OA PATHOGENESIS AND RISK FACTORS
Osteoarthritis is not simply caused by “wear and tear” of the joint but is rather a complex disorder characterized by molecular, anatomic, and physiologic changes. As such a complex disease, there are a variety of risk factors—both modifiable and non-modifiable—that contribute to its onset and progression, some of which can be mediated with appropriate management strategies.DOWNLOAD PDF
Much has been learned about the pathogenesis of osteoarthritis (OA) in the last two decades. While this research has not yet produced effective disease-modifying treatment options for OA, it has given direction to providers and patients alike for identifying the presence of and the risk factors for OA and helping manage the disease and slow its progression.
Osteoarthritis Research Society International (OARSI) defines osteoarthritis as: “a disorder involving movable joints characterized by cell stress and extracellular matrix degradation initiated by micro- and macro-injury that activates maladaptive repair responses including pro-inflammatory pathways of innate immunity. The disease manifests first as a molecular derangement (abnormal joint tissue metabolism) followed by anatomic, and/or physiologic derangements (characterized by cartilage degradation, bone remodeling, osteophyte formation, joint inflammation and loss of normal joint function), that can culminate in illness.”1
Healthy articular (hyaline) cartilage is a frictionless, aneural, and avascular substance that covers the ends of bones in a joint. Cartilage is only 2-5 mm thick and may be compressed as much as 40% when bearing a load.2 Water is the primary component of cartilage, but it also contains collagen, proteoglycan aggregates (aggrecans), proteins, and chondrocytes. Cartilage is metabolically active and undergoes continual internal remodeling under the control of the chondrocytes. Synovial fluid, found in the joint capsule, is viscous, aids in the lubrication and movement of a joint, and allows vital nutrients to reach the cartilage while blocking harmful substances. Along with muscles and subchondral bone, synovial fluid is an important component for joint stress reduction or load absorption. Hyaluronic acid is a key component of both synovial fluid and cartilage which facilitates the viscosity of the synovial fluid, acts as a shock absorber under sudden joint loading, and filters potentially damaging cells and molecules.3
Following joint injury (e.g., trauma or repeated loading), proinflammatory mediators (e.g., cytokines and chemokines) are naturally produced, leading to extensive matrix degradation and loss. As part of this process proteoglycans attract water, and articular cartilage expands. Chondrocytes, which are normally dormant, begin to proliferate due to the loss of matrix. When cartilage degeneration exceeds the rate of chondrocyte remodeling, OA occurs. When collagen is degraded and lost, the cartilage has limited ability to repair and chondrocytes die.
Within the joint, soft tissue damage leads to thickening of the joint capsule which can result in visible, but often minor joint swelling. Bone sclerosis and osteophyte (bone spur) formation can also result when OA is more moderate to severe. 4 Such alterations to the joint often precede the onset of clinically or radiographically detectable OA. 5-7 Age-related changes within a joint can increase the risk of developing OA due to the joint’s susceptibility to injury and decreased capacity for repair. Cellular senescence and mitochondrial dysfunction due to advancing age also contribute to the development of OA.4 Patient-reported symptoms—that is, the illness—do not necessarily align with this underlying disease pathology.8
Pain in OA is likely the result of a complex interplay of factors including mechanical, inflammatory, and centralized pain pathways.2
Figure 1: Pathogenesis of Osteoarthritis9
Reproduced with permission from: Loeser RF. Pathogenesis of osteoarthritis. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on [Date].) Copyright © 2019 UpToDate, Inc. For more information visit www.uptodate.com.
For most patients, OA is linked to multiple risk factors that can be grouped into modifiable and non-modifiable. Non-modifiable risk factors for OA include age, sex, ethnicity, genetics, previous history of injury or joint trauma. Potentially modifiable risk factors for OA include excess weight, certain occupations and sports, joint injury (injury prevention), joint malalignment and quadriceps weakness.
NON-MODIFIABLE RISK FACTORS
- Age is by far the most well-known risk factor for OA; however OA is not a normal part of aging.9
- OA is occurring in younger adults at increasing rates.
- In 2018, among US adults with self-reported OA, 57% were younger than 65.9 Over half of people with OA who were limited in their daily activities were under age 65.10
- OA is twice as common in women as men.10
- Knee and hand OA are more common in women. Hip OA has similar rates in men and women.9
- Older African-American, Native American, and non-white Hispanic women are more likely to develop OA than white women.11,12
- African-Americans are more likely to develop symptomatic knee and hip OA compared to other race/ethnic groups.13
- Hip OA is 33% more prevalent in older African-American men than white men.14
- OA, like many common chronic conditions, is likely influenced by many genetic loci, each with only a small effect.15
- Twin studies have shown the heritability of hip OA to be approximately 60%, knee OA greater than 40%, hand OA 65%, and spine OA 70%.16
- Multiple gene interactions within collagen, cartilage, and bone may contribute to the development of OA.
Prior joint injury
- Post-traumatic arthritis makes up approximately 12% of all OA cases and can result from injuries sustained in automobile or military accidents, falls, or sports.17
- Individuals with a history of knee injury are 3-6 times more likely than those without knee injury to develop OA.18
- History of anterior cruciate ligament (ACL) or meniscus tear confers 2.5 times the risk of developing knee OA and 4 times the risk for eventual total knee arthroplasty.2,13,19
- Within the first decade after an ACL injury about 1 in 3 patients have radiographic OA, regardless of treatment.20,21
POTENTIALLY MODIFIABLE RISK FACTORS
- Men and women who are obese have a 2.8-fold and 4.4-fold increase in developing knee OA, respectively.22
- Ten pounds of additional weight increases the force exerted on the knee by up to 60 pounds with each step.23
- There are likely metabolic (not just mechanical) factors at play, given that excess body weight has been associated with higher risk of hand OA, and not all people who are obese develop OA.9
- In the IDEA trial (Intensive Diet and Exercise for Arthritis), subjects with knee OA who were overweight and who achieved a modest weight loss (10% of body weight) through diet and exercise, achieved a 50% reduction in pain scores.24
Occupation and Sports
- Certain occupations (e.g., construction, healthcare, farming, law enforcement, first responders, military) involving prolonged standing, squatting, lifting, kneeling, and repetitive motion with resultant excessive mechanical stress on a joint, raises the risk of OA and can worsen symptoms.25,26
- Osteoarthritis and back pain are the most common diagnoses related to disability-caused separation from the military, both during periods of peacetime and war.26,27
- High impact professional sports (e.g., hockey, soccer, and football), where there is not only repetitive loading with excessive force, but also increased joint trauma puts players at risk of OA.28
- In addition to elite-level athletes (soccer, long-distance running, weight lifting and wrestling), non-elite soccer athletes are also at risk of developing OA.29
- Proper precautions such as stretching and strengthening exercises, appropriate footwear and other devices, along with supportive workplace or athletic team policies, can help reduce onset and progression of OA in occupational and sports settings.
Joint Injury (Injury Prevention)
- Participating in short neuromuscular training exercise programs can reduce the risk for traumatic knee injury by up to 70%.30 See the OA Prevention module for more information.
- Patients at risk of falling can build strength and improve balance to reduce their risk of fall-related joint injuries and should be counseled to engage in or increase their physical activity. The CDC’s STEADI initiative (Stopping Elderly Accidents, Deaths, & Injuries) includes educational materials for providers and handouts for patients on preventing falls.
Joint Position and Strength
- Knees that are not mechanically aligned properly- resulting in either varus (bowlegged) or valgus (knock-kneed) alignments- can result in increased risk of knee OA. The worse the malalignment, the greater decline in physical function likely to be experienced by patients.31
- Knee braces or shoe inserts may help with pain and stiffness when these conditions exist.31,32
- Weaker quadriceps strength can result in increased functional disability and pain in people with knee OA.33,34 Muscle-strengthening exercises, whether with a physical therapist or through a community-based intervention program, can help reduce pain and functional limitations.
The Prevention & Self-Management handout may be useful for patients with OA or at risk of developing OA.
Figure 2 demonstrates the relationship between non-modifiable and modifiable risk factors in the context of the progression of OA and associated increasing functional limitations.
Figure 2: Risk Factors for Osteoarthritis of the Knee and Related Disability35
Reproduced from Bennell KL, Hunter DJ, Hinman RS. Management of osteoarthritis of the knee. BMJ. 2012;345:e4934 with permission from BMJ Publishing Group Ltd.
Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet. 2019;393(10182):1745-1759.
CLINICAL TAKE-HOME POINTS
- OA is not simply “wear and tear” or “degeneration” of the joint, but rather a complex disorder characterized by a variety of molecular, anatomic, and physiologic changes leading to disease.
- Non-modifiable risk factors should be considered, and modifiable risk factors addressed, to reduce disease burden.
- Osteoarthritis Research Society International. Standardization of Osteoarthritis Definitions. Available at https://www.oarsi.org/research/standardization-osteoarthritis-definitions. Published 2015. Accessed April 1, 2019.
- Buys LM, Wiedenfeld SA. Osteoarthritis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, M P, eds. Pharmacotherapy: A Pathophysiologic Approach, 10e. New York, NY: McGraw-Hill.
- Moreland LW. Intra-articular hyaluronan (hyaluronic acid) and hylans for the treatment of osteoarthritis: mechanisms of action. Arthritis Res Ther. 2003;5(2):54-67.
- Collins JA, Diekman BO, Loeser RF. Targeting aging for disease modification in osteoarthritis. Curr Opin Rheumatol. 2018;30(1):101-107.
- Sharma L, Chmiel JS, Almagor O, et al. Significance of preradiographic magnetic resonance imaging lesions in persons at increased risk of knee osteoarthritis. Arthritis Rheumatol. 2014;66(7):1811-1819.
- Roemer 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):2085-2096.
- Podsiadlo P, Nevitt MC, Wolski M, et al. Baseline trabecular bone and its relation to incident radiographic knee osteoarthritis and increase in joint space narrowing score: directional fractal signature analysis in the MOST study. Osteoarthritis Cartilage. 2016;24(10):1736-1744.
- Lane NE, Brandt K, Hawker G, et al. OARSI-FDA initiative: defining the disease state of osteoarthritis. Osteoarthritis Cartilage. 2011;19(5):478-482.
- Loeser R. Pathogenesis of osteoarthritis. In: Post T, ed. UpToDate. Waltham, Mass: UpToDate; 2018: www.uptodate.com. Accessed January 23, 2019.
- Osteoarthritis Research Society International. Osteoarthritis: A Serious Disease, submitted to the U.S. Food and Drug Administration. 2016. https://www.oarsi.org/sites/default/files/docs/2016/oarsi_white_paper_oa_serious_disease_121416_1.pdf. Accessed March 27, 2019.
- Wright NC, Riggs GK, Lisse JR, Chen Z, Women’s Health I. Self-reported osteoarthritis, ethnicity, body mass index, and other associated risk factors in postmenopausal women-results from the Women’s Health Initiative. J Am Geriatr Soc. 2008;56(9):1736-1743.
- Eustice C. The effect of ethnicity of osteoarthritis. Verywell Health. https://www.verywellhealth.com/the-effect-of-ethnicity-on-osteoarthritis-2552101. Published 2018. Accessed June 21, 2018.
- Vina ER, Kwoh CK. Epidemiology of osteoarthritis: literature update. Curr Opin Rheumatol. 2018;30(2):160-167.
- Arthritis Foundation. Arthritis by the Numbers. In: Atlanta, GA: Arthritis Foundation; 2019: https://www.arthritis.org/getmedia/e1256607-fa87-4593-aa8a-8db4f291072a/2019-abtn-final-march-2019.pdf. Accessed May 13, 2022.
- Warner SC, Valdes AM. Genetic association studies in osteoarthritis: is it fairytale? Curr Opin Rheumatol. 2017;29(1):103-109.
- Spector TD, MacGregor AJ. Risk factors for osteoarthritis: genetics. Osteoarthritis Cartilage. 2004;12 Suppl A:S39-44.
- Punzi L, Galozzi P, Luisetto R, et al. Post-traumatic arthritis: overview on pathogenic mechanisms and role of inflammation. RMD Open. 2016;2(2):e000279.
- Driban JB, Eaton CB, Lo GH, Ward RJ, Lu B, McAlindon TE. Association of knee injuries with accelerated knee osteoarthritis progression: data from the Osteoarthritis Initiative. Arthritis Care Res (Hoboken). 2014;66(11):1673-1679.
- Hunter DJ, Zhang YQ, Niu JB, et al. The association of meniscal pathologic changes with cartilage loss in symptomatic knee osteoarthritis. Arthritis Rheum. 2006;54(3):795-801.
- Luc B, Gribble PA, Pietrosimone BG. Osteoarthritis prevalence following anterior cruciate ligament reconstruction: a systematic review and numbers-needed-to-treat analysis. J Athl Train. 2014;49(6):806-819.
- Harris KP, Driban JB, Sitler MR, Cattano NM, Balasubramanian E, Hootman JM. Tibiofemoral Osteoarthritis After Surgical or Nonsurgical Treatment of Anterior Cruciate Ligament Rupture: A Systematic Review. J Athl Train. 2017;52(6):507-517.
- Garstang SV, Stitik TP. Osteoarthritis: epidemiology, risk factors, and pathophysiology. Am J Phys Med Rehabil. 2006;85(11 Suppl):S2-11; quiz S12-14.
- Johns Hopkins Arthritis Center. Role of body weight in osteoarthritis. Available at https://www.hopkinsarthritis.org/patient-corner/disease-management/role-of-body-weight-in-osteoarthritis/. Accessed June 4, 2018.
- Messier SP, Mihalko SL, Legault C, et al. Effects of intensive diet and exercise on knee joint loads, inflammation, and clinical outcomes among overweight and obese adults with knee osteoarthritis: the IDEA randomized clinical trial. JAMA. 2013;310(12):1263-1273.
- Yucesoy B, Charles LE, Baker B, Burchfiel CM. Occupational and genetic risk factors for osteoarthritis: a review. Work. 2015;50(2):261-273.
- Cameron KL, Driban JB, Svoboda SJ. Osteoarthritis and the Tactical Athlete: A Systematic Review. J Athl Train. 2016;51(11):952-961.
- Patzkowski JC, Rivera JC, Ficke JR, Wenke JC. The changing face of disability in the US Army: the Operation Enduring Freedom and Operation Iraqi Freedom effect. J Am Acad Orthop Surg. 2012;20 Suppl 1:S23-30.
- Amoako AO, Pujalte GG. Osteoarthritis in young, active, and athletic individuals. Clin Med Insights Arthritis Musculoskelet Disord. 2014;7:27-32.
- Driban JB, Hootman JM, Sitler MR, Harris KP, Cattano NM. Is Participation in Certain Sports Associated With Knee Osteoarthritis? A Systematic Review. J Athl Train. 2017;52(6):497-506.
- Sugimoto D, Myer GD, McKeon JM, Hewett TE. Evaluation of the effectiveness of neuromuscular training to reduce anterior cruciate ligament injury in female athletes: a critical review of relative risk reduction and numbers-needed-to-treat analyses. Br J Sports Med. 2012;46(14):979-988.
- Sharma L, Song J, Felson DT, Cahue S, Shamiyeh E, Dunlop DD. The role of knee alignment in disease progression and functional decline in knee osteoarthritis. JAMA. 2001;286(2):188-195.
- Heidari B. Knee osteoarthritis diagnosis, treatment and associated factors of progression: part II. Caspian J Intern Med. 2011;2(3):249-255.
- O’Reilly SC, Jones A, Muir KR, Doherty M. Quadriceps weakness in knee osteoarthritis: the effect on pain and disability. Ann Rheum Dis. 1998;57(10):588-594.
- Bacon KL, Segal NA, Oiestad BE, et al. Thresholds in the relationship of quadriceps strength with functional limitations in women with knee osteoarthritis. Arthritis Care Res (Hoboken). 2018.
- Bennell KL, Hunter DJ, Hinman RS. Management of osteoarthritis of the knee. BMJ. 2012;345:e4934.