Denosumab prevents metacarpal shaft cortical bone loss in patients with erosive rheumatoid arthritis

Objective

Osteoclast‐mediated bone loss in the hand predicts future bone erosions in patients with rheumatoid arthritis (RA). Osteoclast activity depends on RANKL, which is inhibited by denosumab, an investigational fully human monoclonal antibody against RANKL. We measured metacarpal shaft cortical bone thickness using a novel computer‐based technique, digital x‐ray radiogrammetry (DXR), to evaluate the effects of denosumab on cortical bone in RA.

Methods

Patients (n = 227) with active, erosive RA were randomized to receive subcutaneous denosumab 60 mg or 180 mg or placebo every 6 months. All patients received stable doses of methotrexate and daily calcium and vitamin D. For this blinded post hoc analysis (n = 218), cortical bone loss was determined by DXR using computer‐assisted measurement of cortical thickness and shaft width at 21 midshaft levels of the second through fourth metacarpal bones of both hands.

Results

At 12 months, patients receiving denosumab had significantly less metacarpal bone loss versus placebo (denosumab 60 mg: ?0.0034, denosumab 180 mg: 0.0001 gain, placebo: ?0.0108; P ≤ 0.01 for both denosumab doses). Twelve‐month decreases from baseline greater than the smallest detectable change occurred in 2 patients in the denosumab 180 mg group, 9 patients in the denosumab 60 mg group, and 12 patients in the placebo group. Negative correlation was significant between static cortical thickness ratios and static erosion scores (6 and 12 months), and for placebo, between changes in erosion scores and changes in cortical thickness ratio.

Conclusion

Twice‐yearly injections of denosumab with ongoing methotrexate treatment significantly reduced cortical bone loss in RA patients for up to 12 months. These results add to the growing evidence supporting the clinical utility of DXR.

     

Prevention of glucocorticoid‐induced bone loss in mice by inhibition of RANKL

Objective

RANKL has been implicated in the pathogenesis of glucocorticoid‐induced osteoporosis. This study was undertaken to evaluate the efficacy of denosumab, a neutralizing monoclonal antibody against human RANKL (hRANKL), in a murine model of glucocorticoid‐induced osteoporosis.

Methods

Eight‐month‐old male homozygous hRANKL‐knockin mice expressing a chimeric RANKL protein with a humanized exon 5 received 2.1 mg/kg of prednisolone or placebo daily over 4 weeks via subcutaneous slow‐release pellets and were additionally treated with phosphate buffered saline or denosumab (10 mg/kg subcutaneously twice weekly). Two groups of wild‐type mice were also treated with either prednisolone or vehicle.

Results

The 4‐week prednisolone treatment induced loss of vertebral and femoral volumetric bone mineral density in the hRANKL‐knockin mice. Glucocorticoid‐induced bone loss was associated with suppressed vertebral bone formation and increased bone resorption, as evidenced by increases in the number of tartrate‐resistant acid phosphatase (TRAP)–positive osteoclasts, TRAP‐5b protein in bone extracts, serum levels of TRAP‐5b, and urinary excretion of deoxypyridinoline. Denosumab prevented prednisolone‐induced bone loss by a pronounced antiresorptive effect. Biomechanical compression tests of lumbar vertebrae revealed a detrimental effect of prednisolone on bone strength that was prevented by denosumab.

Conclusion

Our findings indicate that RANKL inhibition by denosumab prevents glucocorticoid‐induced loss of bone mass and strength in hRANKL‐knockin mice.

     

Radiographic damage associated with low bone mineral density and vertebral deformities in rheumatoid arthritis: The Oslo‐Truro‐Amsterdam (OSTRA) collaborative study

Objective

To examine variables associated with bone mineral density (BMD) and vertebral deformities in women with rheumatoid arthritis (RA) from 3 northwest European countries.

Methods

Female patients were recruited from rheumatology clinics in Oslo, Norway; Truro, UK; and Amsterdam, The Netherlands (150 total, 50 per center, age 50–70 years, disease duration ≥5 years). Demographic and clinical data were collected and BMD was measured by means of dual energy x‐ray absorptiometry. Associations between demographic and clinical measures on the one hand and BMD and vertebral deformities on the other were investigated by single and multiple regression analyses.

Results

Body mass index (BMI), medication use, RA damage measures, and BMD differed significantly between the 3 centers. Overall, Norwegian patients had the lowest BMI, used more corticosteroids and antiosteoporotic drugs, had lower joint damage measured by Larsen score, and lower BMD at both spine and hip. High age, low BMI, and high cumulative dose of corticosteroids (last 2 years) are related to low BMD. A high Larsen score was associated with low BMD at the hip. Larsen score was the independent determinant of vertebral deformities after correction for center, age, BMI, and BMD.

Conclusion

Data from 3 countries on BMD and vertebral deformities in female patients aged 50–70 years with longstanding RA are presented, demonstrating an association between radiographic RA damage and low BMD and between radiographic RA damage and vertebral deformities.

     

The relationship between focal erosions and generalized osteoporosis in postmenopausal women with rheumatoid arthritis

Objective

Among rheumatoid arthritis (RA) patients who have had the disease for 10 years, more than half have focal erosions, and the risk of fracture is doubled. However, there is little information about the potential relationship between focal erosions and bone mineral density (BMD). The aim of this study was to determine whether lower BMD is associated with higher erosion scores among patients with RA.

Methods

We enrolled 163 postmenopausal women with RA, none of whom were taking osteoporosis medications. Patients underwent dual x‐ray absorptiometry at the hip and spine and hand radiography, and completed a questionnaire. The hand radiographs were scored using the Sharp method, and the relationship between BMD and erosions was measured using Spearman's correlation coefficients and adjusted linear regression models.

Results

Patients had an average disease duration of 13.7 years, and almost all were taking a disease‐modifying antirheumatic drug. Sixty‐three percent were rheumatoid factor (RF) positive. The median modified Health Assessment Questionnaire score was 0.7, and the average Disease Activity Score in 28 joints was 3.8. The erosion score was significantly correlated with total hip BMD (r = −0.33, P < 0.0001), but not with lumbar spine BMD (r = −0.09, P = 0.27). Hip BMD was significantly lower in RF‐positive patients versus RF‐negative patients (P = 0.02). In multivariable models that included age, body mass index, and cumulative oral glucocorticoid dose, neither total hip BMD nor lumbar spine BMD was significantly associated with focal erosions.

Conclusion

Our results suggest that hip BMD is associated with focal erosions among postmenopausal women with RA, but that this association disappears after multivariable adjustment. While BMD and erosions may be correlated with bone manifestations of RA, their relationship is complex and influenced by other disease‐related factors.

     

Two‐year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: A randomized,double‐blind,placebo‐controlled extension trial

Objective

To evaluate the continued efficacy and safety of alendronate (ALN) for up to 2 years in patients receiving glucocorticoids.

Methods

This is a 12‐month extension of a previously completed 1‐year trial of daily ALN, performed to evaluate the effects of ALN over a total of 2 years in 66 men and 142 women continuing to receive at least 7.5 mg of prednisone or equivalent daily. All patients received supplemental calcium and vitamin D. The primary end point was the mean percentage change in lumbar spine bone mineral density (BMD) from baseline to 24 months. Other outcomes included changes in hip and total body BMD, biochemical markers of bone turnover, radiographic joint damage of the hands, and vertebral fracture incidence.

Results

The mean (±SEM) lumbar spine BMD increased by 2.8 ± 0.6%, 3.9 ± 0.7%, and 3.7 ± 0.6%, respectively, in the groups that received 5 mg, 10 mg, and 2.5/10 mg of ALN daily (P ≤ 0.001) and decreased by −0.8 ± 0.6% in the placebo group (P not significant) over 24 months. In patients receiving any dose of ALN, BMD was increased at the trochanter (P ≤ 0.05) and maintained at the femoral neck. Total body BMD was increased in patients receiving 5 or 10 mg ALN (P ≤ 0.01). These 2 dose levels of ALN were more effective than placebo at all sites (P ≤ 0.05). Bone turnover markers (N‐telopeptides of type I collagen and bone‐specific alkaline phosphatase) decreased 60% and 25%, respectively, during treatment with ALN (P ≤ 0.05). There were fewer patients with new vertebral fractures in the ALN group versus the placebo group (0.7% versus 6.8%; P = 0.026). The safety profile was similar between treatment groups.

Conclusion

Alendronate is an effective, well‐tolerated therapy for the prevention and treatment of glucocorticoid‐induced osteoporosis, with sustained treatment advantages for up to 2 years.

     

Efficacy of methotrexate treatment in patients with probable rheumatoid arthritis: A double‐blind,randomized, placebo‐controlled trial

Objective

To determine whether patients with undifferentiated arthritis (UA; inflammatory, nontraumatic arthritis that cannot be diagnosed using current classification criteria) benefit from treatment with methotrexate (MTX).

Methods

The PRObable rheumatoid arthritis: Methotrexate versus Placebo Treatment (PROMPT) study was a double‐blind, placebo‐controlled, randomized, multicenter trial involving 110 patients with UA who fulfilled the American College of Rheumatology (ACR) 1958 criteria for probable RA. Treatment started with MTX (15 mg/week) or placebo tablets, and every 3 months the dosage was increased if the Disease Activity Score was >2.4. After 12 months, the study medication was tapered and discontinued. Patients were followed up for 30 months. When a patient fulfilled the ACR criteria for RA (primary end point), the study medication was changed to MTX. Joint damage was scored on radiographs of the hands and feet.

Results

In 22 of the 55 patients (40%) in the MTX group, UA progressed to RA compared with 29 of 55 patients (53%) in the placebo group. However, in the MTX group, patients fulfilled the ACR criteria for RA at a later time point than in the placebo group (P = 0.04), and fewer patients showed radiographic progression over 18 months (P = 0.046).

Conclusion

This study provides evidence for the efficacy of MTX treatment in postponing the diagnosis of RA, as defined by the ACR 1987 criteria, and retarding radiographic joint damage in UA patients.

     

Change in bone mineral density in patients with rheumatoid arthritis during the first decade of the disease

Objective

Rheumatoid arthritis (RA) has been reported to be associated with bone loss during the first years of the disease. The magnitude of this problem after the initial years has not yet been evaluated. In the present study, the change in bone mineral density (BMD) in patients with recent‐onset RA as well as the effects of inflammation, mobility, and the use of prednisone on this change were studied in the first decade of the disease.

Methods

BMD was measured twice in 76 RA patients with mean disease durations of 2.35 years at the first BMD measurement and 8.90 years at the second BMD measurement. BMD was measured in both hips using dual x‐ray absorptiometry. Results were expressed as mean ± SEM Z scores (using age‐ and sex‐matched reference values) and as mean ± SEM percent change in BMD (in gm/cm²) per year. The effects of inflammation, mobility, and the use of prednisone on change in BMD were evaluated using multiple linear regression analyses.

Results

At the first BMD measurement, RA patients had lower BMD compared with the reference values (Z score −0.42 ± 0.11, 95% confidence interval [95% CI] –0.64, –0.20). Between the 2 measurements, we observed a small decrease in BMD of −0.28 ± 0.11%/year (95% CI –0.07 to –0.49). However, the rate of bone loss was smaller than expected. The Z score increased by 0.13 ± 0.05 between the 2 BMD measurements (95% CI 0.02, 0.23). Only the use of prednisone was significantly associated with increased bone loss. In a separate analysis that included only postmenopausal women, increased physical activity and longer time since menopause were both associated with decreased bone loss. In this subgroup of patients, the use of prednisone was significantly associated with increased bone loss as well. A high erythrocyte sedimentation rate was associated with increased bone loss, but this did not reach statistical significance.

Conclusion

After the initial years of the disease, bone loss in RA patients is lower than expected compared with age‐ and sex‐matched reference values. Postmenopausal RA patients with low levels of physical activity are at increased risk of losing bone. Use of prednisone was the only variable consistently associated with reduction in BMD in RA patients.

     

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.

     

Osteoprotegerin protects against generalized bone loss in tumor necrosis factor–transgenic mice

Objective

To investigate the role of tumor necrosis factor (TNF) in systemic bone loss of chronic inflammatory conditions, such as rheumatoid arthritis (RA), and to address the therapeutic potential of osteoclast blockade.

Methods

We investigated systemic bone changes in human TNF transgenic (hTNFtg) mice, which spontaneously developed severe inflammatory arthritis.

Results

Osteodensitometry revealed a significant decrease in trabecular bone mineral density (BMD) (−37%) in hTNFtg mice, and histomorphometry revealed a dramatic loss of bone volume (−85%) compared with wild‐type controls. Osteoclast‐covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly elevated, suggesting increased osteoclast‐mediated bone resorption in hTNFtg mice. Osteoprotegerin (OPG) completely blocked TNF‐mediated bone loss by increasing BMD (+89%) and bone volume (+647%). Most strikingly, formation of primary spongiosa was dramatically increased (+563%) in hTNFtg mice after OPG treatment. Osteoclast‐covered bone surface and serum levels of deoxypyridinoline crosslinks were significantly decreased by OPG, suggesting effective blockade of osteoclast‐mediated bone resorption. OPG did not influence levels of hTNF, TNF receptor I (TNFRI), interleukin‐1β (IL‐1β), and IL‐6. However, OPG decreased bone formation parameters (osteoblast‐covered bone surface and serum osteocalcin levels), which were elevated in hTNFtg mice. In contrast to OPG, bisphosphonates and anti‐TNF treatment did not affect generalized bone loss in hTNFtg mice. Anti‐TNF, however, did not affect levels of TNF and TNFRI at the concentrations tested. These data indicate that generalized bone loss due to increased TNF can be blocked by OPG.

Conclusion

OPG may represent a potent tool for preventing generalized loss of bone mass in chronic inflammatory disorders, especially RA.

     

Periarticular bone structure in rheumatoid arthritis patients and healthy individuals assessed by high‐resolution computed tomography

Objective

To define the nature of structural bone changes in patients with rheumatoid arthritis (RA) compared with those in healthy individuals by using the novel technique of high‐resolution microfocal computed tomography (micro‐CT).

Methods

Fifty‐eight RA patients and 30 healthy individuals underwent a micro‐CT scan of the proximal wrist and metacarpophalangeal joints. Bone lesions such as cortical breaks, osteophytes, and surface changes were quantified on 2‐dimensional (2‐D) slices as well as by using 3‐D reconstruction images, and exact localization of lesions was recorded.

Results

Micro‐CT scans could detect bone lesions <0.5 mm in width or depth. Small erosions could be observed in healthy individuals and RA patients, whereas lesions >1.9 mm in diameter were highly specific for RA. Cortical breaks were mostly found along the radial sites of the metacarpal heads. No significant difference in the presence of osteophytes between healthy individuals and RA patients was found. Cortical surface changes, presumably cortical thinning and fenestration, became evident from 3‐D reconstructions and were more pronounced in RA patients.

Conclusion

Micro‐CT allows exact detection of morphologic changes of juxtaarticular bone in healthy individuals and RA patients. Even healthy individuals occasionally show bone changes, but the severity of these lesions, with the exception of osteophytes, is greater in RA patients. Thus, micro‐CT allows accurate differentiation among physiologic bone changes in joints and among types of pathologic bone damage resulting from RA.

     

Significant improvement in synovitis,osteitis, and bone erosion following golimumab and methotrexate combination therapy as compared with methotrexate alone: A magnetic resonance imaging study of 318 methotrexate‐naive rheumatoid arthritis patients

Objective

To evaluate the effects of golimumab on inflammation/structural damage detected by magnetic resonance imaging (MRI) in patients with rheumatoid arthritis (RA).

Methods

Methotrexate (MTX)–naive RA patients (n = 637) were randomized to placebo plus MTX, golimumab 100 mg plus placebo, golimumab 50 mg plus MTX, or golimumab 100 mg plus MTX (subcutaneous golimumab every 4 weeks). Of these, 318 patients participated in an MRI substudy. MRIs (contrast‐enhanced; 1.5T) of the wrist and second through fifth metacarpophalangeal joints of the dominant hand were obtained at baseline and weeks 12 and 24. MRIs were scored by 2 independent readers (blinded to image sequence/chronology, patient identity, and treatment group) for synovitis, bone edema/osteitis, and bone erosions using the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring (RAMRIS) system. Radiographs (hands, wrists, forefeet at baseline and week 28) were scored by 2 other readers (blinded as above) using the modified Sharp/van der Heijde (SvdH) scoring system. Changes from baseline were compared between treatment groups (two‐sided analysis of variance on van der Waerden normal scores).

Results

At weeks 12 and 24, combined therapy with golimumab plus MTX versus placebo plus MTX significantly improved RAMRIS scores for synovitis (mean −1.92 versus 0.14 [P < 0.001] at week 12; −2.45 versus −1.04 [P < 0.001] at week 24), osteitis (mean −1.82 versus 0.56 [P < 0.001] at week 12; −2.27 versus −0.32 [P < 0.001] at week 24), and bone erosion (mean −0.40 versus 0.24 [P = 0.016] at week 12; −0.40 versus −0.24 [P = 0.010] at week 24). Results of sensitivity analyses (no missing doses/data and using linear extrapolation) were generally consistent with results of the primary analyses. Changes in SvdH scores among the MRI substudy patients at week 28 showed no significant difference between golimumab plus MTX therapy and placebo plus MTX (mean 0.49 versus 0.92; P = 0.19). Radiographic SvdH scores demonstrated inhibition of structural damage progression by treatment with golimumab plus MTX as compared with placebo plus MTX in the overall study population but required double the number of patients (637 versus 318) and double the length of followup (28 versus 12 weeks) as needed for MRI to demonstrate this.

Conclusion

Improvements in inflammation (synovitis and osteitis) and erosions with golimumab plus MTX therapy exceeded those with placebo plus MTX therapy from week 12 onward, confirming the overall clinical/radiologic findings. MRI was more sensitive than conventional radiography in detecting the progression of erosions.

     

Subchondral bone and cartilage damage: A prospective study in older adults

Objective

There is limited longitudinal evidence relating subchondral bone changes to cartilage damage and loss. The aim of this study was to describe the association between baseline tibial bone area and tibial subchondral bone mineral density (BMD) with tibial cartilage defect development and cartilage volume loss.

Methods

A total of 341 subjects (mean age 63 years, range 52–79 years) underwent measurement at baseline and ∼2.7 years later. Tibial knee cartilage volume, cartilage defects (graded on a scale of 0–4), and bone area were determined using T1‐weighted fat suppression magnetic resonance imaging. Tibial subchondral BMD was determined using dual x‐ray absorptiometry.

Results

In multivariable analysis, baseline bone area positively predicted cartilage defect development at the medial and lateral tibial sites (odds ratio [OR] 1.6 per 1 SD increase, 95% confidence interval [95% CI] 1.0, 2.6, and OR 2.4 per 1 SD increase, 95% CI 1.4, 4.0, respectively) and cartilage volume loss at the medial tibial site (β = −34.9 per 1 SD increase, 95% CI −49.8, −20.1). In contrast, baseline subchondral BMD positively predicted cartilage defect development at the medial tibial site only (OR 1.6 per 1 SD increase, 95% CI 1.2, 2.1) and was not associated with cartilage loss.

Conclusion

The results of this study demonstrated that bone area predicted medial and lateral cartilage defect development and medial cartilage volume loss, while subchondral BMD predicted medial defect development but not cartilage loss. These associations were independent of each other, indicating there are multiple mechanisms by which subchondral bone changes may lead to cartilage damage.

     

Amelioration of collagen‐induced arthritis and immune‐associated bone loss through signaling via estrogen receptor α, and not estrogen receptor β or G protein–coupled receptor 30

Objective

The effects of estrogen may be exerted via the nuclear estrogen receptors (ERs) ERα or ERβ or via the recently proposed transmembrane estrogen receptor G protein–coupled receptor 30 (GPR‐30). The purpose of this study was to elucidate the ER specificity for the ameliorating effects of estrogen on arthritis and bone loss in a model of postmenopausal rheumatoid arthritis (RA).

Methods

Female DBA/1 mice underwent ovariectomy or sham operation, and type II collagen–induced arthritis was induced. Mice were treated subcutaneously 5 days/week with the specific agonists propylpyrazoletriol (PPT; for ERα), diarylpropionitrile (DPN; for ERβ), G1 (for GPR‐30), or with a physiologic dose of estradiol. Clinical arthritis scores were determined continuously. At termination of the study, bone mineral density (BMD) was analyzed, paws were collected for histologic assessment, serum was analyzed for cytokines and markers of bone and cartilage turnover, and bone marrow was subjected to fluorescence‐activated cell sorting.

Results

Treatment with PPT as well as estradiol dramatically decreased the frequency and severity of arthritis. Furthermore, estradiol and PPT treatment resulted in preservation of bone and cartilage, as demonstrated by increased BMD and decreased serum levels of bone resorption markers and cartilage degradation markers, whereas no effect was seen after DPN or G1 treatment.

Conclusion

In a well‐established model of postmenopausal RA, ERα, but not ERβ or GPR‐30 signaling, was shown to ameliorate the disease and the associated development of osteoporosis. Since long‐term treatment with estrogen has been associated with significant side effects, increased knowledge about the mechanisms behind the beneficial effects of estrogen is useful in the search for novel treatments of postmenopausal RA.

     

Slowing of bone loss in patients with rheumatoid arthritis by long‐term high‐intensity exercise: Results of a randomized,controlled trial

Objective

Patients with rheumatoid arthritis (RA) are more at risk for the development of osteoporosis and osteoporotic fractures than are their healthy peers. In this randomized, controlled, multicenter trial, the effectiveness of a 2‐year high‐intensity weight‐bearing exercise program (the Rheumatoid‐Arthritis‐Patients‐In‐Training [RAPIT] program) on bone mineral density (BMD) was compared with usual care physical therapy, and the exercise modalities associated with changes in BMD were determined.

Methods

Three hundred nine patients with RA were assigned to an intervention group, either the RAPIT program or usual care physical therapy. The primary end points were BMD of the hip and spine. The exercise modalities examined were aerobic fitness, muscle strength, and, as a surrogate for those effects not directly measured by the RAPIT program, attendance rate.

Results

The data on the 136 RAPIT participants and 145 usual care participants who completed the study were analyzed. The mean rate of decrease in hip BMD, but not in lumbar spine BMD, was smaller in patients participating in the RAPIT program when compared with that in the usual care group, with a mean decrease of 1.6% (95% confidence interval [95% CI] 0.8–2.5) over the first year and 0.5% (95% CI 1.1–2.0) over the second year. The change in hip BMD was significantly and independently associated with changes in both muscle strength (multivariate odds ratio [OR] 1.75, 95% CI 1.07–2.86) and aerobic fitness (OR 1.79, 95% CI 1.10–2.90), but not with the attendance rate (OR 1.00, 95% CI 0.99–1.00).

Conclusion

A long‐term high‐intensity weight‐bearing exercise program for RA patients is effective in slowing down the loss of BMD at the hip. The exercise modalities associated with this effect are muscle strength and aerobic fitness.

     

Mechanisms of bone fragility in a mouse model of glucocorticoid‐treated rheumatoid arthritis: Implications for insufficiency fracture risk

Objective

Glucocorticoid (GC) therapy is associated with increased risk of fracture in patients with rheumatoid arthritis (RA). To elucidate the cause of this increased risk, we examined the effects of chronic erosive inflammatory arthritis and GC treatment on bone quality, structure, and biomechanical properties in a murine model.

Methods

Mice with established arthritis and expressing human tumor necrosis factor α (TNFα) transgene (Tg) and their wild‐type (WT) littermates were continually treated with GC (prednisolone 5 mg/kg/day via subcutaneous controlled‐release pellet) or placebo for 14, 28, or 42 days. Microstructure, biomechanical properties, chemical composition, and morphology of the tibiae and lumbar vertebral bodies were assessed by micro–computed tomography, biomechanical testing, Raman spectroscopy, and histology, respectively. Serum markers of bone turnover were also determined.

Results

TNF‐Tg and GC treatment additively decreased mechanical strength and stiffness in both the tibiae and the vertebral bodies. GC treatment in the TNF‐Tg mice increased the ductility of tibiae under torsional loading. These changes were associated with significant alterations in the biochemical and structural composition of the mineral and organic components of the bone matrix, a decrease in osteoblast activity and bone formation, and an increase in osteoclast activity.

Conclusion

Our findings indicate that the concomitant decrease in bone strength and increase in bone ductility associated with chronic inflammation and GC therapy, coupled with the significant changes in the bone quality and structure, may increase the susceptibility of the bone to failure under low‐energy loading. This may explain the mechanism of symptomatic insufficiency fractures in patients with RA receiving GC therapy who do not have radiographic manifestations of fracture.

     

Expression of osteopontin at sites of bone erosion in a murine experimental arthritis model of collagen‐induced arthritis: Possible involvement of osteopontin in bone destruction in arthritis

Objective

To investigate the involvement of osteopontin (OPN) in bone destruction in a murine experimental arthritis model of collagen‐induced arthritis (CIA).

Methods

The expression of OPN was examined at both the messenger RNA (mRNA) and protein levels in various arthritic lesions in mice with CIA by in situ hybridization and immunohistochemistry, respectively. In addition, the expression of αvβ3 integrin, a receptor for OPN, the ligation of which is thought to be essential for bone resorption by osteoclasts, was examined by immunohistochemistry. Plasma concentrations of OPN were measured at different time points in the course of CIA by enzyme‐linked immunosorbent assay.

Results

OPN mRNA was detected mainly at sites of bone erosion in arthritic lesions, where activated osteoclasts were present; OPN protein was also detected at sites of bone erosion. In the arthritic synovium, OPN was predominantly expressed in the synovial lining layer, but not in lymphoid aggregates. In addition, αvβ3 integrin was detected coincident with OPN at sites of bone erosion (bone–pannus junction). Plasma OPN levels were markedly elevated at the time points that corresponded to arthritis flares, and higher levels were maintained during the progression of arthritis.

Conclusion

OPN may mediate bone resorption by osteoclasts in arthritis through ligation with its receptor, αvβ3 integrin. OPN may be a useful therapeutic target molecule in the prevention of bone destruction in arthritis.

     

Treatment of rheumatoid arthritis with humanized anti–interleukin‐6 receptor antibody: A multicenter,double‐blind,placebo‐controlled trial

Objective

Interleukin‐6 (IL‐6) is a pleiotropic cytokine that regulates the immune response, inflammation, and hematopoiesis. Overproduction of IL‐6 plays pathologic roles in rheumatoid arthritis (RA), and the blockade of IL‐6 may be therapeutically effective for the disease. This study was undertaken to evaluate the safety and efficacy of a humanized anti–IL‐6 receptor antibody, MRA, in patients with RA.

Methods

In a multicenter, double‐blind, placebo‐controlled trial, 164 patients with refractory RA were randomized to receive either MRA (4 mg/kg body weight or 8 mg/kg body weight) or placebo. MRA was administered intravenously every 4 weeks for a total of 3 months. The clinical responses were measured using the American College of Rheumatology (ACR) criteria.

Results

Treatment with MRA reduced disease activity in a dose‐dependent manner. At 3 months, 78% of patients in the 8‐mg group, 57% in the 4‐mg group, and 11% in the placebo group achieved at least a 20% improvement in disease activity according to the ACR criteria (an ACR20 response) (P < 0.001 for 8‐mg group versus placebo). Forty percent of patients in the 8‐mg group and 1.9% in the placebo group achieved an ACR50 response (P < 0.001). The overall incidences of adverse events were 56%, 59%, and 51% in the placebo, 4‐mg, and 8‐mg groups, respectively, and the adverse events were not dose dependent. A blood cholesterol increase was observed in 44.0% of the patients. Liver function disorders and decreases in white blood cell counts were also observed, but these were mild and transient. There was no increase in antinuclear antibodies or anti‐DNA antibodies. Anti‐MRA antibodies were detected in 2 patients.

Conclusion

Treatment with MRA was generally well tolerated and significantly reduced the disease activity of RA.

     

The selective estrogen receptor α agonist Org 37663 induces estrogenic effects but lacks antirheumatic activity: A phase IIa trial investigating efficacy and safety of Org 37663 in postmenopausal female rheumatoid arthritis patients receiving stable background methotrexate or sulfasalazine

Objective

Multiple lines of evidence suggest that sex hormones may play a role in the pathogenesis or clinical expression of rheumatoid arthritis (RA). Studies on the effects of exogenous estrogens in RA patients have yielded contradictory results. We undertook this study to determine the effects of the selective estrogen receptor α (ERα) agonist Org 37663 in patients with RA, in terms of both its estrogenic effects and its ability to ameliorate disease activity.

Methods

A 10‐week, multicenter, randomized, double‐blind, placebo‐controlled, parallel group, dose‐finding, proof‐of‐concept trial was initiated to obtain data on the efficacy and safety of Org 37663 in postmenopausal female patients with RA who were receiving background treatment with either methotrexate or sulfasalazine. Patients were randomized to receive placebo or Org 37663 at doses of 4 mg/day, 15 mg/day, or 50 mg/week. The primary efficacy variable was the Disease Activity Score in 28 joints (DAS28).

Results

Org 37663 induced a clear biologic, estrogenic response in several organ systems, including a dose‐related increase in levels of sex hormone binding globulin. However, the DAS28 decreased similarly for all treatment groups including placebo, indicating lack of clinical efficacy of Org 37663 in this trial.

Conclusion

The observed lack of clinical benefit in RA patients treated with an ERα agonist, in association with a clear biologic response to the study drug, provides evidence that a biologically relevant ERα‐mediated estrogenic effect is not associated with a clinically relevant effect on RA symptoms and signs.

     

Effect of minodronic acid (ONO‐5920) on bone mineral density and arthritis in adult rats with collagen‐induced arthritis

Objective

To study the effect of minodronic acid (ONO‐5920) on bone loss and arthritis in rats with collagen‐induced arthritis (CIA) treated according to 2 different schedules.

Methods

Four groups of female Sprague‐Dawley rats (7 months old) were studied: rats without CIA treated with vehicle (controls), CIA rats treated with vehicle (CIA‐V), CIA rats treated therapeutically with minodronic acid (CIA‐T), and CIA rats treated prophylactically with minodronic acid (CIA‐P). Minodronic acid was administered orally at 0.2 mg/kg 3 times a week, beginning 2 weeks after initial sensitization in the CIA‐T rats and beginning the day after initial sensitization in the CIA‐P rats. Bone mineral density (BMD) was measured by peripheral quantitative computed tomography in the proximal metaphysis and diaphysis of the tibia every 2 weeks until week 8, when the rats were killed. The BMD and bone microstructure of the excised femur were evaluated by dual x‐ray absorptiometry and microfocal computed tomography, respectively. Histomorphometry of the proximal tibia was also performed.

Results

In CIA‐P rats, the incidence of arthritis and the severity of posterior limb swelling were reduced early after sensitization, and the decrease in BMD was prevented throughout the observation period. Bone and joint destruction evaluated by radiography of the foot was reduced in CIA‐P rats. The eroded surface was reduced and the microstructure was maintained in CIA‐P rats compared with CIA‐V rats. The mineral apposition and bone formation rates were not reduced in the CIA‐P rats. In CIA‐T rats, however, the inflammation was not suppressed and the inhibitory effect on bone loss was smaller than that in CIA‐P rats.

Conclusion

Minodronic acid suppressed the decrease in BMD and the deterioration of the bone microstructure caused by arthritis. Prophylactic administration of minodronic acid had a preventive effect on arthritis at the early stage, although not throughout the observation period.

     

Effect of intermittent administration of human parathyroid hormone on bone mineral density and arthritis in rats with collagen‐induced arthritis

Objective

To investigate the effect of intermittent administration of human parathyroid hormone (PTH) on bone mineral density (BMD) and arthritis in rats with collagen‐induced arthritis (CIA).

Methods

Seven‐month‐old female Sprague‐Dawley rats were divided into 4 groups: rats without CIA (control), rats with CIA treated with vehicle, rats with CIA treated with PTH for 4 weeks, and rats with CIA treated with PTH for 6 weeks. PTH (20 μg/kg) was injected subcutaneously 3 times per week. BMD in the proximal metaphysis and the diaphysis of the tibia was measured by peripheral quantitative computed tomography every 2 weeks until week 8. Eight weeks after initial sensitization, the animals were killed, and the BMD and mechanical properties of excised limbs were evaluated. Histomorphometric analysis of tibiae and histologic evaluation of arthritis were also performed.

Results

In the PTH‐treated rats with CIA, the incidence and severity of arthritis were macroscopically and histologically similar to the findings in the vehicle‐treated rats with CIA. The decrease of BMD caused by CIA was suppressed by treatment with human PTH, in a manner that was dependent on the duration of administration. In the histomorphometric analysis, bone formation parameters were higher and bone resorption parameters were lower in the PTH‐treated arthritic rats compared with vehicle‐treated arthritic rats. Mechanical properties were also maintained in the PTH‐treated rats.

Conclusion

Our findings indicate that, in an animal model of arthritis, intermittent PTH administration activates bone formation, resulting in increased BMD and preventing deterioration of mechanical properties. However, PTH has no effect on the arthritis itself.