B J Riis

Nordic Bioscience, København, Capital Region, Denmark

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Publications (160)757.1 Total impact

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    ABSTRACT: Background Osteoarthritis (OA) is recognized as a heterogeneous disorder, with several possible drivers of disease progression, including involvement of bone, cartilage and synovium. The degree of joint pain has been shown to be both diagnostic and prognostic for OA, but meaningful clinical characteristics to identify the group of patients at risk of rapid progression are still needed. Objectives The aim of this analysis was to identify key pain characteristics (WOMAC 5 pain questions) associated with risk of structural progression, and notable changes in reported pain over time. Methods A combined post-hoc analysis of two phase III RCTs (NCT00486434 and NCT00704847), evaluating the efficacy and safety of oral salmon calcitonin in patients with painful knee OA (N=2,206) was performed. Analysis of structural progression was made based on data from the placebo group only, stratifying patients into quintiles of baseline (BL)-reported WOMAC pain level and further investigating the 5 WOMAC pain subscale 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. The association between joint space narrowing (JSN) and WOMAC pain was assessed in a mixed model with JSN as dependent variable and other relevant BL variables as fixed effects. Results Spearman correlation coefficients indicates that each WOMAC pain sub-score expresses individually different information, as rho coefficients ranged from a minimum of 0.40 between Q2 and Q3, and maximally 0.67 for Q3 and Q4 (p<0.0001 for both). The average observed change in the individual pain sub-scale levels indicated a heterogeneous development of pain characteristics over time, as the observed reduction in Q3 and Q4-pain was lower compared to other sub-scores. The relative change in overall WOMAC pain-score at year 2 was not significantly influenced by level of BL pain score. For each of the sub-score questions, a trend towards higher BL pain level being associated with higher relative and absolute pain relief was observed at year two, with some differences among the individual sub-score questions. Separate analysis of target and contralateral knees revealed interesting differences in association of BL pain level and structural progression. JSN of target knees appeared to be independent of BL levels of Q1-Q5, whereas in contra-lateral knees there was a tendency of higher BL levels of Q1, Q2 and Q5 being associated with higher JSN (Figure). These results highlight differences in perceived pain caused by osteoarthritis over time, and may be indicative of individual pain phenotypical characteristics. The results indicate that acute, likely nociceptive, pain associated with walking and standing was more associated with structural progression than what may be interpreted as a possibly different, perhaps centrally augmented pain experienced without direct mechanical loading of the joint. Conclusions These data from a large clinical trial dataset in OA describe significant associations between pain, pain subtypes and progression in OA, which may be related to different biochemical disease drivers. Acknowledgements We wish to sincerely thank all the participants and investigators of the CSMC021C2301/02 studies. Disclosure of Interest A. Bihlet: None declared, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, B. Riis 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 Employee of: Merck Serono, M. Michaelis Employee of: Merck Serono, C. Ladel Employee of: Merck Serono
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: 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
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases
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    ABSTRACT: Background Cartilage and bone are the central tissues affected by osteoarthritis (OA). Remodeling of these tissues can be measured by soluble biomarkers. Recent data has shown that urinary type II collagen C-terminal telopeptide (u-CTX-II) is a biomarker of cartilage and subchondral bone turnover. Bone resorption may be quantified by type I collagen cross-linked C-terminal degradation in serum (s-CTX-I). Objectives The purpose of this analysis was to investigate the association between cartilage and bone remodeling, measured by u-CTX-II and s-CTX-I, and clinically recorded knee pain and KL score, as well as the OA risk factor Body Mass Index (BMI). Methods Fasting serum (n=767) and urine (n=620) samples were collected at baseline from patients with painful knee OA participating in the placebo arms of two phase III RCTs (NCT00486434 and NCT00704847). Creatinine-corrected u-CTX-II (IDS PLC, United Kingdom]) and s-CTX-I (Roche, United Kingdom) were measured. The relationship between the biomarkers and baseline-reported WOMAC pain level of the target knee, radiographic OA score (KL) and BMI were analyzed by Spearman's correlations on log-transformed biomarker data and by multiple regression analysis (OLS), where WOMAC, KL score or BMI were set as the dependent variable and biomarkers, BMI and age as covariates, adjusted for gender. Results Both CTX-I and CTX-II were significantly correlated to BMI (r=-0.26, p<0.0001, r=-0.09, p=0.0013) after adjustment for age and gender. Levels of CTX-II significantly correlated with WOMAC pain (β=19.8, p=0.022), which remained after adjustment (β=20.4, p=0.019). CTX-II was likewise correlated with KL score before (β=0.26, p<0.0001) and after (β=0.25, p<0.0001) adjustment. Levels of s-CTX-I was not statistical significantly correlated with WOMAC pain (β=4.73, p=0.64), nor after adjustment (β=6.06, p=0.57). s-CTX-I was not statistical significantly with KL score before (β=0.08, p=0.061), but weakly so after (β=0.11, p=0.018) adjustment. Conclusions This cross-sectional analysis of data from a large clinical trial dataset shows strong correlations between the biomarkers CTX-I, CTX-II and pain and obesity. These findings may be a reflection of high mechanical joint loading caused by overweight, contributing to pathological bone and cartilage wear which could lead to increased pain. Longitudinal data to support this hypothesis is needed. These data indicate that CTX-I and CTX-II may assist in identifying disease drivers of a specific, painful OA phenotype to be further investigated. Acknowledgements We wish to thank the participants and investigators of the CSMC021C2301/2 trials. Disclosure of Interest A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, A.-C. Bay-Jensen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, B. Riis 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, K. Musa Employee of: Nordic Bioscience, P. Alexandersen Grant/research support from: Nordic Bioscience
    No preview · Article · Jun 2015 · Annals of the Rheumatic Diseases

  • No preview · Article · Apr 2015 · Osteoarthritis and Cartilage

  • No preview · Article · Apr 2015 · Osteoarthritis and Cartilage

  • No preview · Article · Apr 2015 · Osteoarthritis and Cartilage
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    ABSTRACT: Background Cartilage and synovium are two central tissues remodeled in osteoarthritis (OA). Recent data has shown that type II collagen degradation (CTX-II) is a biomarker of cartilage and subchondral turnover. CRPM and C3M are biomarkers of synovial inflammation and turnover. Objectives To identify different subtypes of OA related to progression by measuring biomarkers of cartilage degradation and synovial inflammation. Methods Fasting serum (n=767) and urine (n=620) samples from knee OA patients, of the placebo arms of two phase III RCTs (NCT00486434 and NCT00704847) were analyzed for Serum C3M, CRPM, (type III collagen and C-reactive protein neo-epitope) and creatinine-corrected urinary CTX-II (type II collagen C-terminal telopeptide). The relationship between the biomarkers and the 5 baseline-reported WOMAC pain subscale questions, using the sum of target and non-target knee, were analyzed: A; during walking on a flat surface, B; using stairs (up or down), C; at night while in bed, D; sitting or lying and E; while standing. Joint space width was analyzed at baseline and at 24 months. Log-transformed data were analyzed by Spearman's rho and by multiple regression analysis, where WOMAC or radiographic scores were the dependent variable and biomarkers, age, gender and BMI as covariates. Cut-offs was based on reference value and difference between the high/low groups was analyzed by Mann-Whitney. Results CTX-II was significantly correlated with WOMAC with all 5 sub-questions (p<0.01), while level of C3M was correlated with question B and E (p<0.05). CTX-II remained significantly associated with all sub-questions after adjustment: A) r=0.20, p<0.0001; B) r=0.16, p=0.0005; C) r=0.11, p=0.017; D) r=0.13, p=0.0046; and E) r=0.17, p=0.0002. But not C3M: B) r=0.08, p=0.063 and E) r=0.08, p=0.069. CTX-II was significantly correlated JSW in both knees (r=-0.17, p<0.0001), whereas C3M was correlated to joint space narrowing of the target knee (r=0.11, p=0.013). CRPM was not associated with the clinical measures. Patients were separated into 2 groups; 1) low CRPM and low C3M, and 2) either high CRPM or high C3M, or with both high. 16% of the patients were found group 2. WOMAC subscale question E was significantly higher in this group (p=0.019). Group 1 patients (low in both CRPM and C3M) progressed structurally more group 1 patients (p=0.046). Conclusions CTX-II was associated with all types of pain, especially with pain associated with walking on a flat surface, indicating that CTX-II is related to pain from continuous skeletal load, supported by the strong correlation with JSW. C3M, from the synovium, was weakly correlated pain by using stairs and standing still. C3M was correlated to progression indicating that patients with certain levels of C3M had a higher likelihood for progression. We found that the two inflammatory markers could facilitate patient segregation. These biomarkers may assist in identification of the inflammation driven OA phenotype, which needs to be treated different than non-inflammatory OA. Acknowledgements The CSMC021C2301/2 investigators Disclosure of Interest A. Bay-Jensen Shareholder of: Nordic Bioscience, Grant/research support from: EC FP7 programs, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, K. Musa Employee of: Nordic Bioscience, A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, P. Alexandersen: None declared, J. Andersen: None declared, B. Riis: None declared, C. Christiansen Shareholder of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Grant/research support from: EC FP7 programs, Employee of: Nordic Bioscience
    No preview · Article · Apr 2015 · Osteoarthritis and Cartilage
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    ABSTRACT: To evaluate the structure-modifying and symptom efficacy, as well as safety and tolerability of oral salmon calcitonin (sCT) formulated with a 5-CNAC carrier (a molecule based on Eligen(®) technology), in osteoarthritis patients with moderate to severe knee pain and joint structural damage classified as Kellgren-Lawrence 2-3. This is the combined reporting of two randomized, double-blind, multi-center, placebo-controlled trials (CSMC021C2301 and CSMC021C2302), evaluating the efficacy and safety of oral salmon calcitonin in patients with painful knee OA with structural manifestations, enrolling 1,176 and 1,030 patients, respectively. Study subjects were randomized (1:1) to oral sCT 0.8 mg twice daily or placebo (PBO) for 24 months. The primary efficacy objectives were to examine the treatment effect compared to placebo on change over 24 months in joint space width (JSW) in the signal knee measured by X-ray, and to examine the change in pain and function using the WOMAC questionnaire. Other study parameters included patient and physician global assessment, and biochemical markers of bone (CTX-I) and cartilage degradation (CTX-II). At the 24 month endpoint there was no statistically significant treatment effect on JSN in any of the two studies. In CSMC021C2301 there was a treatment effect on WOMAC (sum of pain, function, stiffness, and total scores) as well as on the biomarkers of bone and joint metabolism, but due to the hierarchical testing procedure the treatment effect was not claimed statistically significant. The present formulation of oral sCTdid not provide reproducible clinical benefits in patients with symptomatic knee OA. (NCT00486434, NCT00704847). Copyright © 2015 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.
    No preview · Article · Jan 2015 · Osteoarthritis and Cartilage
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    ABSTRACT: Background/purpose: The aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, Joint Space Narrowing (JSN), and BMI. Methods: Data from 2206 subjects (4390 knees) were combined for this post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled phase III trials (NCT00486434 and NCT00704847) that evaluated the efficacy and safety of 2-years treatment with oral salmon calcitonin of subjects with painful knee osteoarthritis (OA). Results: There was a clear positive and significant correlation between KL grade and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). BMI, KL-Score and WOMAC pain was diagnostic, but only KL-score and pain had prognostic value, albeit pain in a non-linear manner. Conclusion: These data clearly describe significant associations between KL grade, JSW, pain and BMI in patients with symptomatic knee OA. KL grade, BMI and WOMAC pain were diagnostically associated with OA based on JSW but only KL-score and pain in a non-linier fashion was prognostic. 50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. These results suggest that disease phenotypes, rather than disease status, are responsible for disease progression.
    No preview · Article · Jan 2015 · Osteoarthritis and Cartilage
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    ABSTRACT: The oral delivery of peptides and proteins has been hampered by an array of obstacles. However, several promising novel oral delivery systems have been developed. This paper reviews the most advanced oral formulation technologies, and highlights key lessons and implications from studies undertaken to date with these oral formulations. Special interest is given to oral salmon CT, GLP-1, insulin, PYY-(3-36), rhPTH(1-31)-NH2 and PTH(1-34), by different technologies. The issues addressed include: 1) interaction with water, 2) interaction with food, 3) diurnal variation, 4) inter and intra subject variability, 5) correlation between efficacy and exposure, and 6) key deliverables of different technologies. These key lessons may aid research in the development of other oral formulations.
    No preview · Article · Nov 2014 · British Journal of Clinical Pharmacology
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    ABSTRACT: Aim: The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach. Methods: We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points. Results: Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P < 0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety. Conclusions: The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy.
    No preview · Article · Oct 2014 · British Journal of Clinical Pharmacology
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    ABSTRACT: Background Osteoarthritis (OA) is a heterogeneous disorder, which has been described in several different population studies. However there is a significant difference between patient populations recruited in OA interventional clinical trials and epidemiological studies. While epidemiological studies focus on incidence, prevalence, risk and cause of OA, clinical trials aim at enrolling patients with certain characteristics based on defined guidelines on clinical outcome measures. There is therefore a need for in-depth, post-hoc analysis of clinical studies in OA. Objectives The aim of the analysis was to investigate the associations between JSW, KL-score, pain and JSN (joint space narrowing), as well as BMI (Body mass index), by combining data from two phase III studies (N=2,206). Methods This is a post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled trials (CSMC021C2301 and CSMC021C2302), evaluating the efficacy and safety of oral salmon calcitonin in subject with painful knee OA, enrolling 1,176 and 1,030 patients, respectively. The analysis includes baseline data on KL-score, pain and function metrics from the WOMAC questionnaire, as well as demographics. The main inclusion criteria for the target knee were: ACR OA criteria, KL-score 2 or 3 and JSW of ≥2.0 mm, and significant WOMAC pain. Both knees were analyzed. Moreover, analysis of the two-year data on JSN was included for the placebo arm Results The mean JSW was comparable in knees of KL-0 and -1 and significantly decreased with increasing KL-2, -3 and -4 (p<0.01) when including all knees in the analysis. JSW was significantly lower in the non-target knees as compared to the target knees (2.48±0.08mm vs. 3.11±0.06mm, p<0.0001). When analyzing the two-year progression data only knees from the placebo group was included. The mean JSN was 0.318±0.018mm, where the mean JSN for the non-target knee was 0.279±0.025mm and 0.356±0.026 for the target knee (p<0.05). While the KL score of the target knee was a more important clinical descriptor for progression than pain, pain was the more important descriptor for the contra-lateral knee. Clearly different levels of progression were observed in relation to KL score and pain, in which the third pain quartile (Q3), but not the fourth quartile (Q4), progressed significantly faster than the first and second pain quartiles. Similar observations were made for BMI and Pain, in relation to JSN, namely that patients with Q3 pain were progressing faster than those in Q4. Conclusions These data from potentially the largest clinical trial dataset in OA to date clearly describe significant associations between KL-score, JSW, pain and BMI in patients with symptomatic knee OA. Consequently, this dataset is ideally suited for identification of different phenotypes of OA, and biomarkers associated with those. Patients with symptomatic OA at baseline progressed significantly faster than patients with asymptomatic disease, however with important variations that need accounting for when designing clinical trials, such as relations to pain, BMI and JSN. These results suggest that disease phenotypes rather than disease status are responsible for disease progression and may act as background material for designing future clinical trials in OA. Disclosure of Interest M. Karsdal Employee of: Nordic Bioscience, A.-C. Bay-Jensen: None declared, A. Bihlet Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, P. Alexandersen Employee of: Nordic Bioscience, C. Christiansen Employee of: Nordic Bioscience DOI 10.1136/annrheumdis-2014-eular.4503
    No preview · Article · Apr 2014 · Osteoarthritis and Cartilage
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    ABSTRACT: 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 aimed to establish the efficacy and safety parameters of a novel oral tablet formulation of rhPTH(1-31)NH(2) and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis. DESIGN: 24weeks of randomized, double-blind treatment with once daily doses of 5mg 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)NH(2) 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 24weeks in the rhPTH(1-31)NH(2) 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)NH(2) resulted in similar PK profiles at both timepoints with mean C(max) values similar to subcutaneous administration. In the rhPTH(1-31)NH(2) 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)NH(2) 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.
    No preview · Article · Dec 2012 · Bone
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    ABSTRACT: The long-term efficacy and safety of once-monthly ibandronate were studied in this extension to the 2-year Monthly Oral Ibandronate in Ladies (MOBILE) trial. Over 5 years, lumbar spine bone mineral density (BMD) increased from baseline with monthly ibandronate 150 mg (8.4%). Long-term monthly ibandronate is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis. Once-monthly therapy with ibandronate has been studied for up to 5 years in a long-term extension (LTE) to the 2 year MOBILE trial. This multicenter, double-blind extension study of monthly ibandronate involved postmenopausal women who had completed 2 years of the MOBILE core study, with ≥75% adherence. Patients were reallocated, or were randomized from daily therapy, to ibandronate 100 mg monthly or 150 mg monthly for a further 3 years. A pooled intent-to-treat (ITT) analysis of 344 patients receiving monthly ibandronate from the core MOBILE baseline showed increases over 5 years in lumbar spine BMD (8.2% with 100 mg and 8.4% with 150 mg). Three-year data relative to MOBILE LTE baseline in the full ITT population of all 698 patients randomized or reallocated from MOBILE (including those previously on daily treatment) showed, on average, maintenance of proximal femur BMD gains achieved in the core 2-year study, with further small gains in lumbar spine BMD. In general, maintenance of efficacy was also indicated by markers of bone metabolism. There were no tolerability concerns or new safety signals. Monthly treatment with ibandronate 100 and 150 mg is effective and well tolerated for up to 5 years in women with postmenopausal osteoporosis.
    No preview · Article · Sep 2011 · Osteoporosis International
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    Full-text · Article · Sep 2011 · Osteoarthritis and Cartilage
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    ABSTRACT: Treatment of patients with perioxisome proliferator-activated receptor-γ full agonists are associated with weight gain, heart failure, peripheral oedema, and bone loss. However, the safety of partial perioxisome proliferator-activated receptor-γ agonists has not been established in a clinical trial. The BALaglitazone glucose Lowering Efficacy Trial aimed to establish the glucose-lowering effects and safety parameters of the perioxisome proliferator-activated receptor-γ partial agonist balaglitazone in diabetic patients on stable insulin therapy. Four hundred and nine subjects from three countries with type 2 diabetes on stable insulin therapy were randomized to 26 weeks of double-blind treatment with once daily doses of 10 or 20 mg balaglitazone, 45 mg pioglitazone, or matching placebo (n ≥ 99 in each group). The primary endpoint was the efficacy of balaglitazone 10 and 20 mg versus placebo on the absolute change in haemoglobin A(1c) . Secondary endpoints included levels of fasting serum glucose, and changes in body composition and bone mineral density as measured by dual energy X-ray absorptiometry, in comparison to pioglitazone 45 mg. This study is registered with Clinicaltrials.gov identifier: NCT00515632. In the 10- and 20-mg balaglitazone groups, and in the 45-mg pioglitazone group, significant reductions in haemoglobin A(1c) levels were observed (−0.99, −1.11, and −1.22%, respectively; p < 0.0001) versus placebo. Fasting serum glucose was similarly reduced in all treatment arms. Dual energy X-ray absorptiometry analyses showed that, while balaglitazone at 10 mg caused weight gain and fluid retention compared to placebo, the magnitude of these effects was significantly smaller than that of pioglitazone 45 mg and balaglitazone 20mg. Balaglitazone at either dose did not appear to reduce bone mineral density, while Pioglitazone showed a trend towards a reduction. Patients treated with balaglitazone at 10 mg and 20 mg and pioglitazone at 45 mg showed clinically meaningful improvements in glucose levels and HbA(1c) . With the 10 mg dose, the benefits (glucose & HgA(1c) lowering) and untoward effects (fluid and fat accumulation) were less, results that encourage further studies of this drug candidate.
    No preview · Article · May 2011 · Diabetes/Metabolism Research and Reviews
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    ABSTRACT: Oral delivery of proteins has been hampered by an array of difficulties. However, promising novel oral delivery systems have been developed. 5-CNAC, formulated with the peptide salmon calcitonin, is in phase III clinical trials for the treatment of osteoporosis or osteoarthritis and could become the first marketed oral peptide. This article reviews key findings and implications from studies undertaken to date with this oral formulation. Findings include these: (1) the optimal calcitonin tablet dose is 0.8 mg; (2) 0.8 mg of oral calcitonin is rapidly absorbed, reaching maximum concentration in 15 to 30 minutes, and is eliminated from plasma with a short half-life-9 to 15 minutes; (3) the 0.8-mg tablet is more highly absorbed than the marketed nasal formulation, with biomarker levels indicating significantly greater efficacy in suppression of bone resorption; (4) drug absorption is increased with dosing at least 10 minutes before a meal rather than postprandially and also with 50 mL of water; (5) the optimal timing of dosing for osteoporosis therapy is in the evening to mitigate the circadian peak in bone resorption; and (6) the oral formulations of synthetic and recombinant calcitonin have similar pharmacokinetic and pharmacodynamic properties. These key findings may aid researchers in the development of other oral formulations.
    No preview · Article · Apr 2011 · The Journal of Clinical Pharmacology
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    ABSTRACT: The present study describes two newly developed N-terminal pro-peptides of collagen type I (PINP) competitive enzyme-linked immunosorbent assays (ELISAs) for the assessment of corresponding PINP epitopes in the rat- and human species. Monoclonal antibodies were raised against corresponding rat and human PINP sequences and competitive assays were developed for each species. They were evaluated in relevant pre-clinical or clinical studies. The antibody characterizations indicated that PINP indeed was recognized. Technical robust assays were obtained. Rat PINP and tALP showed similar patterns in the gold standard osteoporosis rat ovariectomized (OVX) model. No liver contribution was observed in the liver fibrosis rat bile duct ligation model (BDL). In an osteoporosis study, the human serum PINP levels were significantly decreased after ibandronate treatment compared to placebo. The two corresponding PINP assays were specific and these bone turnover markers may improve translational science for the evaluation for bone-related diseases.
    No preview · Article · Oct 2010 · Clinical biochemistry
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    ABSTRACT: Osteoarthritis (OA) involves changes in both bone and cartilage. These processes might be associated under some circumstances. This study investigated correlations between bone and cartilage degradation in patients with OA as a function of sex, Kellgren-Lawrence (KL) score, Body Mass Index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation. This study was a 2-week, double-blind, double-dummy, randomized study including 37 postmenopausal women and 36 men, aged 57-75 years, with painful knee OA, and a KL-score of I - III. Subjects were allocated to one of three treatment arms: 0.6 mg or 0.8 mg oral sCT, or placebo given twice-daily for 14 days. Correlations between gender, KL score, or BMI and the bone resorption marker, serum C-terminal telopeptide of collagen type I (CTX-I), or the cartilage degradation marker, urine C-terminal telopeptide of collagen type II (CTX-II) were investigated. At baseline, biomarkers indicated women with OA experienced higher bone and cartilage degradation than men. CTX-I levels were significantly higher, and CTX-II levels only marginally higher, in women than in men (p = 0.04 and p = 0.06, respectively). Increasing KL score was not correlated with bone resorption, but was significantly associated with the cartilage degradation CTX-II marker in both men and women (p = 0.007). BMI was significantly and negatively correlated to the bone resorption marker CTX-I, r = -0.40 (p = 0.002), but showed only a borderline positive correlation to CTX-II, r = 0.25 (p = 0.12). Before morning treatments on days 1 and 14, no correlation was seen between CTX-I and CTX-II in either the sCT or placebo group. However, oral sCT and food intake induced a clear correlation between these bone and cartilage degradation markers. Four hours after the first sCT dose on treatment days 1 and 14, a significant correlation (r = 0.71, p < 0.001) between changes in both CTX-I and CTX-II was seen. In the placebo group a weakly significant correlation between changes in both markers was found on day 1 (r = 0.49, p = 0.02), but not on day 14. Bone resorption was higher in females than males, while cartilage degradation was correlated with increasing KL-score and only weakly associated with BMI. Bone and cartilage degradation were not correlated in untreated individuals, but dosing with oral sCT with or without food, and a mid-day meal, decreased bone and cartilage degradation and induced a correlation between both markers. Changes in bone and cartilage markers may aid in the identification of potential new treatment opportunities for OA. Clinical trial registration number (EUDRACT2006-005532-24 & NCT00486369).
    Full-text · Article · Jun 2010 · BMC Musculoskeletal Disorders
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    ABSTRACT: We have investigated biochemical indices of bone formation and bone resorption: serum alkaline phosphatase (sAP) plasma bone Gla protein (pBGP), fasting urinary hydroxyproline corrected for creatinine (FuHP/Cr), and fasting urinary calcium corrected for creatinine (FuCa/Cr) in 43 postmenopausal women with spinal fractures. Furthermore, histomorphometric indices of bone resorption and bone formation, as well as whole body retention (WBR) of 99m-technetium-diphosphonate (99mTc-DP), were determined. The results are compared to pre- and postmenopausal normal subjects. The results showed that indices of bone formation were mutually correlated except for sAP vs. WBR. sAP, WBR, and pBGP increased with age. sAP and WBR were not different between osteoporotics and age-matched controls, while pBGP and probably histological indices of bone formation were lower in osteoporotics than in age-matched controls. pBGP--and to a lesser extent sAP--were significantly correlated with all histological parameters reflecting bone formation. Finally, biochemical indices of bone resorption were high in osteoporotic patients and poorly correlated with histological bone resorption. The discrepancy between biochemical markers of bone formation may be related to the low sensitivity of sAP and WBR. Conversely, pBGP, sAP, and WBR may reflect different aspects of osteoblastic activity and bone mineralization. Finally, our data suggest that bone turnover increases with aging and that osteoporotic patients have higher bone resorption and probably lower bone formation than age-matched controls.
    No preview · Article · Dec 2009 · Journal of Bone and Mineral Research

Publication Stats

7k Citations
757.10 Total Impact Points

Institutions

  • 2008-2015
    • Nordic Bioscience
      København, Capital Region, Denmark
  • 1993-2011
    • Center for Clinical and Basic Research
      København, Capital Region, Denmark
  • 2009
    • Novartis
      Bâle, Basel-City, Switzerland
    • Chang Gung University
      Hsin-chu-hsien, Taiwan, Taiwan
  • 1984-2009
    • Glostrup Hospital
      • Department of Paediatrics
      København, Capital Region, Denmark
  • 1987-1988
    • IT University of Copenhagen
      København, Capital Region, Denmark