Toward designing human intervention studies to prevent osteoarthritis after knee injury: A report from an interdisciplinary OARSI 2023 workshop

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Abstract

Objective

The global impact of osteoarthritis is growing. Currently no disease modifying osteoarthritis drugs/therapies exist, increasing the need for preventative strategies. Knee injuries have a high prevalence, distinct onset, and strong independent association with post-traumatic osteoarthritis (PTOA). Numerous groups are embarking upon research that will culminate in clinical trials to assess the effect of interventions to prevent knee PTOA despite challenges and lack of consensus about trial design in this population. Our objectives were to improve awareness of knee PTOA prevention trial design and discuss state-of-the art methods to address the unique opportunities and challenges of these studies.

Design

An international interdisciplinary group developed a workshop, hosted at the 2023 Osteoarthritis Research Society International Congress. Here we summarize the workshop content and outputs, with the goal of moving the field of PTOA prevention trial design forward.

Results

Workshop highlights included discussions about target population (considering risk, homogeneity, and possibility of modifying osteoarthritis outcome); target treatment (considering delivery, timing, feasibility and effectiveness); comparators (usual care, placebo), and primary symptomatic outcomes considering surrogates and the importance of knee function and symptoms other than pain to this population.

Conclusions

Opportunities to test multimodal PTOA prevention interventions across preclinical models and clinical trials exist. As improving symptomatic outcomes aligns with patient and regulator priorities, co-primary symptomatic (single or aggregate/multidimensional outcome considering function and symptoms beyond pain) and structural/physiological outcomes may be appropriate for these trials. To ensure PTOA prevention trials are relevant and acceptable to all stakeholders, future research should address critical knowledge gaps and challenges.

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Most cited references 43

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Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

Theo Vos, Abraham D. Flaxman, Mohsen Naghavi … (2013)

Non-fatal health outcomes from diseases and injuries are a crucial consideration in the promotion and monitoring of individual and population health. The Global Burden of Disease (GBD) studies done in 1990 and 2000 have been the only studies to quantify non-fatal health outcomes across an exhaustive set of disorders at the global and regional level. Neither effort quantified uncertainty in prevalence or years lived with disability (YLDs). Of the 291 diseases and injuries in the GBD cause list, 289 cause disability. For 1160 sequelae of the 289 diseases and injuries, we undertook a systematic analysis of prevalence, incidence, remission, duration, and excess mortality. Sources included published studies, case notification, population-based cancer registries, other disease registries, antenatal clinic serosurveillance, hospital discharge data, ambulatory care data, household surveys, other surveys, and cohort studies. For most sequelae, we used a Bayesian meta-regression method, DisMod-MR, designed to address key limitations in descriptive epidemiological data, including missing data, inconsistency, and large methodological variation between data sources. For some disorders, we used natural history models, geospatial models, back-calculation models (models calculating incidence from population mortality rates and case fatality), or registration completeness models (models adjusting for incomplete registration with health-system access and other covariates). Disability weights for 220 unique health states were used to capture the severity of health loss. YLDs by cause at age, sex, country, and year levels were adjusted for comorbidity with simulation methods. We included uncertainty estimates at all stages of the analysis. Global prevalence for all ages combined in 2010 across the 1160 sequelae ranged from fewer than one case per 1 million people to 350,000 cases per 1 million people. Prevalence and severity of health loss were weakly correlated (correlation coefficient -0·37). In 2010, there were 777 million YLDs from all causes, up from 583 million in 1990. The main contributors to global YLDs were mental and behavioural disorders, musculoskeletal disorders, and diabetes or endocrine diseases. The leading specific causes of YLDs were much the same in 2010 as they were in 1990: low back pain, major depressive disorder, iron-deficiency anaemia, neck pain, chronic obstructive pulmonary disease, anxiety disorders, migraine, diabetes, and falls. Age-specific prevalence of YLDs increased with age in all regions and has decreased slightly from 1990 to 2010. Regional patterns of the leading causes of YLDs were more similar compared with years of life lost due to premature mortality. Neglected tropical diseases, HIV/AIDS, tuberculosis, malaria, and anaemia were important causes of YLDs in sub-Saharan Africa. Rates of YLDs per 100,000 people have remained largely constant over time but rise steadily with age. Population growth and ageing have increased YLD numbers and crude rates over the past two decades. Prevalences of the most common causes of YLDs, such as mental and behavioural disorders and musculoskeletal disorders, have not decreased. Health systems will need to address the needs of the rising numbers of individuals with a range of disorders that largely cause disability but not mortality. Quantification of the burden of non-fatal health outcomes will be crucial to understand how well health systems are responding to these challenges. Effective and affordable strategies to deal with this rising burden are an urgent priority for health systems in most parts of the world. Bill & Melinda Gates Foundation. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Effectiveness-implementation hybrid designs: combining elements of clinical effectiveness and implementation research to enhance public health impact.

Geoffrey M Curran, Mark Bauer, Brian Mittman … (2012)

This study proposes methods for blending design components of clinical effectiveness and implementation research. Such blending can provide benefits over pursuing these lines of research independently; for example, more rapid translational gains, more effective implementation strategies, and more useful information for decision makers. This study proposes a "hybrid effectiveness-implementation" typology, describes a rationale for their use, outlines the design decisions that must be faced, and provides several real-world examples. An effectiveness-implementation hybrid design is one that takes a dual focus a priori in assessing clinical effectiveness and implementation. We propose 3 hybrid types: (1) testing effects of a clinical intervention on relevant outcomes while observing and gathering information on implementation; (2) dual testing of clinical and implementation interventions/strategies; and (3) testing of an implementation strategy while observing and gathering information on the clinical intervention's impact on relevant outcomes. The hybrid typology proposed herein must be considered a construct still in evolution. Although traditional clinical effectiveness and implementation trials are likely to remain the most common approach to moving a clinical intervention through from efficacy research to public health impact, judicious use of the proposed hybrid designs could speed the translation of research findings into routine practice.

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The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study.

Marita Cross, Emma Smith, Damian Hoy … (2014)

To estimate the global burden of hip and knee osteoarthritis (OA) as part of the Global Burden of Disease 2010 study and to explore how the burden of hip and knee OA compares with other conditions. Systematic reviews were conducted to source age-specific and sex-specific epidemiological data for hip and knee OA prevalence, incidence and mortality risk. The prevalence and incidence of symptomatic, radiographic and self-reported hip or knee OA were included. Three levels of severity were defined to derive disability weights (DWs) and severity distribution (proportion with mild, moderate and severe OA). The prevalence by country and region was multiplied by the severity distribution and the appropriate disability weight to calculate years of life lived with disability (YLDs). As there are no deaths directly attributed to OA, YLDs equate disability-adjusted life years (DALYs). Globally, of the 291 conditions, hip and knee OA was ranked as the 11th highest contributor to global disability and 38th highest in DALYs. The global age-standardised prevalence of knee OA was 3.8% (95% uncertainty interval (UI) 3.6% to 4.1%) and hip OA was 0.85% (95% UI 0.74% to 1.02%), with no discernible change from 1990 to 2010. Prevalence was higher in females than males. YLDs for hip and knee OA increased from 10.5 million in 1990 (0.42% of total DALYs) to 17.1 million in 2010 (0.69% of total DALYs). Hip and knee OA is one of the leading causes of global disability. Methodological issues within this study make it highly likely that the real burden of OA has been underestimated. With the aging and increasing obesity of the world's population, health professions need to prepare for a large increase in the demand for health services to treat hip and knee OA. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

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Author and article information

Contributors

Fiona E. Watt

Journal

Journal ID (nlm-ta): Osteoarthr Cartil Open

Journal ID (iso-abbrev): Osteoarthr Cartil Open

Title: Osteoarthritis and Cartilage Open

Publisher: Elsevier

ISSN (Electronic): 2665-9131

Publication date PMC-release: 23 February 2024

Publication date Collection: June 2024

Publication date (Electronic): 23 February 2024

Volume: 6

Issue: 2

Electronic Location Identifier: 100449

Affiliations

[a ]Department of Physical Therapy, University of British Columbia, Vancouver, Canada

[b ]Arthritis Research Canada, Vancouver, Canada

[c ]Department of Immunology and Inflammation, Imperial College London, London, UK

[d ]Department for Health, University of Bath, Bath, UK

[e ]Centre for Sport, Exercise and Osteoarthritis Research Versus Arthritis, UK

[f ]Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, UK

[g ]NIHR Leeds Biomedical Research Centre, Leeds, UK

[h ]La Trobe Sport and Exercise Medicine Research Centre, School of Allied Health, Human Services and Sport, La Trobe University, Melbourne, Australia

[i ]Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

[j ]Mechano Therapeutics LLC, Philadelphia, PA, USA

[k ]Division of Orthopedic Surgery, Bone and Joint Institute, Fowler Kennedy Sport Medicine Clinic, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada

[l ]Program of Advanced Musculoskeletal Imaging (PAMI), Cleveland Clinic, OH, USA

[m ]Department of Biomedical Engineering, Lerner Research Institute, Cleveland Clinic, OH, USA

[n ]Department of Orthopedic Surgery, Brigham and Women's Hospital, Boston, USA

[o ]Department of Orthopedic Surgery, Harvard Medical School, Boston, USA

[p ]Biomechanics and Bioengineering Research Centre Versus Arthritis, School of Biosciences, Cardiff University, Cardiff, UK

[q ]Department of Exercise and Sport Science, University of North Carolina, USA

[r ]Norwegian School Sport Sciences, Oslo, Norway

[s ]Division of Orthopedic Surgery, Oslo University Hospital, Oslo, Norway

[t ]Department of Radiology, Universitätsklinikum Erlangen & Friedrich- Alexander-Universität (FAU) Erlangen-Nürnberg, Erlangen, Germany

[u ]Chobanian & Avedisian School of Medicine, Boston University, Boston, MA, USA

[v ]Section of Rheumatology, Boston University Chobanian & Avedisian School of Medicine, Boston, MA, USA

[w ]Orthopedic and Sport Medicine Department, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands

[x ]Novartis BioMedical Research, Basel, Switzerland

[y ]SDG LLC, Cambridge, MA, USA

[z ]Department of Clinical Sciences Lund, Orthopaedics, Lund University, Lund, Sweden

[aa ]Department of Clinical Sciences Lund, Orthopaedics, Clinical Epidemiology Unit, Lund University, Lund, Sweden

[ab ]Centre for Osteoarthritis Pathogenesis Versus Arthritis, Kennedy Institute of Rheumatology, University of Oxford, UK

Author notes

[∗ ]Corresponding author. Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, Commonwealth Building, Hammersmith Campus, Du Cane Road, London, W12 0NN, UK. f.watt@ 123456imperial.ac.uk

Article

Publisher Item ID: S2665-9131(24)00016-5 Publisher ID: 100449

DOI: 10.1016/j.ocarto.2024.100449

PMC ID: 10910316

PubMed ID: 38440780

SO-VID: 677aa271-1652-4453-907b-f86fefb608e8

License:

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Toward designing human intervention studies to prevent osteoarthritis after knee injury: A report from an interdisciplinary OARSI 2023 workshop

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Abstract

Objective

Design

Results

Conclusions

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Clinical Social Work and Health Intervention

Most cited references 43

Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010

Effectiveness-implementation hybrid designs: combining elements of clinical effectiveness and implementation research to enhance public health impact.

The global burden of hip and knee osteoarthritis: estimates from the global burden of disease 2010 study.

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