The Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) study: 2-year nonvertebral fragility fracture results.

UNLABELLED: This observational study evaluated the occurrence of nonvertebral fragility fractures (NVFX) in over 4,000 men and women with osteoporosis treated with teriparatide (TPTD). The incidence of new NVFX decreased for patients receiving TPTD treatment for greater than 6 months. No new significant safety findings were observed in this large trial. INTRODUCTION: The Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) study evaluated the occurrence of NVFX in patients receiving TPTD for osteoporosis in a real-world setting. METHODS: DANCE is a multicenter, prospective, observational trial that examined the long-term effectiveness of TPTD in men and women with osteoporosis whom study physicians judged to be suitable for TPTD therapy. Patients received 20 µg TPTD per day by subcutaneous injection for up to 24 months and were followed for 24 months after treatment cessation. The incidence of patients experiencing a new NVFX, defined as a fracture associated with low trauma, was evaluated during four 6-month periods in both the treatment and cessation phases with >0 to ≤6 months serving as the reference. We also observed the spectrum and occurrence of serious adverse events. RESULTS: Of the 4,167 patients enrolled, 4,085 took one or more doses of TPTD (safety population); 3,720 were included in the efficacy analysis. The incidence of patients experiencing a NVFX was 1.42, 0.91, 0.70, and 0.81 % for the four treatment periods, respectively, and 0.80, 0.68, 0.33, and 0.33 % for the four periods after treatment cessation. Differences for each period were statistically significant compared with the reference period (first 6-month interval, each p < 0.05). No new significant safety findings were observed. CONCLUSIONS: In this study, the incidence of NVFX decreased for patients receiving TPTD for all three treatment periods >6 months compared to 0 to ≤6 months, and this trend persisted throughout the cessation phase. TPTD was generally well tolerated.

A safety analysis of oral prednisone as a pretreatment for rituximab in rheumatoid arthritis.

The administration of 100 mg of methylprednisolone intravenously (IV) 1/2 h prior to rituximab decreases the incidence of acute infusion reactions (AIRs). However, this pretreatment adds considerable time and conveys potential risk. We performed an open-label prospective assessment of oral prednisone as a pretreatment to rituximab. This was a 26-week open-label trial of 40 mg of oral prednisone given 1/2 h prior to rituximab as a prophylaxis against AIRs in patients with rheumatoid arthritis (RA). The primary endpoint was AIRs in the first 24 h after their initial infusion. Secondary endpoints include AIRs during the 24 h following their second infusion and any adverse events experienced during the 26-week study; efficacy measures were also followed as secondary endpoints. Sixty-four subjects were screened, and 50 subjects qualified. Fourteen out of the 50 (28 %) subjects had AIRs within 24 h of their first infusion. There were four AIRs (8.3 %) within 24 h of their second infusion. One of day 0 AIRs required drug discontinuation (wheezing/bronchospasm). Forty out of 50 (80 %) subjects experienced an adverse event during the 26 weeks. There were three SAEs deemed not to be study-drug related. The DAS28 and HAQ-DI all improved significantly at weeks 8, 16, and 26 compared to baseline. Historical controls demonstrate that 27 % of RA subjects experience AIRs with their first rituximab infusion. Our data suggest a smaller dose of oral prednisone is an effective alternative to IV methylprednisolone as a pretreatment for rituximab in patients with RA.

Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study.

BACKGROUND: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. OBJECTIVE: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed. METHODS: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24. RESULTS: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p<0.001), and 28-joint Disease Activity Score (DAS28) <2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol > or =240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations >3x-<5x upper limit of normal (1.0% vs 2.5%), respectively. CONCLUSION: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit-risk, in patients for whom treatment with methotrexate or biological agents has not previously failed.

Comparing non-vertebral fracture risk reduction with osteoporosis therapies: looking beneath the surface.

UNLABELLED: Data from pivotal trials of pharmacologic agents used to treat osteoporosis differ, suggesting that these agents vary in ability to reduce the risk of non-vertebral fractures (NVFs). However, variability among clinical trials in inclusion criteria, baseline characteristics, and definition of NVFs may account for many of these apparent differences. INTRODUCTION: Data from pivotal trials of individual pharmacologic agents for osteoporosis differ, and suggest that differences may exist between anti-resorptive agents in their ability to reduce the risk of NVFs. Careful examination of these trials' inclusion criteria and patient characteristics indicates substantial differences between patient populations with respect to the baseline risk of NVFs. When baseline fracture risk is lower, the ability to produce a statistically significant reduction in fracture risk over the course of a clinical trial is reduced. METHODS: Analysis of clinical trials reveals that the number and type of baseline vertebral fractures and also baseline bone mineral density, all associated with the risk of vertebral fracture, vary. DISCUSSION AND CONCLUSION: The propensity to fall and patient frailty are additional factors associated with fracture risk that may influence study outcomes. One of the most significant variables, which also often differs considerably between trials, is the definition of an NVF. Variability between clinical trials in inclusion criteria, patients' baseline characteristics, and how NVFs are defined may account for much of the apparent difference between agents in their ability to reduce NVF risk.

Rapid suppression of bone resorption marker levels with ibandronate therapy in a bisphosphonate-naïve population.

This 6-mo open-label study assessed the pattern of bone turnover marker (BTM) level changes in bisphosphonate-naïve women with postmenopausal osteoporosis treated with monthly oral ibandronate 150mg and the correlation between month 1 and month 6 serum C-terminal cross-linking telopeptide of type I collagen (sCTX) levels. The following BTMs were monitored: sCTX, urinary N-terminal telopeptide of type I collagen (uNTX), serum procollagen type 1 N-terminal propeptide (PINP), serum osteocalcin (OC), and serum bone-specific alkaline phosphatase (bALP). BTM levels were measured immediately before dosing at baseline and months 1, 2, 3, and 6, and 7d after dosing at baseline and month 4. A multiple regression model was applied to determine whether month 1 sCTX response predicted month 6 sCTX change. sCTX levels declined 70% 7d after dosing at baseline and month 4. Predosing sCTX declined 55% at month 6. The pattern of uNTX reduction was similar to sCTX. Bone formation markers PINP, OC, and bALP declined gradually over time. Month 1 sCTX change was a significant predictor of Month 6 change (p=0.0001). Once monthly 150mg oral ibandronate treatment reduced BTMs in women with osteoporosis. sCTX reduction occurred within 7d and was sustained over 6mo. Month 1 sCTX predicted month 6 sCTX.

Efficacy and safety of etoricoxib 30 mg and celecoxib 200 mg in the treatment of osteoarthritis in two identically designed, randomized, placebo-controlled, non-inferiority studies.

OBJECTIVE: To compare the efficacy of etoricoxib 30 mg with the generally maximum recommended dose of celecoxib, 200 mg, in the treatment of osteoarthritis (OA) in two identically designed studies. METHODS: Two multi-centre, 26-week, double-blind, placebo-controlled, non-inferiority studies were conducted, enrolling patients who were prior non-steroidal anti-inflammatory drug (NSAID) or acetaminophen users. There were 599 patients in study 1 and 608 patients in study 2 randomized 4:4:1:1 to etoricoxib 30 mg qd, celecoxib 200 mg qd or one of two placebo groups for 12 weeks. After 12 weeks, placebo patients were evenly distributed to etoricoxib or celecoxib based on their initial enrollment randomization schedule. The primary hypothesis was that etoricoxib 30 mg would be at least as effective as celecoxib 200 mg for the time-weighted average change from baseline over 12 weeks for Western Ontario and McMaster (WOMAC) Pain Subscale, WOMAC Physical Function Subscale and Patient Global Assessment of Disease Status. Active treatments were also assessed over the full 26 weeks. Adverse experiences were collected for safety assessment. RESULTS: In both studies, etoricoxib was non-inferior to celecoxib for all three efficacy outcomes over 12 and 26 weeks; both were superior to placebo (P < 0.001) for all three outcomes in each study over 12 weeks. The safety and tolerability of etoricoxib 30 mg qd and celecoxib 200 mg qd were similar over 12 and 26 weeks. CONCLUSIONS: Etoricoxib 30 mg qd was at least as effective as celecoxib 200 mg qd and had similar safety in the treatment of knee and hip OA; both were superior to placebo. ClinicalTrials.gov Identifiers: NCT00092768; NCT00092791.

Dose-loading with hydroxychloroquine improves the rate of response in early, active rheumatoid arthritis: a randomized, double-blind six-week trial with eighteen-week extension.

OBJECTIVE: To investigate the usefulness of hydroxychloroquine (HCQ) dose-loading to increase the percentage of responders or rate of response in treating rheumatoid arthritis (RA). METHODS: Two hundred twelve patients with early RA (mean duration 1.5 years) were enrolled in a 24-week trial. Patients were stabilized with 1,000 mg naproxen/day and then began a 6-week, double-blind trial comparing treatment with HCQ at 400 mg/day (n = 71), 800 mg/day (n = 71), and 1,200 mg/day (n = 66), followed by 18 weeks of open-label HCQ treatment at 400 mg/day. RESULTS: All patients had mild, active disease at the time of initiation of HCQ treatment (31-43% rheumatoid factor positive; no previous disease-modifying antirheumatic drugs; mean swollen joint count 8.6-10.4). Based on the Paulus criteria, response during the 6-week double-blind portion of the study was 47.97%, 57.7%, and 63.6% in the 400 mg/day, 800 mg/day, and 1,200 mg/day groups, respectively (P = 0.052). Discontinuations for adverse events were dose related (3 in the 400 mg/day group, 5 in the 800 mg/day group, 6 in the 1,200 mg/day group). Most involved the gastrointestinal (GI) system, with the background naproxen treatment possibly contributing. Ocular abnormalities occurred in 17 of 212 patients (8%) but were not dose related. CONCLUSION: Dose-loading with HCQ increased the degree of response at 6 weeks in this group of patients with early, predominantly seronegative RA. Adverse GI events were dose related, while adverse ocular events were not.

[Intravenous digital angiography in the kidney transplant patient: results of a systematic prospective study in 164 patients]. / Angiographie numérisée par voie intraveineuse chez le transplanté rénal: résultats d'une étude prospective systématique chez 164 patients.

A prospective study on digital intravenous angiography (DIVA) in 164 renal transplant recipients performed from 1 to 2 months post-transplant was conducted to assess its usefulness in the screening of post-transplant renal artery stenosis (RAS). DIVA was uninterpretable in 32 patients (19%) on technical grounds (blood vessel or metallic clip superimposed). The global prevalence of RAS was 10.7% in 132 patients whose DIVA was informative. No correlation was found between the prevalence of RAS and renal function. The prevalence of RAS was significantly higher (p less than 0.01) in the hypertensive (26%) than in the normotensive group (6.6%), but RAS may occur in normotensive or even asymptomatic patients. Our data confirm the usefulness of routine post-transplant renal artery screening but arterial way will be preferred.