The Open Orthopaedics Journal




ISSN: 1874-3250 ― Volume 13, 2019
REVIEW ARTICLE

The Value of Phenotypes in Knee Osteoarthritis Research



Fred R T Nelson*
Department of Orthopaedics, Henry Ford Hospital, 2799 West Grand Blvd. Detroit Michigan 48202, USA

Abstract

Background:

Over the past decade, phenotypes have been used to help categorize knee osteoarthritis patients relative to being subject to disease, disease progression, and treatment response. A review of potential phenotype selection is now appropriate. The appeal of using phenotypes is that they most rely on simple physical examination, clinically routine imaging, and demographics. The purpose of this review is to describe the panoply of phenotypes that can be potentially used in osteoarthritis research.

Methods:

A search of PubMed was used singularly to review the literature on knee osteoarthritis phenotypes.

Results:

Four phenotype assembly groups were based on physical features and noninvasive imaging. Demographics included metabolic syndrome (dyslipidemia, hypertension, obesity, and diabetes). Mechanical characteristics included joint morphology, alignment, the effect of injury, and past and present history. Associated musculoskeletal disorder characteristics included multiple joint involvement, spine disorders, neuromuscular diseases, and osteoporosis. With the knee as an organ, tissue characteristics were used to focus on synovium, meniscus, articular cartilage, patella fat pad, bone sclerosis, bone cysts, and location of pain.

Discussion:

Many of these phenotype clusters require further validation studies. There is special emphasis on knee osteoarthritis phenotypes due to its predominance in osteoarthritic disorders and the variety of tissues in that joint. More research will be required to determine the most productive phenotypes for future studies.

Conclusion:

The selection and assignment of phenotypes will take on an increasing role in osteoarthritis research in the future.

Keywords: Osteoarthritis, Physical features, Phenotype, Imaging, Progression, Knee, Phenotype, Classification Phenotype in knee osteoarthritis.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 105
Last Page: 114
Publisher Id: TOORTHJ-12-105
DOI: 10.2174/1874325001812010105

Article History:

Received Date: 15/12/2017
Revision Received Date: 15/02/2018
Acceptance Date: 23/02/2018
Electronic publication date: 16/03/2018
Collection year: 2018`

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© 2018 Fred R T Nelson.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: https://creativecommons.org/licenses/by/4.0/legalcode. This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Departement of Orthopaedics, Henry Ford Hospital, Fred R T Nelson, 2799 West Grand Blvd. Detroit Michigan 48202, USA; Tel: 1-313 982 8496; E-mail: fnelson1@hfhs.org




1. INTRODUCTION

The Merriam-Webster dictionary definition of phenotype is “the observable properties of an organism, which are produced by the interaction of the genotype and the environment.” In osteoarthritis (OA) research, the term has been used increasingly to define physical, biochemical, and genetic characteristics along with physical events occurring in both past and present. This review relied on the expanded use of the term phenotype as it is applied to OA research. There are organizations that have suggested key knee osteoarthritis (KOA) phenotypes. In a recent review, pain sensitization, psychological distress, radiographic severity, body mass index (BMI), muscle strength, inflammation, and comorbidities were associated with clinically distinct phenotypes [1Deveza LA, Melo L, Yamato TP, Mills K, Ravi V, Hunter DJ. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis Cartilage 2017; 25(12): 1926-41.[http://dx.doi.org/10.1016/j.joca.2017.08.009] [PMID: 28847624] ]. These along with gender, obesity and other metabolic abnormalities, and pattern of cartilage damage were evaluated by a literature review to determine any validation of these phenotypes [1Deveza LA, Melo L, Yamato TP, Mills K, Ravi V, Hunter DJ. Knee osteoarthritis phenotypes and their relevance for outcomes: a systematic review. Osteoarthritis Cartilage 2017; 25(12): 1926-41.[http://dx.doi.org/10.1016/j.joca.2017.08.009] [PMID: 28847624] ]. This review highlights a number of additional OA phenotypes that could be used depending on the type of progression or the nature of a therapy being investigated and the population under study. Appropriate selection of phenotype could lead to a better understanding of the role of a specific phenotype or phenotype cluster relative to disease progression as well as treatment outcome.

The term personalized medicine is not the same as concierge medicine. Concierge medicine delivers care separate from concerns about insurance and reimbursement. The term personalized medicine is treatment based on specific biomarkers or characteristics that might define the peculiar nature of the recipient of care. This increases the chance of not missing an effective therapy in a heterogeneous population [2Yip WK, Bonetti M, Cole BF, et al. Subpopulation treatment effect pattern plot (STEPP) analysis for continuous, binary, and count outcomes. Clin Trials 2016; 13(4): 382-90.[http://dx.doi.org/10.1177/1740774516643297] [PMID: 27094489] ]. The Subpopulation Treatment Effect Pattern Plot (STEPP) approach was developed to allow researchers to investigate the heterogeneity of treatment effects on survival outcomes across values of a (continuously measured) covariate, such as a biomarker measurement [2Yip WK, Bonetti M, Cole BF, et al. Subpopulation treatment effect pattern plot (STEPP) analysis for continuous, binary, and count outcomes. Clin Trials 2016; 13(4): 382-90.[http://dx.doi.org/10.1177/1740774516643297] [PMID: 27094489] ]. In the case of KAO, there are several predetermined approaches to a more appropriate selection of therapy for any given individual. Hence, the selection of the most appropriate phenotype for any given OA study aides both the clinician and the scientist.

The bulk of therapies for OA are directed at pain relief, and although many are evaluated for disease modification, so far there has been no long-term demonstration of impact on disease progression. However, weight loss has been shown to slow the rate of joint deterioration over a period of 4 years [3Gersing AS, Solka M, Joseph GB, et al. 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; 24(7): 1126-34.[http://dx.doi.org/10.1016/j.joca.2016.01.984] [PMID: 26828356] ]. Many studies show delay to total joint replacement but do not show imaging or other evidence of delayed disease progression. Given the myriad pathways to articular cartilage degradation, the exploration of specific genetic targets has expanded exponentially. With the completion of the human genome, improved proteomics, and more efficient and less costly mRNA and DNA analyses, including microarrays, many biomarkers for OA progression have been explored. There is no specific single gene product that has been found to affect a large majority of patients with OA. Using microarray technology, investigators have turned to the discovery of gene clusters that may identify more rapid OA progression. A problem for any systemic intervention is finding an impact on the specific disease without an impact on the rest of the body. A corollary is finding a gene or gene cluster that targets only 1 tissue. The Osteoarthritis Research Society International (OARSI) has developed guidelines relative to the use of soluble biomarkers in OA research. Within that guideline was the notation that identification of the biomarker may be as soluble or ‘wet’ (biochemical analyte, genomic, etc.) or as non-soluble or ‘dry’ (imaging, a physical examination finding, scales, etc.) [4Kraus VB, Blanco FJ, Englund M, et al. OARSI clinical trials recommendations: Soluble biomarker assessments in clinical trials in osteoarthritis. Osteoarthritis Cartilage 2015; 23(5): 686-97.[http://dx.doi.org/10.1016/j.joca.2015.03.002] [PMID: 25952342] ]. The 5 “dry” clinical phenotypes recommended by OARSI for use in KOA studies are listed below.

  1. Previously uninjured men and women, aged 25 to 35 years old, with acute anterior cruciate ligament injury (< 4 weeks old) with or without primary arthroscopic ligament reconstruction or meniscectomy. The status of other joints is normal.
  2. Postmenopausal women with symptomatic and disabling (> 6 months) bilateral multi-joint erosive hand OA as detected by magnetic resonance imaging (MRI); other joints are asymptomatic.
  3. Individuals aged 40 years old or older with new-onset unilateral knee pain (< 6 months) without knee trauma, but with normal knee radiograph. Knee MRI shows meniscal pathology (extrusion/degenerative tear), subchondral bone marrow lesion, effusion and/or minor tibiofemoral cartilage defect(s).
  4. Symptomatic and radiographic KOA.
  5. Symptomatic and radiographic hip OA.

Using a phenotypic and biomarker approach could help clarify controversial areas of KOA treatment. Several popular therapies for OA pain, viscosupplementation, and glucosamine, have come under scrutiny and have been declared “not recommended” by large medical organizations [5Jevsevar DS. Treatment of osteoarthritis of the knee: evidence-based guideline, 2nd edition. The Journal of the American Academy of Orthopaedic Surgeons. 2013; 21(9): 571-6.]. However, this does not take into account heterogenicity and individual population selections [6Johal H, Devji T, Schemitsch EH, Bhandari M. Viscosupplementation in knee osteoarthritis: Evidence revisited. JBJS Rev 2016; 4(4): e11-e111.[http://dx.doi.org/10.2106/JBJS.RVW.15.00098] [PMID: 27487425] ]. In addition, there is a call to give attention to different phenotypes of KOA since they may respond differently to each treatment [7Migliore A, Bizzi E, Herrero-Beaumont J, Petrella RJ, Raman R, Chevalier X. The discrepancy between recommendations and clinical practice for viscosupplementation in osteoarthritis: mind the gap! Eur Rev Med Pharmacol Sci 2015; 19(7): 1124-9.[PMID: 25912569] ]. By example, this is discussed on the subject of viscosupplementation in a younger military population [8Langworthy MJ, Nelson F, Owens BD. Viscosupplementation for treating osteoarthritis in the military population. Mil Med 2014; 179(8): 815-20.[http://dx.doi.org/10.7205/MILMED-D-14-00052] [PMID: 25102523] ]. Although pain does not correlate to imaging studies, the opportunity to intervene in the early phases of the disease is highlighted by the spectrum of different tissues that are initially involved in the degenerative process. The presence of meniscal change, bone marrow edema, synovitis, and infrapatellar fat pad (Hoffa’s fat pad) synovitis have been found to be predictive of radiographic change within 4 years [9Roemer FW, Kwoh CK, Hannon MJ, et al. What comes first? Multitissue involvement leading to radiographic osteoarthritis: magnetic resonance imaging-based trajectory analysis over four years in the osteoarthritis initiative. Arthritis Rheumatol 2015; 67(8): 2085-96.[http://dx.doi.org/10.1002/art.39176] [PMID: 25940308] ]. The targeting of tissues other than articular cartilage may be an important consideration in the development of therapies for treating KOA. This is particularly important in those cases where radiographs appear normal.

Over the decades the term phenotype has changed in its connotations. When applied to inherited disorders, the term phenotype was applied to the physical appearance or clinical presentation of a person with an inherited disorder. The term penetrance was applied to the variation as to the severity of phenotype relative to normal. Over time it has been found that penetrance was often a reflection of different mutations for the same gene or a mutation in more than 1 specific gene that could contribute to a similar phenotype. The expansion of the term phenotype to research applications was highlighted in an editorial on the spectrum of phenotypes for investigation of OA [10Castañeda S, Roman-Blas JA, Largo R, Herrero-Beaumont G. Osteoarthritis: a progressive disease with changing phenotypes. Rheumatology (Oxford) 2014; 53(1): 1-3.[http://dx.doi.org/10.1093/rheumatology/ket247] [PMID: 23878311] ]. This included age, estrogen status, genetic factors, components of metabolic syndrome, specific tissues affected, serum biomarkers, the shape of joint, joints affected, and the stage of disease [10Castañeda S, Roman-Blas JA, Largo R, Herrero-Beaumont G. Osteoarthritis: a progressive disease with changing phenotypes. Rheumatology (Oxford) 2014; 53(1): 1-3.[http://dx.doi.org/10.1093/rheumatology/ket247] [PMID: 23878311] ]. A separate recommendation by OARSI was based on an Amsterdam cohort study listing 5 phenotypes more likely to be productive in research [11van der Esch M, Knoop J, van der Leeden M, et al. Clinical phenotypes in patients with knee osteoarthritis: a study in the Amsterdam osteoarthritis cohort. Osteoarthritis Cartilage 2015; 23(4): 544-9.[http://dx.doi.org/10.1016/j.joca.2015.01.006] [PMID: 25596322] ]. These were “minimal joint disease phenotype,” “strong muscle phenotype,” “non-obese weak muscle phenotype,” “obese and weak muscle phenotype,” and “depressive phenotype.” In some quarters the term phenotype has expanded to overall health, disease history, behavior, and general disposition. With the advent of electronic records, retrieving some of these details is becoming more practical. However, in research design, it is very easy to overlook easily observed and recorded features that may prove important in finding responders versus non-responders to various therapies. Much of this information can be obtained noninvasively, allowing for better determination of individuals with a favorable response to a treatment that is ineffective for others.

2. METHODS

A search of PubMed alone was used to find all articles relative to KOA and phenotypes. The search included “knee AND phenotype” and “osteoarthritis AND phenotype”. Once these were compiled, 4 groups of characteristics were created. The focus of this review is on the knee. Because the mechanical effects of deformity for the hip and knee have an overlapping impact, both joints will be considered in the section on mechanics Table (1).

Table 1
Knee osteoarthritis phenotypes based on societal recommendations demographics, mechanics or injury, associate musculoskeletal conditions, joint components.


3. RESULT

Having determined the range of suggestions of specific phenotypes in KOA, this review was grouped into 4 sections:

  1. Demographic characteristics including components of metabolic syndrome.
  2. Mechanical characteristics including joint morphology, alignment, the effect of injury, and history of present and past activity on affected joint.
  3. Associated musculoskeletal characteristics including multiple joint involvement, spine disorders, neuromuscular diseases, and osteoporosis.
  4. Joint tissue characteristics including cartilage, meniscus, synovium, bone sclerosis, bone cysts, and osteophytes. Included was the location of pain such as the joint line, focal synovial, bone, and global could indicate the involved tissue(s).

4. DEMOGRAPHIC CHARACTERISTICS

Height and weight. Demographics that may influence OA development and progression are age, sex, race, height, and weight. The latter two are incorporated into a crude measure of proportional body fat, BMI. BMI is the key component of metabolic syndrome, which also includes diabetes, dyslipidemia, and hypertension. Recently the addition of KOA and hand OA to this list has been recognized [12Calvet J, Orellana C, Larrosa M, et al. High prevalence of cardiovascular co-morbidities in patients with symptomatic knee or hand osteoarthritis. Scand J Rheumatol 2016; 45(1): 41-4.[http://dx.doi.org/10.3109/03009742.2015.1054875] [PMID: 26312543] ]. An elevated BMI is associated with OA progression. The inflammatory effects of fat are thought to be an important factor [13Issa RI, Griffin TM. Pathobiology of obesity and osteoarthritis: integrating biomechanics and inflammation. Pathobiol Aging Age Relat Dis. 2012.[http://dx.doi.org/10.3402/pba.v2i0.17470] ]. There is also an association of KOA with leptin, which is elevated in some obese patients [14Ding C, Parameswaran V, Cicuttini F, et al. Association between leptin, body composition, sex and knee cartilage morphology in older adults: the Tasmanian older adult cohort (TASOAC) study. Ann Rheum Dis 2008; 67(9): 1256-61.[http://dx.doi.org/10.1136/ard.2007.082651] [PMID: 18174218] , 15de Boer TN, van Spil WE, Huisman AM, et al. Serum adipokines in osteoarthritis; comparison with controls and relationship with local parameters of synovial inflammation and cartilage damage. Osteoarthritis Cartilage 2012; 20(8): 846-53.[http://dx.doi.org/10.1016/j.joca.2012.05.002] [PMID: 22595228] ]. This is a reflection of the relevance of obesity in the OARSI phenotype recommendations.

Sex. Many studies on intervention for knee pain show that women are more prevalent than men. In a meta-analysis of 46 out of 6554 screened papers, it was determined that individuals aged 50 and over and who were female gender had a pooled odds ratio of 1.68 (95% CI 1.37-2.07). For contrast, the pooled odds ratio for obesity was 2.66 (95% CI 2.15-3.28), making obesity a more relevant factor [16Silverwood V, Blagojevic-Bucknall M, Jinks C, Jordan JL, Protheroe J, Jordan KP. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage 2015; 23(4): 507-15.[http://dx.doi.org/10.1016/j.joca.2014.11.019] [PMID: 25447976] ].

Ethnicity. The role of ethnicity in OA has been studied by the National Health and Nutrition Examination Survey I, which suggested that African-American women are more likely to develop KOA than men and white persons [17Anderson JJ, Felson DT. Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work. Am J Epidemiol 1988; 128(1): 179-89.[http://dx.doi.org/10.1093/oxfordjournals.aje.a114939] [PMID: 3381825] ]. However, in the Johnston County Osteoarthritis Project, there was no evidence of ethnic differences [17Anderson JJ, Felson DT. Factors associated with osteoarthritis of the knee in the first national Health and Nutrition Examination Survey (HANES I). Evidence for an association with overweight, race, and physical demands of work. Am J Epidemiol 1988; 128(1): 179-89.[http://dx.doi.org/10.1093/oxfordjournals.aje.a114939] [PMID: 3381825] , 18Jordan JM, Linder GF, Renner JB, Fryer JG. The impact of arthritis in rural populations. Arthritis Care Res 1995; 8(4): 242-50.[http://dx.doi.org/10.1002/art.1790080407] [PMID: 8605262] ]. The results are quite the opposite in hip OA, where National Health and Nutrition Examination Survey I did not reveal differences [19Tepper S, Hochberg MC. Factors associated with hip osteoarthritis: data from the First National Health and Nutrition Examination Survey (NHANES-I). Am J Epidemiol 1993; 137(10): 1081-8.[http://dx.doi.org/10.1093/oxfordjournals.aje.a116611] [PMID: 8317437] ] whereas the Johnston County Osteoarthritis Project did [20Jordan JM, Helmick CG, Renner JB, et al. Prevalence of knee symptoms and radiographic and symptomatic knee osteoarthritis in African Americans and Caucasians: the Johnston County Osteoarthritis Project. J Rheumatol 2007; 34(1): 172-80.[PMID: 17216685] ]. It probably depends on lifestyle, socioeconomic factors, BMI, and even genetic factors within different geographic locations [21Clark AG, Jordan JM, Vilim V, et al. Serum cartilage oligomeric matrix protein reflects osteoarthritis presence and severity: the Johnston County Osteoarthritis Project. Arthritis Rheum 1999; 42(11): 2356-64.[http://dx.doi.org/10.1002/1529-0131(199911)42:11<2356::AID-ANR14>3.0.CO;2-R] [PMID: 10555031] ].

Age. Age is known to be associated with the development of OA. The long half-life of type II collagen, the major collagen of cartilage, is decades [22Maroudas A, Palla G, Gilav E. Racemization of aspartic acid in human articular cartilage. Connect Tissue Res 1992; 28(3): 161-9.[http://dx.doi.org/10.3109/03008209209015033] [PMID: 1468204] ]. However, during this time there is cleavage of collagen without complete degradation [23Wu W, Billinghurst RC, Pidoux I, et al. Sites of collagenase cleavage and denaturation of type II collagen in aging and osteoarthritic articular cartilage and their relationship to the distribution of matrix metalloproteinase 1 and matrix metalloproteinase 13. Arthritis Rheum 2002; 46(8): 2087-94.[http://dx.doi.org/10.1002/art.10428] [PMID: 12209513] ]. The combination of the loss of tensile properties, passive glycation, and accumulated collagen cleavage lowers the functional capacity to accept forces that were tolerable decades before. In cartilage, type II collagen has high tensile properties. Peaking at age 30, in many individuals, the tensile properties then begin to diminish [24Akizuki S, Mow VC, Muller F, Pita JC, Howell DS. Tensile properties of human knee joint cartilage. II. Correlations between weight bearing and tissue pathology and the kinetics of swelling. J Orthop Res 1987; 5(2): 173-86.[http://dx.doi.org/10.1002/jor.1100050204] [PMID: 3572588] ]. It has been found that increase advanced glycation end products in collagen contribute to a loss of tensile property [25Kempson GE. Age-related changes in the tensile properties of human articular cartilage: a comparative study between the femoral head of the hip joint and the talus of the ankle joint. Biochim Biophys Acta 1991; 1075(3): 223-30.[http://dx.doi.org/10.1016/0304-4165(91)90270-Q] [PMID: 1954224] ]. Overall, the cleavage of collagen results in loss of tensile properties [26Silver FH, Bradica G, Tria A. Elastic energy storage in human articular cartilage: estimation of the elastic modulus for type II collagen and changes associated with osteoarthritis. Matrix Biol 2002; 21(2): 129-37.[http://dx.doi.org/10.1016/S0945-053X(01)00195-0] [PMID: 11852229] ]. In a review on the effect of age on cartilage matrix, cells and the development of OA, it is clear that there are fewer cells and that damaged telomeres result in a senescent secretory phenotype [27Shane Anderson A, Loeser RF. Why is osteoarthritis an age-related disease? Best Pract Res Clin Rheumatol 2010; 24(1): 15-26.[http://dx.doi.org/10.1016/j.berh.2009.08.006] [PMID: 20129196] ]. This degradative phenotype has increased production of cytokines including interleukin-6 and -1 and matrix metalloproteinases. Advanced glycation end-products make for a more brittle type II collagen leading to brittleness and fatigue and failure [28Verzijl N, DeGroot J, Oldehinkel E, et al. Age-related accumulation of Maillard reaction products in human articular cartilage collagen. Biochem J 2000; 350(Pt 2): 381-7.[http://dx.doi.org/10.1042/bj3500381] [PMID: 10947951] ]. Similarly, there is fragmentation and eventual loss of aggrecan. The combination of increased reactive oxygen species is directly related to intracellular proteins and extracellular matrix.

5. MECHANICAL CHARACTERISTICS

Knee noninjury. Varus and valgus deformity of the knee has long been associated with medial versus lateral compartment KOA. It has also been noted that increased adductor moment is also associated with KOA. Adductor moment is the relative medial directed distal tibial motion following heel strike. This results in increased force on the medial compartment. The moment force can be calculated integrating the total force over time. A component of adductor moment force is the maximum impulse, which is the peak force that occurs during stance. Cumulative adductor load is the product of the total adductor moment force multiplied by the number of steps. Cumulative and peak adductor load was higher in an OA group versus a non-OA group and cumulative load was the best predictor [29Maly MR, Robbins SM, Stratford PW, Birmingham TB, Callaghan JP. Cumulative knee adductor load distinguishes between healthy and osteoarthritic knees--a proof of principle study. Gait Posture 2013; 37(3): 397-401.[http://dx.doi.org/10.1016/j.gaitpost.2012.08.013] [PMID: 22995753] ]. In a Japanese population, the combination of varus thrust and degree of varus deformity has the greatest correlation to OA [30Iijima H, Fukutani N, Aoyama T, et al. Clinical phenotype classifications based on static varus alignment and varus thrust in japanese patients with medial knee osteoarthritis. Arthritis Rheumatol 2015; 67(9): 2354-62.[http://dx.doi.org/10.1002/art.39224] [PMID: 26017348] ]. The term impulse has also been applied to a brief acceleration of acceleration that may be high in individuals who are termed impulse loaders. This occurs right after heal strike and as a stand-alone measure may be related to the development of KOA [31Radin EL, Yang KH, Riegger C, Kish VL, O’Connor JJ. Relationship between lower limb dynamics and knee joint pain. J Orthop Res 1991; 9(3): 398-405.[http://dx.doi.org/10.1002/jor.1100090312] [PMID: 2010844] ]. Knee flexion-extension, abduction-adduction, external-internal rotation, lateral-medial translation, anterior-posterior translation, and superior-inferior translation are involved in activities of daily living and thereby influence the resultant joint reaction force. So far, these have not been placed in a discussion of phenotypes.

Similar to the hip, there is a variety of knee shapes that may be related to the development of OA. Shape variations can result in areas of force concentration. One approach to the impact of shape is the use of axial slices obtained by using MRI slice reconstruction and comparing shape in OA and non-OA individuals [32Şahin N, Özdemir ST, Ocakoğlu G, Ercan İ, Atıcı T, Kurdoğlu Ü. Is axial shape of distal femur different in normal and osteoarthritic female patients? Eklem Hastalik Cerrahisi 2016; 27(2): 68-73.[http://dx.doi.org/10.5606/ehc.2016.16] [PMID: 27499317] ]. MRI slices in patients who had a joint replacement were compared to the opposite knee if asymptomatic at the end of the study and to control subjects with no knee pain. Calculated variations in shapes correlated with progression to TKA [33Barr AJ, Dube B, Hensor EM, et al. The relationship between three-dimensional knee MRI bone shape and total knee replacement-a case control study: data from the Osteoarthritis Initiative. Rheumatology (Oxford) 2016; 55(9): 1585-93.[http://dx.doi.org/10.1093/rheumatology/kew191] [PMID: 27185958] ].

Knee injury. Direct injury to articular cartilage or changes in the mechanical integrity of the joint following meniscal or ligament injury can have both an immediate and long-term effect [34Lieberthal J, Sambamurthy N, Scanzello CR. Inflammation in joint injury and post-traumatic osteoarthritis. Osteoarthritis and cartilage / OARS. Osteoarthritis Research Society 2015; 23(11): 1825-34.[http://dx.doi.org/10.1016/j.joca.2015.08.015] ]. These injuries often result in hemarthrosis, chondrocyte death and bruising of the underlying bone. There is a release of inflammatory mediators in the acute post-injury period. These responses often improve over the next 3 to 6 months, but the long-term residuals become apparent later. Repair of meniscal and ligament damage may improve function but does not prevent the long-term effects of the initial injury to the articular cartilage. The long-term response is influenced by the initial degree of articular cartilage damage, the genic profile of the individual, joint stability, and metabolic factors such as obesity. Detection of an injury phenotype may be disguised by recovery from an initial impact wherein the person has long since forgotten the injury. This is particularly true of contact sports participants.

The occupational load history of the joint is significant. By review of the literature, it is apparent that activates involving lifting while squatting are associated with KOA [35Fransen M, Agaliotis M, Bridgett L, Mackey MG. Hip and knee pain: role of occupational factors. Best Pract Res Clin Rheumatol 2011; 25(1): 81-101.[http://dx.doi.org/10.1016/j.berh.2011.01.012] [PMID: 21663852] ]. The incidence of KOA in farmers, construction workers and forestry work has increased. This is also true for hips, particularly in occupations requiring many stairs or ladders. The number of years in these activities has an accumulative effect. There are numerous avocational bent knee activities such as household chores and avocational sports wherein the forces are identical. It has been shown that in the face of knee symptoms, reducing the force or frequency of some activities will help resolve symptoms [36Dye SF. The knee as a biologic transmission with an envelope of function: a theory. Clin Orthop Relat Res 1996; 325(325): 10-8.[http://dx.doi.org/10.1097/00003086-199604000-00003] [PMID: 8998861] ]. As part of the mechanical phenotype, obtaining a retrospective analysis of cumulative loads may not be accurate. A more precise evaluation of the length of time a person has been in specific vocations may shed light on the higher rate of KOA and hip OA in those populations.

Hip morphology. The term idiopathic OA of the hip began to be used less frequently as specific hip shapes and conditions that could lead to abnormal forces and wear were defined [37Harris WH. Etiology of osteoarthritis of the hip. Clin Orthop Relat Res 1986; (213): 20-33.[PMID: 3780093] ]. It has long been recognized that acetabular dysplasia is associated with hip OA [38Jørgensen RW, Dippmann C, Dahl L, Stürup J. Treatment algorithm for patients with non-arthritic hip pain, suspect for an intraarticular pathology. Open Orthop J 2016; 10: 404-11.[http://dx.doi.org/10.2174/1874325001610010404] [PMID: 27583059] ]. However, there are many variations in acetabular and femoral head shapes that may contribute to the development of OA [38Jørgensen RW, Dippmann C, Dahl L, Stürup J. Treatment algorithm for patients with non-arthritic hip pain, suspect for an intraarticular pathology. Open Orthop J 2016; 10: 404-11.[http://dx.doi.org/10.2174/1874325001610010404] [PMID: 27583059] ]. Femoral acetabular impingement may be secondary to a pincer deformity wherein there is over coverage of the femoral head by the acetabulum or a cam deformity where there is extra bone on the anterolateral side of the distal head leading to a flattened cam-like appearance. The cam deformity is associated with earlier hip OA [39Agricola R, Heijboer MP, Bierma-Zeinstra SM, Verhaar JA, Weinans H, Waarsing JH. Cam impingement causes osteoarthritis of the hip: a nationwide prospective cohort study (CHECK). Ann Rheum Dis 2013; 72(6): 918-23.[http://dx.doi.org/10.1136/annrheumdis-2012-201643] [PMID: 22730371] ]. These cam hips often have decreased internal rotation due to impingement. There is a distinct correlation of the degree of femoral head deformity to the development of hip OA. The combination of deformity and loss of internal rotation is additive in their effect. On the other hand pincer deformity is not associated with the development of OA and may even be protective [40Agricola R, Heijboer MP, Roze RH, et al. Pincer deformity does not lead to osteoarthritis of the hip whereas acetabular dysplasia does: acetabular coverage and development of osteoarthritis in a nationwide prospective cohort study (CHECK). Osteoarthritis Cartilage 2013; 21(10): 1514-21.[http://dx.doi.org/10.1016/j.joca.2013.07.004] [PMID: 23850552] ]. Significant variation in femoral head and acetabular version have been discovered to be associated with hip OA [41Tönnis D, Heinecke A. Acetabular and femoral anteversion: relationship with osteoarthritis of the hip. J Bone Joint Surg Am 1999; 81(12): 1747-70.[http://dx.doi.org/10.2106/00004623-199912000-00014] [PMID: 10608388] ]. Radiographic statistical shape modelling has recently been employed to predict hip OA in females [42Agricola R, Leyland KM, Bierma-Zeinstra SM, et al. Validation of statistical shape modelling to predict hip osteoarthritis in females: data from two prospective cohort studies (Cohort Hip and Cohort Knee and Chingford). Rheumatology (Oxford) 2015; 54(11): 2033-41.[http://dx.doi.org/10.1093/rheumatology/kev232] [PMID: 26139655] ]. There are a variety of femoral head shapes that are recognized as a significant risk for hip OA [42Agricola R, Leyland KM, Bierma-Zeinstra SM, et al. Validation of statistical shape modelling to predict hip osteoarthritis in females: data from two prospective cohort studies (Cohort Hip and Cohort Knee and Chingford). Rheumatology (Oxford) 2015; 54(11): 2033-41.[http://dx.doi.org/10.1093/rheumatology/kev232] [PMID: 26139655] ]. It is interesting to note that there are racial and ethnic differences in a specific shape related to OA [43An H, Marron JS, Schwartz TA, et al. Novel statistical methodology reveals that hip shape is associated with incident radiographic hip osteoarthritis among African American women. Osteoarthritis Cartilage 2016; 24(4): 640-6.[http://dx.doi.org/10.1016/j.joca.2015.11.013] [PMID: 26620089] ].

6. ASSOCIATED MUSCULOSKELETAL CHARACTERISTICS

It is obvious that associated skeletal disorders, such as osteoporosis, muscle weakness, muscle imbalance, and multiple osteoarthritic joints, and spinal disorders can influence treatment outcomes. A number of ways of defining these contributing factors have been developed and in some instances, the term phenotype is used.

It has been shown that systemic bone mineral density and bone mineral density in the vicinity of new insufficiency fractures are reduced [44Zanetti M, Romero J, Dambacher MA, Hodler J. Osteonecrosis diagnosed on MR images of the knee. Relationship to reduced bone mineral density determined by high resolution peripheral quantitative CT. Acta Radiol 2003; 44(5): 525-31.[PMID: 14510760] ]. This correlates with early OA wherein there is decreased periarticular bone density relative to systemic bone density [45Karvonen RL, Miller PR, Nelson DA, Granda JL, Fernández-Madrid F. Periarticular osteoporosis in osteoarthritis of the knee. J Rheumatol 1998; 25(11): 2187-94.[PMID: 9818663] ]. The overall implication of most studies is that focal insufficiency fractures around the knee, formerly called spontaneous osteonecrosis of the knee are typically due to systemically insufficient bone. More recently the term subchondral insufficiency fracture of the knee has been applied to this disorder. However, a recent study has demonstrated in a US population that most patients with subchondral insufficiency fracture of the knee are not osteoporotic and, for their age, have above normal bone density [46Nelson FR, Craig J, Francois H, Azuh O, Oyetakin-White P, King B. Subchondral insufficiency fractures and spontaneous osteonecrosis of the knee may not be related to osteoporosis. Arch Osteoporos 2014; 9(1): 194.[http://dx.doi.org/10.1007/s11657-014-0194-z] [PMID: 25234658] ]. The disconnection between low condylar bone density and a higher systemic bone density implies an important dynamic that may be related to early focal vascular signals.

In a large prospective multicenter study it was found that the combination of contralateral KOA, a baseline index KOA grade of 1, higher BMI, and a higher baseline Western Ontario and McMaster Universities Arthritis Index total scores were associated with greater likelihood to develop Kellgren and Lawrence grades of 3 or 4 within 5 years [47Riddle DL, Stratford PW, Perera RA. The incident tibiofemoral osteoarthritis with rapid progression phenotype: development and validation of a prognostic prediction rule. Osteoarthritis Cartilage 2016; 24(12): 2100-7.[http://dx.doi.org/10.1016/j.joca.2016.06.021] [PMID: 27390031] ]. This parallels a Swedish study of an all Caucasian population that found that the relationship of bone mineral density, BMI, and lean body mass is different for hand OA versus lower limb joint OA [48Karlsson MK, Magnusson H, Cöster M, Karlsson C, Rosengren BE. Patients with knee osteoarthritis have a phenotype with higher bone mass, higher fat mass, and lower lean body mass. Clin Orthop Relat Res 2015; 473(1): 258-64.[http://dx.doi.org/10.1007/s11999-014-3973-3] [PMID: 25280553] ]. Individuals with primary OA in the lower extremity have a phenotype with higher bone mineral density, higher BMI, and lower lean body mass content in contrast to no relationship in hand OA. The positive relationship was strongest for knees followed by hips and then ankles.

The degree of overall functional impairment will affect the treatment outcome for OA treatments. In Japan a functional assessment tool called “loco-check” includes the ability to put on a pair of socks while standing on 1 leg; stumbling or slipping at home; need to use a handrail when going upstairs; ability to cross a road before the traffic light changes; difficulty walking continuously for 15 minutes; finding it difficult to walk home carrying a shopping bag weighing about 2 kg; and difficulty doing housework requiring physical strength such as the use of a vacuum cleaner. This assessment will often reflect the combined effect of lumbar disorders, KOA and metabolic syndrome [49Sasaki E, Ishibashi Y, Tsuda E, et al. Evaluation of locomotive disability using loco-check: a cross-sectional study in the Japanese general population. J Orthop Sci 2013; 18(1): 121-9.[http://dx.doi.org/10.1007/s00776-012-0329-2] [PMID: 23114857] ]. With functional limitations, the level of activity may be diminished to the point that it could have a negative impact on KOA [50Hawezi ZK, Lammentausta E, Svensson J, Roos EM, Dahlberg LE, Tiderius CJ. Regional dGEMRIC analysis in patients at risk of osteoarthritis provides additional information about activity related changes in cartilage structure. Acta Radiol 2016; 57(4): 468-74.[http://dx.doi.org/10.1177/0284185115591237] [PMID: 26113741] ].

A musculoskeletal comorbidity index has been developed to define the effect of multiple OA joints and lumbar spine disease on total knee joint replacement outcome. It has been found that after adjusting for age, sex, BMI, and Short Form-36 mental component summary score, moderate to severe preoperative pain in the contralateral knee (p = 0.013), ipsilateral (p = 0.014) and contralateral hip (p = 0.026), and low back (p < 0.001) was significantly associated with poorer function at 6 months after total knee replacement [51Ayers DC, Li W, Oatis C, Rosal MC, Franklin PD. Patient-reported outcomes after total knee replacement vary on the basis of preoperative coexisting disease in the lumbar spine and other nonoperatively treated joints: the need for a musculoskeletal comorbidity index. J Bone Joint Surg Am 2013; 95(20): 1833-7.[http://dx.doi.org/10.2106/JBJS.L.01007] [PMID: 24132356] ].

7. JOINT TISSUES CHARACTERISTICS

It has been highlighted that the paradigm of the focus on articular cartilage as the central feature and target for therapy in KOA has changed [52McAlindon TE. Toward a new paradigm of knee osteoarthritis. Arthritis Rheumatol 2015; 67(8): 1987-9.[http://dx.doi.org/10.1002/art.39177] [PMID: 25940432] ]. Other tissue processes may be more influential, including synovial inflammation and structural damage to the meniscus and subchondral bone. It is likely that there are a number of alternate pathways to OA [52McAlindon TE. Toward a new paradigm of knee osteoarthritis. Arthritis Rheumatol 2015; 67(8): 1987-9.[http://dx.doi.org/10.1002/art.39177] [PMID: 25940432] , 53McGonagle D, Tan AL, Carey J, Benjamin M. The anatomical basis for a novel classification of osteoarthritis and allied disorders. J Anat 2010; 216(3): 279-91.[http://dx.doi.org/10.1111/j.1469-7580.2009.01186.x] [PMID: 20070426] ].

The advent of the MRI has made it possible to detect structural tissue changes that appear prior to the radiographic appearance of KOA. Research purposes now incorporate a system of whole organ involvement including bone, cartilage, meniscal, and synovial changes [54Peterfy CG, Guermazi A, Zaim S, et al. Whole-Organ Magnetic Resonance Imaging Score (WORMS) of the knee in osteoarthritis. Osteoarthritis and cartilage / OARS. Osteoarthritis Cartilage 2004; 12(3): 177-90.[http://dx.doi.org/10.1016/j.joca.2003.11.003] [PMID: 14972335] ]. In an interpretation of the MRIs from the OA initiative, there were 355 patients who had an initial MRI with no radiographic KOA but who later developed radiographic KOA over 4 years of follow-up [9Roemer FW, Kwoh CK, Hannon MJ, et al. What comes first? Multitissue involvement leading to radiographic osteoarthritis: magnetic resonance imaging-based trajectory analysis over four years in the osteoarthritis initiative. Arthritis Rheumatol 2015; 67(8): 2085-96.[http://dx.doi.org/10.1002/art.39176] [PMID: 25940308] ]. These patients were compared to case age- and sex-matched control individuals who did not develop radiographic OA. Cartilage lesions, bone marrow lesions, Hoffa’s fat lesions and combined effusion and synovium volume were scored on initial MRIs. This was contrasted to radiographic progression each year over the next 4 years. They found that the presence of specific structural features of MRI-detected joint damage 2 years prior to incident radiographic OA increased the risk of incident radiographic OA. One year prior to the radiographic change, bone marrow lesions and effusion-synovitis had the highest odds ratios. A similar study used data from the Foundation for the National Institutes of Health Osteoarthritis Biomarkers Consortium. The investigators found that for the 4-year period the number of cartilage surface regions affected, 6 or more, correlated highly with progression. Higher grade meniscal extrusion correlated to progression but not as great as articular cartilage change. The number of areas of bone marrow lesions correlated highly to progression. More advanced Hoffa fat changes correlated to progression more so than capsular distention. Changes in the degree of changes on MRI at 24 months also had specific correlations to subsequent radiographic KOA [55Collins JE, Losina E, Nevitt MC, et al. Semiquantitative imaging biomarkers of knee osteoarthritis progression: Data from the foundation for the national institutes of health osteoarthritis biomarkers consortium. Arthritis Rheumatol 2016; 68(10): 2422-31.[http://dx.doi.org/10.1002/art.39731] [PMID: 27111771] ]. The combination of synovial and infrapatellar fat pad elaboration of degradative cytokines has been found to be important to the rate of articular cartilage degradation and pain [56Roemer FW, Jarraya M, Felson DT, et al. Magnetic resonance imaging of Hoffa’s fat pad and relevance for osteoarthritis research: a narrative review. Osteoarthritis Cartilage 2016; 24(3): 383-97.[http://dx.doi.org/10.1016/j.joca.2015.09.018] [PMID: 26455999] ]. Since pain is the target of most KOA therapies, the patient will set the greatest relevance in any pain modification in contrast to some estimated long-term joint preservation benefit.

8. DISCUSSION

The use of phenotypes in KOA research can help us to understand variations in disease incidence, progression, and response to therapy. There have been specific recommendations by several research societies, but not all of them have been validated. In any given research project, investigators will need to use precaution in phenotype selection interpretations. Hence, investigators should be aware of the potential relevance of these phenotypes and make methodology decisions based on the available information.

The mixing of the term biomarker with MRI imaging and other imaging techniques can be confusing since the term biomarker connotes measurement of specific substances present in the tissues or circulation. Albeit the physical MRI categories are related to known biochemical changes, the use of the term biomarkers for MRI image categories is interesting in that some would consider these images to reflect phenotypes. Dr. Virginia Kraus noted in a personal communication the following:

I think of ‘progressor’ as the phenotype that is based on the current ‘gold’ standard biomarker of progression, i.e. the radiograph. By identifying baseline MR biomarkers that predict progression and/or change concurrently with progression based on radiograph (and in this case also pain progression) you are substituting one biomarker for another. Hopefully, the substitution is with a more sensitive biomarker (which we think is the case for many of these MR biomarkers). So I think of biomarkers as defining a phenotype and hopefully being able to distinguish and better define phenotypes with better biomarkers.

CONCLUSION

Regardless of the terms used, the recording of different biochemical, imaging, and physical features will become increasingly important in OA research. There have been a number of key KOA phenotype clusters recommended by organizations in KOA research. The problem is the continuing need for validation of any given phenotype or phenotype cluster to the outcome. Despite this, investigators should be aware of the potential relevance of these phenotypes and make methodology decisions based on the available information.

LIST OF ABBREVIATIONS

BMI = Body Mass Index
KOA = Knee Osteoarthritis
MRI = Magnetic Resonance Imaging
OA = Osteoarthritis
OARSI = Osteoarthritis Research Society International

CONSENT FOR PUBLICATION

Not applicable.

CONFLICTS OF INTEREST

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

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(Indiana University School of Nursing, USA)

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