What’s New in Musculoskeletal Basic Science 2019

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 summaries. This month, co-author Philipp B. Leucht, MD selected the most clinically compelling findings from the 40 studies summarized in the December 4, 2019 “What’s New in Musculoskeletal Basic Science.

Muscle Regeneration
–Recent findings about the cellular players in muscle regeneration may allow further development of clinical treatment options for patients with muscle sprains, tears, and loss. Toward that end, Wosczyna et al. established the crucial role of fibroadipogenic progenitors (FAPs, also called mesenchymal stromal cells) in muscle repair and maintenance.1 Using a mouse model, the researchers showed that FAPs are necessary for muscle regeneration by supporting muscle stem cells.

Bone-Brain Crosstalk
–The bone-derived hormone osteocalcin supports development of the musculoskeletal system and the brain. Osteocalcin can regulate anxiety and cognition in adult mice, and Obri et al. postulated that declining levels of osteocalcin may be responsible for the cognitive decline seen in aging.2 This finding may spur investigations into exogenous treatment with osteocalcin to restore brain function.

Tendon Regeneration
–Tendon cells express the transcription factor Scleraxis, which has facilitated the identification of the tendon stem progenitor cell (TSPC). Best and Loiselle identified a Scleraxis-positive cell population in the bridging scar tissue after tendon injury.3 These findings suggest that TSPCs are present in the adult tendon and contribute to the healing response; however, their small number does not result in successful tendon regeneration, but rather in scar formation with interspersed tendon tissue.

–Abraham et al. identified the upregulation of NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) and its downstream targets in tendinopathy-affected human rotator cuff tendons.4 Using a transgenic mouse model in which IKKß (inhibitor of nuclear factor kappa-B kinase subunit beta), a key regulator of inflammation, was overexpressed, they demonstrated the development of tendinopathy in mouse rotator cuff tendons. The deletion of IKKß had a protective effect from chronic overuse.

Bone Regeneration
–Successful bone healing after fracture is highly dependent on the presence and activation of skeletal stem cells. Chan et al. precisely defined the human skeletal stem cell (hSSC), demonstrated the hSSC’s role in human fracture repair, and provided evidence that these cells generate a bone marrow-supportive niche.5 These cells also give rise to bone, cartilage, and stromal progenitor cells.

References

  1. Wosczyna MN, Konishi CT, Perez Carbajal EE, Wang TT, Walsh RA, Gan Q, Wagner MW, Rando TA. Mesenchymal stromal cells are required for regeneration and homeostatic maintenance of skeletal muscle. Cell Rep.2019 May 14;27(7):2029-2035.e5.
  2. Obri A, Khrimian L, Karsenty G, Oury F. Osteocalcin in the brain: from embryonic development to age-related decline in cognition. Nat Rev Endocrinol.2018 Mar;14(3):174-82. Epub 2018 Jan 29.
  3. Best KT, Loiselle AE. Scleraxis lineage cells contribute to organized bridging tissue during tendon healing and identify a subpopulation of resident tendon cells. FASEB J.2019 Jul;33(7):8578-87. Epub 2019 Apr 5.
  4. Abraham AC, Shah SA, Golman M, Song L, Li X, Kurtaliaj I, Akbar M, Millar NL, Abu-Amer Y, Galatz LM, Thomopoulos S. Targeting the NF-κB signaling pathway in chronic tendon disease. Sci Transl Med.2019 Feb 27;11(481):eaav4319.
  5. Chan CKF, Gulati GS, Sinha R, Tompkins JV, Lopez M, Carter AC, Ransom RC, Reinisch A, Wearda T, Murphy M, Brewer RE, Koepke LS, Marecic O, Manjunath A, Seo EY, Leavitt T, Lu WJ, Nguyen A, Conley SD, Salhotra A, Ambrosi TH, Borrelli MR, Siebel T, Chan K, Schallmoser K, Seita J, Sahoo D, Goodnough H, Bishop J, Gardner M, Majeti R, Wan DC, Goodman S, Weissman IL, Chang HY, Longaker MT. Identification of the human skeletal stem cell. 2018; Sep 20;175(1):43-56.e21.

3 Reference Axes Help Ensure Rotational Alignment During TKA

Rotational malalignment of the femoral component during total knee arthroplasty (TKA) is associated with poor outcomes, but how best to assess femoral component rotation intraoperatively remains an unanswered question for arthroplasty surgeons. Now, in the largest study of its kind, Jang et al. conclude in the December 4, 2019 issue of JBJS that combining 3 reference axes is the optimal strategy for ensuring accurate femoral component positioning, sex/ethnic generalizability, and intraoperative efficiency.

The authors compared 5 reference axes commonly used for intraoperative assessment of femoral component rotation by mapping them to >2,100 entire-femur CT scans from patients with nonarthritic knees. Using the surgical transepicondylar axis (sTEA) as the gold-standard reference, Jang et al. found that no single other axis was both highly accurate and relatively immune to ethnic and sex variability. Based on their findings, they instead recommend using a combination of 3 axes—posterior condylar axis externally rotated 3° (PCA + 3° ER), the Whiteside or sulcus line, and the anatomical transepicondylar axis (aTEA)—to ensure rotational alignment.

The authors also suggest a straightforward intraoperative process for using these 3 axes:

  1. Start with the PCA + 3° ER, which most accurately approximates the gold-standard sTEA.
  2. Then use the Whiteside or sulcus line, neither of which is significantly affected by sex or ethnicity.
  3. Finally, palpate for the aTEA to narrow the margin of error.

Citing a limitation to this CT-based study of nonarthritic knees, the authors note that “we could not account for the effects of cartilage wear or other changes caused by degenerative arthritis.”

RCT: Single IV Dose of TXA Is Safe, Effective for TKA

Along the spectrum of early and late adopters in medicine, most orthopaedic surgeons fall in the middle. They wait for science to prove the efficacy and safety of an innovation, carefully review the published studies regarding that innovation, and adopt it if it will improve their patients’ outcomes.

In the December 4, 2019 issue of JBJS, Jules-Elysee et al. compare tranexamic acid (TXA) administered intravenously (IV) versus topically in a double-blinded, randomized controlled trial (RCT) of patients undergoing primary total knee arthroplasty (TKA).  Level-I evidence is rare in the orthopaedic literature, so when a well-performed RCT comes out, we should closely evaluate its findings.

A potent antifibrinolytic, TXA has been shown in multiple studies to decrease blood loss associated with major orthopaedic procedures. However, there are persistent (but not necessarily evidence-based) concerns about its potential to cause thrombogenic complications,  and the safest and most effective route of TXA administration remains an open question.

In this study, the IV group received TXA once before tourniquet inflation and again 3 hours later, along with a topical placebo given 5 minutes before tourniquet release.  The topical group received an IV placebo at the same time intervals as the IV group, along with TXA delivered topically in the wound prior to tourniquet release. The authors found lower systemic levels of plasmin-anti-plasmin (PAP, a measure of fibrinolysis) in both groups 1 hour after tourniquet release, but PAP levels remained significantly lower in the IV group (indicating higher antifibrinolytic activity) 4 hours after tourniquet release, which was likely related to the second IV dose of TXA.

The authors also found no between-group difference in systemic or wound levels of prothrombin fragment 1.2 (PF1.2, a marker of thrombin generation), indicating there was no increase in thrombogenicity in the IV group.  Interestingly, Jules-Elysee also found that the IV group had significantly higher hemoglobin and hematocrit levels 1 and 2 days after surgery, and those patients had a significantly shorter hospital stay.

Finding no major between-group differences in the mechanism of action, coagulation, or fibrinolytic profile, the authors concluded that a single IV dose of TXA may be the most simple protocol for hospitals to adopt if they are still concerned about TXA safety. Perhaps these Level-I findings will help some of the late adopters get over their fears about the safety of IV TXA.

Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media

Meta-Analysis Quality Improving, But Issues Remain

Hip and knee arthroplasty are common procedures worldwide and are increasing annually as demographics change and the technical aspects of these surgeries become more accessible to a broader swath of surgeons. The sheer number of these procedures makes them an appropriate focus for randomized controlled trials (RCTs). The aggregation of RCT data into more powerful statistical frameworks is the job of a meta-analysis.

Not surprisingly, we have seen an increasing number of meta-analyses related to hip and knee replacement published across all major orthopaedic journals during the last two decades. Authors have two common motivations for conducting meta-analyses. The first, to summarize data from carefully conducted RCTs into clinically relevant and important recommendations, is hopefully the most common motivation—and certainly the most justifiable. The second, to merely use previously published data as an analytic exercise to advance one’s academic career without investing the time and effort to do prospective research, is not justifiable, in my estimation.

In the December 4, 2019 issue of The Journal, Park et al. conduct quality and usefulness assessments of 114 published meta-analyses about hip and knee arthroplasty that appeared in 3 major orthopaedic journals (one of which was JBJS) from 2000 to 2017. They document a nearly 4-fold increase in the number of meta-analyses published on these topics when comparing 2000 to 2009 with 2010 to 2017. Based on Oxman-Guyatt Index scores of overall study quality, only 12 of the 114 studies were assessed as high quality, 87 as moderate quality, and 15 as low quality.

Here are some additional findings:

  • The majority of these meta-analyses were not performed in accordance with established PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.
  • Only 39% of these articles showed the risk of bias.
  • Many of these meta-analyses covered redundant topics within the same year or within a few years of each other.
  • A review by expert attending surgeons of the 24 studies determined to be high quality per PRISMA found that 71% were either clinically unimportant or inconclusive.

It is a positive step to highlight for our readers the important quality issues surrounding meta-analyses, and I agree with James Stoney, who commented on these findings: “The onus is on surgeons to carefully scrutinize meta-analyses…and come to individual conclusions about the quality of the research rather than accept the conclusions at face value.”

But I am discouraged to see the number of problematic meta-analyses that have appeared in our literature, and I suspect most of these quality problems arise from the second, unjustifiable motivation noted above. We need to do better as a research community, as peer reviewers, and as journal editors to improve the quality of published meta-analyses so that we can favorably impact patient care and advance the clinical practice of hip and knee arthroplasty.

Marc Swiontkowski, MD
JBJS Editor-in-Chief

Factors Affecting Union after Capanna Reconstruction

Resection of long-bone tumors often leaves large skeletal defects. Since the late 1980s, surgeons have used the “hybrid” Capanna technique—a vascularized fibular graft inlaid in a massive bone allograft—to fill those voids, with good functional outcomes reported. In the November 20, 2019 issue of The Journal of Bone & Joint Surgery, Li et al. report on factors influencing union after the Capanna technique.

The authors radiographically evaluated Capanna-technique reconstructions in 60 patients (10 humeral, 33 femoral, and 17 tibial) and correlated allograft-host union time to the following variables:

  • Patient age
  • Tumor site
  • Adjuvant treatment (e.g., chemotherapy)
  • Previous surgical procedures
  • Defect length
  • Fixation method
  • Fibular viability (assessed with a bone scan 10 days after reconstruction)

They also histologically analyzed a retrieved specimen from one patient.

Among these 60 reconstructions, the mean defect length was 16 cm, and the mean time to union of the constructs was 13 months. The overall survival rate of the constructs was 93% at the latest follow-up.

Multivariate linear regression revealed no correlation between allograft-host osseous union time and patient age, defect length, tumor site, or fixation method. Conversely, devitalization of the transplanted fibular graft, chemotherapy administration, and a previous surgical procedure were associated with a prolonged union time. Histologically, the allograft-host cortical junction was united by callus from periosteum of both the host bone and the fibular graft.

Li et al. conclude that “ensuring patent vascular anastomoses of the transplanted fibula is crucial to prevent delayed or nonunion.” They also suggest that Capanna-technique patients who have any of the 3 “adverse factors” noted above should be treated with extended postoperative immobilization and delayed weight-bearing.

Pain Management Symposium Focuses on Study Design

Designing studies to answer questions about surgical procedures takes a lot of thought, effort, and experience. Creating robust study designs to investigate pain management related to musculoskeletal conditions and procedures presents additional, unique challenges.

On November 19, 2019, more than 30 orthopaedic researchers and journal editors convened to identify—and propose solutions for—those challenges. The one-of-a-kind Pain Management Research Symposium was supported by a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS award number 1R13AR076879-01) and hosted by The Journal of Bone & Joint Surgery.

Several themes emerged from the daylong discussions and presentations:

  • Despite the fact that 80% of opioid prescriptions worldwide originate in the US, outcome measures going forward should focus on effective pain management rather than reduced or “zero” opioids.
  • The wide variability of definitions of key research terms such as “opioid naïve” and “persistent opioid use” makes it difficult to reach robust conclusions from prior opioid/pain management research.
  • Beware false equations/assumptions. For example, opioid prescription filling is not the same as opioid consumption, and persistent opioid use after surgery does not equal iatrogenic opioid dependence.
  • Surgeons and other physicians must maintain a biopsychosocial perspective on pain management. Risk factors for persistent use of opioids include mental/emotional states such as depression and catastrophizing.
  • Despite some equivocal reports in the orthopaedic literature, there is no convincing evidence that NSAIDs negatively affect fracture healing. Therefore, absent specific patient contraindications, NSAIDs can be considered for pain management in trauma cases.

Many more details from the Pain Management Research Symposium will appear in a special JBJS supplement, scheduled for publication in the first half of 2020.

The Journal would again like to thank all the participants for their time and energy and NIAMS for its support.

“Homemade” Negative-Pressure Wound Device Works as Well as Commercial NPWT

Innovation in medicine has brought innumerable improvements in patient care. For example, as late as the Vietnam War era, femoral shaft fractures were frequently treated with prolonged periods of traction—until intramedullary rods gained popularity because they helped patients mobilize soon after the injury. Similarly, negative-pressure wound therapy (NPWT) gained popularity in the 1990s because it was so helpful with treating open wounds in orthopaedics. NPWT has been a mainstay in the treatment of Wounded Warriors with blast injuries during the last 18 years of conflicts in Afghanistan, Iraq, and other war zones. But medical innovations such as NPWT often come with a high cost, which has made access to commercial NPWT unfeasible in many low-income, resource-challenged countries. Sadly, those places are also home to many patients who sustain devastating soft-tissue injuries.

In the November 20, 2019 issue of JBJS, Cocjin et al. from the Philippines report results from a randomized controlled trial that compared 7-day outcomes from a commercially available NPWT system to those from an innovative, low-cost system that the authors developed locally and have been using at their institution since the mid-2000s. This home-grown system consists of an aquarium pump converted into a reusable vacuum source, along with basic hospital supplies such as surgical gauze, tubing, and plastic food wrap. The authors also compared the cost of the two systems.

For most of the measured clinical outcomes, Cocjin et al. found that their innovative NPWT system was noninferior to the commercially available system. It was actually better (but not significantly so) in terms of time of application, pain during dressing changes, and wound-contraction percentages. There were no complications with either system, and the system made from the aquarium pump and hospital supplies cost 7 times less than the commercial device ($63.75 compared to $491.38 USD).  The converted aquarium-pump system can be used up to 20 times, making its per-use cost as low as $3.

Innovation is vital to advancing orthopaedics. But we must also remember that low-cost innovation is equally important for a large portion of the worldwide patient and provider population that is resource-constrained. I applaud Cocjin et al. for sharing their locally developed innovation with the wider orthopaedic community. Although further validating studies are needed, this “homemade” NPWT system has the potential to bring to a large portion of the world a cost-effective alternative to a wound-management technique that has become a mainstay in more affluent settings over the past 2 decades.

Matthew R. Schmitz, MD
JBJS Deputy Editor for Social Media

What’s New in Orthopaedic Rehabilitation 2019

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 summaries.

This month, co-author Nitin B. Jain, MD, MSPH selected the most clinically compelling findings from the 40 studies summarized in the November 20, 2019 “What’s New in Orthopaedic Rehabilitation.

Pain Management
–A randomized controlled trial compared pain-related function, pain intensity, and adverse effects among 240 patients with chronic back, hip, or knee pain who were randomized to receive opioids or non-opioid medication.1 After 12 months, there were no between-group differences in pain-related function. Statistically, the pain intensity score was significantly lower in the non-opioid group, although the difference is probably not clinically meaningful. Adverse events were significantly more frequent in the opioid group.

–A series of nested case-control studies found that the use of the NSAID diclofenac was associated with an increase in the risk of myocardial infarction in patients with spondyloarthritis and osteoarthritis, relative to those taking the NSAID naproxen.2

–Intra-articular injections of corticosteroids or hyaluronic acid are often used for pain relief prior to an eventual total knee arthroplasty (TKA). An analysis of insurance data found that patients who had either type of injection within three months of a TKA had a higher risk of periprosthetic joint infection (PJI) after the operation than those who had injections >3 months prior to TKA.

Partial-Thickness Rotator Cuff Tears
–A randomized controlled trial of 78 patients with a partial-thickness rotator cuff compared outcomes of those who underwent immediate arthroscopic repair with outcomes among those who delayed operative repair until completing 6 months of nonoperative treatment, which included activity modification, PT, corticosteroid injections, and NSAIDs.3 At 2 and 12 months post-repair, both groups demonstrated improved function relative to initial evaluations. At the final follow-up, there were no significant between-group differences in range of motion, VAS, Constant score, or ASES score. Ten (29.4%) of the patients in the delayed group dropped out of the study due to symptom improvement.

Stem Cell Therapy
–A systematic review that assessed 46 studies investigating stem cell therapy for articular cartilage repair4 found low mean methodology scores, indicating overall poor-quality research. Only 1 of the 46 studies was classified as excellent, prompting the authors to conclude that evidence to support the use of stem cell therapy for cartilage repair is limited by a lack of high-quality studies and heterogeneity in the cell lines studied.

References

  1. Krebs EE, Gravely A, Nugent S, Jensen AC, DeRonne B, Goldsmith ES, Kroenke K, Bair MJ, Noorbaloochi S. Effect of opioid vs nonopioid medications on pain-related function in patients with chronic back pain or hip or knee osteoarthritis pain: the SPACE randomized clinical trial. JAMA. 2018 Mar 6;319(9):872-82.
  2. Dubreuil M, Louie-Gao Q, Peloquin CE, Choi HK, Zhang Y, Neogi T. Risk ofcmyocardial infarction with use of selected non-steroidal anti-inflammatory drugs incpatients with spondyloarthritis and osteoarthritis. Ann Rheum Dis. 2018 Aug;77(8): 1137-42. Epub 2018 Apr 19.
  3. Kim YS, Lee HJ, Kim JH, Noh DY. When should we repair partial-thickness rotator cuff tears? Outcome comparison between immediate surgical repair versus delayed repair after 6-month period of nonsurgical treatment. Am J Sports Med. 2018 Apr;46(5):1091-6. Epub 2018 Mar 5.
  4. Park YB, Ha CW, Rhim JH, Lee HJ. Stem cell therapy for articular cartilage repair: review of the entity of cell populations used and the result of the clinical application of each entity. Am J Sports Med. 2018 Aug;46(10):2540-52. Epub 2017 Oct 12.

The Evolution of Orthopaedic Surgical Skills Simulation

Surgical skills education in orthopaedics has changed dramatically from the “see one, do one, teach one” process of 30 years ago. These changes have come with a greater degree of supervision and formal skills assessments, and they have been aided by the visionary leadership at the Accreditation Council for Graduate Medical Education (ACGME) and our own orthopaedic Residency Review Committee. These skill-acquisition enhancements have benefited both our trainees and the patients we collectively care for.

A decade ago, we entered a new phase of skill development and enhancement with computer-based surgical simulators. With advances in software and widespread interest across North America in goal-driven learning through simulation, great progress has been made. In the November 20, 2019 issue of JBJS, Weber et al. report on the further validation of a surgical simulator focused specifically on percutaneous, fluoroscopically guided pin placement for femoral neck fractures. The simulator was developed in partnership between the AAOS and OTA.

This study sought to determine whether novice practitioners (medical students, in this case) who completed 9 training modules before using the simulator (the “trained” group) would perform the simulated pinning task better than peers who did not complete the presimulation training (the “untrained” group). It was no surprise to me that the trained group had a significantly higher overall performance score on the simulator. In addition, relative to the untrained group, the trained students also showed improved performance on 4 specific measures—3 of which were related to the angle between the placed pins.

These findings are clearly supportive of continued development of this and additional simulation environments. But at the same time, we need to move forward with improved documentation of surgical skill acquisition among orthopaedic residents and fellows. As simulator technology continues to improve, the next decade should yield even more positive results in skills acquisition than we saw in the last decade. We are clearly on the right path with the use of advanced technology for surgical skill development among orthopaedic trainees.

Marc Swiontkowski, MD
JBJS Editor-in-Chief

Sprifermin: Another Shot at Joint Preservation

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.

To date, we have found only one documented disease-modifying intervention that slows the progression of knee osteoarthritis (OA)—weight loss.1 There are few positive findings about drugs or other therapeutic interventions that might prolong the life of the human joint. However, sprifermin, a recombinant human fibroblast growth factor that can be genetically engineered from bacteria, has been tested in a randomized proof-of-concept trial as an intra-articular injection in humans,2 with modestly promising results.

In a very recent study on the effect of sprifermin and several other potentially disease-modifying compounds on bovine chondrocytes, researchers used 3D cultures to assess chondrocyte proliferation and/or extracellular matrix production.3 All of the growth factors evaluated, including sprifermin, resulted in elevated markers of anabolic chondrocyte activity. For the most part, cyclic doses were more effective than continuous doses over 4 weeks. Of importance, only sprifermin decreased type I collagen expression and had no hypertrophic effects. The authors conclude in the abstract that “these results confirm that sprifermin is a promising disease-modifying OA drug.”

In a 5-year randomized human dose-finding trial,4 patients with symptomatic knee OA were divided into 5 groups, as follows:

  1. 100 μg of sprifermin administered every 6 months (n = 110)
  2. 100 μg of sprifermin administered every 12 months (n = 110)
  3. 30 μg of sprifermin administered every 6 months (n = 111)
  4. 30 μg of sprifermin administered every 12 months (n = 110)
  5. Placebo injections administered every 6 months (n = 108)

The greatest changes in the primary endpoint—increased total femorotibial joint cartilage thickness from baseline to 2 years—was 0.05 mm (95% CI, 0.03 to 0.07 mm) in the group that received 100 μg of sprifermin every 6 months and 0.04 mm (95% CI, 0.02 to 0.06 mm) in the group that received 100 μg of sprifermin every 12 months. However, compared with the placebo group, those receiving sprifermin had no statistically different change in WOMAC scores. On average, 40% of all the patients in the study experienced arthralgia associated with the injections.

More certainty about the efficacy, safety, and durability of sprifermin may come when data from the remaining 3 years of this study are analyzed (see ClinicalTrials.gov identifier NCT01919164).

References

  1. Gersing AS, Solka M, Joseph GB, Schwaiger BJ, Heilmeier U, Feuerriegel G, Nevitt MC, McCulloch CE, Link TM. Progression of cartilage degeneration and clinical symptoms in obese and overweight individuals is dependent on the amount of weight loss: 48-month data from the Osteoarthritis Initiative. Osteoarthritis Cartilage. 2016 Jul;24(7):1126-34. doi: 10.1016/j.joca.2016.01.984. PMID: 26828356 PMCID: PMC4907808.
  2. Lohmander LS, Hellot S, Dreher D, et al. 2014. Intraarticular sprifermin (recombinant human fibroblast growth factor 18) in knee osteoarthritis: a randomized, double-blind, placebo-controlled trial. Arthritis Rheumatol. 66(7):1820–31.
  3. Müller S, Lindemann S, Gigout A. Effects of sprifermin, IGF1, IGF2, BMP7 or CNP on bovine chondrocytes in monolayer and 3D culture. J Orthop Res. 2019 Oct 14. doi: 10.1002/jor.24491. [Epub ahead of print] PMID: 31608492.
  4. Hochberg MC, Guermazi A, Guehring H, Aydemir A, Wax S, Fleuranceau-Morel P, Bihlet AR, Byrjalsen I, Andersen JR, Eckstein F. Effect of Intra-Articular Sprifermin vs Placebo on Femorotibial Joint Cartilage Thickness in Patients With OsteoarthritisThe FORWARD Randomized Clinical Trial. JAMA. 2019;322(14):1360-1370. doi:10.1001/jama.2019.14735