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Overselling Stem Cells?

Stem Cells for OBuzzThis 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.

In orthopaedics, the term “biologics” is often applied to cell-based therapies. There are a number of centers using mesenchymal stem cells (MSCs) in musculoskeletal medicine, and a recent systematic review assessed the quality of literature and procedural specifics surrounding MSC therapy for osteoarthritis (OA)1.

The authors searched four large scientific databases for studies investigating MSCs for OA treatment. Among the 61 articles analyzed, 2,390 OA patients were treated, most with adipose-derived stem cells (ADSCs) (n = 29 studies) or bone marrow-derived stem cells (BMSCs) (n = 30 studies), though the preparation techniques varied within each group. In a subanalysis of 5 Level I and 9 Level II studies (288 patients), researchers found that 8 studies used BMSCs, 5 used ADSCs, and 1 used peripheral blood stem cells. A risk-of-bias analysis showed 5 Level I studies at low risk, 7 Level II studies at moderate risk, and 2 Level II studies at high risk. The authors concluded that although there is a “notion” that MSC therapy has a positive effect on OA patients, there is limited high-quality evidence and a dearth of long-term follow-up.

Despite the low-quality evidence and the many questions surrounding MSCs for treating OA, there are an estimated 570 clinics in the US marketing “stem cell” treatments for orthopaedic problems2. The American Academy of Orthopaedic Surgeons (AAOS) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases recently convened a symposium on this issue. According to Constance Chu, MD, professor of orthopaedic surgery at Stanford University and the symposium program chair, the objective was to establish a clear, collective impact agenda for the clinical evaluation, use, and optimization of biologics in orthopaedics, and to develop a guidance document on clinically meaningful endpoints and outcome metrics for the evaluation of biologics used in orthopaedics.

Symposium attendees examined the possible use of registries to generate clinical evidence on the use of biologics in orthopaedics. Registry models that could be employed to obtain data on practice patterns and early warning of potential issues include the American Joint Replacement Registry, the Kaiser Registry, and the International Cartilage Repair Registry. Another model could be a biorepository-linked registry similar to what has been established at the VA Hospital in Palo Alto, California, where samples from platelet-rich plasma are stored for later comparison with clinical outcomes.

References

  1. Jevotovsky DS, Alfonso AR, Einhorn TA, Chiu ES. Osteoarthritis and Stem Cell Therapy in Humans: A Systematic Review, Osteoarthritis and Cartilage (2018), doi: 10.1016/ j.joca.2018.02.906.
  2. Symposium by The American Academy of Orthopaedic Surgeons and the National Institute of Arthritis and Musculoskeletal and Skin Diseases. “Optimizing Clinical Use of Biologics in Orthopaedic Surgery,” Feb. 15–17, 2018, at Stanford University.

For Biceps Tenodesis, Bone-Tunnel and Cortical-Surface Fixation Are Equally Good

Cortical Surface Attachment for OBuzzMany orthopaedic procedures involve reattaching a tendon to bone, but the decision as to whether that fixation is made through a bone tunnel or by cortical-surface attachment is usually left up to the surgeon’s preference. In the March 21, 2018 issue of The Journal of Bone & Joint Surgery, Tan et al. attempted to determine which fixation technique, in a rabbit model, provides better tendon-to-bone healing.

The rabbits in the bone-tunnel group and the cortical surface attachment group were killed 8 weeks after biceps tenodesis surgery, and the authors performed detailed biomechanical testing, microcomputed tomography analysis, and histological analysis to evaluate the tendon healing. Here’s what they found:

  • There were no significant between-group differences in mean failure loads or stiffness.
  • There were no significant between-group differences in mean volume of newly formed bone or in the mineral density of newly formed bone.
  • In both groups, histological analysis revealed tendon-bone interdigitation and early fibrocartilaginous zone formation on the outer cortical surface. (This article includes interactive digital whole-slide images of cortical surface attachment and bone-tunnel fixation.)

These findings led the authors to conclude that “tendon fixation in a bone tunnel and on the cortical surface resulted in similar healing profiles.” Because both techniques facilitate good tendon-to-bone healing, surgeon preference will probably continue to dictate the decision to use one method over another.

Webinar on March 29 – Spondylolysis in Adolescents: Diagnosis, Treatment, and Outcomes

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Low back pain is not typically thought to be a pediatric issue; however, this condition occurs in 33% of adolescents each year—a rate similar to that seen in adults. The most common identifiable cause of low back pain in the adolescent is spondylolysis, a defect in the pars interarticularis. How is this condition best diagnosed and treated? Do oblique radiographs help diagnose spondylolysis in adolescents? What kind of short- and long-term clinical outcomes can adolescents—and especially adolescent athletes—diagnosed with acute spondylolysis expect to have? What factors might predict long-term outcomes?

These important and clinically applicable questions will be addressed during a complimentary LIVE webinar, hosted jointly by the Journal of Orthopaedic & Sports Physical Therapy (JOSPT) and The Journal of Bone & Joint Surgery (JBJS).

JBJS presenter, Peter Passias, MD, will discuss findings from a retrospective study of adolescents with and without L5 spondylolysis to address whether oblique radiographic views add value in the diagnosis of this cause of low back pain. This paper specifically addresses whether the diagnostic benefit of four-view studies outweighs the additional cost and radiation exposure, especially for young people.

JOSPT co-author Mitchell Selhorst, DPT, OCS, will share the results of a retrospective review of acute spondylolytic injuries in young athletes. This study reports long-term clinical outcomes for these patients and identifies significant predictors of these outcomes.

Moderated by JBJS Deputy Editor Andrew J. Schoenfeld, MD, who specializes in spondylolisthesis, spinal stenosis, and spinal surgery, the webinar will include additional insights from expert commentators, Chris Bono, MD,from Brigham and Women’s Hospital in Boston, and Michael Allen, PT, from Cincinnati Children’s Hospital Medical Center. The last 15 minutes will be devoted to a live Q&A session between the audience and panelists.

Space is limited, so Register Now.

Fragility Fracture Risk Prediction: Beyond BMD

BMD for OBuzzThis basic science tip 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.

Bone mineral density (BMD)—a measure of both cortical and trabecular bone—has been widely used as an index of bone fragility. The femoral neck and lumbar vertebrae are the areas most commonly measured with BMD, but hip osteoarthritis and lumbar spondylosis can mask systemic osteoporosis. In addition, the most common fragility fractures occur at the distal radius.

Investigators conducted a prospective study using high-resolution peripheral quantitative computed tomography (HR-pQCT) of the distal radius and tibia to determine whether baseline skeletal parameters could predict fragility fractures in women. A second goal was to establish whether women who have fragility fractures experience bone loss at a faster rate than those who do not have fractures.

Among 149 women older than 60 years who had baseline and 5-year follow-up HR-pQCT, 22 had a fragility fracture during the study period and 127 did not. HR-pQCT is able to record total bone mineral density (Tt.BMD), trabecular bone mineral density (Tb.BMD), trabecular number (Tb.N), and trabecular separation (Tb.Sp).

The analysis showed that women with fragility fractures had lower baseline Tt.BMD (19%), Tb.BMD (25%), and Tb.N (14%), along with higher Tb.Sp (19%) than women who did not experience a fracture. Analysis of the tibia measures yielded similar results, showing that women with incident fracture had lower Tt.BMD (15%), Tb.BMD (12%), cortical thickness (14%), and cortical area (12%). Also, women with fractures had lower failure load (10%) with higher total area and trabecular area than women without fractures.

For each standard deviation decrease of a measure at the distal radius, the odds ratio for fragility fracture was 2.1 for Tt.BMD. 2.0 for Tb.BMD, and 1.7 for Tb.N. ORs for those measures at the tibia were similar.

In contrast to these findings, the annualized percent rate of bone loss was not different between groups with and without fractures. These results suggest that future fragility-fracture risk prediction should rely at least as much on bone architecture and strength as on simple BMD measurements.

Reference
Burt LA, Manske SL, Hanley DA, Boyd SK. Lower Bone Density, Impaired Microarchitecture, and Strength Predict Future Fragility Fracture in Postmenopausal Women: 5-Year Follow-up of the Calgary CaMos Cohort. J Bone Miner Res. 2018 Jan 24. doi: 10.1002/jbmr.3347 PMID: 29363165

Prosthetic Metal Allergies: The Mystery Continues

Metal Hypersensitivity for OBuzzThis basic science tip 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.

Immunosensitivity to metallic implants has been recognized for years, with the principal research focus on joint arthroplasty components. While cutaneous metal allergies are relatively common (as prevalent as 20%), immunosensitivity to implanted metal is much less common.

On their own, metal ions in the body such as nickel and cobalt do not cause immune responses, although high levels can be toxic to specific organs. However, when these ions associate with proteins in the plasma they may form haptens. These molecules in turn may bring about delayed hypersensitivity reactions.

Reactions to metals appear to be type IV (delayed) hypersensitivity responses leading to activation of T-lymphocytes, which in turn release inflammatory cytokines. While Langerhans cells in skin respond to direct or indirect antigen presentation, we don’t know which cells are involved in intra- and extra-articular manifestations in total joint arthroplasty. The skin response may include eczematous and/or erythematous papular lesions; within the affected limb, pain, swelling, and stiffness may be regional responses.

Determining cause and effect remains problematic. We have not yet conclusively determined whether symptoms from joint implants are due to metal sensitivity.  The diagnosis of metal immunosensitivty is based on exclusion of complications such as infection, aseptic loosening, mechanical malalignment, and, less commonly, complex regional pain syndrome and overstuffing.

The two most utilized tests for implant metal allergies are cutaneous patch testing and lymphocyte transformation testing. Unfortunately, cutaneous testing may not reflect the process in the joint, and preoperative patch screening has not proven to be beneficial. Lymphocyte transformation testing is expensive, not validated, and unavailable for many.

Alternatives include use of implants coated with titanium nitride, zirconia nitride, or zirconium oxide, or the use of “hypoallergenic” metals such as titanium and oxinium. However, except in the setting of revision, the clinical and cost effectiveness of these metals remain to be confirmed. The one relative certainty related to this issue is to use alternative-metal implants in patients with known severe systemic or cutaneous metal sensitivity.

References

Nima Eftekhary, MD; Nicholas Shepard, MD; Daniel Wiznia, MD; Richard Iorio, MD; William J. Long, MD, FRCSC; and Jonathan Vigdorchik, MD. Metal Hypersensitivity in Total Joint Arthroplasty https://icjr.net/articles/metal-hypersensitivity-in-total-joint-arthroplasty

Arif Razak, BSc, MBChB, MRCS; Ananthan D. Ebinesan, MBChB, MRCS; Charalambos P. Charalambous, BSc, MBChB, MSc, MD, FRCS (Tr & Orth). Metal Hypersensitivity in Patients with Conventional Orthopaedic Implants. JBJS Reviews; 2014 Feb 4; 2 (2).10.2106/JBJS.RVW.M.00082

If We “Own the Bone,” How About “Owning the Joint”?

MRI of Knee OA 2.jpgThis basic science tip 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.

Early cartilage changes in early-stage osteoarthritis (OA) often exist before symptoms arise. Using MRI, researchers assessed a random sample of 73 subjects, aged 40 to 79 years and without knee pain, for cartilage changes.1 A self-reported BMI at age 25, a current measured BMI, and change in BMI were recorded. Knee cartilage was scored semi-quantitatively (grades 0 to 4) on MRI. In primary analysis, cartilage damage was defined as ≥2 (at least moderate), and in a secondary analysis as ≥3 (severe). Researchers also conducted a sensitivity analysis by dichotomizing current BMI as <25 vs. ≥25. Logistic regression was used to evaluate the association of each BMI variable with prevalent MRI-detected cartilage damage, adjusted for age and sex.

Their abstract states that among the 73 subjects, knee cartilage damage ≥2 and ≥3 was present in 65.4% and 28.7%, respectively. Note the high prevalence. The median current BMI was 26.1, while the median past BMI was 21.6. For cartilage damage ≥2, current BMI had a non-statistically significant odds ratio (OR) of 1.65 per 5-unit increase in BMI (95% CI 0.93-2.92). For cartilage damage ≥3, current BMI showed a trend towards statistical significance with an OR of 1.70 per 5 units (95% CI 0.99-2.92). Past BMI and change in BMI were not significantly associated with cartilage damage. Current BMI ≥ 25 was statistically significantly associated with cartilage damage ≥2 (OR 3.04 [95% CI 1.10-8.42]), but not with damage ≥3 (OR 2.63 [95% CI 0.86-8.03]).

The take-home is that MRI-detected knee cartilage damage is highly prevalent in asymptomatic populations aged 40 to 79 years. There is a trend towards significance in the relationship between rising BMI and cartilage damage severity.  (It should be added there are localities where a BMI of 26.1, which is technically in the “overweight” zone, would be considered relatively low.) Although this study lends some support to the relationship between BMI and the pathogenesis of knee cartilage damage in asymptomatic people, the role of BMI in symptomatic OA progression is clearer.

In another study, researchers showed that weight loss over 48 months among obese and overweight individuals is associated with slowed knee cartilage degeneration and improved knee symptoms.2 These results point to a promising approach to disease modification that carries little or no risk.

References

  1. Keng A, Sayre EC, Guermazi A, Nicolaou S, Esdaile JM, Thorne A, Singer J, Kopec JA, Cibere J. Association of body mass index with knee cartilage damage in an asymptomatic population-based study. BMC Musculoskelet Disord. 2017 Dec 8;18(1):517. doi: 10.1186/s12891-017-1884-7. PMID: 29221481 PMCID: PMC5723095
  2. 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

What’s New in Musculoskeletal Basic Science 2017

Specialty Update Image for OBuzz

Every month, JBJS publishes a Specialty Update—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 OrthoBuzz Specialty Update summaries.

This month, Matthew J. Allen, VetMB, PhD, author of the December 6, 2017 Specialty Update on Musculoskeletal Basic Science, summarized the five most compelling findings from among the more than 60 noteworthy studies summarized in the article.

Cartilage Repair

–Deriving induced pluripotent stem cells (iPSCs) from peripheral blood cells1 rather than from dermal fibroblasts obviates the need for in vitro expansion. This method may also serve to boost interest in the use of commercial cell-based therapies with defined potency that are available off-the-shelf and don’t require separate cell-harvesting procedures.

–The FDA recommends that large-animal models be used to corroborate basic-science findings from small-animal models. Recent work has demonstrated the efficacy of insulin-like growth factor (IGF)-1 in supporting mechanically competent repair tissue following chondrocyte implantation in a pig model.2

Infection

–Infection, especially from organisms that have developed antimicrobial resistance and/or that produce biofilms, continues to pose a challenging problem for orthopaedic surgeons. To provide a more rational and stratified approach to managing these complex cases, Getzlaf et al. recommend the use of a multidisciplinary approach in which patient-specific information about individual microorganisms is combined with detailed understandings of the vulnerabilities of candidate bacterial species.3

Aseptic Loosening

–There is a resurgence of interest in the role of subclinical infection in the etiopathogenesis of aseptic loosening. At the same time, molecular diagnostic methods for microbial infection are moving forward.4 Such methods may serve to highlight the relevance of subclinical microbial contamination as a cause of aseptic loosening.

Cartilage Imaging

–While the goal of cartilage imaging is to develop tools that are fast, inexpensive, sensitive, accurate, and noninvasive, there is growing interest in the use of more direct, invasive techniques such as optical coherence tomography (OCT),5 which could be used in vivo at the time of surgery to analyze cartilage damage.

References

  1. Li Y, Liu T, Van Halm-Lutterodt N, Chen J, Su Q, Hai Y. Reprogramming of blood cells into induced pluripotent stem cells as a new cell source for cartilage repair. Stem Cell Res Ther.2016 Feb 17;7:31.
  2. Meppelink AM, Zhao X, Griffin DJ, Erali R, Gill TJ, Bonassar LJ, Redmond RW,Randolph MA. Hyaline articular matrix formed by dynamic self-regenerating cartilage and hydrogels. Tissue Eng Part A.2016 Jul;22(13-14):962-70. Epub 2016 Jul 7.
  3. Getzlaf MA, Lewallen EA, Kremers HM, Jones DL, Bonin CA, Dudakovic A,Thaler R, Cohen RC, Lewallen DG, van Wijnen AJ. Multi-disciplinary antimicrobial strategies for improving orthopaedic implants to prevent prosthetic joint infections in hip and knee. J Orthop Res.2016 Feb;34(2):177-86. Epub 2015 Dec 29.
  4. Palmer MP, Melton-Kreft R, Nistico L, Hiller NL, Kim LH, Altman GT, Altman DT, Sotereanos NG, Hu FZ, De Meo PJ, Ehrlich GD. Polymerase chain reaction-electrospray-time-of-flight mass spectrometry versus culture for bacterial detection in septic arthritis and osteoarthritis. Genet Test Mol Biomarkers.2016 Dec;20(12):721-31. Epub 2016 Oct 17.
  5. Novakofski KD, Pownder SL, Koff MF, Williams RM, Potter HG, Fortier LA. High-resolution methods for diagnosing cartilage damage in vivo. 2016 Jan;7(1):39-51.

New Hope for New Bone After Osteomyelitis Debridement

Osteomyelitis Tibia for OBuzzThis basic science tip 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.

One clinical frustration following osteomyelitis debridement is poor bone healing. Impaired bone homeostasis provokes serious variations in bone remodeling that involve multiple inflammatory cytokines.

The chemokines CCL2, CCL3, and CXCL2 are known to be strong chemoattractants for neutrophils during inflammatory states, and they play a role during osteoclastogenesis. B cells are also activators of osteoclastognesis and are regulated, in part, by tissue inhibitor of metalloprotease 1 (TIMP-1).

Researchers drilled a 1 mm hole into the proximal tibia of 126 mice. In half of the mice (63), a dose of S. aureus was injected into the canal, while the controls had no bacteria injected. At two weeks, all proximal tibiae were debrided; cultures were taken 3 and 7 days after debridement to assure no residual infection. Cytokine assays and Western blots for CCL2, CCL3, CXCL2, TIMP-1, RANKL, and TNF-α were performed in selected mice in each group. Flow cytometry and histology were also done in selected mice in each group.

In the osteomyelitis group, Western blot analysis identified increased levels of CCL2, CCL3, and CXCL2. Histology revealed increased osteoclastogenesis after osteomyelitis debridement, with calcitonin-receptor and RANKL detection via immunohistochemical and fluorescence staining. There was diminished osteogenesis and proliferation in the osteomyelitis group, but TNF-α expression seemed to have no effect on altered bone regeneration after bone infection. Flow cytometry revealed elevated B cell activity in the osteomyelitis group, with subsequent increased osteoclast activity and accelerated bone resorption.

The researchers propose a RANKL-dependent osteoclastogenesis after debridement for osteomyelitis that is associated with elevated B cells and decreased osteogenesis. These findings could lead to new interventions to improve bone healing during the course of osteomyelitis treatment, particularly following debridement.

Reference
Wagner JM, Jaurich H, Wallner C, Abraham S, Becerikli M, Dadras M, Harati K, Duhan V, Khairnar V, Lehnhardt M, Behr B. Diminished bone regeneration after debridement of posttraumatic osteomyelitis is accompanied by altered cytokine levels, elevated B cell activity, and increased osteoclast activity. J Orthop Res. 2017 Mar 6. doi: 10.1002/jor.23555. [Epub ahead of print] PMID: 28263017

Pulsatile Lavage Harms Muscle in Rat Model of Blast Injury

Rat Limb for OBuzzBasic science investigations into clinically relevant orthopaedic conditions are very common—and often very fruitful. What’s not very common is seeing results from large, multicenter randomized trials published in the same time frame as high-quality in vivo basic-science research on the same clinical topic.

But the uncommon has occurred. In the November 1, 2017 issue of The Journal, Chiaramonti et al. present research on the effects of 20-psi pulsatile lavage versus 1-psi bulb-syringe irrigation on soft tissue in a rat model of blast injuries. With support from the US Department of Defense, Chiaramonti et al. developed an elegant animal study that found radiological and histological evidence that lavage under pressure—previously thought to be critical to removing contamination in high-energy open fractures—results in muscle necrosis and wound complications.

Although none of the rats developed heterotopic ossification during the 6-month study period, the authors plausibly suggest that the muscle injury and dystrophic calcification they revealed “may potentiate the formation of heterotopic ossification by creating a favorable local environment.” Heterotopic ossification is an unfortunately common sequela in patients who suffer blast-related limb amputations.

The aforementioned rare alignment between basic-research findings and clinical findings in people relates to a large multicenter randomized clinical trial recently published in The New England Journal of Medicine. That study found that one-year reoperation rates among nearly 2,500 patients treated surgically for open-fracture wounds were similar whether high, low, or very low irrigation pressures were used. This is a case where the clinical advice from basic-study authors Chiaramonti et al. to keep “delivery device irrigation pressure below the 15 to 20-psi range” when managing open fractures is based on very solid ground.

Marc Swiontkowski, MD
JBJS Editor-in-Chief

“Phenotype” Redefined in Osteoarthritis Research

Osteoarthritis for BSTOTWThis basic science tip 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.

Over the decades, the meaning of the term “phenotype” has changed. In the past it was solely applied to inherited disorders and was based on physical appearance or clinical presentation. Similarly, the term “penetrance” was applied to the variations in phenotype severity relative to normal. Over time, it has been found that penetrance is usually a reflection of different mutations for the same gene at different parts of the allele, or a mutation in one of several specific genes that could contribute to a similar phenotype.

Now, both terms have been applied to a variety of genetic and environmental circumstances that may affect physical appearance and function. In osteoarthritis research, the term “phenotype” has increasingly been used to define physical, genetic, environmental, and other variables, both past and present.

The authors of a recent abstract use a modern application for the term phenotype to systematically review the literature for studies using knee characteristics relevant for phenotyping osteoarthritis (OA).1 A comprehensive search was performed limited to observational studies of individuals with symptomatic knee OA that identified phenotypes based on OA characteristics, and then the authors assessed phenotypic association with clinically important outcomes.

Based on their abstract, 34 of 2777 citations were included in a descriptive synthesis of the data. Clinical phenotypes were investigated most frequently, followed by laboratory, imaging, and etiologic phenotypes. Eight studies defined subgroups based on outcome trajectories (pain, function, and radiographic progression). Most studies used a single patient or disease characteristic to identify subgroups, while five included characteristics from multiple domains.

Evidence from multiple studies suggested that pain sensitization, psychological distress, radiographic severity, BMI, muscle strength, inflammation, and comorbidities are associated with clinically distinct phenotypes. Gender, obesity and other metabolic abnormalities, the pattern of cartilage damage, and inflammation may delineate distinct structural phenotypes. However, only a few of the 34 studies reviewed investigated the external validity of the chosen phenotypes or their prospective validity using longitudinal outcomes.

While the authors remarked on the heterogeneity of the data included in studies investigating knee OA phenotypes, they say that the phenotypic characteristics identified in their review could form a classification framework for future studies investigating OA phenotypes.

It should be noted that the FRAX score used to calculate fragility fracture risk could be considered a phenotypically based system, the validation of which is continuing.

Reference

  1. Deveza LA, Melo L, Yamato TP, Mills K, Ravi V, Hunter DJ. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis 2017 Aug 25. pii: S1063-4584(17)31156-1. doi: 10.1016/j.joca.2017.08.009. [Epub ahead of print].