What’s New in Musculoskeletal Basic Science 2020
Every month, JBJS publishes a review of the most pertinent and impactful studies published in the orthopaedic literature during the previous year in 13 subspecialties. Click here for a collection of all such OrthoBuzz specialty-update summaries.
This month, co-author Philipp Leucht, MD selected the most compelling findings from the 15 studies summarized in the December 2, 2020 “What’s New in Musculoskeletal Basic Science.”
Spine: Annulus Fibrosus Findings
The relatively high prevalence of repeat discectomies has caused researchers to focus on characteristics of the annulus fibrosus, the healing of which often remains incomplete after disc herniation.
–Knowing that the neonatal annulus fibrosus shows regenerative capacity, researchers recently identified Scleraxis-lineage cells as the main contributors to those regenerative properties.1 They discovered that the neonatal cellular programming that results in complete functional restoration of the annulus fibrosus is completely absent in the adult annulus fibrosus after injury. Knowledge of this regenerative mechanism could help scientists develop new treatments for annulus fibrosus regeneration in adults.
–Related research demonstrated that the residual strain of the healthy nucleus pulposus generates pre-strain in the outer annulus fibrosus, and that the loss of residual strain, as seen in disc herniation, results in short-term apoptosis and the emergence of a fibrotic cell phenotype in the annulus fibrosus.2 Blocking cell contractility pathways may therefore offer a viable target to prevent post-injury fibrosis.
Spine: Somitogenesis
–The somitogenesis process in vertebrate development is believed to be controlled by an oscillating genetic “clock.” Researchers developed an in vitro modeling system to recapitulate the human segmentation clock,3 determining that the clock causes a new somite to be formed every 5 hours. This model allowed investigators to assess the function of mutations involved in segmentation defects such as congenital spondylocostal dysostosis. This easily manipulated model could provide the framework for discoveries of the gene oscillations and molecular underpinnings in both normal and abnormal vertebral development.
Osteoarthritis
–Transforming growth factor beta (TGF-β) signaling has been revealing in studying osteoarthritis. Researchers found that mice lacking in Prx1 osteochondral progenitors during development showed joint developmental defects.4 They further found that both postnatal ablation of Tgfbr2 in osteochondral progenitors and pharmacological inhibition of TGF-β receptor 2 led to an osteoarthritis phenotype with accompanied upregulation of the receptor antagonist IL-36α. They then discovered that an IL-36Ra intra-articular injection attenuates osteoarthritis progression in both Tgfbr2-deletion and posttraumatic arthritis models, confirming the IL-36 family as a viable target in fighting osteoarthritis.
Bone Regeneration
–Skeletal stem and progenitor cells migrate to sites of damage after an injury to participate in the repair process. Researchers recently discovered that the quiescent CXCL12-expressing perisinusoidal bone marrow stromal cells also participate in the repair process5 by converting into a skeletal stem-cell-like state after injury. These CCXL12-positive cells are highly malleable and long-living and thus represent an ideal source for bone tissue regeneration.
References
- Torre OM, Mroz V, Benitez ARM, Huang AH, Iatridis JC. Neonatal annulus fibrosus regeneration occurs via recruitment and proliferation of Scleraxis-lineage cells. NPJ Regen Med.2019 Dec 20;4:23.
- Bonnevie ED, Gullbrand SE, Ashinsky BG, Tsinman TK, Elliott DM, Chao PG, Smith HE, Mauck RL. Aberrant mechanosensing in injured intervertebral discs as a result of boundary-constraint disruption and residual-strain loss. Nat Biomed Eng.2019 Dec;3(12):998-1008. Epub 2019 Oct 14.
- Matsuda M, Yamanaka Y, Uemura M, Osawa M, Saito MK, Nagahashi A, Nishio M, Guo L, Ikegawa S, Sakurai S, Kihara S, Maurissen TL, Nakamura M, Matsumoto T, Yoshitomi H, Ikeya M, Kawakami N, Yamamoto T, Woltjen K, Ebisuya M, Toguchida J, Alev C. Recapitulating the human segmentation clock with pluripotent stem cells. 2020 Apr;580(7801):124-9. Epub 2020 Apr 1.
- Li T, Chubinskaya S, Esposito A, Jin X, Tagliafierro L, Loeser R, Hakimiyan AA, Longobardi L, Ozkan H, Spagnoli A. TGF-β type 2 receptor-mediated modulation of the IL-36 family can be therapeutically targeted in osteoarthritis. Sci Transl Med.2019 May 8;11(491):eaan2585.
- Matsushita Y, Nagata M, Kozloff KM, Welch JD, Mizuhashi K, Tokavanich N, Hallett SA, Link DC, Nagasawa T, Ono W, Ono N. A Wnt-mediated transformation of the bone marrow stromal cell identity orchestrates skeletal regeneration. Nat Commun.2020 Jan 16;11(1):332.
Preop X-Rays Don’t Predict TKA Patient-Reported Outcomes
OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from David Vizurraga, MD in response to a recent study in JBJS Open Access.
Whoever coined the phrase, “a picture is worth a thousand words” never treated a patient with knee osteoarthritis (OA). While knee OA is one of the most common conditions encountered in orthopaedic practice and its diagnosis and treatment are fairly straightforward, predicting the outcomes of total knee arthroplasty (TKA)—the definitive treatment for most cases of end-stage knee OA—can be challenging. The severity of OA on radiographs has long been debated as a tool to aid surgeons in predicting post-TKA outcomes and framing expectations for patients. In general, we tend to say, “The worse the x-ray, the better the patient-reported outcome,” and conversely, “The better the x-ray, the worse the patient-reported outcome.”
Lange et al. investigated this assumption in a study published in JBJS Open Access on July 9, 2020. The authors leveraged data from a 2-arm, randomized controlled trial that evaluated the role of “motivational interviewing” in enhancing rehabilitation following TKA. In their cohort analysis, Lange et al. compared pre- and postoperative WOMAC pain scores and KOOS activities-of-daily-living (ADL) scores with preoperative radiographic severity of knee OA, as measured by the Osteoarthritis Research Society International (OARSI) Atlas score. Among the 240 patients who had 2-year outcome measures and imaging available, the median preoperative OARSI score was 10 (on a scale of 0 to 18), and the authors defined “milder OA” as an OARSI score of <10 and “more severe OA” as a score of ≥10.
The researchers found a cohort-wide postoperative improvement in WOMAC pain and KOOS ADL scores of ~30 points, but they did not find any significant or clinically important differences in pain and function scores between patients with “milder OA” and “more severe OA.” The authors were also unable to demonstrate any correlation between radiographic severity and pain and function scores preoperatively.
Additionally, Lange et al. looked for associations between the WOMAC and KOOS improvements and 4 four other radiographic assessments of knee OA severity (Kellgren-Lawrence grade, compartment-specific OARSI score, compartment-specific joint-space-narrowing score, and 4-level OARSI score). Again, they failed to observe any clinically important postoperative differences in pain or function between the subjects with radiographically milder or more severe OA.
These findings provide further evidence that radiographs should represent only one piece in the puzzle of diagnosis and treatment planning for our patients with knee OA. To me, it’s worth noting that the study capitalized on data from a trial investigating motivational interviewing, which aims to improve outcomes by empowering patients—yet in the multivariable analysis that adjusted for several confounders, use of motivational interviewing was not among them. Still, the many aspects of outcome prediction following knee replacement are most definitely worthy and in need of continued investigation.
David Vizurraga, MD is a San Antonio-based orthopaedic surgeon specializing in adult hip and knee reconstruction and a member of the JBJS Social Media Advisory Board.
Osteoarthritis Progression: Our Current Understanding
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
Our understating of the progression pathways in knee osteoarthritis (OA) has evolved dramatically in recent years, as described in a recent review article.1 Over the past 2 decades, we have come to view the knee joint as an organ unto itself (with cartilage, synovium, bone, ligaments, and capsule). In the knee, we add to the mix the meniscus, which not only guides motion but is responsible for weight distribution on articular cartilage. Investigations into the etiology and progression of knee OA have merged joint mechanics with insights from studies of inflammation and immunology.
Woodell-May and Sommerfeld examine the process of knee OA as a wound-healing response. Triggered by damage-associated molecular patterns, the innate immune system is typically the first responder to this process. The acute phase in wound healing is short and involves infiltration of neutrophils. In response to neutrophil signals, monocytes migrate from the vessels and differentiate into macrophages, initially type I (inflammatory), which help form the granulation tissue seen in wound healing.
One take-home from the review article is that OA progression may be driven by the chronic inflammation associated with continuing efforts to heal. The back-and-forth between stimulating inflammation (M1 macrophages) and modulating inflammation (M2 macrophages) seems to be predominately driven from the synovium. In addition, specific receptors and intracellular kinases (such as toll-like receptors and mitogen-activated protein kinase) are upregulated in many OA samples.
M1 macrophages promote the elaboration of TNFα and IL-1 by synovial cells. Both cytokines are also active in rheumatoid arthritis (RA). Biologic treatment directed at either one of those cytokines can be effective in RA, but such treatment does not appear to be effective in OA. Over the past decade, the use of autologous conditioned serum (serum drawn off after blood is exposed to glass beads and incubated) has been studied in an attempt to reduce IL-1 activity. The conditioned serum also seems to affect TNFα and has shown some early promise in OA cases.
This burgeoning basic-science knowledge about OA has the potential to lead to disease-modifying treatments, which would revolutionize how orthopaedists approach OA treatment.
Reference
1. Woodell-May JE, Sommerfeld SD. Role of Inflammation and the Immune System in the Progression of Osteoarthritis. J Orthop Res. 2020 Feb;38(2):253-257. doi: 10.1002/jor.24457. Epub 2019 Sep 12. Review. PMID: 31469192
Association ≠ Causation: Are Steroid Injections for OA Risky?
A recent report in Radiology citing possible complications from injecting steroids into painful joints with osteoarthritis (OA) has received lots of attention in the mainstream media. Radiologists from Boston, Germany, and France reviewed the existing literature and found an association between intra-articular steroid injections and a small increased risk of four adverse joint findings: accelerated OA progression, subchondral insufficiency fracture, complications from osteonecrosis, and bone loss. However, the study did not include a control group that did not receive injections, and therefore it cannot be used to assess whether injections are associated causally with the adverse joint findings.
In an interview with Boston radio station WBUR, lead author Ali Guermazi, MD stressed the point that readers should not conclude from this report that steroid injections cause these complications, adding that additional research in this area is “urgently needed.” In the same radio coverage, Jeffrey Katz, MD, a professor of orthopaedic surgery at Boston’s Brigham & Women’s Hospital and a Deputy Editor at JBJS, said patients who have received such injections or plan to should not be overly worried. However, he added that “for clinicians and patients who’ve been doing injections for several years, it’s worth it to pause and say, ‘Do we want to discuss [again] what we think are the benefits and risks of this.’”
Let’s Continue Improving Hip-Implant Longevity
In October 2017, JBJS published results from a 10-year randomized controlled trial by Devane et al. documenting the dramatic reduction in polyethylene wear in total hip arthroplasties (THAs) using highly cross-linked polyethylene (HXLPE). This followed decades of research documenting that wear debris was implicated in macrophage activity that was ultimately responsible for implant loosening. In the September 4, 2019 issue of The Journal, Hart and colleagues produce further evidence of the improved performance of HXLPE, this time showing revision rates among THA patients with osteonecrosis that rival the rates among patients with osteoarthritis.
In this matched cohort of 922 THAs performed from 1999 to 2007 that used an HXLPE bearing, the 15-year cumulative rate of revision was 6.6% among patients treated for osteonecrosis and 4.5% among patients treated for osteoarthritis (p = 0.09). There were no radiographic signs of component loosening in the entire cohort, and, despite a lower median preoperative Harris hip score (HHS) among patients with osteonecrosis, both groups had marked improvements in HHS score. These findings are especially noteworthy because patients with osteonecrosis typically undergo THA at an earlier age and have much higher functional demands than the typical 70- or 80-year-old osteoarthritis patient.
However, the 15-year revision rate—even with HXLPE—remains at 4.5% for osteoarthritis patients, which should provide impetus to continue our work identifying all possible factors and mechanisms that lead to THA revision. A partial list would include bearing-surface wear, reliability of implantation, biomechanics, biomaterials, and patient perception of postoperative pain. Also, in a subgroup analysis, Hart et al. found that the 15-year rate of any reoperation among osteonecrosis patients ranged from 0% for hips with radiation-induced osteonecrosis to 25% for hips with idiopathic osteonecrosis. These findings add to the list of factors for THA success that need further investigation.
The work list for improvements in THA will remain substantive for at least the next few decades, and we may never get to 0% revisions for all patients. But we have certainly demonstrated that our research can produce very worthwhile results.
Marc Swiontkowski, MD
JBJS Editor-in-Chief
Sarcopenia’s Role in Knee OA Progression
OrthoBuzz occasionally receives posts from guest bloggers. This guest post comes from Jeffrey Stambough, MD, in response to a recent study in Arthritis & Rheumatology.
The incidence of total knee arthroplasty to treat end-stage knee osteoarthritis (OA) continues to rise even in the face of patient risk-stratification tools and alternative payment models. Consequently, payers, patients, and their doctors are placing a premium on methods to prolong the native knee joint and delay or avoid surgery. This partly explains the explosion of interest in biologics and the subsequent checkreins being put in place regarding their use.
As the AAOS clinical practice guidelines for the management of knee arthritis clearly state, the best management for symptoms of knee arthritis remains weight loss and self-directed physical activity. However, there is uncertainty regarding which subtypes of patients are likely to achieve OA symptom benefits with different weight-loss strategies.
A recent large, multicenter cohort study published in Arthritis & Rheumatology attempted to further characterize patient body composition and its association with knee OA. Using whole-body dual x-ray absorptiometry (DXA) measures of fat and muscle mass, researchers classified patients into one of four categories: nonobese nonsarcopenic, sarcopenenic nonobese, nonsarcopenic obese, or sarcopenic obese. Sarcopenia is the general loss of muscle mass associated with aging. If orthopaedic surgeons better understand how fat and muscle metabolism change with time and affect inflammation and chronic disease, they may be able to provide patients with additional insight into preventive measures.
Using DXA-derived calculations, the authors observed that among older adults, the relative risk of developing clinically significant knee osteoarthritis (Kellgren-Lawrence grade ≥2) at 5 years was about 2 times greater in both sarcopenic and nonsarcopenic obese male and female patients compared to nonobese, nonsarcopenic patients. Sarcopenia alone was not associated with risk of knee OA in women or men. In a sensitivity analysis focusing on BMI, men showed a 3-fold greater risk of knee OA if they were sarcopenic and obese, relative to nonobese nonsarcopenic patients.
The takeaway from this study is that focusing solely on fat/weight loss may overlook a valuable opportunity to slow the progression of knee arthritis in some patients. Further studies are needed to validate the contribution of low muscle mass to the development and progression of symptomatic knee arthritis.
Read this related OrthoBuzz post about sarcopenia’s relationship to mortality in elderly patients with acetabular fractures.
Jeffrey B. Stambough, MD is an orthopaedic hip and knee surgeon, an assistant professor of orthopaedic surgery at University of Arkansas for Medical Sciences, and a member of the JBJS Social Media Advisory Board.
Full-Thickness Cartilage Defects More Predictive of Future TKA than Joint-Space Narrowing
Many older patients present to orthopaedic surgeons with clinical knee pain suggestive of osteoarthritis (OA) but with little or no radiographic evidence of disease. And a substantial proportion of those patients do not respond adequately to the recommended, first-line nonsurgical treatment approaches to knee OA. A prognostic study by Everhart et al. in the January 2, 2019 issue of The Journal of Bone & Joint Surgery helps explain why that might be.
The authors evaluated baseline knee radiographs and MRIs from >1,300 older adults (mean age of 61 years) who were enrolled in the Osteoarthritis Initiative, a multicenter observational cohort study with a median of 9 years of follow-up data. They sought to determine independent risk factors for progression to total knee arthroplasty (TKA) among this cohort, all of whom showed Kellgren-Lawrence grade 0 to 3 OA on knee radiographs. MRIs taken at baseline revealed that 38% of those patients had a full-thickness knee-cartilage defect. After the authors adjusted for various confounders (including age, weight, and symptom severity), they found that regardless of radiographic grade, the presence of a full-thickness cartilage defect was a strong independent risk factor for subsequent TKA. Moreover, patients with a defect ≥2 cm2 had twice the risk of arthroplasty compared with patients with defects <2 cm2.
According to the authors, the findings highlight the “greater importance of full-thickness cartilage loss over radiographic OA grade as a determinant of OA severity, specifically regarding the risk of future knee arthroplasty in older adults.” In his commentary on this study, Drew A. Lansdown, MD emphasizes that Everhart et al. “do not advocate for the routine use of MRI in the diagnosis of knee osteoarthritis,” but he says the findings “do suggest that early MRI may have a diagnostic role for patients who are not responding as expected to nonoperative measures.” Noting that the patients in this cohort would probably not be ideal candidates for current cartilage-restoration procedures, Dr. Lansdown encourages further research focused on identifying “patient-specific factors that can match patients with the treatment…that will provide the greatest likelihood of symptom relief and functional improvement.”
Getting to the Core of Bone Marrow Lesions
This post comes from Fred Nelson, MD, an orthopaedic surgeon in the Department of Orthopedics at Henry Ford Hospital and a clinical associate professor at Wayne State Medical School. Some of Dr. Nelson’s tips go out weekly to more than 3,000 members of the Orthopaedic Research Society (ORS), and all are distributed to more than 30 orthopaedic residency programs. Those not sent to the ORS are periodically reposted in OrthoBuzz with the permission of Dr. Nelson.
The terms “bone marrow edema,” “bone marrow lesion” (BML), and “bone bruise” are often used interchangeably to refer to areas in cancellous bone that have hyperintense marrow signal in fluid-sensitive, fat-suppressed MRI sequences. Although most commonly observed in knee MRIs, BMLs can be seen in a variety of joints. In the hip, they are seen in transient osteoporosis and rapid-onset osteoarthritis. The term “bone bruise” is often specifically applied in the setting of an injury, such as lateral tibial plateau hyperintense changes that are seen after an anterior cruciate ligament rupture.
In the setting of knee osteoarthritis, BMLs are a response to degeneration of menisci, articular cartilage, synovium, or bone itself. One of the mechanisms associated with BMLs seems to be secondary to circulatory response and bone turnover. In one study covered in a 2017 review article1, patients with OA and associated BMLs were randomized to receive the bone antiresorptive agent zoledronic acid (ZA) or placebo. At 6 months, VAS pain scores in the ZA group were reduced by ZA, the reduction in BML area was greater in the ZA group than in the placebo group, and a greater proportion in the ZA group achieved a clinically significant reduction in BML size (39% vs. 18%, p <0.044). A larger study is planned to further define the relationship between reduction in BML size and pain scores.
Regarding “crosstalk” between subchondral bone and articular cartilage in joint disease, recent data suggest that numerous canals and porosities connect the bone to cartilage at the interface. Treatment of the bone compartment with antiresorptives and anti-TGF-β at specific early time points has been shown to have chondroprotective effects in animal models. Additionally, one study identified s14-3-3ε, a short extracellular protein, as a mediator critical in the communication between subchondral bone and cartilage in OA. This may prove to be a potential target for therapeutic or prognostic use.
Numerous articles have outlined the abundance of trabecular microfractures seen in areas where BMLs are present. A commonly held hypothesis is that resorption cavities caused by bone remodeling can act as stress concentrations, promoting further microdamage and leading to a cycle of damage-remodeling-damage. Some individuals may be more prone to rapid bone turnover and thus more prone to developing bone edema.
When your clinical attention is directed to BMLs, their shape and extent may influence nonsurgical treatment decisions. Conservative management may be directed by a better understanding of how BMLs contribute to pain and OA progression.
Reference
- Alliston T, Hernandez CJ, Findlay DM, Felson DT, Kennedy OD. Bone marrow lesions in osteoarthritis: What lies beneath. J Orthop Res. 2017 Dec 21. doi: 10.1002/jor.23844. [Epub ahead of print] PMID: 29266428
June 2018 Article Exchange with JOSPT
In 2015, JBJS launched an “article exchange” collaboration with the Journal of Orthopaedic & Sports Physical Therapy (JOSPT) to support multidisciplinary integration, continuity of care, and excellent patient outcomes in orthopaedics and sports medicine.
During the month of June 2018, JBJS and OrthoBuzz readers will have open access to the JOSPT article titled “Physical Activity and Exercise Therapy Benefit More Than Just Symptoms and Impairments in People With Hip and Knee Osteoarthritis.”
The authors issue a clear “call to action” for exercise therapy in patients with hip and knee osteoarthritis (OA), not only because it reduces arthritis symptoms, but also because physical activity helps prevent at least 35 chronic conditions and helps treat at least 26 chronic conditions.
April 12 Webinar – Managing Osteoarthritis: Moving from Volume to Value
According to the CDC, in 2013, the total national arthritis-related medical care costs and earnings losses among adults were $303.5 billion, or 1% of the 2013 US Gross Domestic Product.
One response to statistics like that is the notion of “value-based health care.” How far has the orthopaedic community moved from a volume/fee-for-service-based model to one in which patients achieve the best possible musculoskeletal outcomes, payers expend the fewest possible dollars, and providers throughout the episodes of care are fairly compensated for their skill and compassion?
On Thursday, April 12, 2018 at 8:00 pm EDT, the American Orthopaedic Association (AOA) and The Journal of Bone & Joint Surgery (JBJS) will host a complimentary one-hour webinar that will answer these thorny questions by discussing the cost drivers behind the problem, where arthritis management stands currently, and where the value-based care bandwagon is heading.
Kevin Shea, MD, an expert in developing clinical practice guidelines, will discuss the crucial differences between “irrational variation” and “rational, patient-centered variation.”
Antonia Chen, MD, director of arthroplasty research at Harvard Medical School, will demystify the many attempts to measure and improve the quality of joint replacement and will address quality and value in the nonoperative management of osteoarthritis.
Gregory Brown, MD, a Tacoma, Washington-based surgeon specializing in knee reconstruction, will peer into the future of health insurance, patient empowerment, and robust orthopaedic registries.
Moderated by Douglas Lundy, MD, orthopaedic trauma surgeon at Resurgens Orthopaedics, this webinar will include a 15-minute live Q&A session during which attendees can ask questions of the panelists.
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