OA

Annotations:

• The imbalance of catabolic and anabolic activities of the articular cartilage cell population, chondrocytes. This suggests that alterations to cellular metabolism is a contributing factor to the onset and progression of OA.
• Alterations in cellular metabolism have been closely linked to previous trauma, weight, physical activity, age, genetics, and strength deficits. Each of these play a role in modulated the load accepted by the knee joint.** Therefore, changes in the distribution of load through any of the above, could change the homeostasis of the catabolic and anabolic activity of the chondrocytes and result in OA. **see each bubble for additional information supporting this statement**
• The mechanical axis (i.e., the straight line connecting the hip joint to the ankle joint) passes slightly medial to the knee joint. This is why 60-80% of load is transmitted to the medial side of the knee and why medial knee joint OA is 10x more likely to occur than lateral knee joint OA (Egloff et al. 2012, Winter?)
• The knee joint in particular is subject to greater shear forces as it incorporates sliding and rotating motions during movement (Egloff et al. 2012)

1. Strength

   Annotations:

   • Muscle strength is critical for maintaining proper dynamic joint function as muscles aid in shock absorption and force transfer across the joint (Farrokhi et al. 2016).
   • Quadriceps weakness is a strong risk factor for knee OA as the muscles play a role in shock absorption to dampen the rate of loading during loading response. TTAs have weaker quads bilaterally compared to a CL which is correlation with greater LR (calculated to vertical impact peak) (Farrokhi et al. 2016, LLoyd et al. 2010).
   • Lowered quad and hamstring strength in the PL impairs the ability of the limb to produce adequate propulsion. This may therefore induce asymmetrical gait (Lloyd et al. 2010).
   • Hip muscle weakness may also be a contributing factor to knee joint OA as the hip abductor muscles are required to provide adequate stability for the knee mechanics (the knee and hip joints are connected through the femur and the knee joint moves medially during stance).  Chang et al. (2005) found greater hip abductor strength is associated with a lowered likelihood of knee OA progression.
2. Mov't Patterns
   1. Kinematics

      Annotations:

      • Most notable differences lie within the PL ankle joint.
   2. TS

      Annotations:

      • TTAs perform smaller step length and decreased stance time on the IL with an overall slower walking speed. It is thought that these asymmetrical movement patterns are in compensation to lower joint loading.
   3. Speed

      Annotations:

      • Many studies find TTA joint loading at natural walking cadence, yet this walking speed is significantly lower in comparison to control groups. A few studies have found more active amputees walk at a similar speed to the control group finding differing results in joint loading variables**. **see Joint Loading variable bubbles**
      • Loading Relation: when account for differences in speed (how?) there are not necessarily any differences between CL and IL at peak KAM. Similarly seen in GRF measures (Farrokhi et al. 2016).
   4. Justification

      Annotations:

      • Previous research has suggested between-limb movement asymmetry is related to greater limb loading (Burke et al. 1978 and others). This can be seen as amputees perform asymmetrical movement patterns and have a greater prevalence of OA in the intact limb which receives an increased load. 
      • Throughout development, typical mechanics (i.e. gait patterns) experienced in individuals create a customary joint loading history that preconditions the tissue to withstand load demand without injury. Following amputation, however, new gait patterns are developed which are outside the joint loading history. This redistributed load changes the homeostasis of the anabolic and catabolic activity of the cartilage chondrocytes predisposing the joint to the development of OA.Throughout development, typical mechanics (i.e. gait patterns) experienced in individuals create a customary joint loading history that preconditions the tissue to withstand load demand without injury. Following amputation, however, new gait patterns are developed which are outside the joint loading history. This redistributed load changes the homeostasis of the anabolic and catabolic activity of the cartilage chondrocytes predisposing the joint to the development of OA.
3. Age

   Annotations:

   • Blagojevic et al. (2010) ran a meta-analysis on age association with OA and noted a linear relationship before levelling off around age 80.
4. Weight

   Annotations:

   • Strength Relation: Obesity can accelerate muscle senescense (the weakening of muscle by arresting tissue regeneration, typically associated with age) 
   • TTAs have been found to have a higher fat content (21%) as compared to controls (13%) and are at a higher risk of weight gain (Kurdibaylo 1996).
   • Gelber et al. (1999) found younger individuals (20-29 years old) with a BMI of 24.7-37.6 kg/m2 are associated with a 3-fold increase risk of OA compared to their leaner counterparts.
   • However, Norvell et al. (2005) followed 63 traumatic male veteran TTAs from 18 to 30 years old and found that after controlling for weight, TTAs were still 3x as likely to have knee pain.** Mussman et al. 1983 additionally found no difference in knee pain in TTAs who had gained or lost weight throughout a longitudinal study. **See Pain for relation to OA**
   • Sharma et al. (2003) found a poorer function outcome, as assessed by WOMAC, in participants (already diagnosed with knee OA) with greater BMI and knee pain.
   • Mov't Pattern Relation: In dynamic loading (e.g., walking), up to 3x the load relative to standing load (Egloff et al. 2012).
5. Activity Level

   Annotations:

   • Articular Cartilage Relation:  Griffin & Guilak (2005) stated that moderate exercise at a young age produces anabolic activity. However, high-intensity or a sudden increase in activity is associated with increased catabolic activity. Immobilsation is also associated with greater catabolic activity. 
   • Is typically used as initial treatment of OA symptoms.  As assessed by WOMAC, a better function outcome, in those who were previously diagnosed with OA, was achieved through performing aerobic exercise (Sharma et al. 2003).
   • Previous Trauma Relation: With moderate exercise (not typically associated with greater risk of OA), previous injury/trauma was found to place participants at a higher risk for OA (epidemiological study - there are mixed results possibly due to different speed, distance, and diagnosis criteria).
   • Melzer et al. (2001) explored the effect of high-impact activity (volleyball) in the TTA population. Overall from both sedentary and active TTA groups, 65.6% higher prevalence of OA in TTAs as compared to a control group. When reviewing the active vs sedentary TTA groups, there was no association to OA.
6. Prosthesis

   Annotations:

   • Alignment issues may contribute to prosthetic fit (socket). Flexion and extension of the socket alignment can affect the GRF and moments on the PL which in turn may effect the loading on the IL (Gailey et al. 2008).
   • Sherman (1999) found 100% of participants recruited (traumatic) had issues with the prosthesis and 91% had residual limb pain that interfered with prosthesis use. This may affect the IL movement patterns/joint loading.
   • Prosthetic foot stiffness and energy return characteristics can affect GRF in the IL during early stance (loading response) by 7% compared to the SACH foot (Powers et al. 1994, Lehmann et al. 1993). These characteristics can also lower peak KAM by 13% in the IL during early stance (Underwood et al. 2004, Morgenroth et al. 2011).
7. Pain

   Annotations:

   • 50% of subjects with radiographic evidence of OA do not have pain symptoms and 50% of subjects with knee pain (at or above 55 years old - average age when OA becomes key diagnosis from knee pain symptoms) do not show radiographic evidence of OA (Peat et al. 2001). Peat et al. (2001) concluded that radiographic evidence of OA may not be necessary to start treatment, and knee pain coupled with disability  measures may be enough (over the age of 55) to suggest OA.
   • Mussman et al. (1983) found 46% of TTAs complained of knee pain (51 years old, traumatic, and time since amputation on average was 24 years). Burke et al. (1978) found 52% of TTAs had knee pain.
   • Hensor et al. 2015 determined that chronic knee pain may appear as evidence of knee OA in amputees first during stair movement. Chronic knee pain may also appear prior to radiographic evidence.
   • 16-18% greater prevalence of chronic knee pain in TTAs as compared to the general population (Farrokhi et al. 2016, Norvell et al. 2005)
8. Previous Trauma

   Annotations:

   • Post-traumatic OA onset and progression is related to the initial trauma (e.g., high-energy impact), inflammation, instability, and biomechanical alterations.
   • High-energy traumatic amputations (e.g., auto accident) are at a higher risk of PTOA and the development of OA occurrs quicker (Farrokhi et al. 2016, Rivera et al. 2012).
   • Blagojevic et al. (2010) meta-analysis found 14 of 16 concluding previous knee injury was an important risk factory in the development of OA.
9. Time Since Amputation

   Annotations:

   • Lemaire & Fisher (1994) found older traumatic TTAs (72 years old) with 46 years on average of time since amputation experienced greater force on the IL knee both vertical and horizontal than age-matched controls.
10. Genetic

    Annotations:

    • The make-up of articular cartilage and inflammatory response is primarily based on genetics and therefore a risk factor for OA. However, genetics can't be controlled within a study.
    • Estimates from the Spector & MacGregor 2003 paper suggests a heritability of OA of 50% or more. Half of the variation in the risk of development of OA is explained by genetic factors. However, OA is a multifactorial disease and could be prevented or slowed by understanding other factors.
11. Joint Loading

    Annotations:

    • Walking results only
    1. KAM

       Annotations:

       • KAM is the most commonly used surrogate for determining medial knee joint loading. It is calculated by the product of the vGRF and the distance between the knee joint and GRF vector.
       • Comparison between the PL and IL consistently find the IL with a greater peak KAM. When comparing the IL and CL, most papers find peak KAM to be greater, but others found no difference. 
       • It has been thought that discrete points, such as peak KAM, may not be truly reflective of the dynamic movement and therefore analysis of the full KAM curve may be a better indicator in the development of OA. 
    2. GRF

       Annotations:

       • Peak vGRF is also typically used as a risk factor for OA. The first peak vGRF is consistently found to be greater in the IL compared to the PL. However, differing results are found between the IL and CL as some papers found greater peak (Grabowski & D'Andrea 2013, Royer & Koenig, 2005, Hobara et al., 2014, Lloyd et al., 2010) and others found no difference (Sanderson & Martin 1997, Esposito & Wilken 2014). 
       • These differing results could be as a result of speed differences between control and amputee groups; if the amputee group walked at a matched speed, there MAY be a consistent higher loading. Other possible reasons are age, weight, and activity level differences. The current study will control for age, weight, and activity level while using speed as a covariate.
    3. Loading Rates

       Annotations:

       • The loading rate determines how quickly force is transferred to the joints. Previous studies have found greater loading rates in the IL compared to the prosthetic and control limbs. 
       • However, the rate of load can be attenuated by muscle control. Active amputees (with possibly greater muscle control/strength than a more sedentary amputee population) recruited in the current study may therefore have inconsistent loading rate results. Morgenroth et al. (2014) suggested KAM loading rate may therefore provide a better way to denote the initial acceptance of load. 
    4. Impulse

       Annotations:

       • Impulse represents the force-time integral (i.e., the force developed over time). It has been thought that impulse would provide a measure of sustained force (force over time), but this does not take into account the multiple variations within force curves (i.e. a short time with a high force could have the same impulse as a low force over an extended time). Therefore, analysing the GRF curve rather than discrete points may provide a more accurate measure of sustained force. 
    5. Others

       Annotations:

       • Strength asymmetries, hip internal abduction moment, and knee flexor moment have also been used as risk factors for OA (not necessarily loading). Limited studies have examined these variables, but have found connections to increased risk of developing OA and severity of OA. 
12. Theories of Occurence
    1. Loading

       Annotations:

       • Articular Cartilage Relation: Too high or too low mechanical loading leads to an increased catabolic activity.** **See Activity Level for additional information**
    2. Inflammation

       Annotations:

       • Proinflammatory mediators aid in the development of OA as they are associated with cartilage matrix degradation and joint inflammation while also diminishing anabolic activity. Genetics plays a role in the inflammatory response and make-up of the extracellular matrix. See genetics bubble.
       • Weight Relation: As life-long runners most likely load their joints to a greater extent than those with obesity, additional load through weight may not be the sole reason obesity increases the risk of OA. In addition, obesity increases the risk of OA in nonweight bearing joints. Obesity is related with a variety of metabolic diseases and as such are considered an inflammatory condition. BMI is positively correlated with a number of proinflammatory mediatiors with abdominal fat as the primary source. 
13. Articular Cartilage

    Annotations:

    • Articular cartilage is made up of an extracellular matrix (water) and a solid matrix (crosslinked matrix of collagen and proteoglycens)
    • Articular cartilage provides a nearly frictionless surface for transmission and distribution of joint loads with little wear over decades of use.
    • However, articular cartilage is limited in self-repair as it is avascular with sparsely populated chondrocytes. 
    • Therefore, changes in the homeostasis of catabolic and anabolic activity could result in permanent change of the articular cartilage make-up if maintained for an extended time.
14. Bone Mineral Density

    Annotations:

    • Increased density of the underlying subchondral bone is another mechanism in the onset and development of OA (Miyazaki et al. 2002). Essentially as load increases, bone formation increases.
    • Blagojevic et al (2010) met-analysis found a consistent strong association of increased BMD with onsent of knee OA.
    • Royer & Koenig (2005) found a 45% increase in BMD in the IL knee compared to the PL which suggests greater loading occuring in the IL.