Continuing versus tapering glucocorticoids after achievement of low disease activity or remission in rheumatoid arthritis (SEMIRA): a double-blind, multicentre, randomised controlled trial.

BACKGROUND: Patients with inflammatory diseases, such as rheumatoid arthritis, often receive glucocorticoids, but long-term use can produce adverse effects. Evidence from randomised controlled trials to guide tapering of oral glucocorticoids is scarce. We investigated a scheme for tapering oral glucocorticoids compared with continuing low-dose oral glucocorticoids in patients with rheumatoid arthritis. METHODS: The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial was a double-blind, multicentre, two parallel-arm, randomised controlled trial done at 39 centres from six countries (France, Germany, Italy, Russia, Serbia, and Tunisia). Adult patients with rheumatoid arthritis receiving tocilizumab and glucocorticoids 5-15 mg per day for 24 weeks or more were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had stable low disease activaity, confirmed by a Disease Activity Score for 28 joints-erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less 4-6 weeks before and on the day of randomisation. Patients were randomly assigned 1:1 to either continue masked prednisone 5 mg per day for 24 weeks or to taper masked prednisone reaching 0 mg per day at week 16. All patients received tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks) with or without csDMARDs maintained at stable doses during the entire 24-week study. The primary outcome was the difference in mean DAS28-ESR change from baseline to week 24, with a difference of more than 0·6 defined as clinically relevant between the continued-prednisone group and the tapered-prednisone group. The trial is registered with ClinicalTrials.gov, NCT02573012. FINDINGS: Between Oct 21, 2015, and June 9, 2017, 421 patients were screened and 259 (200 [77%] women and 59 [23%] men) were recruited onto the trial. In all 128 patients assigned to the continued-prednisone regimen, disease activity control was superior to that in all 131 patients assigned to the tapered-prednisone regimen; the estimated mean change in DAS28-ESR from baseline to week 24 was 0·54 (95% CI 0·35-0·73) with tapered prednisone and -0·08 (-0·27 to 0·12) with continued prednisone (difference 0·61 [0·35-0·88]; p<0·0001), favouring continuing prednisone 5 mg per day for 24 weeks. Treatment was regarded as successful (defined as low disease activity at week 24, plus absence of rheumatoid arthritis flare for 24 weeks and no confirmed adrenal insufficiency) in 99 (77%) patients in the continued-prednisone group versus 85 (65%) patients in the tapered-prednisone group (relative risk 0·83; 95% CI 0·71-0·97). Serious adverse events occurred in seven (5%) patients in the tapered-prednisone group and four (3%) patients in the continued-prednisone group; no patients had symptomatic adrenal insufficiency. INTERPRETATION: In patients who achieved low disease activity with tocilizumab and at least 24 weeks of glucocorticoid treatment, continuing glucocorticoids at 5 mg per day for 24 weeks provided safe and better disease control than tapering glucocorticoids, although two-thirds of patients were able to safely taper their glucocorticoid dose. FUNDING: F Hoffmann-La Roche.

Translating IL-6 biology into effective treatments.

In 1973, IL-6 was identified as a soluble factor that is secreted by T cells and is important for antibody production by B cells. Since its discovery more than 40 years ago, the IL-6 pathway has emerged as a pivotal pathway involved in immune regulation in health and dysregulation in many diseases. Targeting of the IL-6 pathway has led to innovative therapeutic approaches for various rheumatic diseases, such as rheumatoid arthritis, juvenile idiopathic arthritis, adult-onset Still's disease, giant cell arteritis and Takayasu arteritis, as well as other conditions such as Castleman disease and cytokine release syndrome. Targeting this pathway has also identified avenues for potential expansion into several other indications, such as uveitis, neuromyelitis optica and, most recently, COVID-19 pneumonia. To mark the tenth anniversary of anti-IL-6 receptor therapy worldwide, we discuss the history of research into IL-6 biology and the development of therapies that target IL-6 signalling, including the successes and challenges and with an emphasis on rheumatic diseases.

Comparative effectiveness of TNF inhibitors and tocilizumab with and without conventional synthetic disease-modifying antirheumatic drugs in a pan-European observational cohort of bio-naïve patients with rheumatoid arthritis.

OBJECTIVES: To compare treatment effectiveness in rheumatoid arthritis (RA) patients naïve to biological disease-modifying antirheumatic drugs (bDMARDs) treated with tocilizumab (TCZ) or TNF-inhibitor (TNFi) with (-combo) or without (-mono) conventional synthetic DMARDs (csDMARDs). METHODS: Patients with RA across 7 European registries, naïve to bDMARDs who initiated treatment with TCZ or TNFi from 2009 to 2016 were included. Drug retention rate was analyzed using Kaplan-Meier and Cox models, and CDAI over time by mixed models. The proportions of patients reaching CDAI low disease activity (LDA) and remission after one year were corrected for attrition. RESULTS: 6713 TNFi-combo, 3762 TNFi-mono, 646 TCZ-combo and 384 TCZ-mono were eligible. Crude median retention was 3.67 years (95%CI 3.41-3.83) for TNFi-combo, 4.14 (3.77-4.62) for TNFi-mono, 2.98 (2.76-3.34) for TCZ-combo and 3.63 years (3.34-5.03) for TCZ-mono. After adjustment for covariates, country and year of treatment initiation stratification, hazards of discontinuation were lower for TCZ-mono (0.60, 95% CI 0.52-0.69) and TCZ-combo (0.66, 95% CI 0.54-0.81) compared to TNFi-combo. Adjusted CDAI evolution was not significantly different between groups. CDAI LDA and remission corrected for attrition were similar between TCZ with or without csDMARDs and TNFi-combo. CONCLUSION: In routine care across 7 European countries, the adjusted drug retention, adjusted CDAI over time and attrition-corrected response proportion for RA patients were similar for bio-naïve patients if treated with TNFi-combo, TCZ-combo or TCZ-mono.

Visual Quality Guidance for Document Exploration with Focus+Context Techniques.

Magic lens based focus+context techniques are powerful means for exploring document spatializations. Typically, they only offer additional summarized or abstracted views on focused documents. As a consequence, users might miss important information that is either not shown in aggregated form or that never happens to get focused. In this work, we present the design process and user study results for improving a magic lens based document exploration approach with exemplary visual quality cues to guide users in steering the exploration and support them in interpreting the summarization results. We contribute a thorough analysis of potential sources of information loss involved in these techniques, which include the visual spatialization of text documents, user-steered exploration, and the visual summarization. With lessons learned from previous research, we highlight the various ways those information losses could hamper the exploration. Furthermore, we formally define measures for the aforementioned different types of information losses and bias. Finally, we present the visual cues to depict these quality measures that are seamlessly integrated into the exploration approach. These visual cues guide users during the exploration and reduce the risk of misinterpretation and accelerate insight generation. We conclude with the results of a controlled user study and discuss the benefits and challenges of integrating quality guidance in exploration techniques.

Discriminating phenotypic signatures identified for tocilizumab, adalimumab, and tofacitinib monotherapy and their combinations with methotrexate.

BACKGROUND: Clinical trials have shown combinations of anti-tumor necrosis factor biologicals plus methotrexate (MTX) are more effective treatments for rheumatoid arthritis than biological monotherapies, based, in part, on the assumption that MTX reduces the immunogenicity of biologicals. However, co-treatment with the anti-interleukin-6 receptor-alpha antibody tocilizumab (TCZ) and MTX does not demonstrate the same level of incremental benefit over TCZ monotherapy. Using the human primary cell based BioMAP phenotypic profiling platform, we investigated the impact of TCZ, adalimumab (ADA), and the small molecule drug tofacitinib (TOF), alone and in combination with MTX, on translational biomarkers that could indicate unique pharmacodynamic interactions outside those of reduced immunogenicity. METHODS: TCZ, ADA, and TOF, alone and in combination with MTX, were profiled in BioMAP systems at concentrations close to clinical exposure levels: TCZ, 200 µg/ml; TOF1, 1.1 µM; TOF2, 0.12 µM; MTX, 10 µM. Changes in biomarkers were evaluated by statistical methods to determine whether combinations differed from the individual agents. RESULTS: Although the BioMAP activity profile for TCZ + MTX was not significantly different from that for TCZ alone, profiles for ADA + MTX and TOF1 + MTX or TOF2 + MTX had a greater number of statistically significant different activities (P < 0.01) than did agents profiled individually. CONCLUSIONS: These data support the comparable efficacy of TCZ as monotherapy and as combination therapy and suggest that TOF, like ADA, may be more beneficial in combination with MTX. Taking an orthogonal approach to directly compare monotherapy and combination therapies indicates that MTX contributes to the efficacy of some, but not all, RA therapies and can be affected by factors additional to reduced immunogenicity.

From Early Radiographic Knee Osteoarthritis to Joint Arthroplasty: Determinants of Structural Progression and Symptoms.

OBJECTIVE: To assess structural progression in knees with no/mild radiographic osteoarthritis (OA) (i.e., Kellgren/Lawrence [K/L] grades 0-2) that will undergo knee replacement during a 5-year period; to assess differences in structural damage on magnetic resonance imaging (MRI) in knees with no/mild radiographic OA versus those with severe radiographic OA (i.e., K/L grades 3 and 4) at baseline; and to assess differences in pain levels between those groups. METHODS: All participants who underwent knee replacement from baseline to 60 months were drawn from the Osteoarthritis Initiative. MRIs were assessed for bone marrow lesions (BMLs), Hoffa synovitis, and effusion synovitis (i.e., hyperintensity signal changes in the fat pad and abnormal amount of capsular distension due to intraarticular joint fluid and/or synovial thickening) at baseline and at the time point before knee replacement (T0). The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Knee Injury and Osteoarthritis Outcome Score (KOOS) pain were used for pain characterization. WOMAC activities of daily living and KOOS quality of life were applied to characterize functional status of the included participants. Logistic regression was used to assess the association of no/mild radiographic OA with these MRI features and pain. RESULTS: Based on inclusion criteria, 181 knees were selected. Participants were predominantly female (57.8%) with a mean age of 64.4 years. A total of 51 knees (28.2%) had no/mild radiographic OA at baseline. Of these, 51.0% progressed to severe radiographic OA. No/mild radiographic OA knees showed higher odds of BMLs in the patellofemoral joint at baseline (odds ratio [OR] 7.92 [95% confidence interval (95% CI) 3.45-18.16]) and T0 (OR 9.44 [95% CI 4.00-22.28]) compared to severe radiographic OA knees. In addition, no/mild radiographic OA knees were associated with change from no pain to pain from baseline to T0 (adjusted OR 5.48 [95% CI 1.25-24.00]). CONCLUSION: More than half of the knees with no/mild radiographic OA before knee replacement progressed to severe radiographic OA during 4 years of follow-up. BMLs in the patellofemoral joint were more often seen among knees that had no/mild radiographic OA. Worsening pain status may contribute to knee replacement in knees with no/mild radiographic OA.

VA²: A Visual Analytics Approach for // Evaluating Visual Analytics Applications.

Evaluation has become a fundamental part of visualization research and researchers have employed many approaches from the field of human-computer interaction like measures of task performance, thinking aloud protocols, and analysis of interaction logs. Recently, eye tracking has also become popular to analyze visual strategies of users in this context. This has added another modality and more data, which requires special visualization techniques to analyze this data. However, only few approaches exist that aim at an integrated analysis of multiple concurrent evaluation procedures. The variety, complexity, and sheer amount of such coupled multi-source data streams require a visual analytics approach. Our approach provides a highly interactive visualization environment to display and analyze thinking aloud, interaction, and eye movement data in close relation. Automatic pattern finding algorithms allow an efficient exploratory search and support the reasoning process to derive common eye-interaction-thinking patterns between participants. In addition, our tool equips researchers with mechanisms for searching and verifying expected usage patterns. We apply our approach to a user study involving a visual analytics application and we discuss insights gained from this joint analysis. We anticipate our approach to be applicable to other combinations of evaluation techniques and a broad class of visualization applications.

Comparison of radiographic joint space width and magnetic resonance imaging for prediction of knee replacement: A longitudinal case-control study from the Osteoarthritis Initiative.

OBJECTIVE: To evaluate whether change in fixed-location measures of radiographic joint space width (JSW) and cartilage thickness by MRI predict knee replacement. METHODS: Knees replaced between 36 and 60 months' follow-up in the Osteoarthritis Initiative were each matched with one control by age, sex and radiographic status. Radiographic JSW was determined from fixed flexion radiographs and subregional femorotibial cartilage thickness from 3 T MRI. Changes between the annual visit before replacement (T0) and 2 years before T0 (T-2) were compared using conditional logistic regression. RESULTS: One hundred and nineteen knees from 102 participants (55.5 % women; age 64.2 ± 8.7 [mean ± SD] years) were studied. Fixed-location JSW change at 22.5 % from medial to lateral differed more between replaced and control knees (case-control [cc] OR = 1.57; 95 % CI: 1.23-2.01) than minimum medial JSW change (ccOR = 1.38; 95 % CI: 1.11-1.71). Medial femorotibial cartilage loss displayed discrimination similar to minimum JSW, and central tibial cartilage loss similar to fixed-location JSW. Location-independent thinning and thickening scores were elevated prior to knee replacement. CONCLUSIONS: Discrimination of structural progression between knee pre-placement cases versus controls was stronger for fixed-location than minimum radiographic JSW. MRI displayed similar discrimination to radiography and suggested greater simultaneous cartilage thickening and loss prior to knee replacement. KEY POINTS: • Fixed-location JSW predicts surgical knee replacement more strongly than minimum JSW. • MRI predicts knee replacement with similar accuracy to radiographic JSW. • MRI reveals greater cartilage thinning and thickening prior to knee replacement.

Greater Lateral Femorotibial Cartilage Loss in Osteoarthritis Initiative Participants With Incident Total Knee Arthroplasty: A Prospective Cohort Study.

OBJECTIVE: To explore whether baseline to 12-month followup change in femorotibial cartilage thickness differs between subjects who received a total knee arthroplasty (TKA) between 24 and 60 months from those without TKA (non-TKA). METHODS: In this prospective cohort study, 531 right knees from Osteoarthritis Initiative participants with definite radiographic knee osteoarthritis (Kellgren/Lawrence [K/L] grades 2-4) were studied. Segmentation was applied to coronal fast low-angle shot magnetic resonance images, to quantitatively determine cartilage thickness in 16 femorotibial subregions. Unadjusted P values (t-tests) and P values adjusted for age, baseline body mass index (BMI), K/L grade, and sex (generalized estimating equation models) were used to evaluate differences in longitudinal 1-year rates of cartilage thickness between TKAs and non-TKAs, with total knee arthroplasty status as fixed effect. RESULTS: Of the 531 participants (mean ± SD ages 63 ± 9 years, BMI 30 ± 4.8 kg/m(2)), 40 received a femorotibial TKA within 4 years. At baseline, TKAs had thinner medial and lateral femorotibial cartilage (-15%; P < 0.001) than non-TKAs. Longitudinal cartilage thickness change was significantly greater in TKAs than in non-TKAs in the total femorotibial joint (area under the curve [AUC] 0.64), the lateral compartment (AUC 0.66), both tibiae (AUC ≥ 0.61), and the first 9 (of 16) ordered values of subregion change (AUC 0.64-0.69). Discrimination was stronger for TKAs that occurred at 24 and 36 months (n = 18) than for those at 48 and 60 months (n = 22). CONCLUSION: Knees with incident TKA displayed smaller baseline cartilage thickness and greater lateral as well as location-independent ordered value femorotibial cartilage loss than non-TKAs. Discrimination of cartilage loss was greater for TKAs occurring within 2 years after the measurement than for those occurring later.

Can structural joint damage measured with MR imaging be used to predict knee replacement in the following year?

PURPOSE: To assess whether magnetic resonance (MR) imaging-based cross-sectional measures of structural joint damage can be used to predict knee replacement during the following year. MATERIALS AND METHODS: Participants were drawn from the Osteoarthritis Initiative, a longitudinal observational study that includes 4796 participants who have knee osteoarthritis or are at risk. The HIPAA-compliant protocol was approved by the institutional review boards of all participating centers, and written informed consent was obtained from all participants. During the 5 years of follow-up, 199 knees underwent knee replacement and were matched with 199 control knees that did not undergo knee replacement. Knees were matched according to radiographic disease stage and patient sex and age. All knees that underwent knee replacement and had MR images available from the year before surgery were included. MR images were assessed for cartilage damage, bone marrow lesions, meniscal damage, meniscal extrusion, synovitis, and effusion prior to reported knee replacement. Conditional logistic regression was applied to assess the risk of knee replacement. Analyses were performed on a compartmental and knee level. RESULTS: Participants had a mean age ± standard deviation of 64.2 years ± 8.4 (range, 47-82 years) and were predominantly women (232 of 398 participants, 58.3%). Risk for knee replacement was significantly increased for knees that exhibited two or more subregions with severe cartilage loss (odds ratio [OR], 16.5; 95% confidence interval [CI]: 3.96, 68.76), more than two subregions with bone marrow lesions (OR, 4.00; 95% CI: 1.75, 9.16), medial meniscal maceration (OR, 1.84; 95% CI: 1.13, 2.99), effusion (OR, 4.75; 95% CI: 2.55, 8.85), or synovitis (OR, 2.17; 95% CI: 1.33, 3.56), but not extrusion (OR, 1.00; 95% CI: 0.60,1.67), when compared with knees that did not exhibit these features as the reference standard. CONCLUSION: Apart from meniscal extrusion, all features of tissue abnormalities at MR imaging were related to clinical prognosis and could be used to predict knee replacement in the following year.

AXT914 a novel, orally-active parathyroid hormone-releasing drug in two early studies of healthy volunteers and postmenopausal women.

Antagonism of the calcium-sensing receptor in the parathyroid gland leads to parathyroid hormone (PTH) release. Calcilytics are a new class of molecules designed to exploit this mechanism. In order to mimic the known bone-anabolic pharmacokinetic (PK) profile of s.c. administered PTH, such molecules must trigger sharp, transient and robust release of PTH. The results of two early clinical studies with the orally-active calcilytic AXT914, a quinazolin-2ne derivative are reported. These were GCP-compliant, single and multiple dose studies of PK/PD and tolerability in healthy volunteers and postmenopausal women. The first study, examined single ascending doses (4 to 120 mg) and limited multiple doses (60 or 120 mgq.d. for 12 days) of AXT914. The second study was a randomized, double-blind, active- and placebo-controlled, 4-week repeat-dose parallel group study of healthy postmenopausal women (45 and 60 mg AXT914, placebo, 20 µg Forteo/teriparatide/PTH(1-34) fragment). AXT914 was well tolerated at all doses and reproducibly induced the desired PTH-release profiles. Yet, 4 weeks of 45 or 60 mg AXT914 did not result in the expected changes in circulating bone biomarkers seen with teriparatide. However total serum calcium levels increased above baseline in the 45 and 60 mg AXT914 treatment groups (8.0% and 10.7%, respectively), compared to that in the teriparatide and placebo groups (1.3% and 1.0%, respectively). Thus the trial was terminated after a planned interim analysis due to lack of effect on bone formation biomarkers and dose-limiting effects on serum calcium. In conclusion, AXT914 was well tolerated but the observed transient and reproducible PTH-release after repeat oral administration of AXT914 which showed an exposure profile close to that of s c. PTH, did not translate into a bone anabolic response and was associated with a persistent dose-related increase in serum calcium concentrations.

Application of the OMERACT filter to measures of core outcome domains in recent clinical studies of acute gout.

OBJECTIVE: To determine the extent to which instruments that measure core outcome domains in acute gout fulfill the Outcome Measures in Rheumatology (OMERACT) filter requirements of truth, discrimination, and feasibility. METHODS: Patient-level data from 4 randomized controlled trials of agents designed to treat acute gout and 1 observational study of acute gout were analyzed. For each available measure, construct validity, test-retest reliability, within-group change using effect size, between-group change using the Kruskall-Wallis statistic, and repeated measures generalized estimating equations were assessed. Floor and ceiling effects were also assessed and minimal clinically important difference was estimated. These analyses were presented to participants at OMERACT 11 to help inform voting for possible endorsement. RESULTS: There was evidence for construct validity and discriminative ability for 3 measures of pain [0 to 4 Likert, 0 to 10 numeric rating scale (NRS), 0 to 100 mm visual analog scale (VAS)]. Likewise, there appears to be sufficient evidence for a 4-point Likert scale to possess construct validity and discriminative ability for physician assessment of joint swelling and joint tenderness. There was some evidence for construct validity and within-group discriminative ability for the Health Assessment Questionnaire as a measure of activity limitations, but not for discrimination between groups allocated to different treatment. CONCLUSION: There is sufficient evidence to support measures of pain (using Likert, NRS, or VAS), joint tenderness, and swelling (using Likert scale) as fulfilling the requirements of the OMERACT filter. Further research on a measure of activity limitations in acute gout clinical trials is required.

VarifocalReader--In-Depth Visual Analysis of Large Text Documents.

Interactive visualization provides valuable support for exploring, analyzing, and understanding textual documents. Certain tasks, however, require that insights derived from visual abstractions are verified by a human expert perusing the source text. So far, this problem is typically solved by offering overview-detail techniques, which present different views with different levels of abstractions. This often leads to problems with visual continuity. Focus-context techniques, on the other hand, succeed in accentuating interesting subsections of large text documents but are normally not suited for integrating visual abstractions. With VarifocalReader we present a technique that helps to solve some of these approaches' problems by combining characteristics from both. In particular, our method simplifies working with large and potentially complex text documents by simultaneously offering abstract representations of varying detail, based on the inherent structure of the document, and access to the text itself. In addition, VarifocalReader supports intra-document exploration through advanced navigation concepts and facilitates visual analysis tasks. The approach enables users to apply machine learning techniques and search mechanisms as well as to assess and adapt these techniques. This helps to extract entities, concepts and other artifacts from texts. In combination with the automatic generation of intermediate text levels through topic segmentation for thematic orientation, users can test hypotheses or develop interesting new research questions. To illustrate the advantages of our approach, we provide usage examples from literature studies.

Quantitative MRI measures of cartilage predict knee replacement: a case-control study from the Osteoarthritis Initiative.

OBJECTIVE: Knee osteoarthritis commonly requires joint replacement, substantially reduces quality of life and increases healthcare utilisation and costs. This study aimed to identify whether quantitative measures of articular cartilage structure predict knee replacement, and to establish their utility as outcomes in clinical trials of disease-modifying therapy. METHODS: A nested case-control study was performed in Osteoarthritis Initiative participants, a multicentre observational cohort of 4796 participants with or at risk of knee osteoarthritis. 127 knees were replaced between baseline and 4 years follow-up, and one control knee per case matched for baseline radiographic disease stage (Kellgren-Lawrence grade; KLG), gender and age. Quantitative cartilage measures were obtained from 3 T magnetic resonance images at the exam before knee replacement, and longitudinal change during the previous 12 months when available (n=110). RESULTS: Cartilage thickness loss in the central and total medial femorotibial compartment (primary and secondary predictor variables) was significantly greater in case than control knees (AUC=0.59/0.58). Differences in cartilage loss were greater at earlier than later radiographic disease stages (p<0.01 for interaction with KLG). Cartilage thickness loss in the central tibia was the most predictive longitudinal measure (AUC=0.64). Denuded bone areas in the medial femur were the most predictive and discriminatory cross-sectional measure between case and control knees (AUC=0.66). CONCLUSIONS: This study demonstrates the predictive value of quantitative, MRI-based measures of cartilage for the clinically relevant endpoint of knee replacement, providing support for their utility in clinical trials to evaluate the effectiveness of structure-modifying intervention.

The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women.

Parathyroid hormone (PTH), currently the only marketed anabolic treatment for osteoporosis, is available as the full-length hormone, human PTH1-84, or as the human PTH1-34 fragment (teriparatide). Both must be administered as a daily subcutaneous (sc) injection. A new oral formulation of human PTH1-34 (PTH134) is being developed as a more convenient option for patients. In this single-center, partially-blinded, incomplete cross-over study, the safety, tolerability, and exposure of oral PTH134 (teriparatide combined with 2 different quantities of the absorption enhancer 5-CNAC) were assessed in 32 healthy postmenopausal women. 16 subjects were randomized to receive 4 single doses out of 6 different treatments: placebo, teriparatide 20 µg sc, or 1, 2.5, 5 or 10 mg of oral PTH134 formulated with 200 mg 5-CNAC. Subsequently, another 16 subjects were randomized to receive 4 out of 6 different treatments: placebo, teriparatide 20 µg sc, or 2.5 or 5 mg of oral PTH134 formulated with either 100 or 200 mg 5-CNAC. Doses were given ≥6 days apart. All doses of PTH134 were rapidly absorbed, and showed robust blood concentrations in a dose-dependent manner. Interestingly, PTH1-34 disappeared from blood faster after oral than after sc administration. Specifically, 2.5 and 5 mg PTH134 (containing 200 mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of sc teriparatide 20 µg (Forsteo®). Mean+/-SD hPTH134 Cmax values were, respectively, 74+/-59, 138+/-101, 717+/-496, and 1624+/-1579 pg/mL for 1, 2.5, 5, and 10 mg doses of this peptide administered with 200 mg 5-CNAC; while mean+/-SD AUC (0-last) values were, respectively, 30+/-40, 62+/-69, 320+/-269, and 627+/-633 h*pg/mL. The corresponding estimates for teriparatide 20 µg sc were 149+/-35 for Cmax and 236+/-58 for AUC (0-last) Ionized calcium remained within normal limits in all treatment groups except for 3 isolated events. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5 mg: three withdrew for symptomatic hypotension (two of whom were in the 200 mg 5-CNAC group), three because of delayed vomiting (two from the 200 mg 5-CNAC group), one was proactively withdrawn by the investigator for symptomatic hypercalcemia (receiving 2.5 mg/100 mg 5-CNAC) at slightly supra-normal total calcium but normal ionized serum calcium levels. One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported. In conclusion, the study demonstrated potential therapeutically relevant PTH1-34 systemic exposure levels after oral administration of PTH1-34 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5 mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20 µg sc, with a comparable incidence of AEs in healthy postmenopausal women.

Greater rates of cartilage loss in painful knees than in pain-free knees after adjustment for radiographic disease stage: data from the osteoarthritis initiative.

OBJECTIVE: To investigate whether rates of cartilage loss differ in knees with frequent baseline pain versus those without pain, after adjustment for radiographic osteoarthritis (OA) stage. METHODS: One knee in each of 718 Osteoarthritis Initiative participants was examined: 310 with calculated Kellgren/Lawrence (K/L) grade 2, 299 with calculated K/L grade 3, and 109 with calculated K/L grade 4. Twelve-month change in (subregional) cartilage thickness was assessed by magnetic resonance imaging. Change in cartilage thickness in the central subregion of the weight-bearing medial femoral condyle and ordered value 1 (OV1) were selected as primary end points. Frequent knee symptoms were defined as pain, aching, or stiffness on most days of at least 1 month during the previous year. RESULTS: The mean 12-month rate of change in cartilage thickness in the central subregion of the medial femoral condyle was -12 µm (standardized response mean [SRM] -0.15) in knees without pain (n = 146), -27 µm (SRM -0.25) in those with infrequent pain (n = 255), and -54 µm (SRM -0.32) in those with frequent pain (n = 317). Rates differed significantly between frequently painful knees and pain-free knees after adjustment for age, sex, body mass index, and calculated K/L grade (P = 0.011, R(2) = 2.6%, partial R(2) for frequent pain = 1.4%). Similar results were found in stratified samples of calculated K/L grade 2/calculated K/L grade 3 knees, and in analyses restricted to knees with consistent pain frequency between baseline and followup. OV1 results showed similar trends but were not significant. CONCLUSION: Knees with frequent pain display greater rates of medial cartilage loss longitudinally than knees without pain, with or without adjustment or stratification for radiographic disease stage. Enrollment of participants with frequent knee pain in clinical trials can increase the observed rate of structural progression (i.e., cartilage loss) and sensitivity to change.

ATF936, a novel oral calcilytic, increases bone mineral density in rats and transiently releases parathyroid hormone in humans.

Parathyroid hormone (PTH), when injected daily as either the intact hormone PTH(1-84) or the active fragment PTH(1-34) (teriparatide), is an efficacious bone anabolic treatment option for osteoporosis patients. Injections lead to rapid and transient spikes in hormone exposure levels, a profile which is a prerequisite to effectively form bone. Oral antagonists of the calcium-sensing receptor (calcilytics) stimulate PTH secretion and represent thus an alternative approach to elevate hormone levels transiently. We report here on ATF936, a novel calcilytic, which triggered rapid, transient spikes in endogenous PTH levels when given orally in single doses of 10 and 30mg/kg to growing rats, and of 1mg/kg to dogs. Eight weeks daily oral application of 30mg/kg of ATF936 to aged female rats induced in the proximal tibia metaphysis increases in bone mineral density, cancellous bone volume and cortical and trabecular thickness as evaluated by computed tomography. In healthy humans, single oral doses of ATF936 produced peak PTH levels in plasma after a median time of 1h and levels returned to normal at 24-h post-dose. The average maximum PTH concentration increase from baseline was 1.9, 3.6, and 6.0-fold at doses of 40, 70, and 140mg. ATF936 was well tolerated. The sharp, transient increase in PTH levels produced by the oral calcilytic ATF936 was comparable to the PTH profile observed after subcutaneous administration of teriparatide. In conclusion, ATF936 might hold potential as an oral bone-forming osteoporosis therapy.

1-Alkyl-4-phenyl-6-alkoxy-1H-quinazolin-2-ones: a novel series of potent calcium-sensing receptor antagonists.

Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily sc injections exposure of short duration is achieved, a prerequisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the bloodstream. Screening of the internal compound collection for inhibition of CaSR signaling function afforded 2a. In vitro potency could be improved >1000 fold by optimization of its chemical structure. The binding mode of our compounds was predicted based on molecular modeling and confirmed by testing with mutated receptors. While the compounds readily induced PTH release after iv application a special formulation was needed for oral activity. The required profile was achieved by using microemulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within minutes which reverted to baseline in about 1-2 h in both species.

Rapid and robust response of biochemical markers of bone formation to teriparatide therapy.

Teriparatide, a parathyroid hormone analogue, is a potent anabolic treatment for postmenopausal osteoporosis. Studies have shown that teriparatide induces large increases in biochemical markers of bone formation after 1 month of therapy followed by a delayed increase in bone resorption markers. The aims of this study were to (1) describe changes in bone turnover markers during 28 days of treatment with teriparatide; (2) identify the earliest time point by which most subjects showed a biochemical response to teriparatide; (3) identify potential biomarkers of positive bone response; (4) describe changes in bone turnover markers 4 weeks after stopping teriparatide. We recruited 15 osteopenic postmenopausal women, ages 55-69 (mean 62) years. All received 20 microg teriparatide subcutaneously for 28 days. Serum levels of the bone formation markers type I collagen N-terminal propeptide (PINP), type I collagen C-terminal propeptide (PICP), osteocalcin (OC), bone alkaline phosphatase (bone ALP), and the bone resorption markers crosslinked C-telopeptide of type I collagen (Sbeta-CTX), crosslinked N-telopeptide of type I collagen (S-NTX) and tartrate-resistant acid phosphatase type 5b (TRACP5b) were measured on 11 occasions: three times before dosing (baseline) and on days 3, 7, 10, 14, 19, 24 and 28 and at day 56 (i.e., 28 days after stopping teriparatide ). During the first 2 days of teriparatide treatment, PINP levels increased rapidly, by 8.2% (90% confidence interval (CI) 6.9%, 9.5%) and continued to increase until the end of treatment to 110.8%. PICP and OC showed a similar, but less pronounced, pattern. All three markers increased by at least 75% at day 28. A small, transient decrease in bone resorption markers occurred over the same period. Following cessation of treatment, concentrations of bone formation markers decreased to within 20% of baseline values by day 56. In conclusion, the bone formation markers PINP, PICP and OC show a rapid and robust increase in response to teriparatide, which is noticeable during the first week of therapy. PINP is the most responsive marker. These findings have important implications for monitoring patients treated with teriparatide and may also inform the design of studies of new anabolic agents for osteoporosis.