Upper limb fractures (including wrist, forearm, and humerus) represent a significant burden among postmenopausal women with osteoporosis. Up to 7 years of treatment with denosumab resulted in an increase in bone mineral density and decrease in fractures in upper limb sites. Upper limb (wrist, forearm, and humerus) fractures are a significant burden in osteoporosis, associated with significant morbidity and mortality. Denosumab, a monoclonal antibody against RANK ligand, increases bone mineral density (BMD) and decreases vertebral, nonvertebral, and hip fractures. Here, we evaluated the long-term effect of denosumab treatment on upper limb fracture risk and BMD. In the FREEDOM trial, subjects were randomized 1:1 to receive every-6-month denosumab 60 mg or placebo subcutaneously for 3 years, after which all subjects could receive denosumab for up to 7 years (Extension). Among placebo subjects who completed FREEDOM and enrolled in the Extension, wrist, forearm, humerus, and upper limb fracture rates and rate ratios between different time periods (FREEDOM years 1–3, Extension years 1–3, and Extension years 4–7) were computed. BMD at the ultradistal radius, 1/3 radius, and total radius was analyzed in a subset of subjects in a BMD substudy. This analysis included 2207 subjects (116 in the BMD substudy). Fracture rates decreased over the 7-year Extension; fracture rate ratios between Extension years 4–7 (denosumab) and FREEDOM years 1–3 (placebo) reduced significantly for the wrist (0.57), forearm (0.57), humerus (0.42), and upper limb (0.52; p < 0.05 for all). Percentage increase in BMD from Extension baseline at the ultradistal radius, 1/3 radius, and total radius was significant by Extension year 7 (p < 0.05 for all). Long-term treatment with denosumab decreases upper limb fracture risk and increases forearm BMD, suggesting beneficial effects on both cortical and trabecular bone accruing over time.

Purpose: Placebo-response (PR) in clinical trials of pain, particularly osteoarthritis (OA) pain, is recognized as a substantial challenge in drug development. Biochemical or phenotypical factors associated with increased PR are not certain, and the level of PR in separate pain subtypes, i.e. pain while the joint is moving and under load, and while the joint is idle and not under load, have not been described in the literature. The purpose of this analysis was to investigate clinical characteristics associated with PR as measured by the individual five pain questions of the Western Ontario and McMasters Arthritis (WOMAC) Index in the pooled data of two phase III randomized clinical trials in OA. Methods: Pooled data from the placebo-groups (N = 771) of two phase III RCTs (NCT00486434 and NCT00704847) in patients with knee OA followed for two years were analyzed. Main inclusion criteria were a Kellgren-Lawrence (KL) grade of 2 or 3, Joint-Space Width (JSW) of minimum of 2.0 mm at the medial tibio-femoral joint, and WOMAC pain ≥ 150 out of 500 mm. Pain of the target knee was measured using the WOMAC pain sub-index, consisting of five questions: Q1; during walking on a flat surface, Q2; using stairs (up or down), Q3 at night while in bed, Q4; sitting or lying and Q5; while standing. Baseline mean pain values within each question were normalized (0–100) and compared in a mixed model using subject as random effect. Changes in percent from baseline pain were calculated at months 1, 6, 12 and 24, and differences between individual questions were assessed using a repeated measures ANOVA. Pain by category (“under load”; WOMAC questions 1, 2 and 5 and “idle”; WOMAC questions 3 and 4) were similarly analyzed for change over time, and compared in a repeated measures ANOVA. Selected patient baseline characteristics; pain by WOMAC question, Joint-space width (JSW), age, and BMI were assessed for association with PR defined as change in percent from baseline to year two using Spearman's correlation. All analyses were performed on data from the target knees of the Per-Protocol population(N = 771). Results: Baseline levels of pain by WOMAC question was significantly higher in Q2, walking on stairs, compared to all other pain questions (p<0.001) (Fig. 1). The level of PR was significantly higher in questions related to pain while under load (Q1, Q2, Q5) compared to pain while idle (Q3, Q4), while no differences were observed between questions within the two categories (pain under load vs. idle) at any time-points. Differences in the two categories observed were statistically significant (p<0.005) at month 1 and onwards (Fig. 2). The PR for each individual pain question at month 24 was significantly, positively associated with baseline level of that particular question (p<0.0001). WOMAC pain question 2, which had the highest baseline level, also achieved the highest level of placebo response (36.8 % ±52.4 (SD) at year 2). Baseline BMI, age and JSW was not associated with PR. These data indicate that as no common clinical characteristics were associated with PR, other, perhaps psychological, factors are affecting the susceptibility to PR. Conclusions: These results indicate that the level of PR is significantly different between pain subtypes, as pain under load is significantly more susceptible to lead to PR than pain while idleFig. 2. Placebo-effect by pain category.View Large Image Figure ViewerDownload Hi-res image Download (PPT).

Background Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Trials of new analgesics for OA pain is impaired by substantial placebo-response (PR), and data describing characteristics and pain sub-types particularly associated with placebo-response is needed. Objectives The purpose of this post-hoc analysis was to investigate clinical characteristics and pain subtypes associated with PR as measured by the five pain questions of the Western Ontario and McMasters Arthritis (WOMAC) Index of the target (T)- and the non-target (NT) knees in the pooled data of two phase III randomized clinical trials of an oral treatment in OA. Methods Pooled data from the placebo-groups of two phase III randomized clinical trials (NCT00486434 and NCT00704847) in patients with knee OA followed for two years were analyzed. Main inclusion criteria for T knees were a Kellgren-Lawrence grade of 2 or 3, Joint-Space Width (JSW) of minimum of 2.0 mm at the medial tibio-femoral joint, and WOMAC pain ≥150 out of 500 mm. All analyses were performed on data from the T knees (N=771) and a sub-group of NT knees matching the pain inclusion criteria of the T knees (N=256). All subjects in the analysis belonged to the Per-Protocol population. Pain of the T and NT knees was measured using the WOMAC pain sub-index, five questions: Q1; during walking on a flat surface, Q2; using stairs, Q3 at night while in bed, Q4; sitting or lying and Q5; while standing. Changes in percent from baseline pain were calculated at months 1, 6, 12 and 24, and differences between individual questions were assessed using a repeated measures ANOVA. Pain by category (“under load”; WOMAC questions 1, 2 and 5 and “idle”; WOMAC questions 3 and 4) were similarly analyzed for change over time, and compared in a repeated measures ANOVA. Selected patient baseline characteristics; pain by WOMAC question, Joint-space width (JSW), age, and BMI were assessed for association with PR defined as change in percent from baseline to year two using Spearman9s correlation. Results Baseline pain was significantly higher in WOMAC Q2, compared to other pain questions (p<0.001). This was observed for both T- and NT knees. WOMAC Q2 was furthermore associated with the highest PR for both T, and NT knees (36.8% ±52.4 (SD) and 28.0% ±44.4, respectively) at year two. The observed PR was higher in the T knee, compared to the NT knee at all corresponding time-points. The level of PR was significantly higher in questions related to pain while under load (Q1, Q2, Q5) compared to pain while idle (Q3, Q4), and this was statistically significant in the T knee (p<0.005) at month 1 and onwards (Fig. 1), but did not reach statistical significance for the NT knee. Baseline BMI, age and JSW was not associated with PR. This indicates while no common clinical characteristics were associated with PR, other, perhaps psychological, factors may affect the susceptibility to PR. Conclusions These results indicate that the level of PR is significantly different between pain subtypes, as pain under load is significantly more susceptible to lead to PR than pain while idle. Disclosure of Interest A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, H. Gühring: None declared, C. Ladel: None declared, M. Michaelis: None declared, B. Riis Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Valter: None declared

Background Early gains in total hip BMD are desirable to improve hip strength early in the treatment of osteoporosis. Objectives To determine if women treated with 18-months of abaloparatide (ABL) were more likely to increase BMD than those treated with either TPTD or placebo (PBO), we performed a responder analysis comparing the percentage of subjects experiencing BMD gains of >3% at all three anatomic sites (total hip (TH), femoral neck (FN), lumbar spine (LS)). Methods In an 18 month phase 3 study of postmenopausal women aged 50-85 with a T-score ≤-2.5 at the spine or hip with either a prior vertebral or non-vertebral fracture, subjects were randomized to receive the PTHrP analog, ABL (80-μg SC daily), TPTD (20-μg SC daily), or placebo. All subjects were also treated with calcium and vitamin D supplementation per local practice. Treatment comparisons were performed using a 2-sided Chi-square test. Results 18-months of treatment with ABL (N=824) resulted in significantly greater increases in BMD relative to placebo (N=821) at 6, 12 and 18 months at TH, FN and LS. There were also significantly greater increases in BMD with ABL relative to TPTD (N=818) at TH and FN at 6, 12 and 18 months and at LS at 6 and 12 months. Overall, a significantly higher percentage of patients experienced >3% BMD gain in the ABL group (54%) compared to the PBO group (3.38%, p<0.0001) and the TPTD group (39.7%, p<0.0001) at TH, FN and LS combined. The percentage of subjects with increases in BMD with TPTD was also significantly higher relative to PBO, p<0.0001. Conclusions In postmenopausal women with osteoporosis, more subjects treated with ABL experienced BMD increases at all 3 sites compared to those treated with TPTD or PBO. Disclosure of Interest P. Miller Grant/research support from: Radius Health, G. Hattersley Employee of: Radius Health, E. Lau Grant/research support from: Radius Health, P. Alexandersen Grant/research support from: Radius Health, T. Hala Grant/research support from: Radius Health, S. Mustatea Grant/research support from: Radius Health, B. Nedergaard Grant/research support from: Radius Health, A. Krogsaa Grant/research support from: Radius Health, J. Slessinger Grant/research support from: Radius Health, C. Zerbini Grant/research support from: Radius Health, I. Valter Grant/research support from: Radius Health, Z. Visockiene Grant/research support from: Radius Health, B. Jendrych Grant/research support from: Radius Health, C. Kulak Grant/research support from: Radius Health, F. Marquez Grant/research support from: Radius Health, A. Harris Employee of: Radius Health, G. Williams Employee of: Radius Health, M.-Y. Hu Employee of: Radius Health, D. Black Consultant for: Radius Health, B. Riis Consultant for: Radius Health, L. Russo Grant/research support from: Radius Health, C. Christiansen Consultant for: Radius Health

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Context: Treatment of osteoporosis with subcutaneous (SC) injections of rhPTH(1-34) or rhPTH(1-84) is associated with significant improvements in BMD and reductions in osteoporotic fractures. However, subcutaneous injections can be associated with discomfort and thus deteriorating compliance.Objective: The UGL-OR1001 trial alined to establish the efficacy and safety parameters of a novel oral tablet formulation of rhPTH(1-31)NH2 and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis.Design: 24 weeks of randomized, double-blind treatment with once daily doses of 5 mg oral treatment or corresponding placebo, or open-label subcutaneous teriparatide.Patients or other participants: Women diagnosed with postmenopausal osteoporosis as detected by lumbar spine DXA, with an exclusion of those with prior treatment with bone active agents.Intervention(s): Orally formulated recombinant human PTH(1-31)NH2 and placebo, or open-label subcutaneous teriparatide as a positive control.Main outcome measure(s): The primary endpoint was to characterize the percent change from baseline in bone mineral density (BMD) at L1-L4 axial lumbar spine after 24 weeks in the rhPTH(1-31)NH2 arm. Secondary and exploratory endpoints included safety and tolerability of the oral formulation, measurement of biochemical markers of bone turnover, and evaluation of the PK profile at first and last dose. The study was registered at ClinicalTrials.gov with the identifier: NCT01321723.Results: The oral tablet formulation of rhPTH(1-31)NH2 resulted in similar PK profiles at both timepoints with mean Cm a values similar to subcutaneous administration. In the rhPTH(1-31)NH2 arm, a 2.2% increase in lumbar spine BMD was observed compared to baseline (p<0.001), while no change was observed in the placebo arm. Open-label teriparatide resulted in a 5.1% increase in LS BMD (p<0.001). In the oral PTH study arm, the bone formation marker osteocalcin was increased by 32%, 21% and 23% at Weeks 4, 12 and 24, respectively. There was no significant increase in the level of the bone resorption marker CTx-1.Conclusions: In summary, these data demonstrate that enteric-coated oral tablet formulation technology consistently generated robust levels of exposure of rhPTH(1-31)NH2 leading to induction of bone formation without inducing bone resorption resulting in significantly increased levels of LS BMD. Few adverse events were observed, recommending this orally delivered drug candidate for further development. (C) 2012 Elsevier Inc. All rights reserved.

Purpose: A new Diacerein Modified -Release (MR) formulation has been developed in India.The present prospective, randomized, double blind, multicentric, comparative study was undertaken to evaluate efficacy, safety and tolerability of Diacerein MR 100mg and conventional Diacerein 50mg in 224 adult patients with Osteoarthritis(OA) of the Knee after approval by the respective institutional ethics committee.Methods: Patients fulfilling selection criteria were treated with Diacerein MR 100mg once daily or Diacerein 50mg twice daily for 8 weeks after obtaining their informed consent.The primary efficacy variables included Improvement in Western Ontario and McMasters (WOMAC) individual osteoarthritis (OA) indices and Composite Index (for pain, stiffness and physical function) and the Visual Analog Scale (VAS) scores (for pain) while the secondary variable included improvement in Patient's and Physician's Global Assessment of Arthritis.Results: Seven patients in Diacerein MR and 8 in Diacerein group were lost to follow up.Thus a total 105 patients in Diacerein MR 100mg group and 106 in Diacerein 50mg group were included in the analysis.Results indicated that there was a statistically significant(p<0.05)early reduction in the mean VAS scores, WOMAC-OA pain, stiffness and physical function scores in both the groups at the end of 8 weeks.The reduction in mean total score of WOMAC -OA was significantly (P<0.05)greater in Diacerein MR group as compared to Diacerein group at the end of the study.A greater number of patients in Diacerein MR group had good to very good effects of treatment and the difference was statistically significant (P<0.05) as per both patients and physicians global assessment as compared to Diacerein group.The incidence of diarrhea was less in Diacerein MR group compared to Diacerein group.Conclusions: Once-daily Diacerein MR 100 mg was as effective as twice daily Diacerein 50 mg but better tolerated and could be a valuable therapeutic option in patients with osteoarthritis of the knee.

the most frequent side effects (84.21%). First visit before age 60 years ensures a better adherence during the FU (p=0.018). Co-morbidities reduce adherence (p=0.047). Weekly bisphosponates absuntion presents better compliance rates than daily (p=0.005). Patients with history of fractures have better adherence (p<0.001). Adherence results higher since the first year post-fracture (p=0.048) and remain higher during FU (p=0.004). Dividing population in adherent and non-adherent at the 85% MPR cut-off results that non-adherent have an RR=1.75 of fracture. Considering the 3 periods of FU, adherence seems to increase over time (84.53% – 87,64% – 91.19%; p=0.025) Major determinants of adherence already described in clinical trials and relationship between adherence and fracture risk are confirmed in this real life study. An adherence rate increase is also detected with fractures history (more motivation) and in patients in therapy from many years. Conflict of interest: None declared.

In this 3‐yr, randomized, double‐blind, placebo‐ and active‐controlled study, healthy postmenopausal women with osteoporosis (55–85 yr of age) were treated with bazedoxifene 20 or 40 mg/d, raloxifene 60 mg/d, or placebo. The primary endpoint was incidence of new vertebral fractures after 36 mo; secondary endpoints included nonvertebral fractures, BMD, and bone turnover markers. Among 6847 subjects in the intent‐to‐treat population, the incidence of new vertebral fractures was significantly lower (p < 0.05) with bazedoxifene 20 mg (2.3%), bazedoxifene 40 mg (2.5%), and raloxifene 60 mg (2.3%) compared with placebo (4.1%), with relative risk reductions of 42%, 37%, and 42%, respectively. The treatment effect was similar among subjects with or without prevalent vertebral fracture (p = 0.89 for treatment by baseline fracture status interaction). The incidence of nonvertebral fractures with bazedoxifene or raloxifene was not significantly different from placebo. In a posthoc analysis of a subgroup of women at higher fracture risk (femoral neck T‐score ≤ –3.0 and/or ≥1 moderate or severe vertebral fracture or multiple mild vertebral fractures; n = 1772), bazedoxifene 20 mg showed a 50% and 44% reduction in nonvertebral fracture risk relative to placebo (p = 0.02) and raloxifene 60 mg (p = 0.05), respectively. Bazedoxifene significantly improved BMD and reduced bone marker levels (p < 0.001 versus placebo). The incidence of vasodilatation, leg cramps, and venous thromboembolic events was higher with bazedoxifene and raloxifene compared with placebo. In conclusion, bazedoxifene significantly reduced the risk of new vertebral fracture in postmenopausal women with osteoporosis and decreased the risk of nonvertebral fracture in subjects at higher fracture risk.

Objectives: An open study was carried out to evaluate changes in bone remodeling markers such as N-telopeptide (NTx), tartrate-resistant acid phosphatase (TRAP), total alkaline phosphatase (TAP), and bone alkaline phosphatase (BAP) during a 1-year continuous tibolone treatment in postmenopausal women. Material and methods: Thirty-six postmenopausal women were recruited for receiving tibolone 2.5 mg per day for 1 year. Densitometry and determination of biochemical markers of bone metabolism in serum and urine were performed at 1, 3, 6, and 12 months. Results: Comparing baseline with 12 month's values, BAP and all resorption markers decreased significantly. NTx began to decrease since the initiation of the treatment (baseline: 74.4±5.3; 1 month: 57.5±4.2; 12 months: 36.6±2.8). BAP increased at the first month (baseline: 37.3±2.1; 1 month: 42.6±3.0) but diminished in the following months (12 months: 23.1±1.5). TAP started to decrease significantly only after 6 months of treatment (baseline: 37.3±2.1; 12 months: 31.4±2.3) and TRAP after 3 months (baseline: 9.8±0.4; 6 months: 9.1±0.5; 12 months: 8.2±0.4). Normal bone mineral density at distal and ultradistal forearm was maintained during the 1-year treatment (baseline: 0.42±0.01; 12 months: 0.42±0.01 and baseline: 0.33±0.01; 12 months: 0.33±0.01, respectively). Conclusion: The use of tibolone 2.5 mg per day diminished progressively and significantly bone resorption and formation markers during 1-year treatment period.