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BackgroundThe heterogeneous nature of osteoarthritis (OA) and the need to subtype patients is widely accepted. The biomarker CRPM, a metabolite of C-reactive protein (CRP), is released to the circulation during inflammation. Blood CRPM levels have shown to be associated with disease activity and response to treatment in rheumatoid arthritis (RA). We hypothesized that circulating levels of CRPMs could be used to identify OA patients with an inflammatory phenotype. We investigated the level and the prognostic effect of CRPM using combined data from two phase III OA and two RA studies (N = 1591). The association between serum CRPM levels and radiographic progression was investigated in knees of OA patients without radiographic OA in contra-lateral knee at baseline by dividing the patients into cases (knees with two-year radiographic progression) and controls (knees without radiographic progression). ResultsThe mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3-8.8] ng/mL) compared to the RA patients (15.6 [9.5-21.6] ng/mL); however, a significant subset of OA patients (31%) had CRPM levels ≥ 9ng/mL, as 75% of patients with early RA. Furthermore, OA patients with CRPM levels ≥ 9ng/mL were more likely to progress on X-ray over a two-year follow-up period; CRPM was prognostic for contralateral incidence knee OA with an odds ratio of 2.2 [1.0 - 4.7]. ConclusionA subset of OA patients, approximately 30%, appear to have tissue inflammation comparable to that of RA patients, reflected by the level of CRPM. Furthermore, high CRPM levels were prognostic of incident knee OA. These data suggest that CRPM is a blood-based biochemical marker for early identification OA patients with an inflammatory phenotype.

This study investigated the association between body composition and risk of atrial fibrillation (AF) in postmenopausal women. In a retrospective analysis we assessed data from 5704 postmenopausal women (age 70.7 ± 6.5 yrs.) who in 1999–2001 participated in The Prospective Epidemiological Risk Factor study with body composition assessed by dual-energy X-ray absorptiometry. Outcomes were obtained from Danish Health Registries and body composition association to risk of AF was evaluated by univariable and multivariable Cox Hazard regression. 850 women developed AF after baseline. High lean body mass was associated with increased risk of AF in multivariable analyses, adjusting for body mass index (BMI), height or weight (adjusted for: BMI, hazard ratio (HR) 1.49, 95% Confidence Interval (1.22–1.80); height, HR 1.27 (1.03–1.56); weight, 1.33 (1.06–1.65)). Height and weight were associated with increased risk of AF in multivariable analyses adjusting for body composition measures. When adjusting for total lean mass, only height remained statistically significant (HR 1.34 (1.09–1.64)). In a cohort of elderly Caucasian women, high lean body mass, height and weight were associated with increased risk of AF and the variables remained significant after adjusting for age and other known risk factors of AF.

Objective To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis). Patients and Methods ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients. Results Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95% CI, 0.04-0.41; P Conclusion Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis. Trial Registration clinicaltrials.gov Identifier: NCT01657162.

Background Osteoarthritis (OA) can lead to joint failure and ultimately total joint replacement (TJR). Identifying risk-factors of developing joint failure is of interest for clinicians and researchers. Currently late-stage clinical trial design for evaluating new treatments in OA is evolving with the possible utilization of accelerated approval pathways. This may require outcome studies with longer duration, in which joint failures may qualify as an endpoint. However, TJRs are relatively rare events and are known to be biased by doctor/patient interactions as well as local practice guidelines, and consequently, there is a need for objective non-invasive measures, such as soluble biomarkers (BM), to enrich the population for this outcome. BM may act as important tools in investigating the association between biochemical/pathological processes and risk of joint failure. Degradation of collagens type I and II are known to be involved in OA disease progression, and the biomarkers CTX-I (C-telopeptide of crosslinked collagen type I), a marker of bone degradation, and CTX-II (C-telopeptide of crosslinked collagen type II), a marker of cartilage degradation, may reflect disease progression with clinical relevance for the risk of joint failure. Objectives To evaluate baseline (BL) BM sCTX-I and uCTX-II as predictors of TJR. Methods Data from two clinical trials investigating oral salmon calcitonin (SMC) in OA, NCT00486434 and NCT00704847, was analyzed post-hoc. Data was dichotomized by the bottom and top quartile of the respective BM concentration at BL to compare the number TJRs of the knee or hip in groups with high vs. low sCTX-I or uCTX-II, respectively. For means of visualization, plotted in Kaplan-Meier curves. Cox Proportional Hazard Regression was performed to determine the association of BL sCTX-I and uCTX-II to the incidence of TJR while adjusting for co-variates; age, BMI, and gender. Data from both treatment groups were analyzed. Only the first reported incident was included in the analysis for each subject. Results A total of 68 TJRs of knee or hip were reported, of which 49 were knees and 18 were hips. One patient underwent two TJRs, resulting in 67 subjects with events. Results from the Cox Proportional Hazard Regression adjusted for covariates of age, BMI, and sex (table 1), indicate that high BL sCTX-I compared to low was associated with a 3.4 times higher risk of undergoing an arthroplasty of the knee or hip within a two-year period (p=0.04). High BL uCTX-II compared to low was associated with a 3.1 times higher risk of undergoing a TJR of the knee or hip during the study period (p=0.04), and an 8.9-fold increased risk of undergoing a knee replacement during the study period (p=0.02). TJR events over time in groups of high or low uCTX-II through the study are illustrated in figure 1. Conclusion High levels of sCTX-I and uCTX-II at BL were associated with increased risk of undergoing TJR of the knee or hip during the two year study. Our findings support the role of sCTX-I and uCTX-II as important biomarkers in clinical OA trials evaluating incidence of TJRs. Disclosure of Interests Jonathan Bjerre-Bastos Employee of: I am a full-time employee in Nordic Bioscience, Anne-Christine Bay-Jensen Shareholder of: I own shares of Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Morten Karsdal Shareholder of: I own shares of Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Inger Byrjalsen Employee of: I am a full-time employee in Nordic Bioscience, Jeppe Ragnar Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Bente Juel Riis Shareholder of: Yes, I own shares in Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Claus Christiansen Shareholder of: Yes, I own shares in Nordic Bioscience, Employee of: I am a full-time employee in Nordic Bioscience, Asger Reinstrup Bihlet Shareholder of: Yes, I own shares in Nordic Bioscience., Employee of: I am a full-time employee in Nordic Bioscience

Background Excessive cartilage degradation is a known characteristic of osteoarthritis (OA). Biochemical markers, such as uCTX-II, have been shown to be associated with disease severity, yet the tissue origin of CTX-II has been disputed. This analysis investigates the association between OA knee joints at different radiographic stages and pain categories with levels of uCTX-II and biomarkers of bone resorption and formation. Methods Baseline data of two randomised clinical trials (NCT00486434 and NCT00704847) in patients with radiographic OA and presence of pain were analysed post hoc. A subgroup with available urine samples and evaluable radiographs for both knees (N = 1241) was analysed. Urine CTX-I, urine CTX-II and serum osteocalcin were analysed for associations with combined Kellgren-Lawrence (KL) scores, gender and pain for both knees to assess the contribution of joints at different stages. Results Pain, BMI, age, gender and KL grade were all significantly associated with uCTX-II. The association between pain and CTX-II appeared to be driven by weight-bearing pain. The level of uCTX-II incrementally increased with higher radiographic severity of each knee. Levels of bone markers CTX-I and osteocalcin were both significantly associated with BMI and gender, but neither were associated with radiographic severity. Biomarker levels between male or female groups of identical KL scores were found to be higher in females compared to males in some but not all KL score groups. Conclusions These results indicate that levels of uCTX-II are independently associated with radiographic severity of OA and pain intensity. CTX-II was associated with weight-bearing pain, but not non-weight-bearing pain, independent of co-variates. Bilateral OA knee joints appear to contribute to uCTX-II levels in an incremental manner according to radiographic severity of single joints. The data suggest that biomarker differences between genders should be taken into account when evaluating these markers in the context of structural features of OA.

Abaloparatide is a 34-amino acid peptide that selectively binds to the RG conformation of the parathyroid hormone receptor type 1. It was developed for the treatment of women with postmenopausal osteoporosis at high risk of fracture. In ACTIVE, an 18-month phase 3 study (NCT01343004), abaloparatide increased bone mineral density (BMD), decreased the risk of vertebral and nonvertebral fractures compared with placebo, and decreased the risk of major osteoporotic fractures compared with placebo and teriparatide. Here, we report a prospective, exploratory BMD responder analysis from ACTIVE.Proportions of patients experiencing BMD gains from baseline of0%,3%, and6% at the total hip, femoral neck, and lumbar spine at 6, 12, and 18 months of treatment were compared among the placebo, abaloparatide, and teriparatide groups in ACTIVE. Responders were defined prospectively as patients experiencing BMD gains at all 3 anatomic sites.At months 6, 12, and 18, there were significantly more3% BMD responders in the abaloparatide group compared with placebo and teriparatide: month 6, 19.1% vs 0.9% for placebo and 6.5% for teriparatide; month 12, 33.2% vs 1.5% and 19.8%; month 18, 44.5% vs 1.9% and 32.0% (P 0.001 for all comparisons of abaloparatide to placebo and to teriparatide). Findings were similar for the0% and6% responder thresholds.In postmenopausal women with osteoporosis, a significantly greater proportion of patients treated with abaloparatide experienced increases in BMD than did those treated with placebo or teriparatide.

Background Osteoarthritis (OA) is a heterogeneous disease described by a combination of joint pain, physical disability and radiographic alterations leading to joint failure and total joint replacement (TJR). Commonly used endpoints in OA trials are worsening of pain and joint space narrowing. TJR is normally not considered an endpoint. Age and female gender are considered as major risk factors for developing OA. Objectives We hypothesise that TJR can be used as an endpoint in OA outcome studies within reasonable time frame. To investigate the basis for this hypothesis, we explored the prevalence and incidence of TJR as a reflection of joint failure in the Prospective Epidemiologic Risk Factor (PERF I) study. Methods A total of 5,855 Danish postmenopausal women aged 49–88 enrolled in the Prospective Epidemiologic Risk Factor (PERF I) study during 1999–2001 (baseline). Three, six and twelve year follow-up data from the Danish National registry was collected in end of 2014, including occurrence of TJR, OA and other relevant diagnosis. Also, women where at baseline and in 2014 asked whether they had a TJR or OA. The biomarker C1M was measured in baseline serum samples. The PERF I study was carried out in accordance with ICH-GCP and the study protocol was approved by the local ethics committees. Results There were 798 women that had their first TJR between baseline and 12 year follow-up; giving an incidence proportion of 13.6%. The TJR women were on average 1 year older (p=0.010) and heavier (1.7 kg/cm2, p 40 ng/mL, median) that after baseline underwent there first ever TJR (841). Group 1 is as described above. The 3, 6 and 12 incidence rates were 9.0, 17.3% and 29.7% for the prior TJR group, 6.2, 12.1% and 23.3% for the OA group, and 7.6, 13.6% and 25.1% for the OA +C1M group. The age-dependent prevalence and incidence for the first TJR. The prevalence was insignificant for the age group younger than 60 years old ( Conclusions Within a timeframe of 3, 6 or 12 years TJR incidence for women with an OA diagnosis reached 6, 12% and 23%, which was a doubling compared to the All population. The incidence increased by adding a single diagnostic measure. This reflects that TJRs are frequent amongst elderly women and that if designed minutiously, such as including specific diagnostic criteria (e.g. biomarker, OA diagnose), it may be feasible to conduct clinical studies with TJR as an endpoint. However, special attention much be directed to the objectiveness of the criteria for TJR. This may build a case for design of outcome studies (joint failure) for developing drugs in OA. Disclosure of Interest A. Bay-Jensen Shareholder of: Nordic Bioscience, Grant/research support from: ApproacH (IMI support), Employee of: Nordic Bioscience, C. Bager Employee of: Proscion, A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, C. Thudium Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, H. Nielsen Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, B. Riis Shareholder of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Grant/research support from: ApproacH (IMI support), Employee of: Nordic Bioscience

Pain is the principal clinical symptom of osteoarthritis (OA), and development of safe and effective analgesics for OA pain is needed. Drug development of new analgesics for OA pain is impaired by substantial change in pain in patients receiving placebo, and more data describing clinical characteristics and pain categories particularly associated with this phenomenon is needed. The purpose of this post-hoc analysis was to investigate clinical characteristics and pain categories and their association with radiographic progression and placebo pain reduction (PPR) in OA patients as measured the Western Ontario and McMasters Arthritis (WOMAC). Pooled data from the placebo groups of two phase III randomized clinical trials in patients with knee OA followed for 2 years were analyzed. Differences between individual sub-scores and pain categories of weight-bearing and non-weight bearing pain over time were assessed. Selected patient baseline characteristics were assessed for association with PPR. Association between pain categories and radiographic progression was analyzed. The reduction of pain in placebo-treated patients was significantly higher in the composite of questions related to weight-bearing pain compared to non-weight-bearing pain of the target knee. Baseline BMI, age and JSW were not associated with pain change. Pain reduction was higher in the Target knee, compared to the Non-Target knee at all corresponding time-points. A very weak correlation was found between weight-bearing pain and progression in the non-target knee. These results indicate that the reduction in pain in patients treated with placebo is significantly different between pain categories, as weight-bearing pain was significantly more reduced compared to non-weight-bearing pain. Further research in pain categories in OA is warranted. NCT00486434 (trial 1) and NCT00704847 (trial 2)

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.

Background There are two major needs in clinical development of DMOADs: 1) Identifying a suitable population with an active and progressive disease in order to demonstrate significant improvements by an efficacious intervention; and 2) Phenotyping patients and linking them to a corresponding treatment mode-of-action (e.g. anti-inflammatory). The biochemical marker CRPM is a neoepitope of C-reactive protein (CRP) and is released from the local inflamed tissue when CRP is degraded by proteases such as matrix metalloproteinases Objectives The purpose of this study was to translate the CRPM, from rheumatoid arthritis (RA), where it has been extensively tested, to OA, and to test whether it is predictive of radiographic OA. Methods The placebo arms of two phase III OA trial (clinicaltrial.gov: NCT00486434 and NCT00704847), a phase III RA study (the LITHE study, N=490), which included patients with active, moderate-severe RA (NCT00106535), as well as in an early RA cohort (N=92) were used. Subjects with symptomatic and radiographic knee OA: WOMAC pain ≥150mm and/or WOMAC function ≥510mm, and Kellgren-Lawrence grade (KLG) 2 or 3. KLG were scored for both knees at baseline and year 2 (Y2). Serum CRPM and hsCRP were measured at baseline. The association between serum CRPM levels and disease activity score (DAS28) and hsCRP was investigated by Spearman9s correlations. Quartile ranges of CRPM in the early RA cohort were used to define the cut-off between inflammatory OA and non-inflammatory OA. OA knees were divided into cases and controls based on a terminology proposed by the FNIH-OAI consortium (1); knees with KLG≥2 at BL were excluded, and incidence OA at Y2 was defined KLG≥2. Logistic regression was used to compare cases and controls. Results There was a significant correlation between disease activity measures and CRPM in both RA studies. Seventy-five percent of the LITHE patients had high or very high levels of CRPM at BL, which was changed to a pattern similar to early RA after treatment. The mean CRPM levels were significantly lower in OA (8.5 [95% CI 8.3–8.8] ng/mL) compared to the RA patients (15.6 [9.5–21.6] ng/mL); however, a significant subset of OA patients (41% and 31% in SMC2301 and SMC2302) had CRPM levels ≥9ng/mL, as 75% of patients with early RA. Patients with BL or Y2 CRPM levels ≥9ng/mL were more likely to develop knee OA than patients with low level of CRPM. Overall, moderate to very high levels of CRPM at BL and Y2 were predictive of incidence OA with odds ratio of 4.6 [1.2–17] and 2.5 [1.2–4.8]. Conclusions A subset of OA patients, up to 41%, appear to have tissue inflammation comparable to that of RA, reflected by the level of CRPM. Furthermore, high CRPM levels was prognostic of incident knee OA. These data suggest that CRPM is blood-based biochemical marker for finding OA patients with an inflammatory phenotype. References Longitudinal validation of periarticular bone area and 3D shape as biomarkers for knee OA progression? Data from the FNIH OA Biomarkers Consortium.Hunter D et al.Ann Rheum Dis. 2016 Sep;75(9):1607–14. Disclosure of Interest A. Bay-Jensen Shareholder of: Nordic Bioscience, Grant/research support from: DBOARD, Employee of: Nordic Bioscience, A. Bihlet Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Byrjalsen Employee of: Nordic Bioscience, J. Andersen Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, Y. He Employee of: Nordic Bioscience, A. S. Siebuhr Employee of: Nordic Bioscience, C. Thudium Employee of: Nordic Bioscience, B. Riis Shareholder of: Nordic Bioscience, C. Christiansen Shareholder of: Nordic Bioscience, M. Karsdal Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience

The treatment of type 2 diabetes with full peroxisome proliferator-activated receptor gamma (PPARγ) agonists improves insulin sensitivity, but is associated with weight gain, heart failure, peripheral oedema and bone loss. Endotrophin, the C-terminal fragment of the α3 chain of procollagen type VI (also called Pro-C6), is involved in both adipose tissue matrix remodelling and metabolic control. We established a serum assay for endotrophin to assess if this novel adipokine could identify type 2 diabetic patients who respond optimally to PPARγ agonists, improving the risk-to-benefit ratio. The BALLET trial (NCT00515632) compared the glucose-lowering effects and safety of the partial PPARγ agonist balaglitazone with those of pioglitazone in individuals with type 2 diabetes on stable insulin therapy. The per protocol population (n = 297) was stratified into tertiles based on baseline endotrophin levels. Participants were followed-up after 26 weeks, after which correlational analysis was carried out between endotrophin levels and measures of glucose control. This is a secondary post hoc analysis. Endotrophin was significantly associated with therapeutic response to balaglitazone and pioglitazone. At week 26, only individuals in the upper two tertiles showed significant reductions in HbA1c and fasting serum glucose compared with baseline. The OR for a 1% and a 0.5% reduction in HbA1c for individuals in the upper two tertiles were 3.83 (95% CI 1.62, 9.04) p

SummaryIntroductionIn a double-blind, placebo-controlled trial (EudraCT identifier: 2006-001795-20), the standardised quality (SQ) house dust mite (HDM) sublingual immunotherapy (SLIT)-tablet (ALK, Denmark) was investigated.MethodThe trial included 604 subjects, ≥14 years, with mild-moderate HDM allergic asthma. Subjects were randomised 1:1:1:1 to 1, 3 or 6 SQ-HDM or placebo once daily. The primary endpoint was reduction in inhaled corticosteroid (ICS) after one year. ICS reduction, asthma quality of life questionnaire (AQLQ) and asthma control questionnaire (ACQ) score was analysed post hoc in a subgroup with daily ICS use of 400–800 μg and ACQ score of 1–1.5, corresponding to partly controlled asthma (N = 108).ResultsThe trial met its primary endpoint. In the subgroup, the difference between placebo and 6 SQ-HDM in change from baseline in daily ICS use was 327 μg (p

Background: The SQ house dust mite (HDM) SLIT-tablet (ACARIZAX, ALK) was shown to improve asthma control, by a clinically significant risk reduction for an asthma exacerbation during ICS reduction, in a phase III trial (EudraCT 2010-018621-19). The treatment has a safety and tolerability profile acceptable for home administration. Post hoc subjects were grouped according to GINA treatment step at enrolment, to investigate efficacy in the subpopulations. Methods: The trial included 834 subjects with HDM allergic asthma (AA) >1 year and positive tests of HDM sensitisation (SPT and IgE), randomised 1:1:1 to placebo, 6 or 12 SQ-HDM/day for up to 18 months. Subjects with FEV 1 1) on GINA treatment step 2-4. Prior to randomisation subjects were switched to budesonide and SABA only. GINA treatment step was assessed based on reported medication use at enrolment. The interaction between treatment groups and GINA step was analysed by a Cox regression. Results: There were no significant interactions of GINA treatment step for asthma exacerbation (p=0.44), daytime asthma symptoms (p=0.80) or nocturnal asthma symptoms (p=0.51). Conclusions: Treatment was efficacious in subjects with HDM AA that was not well-controlled on GINA treatment steps 2-4 at enrolment.

To assess the efficacy and safety of 18 months of subcutaneous abaloparatide (ABL-SC) or placebo (PBO) followed by 6 months of alendronate (ALN) (preplanned interim analysis).ACTIVExtend, an extension of ACTIVE, enrolled patients who completed 18 months of ABL-SC or PBO in ACTIVE to receive up to 24 additional months of open-label ALN; there was 1 month between the studies to re-consent patients.Of 1243 eligible ACTIVE patients, 1139 (92%) were enrolled in ACTIVExtend beginning November 20, 2012. These results are from a prespecified 6-month interim analysis (cutoff date, June 2, 2015); the study is ongoing. Findings indicated percentages of patients with new morphometric vertebral fractures: PBO/ALN, 4.4% vs ABL-SC/ALN, 0.55%; relative risk reduction, 87% (relative risk, 0.13; 95% CI, 0.04-0.41; P.001). Kaplan-Meier estimated rates of nonvertebral fractures were PBO/ALN, 5.6% vs ABL-SC/ALN, 2.7%; risk reduction, 52% (hazard ratio [HR], 0.48; 95% CI, 0.26-0.89; log-rank P=.02). There was also a 58% risk reduction of major osteoporotic fractures (HR, 0.42; 95% CI, 0.21-0.85; log-rank P=.01) and a 45% risk reduction of clinical fractures (HR, 0.55; 95% CI, 0.33-0.92; log-rank P=.02) in the ABL-SC/ALN group vs the PBO/ALN group. At 25 months, bone mineral density percentage change from ACTIVE baseline for ABL-SC/ALN vs PBO/ALN was as follows: lumbar spine, 12.8%; total hip, 5.5%; femoral neck, 4.5% vs 3.5%, 1.4%, 0.5%, respectively (group differences at all sites P.001).Use of ABL-SC for 18 months followed by ALN for 6 months improved bone mineral density and reduced fracture risk throughout the skeleton and may be an effective treatment option for postmenopausal women with osteoporosis.clinicaltrials.gov Identifier: NCT01657162.

Importance The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy–related asthma. Objectives To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticosteroid (ICS) reduction period. Design, Settings, and Participants Double-blind, randomized, placebo-controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy–related asthma not well controlled by ICS or combination products, and with HDM allergy–related rhinitis. Key exclusion criteria were FEV 1 less than 70% of predicted value or hospitalization due to asthma within 3 months before randomization. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and then completely withdrawn for 3 months. Interventions 1:1:1 randomization to once-daily treatment with placebo (n = 277) or HDM SLIT tablet (dosage groups: 6 SQ-HDM [n = 275] or 12 SQ-HDM [n = 282]) in addition to ICS and the short-acting β 2 -agonist salbutamol. Main Outcomes and Measures Primary outcome was time to first moderate or severe asthma exacerbation during the ICS reduction period. Secondary outcomes were deterioration in asthma symptoms, change in allergen-specific immunoglobulin G4 (IgG4), change in asthma control or asthma quality-of-life questionnaires, and adverse events. Results Among 834 randomized patients (mean age, 33 years [range, 17-83]; women, 48%), 693 completed the study. The 6 SQ-HDM and 12 SQ-HDM doses both significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo (hazard ratio [HR]: 0.72 [95% CI, 0.52-0.99] for the 6 SQ-HDM group, P = .045, and 0.69 [95% CI, 0.50-0.96] for the 12 SQ-HDM group, P = .03). The absolute risk differences based on the observed data (full analysis set) in the active groups vs the placebo group were 0.09 (95% CI, 0.01-0.15) for the 6 SQ-HDM group and 0.10 (95% CI, 0.02-0.16) for the 12 SQ-HDM group. There was no significant difference between the 2 active groups. Compared with placebo, there was a reduced risk of an exacerbation with deterioration in asthma symptoms (HR, 0.72 [95% CI, 0.49-1.02] for the 6 SQ-HDM group, P = .11, and 0.64 [95% CI, 0.42-0.96] for the 12 SQ-HDM group, P = .03) and a significant increase in allergen-specific IgG4. However, there was no significant difference for change in asthma control questionnaire or asthma quality-of-life questionnaire for either dose. There were no reports of severe systemic allergic reactions. The most frequent adverse events were mild to moderate oral pruritus (13% for the 6 SQ-HDM group, 20% for the 12 SQ-HDM group, and 3% for the placebo group), mouth edema, and throat irritation. Conclusions and Relevance Among adults with HDM allergy–related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate or severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6 months of 9 to 10 percentage points; the reduction was primarily due to an effect on moderate exacerbations. Treatment-related adverse events were common at both active doses. Further studies are needed to assess long-term efficacy and safety. Trial Registration clinicaltrialsregister.eu Identifier:2010-018621-19.

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.

Vertebral osteoporosis, a common disorder in elderly women, is characterized by a wide spectrum of bone turnover abnormalities on iliac crest biopsy. The level of bone formation can be assessed noninvasively by measuring serum osteocalcin, whereas conventional biochemical markers of bone resorption lack specificity and do not reflect bone resorption assessed from histology. We measured the urinary excretion of pyridinoline crosslinks Pyr and D-Pyr, a specific marker of bone and cartilage collagen degradation, along with serum osteocalcin and urinary hydroxyproline, in 36 elderly women with vertebral osteoporosis who had a simultaneous iliac crest biopsy. Urinary pyridinoline crosslinks, but not hydroxyproline, correlated significantly with histologic resorption, assessed by the osteoclast surface (r = 0.35, p less than 0.05 for Pyr; r = 0.46, p less than 0.01 for D-Pyr). In addition, Pyr and D-Pyr were correlated with the bone formation rate as well as serum osteocalcin, with correlation coefficients ranging from 0.69 to 0.80, p less than 0.0001. These data indicate that Pyr and D-Pyr are sensitive markers of bone turnover in elderly women with vertebral osteoporosis. The poor correlation between the level of urinary collagen crosslinks and histological assessment of bone resorption indicates the low sensitivity of iliac crest histomorphometry in the measurement of resorption rate of the skeleton.

We have studied bone turnover and bone status in 29 patients with hip fractures and compared them with normal subjects and patients with arthritis of the hip. Markers for bone formation, bone Gla protein, alkaline phosphatase and whole body retention of 99mTc-diphosphonate, and fasting urinary hydroxyproline, a marker for bone resorption, were all significantly higher in the hip fracture group than in the control group. The serum concentrations of 1,25-dihydroxyvitamin D were similar in the three groups, whereas the serum 25-hydroxyvitamin D concentration in the control group was higher than in the patient groups. The bone mineral content (BMC) measured in the distal forearm and the spine was lower than normal in the hip fracture group. We conclude that patients with hip fractures have an increased bone turnover with no signs of bimodality and low BMC values at all locations.

The aim of this study was to assess the bioavailability and pharmacodynamic efficacy of synthetic salmon calcitonin (ssCT) and recombinant salmon calcitonin (rsCT) in healthy postmenopausal women. The study was a single-blind, randomized study. Participants were 36 postmenopausal women 62 to 74 years old, randomly assigned to a comparison of dosing with ssCT (n = 12) or rsCT (n = 24) given in the morning at 08:00. Study parameters were plasma CT levels measured up to 2 hours postdose and changes in the bone resorption marker serum CTX-I and the cartilage degradation marker urine CTX-II measured up to 4 hours postdose. For both formulations, peak plasma concentrations were obtained 15 minutes after dosage, and no statistically significant differences in the uptake of CT were observed. Measurement of bone resorption and cartilage degradation markers displayed comparable responses, with AUCs of relative change of serum CTX-I of -250% x hours and relative change of urine CTX-II of -180% x hours during the 4-hour observation period. In conclusion, oral synthetic and recombinant calcitonin displayed comparable pharmacodynamic and kinetic properties.

The promutagenic DNA modification 8-oxo-7,8-dihydrodeoxyguanosine is the most frequently used marker for oxidative stress to DNA. The unmodified base and nucleoside and the 8-hydroxylated guanine base and nucleoside are found in urine, the latter used as a global measure of oxidative stress to DNA. Nucleotide excision repair (NER) excises a 27- to 29-mer oligonucleotide with oxidative lesions, and if found in urine, it could be used as a measure of DNA repair in vivo. Enzymatic hydrolysis of human urines followed by HPLC–tandem mass spectrometry was not able to reveal oligonucleotides and/or mononucleotides with the 8-oxo-7,8-dihydrodeoxyguanosine modification. The recovery of a synthetic oligonucleotide with the modification was complete (95% confidence limits: 98–124%). These experiments show that oligonucleotides are excreted into urine, but that 8-oxo-7,8-dihydrodeoxyguanosine is found only as the mononucleoside and is not present in any significant amounts in oligonucleotides. We conclude that oligonucleotides are excreted into urine, and they do not contain oxidized lesions. Either NER products are degraded after excision or NER functions differently in vivo in humans compared with cellular systems.

Objective: Levormeloxifene is a selective estrogen receptor modulator (SERM). The development of the drug was discontinued due to intolerable adverse effects. This paper follow-up on the adverse events in a group of 234 women that was followed for 12 months without treatment after 12 months of treatment with levormeloxifene. Methods: Adverse events were recorded at all clinical visits. The double-layer thickness of the uterine endometrium was determined by transvaginal ultrasonography. Endometrial biopsies were obtained by pipelle. The biopsies taken at the entrance to the follow-up phase were taken under hysteroscopy-guidance. Bone mineral density of the total body, lumbar spine (L1–L4), hip and forearm was measured by dual-energy X-ray absorptiometry. Results: The most prominent adverse event was increased endometrial thickness over the pre-defined threshold of 8 mm. No cases of proliferative endometrium were reported. Following withdrawal of treatment the mean endometrial thickness approached baseline levels in a dose dependent manner. Hysteroscopic examinations showed that levormeloxifene was related to increased incidence of edema, vascularization and cysticity. In the levormeloxifene groups, a total of eight women had utero-vaginal prolapse and five women reported urinary incontinence (including worsening of a previously existing condition). Bone density in the spine and hip approached baseline levels during the 12 months of follow-up without treatment. Conclusion: Endometrial thickening, seen in association with the use of some SERM's, may lead to harmful adverse effects more than 12 months after treatment is initiated. Levormeloxifene prevents the postmenopausal bone loss, but the lowest effective dose is unknown.

This article is focused on the use of norethisterone acetate as progestogen in hormone replacement therapy. Emphasis is made on the fact that the primary reason for adding a progestogen to hormone replacement therapy is to protect the endometrium against hyperplasia. In this paper we review data that demonstrate that hormone replacement therapy that includes norethisterone acetate has positive effects on the postmenopausal bone metabolism and that it increases bone mass more than expected and more than treatment with alendronate. All available evidence is reviewed to show that norethisterone acetate, if given in the correct dosage, does not influence serum lipids and lipoproteins in any negative way. It is furthermore shown that norethisterone acetate seems to be superior compared to other progestogens to provide optimum bleeding control and endometrial protection. Also, hormone replacement therapy combinations with norethisterone acetate efficiently alleviate hot flushes. Hormone replacement therapy and the risk of breast cancer and the role of progestogens are discussed.

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.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.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% (P0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety.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.

Three hundred and one healthy women between 45 and 65 yr of age and at least 1 yr postmenopausal were randomly assigned to 12-month double-blind therapy with levormeloxifene [1.25 (n = 51), 5, 10, or 20 mg/day], low dose continuous combined hormone replacement therapy [HRT; 1 mg 17 beta-estradiol and 0.5 mg norethisterone acetate/day], or placebo (all n = 50). All of the women were also given a daily supplement of calcium (500 mg). Serum CrossLaps decreased by about 50% in the levormeloxifene groups, with no dose-response effect. The group receiving HRT decreased more (>60%), and the placebo group (500 mg calcium alone) decreased by about 10%. The pattern was similar for bone alkaline phosphatase, except that the decreases were smaller, about 30% for the levormeloxifene groups and 50% for the HRT group. Serum osteocalcin also showed highly significant decreases, of the same magnitude in the levormeloxifene and HRT groups. Spinal bone mineral density (BMD) decreased by less than 1% in the placebo group and increased by about 2% in the levormeloxifene groups and by almost 5% in the HRT group (P < 0.001 for the difference between levormeloxifene and HRT vs. placebo). BMD of the total hip and total body changed in the same direction, although differences between groups were not as pronounced as those for BMD spine. Total cholesterol decreased by about 13--20% during levormeloxifene therapy, whereas daily doses of 1 mg estradiol and 0.5 mg norethisterone acetate produced a decrease of only about 8%. Levormeloxifene decreased low density lipoprotein cholesterol by about 22-30% compared with about 12% in the low dose HRT group. High density lipoprotein cholesterol was unchanged in all groups. Endometrial thickness increased both clinically and statistically significantly in the levormeloxifene groups independently of the dose; the difference from the placebo and HRT groups was significant (P < 0.001). There was no significant difference between the HRT and placebo groups. Other adverse events of interest include hot flushes, which did not occur more frequently in the levormeloxifene than the placebo groups, but occurred significantly less frequently in the HRT group (P < 0.05). Breast tenderness was much more common in the HRT group (

Sodium fluoride stimulates bone formation and has been used to treat osteoporosis for decades despite debate about the antifracture efficacy. Hormone replacement therapy (HRT) results in only modest increases in bone mineral density (BMD). However, for women with low bone mass, the ideal therapy should not only inhibit bone resorption but simultaneously stimulate bone formation to increase bone mass above the fracture threshold. We thus performed a randomized, double-blind, placebo-controlled intervention study to prospectively investigate the effect of a low dose of fluoride, in combination with HRT, on BMD and biochemical markers of bone turnover. One hundred healthy postmenopausal women (60-70 yr old) were thus randomly assigned to: 1) HRT [transdermal 17beta-estradiol, releasing 50 microg/day; plus oral norethisterone acetate (NETA), 1 mg/day]; or 2) oral monofluorophosphate (MFP; equivalent to fluoride, 20 mg/day); or 3) HRT+MFP; or 4) placebo, for 96 weeks. All participants received a calcium supplement of 1000 mg/day. Sixty-eight women completed the study. We found a pronounced, linear increase in spinal BMD during treatment with HRT+MFP [11.8% (1.7% SEM)], which was significantly greater than the increase in the HRT group [4.0% (0.5% per yr); P < 0.05]. MFP produced a smaller increase [2.4% (0.6% per yr)], whereas there was no change in the placebo group [0.0% (0.5% SEM)]. Similar changes were found at the other skeletal sites (distal forearm, hip, and total body). Markers of bone formation showed a fall in the HRT group, which was significantly more pronounced than in the combined HRT+MFP group. A nonsignificant increase was found in the MFP group, whereas the placebo group showed a decrease caused by calcium treatment. The marker of bone resorption decreased significantly more in the HRT and the HRT+MFP groups than in the placebo group but tended to increase in the MFP group. In conclusion, this study shows, by use of biochemical markers of bone turnover, that bone resorption and formation may be dissociated, as a result of actions of two compounds with diverging effects on bone turnover. Furthermore, the synergistic effects of relatively low doses of the compounds suggested statistically and clinically significant increases in trabecular and probably also cortical bone. Adverse effects were relatively rare and mild.

Introduction L’asthme severe est une contre-indication generale a l’utilisation de l’immunotherapie. Nous avons etudie l’effet du comprime d’immunotherapie sublinguale (ITSL) SQ-HDM (ALK, Danemark) chez des sujets souffrant d’asthme allergique aux acariens (AAA). Methodes L’essai randomise en double insu versus placebo (EudraCT 2010-018621-19) a inclus 834 sujets de 13 pays europeens ayant un AAA depuis plus d’un an, des tests de sensibilisation aux acariens positifs et un asthme mal controle (score ACQ > 1) par corticosteroides inhales (CSI ; budesonide 400-1200 μg ou equivalent). Les sujets ont ete randomises 1:1:1 pour recevoir un placebo ou le comprime dose a 6 ou 12 SQ quotidiennement jusqu’a 18 mois. Apres 7 a 12 mois de traitement, les CSI ont ete reduits de 50 % pendant 3 mois, puis de 100 % les 3 derniers mois. Resultats Selon les criteres GINA, 28 % des sujets n’etaient pas controles et 72 % l’etaient partiellement a la randomisation (ils etaient egalement repartis entre les groupes de traitement). Aucun probleme de tolerance n’a ete observe. A la randomisation, tous les sujets avaient un VEMS ≥ 70 % mais au cours de l’essai 129 sujets ont eu au moins 1 fois un VEMS Conclusion Il s’agit du premier essai montrant une reduction cliniquement pertinente du risque d’exacerbation de l’asthme avec un comprime d’ITSL aux acariens SQ. Le traitement a ete bien tolere chez des sujets ayant un asthme allergique partiellement ou non controle (definitions GINA) et des valeurs occasionnelles de VEMS

We studied bone mineral content and density (BMC/BMD) and bone turnover markers in normal Chinese women from the age of 20 to 80 years and compared the data with those for normal women from the Western part of the world (Denmark). In all subjects (5 at each age;n=305) BMC and BMD were determined at three sites of the nondominant forearm with single X-ray absorptiometry (SXA). In addition, 10 women had five repeated measurements to determine the reproducibility of the equipment, demonstrating coefficients of variation of 1%–2% depending on the measurement site. The Chinese premenopausal women were on the average heavier (1 kg) than the postmenopausal women, but they were also taller (6 cm). The postmenopausal women had highly significantly less bone mass than the premenopausal women; 15% at the 1/4-distal site, 25% at the 8-mm-distal site, and 35% at the ultradistal site. At age 50, bone mass in Chinese women was very similar to that of a comparable group of Danish women. After age 50, bone loss accelerated and the rate of loss seemed more rapid in the Chinese than in the Danish women. Within the first 5 postmenopausal years, the most cortical part decreased by approximately 3.9%, the mixed cortical and trabecular site by 9.5%, and the mainly trabecular site by 16.2%. In the following 5 years the decreases were 6.3%, 5.5%, and 6.6%, respectively, and 5.6%, 11.3%, and 8.9% for year 11–15 after menopause. The bone decrement continued throughout the 25th year of menopause, and except for the ultradistal site, the rate of loss did not change very much. The postmenopausal women had highly significantly higher levels of all bone turnover markers than premenopausal women. The markers stayed high at all ages. We conclude that the present study gives the normal values of Chinese women's bone mass at three sites of the distal forearm. The data were collected in a way which allows them to be used as reference for normal Chinese women. The data demonstrate that women from the East and West are relatively similar in terms of bone mass.

The aim of the study was to examine the role of peak bone mass and rate of postmenopausal bone loss for the subsequent risk of osteoporotic fracture. 182 women within 3 years of menopause were followed longitudinally for 15 years. Over the first 2 years, forearm bone mass (single photon absorptiometry) was measured nine times, the rate of bone loss was calculated, and the women were stratified into a group of "fast bone losers" (n = 49) and a group of "normal bone losers" (n = 133). Later, bone mass was also measured in the lumbar spine and hip with dual energy X-ray absorptiometry. At 15 years, the fast losers had significantly lower body weight (4.4 kG; p < 0.05) than the normal losers. Furthermore, the fast losers had significantly increased values of bone turnover (osteocalcin and C-terminal type I collagen breakdown products). In both the forearm, spine, and hip, the fast bone losers had at all sites significantly less bone mass than the normal bone losers (p < 0.001). 23 women had experienced a peripheral (Colles') fracture and 25 a spinal fracture. The fracture groups had generally significantly (p < 0.05) less bone mass than the group without fracture, both in the forearm, spine, and hip and they also had the highest rate of bone loss after menopause (p < 0.05). Baseline bone mass and rate of loss predisposed to the same extent to fractures with ODD's ratios of about 2. If both low bone mass and rate of loss were present, the ODD's ratio increased to about 3. We conclude that fast rate of bone loss and low bone mass are equally important for the risk of fracture. The identification of women at risk of osteoporosis should therefore consider both a measurement of bone mass status, and a determination of the postmenopausal rate of loss.

Importance Additional therapies are needed for prevention of osteoporotic fractures. Abaloparatide is a selective activator of the parathyroid hormone type 1 receptor. Objective To determine the efficacy and safety of abaloparatide, 80 μg, vs placebo for prevention of new vertebral fracture in postmenopausal women at risk of osteoporotic fracture. Design, Setting, and Participants The Abaloparatide Comparator Trial In Vertebral Endpoints (ACTIVE) was a phase 3, double-blind, RCT (March 2011-October 2014) at 28 sites in 10 countries. Postmenopausal women with bone mineral density (BMD) T score ≤−2.5 and >−5.0 at the lumbar spine or femoral neck and radiological evidence ≥2 mild or ≥1 moderate lumbar or thoracic vertebral fracture or history of low-trauma nonvertebral fracture within the past 5 years were eligible. Postmenopausal women (>65 y) with fracture criteria and a T score ≤−2.0 and >−5.0 or without fracture criteria and a T score ≤−3.0 and >−5.0 could enroll. Interventions Blinded, daily subcutaneous injections of placebo (n = 821); abaloparatide, 80 μg (n = 824); or open-label teriparatide, 20 μg (n = 818) for 18 months. Main Outcomes and Measures Primary end point was percentage of participants with new vertebral fracture in the abaloparatide vs placebo groups. Sample size was set to detect a 4% difference (57% risk reduction) between treatment groups. Secondary end points included change in BMD at total hip, femoral neck, and lumbar spine in abaloparatide-treated vs placebo participants and time to first incident nonvertebral fracture. Hypercalcemia was a prespecified safety end point in abaloparatide-treated vs teriparatide participants. Results Among 2463 women (mean age, 69 years [range, 49-86]), 1901 completed the study. New morphometric vertebral fractures occurred in 0.58% (n = 4) of the abaloparatide group, 4.22% (n = 30) of the placebo group (risk difference [RD] vs placebo, −3.64 [95% CI, −5.42 to −2.10]; relative risk, 0.14 [95% CI, 0.05-0.39]; P P = .049), and 3.3% for teriparatide. BMD increases were greater with abaloparatide than with placebo (all P P = .006). Conclusions and Relevance Among postmenopausal women with osteoporosis, the use of subcutaneous abaloparatide, compared with placebo, reduced the risk of new vertebral and nonvertebral fractures over 18 months. Further research is needed to understand the clinical importance of RD, the risks and benefits of abaloparatide treatment, and the efficacy of abaloparatide vs other osteoporosis treatments. Trial Registration clinicaltrials.gov Identifier:NCT01343004

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 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 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. Guhring: None declared, C. Ladel: None declared, M. Michaelis: None declared, B. Riis Shareholder of: Nordic Bioscience, Employee of: Nordic Bioscience, I. Valter: None declared

An enzyme-linked immunosorbent immunoassay (ELISA) for a new marker of bone resorption (CrossLaps) was evaluated. The ELISA procedure determines degradation products of type I collagen in urine. Values obtained in the ELISA and in pyridinoline by high pressure liquid chromatography were correlated after a correction for creatinine. A high correlation was found (r = 0.77; n = 81). A group of postmenopausal women (n = 180) showed an increase of more than 70% compared to values in premenopausal women (n = 104). Hydroxyproline was increased by 23%, osteocalcin by 52%, pyridinoline by 31%, and deoxypyridinoline by 50%. A highly significant decrease (60.7%) in the CrossLaps values was seen after 12 months in samples from patients receiving hormone replacement therapy compared to a placebo group. The spontaneous bone loss in an untreated group of women was determined by repeated forearm bone mass measurement over 24 months. Baseline values obtained in the CrossLaps ELISA were correlated to the rate of loss, yielding a highly significant r value of -0.61, indicating that CrossLaps might be a useful parameter for assessment of the risk of osteoporosis in postmenopausal women.

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.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.24 weeks of randomized, double-blind treatment with once daily doses of 5mg oral treatment or corresponding placebo, or open-label subcutaneous teriparatide.Women diagnosed with postmenopausal osteoporosis as detected by lumbar spine DXA, with an exclusion of those with prior treatment with bone active agents.Orally formulated recombinant human PTH(1-31)NH(2) and placebo, or open-label subcutaneous teriparatide as a positive control.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)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.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 (p0.001), while no change was observed in the placebo arm. Open-label teriparatide resulted in a 5.1% increase in LS BMD (p0.001). 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.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.

The urinary excretion of pyridinolines either in the free form or linked to different peptide fragments of type I collagen are intensively studied as new biochemical markers of bone resorption. In the present study we compared the urinary excretion of free pyridinoline (F-Pyr) determined by enzyme-linked immunosorbent assay (ELISA) (Collagen Crosslinks Kit, Metra Biosystems) to pyridinoline (Pyr), and deoxypyridinoline (D-Pyr) determined by high performance liquid chromatography (HPLC) in early postmenopausal women treated with either hormone replacement therapy or placebo and in healthy age-matched premenopausal women. Other markers of bone metabolism were included for comparison. Compared with the premenopausal women, the postmenopausal women had significantly increased values of the biochemical parameters. F-Pyr, Pyr, D-Pyr, and T-Pyr (= Pyr + D-Pyr) decreased during hormone therapy. D-Pyr correlated with the rate of bone loss, whereas this was not the case for F-Pyr. The correlations between the markers yielded r values of 0.71 (F-Pyr vs Pyr), 0.67 (F-Pyr vs D-Pyr), and 0.71 (F-Pyr vs T-Pyr). In conclusion, the present study shows that the newly introduced ELISA for determination of the free pyridinolines is less sensitive than pyridinium crosslinks measured by high performance liquid chromatography (HPLC) in hydrolyzed urine for the changes in calcium metabolism that occur at menopause and during hormone replacement therapy. Whether this limitation will be balanced out by avoiding the inconvenience of the complicated, expensive, and time-consuming HPLC procedure is still being debated.

The aims of the study were to investigate interindividual variations in the bioavailability of salmon calcitonin (sCT) following single oral 0.8 mg doses at three different times of the day, and intraindividual variation in sCT bioavailability at each end of a 14-day treatment period. We also investigated correlations between exposure to sCT and levels of the bone resorption biomarker serum C-terminal telopeptide of collagen type I (CTX-I). Participants were from two randomized, double-blind, placebo-controlled studies. In study I, healthy postmenopausal women received a single dose of 0.8 mg of oral sCT or placebo at 08:00 (n = 42), 17:00 (n = 20), or at 22:00 (n = 19). In study II, age-matched men or postmenopausal women with osteoarthritis received 0.8 mg oral sCT (n = 26) or placebo (n = 23) twice daily for 14 days, with dosing at 08:00 and 17:00. In both studies, drug exposure was assessed by plasma sCT concentrations, and bone resorption by CTX-I levels. The variability in exposure between patients, measured as coefficient of variation (CV), was as follows: 22% for the morning dose, 30% for the predinner dose, and 34% for the evening dose. In study 1, a high degree of correlation was seen between the level of exposure following a single 0.8 mg dose of sCT and suppression of serum CTX-I, with Pearson correlation coefficients of r = −0.74, −0.96, and −0.78, following doses at 08:00, 17:00, and 22:00, respectively. In study II, exposure to sCT varied widely within the same individuals between dosing days 1 and 14, with weak correlations of r = 0.40 and 0.38 at the dose times 08:00 and 17:00, respectively. As expected from this finding, the intraindividual response in serum CTX-I levels was non-significantly associated on dosing days 1 and 14 (r = 0.34 and r = 0.27 at dose times 08:00 and 17:00, respectively). Increased bioavailability of orally administered 0.8 mg sCT was highly correlated with increased suppression of the bone resorption marker serum CTX-I irrespective of the time of day. However, the high inter- and intraindividual variability in sCT exposure demonstrates the importance of determining the optimum conditions for ensuring the most beneficial sCT uptake.

Bleeding and climacteric symptoms were recorded in two groups of postmenopausal women receiving either continuous combined estradiol and norethisterone acetate or estradiol and cyproterone acetate. Out of a sample of 99 postmenopausal women aged 45 to 54 years, 86 completed a 2-year, double-blind, placebo-controlled study. Comparison of the bleeding patterns in the two groups revealed a statistically significant difference: More women in the estradiol-cyproterone acetate group experienced bleeding and for a longer duration. Thirteen women in the estradiol-norethisterone acetate group were amenorrheic, compared with two in the other group. The Kupperman index score in both groups declined to about 30% to 40% of initial values (p less than 0.001). The hot flushes in both treatment groups decreased to a highly significant degree (p less than 0.001), to a value below 20% of baseline values. We conclude that a continuous combination of estrogen and progestogen can produce amenorrhea and symptomatic relief. However, the progestogen components seem to differ in their ability to control bleeding.

Progestogen treatment is associated with a number of subjective symptoms. In the present study, 148 healthy post-menopausal women suffering from mild climacteric symptoms were randomly allocated to 12 weeks of treatment with (a) 2 mg oestradiol valerate combined with cyproterone acetate, medroxyprogesterone acetate or levonorgestrel; (b) 1.5 mg 17 beta-oestradiol combined with desogestrel; or (c) placebo. Climacteric symptoms, Kupperman index scores and potential adverse progestogen effects were recorded before treatment and three times per month during therapy. All the hormone regimens had a rapid effect, reducing the severity of climacteric symptoms to about 30% of the baseline values (P less than 0.001) within one month. Hot flushes were reduced in severity and/or frequency by 76 100% within 3 months (P less than 0.001). The regimens which included hydroxyprogesterone derivatives produced a transient increase in breast tenderness. Other recorded potential adverse progestogen effects showed no significant changes during the study. We concluded that the addition of progestogens (whether 19-nortestosterone or hydroxyprogesterone derivatives) does not produce significant side effects during combined hormone replacement therapy.

We studied 20 healthy premenopausal women aged 36.5 +/- 4.0 years (mean +/- 1 SD), 123 healthy postmenopausal women aged 50.0 +/- 2.4 years, and 103 postmenopausal women aged 65.1 +/- 5.6 years with symptomatic osteoporosis (forearm and spinal fracture). Serum levels of vitamin D metabolites [25(OH)D, 24,25(OH)2D3, and 1,25-(OH)2D] were compared with (1) bone mass in the forearm (single photon absorptiometry) and in the spine (dual photon absorptiometry); (2) biochemical indices of bone formation (serum alkaline phosphatase, plasma bone Gla protein), and bone resorption (fasting urinary hydroxyproline); and (3) other biochemical estimates of calcium metabolism (serum calcium, serum phosphate, 24-hour urinary calcium, intestinal absorption of calcium). The present study revealed no difference in any of the vitamin D metabolites between the premenopausal women, the healthy postmenopausal women and the osteoporotic women as a group. The concentrations of 1,25(OH)2D and 25(OH)D were significantly lower in patients with spinal fracture than in those with forearm fracture. In the early postmenopausal women serum 1,25(OH)D was related to forearm bone mass (r = -0.20; P less than 0.05), intestinal calcium absorption (r = 0.18; P less than 0.05), and 24-hour urinary calcium (r = 0.21; P less than 0.05); serum 25(OH)D was related to spinal bone mass (r = 0.23; P less than 0.01). In the osteoporotic women, serum vitamin D metabolites were not related to bone mass, but 1,25(OH)2D was related to bone Gla protein (r = 0.33; P less than 0.001), serum phosphate (r = -0.27; P less than 0.01), and 24-hour urinary calcium (r = 0.43; P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Serum bone Gla protein (BGP), a sensitive and specific biochemical marker of bone formation, was measured in 66 children deficient in GH before and after 3, 6, 9, and 12 months of treatment with biosynthetic human GH. Initial serum BGP levels were significantly lower than those of normal age-matched children. After 3 months of treatment, the mean serum BGP level had increased to normal. There was no relation between baseline serum BGP and the growth response, but the GH-induced increment in serum BGP levels at 3 months was highly significantly related to growth response after 12 months of therapy. The study shows that serum BGP could be a helpful biochemical marker in prediction of the growth response to long term GH therapy.

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 Spearman9s 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 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

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 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. Guhring Employee of: Merck Serono, M. Michaelis Employee of: Merck Serono, C. Ladel Employee of: Merck Serono

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 Spearman9s 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 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

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 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

Mutations in the CSA and CSB genes cause Cockayne syndrome, a rare inherited disorder characterized by UV sensitivity, severe neurological abnormalities, and progeriod symptoms. Both gene products function in the transcription-coupled repair (TCR) subpathway of nucleotide excision repair (NER), providing the cell with a mechanism to remove transcription-blocking lesions from the transcribed strands of actively transcribed genes. Besides a function in TCR of NER lesions, a role of CSB in (transcription-coupled) repair of oxidative DNA damage has been suggested. In this study we used mouse models to compare the effect of a CSA or a CSB defect on oxidative DNA damage sensitivity at the levels of the cell and the intact organism. In contrast to CSB(-/-) mouse embryonic fibroblasts (MEFs), CSA(-/-) MEFs are not hypersensitive to gamma-ray or paraquat treatment. Similar results were obtained for keratinocytes. In contrast, both CSB(-/-) and CSA(-/-) embryonic stem cells show slight gamma-ray sensitivity. Finally, CSB(-/-) but not CSA(-/-) mice fed with food containing di(2-ethylhexyl)phthalate (causing elevated levels of oxidative DNA damage in the liver) show weight reduction. These findings not only uncover a clear difference in oxidative DNA damage sensitivity between CSA- and CSB-deficient cell lines and mice but also show that sensitivity to oxidative DNA damage is not a uniform characteristic of Cockayne syndrome. This difference in the DNA damage response between CSA- and CSB-deficient cells is unexpected, since until now no consistent differences between CSA and CSB patients have been reported. We suggest that the CSA and CSB proteins in part perform separate roles in different DNA damage response pathways.

Nasal sCT is a safe drug with few and mild side effects and compared with HRT is often more attractive to elderly, osteoporotic women. Under controlled conditions, nasal sCT reduces the rate of new fractures by two-thirds compared with calcium treatment alone [10] and increases spinal bone mass dose dependently.