Oral salmon calcitonin reduces cartilage and bone pathology in an osteoarthritis rat model with increased subchondral bone turnover

SummaryObjectivesTraumatic osteoarthritis (OA) is possibly augmented by effects from loss of sex hormones. Salmon calcitonin is shown to reduce OA pathogenesis and bone resorption. We investigated the effects of oral salmon calcitonin treatment and ovariectomy on cartilage and bone pathology in a traumatic OA model.MethodsSix groups with 10 7-month-old female Sprague Dawley rats each were subjected to bilateral meniscectomy (MNX), ovariectomy (OVX) or Sham surgery and treated for 8 weeks with oral salmon calcitonin (CT) or vehicle (V) in the following way: (1) Sham+V; (2) MNX+V; (3) MNX+CT; (4) OVX+V; (5) MNX/OVX+V; (6) MNX/OVX+CT. Weights were recorded weekly and CTX-II was measured in serum. At termination 56 days post-surgery, the right tibia was analyzed for changes in articular cartilage thickness, extent of cartilage damage and subchondral bone changes in predefined zones, as recommended in the novel OARSI histopathology score.ResultsThe combined MNX/OVX model produced a significantly reduced cartilage thickness (P=0.033) in the outer zone (Z1) of the tibial plateau and increased calcified cartilage damage (P=0.0004) and serum CTX-II (P=0.003). Addition of OVX to MNX significantly increased the width of matrix damage at the surface (P=0.025) and 50% cartilage depth (P=0.004). Treatment with oral salmon calcitonin counteracted the loss of cartilage thickness (P=0.055), significantly reduced subchondral bone damage score (P=0.019) and reduced the type II collagen degradation (P=0.009).ConclusionsAddition of ovariectomy augmented site-specific traumatic OA pathology, which was reduced by oral salmon calcitonin treatment. Treatments for OA might ideally affect both bone and cartilage

Identification of pathological RA endotypes using blood-based biomarkers reflecting tissue metabolism. A retrospective and explorative analysis of two phase III RA studies

There is an increasing demand for accurate endotyping of patients according to their pathogenesis to allow more targeted treatment. We explore a combination of blood-based joint tissue metabolites (neoepitopes) to enable patient clustering through distinct disease profiles. We analysed data from two RA studies (LITHE (N = 574, follow-up 24 and 52 weeks), OSKIRA-1 (N = 131, follow-up 24 weeks)). Two osteoarthritis (OA) studies (SMC01 (N = 447), SMC02 (N = 81)) were included as non-RA comparators. Specific tissue-derived neoepitopes measured at baseline, included: C2M (cartilage degradation); CTX-I and PINP (bone turnover); C1M and C3M (interstitial matrix degradation); CRPM (CRP metabolite) and VICM (macrophage activity). Clustering was performed to identify putative endotypes. We identified five clusters (A-E). Clusters A and B were characterized by generally higher levels of biomarkers than other clusters, except VICM which was significantly higher in cluster B than in cluster A (p<0.001). Biomarker levels in Cluster C were all close to the median, whilst Cluster D was characterised by low levels of all biomarkers. Cluster E also had low levels of most biomarkers, but with significantly higher levels of CTX-I compared to cluster D. There was a significant difference in ΔSHP score observed at 52 weeks (p<0.05). We describe putative RA endotypes based on biomarkers reflecting joint tissue metabolism. These endotypes differ in their underlining pathogenesis, and may in the future have utility for patient treatment selection

Reflections from the 2021 OARSI clinical trial symposium:Considerations for understanding biomarker assessments in osteoarthritis drug development - Should future studies focus on disease activity, rather than status?

OBJECTIVE: Osteoarthritis (OA) is heterogeneous disease, for which drug development has proven to be challenging, both facilitated and hampered by changing guidelines. This is evident by the current lack of approved treatments, which improve joint function and delay joint failure. There is a need to bring together key stakeholders to discuss, align and enhance the processes for OA drug development to benefit patients. DESIGN: To facilitate drug development, the Osteoarthritis Research Society International (OARSI) initiated a series of annual clinical trials symposia (CTS). The aim of these symposia was to bring together academics, translational and clinical scientists, regulators, drug developers, and patient advocacy groups to share, refine and enhance the drug development process for the benefit of patients. RESULTS: OARSI is now considered the leading organization to facilitate open dialogue between all these stakeholders, in the intersection of understanding of the pathologies and drug development. Clearly, such a pivotal task needs an annual forum to allow stakeholders to share and discuss information, as possible solutions are joint efforts rather than a single stakeholder contribution. CONCLUSIONS: The main topic of the 2021 CTS was how to improve clinical studies to help patients through overcoming barriers to development of new disease modifying treatments for OA. One key aspect was the focus on definitions of disease activity, status and the definitions of “illness vs disease”. There is a clear medical need to couple a given disease activity with the optimal intervention for the right patient

From biochemical markers to molecular endotypes of osteoarthritis: a review on validated biomarkers

\ua9 2024 The Author(s). Published by Informa UK Limited, trading as Taylor &amp; Francis Group.Introduction: Osteoarthritis (OA) affects over 500 million people worldwide. OA patients are symptomatically treated, and current therapies exhibit marginal efficacy and frequently carry safety-risks associated with chronic use. No disease-modifying therapies have been approved to date leaving surgical joint replacement as a last resort. To enable effective patient care and successful drug development there is an urgent need to uncover the pathobiological drivers of OA and how these translate into disease endotypes. Endotypes provide a more precise and mechanistic definition of disease subgroups than observable phenotypes, and a panel of tissue- and pathology-specific biochemical markers may uncover treatable endotypes of OA. Areas covered: We have searched PubMed for full-text articles written in English to provide an in-depth narrative review of a panel of validated biochemical markers utilized for endotyping of OA and their association to key OA pathologies. Expert opinion: As utilized in IMI-APPROACH and validated in OAI-FNIH, a panel of biochemical markers may uncover disease subgroups and facilitate the enrichment of treatable molecular endotypes for recruitment in therapeutic clinical trials. Understanding the link between biochemical markers and patient-reported outcomes and treatable endotypes that may respond to given therapies will pave the way for new drug development in OA

OA phenotypes, rather than disease stage, drive structural progression – identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA

SummaryBackground/PurposeThe aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren–Lawrence (KL) grade, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, Joint Space Narrowing (JSN), and BMI.MethodsData from 2206 subjects (4390 knees) were combined for this post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled phase III trials (NCT00486434 and NCT00704847) that evaluated the efficacy and safety of 2-years treatment with oral salmon calcitonin of subjects with painful knee osteoarthritis (OA).ResultsThere was a clear positive and significant correlation between KL grade and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). BMI, KL-Score and WOMAC pain was diagnostic, but only KL-score and pain had prognostic value, albeit pain in a non-linear manner.ConclusionThese data clearly describe significant associations between KL grade, JSW, pain and BMI in patients with symptomatic knee OA. KL grade, BMI and WOMAC pain were diagnostically associated with OA based on JSW but only KL-score and pain in a non-linier fashion was prognostic. 50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. These results suggest that disease phenotypes, rather than disease status, are responsible for disease progression

Biochemical markers of type II collagen breakdown and synthesis are positioned at specific sites in human osteoarthritic knee cartilage

SummaryObjectiveTo investigate whether type II collagen turnover markers used for osteoarthritis (OA) activity evaluation in body fluids can be detected at the level of specific histological features of OA cartilage tissue, as well as how they relate with each other at this level.MethodsAdjacent sections were obtained from full-depth cartilage biopsies from 32 OA knees. Immunohistochemistry was performed for Helix-II and CTX-II, which are type II collagen fragments originating from the triple helix and the telopeptide region, respectively, and believed to reflect distinct breakdown events, as well as for type IIA N propeptide (PIIANP), a biochemical marker reflecting synthesis of type IIA collagen.ResultsHelix-II and CTX-II were detected in areas where collagen damage was reported previously, most frequently around chondrocytes, but also frequently in regions not previously investigated such as the margin area and close to subchondral bone, including vascularization sites and bone–cartilage interface. The latter is CTX-II's prevailing position and shows rarely Helix-II. PIIANP co-localized with Helix-II and CTX-II on a limited number of features, mainly in deep zone cartilage. Overall, our analysis highlights clear patterns of association of the markers with specific histological features, and shows that they spread to these features in an ordered way.ConclusionHelix-II and CTX-II show to some degree differential selectivity for specific features in cartilage tissue. CTX-II detection close to bone may be relevant to the possible role of subchondral bone in OA. The restricted co-localization of breakdown markers and PIIANP suggests that collagen fragments can result only partially from newly synthesized collagen. Our study strengthens the interest for the question whether combining several markers reflecting different regional cartilage contributions or metabolic processes should allow a broader detection of OA activity