Opportunities and Challenges in Musculoskeletal Biology and Diseases

Friday, December 9, 2011

NIH Campus, Building 31, Room 6C10
9:00 AM — 4:00 PM

Background and Approach

The goal of this meeting was to discuss basic, translational, and clinical research opportunities and challenges in musculoskeletal biology and diseases. Topics included developmental biology of connective tissues; joint structure and function; development, progression, and treatment of degenerative joint diseases and spinal disorders; imaging methods; prevention and repair of orthopaedic injuries; orthopaedic implants; and tissue engineering and regenerative medicine strategies to repair damaged bones and joints.

In advance of the meeting, participants were encouraged to consult with colleagues on the following questions:

• What are the most promising areas of science and the most pressing research needs, including rare diseases?
• What is needed to translate advances in the basic sciences into clinical practice? How can this be facilitated by enhanced collaborations between basic scientists, engineers, and clinicians?
• What are the greatest barriers, other than workforce issues, to research progress? What are the potential options for overcoming these barriers?
• What innovative, creative approaches are needed to understand and eliminate health disparities in treatments and outcomes among racial and ethnic groups?
• Are there more effective and efficient ways to carry out science in the present environment? How can these be implemented or encouraged within the current academic research system?

Although only a subset of topics were discussed in depth and are summarized here, NIAMS leadership and the appropriate program staff read each comment. The NIAMS greatly appreciates the community’s input on these questions.

Time was also reserved to discuss strategies to maintain the vitality of the scientific enterprise in an era of fiscal challenges.

Promising Areas of Science and Pressing Research Needs

The meeting started with participants briefly describing the most promising scientific areas and pressing research needs in their fields. Many comments related to four themes—tissue engineering; tissue interfaces; biomechanics and implant science; and musculoskeletal clinical research and evidence-based orthopaedic practice—which are summarized separately below.

The need for biomarkers of infection and osteolysis, which could provide insights into disease mechanisms or guide clinical care, was mentioned. Other topics included the mechanisms that limit the healing of soft tissues following injury; the mechanisms of muscle-fatty atrophy; the roles of progenitor cells in repair; and how age, sex, and disease influence susceptibility to injury and repair. Research into pain, the chief complaint of many people who have musculoskeletal injuries and disorders, was viewed as another need.

Tools for studying genomics and epigenomics have improved dramatically over the past five years. Participants saw numerous benefits of applying new analytic techniques to musculoskeletal biology—particularly to understand changes that occur during aging. The ability to analyze large data sets will also advance studies into the gene-environment interactions that influence bone and joint conditions, the genomics of rare diseases, and the role of inflammation in musculoskeletal disorders other than rheumatic diseases.

Tissue Engineering

Biomaterials are becoming increasingly sophisticated, and engineers have made great strides toward producing functional tubular structures (e.g., bladder, esophagus). Although cartilage could be considered a “simpler” tissue, researchers have difficulty integrating the implant into the surrounding bone and endogenous cartilage. Tissue engineers have looked to developmental biologists for insights. One participant suggested that research into the cues that influence limb regeneration in non-mammalian species might be more productive. Other opportunities might be found in studying the cellular processes of fibrosis or functional repair; the spatial and temporal cues for regeneration, healing, and development; and the chemical and mechanical signals influencing interactions between bone, nerves, connective tissue, and muscle.

Cellular and bioengineering products for the repair of critical-sized defects in bone and cartilage were viewed as a pressing clinical need. Because the damage often arises from trauma that also injures the surrounding soft tissue, tissue engineering advances that focus on multiple tissues should be considered. Mechanical forces play a large role in patients’ recoveries from less severe bone and joint injuries, and are likely to be equally important for conditions requiring musculoskeletal tissue engineering and regenerative medicine therapies.

Moving cell-based findings into clinical testing is going to depend on technical advances related to the standardization and scalability of cell sources and tissues. A discovery’s reproducibility and ultimate utility will be influenced by the extent to which the cell source is characterized. This will require advances in cell sorting techniques.

Imaging tools to assess tissue biology and functional status could be leveraged for studies on the sources of cells available to repair injured tissue, or the inflammatory cells that appear following an injury. Discussion of these needs was timely because, as part of the Multi-Agency Tissue Engineering Science (MATES) working group, the NIAMS and other agencies are sponsoring a workshop on Functional Imaging for Regenerative Medicine in May 2012.

Tissue Interfaces

The research community is beginning to recognize osteoarthritis (OA) as a disease of the entire joint. Whereas studies historically have focused on chondrocytes, cellular interactions among the synovium, bone and cartilage in healthy and degenerating joints are important during OA onset and progression. Bone’s response to mechanical forces is likely to contribute to joint health and disease. The influence of mechanical forces on chondrocyte differentiation is poorly understood.

Reattaching soft tissue to bone is an ongoing clinical challenge. When used, hardware selection is based on a surgeon’s professional judgment and experience; rigorously controlled studies could provide essential guidance. Research on the chemical and mechanical signals that stimulate fiber attachment could lead to molecular or cell-based therapies that promote post-surgical healing of connective tissue and would meet an important need. Participants emphasized the importance of studing these mechanisms in multiple sites, as the signals likely differ among joints (e.g., knee vs. shoulder vs. ankle) and among attachment sites within a joint (e.g., ACL vs. MCL).

Intervertebral disc (IVD) degeneration is a common cause of chronic back pain. Historically, the IVD has been very difficult to study, but recent findings about the molecular basis of disc degeneration, and the identification of signaling pathways, present a unique opportunity to address basic and translational research needs related to the IVD. Additional understanding of this area, combined with research into the corresponding changes in the vertebra and connective tissues that stabilize the spine, could lead to strategies for preventing or treating chronic back pain.

Biomechanics and Implant Science

Much of the discussion on biomechanics and implant science is focused on restoring function for people who have OA. Orthopaedic implants are being developed with materials that have antioxidants incorporated into them to make the implants more stable. The mechanisms contributing to wear and corrosion, and the body’s response as materials degrade, are of considerable interest to the orthopaedic community. Patient responses to materials are likely to vary; tools that allow surgeons to determine who should get what types of implants will require an understanding of host factors that contribute to positive outcomes and adverse events.

Research leading to the development of biologically active devices, such as for securing soft tissues to bone or for fracture fixation, holds promise for improved treatments. Biodegradable materials that are strong when initially implanted, but dissolve in a controlled manner as the patient heals, are one example. The development of materials that create an environment for coupled osteoclast-osteoblast activity also could have therapeutic value. An appreciation of how bone interacts with nanoscale features on an implant’s surface could lead to strategies for adjusting the implant to control the bone’s response. Another promising area involves embedding drugs on the implants with a release system that can be triggered if a patient needs them (e.g., if the patient develops osteolysis).

Results from studies on the influence of mechanical force on bone growth also could be applied to material science, and could lead to improved implants. In addition, advances in computer modeling will contribute to studies of how anatomic structure and external stimuli influence a body’s adaptation to implants, and an implant’s effect on contralateral joints.

Musculoskeletal Clinical Research and Evidence-based Orthopaedic Practice

Participants discussed research needs related to a variety of factors that influence a surgery’s success: the patient, the surgical technique or device, the surgeon, and the hospital and health system.

The NIAMS partners with the NIH Office of Behavioral and Social Sciences Research (OBSSR) and other NIH Institutes and Centers to encourage study of the interactions among biological, behavioral, and social factors that influence musculoskeletal health and disease. Although obesity is a well-known risk factor for OA, programs that lead to sustainable weight loss and can be implemented at a population level are lacking. Collaborations among behavioral, orthopaedic, and obesity researchers may help to address this public health problem.

As the research community moves closer toward pharmacological or tissue engineering approaches to halt or repair cartilage degeneration, the ability to identify people who are at greatest risk of OA and could benefit from such treatments will become more urgent.

Research that would contribute to the development of criteria regarding use of diagnostic procedures and treatments would help to counter a perception that orthopaedics is elective, expensive, and not evidence-based. Participants noted several orthopaedic conditions where there are critical needs for comparative effectiveness research (e.g., rotator cuff or meniscal tears, spinal compression fractures, distal radius fractures, and musculoskeletal injuries in children).

Several participants mentioned the need for evidence-based physical rehabilitation strategies following repair of various joints or tissues (e.g., hip, rotator cuff and Achilles’ tendon). Most important, however, is to prescribe regimens that patients will follow; even technically “perfect” operations produce poor outcomes if patients refuse to participate in post-surgical rehabilitation or are not given the appropriate regimen.

Health care providers could benefit from sound, epidemiologic evidence regarding the long-term impact of the treatments they offer patients. Mining of data records and the development of registries were mentioned as two ways to study interventions, such as certain pediatric orthopaedic procedures, that may not be amenable to clinical trials. Databases and registries also may allow researchers to identify associations that individual practitioners might not notice.

Translating Basic Science Advances into Clinical Practice

Small animal models, while essential for looking at molecular pathways and studying systemic diseases in combination with surgical models, fail to recapitulate the anatomic features of and forces experienced by some human joints (e.g., the upper extremities). The use of challenging in vivo and human-scale models aids the translation. Animal studies show us a great deal about tissue healing, but little about pain and function. The translation of animal data to humans is further complicated by repeated clinical observations of cases in which a repair fails, but the patient continues to do well. Differences between immune responses of humans and model systems also present a challenge when translating observations into clinical testing.

Other model systems, such as three-dimensional tissue culture or computer simulation of living system behavior, also have a place in musculoskeletal research. Several participants noted that many current models could be strengthened and validated by additional biological data about cell, tissue, or joint behavior during health and disease.

The inability to non-invasively monitor healing in patients remains a challenge for some tissues and joints (e.g., the rotator cuff). While ultrasound is inexpensive relative to magnetic resonance imaging, the research community has difficulties getting reproducible data to monitor changes associated with healing or failure.

Recognizing that academic collaborations require considerable effort, some institutions mentor clinicians who are working with basic researchers. At the early stage of a project, partnerships are thought to increase the likelihood that basic researchers will focus on developing techniques or materials that surgeons will use. Even at research-intensive universities, however, basic researchers and clinicians have different institutional pressures and reward systems. The perception that clinical, health services, and public health research are less exacting than laboratory science also can be difficult to overcome.

Participants expressed a desire to better understand the steps they need to take to commercialize resultant products. In response to concerns that a focus on translation of new discoveries to therapies could disadvantage basic science, NIAMS leadership emphasized that the balance between basic and applied research supported by the NIH has remained essentially constant for many years, and that the NIAMS is committed to maintaining the current balance.

Clinical trials remain the most scientifically rigorous way to answer many questions. But, the length of time required to get results renders some studies irrelevant by the time they are completed. Because resources to support clinical studies are finite, some researchers and funding entities are exploring systematic ways to gather information to guide priority setting. Modeling can provide information on the expected short- and long-term returns (including adverse events averted, quality of life years added, and dollars saved), which the funding entities can incorporate into their decision-making process.

Some barriers to clinical research exist at the institutional level. Others, such as human subjects protections, can be addressed in part by the federal government. NIH is leading an effort to improve the policy known as the Common Rule (45 CFR 46), which governs U.S. human subjects research.

The exchange of research findings among health care specialties will be increasingly important as new operative and non-operative treatments become available for people who have musculoskeletal conditions. Participants shared examples in which rheumatologists and orthopaedic surgeons are collaborating on medical research, patient care, and training activities.

Eliminating Disparities in Treatments and Outcomes Among Racial and Ethnic Groups

In May 2010, the American Academy of Orthopaedic Surgeons, the Orthopaedic Research Society, and the Association of Bone and Joint Surgeons sponsored a research symposium on disparities in musculoskeletal health care ¹. Topics included gender and ethnic disparities in joint replacement surgeries as a treatment for people who have OA; pain management; osteoporosis screening and diagnosis of fragility fractures; and lower limb amputation due to diabetes.

Disparities have many facets. Often, strategies to reduce disparities focus on a patient’s understanding of the risks and benefits of treatment. Many people interpret disparate surgical rates as meaning worse care for minorities. For some conditions, however, the more informed patients are less likely to choose surgery. Although shared decision-making is an essential element of patient care, an individual’s preferences do not excuse health care inequalities.

One participant noted that factors beyond knowledge of a procedure’s risks and benefits greatly influence health care choices. For example, disparate access to high-volume surgical centers can affect whether one group experiences better post-surgical outcomes than another. As models of care change, organizations will be challenged to develop long-term, sustainable strategies to resolve disparities. Understanding the factors driving differences in use and outcomes of surgical and non-surgical treatments could improve the clinical outcomes for all people.

Ethnic differences with respect to OA prevalence, severity, and treatment choices have been documented. The Institute encourages research to evaluate risk factors for the development and progression of OA in vulnerable populations. The Osteoarthritis Initiative (OAI), led by NIAMS and the National Institute on Aging (NIA), and the Multicenter OA Study (MOST), led by NIA, contain data from large subcohorts of African Americans who have or are at high risk of knee OA.

Training the Next Generation of Researchers

Participants discussed strategies to develop a diverse, culturally competent workforce in musculoskeletal research and health care. Participants who had experience with the NIH Minority Access to Research Careers (MARC) program and other diversity supplements were supportive of NIH efforts.

Professional societies and institutions have a responsibility to support early-stage investigators. NIAMS has a history of partnering with entities to foster training and career development activities for researchers who are interested in musculoskeletal research [e.g., the National Research Service Award Postdoctoral Fellowships in Epidemiology, Clinical Trials, and Outcomes Research in Orthopaedic Surgery (F32)]. Organizations that are curious about developing similar programs are encouraged to talk to NIAMS staff about shared interests.

Health care providers and their institutions have invested heavily in developing electronic medical records (EMR) systems. Recognizing the impact of pain, fatigue, physical functioning, emotional distress, and social role participation on quality-of-life, some have expressed an interest in incorporating the NIH’s Patient-Reported Outcomes Measurement Information System (PROMIS) into their EMRs. The NIH is developing a Common Fund Program, called the HMO Collaboratory, to enhance cooperation between the NIH and health care organizations. A goal is to leverage data in EMRs to facilitate clinical research.

Maintaining the Vitality of the Scientific Enterprise in an Era of Fiscal Challenges

Given the interest in maintaining robust research programs and the scientific work force during the current budget climate, time was reserved for participants to discuss ideas outlined in the NIH Office of Extramural Research “Rock Talk” blog and a presentation on “Ways of Managing NIH Resources.” Although not mentioned in the background materials, participants expressed concern about NIH’s decision to eliminate the A2 resubmission applications.

Much of the discussion focused on NIH’s investment in expensive studies. Consistent with NIH policy, all investigators requesting direct costs of $500,000 or more for a single year must have NIAMS’ prior agreement to submit an application. The decision to accept an application for a costly project is based on whether the proposed research directly relates to the mission of the Institute and fits within the NIAMS budget; peer reviewers independently advise on the application’s technical and scientific merit and impact. In response to a question about how a project’s size relates to investigator productivity, participants were referred to an analysis done by the National Institute of General Medical Sciences on a related topic.

As part of its mandate to devise strategies to treat diseases within its mission, NIAMS is committed to supporting timely and informative investigator-initiated clinical trials. Recognizing that a clinical trial can require a substantial commitment by the Institute in terms of financial and personnel resources, NIAMS has enhanced its clinical trials portfolio by initiating a two-part grant process. Beginning with its FY 2012 awards, NIAMS is strongly encouraging investigators to apply for a planning grant in advance of requesting support for a full trial.

AAOS/ORS/ABJS Musculoskeletal Healthcare Disparities Research Symposium: Editorial comment: A call to arms: eliminating musculoskeletal healthcare disparities. O'Connor MI, Lavernia CJ, Nelson CL. Clin Orthop Relat Res. 2011 Jul;469(7):1805-8. PMID: 21468786