Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor-mediated arthritis

OBJECTIVE: Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast-targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions. METHODS: Human tumor necrosis factor (TNF)-transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti-TNF, at the onset of arthritis. RESULTS: Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (-60%) and was almost completely blocked by repeated administration of ZA (-95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti-TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass. CONCLUSION: ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.     

Biomarkers in osteoarthritis

PURPOSE OF REVIEW: Osteoarthritis is a chronic disease characterized by progressive destruction of articular cartilage and subchondral bone, and synovial reaction. Clinical and radiologic findings that form the basis of the diagnosis of osteoarthritis are poorly sensitive for monitoring the progression of the disease. Biologic markers reflecting quantitative and dynamic changes of joint tissue turnover represent promising adjunct tools. RECENT FINDINGS: New tissue-specific markers have been developed and include assays for type II collagen synthesis and degradation and synovitis. Prospective studies indicate that increased or decreased levels of some of these markers are associated with rapid progression of joint destruction in patients with knee osteoarthritis. Because progression of joint damage is likely to result primarily from an imbalance between degradation and reparative processes, a combination of markers reflecting these two components appears promising. For example, combining two new markers for type II collagen synthesis and degradation in an uncoupling index of cartilage turnover was more effective in predicting 1-year radiologic progression in knee osteoarthritis than the measurement of a single marker. Preliminary data in rheumatoid arthritis show a rapid response of a marker of type II collagen degradation under disease-modifying antirheumatic drugs, with early changes of this marker being predictive of long-term radiologic progression. SUMMARY: Recent evidence suggests that the combination of some biologic markers will be useful for identifying patients at risk for rapid joint destruction in osteoarthritis. Because of their rapid changes under treatment, biologic markers will play an important role in the development and monitoring of new structure-modifying therapies for osteoarthritis.     

Association of baseline levels of urinary glucosyl-galactosyl-pyridinoline and type II collagen C-telopeptide with progression of joint destruction in patients with early rheumatoid arthritis

OBJECTIVE: To evaluate whether measurements of urinary glucosyl-galactosyl-pyridinoline (Glc-Gal-PYD) and urinary C-terminal crosslinking telopeptide of type II collagen (CTX-II), 2 new markers of destruction of the synovium and cartilage collagen breakdown, respectively, are associated with the progression of joint damage in patients with early rheumatoid arthritis (RA), and to compare this association with that with serum matrix metalloproteinase 3 (MMP-3), a proteinase expressed by synovial tissue and chondrocytes, and that with serum C-reactive protein (CRP), an index of systemic inflammation. METHODS: The prospective study cohort comprised 116 patients with early RA who were part of a large, double-blind, randomized study comparing the efficacy of etanercept and methotrexate. The relationship between baseline levels of urinary Glc-Gal-PYD, urinary CTX-II, and serum MMP-3 and the progression of joint destruction, as measured by changes in the modified Sharp score (average findings of 2 independent readers) over 1 year, was investigated. RESULTS: Levels of urinary Glc-Gal-PYD (+70%), urinary CTX-II (+104%), and serum MMP-3 (+219%) were elevated compared with the levels in 76 healthy controls. The baseline levels of Glc-Gal-PYD (r = 0.30), CTX-II (r = 0.25), and MMP-3 (r = 0.29) correlated with the changes over 1 year in the total Sharp score (joint space narrowing and bone erosion). Patients with baseline levels of Glc-Gal-PYD, CTX-II, and MMP-3 that were higher than the mean + 2 SD in healthy controls had a significantly greater progression of joint damage, with an increase in the total Sharp score over 1 year that was from 3- to 8-fold higher than that in patients with low baseline levels of these markers. Moreover, patients with these higher levels of Glc-Gal-PYD, CTX-II, and MMP-3 had a higher risk of progression of the disease (increase in total Sharp score > or =0.5 units) than did the other patients (relative risks and 95% confidence intervals [95% CI] 3.3 [95% CI 1.5-7.4], 2.5 [95% CI 1.1-5.7], and 2.5 [95% CI 1.1-5.6], respectively). The baseline serum level of CRP was not significantly associated with the progression of joint damage. Adjustment of the levels of Glc-Gal-PYD, CTX-II, and MMP-3 according to radiologic damage at baseline did not alter their association with progression. After adjustment for serum CRP, the relative risk slightly decreased, but remained significant, for Glc-Gal-PYD (2.6 [95% CI 1.1-6.3]). Patients with both increased levels of the molecular markers and radiologic damage at baseline had a higher risk of progression of joint damage than did those with either high molecular marker levels or radiologic damage. CONCLUSION: High baseline levels of Glc-Gal-PYD, CTX-II, and MMP-3 are associated with increased risk of progression of joint destruction over 1 year in early RA. The association between baseline levels of urinary Glc-Gal-PYD and progression of joint erosion was independent of the severity of radiologic damage and inflammation at baseline. Combining the measurements of these molecular markers with radiologic assessment of joint damage may be useful for identifying patients with RA who are at high risk of rapid progression and for whom early aggressive treatment would be beneficial.     

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.     

Two year randomized controlled trial of etidronate in rheumatoid arthritis: changes in serum aminoterminal telopeptides correlate with radiographic progression of disease

OBJECTIVE: To investigate the effect of intermittent cyclical etidronate treatment on radiographic progression, bone collagen markers, and clinical disease activity in patients with rheumatoid arthritis (RA). METHODS: Forty patients with RA of less than 5 years' duration were randomized to receive intermittent cyclical etidronate therapy in conjunction with antirheumatic therapy or antirheumatic therapy alone (without etidronate) in a 2 year open-label protocol. Radiographs of hands and feet and serum samples for determination of aminoterminal propeptide (PINP), crosslinked C-telopeptide (ICTP), and aminoterminal telopeptides (NTx) of type I collagen were obtained at baseline and at 24 months. RESULTS: There was significant and similar worsening of the radiologic scores in both treatment groups. Both PINP, a marker of bone formation, and ICTP, an indicator of collagen degradation, declined in the etidronate group compared to the control group (p = 0.001 and p = 0.042, respectively). The groups did not differ for the change in serum NTx, a specific systemic marker of osteoclastic bone resorption. However, the change in serum NTx correlated significantly with the increase in erosion score in the total study population and in the control group (r = 0.41, p = 0.01 and r = 0.48, p = 0.034, respectively). CONCLUSION: Etidronate therapy did not prevent radiologic progression in patients with RA, but the decline in serum PINP and ICTP concentrations suggests a favorable effect on general bone metabolism. Correlation between the change in serum NTx and worsening of the erosion score provides biochemical evidence that osteoclast is the principal cell type responsible for focal bone resorption in RA.     

Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor–mediated arthritis

Objective

Increased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast‐targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions.

Methods

Human tumor necrosis factor (TNF)–transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti‐TNF, at the onset of arthritis.

Results

Synovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (−60%) and was almost completely blocked by repeated administration of ZA (−95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti‐TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass.

Conclusion

ZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.

     

Drug therapy for osteoporosis associated with reumatoid arthritis (bisphosphonates)

Rheumatoid arthritis (RA) causes local and systemic bone loss due the increased bone resorption. Because the bisphosphonates are potent inhibitors for bone resorption, these drugs will be the major regimen to treat RA-associated osteoporosis. In addition, some reports suggest that bisphosphonates may modulate the pathogenesis of RA itself. Further study of bisphosphonates may help improve the treatment of RA.     

The urinary excretion of pyridinoline and deoxypyridinoline during rheumatoid arthritis therapy with infliximab

Rheumatoid arthritis is a systemic disease that causes inflammation and joint destruction. As a result of pathological destruction in bone and cartilage, crosslinks in collagen are resorbed more rapidly. This causes a rise in circulating collagen crosslink levels and their urinary excretion. In RA, apart from the crosslink resorption at the site of inflamed joints, there may be increased resorption due to general bone loss associated with disease activity. The aim of this study was to evaluate the influence of therapy with infliximab on urinary excretion of pyridinoline (PYD) and deoxypyridinoline (DPYR) as a markers of collagen degradation and its correlation with clinical and biochemical parameters of disease activity. Seventeen patients with active rheumatoid arthritis treated with infliximab were recruited into the study. The therapy resulted in the reduction in the symptoms of RA and urinary excretion of PYD and DPYR. The urinary excretion of PYD correlated with a number of swollen joints, morning stiffness, CRP and ESR. The urinary excretion of DPYR correlated during infliximab therapy with the number of swollen and tender joints and morning stiffness. The measurement of urinary excretion of PYR and DPYR may give insight into bone metabolism and help us to better understand the actual changes in bone and cartilage caused by RA and its treatment.Abbreviations DPYR Deoxypyridinoline - PYR Pyridinoline - RA Rheumatoid arthritis     

Biochemical markers for bone metabolism in severe osteoporosis

Degrees of changes in biochemical bone markers following osteoporosis-related fractures depend on types and severity of fractures and markers selected. Although immobilization is known to raise values of bone resorption markers, it is likely that incomplete immobilization commonly induced by fracture has little impact on systemic bone metabolism. Since marked increase in bone markers in patients with osteoporosis implies presence of underlying diseases and/or "occult" fracture other than "high turnover" osteoporosis, clinician should make efforts to explore secondary cause of increased systemic bone metabolism and fractures occurred locally.     

Insights into Rheumatoid Arthritis from Use of MRI

Magnetic resonance imaging (MRI) is ideal for imaging the joints of rheumatoid arthritis (RA) patients. It produces anatomically detailed images of bone, cartilage, tendons and synovial membrane. It can reveal structural damage, in the form of bone erosion, cartilage thinning and/or tendon rupture, and regions of inflammation, using sequences that reveal water content and vascularity. MRI synovitis, tenosynovitis and bone oedema/osteitis all have prognostic significance, and MRI studies of RA have helped elucidate the mechanisms whereby bone and synovial inflammation lead to joint damage. Bone oedema/osteitis has become an important imaging biomarker, and can be used to help predict progression from undifferentiated arthritis to definite RA. Recent MRI studies have confirmed that subclinical inflammation is often present in patients in clinical remission, and these data may affect disease management. Finally, recent clinical trials are reviewed, in which MRI outcome measures are being established as sensitive response markers.     

Prediction of progression of radiologic damage in newly diagnosed rheumatoid arthritis

Objective. To investigate the extent to which early radiologic damage is predicted by joint inflammation in patients with newly diagnosed rheumatoid arthritis (RA). Methods. Regression analysis was performed on 1-year progression of total radiologic damage for baseline characteristics and cumulative disease activity measures, and the effects of continued joint inflammation on the progression of damage in separate joint groups were investigated. Results. Odds ratios for progression of total damage were 12 for the presence of rheumatoid factor, 5 for the presence of damage at baseline, and 2 for cumulative joint inflammation. A positive association between continued joint inflammation and progression of damage was found to be statistically significant for most joint groups. Conclusion. Progression of radiologic damage in patients with newly diagnosed RA is independently associated with the presence of rheumatoid factor and damage at baseline and with cumulative joint inflammation.     

Differential Effects of Inflammation on Bone and Response to Biologics in Rheumatoid Arthritis and Spondyloarthritis

Purpose of review

We review the pathways, cytokines, and concepts important to the pathogenesis of bone resorption and formation in rheumatoid arthritis (RA) and spondyloarthritis (SpA).

Recent findings

Research in bone biology has shed light on the pathogenesis of the joint destruction that occurs in RA and in peripheral SpA. However, understanding the mechanisms behind the bone formation seen in peripheral and axial SpA has been challenging. Mouse models have been used to gain an understanding of key signaling pathways, cytokines and cells regulating inflammation in these diseases. Biologic therapies directed against these targets have been developed to control both inflammation and effects on bone.

Summary

Although biologic therapies improve joint inflammation in both RA and SpA, leading to a decrease in pain and improving quality of life for patients, the long-term effects of such therapies must also be evaluated by assessing their impact on structural progression. Inhibition of radiographic progression in both RA and peripheral SpA has been easier to demonstrate than in axial SpA. Here, we discuss the similarities and differences among biologic therapies as they pertain to radiographic progression.

     

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.      

Association of baseline levels of urinary glucosyl‐galactosyl‐pyridinoline and type II collagen C‐telopeptide with progression of joint destruction in patients with early rheumatoid arthritis

Objective

To evaluate whether measurements of urinary glucosyl‐galactosyl‐pyridinoline (Glc‐Gal‐PYD) and urinary C‐terminal crosslinking telopeptide of type II collagen (CTX‐II), 2 new markers of destruction of the synovium and cartilage collagen breakdown, respectively, are associated with the progression of joint damage in patients with early rheumatoid arthritis (RA), and to compare this association with that with serum matrix metalloproteinase 3 (MMP‐3), a proteinase expressed by synovial tissue and chondrocytes, and that with serum C‐reactive protein (CRP), an index of systemic inflammation.

Methods

The prospective study cohort comprised 116 patients with early RA who were part of a large, double‐blind, randomized study comparing the efficacy of etanercept and methotrexate. The relationship between baseline levels of urinary Glc‐Gal‐PYD, urinary CTX‐II, and serum MMP‐3 and the progression of joint destruction, as measured by changes in the modified Sharp score (average findings of 2 independent readers) over 1 year, was investigated.

Results

Levels of urinary Glc‐Gal‐PYD (+70%), urinary CTX‐II (+104%), and serum MMP‐3 (+219%) were elevated compared with the levels in 76 healthy controls. The baseline levels of Glc‐Gal‐PYD (r = 0.30), CTX‐II (r = 0.25), and MMP‐3 (r = 0.29) correlated with the changes over 1 year in the total Sharp score (joint space narrowing and bone erosion). Patients with baseline levels of Glc‐Gal‐PYD, CTX‐II, and MMP‐3 that were higher than the mean + 2 SD in healthy controls had a significantly greater progression of joint damage, with an increase in the total Sharp score over 1 year that was from 3‐ to 8‐fold higher than that in patients with low baseline levels of these markers. Moreover, patients with these higher levels of Glc‐Gal‐PYD, CTX‐II, and MMP‐3 had a higher risk of progression of the disease (increase in total Sharp score ≥0.5 units) than did the other patients (relative risks and 95% confidence intervals [95% CI] 3.3 [95% CI 1.5–7.4], 2.5 [95% CI 1.1–5.7], and 2.5 [95% CI 1.1–5.6], respectively). The baseline serum level of CRP was not significantly associated with the progression of joint damage. Adjustment of the levels of Glc‐Gal‐PYD, CTX‐II, and MMP‐3 according to radiologic damage at baseline did not alter their association with progression. After adjustment for serum CRP, the relative risk slightly decreased, but remained significant, for Glc‐Gal‐PYD (2.6 [95% CI 1.1–6.3]). Patients with both increased levels of the molecular markers and radiologic damage at baseline had a higher risk of progression of joint damage than did those with either high molecular marker levels or radiologic damage.

Conclusion

High baseline levels of Glc‐Gal‐PYD, CTX‐II, and MMP‐3 are associated with increased risk of progression of joint destruction over 1 year in early RA. The association between baseline levels of urinary Glc‐Gal‐PYD and progression of joint erosion was independent of the severity of radiologic damage and inflammation at baseline. Combining the measurements of these molecular markers with radiologic assessment of joint damage may be useful for identifying patients with RA who are at high risk of rapid progression and for whom early aggressive treatment would be beneficial.

     

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.     

Association of baseline levels of markers of bone and cartilage degradation with long-term progression of joint damage in patients with early rheumatoid arthritis: the COBRA study

OBJECTIVE: The known risk factors for radiologic progression in rheumatoid arthritis (RA) are not optimally discriminative in patients with early disease who do not have evidence of radiologic damage. We sought to determine whether urinary C-terminal crosslinking telopeptide of type I (CTX-I) and type II (CTX-II) collagen (markers of bone and cartilage destruction, respectively) are associated with long-term radiologic progression in patients with early RA. METHODS: This was a prospective study of 110 patients with early RA who were participating in the COBRA (Combinatietherapie Bij Reumato?de Artritis) clinical trial and followup study, a randomized controlled trial comparing the efficacy of oral pulse prednisolone, methotrexate, plus sulfasalazine with sulfasalazine alone. We investigated the relationship between baseline levels of urinary CTX-I and CTX-II and the mean annual progression of joint destruction over a median of 4 years, as measured by changes in the modified Sharp score (average of 2 independent readers). RESULTS: In multivariate logistic regression analysis, baseline urinary CTX-I and CTX-II levels in the highest tertile were the strongest predictors of radiologic progression (Sharp score increase >2 units/year; odds ratio 7.9 and 11.2, respectively), independently of treatment group, erythrocyte sedimentation rate (ESR), Disease Activity Score in 28 joints, rheumatoid factor (RF), and baseline joint damage (Sharp score). The likelihood ratios for a positive test were 3.8 and 8.0 for CTX-I and CTX-II, respectively, which compared favorably with the likelihood ratios for the ESR (3.0), baseline joint damage (1.6), and RF (1.8). When patients were grouped according to the presence (Sharp score >/=4, n = 49) and absence (Sharp score <4, n = 61) of joint damage at baseline, CTX-I and CTX-II levels were predictive only in those without baseline joint damage (odds ratio 14.9 and 25.7, respectively). CONCLUSION: High baseline levels of urinary CTX-I and CTX-II independently predict an increased risk of radiologic progression over 4 years in patients with early RA, especially those without radiologic joint damage. Urinary CTX-I and CTX-II may be useful for identifying individual RA patients at high risk of progression very early in the disease, before erosions can be detected radiographically. Such patients may be in special need of treatments that inhibit bone and cartilage degradation.     

BONE MASS MEASUREMENT AND BONE METABOLISM IN RHEUMATOID ARTHRITIS: A REVIEW

The involvement of bone in rheumatoid arthritis (RA) is wellrecognized, and hand bone densitometry appears to be a promisingnew technique to monitor disease progression by assessing serialchanges in hand bone mass in patients with RA. New biochemicalmarkers of bone formation (i.e. osteocalcin) show contradictoryresults in different studies, although markers of bone resorption(i.e. urinary collagen cross-links) have shown significant increasein patients with RA. Bone histomorphometric studies suggestthat the periarticular osteopenia in RA could be related toincreased bone turnover locally, whereas generalized osteoporosiscould be due to a global negative remodelling balance. The importantfactors implicated in the pathogenesis of the bone loss arecirculating cytokines [e.g. tumour necrosis factor alpha (TNF     

Comparison of the efficacy of denosumab and bisphosphonates for treating secondary osteoporosis in patients with rheumatoid arthritis

Objectives: This study aimed to investigate the efficacy of denosumab (compared with that of bisphosphonates) for preventing secondary osteoporosis and inflammation caused by excessive bone resorption in Japanese rheumatoid arthritis (RA) patients never previously treated for osteoporosis.

Methods: Ninety-eight patients with coexisting RA and osteoporosis were enrolled. The patients were subdivided by whether they were treated with denosumab (n?=?49) or traditional bisphosphonates (n?=?49). RA disease activity, bone turnover markers, and bone mineral density (BMD) were compared between the two groups before treatment, and after 6 and 12 months of treatment.

Results: There was no significant difference between the groups in any of the disease activity indices and BMD at any of the measured time points. With regard to bone metabolism, denosumab significantly reduced bone-specific alkaline phosphatase at 6 and 12 months compared with pretreatment, but had no effect on tartrate-resistant acid phosphatase 5b levels, suggesting an effect on the bone formation rate, but not on the bone resorption rate.

Conclusions: Neither denosumab nor bisphosphonates could suppress inflammation or RA disease activity, but denosumab significantly suppressed a marker of bone metabolism in Japanese RA patients never previously treated for osteoporosis.     

Risk factors for osteoporosis and fractures in rheumatoid arthritis

People with rheumatoid arthritis (RA) have both disease-specific risk factors for osteoporosis and fractures in addition to those that affect the general population. Disease specific risks include directly pathogenic auto-antibodies, chronic exposure to systemic inflammation, and joint damage causing early disability. Risk factors that affect the general population which may have a higher prevalence in RA include smoking, calcium and vitamin D deficiency as well as hypogonadism. Additionally, chronic exposure to glucocorticoids results in reduced bone mineral density and body composition changes which can further increase fracture risk. In this review we discuss these risk-factors for osteoporosis as well as factors that may impact fall and fracture risk in people with RA.     

The ratio of circulating osteoprotegerin to RANKL in early rheumatoid arthritis predicts later joint destruction

OBJECTIVE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that may result in debilitating joint deformities with destruction of bone and cartilage. Inflammation is still considered the pivotal inducer of both components of joint damage. Results of recent animal studies suggested a prominent contribution of osteoclastic bone resorption that could be dissociated from inflammation. RANKL and its natural decoy receptor, osteoprotegerin (OPG), play key roles in osteoclast activation. In a group of patients with early RA not treated with disease-modifying drugs, we tested the hypothesis that osteoclast activation, reflected by the serum OPG:RANKL ratio at baseline, is negatively associated with progression of bone damage, independent of inflammation. METHODS: OPG and RANKL levels, together with a parameter of inflammation (first-year time-averaged erythrocyte sedimentation rate [tESR]), were measured in 92 patients with newly diagnosed early active RA who were participants in a randomized study. The tESR and the OPG:RANKL ratio were evaluated for the ability to predict 5-year radiographic progression of joint damage. RESULTS: The first-year tESR and the OPG:RANKL ratio, as measured at baseline, independently predicted 5-year radiographic progression of joint damage (both P < or = 0.001). Progression of radiographic damage was greatest in patients with a high tESR and a low OPG:RANKL ratio and was lowest in patients with a low tESR and a high OPG:RANKL ratio. CONCLUSION: This study in patients with early untreated RA is the first to confirm the findings in animal models of arthritis, that radiographic progression of the bone component of joint destruction is dependent on both inflammation (tESR) and osteoclast activation (the OPG:RANKL ratio).