen treatment on bone metabolism and bone mineral density in postmenopausal women with RA. METHODS--Forty postmenopausal women with active RA were admitted to a placebo controlled, double blind study investigating the beneficial effect of adjuvant oestradiols or placebo on bone metabolism and bone mineral density. Thirty three patients completed 52 weeks of treatment. RESULTS--At the start both treatment groups were comparable for all parameters. In the oestrogen group serum concentrations of osteocalcin decreased and concentrations of sex hormone binding globulin increased during the study. Bone mineral density measured by dual energy x ray absorptiometry increased significantly in the lumbar vertebral spine and femoral neck in the oestrogen group compared with the placebo group. CONCLUSIONS--This study shows that the use of adjuvant oestrogens in post-menopausal women with active RA increases bone mineral density.     

Estimation of bone mineral density in children with juvenile rheumatoid arthritis

Bone mineral content of different areas of the skeleton was measured by dual photon absorptiometry in 20 children with juvenile rheumatoid arthritis (JRA) and compared to 20 age and sex matched healthy children. Spinal density was similar in both groups in prepubertal children but decreased in the postpubertal girls with JRA. Total bone density was also decreased in the postpubertal girls. Six children with JRA had repeat scans 12 to 24 months later; in 3 children total bone mineral content increased significantly with an intensive management program. Our study suggests that bone mineral density does not show a pubertal increase in children with JRA, as it does in healthy children.     

IgA rheumatoid factor is associated with bone mineral density preservation in rheumatoid arthritis

Clinical Rheumatology - Autoantibodies such as IgM rheumatoid factor (RF) and anti-citrullinated proteins/peptides antibodies (ACPA) have previously been incriminated in systemic bone loss in...     

类风湿关节炎患者骨密度及骨矿物质含量的变化及意义

目的探讨类风湿关节炎(RA)患者骨密度(BMD)及骨矿物质(BMC)含量的变化及意义。方法选择71例RA患者(RA组)及20例正常人(对照组),采用双能X线骨密度仪检测各组前臂BMD、BMC含量,魏氏法检测血沉(ESR),免疫比浊法检测血清C反应蛋白(CRP),速率散射比浊法检测类风湿因子(RF),ELISA法检测抗环瓜氨酸肽抗体(ACCP);同时进行X线分期,计算患者疾病活动分数(DAS28)。结果 RA组前臂BMD、BMC均低于对照组(P均<0.01),ESR、CRP、RF、ACCP均高于对照组(P均<0.01)。Pearson’s相关分析显示,前臂BMD与DAS28、ESR、RF呈负相关(r分别为-0.357、-0.390、-0.255,P<0.05或<0.01),前臂BMC与DAS28、ESR呈负相关(r分别为-0.344、-0.401,P均<0.01)。多元线性回归分析显示,前臂BMD与RF、年龄呈负相关(T分别为-7.544、-3.254,P均<0.01);前臂BMC与DAS28呈负相关(T=-4.44,P<0.01)。RA组中X线分期为Ⅰ期的有15例,其中BMD示骨质疏松6例、骨量减少2例。结论 RA患者BMD、BMC含量明显减少,其含量减少与RA活动密切相关;RF可能是导致RA骨量丢失的危险因素;BMD检测能更早反映RA患者的骨量丢失情况。     

The bone mineral density effects of calcitonin and alendronate combined therapy in patients with rheumatoid arthritis

Aim The bone mineral density (BMD) effects of calcitonin (CT) and alendronate (ALEN) therapy either alone or in combination were evaluated in patients with rheumatoid arthritis (RA). Method Eighty out of 100 patients with RA using methotrexate 5–12.5 mg/week and prednisone 5–10 mg/day were included in the study. These were randomly divided into four groups: the first group was given ALEN 70 mg/week; the second was given 200 IU/day CT nasal spray; and the third group was given combined therapy of 70 mg/week ALEN and 200 IU/day CT nasal spray. The fourth group (control) as well as the other three groups were given 600 mg calcium and 400 IU vitamin D. Dual‐energy X‐ray absorptiometry BMD of lumbar, hip and forearm regions and laboratory investigations were performed before and at the 12th month of the therapy. Reuslts Only the combined therapy group displayed significant decreases of alkaline phosphatase levels, pointing out that the high bone turnover seen in RA patients can only be normalized by combination therapy. Also the combined therapy group showed significant increases at the lumbar and hip regions, whereas at the forearm regions BMD values stabilized. Conclusion We recommend the use of CT and ALEN combined therapy, especially in severe active cases of RA, but further prospective studies consisting of larger patient populations are needed to confirm the additive effects of this combined therapy on fracture risk in these patients.     

Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone.

OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).     

Assessing periarticular bone mineral density in patients with early psoriatic arthritis or rheumatoid arthritis

BACKGROUND: Periarticular osteoporosis is an early finding in the hands of patients with rheumatoid arthritis (RA), due to release of bone resorbing cytokines from the inflamed synovium. There has been disagreement as to whether periarticular bone loss occurs in psoriatic arthritis (PsA). Bone mineral density (BMD) can now be measured accurately using dual energy x ray absorptiometry (DEXA). Recently, DEXA has been used to measure periarticular BMD at predefined regions of interest (ROIs) around the joints. OBJECTIVES: Firstly, to compare periarticular BMD around the finger joints of patients with early RA or PsA. Secondly, to determine whether periarticular bone loss is related to joint inflammation and radiological erosions in RA and PsA. METHODS: Seventeen patients with RA and 15 with PsA were recruited, all with disease duration of less than five years. All finger joints were examined by one person for swelling, or tenderness, or both. Hand radiographs were scored for the presence of erosions. Periarticular BMD was measured at 10 predetermined ROIs using a Hologic QDA-4500A fan-beam densitometer. RESULTS: Patients with PsA were less likely to be positive for rheumatoid factor (RF) (13% v 94%) and more likely to be men (60% v 23%) than patients with RA. There were no other clinical differences between patients with RA or PsA. Patients with RA had significantly lower BMD at each of the ROIs than those with PsA (p<0.05). However, these differences disappeared after adjusting for age and sex. Among patients with RA, those with a higher total number of swollen and/or tender hand joints had significantly lower periarticular BMD at the metocarpophalangeal (MCP) and proximal interphalangeal (PIP) joints. No such association was found for patients with PsA. CONCLUSIONS: In early disease, periarticular bone loss occurred both in patients with RA and those with PsA. Among patients with RA, periarticular osteoporosis was related to measures of joint inflammation. There was no association between joint inflammation and periarticular bone loss in patients with PsA, which lends support to the hypothesis that the primary site of inflammation in PsA is extrasynovial.     

Association of bone mineral density and vertebral deformity in patients with rheumatoid arthritis

The aim of this study was to investigate the association of vertebral deformities developed as a result of osteoporosis in female patients with rheumatoid arthritis (RA) with bone mineral density (BMD) and disease activity parameters. In the study, 100 female patients with the diagnosis of RA and 56 healthy subjects were recruited. Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and rheumatoid factor (RF) tests were performed and the number of swollen and tender joints, level of pain and health assessment questionnaire (HAQ) were recorded in order to evaluate disease activity. Anteroposterior and lateral thoracic and lumbosacral roentgenograms of all patients were taken for radiological examination and deformities of vertebrae were assessed. BMD measurements of patients were performed on vertebrae L1–4 of lumbar region and on total hip, femur neck, trochanter and Ward’s triangle of the right side. Vertebral deformity was established in 30% of RA patient group and 7.1% of control group and this was statistically significant. In the statistical analysis, no statistically significant difference was found between BMD measurements of RA and control groups. Patients with RA were divided into two subgroups with regard to using corticosteroids (CS) or not. Vertebral deformity was 32.4% in the subgroup using CS and 24.1% in the subgroup not using CS, and the difference was not statistically significant. There was a correlation between number of deformed joint and age and vertebral deformity incidence. RA is a risk factor on its own for the development of osteoporosis and vertebral deformity and this risk increases by age, excess number of deformed joints and severe course of disease. We think that precautions should be taken immediately to suppress the disease activity as well as to protect the quality and density of bone and to prevent the development of vertebral deformity and fracture while planning the treatment of patients with RA.     

Hand bone loss in early undifferentiated arthritis: evaluating bone mineral density loss before the development of rheumatoid arthritis

OBJECTIVES: (1) To examine the change in regional bone mineral density (BMD), including the hands, and assess its role as a predictor of outcome in patients presenting with an early undifferentiated inflammatory arthritis; (2) to examine for associations with the changes in hand BMD. METHODS: 74 patients with undifferentiated hand arthritis of less than 12 months' duration were examined at baseline and then at three, six, and 12 months follow up, including BMD measurement of the femoral neck, spine (L2-4), and the whole hands using dual energy absorptiometry (DXA). RESULTS: During the study, 13 patients were diagnosed as having rheumatoid arthritis, 19 as having inflammatory non-rheumatoid joint disorders, and 42 as having non-inflammatory joint disorders. At the femoral neck and lumbar spine no significant bone loss was seen in any of the three subgroups. At the 12 months follow up the mean (95% confidence interval) hand BMD loss in the patients with rheumatoid arthritis was -4.27% (-1.41 to -7.13); in the inflammatory non-rheumatoid group, -0.49% (-1.33 to +0.35); and in the non-inflammatory joint disorder group, -0.87% (-1.51 to -0.23). In a multivariate linear regression model (including age, rheumatoid factor, mean C reactive protein, mean HAQ score, and cumulative glucocorticoid dose), only mean C reactive protein (p<0.001) and rheumatoid factor (p = 0.04) were independently associated with change in hand BMD during follow up. CONCLUSIONS: Hand DXA provides a very sensitive tool for measuring bone loss in early rheumatoid arthritis and may be useful in identifying patients at high risk of developing progressive disease. Further studies are needed to evaluate the role of hand bone loss as a prognostic factor and outcome measure in rheumatoid arthritis.     

The effect of low-dose prednisone on bone mineral density in Peruvian rheumatoid arthritis patients

Objective The aim of this study was to determine the difference between bone mineral density (BMD) of rheumatoid arthritis (RA) patients on low-dose prednisone and matched RA patients without prior systemic corticosteroid therapy.Methods Ninety patients attending our clinics and receiving 10 mg/day of prednisone or less for at least the previous 3 consecutive months were studied. The control group comprised 90 selected RA patients without corticosteroid therapy matched for age, race, gender, disease duration, use of methotrexate, postmenopause, and Health Assessment Questionnaire score. The BMD was measured using dual X-ray absorptiometry.Results Patients on prednisone had lower BMD than controls (0.94±0.17 vs 0.96±0.17 for L2–4 and 0.73±0.14 vs 0.76±0.16 for femoral neck), but these differences were not statistically significant (P>0.05). In post hoc analysis, postmenopausal women on prednisone had more bone loss in femoral neck than controls (0.68±0.13 vs 0.74±0.15).Conclusion Bone mineral density was not significantly reduced by low-dose prednisone in this diverse group of RA patients. A reduction in hip BMD was seen in postmenopausal women on prednisone.     

Influence of hormone replacement therapy on disease progression and bone mineral density in rheumatoid arthritis

OBJECTIVE: Hormone replacement therapy (HRT) is known to exert a positive effect in preventing bone loss and a beneficial effect on the disease activity in rheumatoid arthritis (RA). We evaluated the effects of HRT on bone mineral density (BMD) and on the course of established RA. METHODS: Eighty-eight postmenopausal women with RA were randomly allocated to receive HRT, vitamin D3, and calcium supplementation or vitamin D3 and calcium supplementation alone for 2 years. The effects of additional HRT on laboratory and clinical measures of disease activity, quality of life, and BMD and on radiographic joint damage were investigated. RESULTS: Treatment with HRT suppressed signs of inflammation as shown by reduction in erythrocyte sedimentation rate (ESR) (p = 0.025) and an elevation in hemoglobin concentration (p = 0.007), a better clinical outcome assessed by response on the Disease Activity Score 28 (DAS28) (p = 0.036), increased BMD in the forearm, proximal femur and spine (p < 0.01), and retarded (p = 0.026) progression of joint destruction among patients with radiological progressive disease. No significant effect on quality of life was seen. CONCLUSION: Two years of HRT in women with active RA had significant ameliorating effects on inflammation, DAS28 response, and BMD and was associated with slower progression of radiological joint destruction. The mechanisms by which HRT exerts its effects remain to be elucidated. We suggest HRT can be used in addition to conventional therapy in the management of postmenopausal patients with RA.