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Learning from the past to plan for the future: A scoping review of musculoskeletal clinical research in Sweden 2010–2020

Background The aims of this study are to 1) determine the scope of musculoskeletal (MSK)-related clinical research in Sweden; 2) collate the amount of first-tier funding received; 3) discuss strategies and infrastructure supporting future MSK clinical trials in Sweden. Methods A systematic scoping review protocol was applied in PubMed, Scopus, and SweCRIS databases. The articles were examined, and data were extracted in multiple stages by three blinded authors. Results The search strategy resulted in 3,025 publications from 479 Swedish-affiliated authors. Primary health care was the basis for 14% of the publications, 84% from secondary health care, and 2% from occupational health care with a similar proportional distribution of first-tier research grant financing. Approximately one in six publications were randomized controlled trials (RCTs), while the majority were of observational cohort design. The majority of publications in primary and occupational health care were related to pain disorders (51 and 67%, respectively), especially diagnosis, prognosis, and healthcare organizational-related interventions (34%) and rehabilitation (15%) with similar proportional distribution of first-tier research grant financing. In secondary health care, rheumatic inflammatory disorder-related publications were most prevalent (30%), most frequently concerning diagnosis, prognosis, and healthcare organizational-related interventions (20%), attracting approximately half of all first-tier funding. Publications related to degenerative joint disorders (25%), fractures (16%), and joint, tendon, and muscle injuries (13%) frequently concerned surgical and other orthopedic-related interventions (16, 6, and 8%, respectively). Pain disorder-related publications (10%) as well as bone health and osteoporosis-related publications (4%) most frequently concerned diagnosis, prognosis, and healthcare organizational-related interventions (5 and 3%, respectively). Conclusions Swedish-affiliated MSK disorder research 2010–2020 was predominantly observational cohort rather than RCT based. There was skewed first-tier funding allocation considering prevalence/incidence and burden of disease. Use of infrastructure supporting register-based RCTs, placebo-controlled RCTs, and hybrid effectiveness-implementation studies on prevention and clinical intervention is important strategies for the future in all healthcare sectors.


Introduction
Epidemiological research on the global burden of disease between 1990 and 2019 has displayed a lowering of disease mortality rates but an increasing prevalence of disabling morbidity (1). Musculoskeletal (MSK) disorders involving all diseases and injuries related to the connective tissues of the locomotor system are among the most common cause of years lived with disability in Sweden and worldwide (1). MSK disorders affect a large proportion of the population, with work absenteeism affecting 40%, resulting in an economic cost of approximately 2% of the annual gross national product in EU member states (2). Ageing population trends and lifestyle factors are significant contributors to MSK disorders causing major burden for public health globally (3). MSK disorders are also linked to increased prevalence of pain and mental health disorders, muscle and bone mass loss, obesity, insulin resistance, risk of falls and fracture, and longer rehabilitation following injury or surgery (3).
Optimizing MSK health and wellbeing is considered key aims for the prevention and treatment of MSK disorders (4). MSK disorders are one of most common reasons for accessing primary health care in Sweden (5,6). Many clinicians in primary care do not feel confident to diagnose and manage patients with MSK disorders, unnecessarily refer to secondary healthcare services, are not aware of recent evidence for effectiveness of different treatments, rely on shared beliefs and personal opinion rather than research evidence, or poorly adhere to existing guidelines (7)(8)(9). The result is a discordance between what is known to be effective from clinical research and what is done in clinical practice, i.e. a substantial knowledge-action gap (10,11). Furthermore, only an estimated 14% of research knowledge is used toward improvement of health care and patient outcomes with an average delay of 17 years (10,12). This gap between scientific knowledge and practice is estimated to result in high national spending on research without clear knowledge-action plans and continued use of low-value or ineffective care that may be insufficient or redundant, and even harmful to patients (10). To meet such challenges, building capacity and infrastructure through developing a national MSK clinical trial network in Sweden (SweMSK) may help improve the quality of future MSK research and reduce knowledge-action gaps (13).
In a first step in developing the SweMSK network and to understand the current knowledge-action gaps in Swedish MSK-related research, the following systematic scoping review aims to: 1) identify recently published (2018-2020) Swedishaffiliated MSK researchers and the scope of their MSK-related clinical research in terms of volume, design, healthcare context, types of MSK disorders, and interventions 2010-2020; 2) collate the amount of funding received for MSK disorder-related research through first-tier Swedish national competitive grants 2010-2020; 3) discuss potential strategies and infrastructure supporting future MSK-related clinical trials in Sweden.

Materials and methods
Scoping review is a form of exploratory knowledge synthesis aimed at mapping key concepts, types of evidence, and gaps in research by systematically searching, selecting, and synthesizing existing knowledge to inform practice, policy making, and future research (14). The scoping review methodology for this study is based on a commonly used framework (15) and best praxis recommendations (16). A multidisciplinary research team with national geographic representation and expertise in the MSK disorders, epidemiology, and research synthesis was formed for the study. Reporting follows the PRISMA extension for scoping reviews (17). This scoping review used a two-step process. The first phase was to identify recently published Swedish MSK researchers through a systematic search in multiple databases. The included researchers who completed published research between 2010 and 2020 were then analyzed according to the eligibility criteria.

Context
What is the scope of publications and amount of first-tier national competitive funding? And based on this, what are potential strategies and infrastructure supporting future MSKrelated clinical trials in Sweden?

Identification of relevant studies
Eligibility Inclusion criteria were MSK disorder-related clinical trials, and observational studies and qualitative studies published in English by recently published (2018-2020) Swedish-affiliated researchers. The reasoning for limiting to recent publications was to aid identifying currently active researchers for the development of the SweMSK network. Based on this cohort of recently published authors, the search was expanded to capture each individual author's scope of MSK-related publications 2010-2020. Phase 1 clinical trials, reviews, study protocols, odontology studies, and studies not fully meeting the inclusion criteria were excluded.

Information sources and search strategy
In a first step, the following search strategies were conducted: 1. Research article publication databases PubMed search -Search terms were applied to the title and abstract of PubMed indexed publications. Using the Boolean operator 'AND' , Swedish affiliation was added to MSK disorderrelated search terms for different bodily locations which were bundled using the Boolean operator 'OR' . After screening resulting titles, the research team refined the MSK disorderrelated search terms. Furthermore, the Boolean operator 'NOT' was used to improve sensitivity of the search by filtering out non-MSK disorder-related studies. The truncation symbol * was used for search terms that have a similar root. Due to the large number of results, filters for randomized controlled trial (RCT), clinical trial, and observational study were applied. The specific search strategy is outlined in Appendix 1.
Scopus search -Search terms were applied to the title, abstract, and keywords of Scopus indexed publications. MSK symptom and diagnosis-related search terms for different bodily locations were combined using the Boolean operator 'OR' and restricted to Swedish affiliation using the Boolean operator 'AND' . After screening resulting titles, the Boolean operator 'AND NOT' was used to improve sensitivity of the search by filtering out non-MSK disorderrelated studies. The truncation symbol * was used for search terms that have a similar root. Limitations to articles published in scientific journals in the subject areas 'Medicine' and 'Health professions' were applied. No filters were used for specific research designs as a sensitivity measure in the case that research design filter posed on the PubMed search had missed studies. The specific search strategy is outlined in Appendix 1. Second tier research funding from company-based research fonds, regional funding bodies, and the contract between the Swedish government and seven regions concerning the financing of physician education, clinical research, and healthcare system development (18) are not included in the SweCRIS database. Information in SweCRIS is structured according to grant contracts. SweCRIS is managed by the Swedish Research Council on behalf of the Government. The database was filtered for the subject areas orthopedics, rheumatology, physiotherapy, and pain. All years from the start of the database in 2010 up to the end of 2020 were included.

Study selection
Results from searches of the information sources were entered into an Excel file. Studies underwent independent review by either authors ED, OT, or AA using the above-named eligibility criteria, and any ambiguities were resolved by consensus between reviewers.

Charting the data from the search results
For each of the included studies, the following data were extracted: Data extraction from included studies was independently performed by one reviewer using a standardized data extraction form and afterward cross-checked by an additional reviewer. Ambiguities were resolved afterward through discussion between reviewers.

Collating and summarizing results
Descriptive statistics including frequencies, proportions, and total sums were performed for the above stated data in IBM SPSS Statistics version 25.

Results
Initially, 282 publications from PubMed and 106 publications from Scopus databases were identified between the years 2018 and 2020. After screening, 296 of these publications remained after removal of duplicates, and 247 remained after removal of studies not fulfilling eligibility criteria. From these studies, 479 Swedish-affiliated authors were identified. A PubMed search based on these 479 authors for their MSK publications 2010-2020 resulted in 3,025 publications. A PRISMA flow chart is presented in Figure 1. The distribution of publication based on healthcare context was 412/3,025 (14%) from primary care, 2,552/3,025 (84%) from secondary care, and 60/3,025 (2%) from occupational healthcare system.

Summary of the main results
In summary, the study included 3,025 publications from 479 Swedish affiliated authors. Primary health care was the basis for 14% of the publications, 84% from secondary health care, and 2% from occupational health care with a similar proportional distribution of first-tier research grant financing. Approximately one in six publications were RCTs, while the majority were of observational cohort design. Most publications in primary and occupational health care were related to pain disorders (51 and 67%), and in secondary health care, rheumatic inflammatory disorder-related publications were most prevalent (30%).

Discussion
Scoping review of published MSK disorder research with Swedish affiliation demonstrates similar publication volume in the primary and secondary healthcare contexts regarding pain disorders, while other diagnostic categories for MSK disorder research are predominantly secondary health care based. In primary and occupational health care, most publications were related to first-line diagnostic and rehabilitation interventions for pain disorders, especially for back and neck pain and to a smaller extent joint, tendon, and muscle injuries as well as degenerative joint disorders. This distribution is motivated considering the extent of prevalence and burden of these conditions (1) which is a major consideration in identifying research priorities (19). Furthermore, MSK-related pain is one of the most common reasons for patients consulting a physiotherapist (89%) or general practitioner (20-40%) in primary care and is a common symptom for most MSK disorders (20)(21)(22). Only 21% of the Swedish-affiliated primary healthcare research publication on MSK disorders 2010-2020 has applied RCT designs and few with placebo controls and hybrid effectiveness-implementation designs. In descriptive contrast to secondary care, large-scale cohort studies in primary care have been less frequent, and national quality register infrastructure development in primary health care has been slow. In primary care, healthcare process indicators and patientrated outcomes are currently only collected for osteoarthritis, and the limited number of primary healthcare clinics providing multimodal team treatment of complex chronic pain conditions (23, 24) (Appendix 2). A primary healthcare quality registry is under development but currently only contains limited process indicator data for osteoarthritis but no other MSK disorders (25). Policy makers should, therefore, prioritize that these primary care national registries should capture a broader scope of MSK disorder data to help ensure the quality of primary care and support future research.
MSK pain disorder research in Swedish secondary health care has had a large focus on cohort studies, especially on the diagnosis, prognosis, and clinical course of chronic pain   conditions. However, the use of RCT designs has been increasing in frequency regarding rehabilitation for complex chronic conditions. The national quality register for pain rehabilitation in secondary care has developed with good national coverage and completeness and has future potential for supporting registerbased RCTs. MSK pain disorder research has received 18% of first-tier grants, and future research aiming to improve the quality of care and improve patient functioning, activity, and self-care ability should continue as high priority for researchers, funding bodies, and policymakers. Publications concerning preventative interventions were relatively few in primary (10%), occupational (0%), and secondary (<1%) healthcare systems, despite this being an integral part of especially primary and occupational health care (26,27). Furthermore, only 7% of first-tier research funding went toward preventative interventions 2010-2020. These preventative interventions were mainly related to bone health and osteoporosis, acute injuries, and falls/fracture prevention in the elderly. Healthcare consumer literature suggests that 90% of patients consulting a physiotherapist in primary care consider both preventative and treatment interventions important (22). MSK disorders among Europe's working-age population have a large economic burden, and productivity may be further undermined because of increasing chronic illness in an ageing population with increasing retiring age (2). Furthermore, screening and treating osteoporosis to prevent fractures is also of importance in an ageing population (28). Preventative interventions should, therefore, be a higher priority for researchers, funding bodies, policymakers, and clinicians aiming to implement evidence-based interventions in order to prevent MSK injuries, reduce chronicity, and improve patient self-care ability.
A total of 21% of primary healthcare research publications, 13% of secondary care publications, and small proportion of first-tier funding (3%) have been based on joint, tendon, and muscle injuries. In Sweden in 2009, the total population incidence of healthcare consultations for injuries such as joint distortions, joint luxation, and tendon and muscle injuries was 8.3/1,000, 1.6/1,000, and 1.8/1,000 population, respectively, with highest proportion of injuries in the younger population (29). Databases covering claims from compulsory insurance for sporting injuries suggest a national incidence for all types of sports and knee injuries of 10.2/1,000 athlete years (30). A large proportion of research publications have focused on knee injuries such as surgical treatment of anterior cruciate ligament (ACL) rupture and meniscal and/or cartilage damage, while achilles tendon ruptures have also been an area of interest. Over 50,000 primary ACL reconstructive surgeries have been reported in Swedish national knee ligament registry, which has good national coverage (Appendix 2). The registry is aiming for future inclusion of non-surgical intervention data collection as well as infrastructure for register RCT-based data collection (31). Despite the high volume of research activity, only few Swedish RCTs have compared effectiveness of surgical and rehabilitative interventions as well as attempted placebo-controlled designs. Improved registry infrastructure may aid better feasibility of conducting such research to improve quality of care.  Degenerative joint disorders including osteoarthritis and degenerative spinal conditions have attracted 12% of first-tier grants and produced 25% of secondary care publications. The prevalence of symptomatic degenerative joint disorders increases with age affecting up to one-third of the population and are ranked 11th among the leading causes of disability in the world (1). Biomarkers for the development of degenerative joint disorders have been a prevalent research theme in cohort studies. Surgical interventions have been the most prevalent interventions in cohort and RCT publications, which is reflected in the high surgery rates for degenerative joint disorders in Sweden and internationally (32). Again, only few Swedish RCTs have compared effectiveness of surgical and rehabilitative interventions as well as attempted placebo-controlled designs. Hip and knee arthroplasty as well as the spinal surgery national quality registries in Sweden provide good coverage and satisfactory completeness (Appendix 2), which could be utilized in the future to conduct national register RCTs rather than the current smaller single and multi-center ongoing RCTs that have received first-tier funding.
Research on fractures has produced 16% of secondary healthcare publications and 10% of first-tier grants, especially on diagnostic as well as surgical and other orthopedic-related interventions. In Sweden in 2009, the total population incidence of healthcare consultations for fractures was 18/1,000 population (29). Injuries due to falls have a high prevalence of disabling morbidity (1). The Swedish national fracture register records around 75,000 fractures each year that will continue to increase due to a greater coverage and completeness (Appendix 2). The register is the first in the MSK disorder field to conduct national register-based RCTs, providing a good example for future effectiveness research designs utilizing MSK-related national registers (33,34). There are several problems regarding fracture treatment that need further research priority such as effectiveness and implementation studies concerning the management of upper extremity fractures among the elderly (35).
Compared to other MSK disorders, rheumatic and inflammatory disorders have a lower incidence (1.2/1,000 population) and burden of disease (1). Approximately 30% of Swedish-affiliated secondary healthcare research publications and approximately half of the first-tier funding have been in the field of rheumatic and inflammatory disorders. There has been a large investment in Sweden on translational research programs covering the etiology, pathogenesis, and potential treatment mechanisms. Collaboration with industry has also helped the development and clinical implementation of disease-modifying antirheumatic drugs, which have been proven efficacious through large multicenter placebo controlled RCTs (36). The Swedish rheumatic quality register (SRQ) contains around 80,000 unique patients with high national coverage and satisfactory data completeness (Appendix 2). This provides strong infrastructure for monitoring the quality of care, aiding the implementation of knowledge into clinical practice and the future possibility of performing national registerbased RCT data collections.
To support the development of future register-based RCTs, Swedish guidelines have been developed (37). Use of the recently developed DITTO framework may help support the design of invasive placebo interventions, and recommendations for placebo-controlled trials in the rehabilitation field may help the planning of future high-quality RCT studies (38,39). Resource efficient hybrid designs for RCTs involving both effectiveness and implementation process evaluations are also attracting more attention to accelerate the translation of the research findings to real world practice (40).
There are several strengths and weaknesses one must consider in the interpretation of the current study's results. A strength of the methods is the use of a broad search criterion including MESH terms and relevant synonyms applied to relevant databases to capture the scope of recently published Swedish-affiliated MSK disorder researchers. The study selection process also involved independent reviewers and consensus meetings to solve ambiguities. This sampling procedure provided valid scope to aid future development of a national MSK clinical trial network in Sweden (SweMSK). This was followed by a process of database searches capturing the past 10 years of publications from this sample of recently published authors, and a manual study selection process was performed in a controlled manner by the review team. One must, however, keep in mind that the resulting scope of MSK research does not fully capture publications from previous authors who did have not recent publication activity.

Conclusions
There has been strong tradition in Swedish-affiliated MSK disorder research 2010-2020 regarding observational cohort research but substantially less RCT research and also skewed first-tier funding allocation considering prevalence/incidence and burden of disease. A larger focus on prevention and clinical intervention-based RCT research in primary and occupational health care may be warranted. Use of infrastructure supporting register-based RCTs, placebo-controlled RCTs, and hybrid effectiveness-implementation studies is important strategies for the future for primary, occupational, and secondary care.

Disclosure statement
LD is the co-founder and Chief Medical Officer of Joint Academy, a company that provides digital first-line intervention for patients with hip and knee osteoarthritis. The other authors declare that they have no conflicts of interest.

Funding
This study was financially supported by the Swedish Research Council, grant number (DNR 2019-06101).

Notes on contributors
Elias Diarbakerli, MSc, PhD, is a Physiotherapist and researcher at Karolinska University Hospital and the Department of Clinical Sciences, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden.