Bone Marrow Lesions and Central and Peripheral Drivers of Knee Osteoarthritis Pain. A Pre and Post Total Knee Replacement Study.

In osteoarthritis, the cartilage which covers joints and acts like a shock absorber, wears out ultimately leading to severe pain. The only effective treatment is replacement of the damaged joint by an artificial prosthesis.
Disease is not limited to cartilage and in fact MRI shows abnormal signals deep in the bone underneath the cartilage, so called subchondral bone marrow lesions (BMLs). Presence of BMLs are more common in people with more pain. How and why these lesions may cause pain is unknown limiting our ability to intervene. I aim to assess whether pain nerve fibres and a particular type of cell (osteoclasts) are present within these BMLs, which could account for the pain.
Knee replacement surgery is normally highly successful at relieving severe pain but unfortunately up to 20% of patients continue to have pain post-surgery. This may be due to the fact that knee surgery does not aim to remove BMLs. I aim to assess whether the continued presence of BMLs after surgery is linked with pain post-surgery. Persistence of BMLs will also be correlated to changes in pain thresholds and brain activation during painful knee stimulation post-knee surgery.

Despite the success of total knee replacement surgery (TKR), 20% of patients continue to experience chronic pain post operatively. The cause of this pain remains unclear and requires further investigation. Bone marrow lesions (BMLs) within the subchondral bone visualised by MRI correlate with OA pain. Whether BMLs also contribute to post-operative pain after TKR and the biological processes involved is unknown. I aim to study 50 patients with painful knee OA to investigate BMLs, and central and peripheral drivers of knee OA pain, pre and post TKR surgery.
I hypothesise:

1.That TKR normalises altered central pain processing (assessed by functional nociceptive MRI using mechanical knee stimulation) and central sensitisation (assessed by QST and questionnaires) in patients without BMLs after TKR.

2.That the continued (or new) presence of residual bone marrow lesions (BMLs) within the subchondral bone after TKR surgery (assessed by quantitative MRI and preoperative histology) is a source of continuous nociceptive input maintaining pain, altered central processing and central sensitization post TKR surgery (assessed by fMRI, QST, questionnaires).

3.That BMLs contain increased numbers of osteoclasts and nerves when compared to areas of subchondral bone that do not have bone marrow lesions (assessed by histology).

Design of the Study

Fifty patients with unilateral painful osteoarthritis of the knee awaiting TKR will be recruited as part of this prospective cohort study. The number of patients in the study is achievable within the timeline of the fellowship. It will give clear evidence of the variability of the techniques and provides data to inform further studies.

Osteoarthritis (OA) is the most common form of arthritis worldwide with 8 million people in the United Kingdom suffering with the condition. The cause of the pain associated with the disease is still unknown and conventional radiographs showing joint space narrowing and cartilage degradation do not correlate with patient's individual symptoms of pain. Hence the peripheral and central drivers of pain still remain unclear.Currently there are no disease modifying drugs to prevent the progression of knee OA or eliminate the pain. Total Knee Replacement (TKR) is the most effective treatment for severe painful knee OA and almost 78,000 operations were performed in the UK in 2011. Despite the success of the surgery up to 20% of patients still have ongoing pain post-operative, even in cases when the implants components are aligned, well fixed and not infected. The recent use in research of MRI scans pre-operatively has shown that bone marrow lesions (BMLs) are clinically correlated with OA pain. The presence of BMLs after TKR surgery has never been explored as until know post TKR MRI scans resulted in poor image quality secondary to severe metal artefact. With the recent introduction of modern sequence techniques including the Multi-Acquisition Variable-Resonance Image Combination (MAVRIC(R)) sequence, this artefact can be significantly reduced allowing scientists and clinicians for the first time to see whether bone marrow lesions are still represent around the metal prothesis after surgery. Its is proposed that during the process of movement of the knee, these lesions are compressed against the prosthesis causing continued nociceptive stimulation leading to peripheral sensitisation and prolonged central sensitisation of pain.

It is intended that through this research a more individualised approach to patients suffering with chronic painful osteoarthritis can be reached. All patients undergoing surgery could undergo a pre-operative knee MRI scan as opposed to the standard knee radiographs taken in clinics worldwide. The identification of bone marrow lesions within the subchondral bone pre operatively will allow surgeons to create individualised custom made knee replacements.This would allow for variation in the distal femoral and proximal tibia bone cuts taken at surgery to ensure complete resection of these bone marrow lesions and hence the removal of the peripheral stimulus of pain.
This work will ensure that more patients receive the best treatment for their knee osteoarthritis and will allow many more patients to experience the full benefit of knee replacement surgery allowing them to continue making a positive contribution to society. There would be a considerable interest from the knee replacement manufacturers who are always looking for new innovitive ways to improve pain and range of movement of the knee joint with their implants. Furthermore, as arthritis is a condition that affects many joints, not just the knee, the potential benefit of this work will be significant if improved custom implants can be manufactured that allow resection of bone marrow lesions in other arthritic joints, therefore improving the quality of life of millions of sufferers worldwide.

The National Health Service will also be a beneficiary from this research. As fewer patients will suffer with chronic knee pain after knee replacement surgery this would reduce the number of admissions to hospital and the number of revision knee operations performed. The cost savings to the health service would be substantial. There NHS will also benefit from having the applicant trained in a variety of advanced MRI techniques and the addition of a fully trained academic surgeon to the NHS workforce will allow patients to benefit from novel paradigms of treatment with a sound evidence base, which will add to the reputation of the NHS as a world leader in the provision of healthcare.