Dance between biology, mechanics, and structure: A systems-based approach to developing osteoarthritis prevention strategies

Abstract

Osteoarthritis (OA) is a leading cause of human suffering and disability for which disease-modifying treatments are lacking. OA occurs through complex and dynamic interplays between diverse factors over long periods of time. The traditional research and clinical focus on OA, the end stage disease, obscured understanding pathogenesis prior to reaching a common pathway defined by pain and functional deficits, joint deformity, and radiographic changes. To emphasize disease modification and prevention, we describe a multi-disciplinary systems-based approach encompassing biology, mechanics, and structure to define pre-osteoarthritic disease processes. Central to application of this model is the concept of "pre-osteoarthritis," conditions where clinical OA has not yet developed. Rather, joint homeostasis has been compromised and there are potentially reversible markers for heightened OA risk. Key messages from this perspective are (i) to focus research onto defining pre-OA through identifying and validating biological, mechanical, and imaging markers of OA risk, (ii) to emphasize multi-disciplinary approaches, and (iii) to propose that developing personalized interventions to address reversible markers of OA risk in healthy joints may be the key to prevention. Ultimately, a systems-based analysis of OA pathogenesis shows potential to transform clinical practice by facilitating development and testing of new strategies to prevent or delay the onset of osteoarthritis.

Keywords: ACL; PTOA; high heels; osteoarthritis; prevention; women's health.

Figure 1

The Slot Machine System metaphor for joint health illustrates the role of OA risk in defining pre-osteoarthritis. (a) A system with “No Risk Factors” has a high probability of maintaining a “Healthy Joint” in response to “Activity” over time since the Biological, Mechanical, and Structural components of the system consistently fall within a large “Homeostasis Envelope.” (b) If the System includes a “Risk Factor” for OA (e.g., intra-articular fracture) where one of the system components (e.g., “biology” due to aging) moves out of the healthy envelope into an early disease state, this is accompanied by a reduction in the overall homeostasis envelope. This constitutes “pre-osteoarthritis” where the probability of maintaining joint health with activity over time is reduced both because one component is already out of homeostasis and because the envelope itself has shrunk.

Figure 2

Alteration of Knee Flexion Angle at Heel Strike as a mechanical marker of OA risk. (a) Compared to young, healthy subjects, knee flexion during the heel strike phase of walking is increased in older subjects and in patients with knee OA. Knee flexion at heel strike is also increased compared to the contralateral side in patients after ACLR, and associated clinically with premature OA. Wearing high heels results in a similar increase in knee flexion at heel strike compared to the same person wearing flat shoes indicating complete reversibility in this group. The system metaphor (Fig. 1) helps to place the use and evaluation of a potential intervention in context. (b) In younger subjects the mechanical component (knee flexion) appears to be a promising target for intervention. (c) In older subjects there are biological changes that also need to be considered in assessing the effectiveness of potential interventions.

Figure 3

The ACL Injured Knee shows strong potential for disease modification. (a) This is due to the relatively mild and potentially reversible deficits to biology, mechanics, and structure. The biological insult is mostly transient. Structurally, the articular cartilage generally appears grossly intact at the time of ACL surgery albeit with subsurface matrix injuries that new data shows may heal over time (Fig. 4). (b) Joint mechanics is altered and inconsistently restored after ACLR. As previously reported, a more vertical orientation of the graft (dotted circle) is associated with a shift in the averaged tibial-femoral rotation outside of the normal range during walking while a more anatomic placement (solid circle) better restores knee kinematics. The system metaphor (Fig. 3a) suggests that improved restoration of mechanical markers after ACL injury may be a promising target for disease modification.

Figure 4

Novel UTE-T2* mapping shows subsurface meniscus and articular cartilage structural changes due to injury that cannot be seen with conventional magnetic resonance imaging (reproduced from). Left: UTE-T2* maps of the articular cartilage deep tissue (A, arrows) and meniscus (B) of a human subject after ACL tear, show a mottled pattern and higher UTE values than that seen in the uninjured control. Right: UTE-T2* maps of the articular cartilage (C, arrows) and meniscus (D) of the same subject two years after anatomic anterior cruciate ligament reconstruction, show return of the laminar pattern with lower UTE values (mapped to red), comparable to the uninjured control (Meniscal images shown in B and D were reproduced from).