Exercise Loading Biology Post-Traumatic OsteoArthritis Study - a Pilot and Feasibility Study

FROM RISK FACTORS TO THE PREVENTION OF LONG-TERM CONSEQUENCES AFTER CRUCIATE LIGAMENT INJURY (ACL injury) - This is a research project where we seek new knowledge about why some people have a high risk and others a low risk of developing long-term consequences such as persistent pain, thigh muscle dysfunctions and osteoarthritis after ACL surgery. Through more knowledge about risk factors for persistent pain, thigh muscle dysfunctions, and, in the long term, osteoarthritis, we have a greater opportunity to tailor preventive treatment measures to the individual.

We know that a subgroup of those who have undergone ACL surgery does not regain the normal function of the quadriceps muscle, that it does not become as strong as it used to or not quite the same as on the other healthy side. Some may notice this very well, others may not notice as much in the short term. We know that quadriceps dysfunctions can affect the biomechanical joint loading in your knee and can be a contributing risk factor to developing long-term consequences such as persistent pain, thigh muscle function and osteoarthritis after ACL injury.

We have methods to measure joint loading conditions in the knee and to identify changes in the cartilage, in the underlying bone tissue of the knee joint, and to measure various aspects of quadriceps muscle strength and dysfunctions.

In this study, we want to develop new knowledge about whether there is a difference in knee joint loading conditions and quadriceps muscle function between those who have low risk and those with a higher risk of developing post-traumatic osteoarthritis and whether there is an association between joint loading conditions in the knee after ACL surgery and quadriceps muscle function and symptoms.

The main risk factors for knee OA disease are well-known: joint injuries and obesity. For those with ACL injury, systematic reviews have reported between 4 to 6 times increased risk of developing OA after ACL injury (PTOA). The following risk factors have been identified for PTOA in a recent systematic review by our OPTIKNEE group: ACL injury with concomitant injuries (meniscus and cartilage injuries), re-injuries after ACL injury, long-lasting quadriceps dysfunction, and inflammation after joint injury.

A better understanding of mechanisms to stratify the patients into different subgroups based on risk factors is critical. The mechanisms driving OA disease development are known to be 1) mechanical and 2) inflammatory. The mechanisms leading to PTOA combine mechanical, biological, structural, and neuromuscular factors.

Mechanical stress with persistent abnormal joint loading is an undisputed mechanism driving OA disease development. Altering joint mechanics (underloading and overloading) after ACL injury and reconstruction (ACLR) can lead to uneven stress and changes in stress across the articular cartilage of the joint surfaces, contributing to abnormal joint function and muscular dysfunction over time.

Whether such persistent abnormal knee joint loading patterns differ between individuals categorized as high risk compared to those at low risk of PTOA has not been investigated.

We do not understand the main drivers of the shifts in joint loading (underloading or overloading) or biochemical changes and whether this knowledge can be translated into developing joint-loading therapeutic interventions. However, we do know that quadriceps muscle weakness is a modifiable risk factor for non-traumatic OA and PTOA. ACL injury has shown a decline in quadriceps muscle function, which mimics ageing, known as sarcopenia. Quadriceps muscle dysfunction persists for some individuals for several years after ACLR, even after the cessation of structured rehabilitation, and has been questioned if it ever returns to normal. Despite decades of high-quality rehabilitation, normalizing quadriceps function in all ACL-injured and reconstructed patients remains unsolved.

This study has an overall aim of understanding more of the mechanisms for abnormal knee joint loading and quadriceps muscle dysfunctions in individuals at high- compared to low-risk PTOA (those with concomitant injuries and persistent symptoms compared to those with isolated ACL injury).

This cross-sectional study includes 40 participants 9 months to 2 years after ACLR with an extensive test-protocol of biomechanical-, neuromuscular- and biological assessments and tests. Hence, it is also a feasibility study for a planned randomized controlled trial of the effect of joint-loading therapeutic interventions on changes in knee joint loading for those at risk of developing PTOA. Furthermore, a sample of 40 individuals will be included to investigate primary outcomes' mean and standard deviation needed to calculate sample size for future randomized controlled trials.

Specific aims for the cross-sectional study are:

1. Investigate knee joint loading during gait, running and hopping, cellular, morphological, muscle inhibition and strength of the quadriceps muscle, and inflammatory knee joint markers in individuals who are 9 months to 2 years after an ACLR.
2. Characterize biomechanical, neuromuscular, and inflammatory factors in individuals classified as high-risk (concomitant injuries, persistent symptoms) for developing PTOA compared to those classified as low-risk (isolated ACL injury and no or minimal knee pain).
3. Explore the associations between abnormal knee joint loading, quadriceps muscle dysfunctions, and inflammatory markers in the knee joint 9 months to 2 years after ACLR
4. Describe the feasibility of the study regarding the recruitment of an extensive test-protocol
5. A pilot study for a future mechanistic RCT on the efficacy of a muscle- and joint-loading therapeutic exercise program on changes in knee joint loading and on surrogate outcomes of PTOA.

Eligibility Criteria:
Inclusion Criteria:

* Unilateral ACL injury and ACLR (≤ one year between injury and surgery)

  * Surgery performed using the BPTB or hamstring grafts
  * Age between 16 and 40 years
  * Isolated ACL or with concomitant meniscal injury/cartilage injuries at surgery
  * Location (living) in the Oslo or Viken areas (due to the need for testing performed at the Norwegian School of Sport Sciences and Oslo University Hospital)
  * Healthy, uninjured contralateral knee

Exclusion Criteria:

* Above 40 years and below 16 years of age
* Previous ACL injury (re-rupture of graft or an ACL injury more than one year between injury and surgery)
* MCL/LCL grade 3 injuries
* Other lower extremity injuries less than one year before inclusion, or previous inflammatory arthropathy or systemic infection or inflammation
* Participants with bilateral ACL injuries