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SummaryFRAX® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX®-defined MOF compared with those treated with risedronate.IntroductionThe VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX®-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures.MethodsIn total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 μg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX®-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval.ResultsAfter 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX®-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23–0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX®-defined MOF sites. The largest difference in incidence rates of both FRAX®-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed.ConclusionIn postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX®-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment.Clinical trial informationClinicalTrials.gov Identifier: NCT01709110EudraCT Number: 2012-000123-41

Summary Changes of the bone formation marker PINP correlated positively with improvements in vertebral strength in men with glucocorticoid-induced osteoporosis (GIO) who received 18-month treatment with teriparatide, but not with risedronate. These results support the use of PINP as a surrogate marker of bone strength in GIO patients treated with teriparatide. Introduction To investigate the correlations between biochemical markers of bone turnover and vertebral strength estimated by finite element analysis (FEA) in men with GIO. Methods A total of 92 men with GIO were included in an 18-month, randomized, open-label trial of teriparatide (20 μg/day, n  = 45) and risedronate (35 mg/week, n  = 47). High-resolution quantitative computed tomography images of the 12th thoracic vertebra obtained at baseline, 6 and 18 months were converted into digital nonlinear FE models and subjected to anterior bending, axial compression and torsion. Stiffness and strength were computed for each model and loading mode. Serum biochemical markers of bone formation (amino-terminal-propeptide of type I collagen [PINP]) and bone resorption (type I collagen cross-linked C-telopeptide degradation fragments [CTx]) were measured at baseline, 3 months, 6 months and 18 months. A mixed-model of repeated measures analysed changes from baseline and between-group differences. Spearman correlations assessed the relationship between changes from baseline of bone markers with FEA variables. Results PINP and CTx levels increased in the teriparatide group and decreased in the risedronate group. FEA-derived parameters increased in both groups, but were significantly higher at 18 months in the teriparatide group. Significant positive correlations were found between changes from baseline of PINP at 3, 6 and 18 months with changes in FE strength in the teriparatide-treated group, but not in the risedronate group. Conclusions Positive correlations between changes in a biochemical marker of bone formation and improvement of biomechanical properties support the use of PINP as a surrogate marker of bone strength in teriparatide-treated GIO patients.

No clinical trials have compared osteoporosis drugs with incident fractures as the primary outcome. We compared the anti-fracture efficacy of teriparatide with risedronate in patients with severe osteoporosis. In this double-blind, double-dummy trial, we enrolled post-menopausal women with at least two moderate or one severe vertebral fracture and a bone mineral density T score of less than or equal to −1·50. Participants were randomly assigned to receive 20 μg of teriparatide once daily plus oral weekly placebo or 35 mg of oral risedronate once weekly plus daily injections of placebo for 24 months. The primary outcome was new radiographic vertebral fractures. Secondary, gated outcomes included new and worsened radiographic vertebral fractures, clinical fractures (a composite of non-vertebral and symptomatic vertebral), and non-vertebral fractures. This study is registered with ClinicalTrials.gov (NCT01709110) and EudraCT (2012-000123-41). We enrolled 680 patients in each group. At 24 months, new vertebral fractures occurred in 28 (5·4%) of 680 patients in the teriparatide group and 64 (12·0%) of 680 patients in the risedronate group (risk ratio 0·44, 95% CI 0·29–0·68; p<0·0001). Clinical fractures occurred in 30 (4·8%) of 680 patients in the teriparatide group compared with 61 (9·8%) of 680 in the risedronate group (hazard ratio 0·48, 95% CI 0·32–0·74; p=0·0009). Non-vertebral fragility fractures occurred in 25 (4·0%) patients in the teriparatide group and 38 (6·1%) in the risedronate group (hazard ratio 0·66; 95% CI 0·39–1·10; p=0·10). Among post-menopausal women with severe osteoporosis, the risk of new vertebral and clinical fractures is significantly lower in patients receiving teriparatide than in those receiving risedronate. Lilly.

BackgroundGouty arthritis (GA) patients who experience frequent flares and have comorbidities have limited treatment options and need effective alternative treatments. Canakinumab (CAN), a selective, human, anti-interleukin-1β monoclonal antibody, has been approved in the European Union for the treatment of difficult-to-treat GA patients.ObjectivesA liquid formulation of CAN, presented as pre-filled syringe (CAN-PFS) has been developed to improve upon the lyophilized form (CAN-LYO) that requires reconstitution. A cumulative safety and efficacy results covering a total of 48 weeks are presented.MethodsGA patients completing the 12 week core study1 were enrolled in a 36 week open label extension (E1) study. All patients entering E1 received CAN-PFS 150 mg sc on demand upon new GA flare irrespective of assigned treatment during randomization [CAN-PFS, CAN-LYO or triamcinolone acetonide 40 mg (TA)]. The primary objective was to confirm the long-term safety of CAN-PFS vs TA. Secondary objectives included evaluation of CAN-PFS vs TA and CAN-LYO vs PFS for the time to first new flare over 48 weeks. Long-term safety outcomes and safety upon re-treatment were assessed as exposure-adjusted incidence rate of adverse events (AEs) and serious AEs (SAEs).ResultsOf 397 patients randomized in the core study, 232 (58.4%) entered E1, of which 198 (50%) completed E1. Baseline characteristics were comparable between the treatment groups. The exposure-adjusted incidence of AEs was lower for both CAN-PFS (254.9/100 pyr) and CAN-LYO (224.8/100 pyr) groups when compared with TA (362.7/100 pyr) over the 48 weeks. The exposure-adjusted incidence of SAEs was 14.7/100, 16.1/100, 15.5/100 pyr in patients randomized to CAN-PFS, CAN-LYO and TA groups, respectively. Infections and infestations were the most frequently reported SAE in the CAN-PFS (3.4/100 pyr), CAN-LYO (3.2/100 pyr), TA (0/100 pyr) groups. Over 48 weeks, one death (cardiac failure), not suspected to be related to study drug, was reported in a patient randomized to CAN-PFS who was not re-treated over 48 weeks. Overall, no new safety signals were observed in this extension study. CAN-PFS treatment significantly delayed time to first new flare vs TA patients with a relative risk reduction of 55% (HR, 0.45; 95% CI, 0.32 to 0.64; p<0.0001) over 48 weeks. The mean number of new GA flares per patient was lower for both CAN-LYO (0.50) and CAN-PFS (0.76) groups when compared with the TA group (0.96). Patients in the CAN-PFS group had a 56% reduction in the number of new flares compared to the TA group (rate ratio of 0.44, 95% CI 0.32 to 0.61, p<0.0001). However, both CAN treatments showed a similar mean flare rate per year (CAN-PFS, 0.95; CAN-LYO, 1.13).ConclusionsThese results further corroborate the long-term safety and efficacy of canakinumab liquid formulation in patients with frequent GA flares. The safety profile of canakinumab was consistent with the one observed in the core study and the efficacy of canakinumab pre-filled syringe was maintained upon re-treatment.ReferencesSunkureddi P, et al. Arthritis & Rheumatism 2013;65(10):S498.Disclosure of InterestR. Möricke: None declared, P. Sunkureddi Grant/research support from: Novartis, E. Toth: None declared, J. Brown Grant/research support from: Abvie, Amgen, Eli Lilly, Novartis, Pfizer, Roche, Takeda, Consultant for: Amgen, Eli Lilly, Speakers bureau: Amgen, Eli Lilly, U. Machein Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, G. Junge Employee of: Novartis, A. Kivitz: None declared

Background Chronic kidney disease (CKD) limits the treatment options in acute gouty arthritis (GA) patients due to intolerance and contraindications to available therapies. Efficacy and safety of canakinumab (CAN), a selective, fully human, anti-IL-1β monoclonal antibody, formulated as a lyophilized (CAN-LYO) powder requiring reconstitution with water vs triamcinolone acetonide (TA) in patients with acute GA was demonstrated in previous phase III trials. Objectives To evaluate efficacy and safety of CAN liquid formulation (CAN-PFS) vs TA in a subgroup of patients with CKD stage ≥3. Methods This was a 12-week, multicenter, double-blind, active controlled study. The design and methodology of the study have been reported earlier1. Here, we report results from a post-hoc analysis of the 12-week data for GA patients with CKD stage ≥3 (estimated Glomerular Filtration Rate (eGFR) <60ml/min). The primary endpoint was pain intensity in the target joint, measured on 0-100 mm VAS scale at 72 h post-dose. Secondary endpoints included time to first new attack, and safety over 12 weeks. Results Of 388 patients, 76 had CKD stage ≥3 at baseline (CAN-PFS, n=24; CAN-LYO, n=28; TA, n=24). CAN-PFS provided a statistically significant reduction in pain intensity in the target joint vs TA from 72 h post-dose (estimated difference, -14.6mm; 95% CI:-29.0, -0.1, p≤0.05) until 7 days post-dose (-16.1mm; 95% CI: -28.4, -3.7, p=0.0115). The two CAN treatment arms were comparable. Over 12 weeks, a single dose of CAN-PFS showed a significant relative risk reduction of 90% for time to first new gout attack vs TA [HR 0.10, 95% CI (0.01, 0.78); p≤0.05]. Adverse events (AEs) were reported in 12 (50%), 11 (39.3%) and 10 (41.7%) patients in CAN-PFS, CAN-LYO and TA groups, respectively. The most frequent AEs were infections (CAN-PFS, n=3 (12.5%); CAN-LYO, n=6 (21.4%); TA, n=2 (8.3%). Serious AEs were reported in a total of 7 patients (CAN-PFS, n=2 (8.3%); CAN-LYO, n=4 (14.3%); TA, n=1 (4.2%), with infections (CAN-PFS, n=1 (4.2%); CAN-LYO, n=2 (7.1%); TA, n=0), being the most common SAEs. No deaths were reported during the study. Conclusions This post-hoc analysis provides evidence for the efficacy of CAN-PFS compared with a potent long-acting corticosteroid in providing significant pain relief and reducing incidence of new attacks in GA patients with CKD stage ≥3 with limited treatment options. The safety profile in this sub population was consistent with that of the overall study population and with that known from previous studies. References Sunkureddi et al. Arthirits & Rheum 2013; 65. Disclosure of Interest P. Sunkureddi Consultant for: Novartis, Bristol Myers Squibb, Speakers bureau: Pfizer, Takeda, Bristol Myers Squibb, UCB, Amgen, Abbott, Shinogi, Savient, E. Toth: None declared, J. Brown Grant/research support: Amgen, Bristol Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, Servier, Sanofi-Aventis, Takeda, Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Warner Chilcott, Sanofi–Aventis, Speakers bureau: Amgen, Eli Lilly, Novartis, Merck, A. Kivitz Grant/research support: Novartis, A. Stancati Shareholder of: Novartis, Employee of: Novartis, D. Richard Shareholder of: Novartis, Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, R. Möricke: None declared DOI 10.1136/annrheumdis-2014-eular.1850

Background Canakinumab (CAN), a selective, fully human anti-IL-1β monoclonal antibody, is the only approved biologic in the European Union for the symptomatic treatment of adult patients (pts) with difficult-to-treat gouty arthritis (GA). A liquid formulation, presented as pre-filled syringe (CAN-PFS) has been developed to improve upon the lyophilized form (CAN-LYO) that requires reconstitution. Here, we report results from a post-hoc analysis of the 12-week data of a Phase III trial. Objectives To evaluate the efficacy and safety of CAN-PFS vs triamcinolone acetonide (TA) in a subset of difficult-to-treat GA pts defined as a) unable to use NSAIDs and colchicine due to contraindication, intolerance or lack of efficacy, and b) currently on urate-lowering therapy (ULT), or previously failed ULT or in whom ULT is otherwise contraindicated. Methods This was a 12-week, multicenter, double-blind, active controlled study. The design and methodology of the study have been reported earlier1. The primary efficacy measure was overall pain intensity in the most affected joint measured on VAS scale (0-100 mm) at 72 h post-dose. Secondary endpoints included time to first new attack and safety over 12 weeks. Results Of the 397 GA pts randomized, 106 (CAN-PFS, n=34; CAN-LYO, n=43; TA, n=29) met the subgroup definition. CAN-PFS provided a statistically significant reduction in pain intensity at 72 h post dose vs TA (estimated difference, -30.7mm; 95%CI: -42.1, -19.3, p≤0.05). The least square mean pain scores at 72 h post-dose for CAN -PFS and LYO, were14.7mm and 19.3mm, respectively; both lower than that for TA (45.4mm). CAN-PFS treatment significantly delayed time to first new attack vs TA with a relative risk reduction of 92% (HR, 0.08; 95%CI: 0.01, 0.63, p≤0.05) over 12 weeks. Adverse events (AEs) were reported in 12 (35.3%), 16 (37.2%) and 14 (48.3%) pts in CAN-PFS, CAN-LYO and TA groups, respectively. Serious AEs were reported in 7 pts [CAN-PFS, n=1 (2.9%); CAN-LYO, n=5 (11.6%); TA, n=1 (3.4%)], with infections [CAN-PFS, n=1 (2.9%); CAN-LYO, n=2 (4.7%); TA, n=0)] being the most common SAEs. One patient in the CAN-LYO group had serious aortitis, which was coded under vascular disorders system organ class, but adjudicated as an opportunistic infection by the independent adjudication committee. No deaths were reported during the study. Conclusions This analysis provides evidence for the efficacy of CAN in difficult-to-treat GA pts either in pre-filled syringe or lyophilized formulation compared to a potent long acting systemic corticosteroid. CAN-PFS provided better pain relief and reduced the risk of new attacks compared to TA. The safety profile in this population was consistent with that of the overall study population and with that known from previous studies. References Sunkureddi et al. Arthirits & Rheum 2013; 65. Disclosure of Interest P. Sunkureddi Consultant for: Novartis, Bristol Myers Squibb, Speakers bureau: Pfizer, Takeda, Bristol Myers Squibb, UCB, Amgen, Abbott, Shinogi, Savient, E. Toth: None declared, J. Brown Grant/research support: Amgen, Bristol Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, Servier, Sanofi-aventis, Takeda, Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Warner Chilcott, Sanofi-aventis, Speakers bureau: Amgen, Eli Lilly, Novartis, Merck, A. Kivitz Grant/research support: Novartis, A. Stancati Shareholder of: novartis, Employee of: novartis, D. Richard Shareholder of: Novartis, Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, R. Möricke: None declared DOI 10.1136/annrheumdis-2014-eular.1846

Introduction The open-label Rapid Onset and Sustained Efficacy (ROSE) study was designed to compare a once-yearly intravenous (iv) dose of zoledronic acid with a once-weekly oral dose of alendronate with respect to markers of bone turnover in approximately 600 postmenopausal women in Germany. Methods Levels of N-telopeptide of collagen type I (NTx) and procollagen 1 C terminal extension peptide (P1NP) were assessed during the study. The primary objective was to assess if zoledronic acid was superior to alendronate in reducing serum NTx levels after 12 months’ treatment. Results A significantly greater reduction in NTx levels from baseline to month 12 (as determined by the area under the curve) was observed in patients treated with zoledronic acid ( n  = 408) versus those receiving alendronate ( n  = 196; 0.282 ng/mL vs. 0.270 ng/mL; P  = 0.012). The reduction in levels of P1NP after 1 year was also significantly greater in patients treated with zoledronic acid compared with those receiving alendronate (28.21 vs. 25.53 ng/mL; P  = 0.0024). The overall incidence of adverse events was similar between groups; both treatments were generally well tolerated. Although post-dose symptoms, including the incidence of influenza-like symptoms, were higher with zoledronic acid than alendronate initially, the incidence was similar between groups from days 4–360. Gastrointestinal symptoms were more frequent with alendronate than zoledronic acid throughout the study. Conclusion In this study, once-yearly iv zoledronic acid provided a greater and faster reduction in the levels of NTx and P1NP versus once-weekly oral alendronate.

Long-term treatment with 6-thioguanine (6-TG) for pediatric acute lymphoblastic leukemia (ALL) is associated with high rates of hepatic sinusoidal obstruction syndrome (SOS). Nevertheless, current treatment continues to use short-term applications of 6-TG with only sparse information on toxicity. 6-TG is metabolized by thiopurine methyltransferase (TPMT) which underlies clinically relevant genetic polymorphism. We analyzed the association between hepatic SOS reported as a serious adverse event (SAE) and short-term 6-TG application in 3983 pediatric ALL patients treated on trial AIEOP-BFM ALL 2000 (derivation cohort) and defined the role of TPMT genotype in this relationship. We identified 17 patients (0.43%) with hepatic SOS, 13 of which with short-term exposure to 6-TG ( P  < 0.0001). Eight of the 13 patients were heterozygous for low-activity TPMT variants, resulting in a 22.4-fold (95% confidence interval 7.1–70.7; P  ≤ 0.0001 ) increased risk of hepatic SOS for heterozygotes in comparison to TPMT wild-type patients. Results were supported by independent replication analysis. All patients with hepatic SOS after short-term 6-TG recovered and did not demonstrate residual symptoms. Thus, hepatic SOS is associated with short-term exposure to 6-TG during treatment of pediatric ALL and SOS risk is increased for patients with low-activity TPMT genotypes.