Bone marrow oedema syndrome as a cause of chronic knee pain in a person with severe Haemophilia A.

People with severe haemophilia (PWSH) A experience haemarthrosis particularly of the knees, ankles, and elbows from early childhood, unless treated with factor replacement or non-factor therapies.1 Chronic joint pain is reported in 48% of all people with haemophilia, and 53% in those with severe haemophilia.2 Chronic joint pain in PWSH is most often associated with the development of haemophilic arthropathy. This progressive disease process is triggered by recurrent joint bleeds and includes inflammation, chronic synovitis, and eventual destruction of articular surfaces and subchondral bone, as well as related phenomena such as soft tissue fibrosis and biomechanical alterations due to the abnormal kinetics of the haemophilic joint.3 There are, however, other rarer causes of chronic joint or limb pain in this population and these should be considered if the clinical presentation is atypical. We report a case of bone marrow oedema syndrome causing chronic atraumatic knee pain is a person with severe haemophilia A, with clinical and radiologic improvement with zoledronic acid and conservative management. The individual is a 36-year-old White British male with known severe haemophilia A (one-stage and chromogenic assay <1 IU/dL, hemizygous for intron 22 inversion) and no present or past inhibitor. He is managed with on demand standard half-life recombinant factor VIII (Moroctocog alfa, RefactoAF®) due to patient preference. His other comorbidities include HIV-1 infection, depression, chronic lumbar pain with normal MRI, and low bone mineral density (Z score −2.4 at the lumbar spine and −1.2 at the femoral neck). He has bilateral ankle haemarthropathy and his pain is managed with celecoxib 100 mg twice daily, tramadol slow release 100 mg twice daily and amitriptyline 10 mg nocte. His other medications include antiretroviral drugs and vitamin D 1000 units daily. He is a non-smoker. He presented to the haemophilia centre with gradual onset atraumatic pain in the right medial knee, radiating to the thigh and proximal lower leg. The pain was initially intermittent but progressed over a period of 12 months to unremitting severe pain in the right knee, exacerbated by weight bearing and upright posture. There was no response to his standard analgesia, and he was struggling to mobilise. There was no prior history of haemarthropathy affecting the right knee. On examination, he was afebrile with normal external knee appearances and no signs of clinical bleeding. There were no features of ligamentous injury on the physical examination. Laboratory investigations revealed a normal full blood count, normal c-reactive protein, normal liver and renal function tests, normal calcium, phosphate, parathyroid hormone and vitamin D levels. Plain radiographs of the knee and femur were normal. The pain did not respond to 7 days of daily infusions of RefactoAF™ followed by alternate day treatment for two further weeks. The history, examination, normal inflammatory markers, normal X-ray, and lack of response to factor replacement ruled out acute joint bleed, septic arthritis/osteomyelitis, crystal arthropathy and acute bony injury. An MRI scan was conducted of the right knee (Figure 1). This demonstrated a small joint effusion but no significant synovial hypertrophy or synovial haemosiderin deposition, no significant meniscal pathology, normal collateral and cruciate ligaments, and preserved articular cartilage. Interestingly, there was bone marrow oedema evident within the patella and medial aspect of the medial femoral condyle with no identifiable cause. The radiologist highlighted the presence of bone marrow oedema syndrome, not an infrequent finding in this group of patients. A literature suggested that bone marrow oedema syndrome can be associated with severe pain. Following a discussion with the patient, a therapeutic trial was attempted with a single dose of zoledronic acid 5 mg which was administered 3 months following the initial MRI given persistent symptoms. Following administration of zoledronic acid, he experienced gradual improvement in the knee pain and was able to comfortably weight bear within 8 weeks, although he did not experience full pain resolution. MRI was repeated at 12 months from the onset of symptoms (approximately 8 months following zoledronic acid) (Figure 2). This demonstrated significant improvement in the bone marrow oedema in the medial femoral condyle but mildly increased marrow oedema in the lateral tibial condyle. Following a second intravenous dose of zoledronic acid 5 mg, the patient's symptoms completely resolved over the next six months, 18 months from symptom onset. The term ‘bone marrow oedema syndrome’ (BMOS), also known as transient osteoporosis (TO), refers to a clinico-radiologic syndrome characterised by idiopathic subacute or chronic pain, most often affects the hip or knee,4, 5 and is associated with a decreased signal intensity on T1 MRI sequences and increased signal intensity on T2 and short-tau inversion recovery (STIR) sequences,4, 5 reflecting the increased water content within the bone. Its prevalence is unknown, but it has been predominantly reported in middle aged men as well as pregnant women particularly in the third trimester, with a male to female ratio of 3 to 1.4,5 It affects the lower limb in 98% of cases.4, 5 This is a diagnosis of exclusion; other differential diagnoses such as trauma, infection, bone infarction and avascular necrosis need to be considered and excluded. The knee, a joint commonly afflicted in people with moderate and severe haemophilia is the second most commonly reported site of BMOS/TO.4-6 The hip is most commonly affected and ankle/foot are third-most affected sites.4-6 The condition is variable in onset and severity, but in the more severe cases, as in this patient, pain is worse with weight bearing and is out of keeping with the physical exam findings, although tapping of the affected bone can illicit pain.7 Laboratory tests are often unremarkable.5 The pathophysiology of the condition Is poorly understood but is thought to represent a response to an insult to the bone, which maybe vascular, inflammatory or metabolic.4, 5 Some of the reported risk factors include pregnancy, vitamin D deficiency, cirrhosis, hypothyroidism, and excess alcohol.4, 5 Whilst having none of these factors, this individual did sustain recurrent joint bleeds due to his choice of On-Demand treatment. However, due to lack of MRI evidence of haemarthropathy there is little to suggest that this current issue was triggered by a joint bleed. Furthermore, treatment with factor VIII concentrates did not alleviate the symptoms. If bone marrow oedema syndrome was easily triggered by a bleed in an adjacent joint, one would expect the incidence of this syndrome to be significantly higher among people in haemophilia, which is not the case. Indeed, to our knowledge, this is the first reported case of bone marrow oedema syndrome in a PWSH A in the literature. It is noteworthy that this person is HIV positive, as bone marrow oedema syndrome has been reported in people with HIV.8 Both HIV and haemophilia are associated with increased bone resorption and osteoporosis, with similarities in the pathophysiology including the activation of osteoclasts and reduced osteoblast activity.3, 9 The use of certain antiretroviral drugs, such as tenofovir disoproxil fumarate10 and the protease inhibitors,6 have been associated with reduced bone mineral density. This individual has been on a protease inhibitor (darunavir). The management of bone marrow oedema syndrome is not standardised. Management options include conservative management, bisphosphonates, iloprost infusions, extracorporeal shock wave therapy (ESWT), and cortical decompression.6 A recent systematic review6 has shown that bisophosphonates had the best impact on short term (<1 month) pain resolution. At 3−6 months all treatments showed equal efficacy in terms of pain resolution, but at 6–12 months cortical decompression and ESWT had the best results in terms of symptom resolution and MRI improvement.6 This man achieved improvement in pain relief within 2 months of zoledronic acid resolution. However, his MRI was not repeated until his symptoms plateaued at 12 months and showed improvement in the initial lesion. The appearance of new bone marrow oedema in the lateral tibial condyle is not surprising as this condition has been shown to be migratory and can even occur bilaterally in 41% of cases.4 Our choice of bisphosphonates as a treatment modality was based on ease of accessibility as the medical treatment options are not easily available in our centre, and cortical decompression would not be the first treatment of choice in a PWSH A. Given the high degree of functional impairment due to pain at the time, coupled with his low bone density, the team considered the use of zoledronic acid to be worthwhile in the hope that it would help with the bone marrow oedema syndrome as well as improve the reduced bone mineral density. Bone marrow oedema syndrome is a rare but recognised clinico-radiologic entity that ought to be considered in the differential diagnosis of lower limb pain among people with haemophilia. MRI is the imaging modality of choice and will identify both joint pathology as well as BMOS. The syndrome is of variable severity from mild to disabling but ultimately self-limiting. Treatment with bisphosphonates may accelerate symptom resolution. The authors declare no conflicts of interest. Consent was obtained from the patient for the use of their anonymised information in this case report. Ethics committee approval was not required for this study. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.