Bone Metabolism In Rheumatoid Arthritis Research Articles

Inflammation is responsible for systemic bone loss in patients with seropositive rheumatoid arthritis treated with rituximab.

We investigated the effect of rituximab on systemic bone metabolism in patients with seropositive rheumatoid arthritis (RA). Twenty seropositive patients with RA were enrolled and administered one cycle of rituximab. If RA became active for > 6 months after the first rituximab cycle, a second cycle was initiated; otherwise, no additional treatment was administered. Patients were divided into two groups according to the number of rituximab treatment cycles. In patients treated with a second cycle, the total hip bone mineral density (BMD) was clinically low, whereas the serum levels of receptor activator of nuclear factor kappa-B ligand (RANKL) were increased at 12 months. BMD in patients treated with one cycle did not change at 12 months, whereas serum RANKL levels decreased at all time points. DAS28 activity improved in both groups from baseline to 4 months; however, from 4 to 12 months, DAS28 activity worsened in the develgroup with the second cycle but remained stable in the group with one cycle. Systemic inflammation, reflected by increased disease activity, may be responsible for the increase in RANKL levels, which causes systemic bone loss in rituximab-treated patients with RA. Although rituximab affects inflammation, it does not seem to alter systemic bone metabolism in RA.

Inflammation and Bone Metabolism in Rheumatoid Arthritis: Molecular Mechanisms of Joint Destruction and Pharmacological Treatments.

Rheumatoid arthritis (RA) is an inflammatory disease characterized by a variety of symptoms and pathologies often presenting with polyarthritis. The primary symptom in the initial stage is joint swelling due to synovitis. With disease progression, cartilage and bone are affected to cause joint deformities. Advanced osteoarticular destruction and deformation can cause irreversible physical disabilities. Physical disabilities not only deteriorate patients’ quality of life but also have substantial medical economic effects on society. Therefore, prevention of the progression of osteoarticular destruction and deformation is an important task. Recent studies have progressively improved our understanding of the molecular mechanism by which synovitis caused by immune disorders results in activation of osteoclasts; activated osteoclasts in turn cause bone destruction and para-articular osteoporosis. In this paper, we review the mechanisms of bone metabolism under physiological and RA conditions, and we describe the effects of therapeutic intervention against RA on bone.

Associations of vascular and bone status in arthritis patients

Cardiovascular (CV) disease and osteoporosis (OP) have been associated with rheumatoid arthritis (RA) and ankylosing spondylitis (AS). Bone and vascular biomarkers and parameters along with the effect of 1-year anti-TNF therapy on these markers were assessed in order to determine correlations between vascular pathophysiology and bone metabolism in RA and AS. Thirty-six patients treated with etanercept or certolizumab pegol and 17 AS patients treated with ETN were included in a 12-month follow-up study. Bone and vascular markers were previously assessed by ELISA. Bone density was measured by DXA and quantitative CT (QCT). Flow-mediated vasodilation (FMD), common carotid intima-media thickness (IMT) and pulse-wave velocity (PWV) were assessed by ultrasound. Multiple correlation analyses indicated associations between bone and vascular markers. Osteoprotegerin, sclerostin and cathepsin K were significantly associated with FMD, IMT and PWV, respectively (p < 0.05). Moreover, total and trabecular BMD determined by QCT inversely correlated with IMT (p < 0.05). On the other hand, among vascular parameters, platelet-derived growth factor BB and IMT correlated with DXA femoral and QCT total BMD, respectively (p < 0.05). In the RM-ANOVA analysis, anti-TNF treatment together with baseline osteocalcin, procollagen 1 N-terminal propeptide (P1NP) or vitamin D3 levels determined one-year changes in IMT (p < 0.05). In the MANOVA analysis, baseline disease activity indices (DAS28, BASDAI), the one-year changes in these indices, as well as CRP exerted effects on multiple correlations between bone and vascular markers (p < 0.05). As the pattern of interactions between bone and vascular biomarkers differed between baseline and after 12 months, anti-TNF therapy influenced these associations. We found a great number of correlations in our RA and AS patients undergoing anti-TNF therapy. Some of the bone markers have been associated with vascular pathophysiology, while some vascular markers correlated with bone status. In arthritis, systemic inflammation and disease activity may drive both vascular and bone disease.

Effects of one-year tofacitinib therapy on bone metabolism in rheumatoid arthritis

SummaryJanus kinase (JAK) inhibitors are used to treat rheumatoid arthritis (RA). We assessed the effects of tofacitinib on bone density and bone markers in association with clinical and laboratory parameters in RA. Tofacitinib stabilized bone density and resulted in a positive balance of bone turnover.IntroductionJanus kinase (JAK) inhibitors emerged as new therapeutic options in rheumatoid arthritis (RA). We have little information on how it affects areal and volumetric bone mineral density (BMD) and bone turnover markers. The aim of this study was to assess the effects of 1-year tofacitinib therapy on bone metabolism in RA.MethodsThirty RA patients with active disease were treated with either 5 mg bid or 10 mg bid tofacitinib for 12 months. We determined DAS28, CRP, IgM rheumatoid factor (RF), and anti-cyclic citrullinated peptide (CCP) levels, as well as serum levels of sclerostin, osteocalcin (OC), P1NP, DKK-1, OPG, RANKL, and 25-hydroxy-vitamin D3. Areal and volumetric BMD were assessed by DXA and peripheral quantitative CT (QCT), respectively.ResultsTwenty-six patients (13 on each arm) completed the study. Tofacitinib was clinically effective by suppressing DAS28, CRP, and HAQ. This was accompanied by the attenuation of further bone loss. Tofacitinib therapy significantly increased OC, OPG, and vitamin D3, while decreased CTX levels (p < 0.05). Age and multiple bone markers (OC, CTX, P1NP, RANKL) inversely correlated with L2–4 and femoral neck BMD by DXA. CRP, DAS28, and RANKL inversely determined volumetric BMD by QCT. Age, CRP, anti-CCP, and DKK-1 influenced the effects of tofacitinib therapy on BMD changes.ConclusionsOne-year tofacitinib treatment stabilized BMD in RA patients and resulted in a positive balance of bone turnover as indicated by bone biomarkers. Further studies are needed to evaluate the potential beneficial effects of JAK inhibitors on inflammatory bone loss.

Hepatocyte growth factor overexpression promotes osteoclastogenesis and exacerbates bone loss in CIA mice

BackgroundHepatocyte growth factor (HGF) is a multifunctional growth factor that promotes various biological processes. However, the effect of HGF on bone metabolism in rheumatoid arthritis (RA) remains unknown. Here, we investigated the role of HGF in regulating osteoclastogenesis and bone resorption in RA.MethodsThe expression of HGF in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of HGF on osteoclastogenesis was analysed by osteoclastogenesis and bone resorption assays. The effect of HGF inhibition was evaluated in a CIA mice model. The mechanism of HGF in regulating osteoclastogenesis and bone resorption was explored by a series of in vitro studies.ResultsHGF was overexpressed in CIA and RA. HGF stimulated osteoclastogenesis in vitro. SU11274, a selective small molecule blocker of c-Met, impeded the effect of HGF on osteoclastogenesis and bone resorption. HGF regulated osteoclastogenesis by JNK and AKT-GSK-3β-NFATc1 signallings. SU11274 protected CIA mice from pathological bone loss.ConclusionsThese data strongly suggest that the highly expressed HGF in the joint tissues contributes to bone loss in RA. Inhibition of HGF/c-Met could effectively alleviate pathological bone loss and inflammatory symptoms in CIA mice. HGF/c-Met may be used as a new target for the treatment of bone loss in RA.

Tumor Necrosis Factor Blockade Stimulates Circulating Osteoblastic Lineage Cells Activity while Reducing Circulating Osteoclasts

Objective. This study examines the effects of tumor necrosis factor (TNF) blockade on markers of bone metabolism in peripheral blood from active rheumatoid arthritis (RA) patients. Methods. Eighteen patients (16 women, 2 men) aged 50 years (range 37-63 years), with persistently active RA (mean disease duration 7 years) were studied. Most took methotrexate (mean dose 12.5 mg) and all except one received corticosteroid (mean dose 5.7 mg). Four were treated with etanercept, eight received adalimumab and six received infliximab. Before and six months after taking TNF blockers, blood was sampled to obtain peripheral blood mononuclear cells (PBMCs), and serum bone turnover markers and acute phase reactants were measured. PBMCs were seeded and cultured to produce osteoblastic lineage cells and osteoclasts. Results. The formation of calcified nodules by osteoblastic lineage cells from PBMC increased from 205.7±196.3 μmol/well at the baseline to 752.5±671.9 μmol/well after TNF blockade (p＜0.024). The serum levels of bone formation markers, including bone specific alkaline phosphatase and osteocalcin also increased. The number of circulating osteoclasts and area of bone resorption pits made by osteoclasts were reduced after TNF blockade. Conclusion. The activity of circulating osteoblastic lineage cells increased after TNF blockade, whereas peripheral osteoclastogenesis tended to be suppressed. This is the first study of cultured human peripheral osteoblastic lineage cells in RA patients. Given that peripheral bone formation is difficult to study using radiologic methods, culture of these cells may provide a new modality for studying bone metabolism in RA. (J Rheum Dis 2016;23:356-362)

AB0270 Serum Sclerostin Level among Egyptian Rheumatoid Arthritis Patients: Relation to Bone Mineral Density, Disease Activity and Radiological Grading

BackgroundBone loss in rheumatoid arthritis (RA) is caused by increased bone resorption, however, there is no increased bone formation1. The Wnt pathway is important in the control of bone formation...

OP0052 Prospective Evaluation of 18F-FDG and 18F-Naf Pet/Ct: Imaging Analysis of Inflammation and Bone Metabolism in Rheumatoid Arthritis

BackgroundSynovitis causes joint destruction in rheumatoid arthritis (RA). While FDG-PET illustrates synovitis sensitively, NaF-PET detects accelerated bone metabolism in osteoplastic lesions of osteoarthrists (OA) as well as osteolytic lesions.ObjectivesThis study...

Early effects of tumor necrosis factor inhibition on bone homeostasis after soluble tumor necrosis factor receptor use.

Background/AimsOur aim was to assess whether short-term treatment with soluble tumor necrosis factor (TNF) receptor affects circulating markers of bone metabolism in rheumatoid arthritis (RA) patients.MethodsThirty-three active RA patients, treated with oral disease-modifying antirheumatic drugs (DMARDs) and glucocorticoids for > 6 months, were administered etanercept for 12 weeks. Serum levels of bone metabolism markers were compared among patients treated with DMARDs at baseline and after etanercept treatment, normal controls and naive RA patients not previously treated with DMARDs (both age- and gender-matched).ResultsBone-specific alkaline phosphatase (BSALP) and serum c-telopeptide (CTX)-1 levels were lower in RA patients treated with DMARDs than in DMARD-naive RA patients. After 12 weeks of etanercept treatment, serum CTX-1 and sclerostin levels increased. In patients whose DAS28 improved, the sclerostin level increased from 1.67 ± 2.12 pg/mL at baseline to 2.51 ± 3.03 pg/mL, which was statistically significant (p = 0.021). Increases in sclerostin levels after etanercept treatment were positively correlated with those of serum CTX-1 (r = 0.775), as were those of BSALP (r = 0.755).ConclusionsRA patients treated with DMARDs showed depressed bone metabolism compared to naive RA patients. Increases in serum CTX-1 and sclerostin levels after short-term etanercept treatment suggest reconstitution of bone metabolism homeostasis.

Bone Loss in Rheumatoid Arthritis: Systemic, Periarticular, and Focal

Rheumatoid arthritis is a chronic inflammatory disease that results in generalized bone loss and increased fracture risk. Characteristic radiologic features of rheumatoid arthritis include periarticular osteopenia and marginal erosions. An emerging literature highlights the importance of osteoclasts as mediators of the erosive process, with an impairment of bone formation by inhibition of the Wnt signaling pathway as a cause of lack of repair of erosions. MRI has demonstrated the importance of inflammation in the bone marrow compartment as a cause of periarticular osteopenia. The term osteoimmunology has evolved to highlight the association between cells and cytokines of the immune system and their relationship to bone metabolism in rheumatoid arthritis and other forms of chronic inflammatory arthritis.

Serum concentrations of formation (PINP) and resorption (Ctx) bone turnover markers in rheumatoid arthritis

Joint inflammation in rheumatoid arthritis (RA) induces local periarticular osteoporosis. Generalised bone mineral density (BMD) decrease concerns approximately 50% of rheumatic patients. Both types of bone mass depletion can issue from cytokine-induced (TNF-α, IL-1, IL-6) osteoclasts’ activation, osteoprotegerin and its ligand’s (RANKL) function disorders, patients’ immobilisation and glucocorticosteroid (GCS) intake, as well as from hormonal alterations in postmenopausal women, predominate among RA individuals. The aim of the study was to compare serum concentrations of marker of bone formation—serum aminoterminal propeptide of type I collagen (PINP), and bone resorption, carboxy (C) terminal telopeptide (Ctx), bone turnover markers in RA and osteoarthritis (OA) patients and in RA groups of different disease activity, different degree of joint damage and the history of GCS intake. A total of 50 RA female patients and 50 women with knee OA were included in the study. Blood for morphology and biochemistry laboratory tests was taken. Joint X-rays to establish OA and RA diagnosis and the degree of RA progression, as well as DEXA BMD measurements were performed. PINP and Ctx concentrations were assessed. In RA patients the number of swollen and painful joints, the duration of morning stiffness, visual analogue scale values and Waaler–Rose’s test activity were recorded. The Disease Activity Index (DAS 28) was counted from the appropriate formula. No differences in bone turnover markers’ concentrations were noted neither between RA and OA patients nor between the RA group when compared to the one without the history of GCS use. Bone turnover markers’ concentrations in RA were proportional to the number of swollen and painful joints. However, no correlation was found between the markers’ concentrations and RA activity assessed by DAS 28 or by laboratory means. Ctx concentrations were higher in patients at II degree joint damage according to Larsen and Dale’s than at more advanced stages. Ctx concentrations decreased with the disease duration. Serum morphogenesis and resorption markers’ concentrations change in course of RA indicating the decrease in bone metabolic activity with the disease duration and progression. High RA activity and severity correlate with increased markers’ levels—the resorption one. The influence of GCS on bone metabolism in RA requires further study.

Serum concentrations of formation (PINP) and resorption (Ctx) bone turnover markers in rheumatoid arthritis

Joint inflammation in rheumatoid arthritis (RA) induces local periarticular osteoporosis. Generalised bone mineral density (BMD) decrease concerns approximately 50% of rheumatic patients. Both types of bone mass depletion can issue from cytokine-induced (TNF-alpha, IL-1, IL-6) osteoclasts' activation, osteoprotegerin and its ligand's (RANKL) function disorders, patients' immobilisation and glucocorticosteroid (GCS) intake, as well as from hormonal alterations in postmenopausal women, predominate among RA individuals. The aim of the study was to compare serum concentrations of marker of bone formation--serum aminoterminal propeptide of type I collagen (PINP), and bone resorption, carboxy (C) terminal telopeptide (Ctx), bone turnover markers in RA and osteoarthritis (OA) patients and in RA groups of different disease activity, different degree of joint damage and the history of GCS intake. A total of 50 RA female patients and 50 women with knee OA were included in the study. Blood for morphology and biochemistry laboratory tests was taken. Joint X-rays to establish OA and RA diagnosis and the degree of RA progression, as well as DEXA BMD measurements were performed. PINP and Ctx concentrations were assessed. In RA patients the number of swollen and painful joints, the duration of morning stiffness, visual analogue scale values and Waaler-Rose's test activity were recorded. The Disease Activity Index (DAS 28) was counted from the appropriate formula. No differences in bone turnover markers' concentrations were noted neither between RA and OA patients nor between the RA group when compared to the one without the history of GCS use. Bone turnover markers' concentrations in RA were proportional to the number of swollen and painful joints. However, no correlation was found between the markers' concentrations and RA activity assessed by DAS 28 or by laboratory means. Ctx concentrations were higher in patients at II degree joint damage according to Larsen and Dale's than at more advanced stages. Ctx concentrations decreased with the disease duration. Serum morphogenesis and resorption markers' concentrations change in course of RA indicating the decrease in bone metabolic activity with the disease duration and progression. High RA activity and severity correlate with increased markers' levels-the resorption one. The influence of GCS on bone metabolism in RA requires further study.

Pathogenesis of osteoporosis in rheumatoid arthritis

Osteoporosis is a major clinical problem in rheumatoid arthritis. Patients with rheumatoid arthritis frequently not only present with juxta articular osteopenia and bone erosions but also with generalized axial and appendicular osteoporosis at sites distant from inflamed joints. The pathogenesis of bone loss in rheumatoid arthritis is multifactorial; disease activity certainly is a major determinant of bone mass. Further pathogenetic factors include effects of anti-inflammatory therapies (in particular glucocorticoids), reduced mobility, estrogen and/or androgen deficiency. Recently, receptor activator of nuclear factor kappa B ligand (RANKL) and osteoprotegerin (OPG), a decoy receptor for receptor activator of nuclear factor kappa B ligand, were identified as central regulators of osteoclast recruitment and activation. Osteoprotegerin and receptor activator of nuclear factor kappa B ligand production is modulated by several cytokines, growth factors and hormones. In rheumatoid synovium both fibroblasts and activated T cells express receptor activator of nuclear factor kappa B ligand and thereby promote osteoclast recruitment and activation. Thus, osteoprotegerin and receptor activator of nuclear factor kappa B ligand appear to represent important molecular links between the immune system and bone metabolism in rheumatoid arthritis.

Relationship between soluble markers of immune activation and bone turnover in post-menopausal women with rheumatoid arthritis.

Regarding interactions between pro-inflammatory cytokines and bone metabolism in rheumatoid arthritis (RA), we investigated the relationship between the serum levels of interleukin (IL)-1beta, IL-6, soluble interleukin-2 receptor (sIL-2r), C-reactive protein (CRP), the vitamin D metabolites 25-hydroxyvitamin D3 (25OHD3) and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], intact parathyroid hormone (iPTH) as well as serum and urinary parameters of bone turnover in 74 post-menopausal women with RA. SIL-2r correlated negatively with 1,25(OH)2D3 (P < 0.01), whereas IL-6 showed a positive correlation with urinary excretion of deoxypyridinoline collagen cross-links (P < 0.01). 1,25(OH)2D3 (P < 0.01) and iPTH (P < 0.01) were negatively related to CRP, whereas the urinary excretion of pyridinoline (P < 0.01) and deoxypyridinoline (P < 0.01)-collagen cross-links showed a positive correlation with CRP. 1,25(OH)2D3 (P < 0.01) and iPTH (P < 0.05) were positively related to bone alkaline phosphatase as a marker of osteoblast function. Our data indicate that IL-6 is a critical determinant of increased bone resorption in post-menopausal RA women with high disease activity and that serum levels of 1,25(OH)2D3 are inversely related to T-cell activation.

The effects of menopausal status and disease activity on biochemical markers of bone metabolism in female patients with rheumatoid arthritis

The effects of menopause and disease activity on bone metabolism in rheumatoid arthritis (RA) were studied by using biochemical markers of bone metabolism. We measured osteocalcin, bone-specific alkaline phosphatase, urinary total pyridinoline and deoxypyridinoline, and urinary free deoxypyridinoline in 78 female patients with RA (39 pre-menopause, Pre-RA; 39 post-menopause, Post-RA) and 54 female normal controls (28 pre-menopause, Pre-NC; 26 post-menopause, Post-NC). In Pre-RA, although bone formation was equal to Pre-NC, bone resorption increased. In Post-RA, however, bone formation was lower while bone resorption was higher than in Post-NC. The high disease activity RA group showed higher bone turnover than the low disease activity RA group. We conclude that menopause affects the bone turnover in RA as well as in normal controls. In Pre-RA, osteopenia is caused by the increase in bone resorption. In Post-RA, osteopenia is caused by the increase in uncoupling between bone formation and bone resorption. Furthermore, the high disease activity of RA induces high bone turnover.

Inflammation and bone metabolism in rheumatoid arthritis. Pathogenetic viewpoints and therapeutic possibilities

Systemic osteoporosis is a common and pathogenetically heterogenous complication in rheumatoid arthritis. Various factors such as disease activity, dosage and duration of glucocorticoid treatment and immobilization are involved in pathogenesis of osteoporosis in rheumatoid arthritis. Proinflammatory cytokines secreted by immunocompetent cells have a role in the regulation of the activity of osteoblasts and osteoclasts. The effects of these proinflammatory cytokines include the inhibition of bone formation and an increase in bone resorption. Interleukin-6 and nitric oxide induced in osteoblasts by proinflammatory cytokines are likely to be important mediators between these cytokines and the function of osteoblasts and osteoclasts. Furthermore, disease activity dependent changes in the secretion of glucocorticoids and in vitamin D metabolism may be involved in the pathogenesis of osteoporosis in this disease. Alteration of bone remodeling associated with immobilization is an important factor of systemic bone loss in rheumatoid arthritis. The inflammatory process in rheumatoid arthritis may cause penarticular and systemic bone loss by various cytokine and hormone mediated mechanisms. Concluding from these pathogenetic mechanisms, bisphosphonates and active vitamin D metabolites are likely to be effective therapeutic options in osteoporosis associated with rheumatoid arthritis.

Cartilage and bone metabolism in rheumatoid arthritis. Differences between rapid and slow progression of disease identified by serum markers of cartilage metabolism.

Serum concentrations of specific cartilage and bone molecules reflecting tissue turnover were measured in two well-defined patient groups with early rheumatoid arthritis with distinctly different disease outcome to see if early differences in their levels are prognostic of the rate of joint destruction. Compared with a matched normal population, increased concentrations of cartilage oligomeric matrix protein (COMP) were found in all patients who developed rapid hip joint destruction. In contrast, levels of a putative marker of cartilage aggrecan synthesis, the chondroitin sulfate epitope 846, were increased only in patients with slow joint destruction. Levels of bone sialoprotein (BSP) were increased in both groups, as were levels of the C-propeptide of type II procollagen (CPII), a marker of collagen II synthesis. The increased concentrations of the 846 epitope in patients with slow joint destruction suggest increased aggrecan synthesis. The low levels of the 846 epitope in patients with rapid joint destruction, concomitant with elevated levels of CPII, suggest a selective increase in collagen synthesis. The elevated BSP levels indicate an increased bone turnover in both groups. Thus elevated serum levels of COMP may indicate an unfavorable prognosis for rapid joint destruction, whereas elevated 846 epitope indicates a more favorable prognosis.

Bone metabolism in rheumatoid arthritis; relation to disease activity.

Biochemical parameters of bone metabolism were investigated in 105 ambulant, non-steroid treated patients with RA and compared with parameters of disease activity. Urinary calcium (Ca) and hydroxyproline (OHP) excretions, as parameters of bone resorption and serum alkaline phosphatase (AP), as a parameter of bone formation, were positively related to parameters of disease activity. Serum osteocalcin, another parameter of bone formation, was not related to parameters of disease activity. Patients with active disease (ESR > or = 28 mm and Ritchie articular index > or = 8) had a significant higher urinary Ca and OHP excretion (62 and 42% higher, respectively) than patients with inactive disease. Serum AP and OC were slightly higher (19 and 16%, respectively) in patients with active disease. These results suggest that in RA patients bone metabolism is related to disease activity. In active disease bone resorption seems to be increased more than bone formation, suggesting that prolonged disease activity may contribute to generalized and/or localized osteopenia.

Osteocalcin and bone mineral content in rheumatoid arthritis.

Abnormal bone metabolism was reported in rheumatoid arthritis (RA). In order to evaluate the interest of serum osteocalcin, also called bone GLA-protein (BGP), to assess bone metabolism in RA, we studied 20 postmenopausal RA out-patients and 20 matched controls. Nine patients were treated with low-dose corticosteroids (C+) for at least one year (less than 10 mg/day, prednisolone equivalent), the remaining 11 (C-) received non-steroidal anti-inflammatory drugs (NSAID). The distal and proximal forearm bone mineral content (BMC) was measured by single photon absorptiometry, the vertebral BMC was measured by dual photon absorptiometry. A trend to low BGP was observed in the C+ group. The lowest values were observed in patients with vertebral fractures. Compared with controls, both RA groups had similar low significant BMC at the forearm sites. At the vertebral sites, the bone mineral content decrease observed in the two groups, was more marked in the C+ group. From our results, BGP did not appear as a useful index of osteoporosis in RA, except in some patients with vertebral fractures, treated with low-dose corticosteroids.

Bone metabolism in rheumatoid arthritis compared with postmenopausal osteoporosis.

Calcium and bone metabolism in 29 rheumatoid arthritis (RA) patients were compared with those in 27 postmenopausal osteoporotic patients. Signs of vitamin D deficiency were found in 20 RA patients, including 12 who took recommended amounts of vitamin D in their diets and were exposed to sufficient sunlight, and in none of the osteoporotic patients. There were no signs of malabsorption. In six out of 15 patients we found increased liver enzyme activity, which may have a role in vitamin D metabolism. We propose the influence of non-steroidal anti-inflammatory drugs (NSAIDs) on vitamin D metabolism in the liver as a possible explanation.