Denosumab‐mediated increase in hand bone mineral density associated with decreased progression of bone erosion in rheumatoid arthritis patients

Objective

Periarticular osteoporosis is one of the earliest radiographic signs of bone damage in rheumatoid arthritis (RA). Denosumab, an investigational fully human monoclonal antibody that binds to RANKL, inhibits bone erosion and systemic bone loss in clinical studies of patients with RA. In this hand bone mineral density (BMD) substudy, we investigated the effects of denosumab on hand BMD and its correlation with hand erosion scores.

Methods

Patients receiving methotrexate for erosive RA were randomized in a 1:1:1 ratio to receive subcutaneous placebo, denosumab 60 mg, or denosumab 180 mg at 0 and 6 months. Measurements included BMD (by dual x‐ray absorptiometry [DXA]) of both hands (0, 1, 6, and 12 months), magnetic resonance images of the hands/wrists (0 and 6 months), and radiographs of the hands/wrists and feet (0, 6, and 12 months).

Results

There were 56 patients (13 placebo, 21 denosumab 60 mg, and 22 denosumab 180 mg). Mean changes in hand BMD at 6 and 12 months were: +0.8% and +1.0%, respectively, for denosumab 60 mg; +2.0% and +2.5%, respectively, for denosumab 180 mg; and ?1.2% and ?2.0%, respectively, for placebo. Erosion scores remained near baseline in the denosumab groups and increased from baseline in the placebo group. A negative correlation was observed between hand BMD and erosion scores.

Conclusion

In patients with RA, denosumab provided protection against erosion, and not only prevented bone loss but increased hand BMD as measured by DXA.

     

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.

     

Effects of denosumab on bone mineral density and bone turnover in postmenopausal women

CONTEXT: Denosumab is an investigational fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, a mediator of osteoclastogenesis and osteoclast survival. OBJECTIVE: This study evaluated the ability of denosumab to increase bone mineral density (BMD) and decrease bone turnover markers (BTMs) in early and later postmenopausal women with low BMD. DESIGN AND SETTING: This 2-yr randomized, double-blind, placebo-controlled study was conducted in North America. PARTICIPANTS: Subjects included 332 postmenopausal women with lumbar spine BMD T-scores between -1.0 and -2.5. Interventions: SUBJECTS were randomly assigned to receive denosumab sc, 60 mg every 6 months, or placebo. Randomization was stratified by time since onset of menopause (< or =5 yr or > 5 yr). MAIN OUTCOME MEASURES: The primary end point was the percent change in lumbar spine BMD by dual-energy x-ray absorptiometry at 24 months. Additional end points were percent change in volumetric BMD of the distal radius by quantitative computed tomography; percent change in BMD by dual-energy x-ray absorptiometry for the total hip, one-third radius, and total body; hip structural analysis; percent change in BTMs; and safety. RESULTS: Denosumab significantly increased lumbar spine BMD, compared with placebo at 24 months (6.5 vs. -0.6%; P<0.0001) with similar results for both strata. Denosumab also produced significant increases in BMD at the total hip, one-third radius, and total body (P < 0.0001 vs. placebo); increased distal radius volumetric BMD (P < 0.01); improved hip structural analysis parameters; and significantly suppressed serum C-telopeptide, tartrate-resistant acid phosphatase-5b, and intact N-terminal propeptide of type 1 procollagen. The overall incidence of adverse events was similar between both study groups. CONCLUSIONS: Twice-yearly denosumab increased BMD and decreased BTMs in early and later postmenopausal women.     

Present and future of the treatment of osteoporosis with monoclonal antibodies

An improved knowledge of bone physiopathology has led to new therapeutic targets in osteoporosis, blocking some of them with monoclonal antibodies. The RANK-RANKL-OPG system is considered the final effector pathway of bone resorption regulating factors. Denosumab is a humanized monoclonal antibody (IgG2) with a high affinity for RANKL. Upon binding RANKL it simulates the action of OPG, impedes the interaction between RANK-RANKL, blocks osteoclast activation and inhibits bone resorption. Denosumab has shown, in several phase III trials, to be a rapid, potent and safe antiresorptive agent. When administered subcutaneously every 6 months, it increases bone mineral density and is accompanied by a fast reduction in bone remodeling markers. According to the FREEDOM trial, in postmenopausal women with osteoporosis, treatment with 60 mg/sc of denosumab every 6 months for 3 years is accompanied by a reduction in the relative risk of fracture of 68% (incidence 2,3% in patients treated with denosumab and 7,2% in the placebo group), 20% in the case of non vertebral fractures (incidence 6,5% with denosumab vs. 8% with placebo) and 40% in hip fractures (incidence 0,7% with denosumab vs. 1,2% with placebo). It is a safe drug, with a frequency of adverse events similar to placebo, although an increased risk for skin reactions. Research is being done into blocking the Wnt/β-catenin pathway with monoclonal antibodies, specifically antisclerostin antibodies and anti-Dkk antibodies. This block of the Wnt/β-catenin pathway would have an anabolic action on bone remodeling.     

Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the efficacy and safety of anakinra in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA). METHODS: Patients with moderate-to-severe active RA who were receiving MTX for 6 consecutive months, with stable doses for > or = 3 months (those with disease duration of >6 months but <12 years) were randomized into 6 groups: placebo or 0.04, 0.1, 0.4, 1.0, or 2.0 mg/kg of anakinra administered in a single, daily, subcutaneous injection. The primary efficacy end point was the proportion of subjects who met the American College of Rheumatology 20% improvement criteria (attained an ACR20 response) at week 12. RESULTS: A total of 419 patients were randomized in the study. Patient demographics and disease status were similar in the 6 treatment groups. The ACR20 responses at week 12 in the 5 active treatment plus MTX groups demonstrated a statistically significant (P = 0.001) dose-response relationship compared with the ACR20 response in the placebo plus MTX group. The ACR20 response rate in the anakinra 1.0-mg/kg (46%; P = 0.001) and 2.0-mg/kg (38%; P = 0.007) dose groups was significantly greater than that in the placebo group (19%). The ACR20 responses at 24 weeks were consistent with those at 12 weeks. Similar improvements in anakinra-treated subjects were noted in individual ACR components, erythrocyte sedimentation rate, onset of ACR20 response, sustainability of ACR20 response, and magnitude of ACR response. Anakinra was safe and well tolerated. Injection site reaction was the most frequently noted adverse event, and this led to premature study withdrawal in 7% (1.0-mg/kg group) to 10% (2.0-mg/kg group) of patients receiving higher doses. CONCLUSION: In patients with persistently active RA, the combination of anakinra and MTX was safe and well tolerated and provided significantly greater clinical benefit than MTX alone.     

Denosumab did not improve computerized tomography erosion scores when added to intensive urate-lowering therapy in gout: Results from a pilot randomized controlled trial

Background/PurposeDisordered osteoclast activity has been implicated in the pathogenesis of gouty bone erosion. We sought to determine if the addition of denosumab (a monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand - RANKL) to intensive urate-lowering therapy (ULT) improves gouty bone erosion.MethodsOpen-label, parallel-group pilot randomized controlled trial in which 20 participants with gout with at least one confirmed conventional radiographic foot bone erosion were assigned in a 1:1 allocation to receive denosumab (60 mg subcutaneous every 6 months) added to intensive ULT (serum urate ≤5 mg/dL or 300 µmol/L at the time of randomization and continued for the duration of the study), or intensive ULT alone. The primary outcome was the change in the bilateral foot and ankle computed tomography (CT) bone erosion score from baseline to 12 months, assessed by an experienced musculoskeletal radiologist blinded to study assignment. Secondary outcomes included change in serum C-terminal telopeptide (CTX), and patient reported outcomes of pain and function.ResultsAlthough serum CTX declined markedly in the denosumab/ULT group compared with the ULT alone group, there was no interval change in CT erosion score in either the denosumab/ULT or ULT alone group after one year of follow-up. Other secondary outcomes did not differ between groups. There were two severe adverse events: One patient developed atrial fibrillation (on denosumab/ULT) and another atrial flutter (on ULT alone).ConclusionsIn this pilot study, denosumab did not offer additional benefit to intensive urate lowering therapy for gouty bone erosion.     

Denosumab for joints and bones

Denosumab is an investigational, fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor κ B ligand (RANKL), a cytokine member of the tumor necrosis factor family. RANKL, an essential mediator of osteoclast formation, function, and survival, plays a major role in the pathogenesis of postmenopausal osteoporosis, structural damage in rheumatoid arthritis, and bone loss associated with other skeletal disorders. Denosumab suppresses bone turnover by inhibiting the action of RANKL on osteoclasts. Denosumab reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density, reduces fracture risk in women with postmenopausal osteoporosis, and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment. It is generally well tolerated, with a good safety profile. Adverse and serious adverse events, including infections and malignancy, are similar in patients treated with denosumab or placebo.     

狄诺塞麦:治疗绝经期女性骨质疏松的新希望

狄诺塞麦是目前用于治疗绝经期骨质疏松的第一种单克隆抗体药物.它能与细胞核因子-κB受体活化因子配体(RANKL)结合,通过抑制破骨细胞的产生、功能和存活,减少骨吸收达到治疗作用.临床试验显示,在绝经后骨质疏松妇女中,狄诺塞麦增加骨密度(BMD)和降低骨折风险的作用优于安慰剂和阿仑膦酸,不良反应与安慰剂和阿仑膦酸相当.药...     

Etanercept versus methotrexate in patients with early rheumatoid arthritis: two-year radiographic and clinical outcomes

OBJECTIVE: To compare the clinical and radiographic outcomes in patients with rheumatoid arthritis (RA) who received monotherapy with either etanercept or methotrexate (MTX) for 2 years and to assess the safety of this therapy. METHODS: In the Enbrel ERA (early rheumatoid arthritis) trial, 632 patients with early, active RA were randomized to receive either twice-weekly subcutaneous etanercept (10 mg or 25 mg) or weekly oral MTX (mean dosage 19 mg per week) for at least 1 year in a double-blind manner. Following the blinded phase of the trial, 512 patients continued to receive the therapy to which they had been randomized for up to 1 additional year, in an open-label manner. Radiograph readers remained blinded to treatment group assignment and the chronologic order of images. RESULTS: At 24 months, more 25-mg etanercept patients than MTX patients met American College of Rheumatology 20% improvement criteria (72% and 59%, respectively; P = 0.005), and more had no increase in total score and erosion scores on the Sharp scale (P = 0.017 and P = 0.012, respectively). The mean changes in total Sharp score and erosion score in the 25-mg etanercept group (1.3 and 0.66 units, respectively) were significantly lower than those in the MTX group (3.2 and 1.86 units, respectively; P = 0.001). Significantly more patients in the 25-mg etanercept group (55%) than in the MTX group (37%) had at least 0.5 units of improvement in the Health Assessment Questionnaire disability index (P < 0.001). Fewer patients in the etanercept group than in the MTX group experienced adverse events or discontinued treatment because of adverse events. CONCLUSION: Etanercept as monotherapy was safe and was superior to MTX in reducing disease activity, arresting structural damage, and decreasing disability over 2 years in patients with early, aggressive RA.     

Disease-modifying anti-rheumatic drug effect of denosumab on radiographic progression in rheumatoid arthritis: a systematic review of the literature

The aim of this study was to evaluate the structural effect of denosumab on patients with rheumatoid arthritis (RA). We performed a systematic review of the literature in the following databases: PubMed, Cochrane, Web of Science, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform. All studies evaluating the structural effect of denosumab on RA and meeting predefined criteria were included. Data regarding disease activity, progression of joint damage, joint space narrowing, and safety were recorded. Among 168 studies identified, only 4 were finally included in this review, involving a total of 687 patients. These 4 studies showed that denosumab is effective on joint damage at 6 and 12 months as compared to placebo, alendronate, and biological disease-modifying anti-rheumatic drugs (bDMARDs) alone. No effect was observed in terms of joint space narrowing, and DAS28 and HAQ scores remained unchanged. No case of osteonecrosis of the jaw or atypical fracture was recorded, and safety was similar in both denosumab and control groups. Denosumab appears to be effective on joint erosion at 6 and 12 months in patients with RA meeting the ACR criteria, treated or not by a biologic, with excellent safety.     

RANKL: A therapeutic target for bone destruction in rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Recent studies have indicated the critical involvement of osteoclasts in bone destruction in RA. The osteoclast differentiation factor receptor activator of NF-κB ligand (RANKL), which belongs to the tumor necrosis factor superfamily, plays a critical role in osteoclast differentiation and bone destruction in RA. Denosumab, an antibody against human RANKL, efficiently suppressed the progression of bone erosion in RA patients in randomized controlled studies, and is considered as a putative therapeutic option for preventing bone destruction in RA.     

The role of rank-ligand inhibition in the treatment of postmenopausal osteoporosis

Osteoporosis is a skeletal disease affecting millions of people worldwide in which a decreased bone mass and a microarchitectural deterioration compromise bone strength leading to bone fragility and increased susceptibility to fracture. Bone turnover increases at menopause, with osteoclast-mediated bone resorption exceeding bone formation. Recent discoveries in bone biology have demonstrated that RANKL, a cytokine member of the tumor necrosis factor superfamily, is an essential mediator of osteoclast formation, function and survival. Denosumab is a fully human monoclonal antibody with a high affinity and specificity for human RANKL. By binding to its target, denosumab prevents the interaction of RANKL with its receptor RANK on osteoclasts and their precursors and inhibits osteoclast-mediated bone resorption. Administered as a subcutaneous injection every six months, denosumab has been shown to decrease bone turnover and to increase bone mineral density in postmenopausal women with low bone mass and osteoporosis. In these patients denosumab significantly reduced the risk of vertebral fractures, hip fractures and nonvertebral fractures. In all clinical trials published to date, denosumab was well tolerated with an incidence of adverse events, including infections and malignancy, generally similar to subjects receiving placebo or alendronate. The denosumab therapeutic regimen consisting in a subcutaneous injection every 6 months may increase patient compliance and persistence with a further benefit from treatment. By providing a new molecular target for osteoporosis treatment, denosumab is a promising drug for the treatment of postmenopausal osteoporosis and the prevention of fragility fractures.     

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.     

A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density

Context: Men with low bone mineral density (BMD) were treated with denosumab. Objective: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment. Design, Subjects, and Intervention: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD. Main Outcome Measure: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. Results: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P ≤ 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups. Conclusions: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.     

Adalimumab,a fully human anti-tumor necrosis factor alpha monoclonal antibody,for the treatment of rheumatoid arthritis in patients taking concomitant methotrexate: the ARMADA trial

OBJECTIVE: To evaluate the efficacy and safety of adalimumab (D2E7), a fully human monoclonal tumor necrosis factor alpha antibody, in combination with methotrexate (MTX) in patients with active rheumatoid arthritis (RA) despite treatment with MTX. METHODS: In a 24-week, randomized, double-blind, placebo-controlled study, 271 patients with active RA were randomly assigned to receive injections of adalimumab (20 mg, 40 mg, or 80 mg subcutaneously) or placebo every other week while continuing to take their long-term stable dosage of MTX. The primary efficacy end point was the American College of Rheumatology criteria for 20% improvement (ACR20) at 24 weeks. RESULTS: An ACR20 response at week 24 was achieved by a significantly greater proportion of patients in the 20-mg, 40-mg, and 80-mg adalimumab plus MTX groups (47.8%, 67.2%, and 65.8%, respectively) than in the placebo plus MTX group (14.5%) (P < 0.001). ACR50 response rates with the 20-mg, 40-mg, and 80-mg adalimumab dosages (31.9%, 55.2%, and 42.5%, respectively) were significantly greater than that with placebo (8.1%) (P = 0.003, P < 0.001, and P < 0.001, respectively). The 40-mg and 80-mg doses of adalimumab were associated with an ACR70 response (26.9% and 19.2%, respectively) that was statistically significantly greater than that with placebo (4.8%) (P < 0.001 and P = 0.020). Responses were rapid, with the greatest proportion of adalimumab-treated patients achieving an ACR20 response at the first scheduled visit (week 1). Adalimumab was safe and well tolerated; comparable numbers of adalimumab-treated patients and placebo-treated patients reported adverse events. CONCLUSION: The addition of adalimumab at a dosage of 20 mg, 40 mg, or 80 mg administered subcutaneously every other week to long-term MTX therapy in patients with active RA provided significant, rapid, and sustained improvement in disease activity over 24 weeks compared with MTX plus placebo.     

Double-blind,placebo-controlled multicenter trial using chimeric monoclonal anti-cd4 antibody,cm-t412, in rheumatoid arthritis patients receiving concomitant methotrexate

Objective. To evaluate the clinical response to and safety of single and repeat doses of a chimeric anti-CD4 monoclonal antibody, cM-T412, in patients with rheumatoid arthritis (RA) concomitantly treated with a stable regimen of low-dose methotrexate. Methods. Sixty-four patients with refractory RA, who were already receiving stable doses of methotrexate, were randomized into a multicenter, double-blind, placebo-controlled trial to receive 3 monthly treatments with either a placebo, or 5, 10, or 50 mg cM-T412, given intravenously. Results. Using ≥50% improvement in swollen joint counts as a criterion for clinical response, 13%, 13%, 18%, and 13% of patients receiving 50, 10, or 5 mg cM-T412, or the placebo, respectively, exhibited a clinical response at 3 months of therapy. Using ≥50% improvement in tender joint counts as a measure of clinical efficacy at 3 months, 19%, 13%, 12%, and 6% of patients receiving 50, 10, or 5 mg cM-T412, or the placebo, respectively, exhibited a clinical response. “Flu-like” symptoms (fever, chills, rigor) within 24 hours of the infusion occurred more frequently in the groups receiving 50-mg (29%) and 10-mg (31%) doses of cM-T412 than those receiving 5 mg cM-T412 (12%) or the placebo (13%). Significant CD4+ T cell depletion occurred in the 50-mg group (mean of 353 CD4+ T cells/mm³ at 6 months versus 856 CD4+ T cells/mm³ at baseline). All patients were followed up for 12 months after the final treatment; no opportunistic infectious complications occurred. Conclusion. Treatment with cM-T412 in this cohort of RA patients who were also taking methotrexate was not associated with clinical efficacy or enhanced toxicity from infectious complications, despite significant peripheral CD4+ T cell depletion.     

Efficacy and safety of denosumab for the treatment of osteoporosis: A systematic review

Denosumab is an anti-RANK ligand (RANKL) monoclonal antibody approved for the treatment of postmenopausal osteoporosis and prevention of skeletal metastasis complications. Administered subcutaneously every 6 months, it reduces the risk of vertebral fracture by 70% and of hip fracture by 40%. Its safety profile is acceptable. Denosumab may be used to treat patients with moderate to severe renal insufficiency. It has anti-fracture activity equivalent to that of zoledronic acid, but no residual effect, and no action at all beyond 6 months. In France, denosumab is reimbursed as a second-line treatment after a first attempt with bisphosphonate.     

Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study.

OBJECTIVE: Risedronate, a new pyridinyl bisphosphonate, is a potent antiresorptive bone agent. This study examines the safety and efficacy of daily, oral risedronate therapy for the prevention of corticosteroid-induced bone loss. METHODS: This multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted in 224 men and women who were initiating long-term corticosteroid treatment. Patients received either risedronate (2.5 mg or 5 mg) or placebo daily for 12 months. Each patient also received 500 mg of elemental calcium daily. The primary outcome measure was the percentage of change in lumbar spine bone mineral density (BMD). Secondary measures included proximal femur BMD and incidence of vertebral fractures. RESULTS: After 12 months, the lumbar spine BMD (mean +/- SEM) did not change significantly compared with baseline in the 5-mg (0.6 +/- 0.5%) or the 2.5-mg (-0.1 +/- 0.7%) risedronate groups, while it decreased in the placebo group (-2.8 +/- 0.5%; P < 0.05). The mean differences in BMD between the 5-mg risedronate and the placebo groups were 3.8 +/- 0.8% at the lumbar spine (P < 0.001), 4.1 +/- 1.0% at the femoral neck (P < 0.001), and 4.6 +/- 0.8% at the femoral trochanter (P < 0.001). A trend toward a decrease in the incidence of vertebral fracture was observed in the 5-mg risedronate group compared with the placebo group (5.7% versus 17.3%; P = 0.072). Risedronate was well tolerated, and the incidence of upper gastrointestinal adverse events was comparable among the 3 groups. CONCLUSION: Risedronate therapy prevents bone loss in patients initiating long-term corticosteroid treatment.     

The effects of drug therapy on radiographic progression of rheumatoid arthritis. results of a 36-week randomized trial comparing methotrexate and auranofin

Objective. To determine the effects of drug therapy (methotrexate [MTX] versus auranofin [AUR]) on radiographic progression in patients with active rheumatoid arthritis (RA). Methods. We conducted a 9-month randomized, multicenter, double-blind trial comparing MTX and AUR. Standardized radiographs of the hands and wrists were obtained at baseline and at completion of the study. Four experienced bone radiologists graded the radiographs for erosions, joint space narrowing, erosion healing, and reparative bone formation. Results. Two hundred eighty-one patients were enrolled in the study. Radiographs were available on 167 of the 183 who completed the trial. After 9 months of therapy, there was a significantly greater worsening of the erosion score in the AUR group (mean ± SEM change of 1.67 ± 0.4) compared with the change in the MTX group (0.60 ± 0.3) (P = 0.040). There was also a significantly greater worsening of the joint space narrowing score in the AUR group compared with the MTX group (1.36 ± 0.3 versus 0.42 ± 0.2) (P = 0.007). There was no difference demonstrated between groups in healing of erosions or in reparative bone formation. Conclusion. The rate of radiographic progression in patients with RA, as measured by erosion score and joint space narrowing score, was demonstrated to be lower in those treated with MTX, as compared with AUR, over a 36-week period.     

Low-dose hydrochlorothiazide and preservation of bone mineral density in older adults. A randomized, double-blind, placebo-controlled trial

BACKGROUND: Thiazide may have beneficial effects on bone mineral density and may reduce risk for hip fracture. However, the existence of a causal role remains uncertain because experimental evidence is limited. OBJECTIVE: To determine the effect of hydrochlorothiazide on rates of bone loss in older adults. DESIGN: Randomized, double-blind, placebo-controlled trial with 3-year follow-up. SETTING: A large health maintenance organization in western Washington State. PARTICIPANTS: 320 healthy, normotensive adults (205 women, 115 men) 60 to 79 years of age. INTERVENTION: Random assignment to one of three study groups: 12.5 mg of hydrochlorothiazide per day, 25 mg of hydrochlorothiazide per day, or placebo. MEASUREMENTS: Bone mineral density using dual-energy x-ray absorptiometry at the total hip, posterior-anterior spine, and total body; blood and urine markers of bone metabolism; incident falls, clinical fractures, and radiographic vertebral fractures. RESULTS: 309 of 320 participants completed the 36-month visit (97%). Adherence to study medication throughout follow-up was high in all participants (81.6% to 89.7%) except men in the high-dose hydrochlorothiazide group (60.5%). According to intention-to-treat analysis, the 36-month differences in percentage change in total hip bone mineral density were 0.79 percentage point (95% CI, -0.12 to 1.71) for the 12.5-mg hydrochlorothiazide group and 0.92 percentage point (CI, -0.001 to 1.85) for the 25-mg group compared with placebo (P = 0.03). Percentage change at the posterior-anterior spine was significantly greater for the 25-mg hydrochlorothiazide group at 6 months (intergroup difference, 1.04 percentage points [CI, 0.22 to 1.86]) compared with placebo (P = 0.005); at 36 months, this difference was 0.82 percentage point (CI, -0.36 to 2.01; P = 0.12). No significant differences were seen in total-body bone mineral density between the treatment groups. Treatment effects were stronger in women than in men. CONCLUSIONS: In healthy older adults, low-dose hydrochlorothiazide preserves bone mineral density at the hip and spine. The modest effects observed over 3 years, if accumulated over 10 to 20 years, may explain the one-third reduction in risk for hip fracture associated with thiazide in many epidemiologic studies.