Cause of osteoarthritis related pain

putated cause of osteoarthritis PAIN

bone marrow lesions
subchondral cysts
meniscal tears

What makes osteoarthritis painful? The evidence for local and central pain processing

Rheumatology, Volume 50, Issue 12, December 2011, Pages 2157–2165


OA is a chronic arthritic disease characterized by pain, local tissue damage and attempts at tissue repair. Historically, cartilage damage was believed to be the hallmark of OA. However, since cartilage is an avascular, aneural tissue, the mechanisms of pain are likely to be complex and influenced by non-cartilaginous structures in the joint including the synovium, bone and soft tissue. Imaging studies reveal the presence of synovitis and bone marrow lesions that may mediate pain. The presence of local joint inflammation and altered cartilage and bone turnover in OA implicates a potential role for a range of molecular mediators in OA pain. Mechanisms of pain perception may include the activation and release of local pro-inflammatory mediators such as prostaglandins and cytokines accompanied by the destruction of tissue, which is mediated by proteases. However, clinically, there is often disparity between the degree of pain perception and the extent of joint changes in subjects with OA. Such observations have prompted work to investigate the mechanisms of central pain perception in OA. Functional MRI has identified multiple areas of the brain that are involved in OA pain processing. These data demonstrate that pain perception in OA is complex in being influenced by local factors and activation of central pain-processing pathways. In this review, we will discuss current concepts underlying the pathophysiology of pain perception in OA and suggest possible directions for the future management of pain in this condition based on recent clinical studies.


OA is the commonest form of arthritis worldwide, affecting growing numbers of people in our ageing populations. The commonest joints affected are large weight-bearing joints, such as the hip and knee, and smaller peripheral joints, including the hands [1]. OA affects at least 50% of people >65 years of age, and occurs in younger individuals following joint injury. This figure is set to rise with increases in obesity and the ageing of our population. The disease is characterized initially by cartilage degradation, which often precedes changes in the underlying bone. Patients largely present with pain and disability after significant loss of cartilage has occurred, but it is estimated that up to 40% of individuals with radiological damage have no pain [2]. There are currently no disease-modifying agents for OA, hence management is by physical approaches, pain relief and surgical joint replacement in suitable individuals. Pain is the main reason for presentation of OA patients to clinical services. However, despite treatment with conventional analgesic drugs, most subjects with OA continue to experience pain. There is, therefore, an unmet need to gain a deeper understanding of pain pathways in this condition.
Historically, OA has been described as a primary disorder of cartilage. Although there is loss of tissue components in OA, there is also production of new tissue, including fibrocartilage and attempts by the cartilage to regenerate as evidenced by increased protein synthesis by chondrocytes, especially in the early stages of disease. Such changes are accompanied by joint remodelling. Therefore, OA has been regarded as a hypertrophic arthritis (with RA as an atrophic arthritis), emphasizing that new tissue production and remodelling are characteristic features. Imaging studies in OA joints have shown that joint inflammation occurs in OA and is influenced by local structures including ligaments, bones, tendons and effusions [3]. Studies using US and MRI have demonstrated that synovitis and bone marrow oedema are important factors contributing to pain in OA. More recently, neuroimaging has provided evidence of the contribution of the central brain network to pain perception in OA.
The main factors that we will consider with respect to OA pain in this review are: current understanding of the molecular pathways for pain mediation; how imaging techniques including MRI and US have helped to understand pain perception; and a review of the emerging data for central pain processing from clinical studies. Finally, we will relate how the data available can be applied to understanding potential therapeutic targets for the treatment of OA pain in the future.

Molecular pathways in OA pain

Recent developments have led to an improved understanding of pain pathways at the molecular level [4]. There is undoubtedly activation of local pain perception phenomena in the most common arthritides including OA and RA. An important consideration is that the pain experience in OA is probably no different from many other chronic conditions that are associated with peripheral tissue injury and repair. In this review, we will review the physiology of pain in OA and highlight how it is characterized by ascending processes and descending inhibition, often mirrored in other inflammatory and non-inflammatory joint conditions. Such observations emphasize that such features observed in OA are likely to be generalized to other joint conditions.
Historically, cartilage loss with accompanying bone changes such as osteophytes, sclerosis and cysts have been described as the hallmark lesions in OA [7]. More recent work has shown that not only do changes in cartilage in the OA joint include chondrocyte cell death and loss of cartilage extracellular matrix [8], but also there is production of new tissue including fibrocartilage and attempts by tissue to regenerate, e.g. increased protein synthesis and attempts at cartilage matrix repair by chondrocytes [8]. In normal physiology, cartilage is an avascular and aneural tissue, and thus pain mediation may well be arising from other joint structures. As ongoing joint destruction occurs in OA, features observed in the surrounding bone include osteophyte formation, which may impair joint mobility and induce pain by impinging on other local joint structures. Additional potentially relevant features include bone sclerosis and subchondral cysts. Physiological mechanisms of pain operate at the local joint level, the dorsal root ganglion (DRG) level and higher brain processing centres. Several pro-inflammatory mediators may be recruited into the OA joint associated with damage, including nerve growth factor (NGF), nitric oxide (NO) and prostanoids [11, 12] (Fig. 1). These inflammatory mediators cause localized damage to tissues, such as synovium, as well as activating peripheral nociceptors. During chronic disease, the nociceptive system can become sensitized, leading to a heightened sensitivity to noxious stimuli (hyperalgesia) [5], and to pain in response to non-noxious stimuli (allodynia) [6]. The activation of these nociceptors is subsequently transmitted via the DRG, up through the spinothalamic tract to higher cortical centres where signals are processed and perceived as pain. Mediators of pain at the DRG level in OA are believed to include NGF, calcitonin gene-related peptide (CGRP), vasoactive intestinal peptide (VIP), vanilloid receptor 1 (TRPV1) and opioid receptors (ORs). Transient receptor potential cation channel subfamily V member 1 (TRPV1) is also known as vanilloid receptor 1 and the capsaicin receptor. Chemical mediators of pain in the brain include agents such as substance P, serotonin and glutamate [15]. These are illustrated in Fig. 1.

Recent reports have also suggested that growth factors are implicated in neovascularization in the OA joint. Specifically, VEGF and PDGF are important mediators of blood vessel growth. Previous literature describing observations that cartilage is entirely avascular and aneural has recently been challenged, suggesting that modifications occur during OA disease. Walsh et al. [13] have shown VEGF expression in OA chondrocytes and increased osteochondral angiogenesis in OA subjects. It has been suggested that molecules expressed by sensory nerves, e.g. NGF, may be associated with neovascularization, thereby linking osteochondral angiogenesis to pain in OA.
In addition in the joint, molecules such as prostaglandins, bradykinin and CGRP may stimulate primary sensory neurones by activating ion channel-linked receptors on the sensory afferent neurone [16]. TRPV1 can be activated in the primary sensory neuron and is heat sensitive [17]. Thus, changes in the local joint temperature may activate this receptor during chronic inflammation. Stimuli for the TRPV1 include capsaicin and acidic conditions, which can induce pain by activating polymodal nociceptive neurons [17]. Since these neurons contain VR1 (or VR1 variants) they may act as integrators of nociceptive stimuli. Upon prolonged exposure to capsaicin, TRPV1 activity decreases, a phenomenon called desensitization [18].
The CNS is an organ demonstrating plasticity in a system that has the capacity to change, e.g. following peripheral tissue damage. For example, receptor expression may be up- or down-regulated and new synapses may form within the dorsal horn. Neurones may also alter their threshold of firing. Inflammation may lead to hypersensitivity of peripheral afferent neurones. In central sensitization, there may be persistent activation of primary afferent neurons that is believed to be mediated by the N-methyl-D-aspartic acid (NMDA) receptor at the dorsal horn level [22]. Activation of such neurons may be influenced not only by localized noxious stimuli associated with inflammation, but structural and biochemical changes also seem to occur in the systems that perceive pain. This theory has been demonstrated by Ivanavicius et al. [23], who showed the variable efficacy of NSAIDs over time in a rat model of OA with the peak effect at 14 days post-injury. Beyond this time, the analgesic effect became minimal. However, throughout the time course of the experiment, amitriptyline and gabapentin remained efficacious. These results give weight to the theory that although inflammation and joint damage cause the initial trigger for pain, sustained exposure to noxious stimuli can cause neuronal plasticity and a subsequent abnormal sensation of pain, unrelated to the inflammation.

Radiological evidence for local inflammation in OA

Imaging techniques have recently provided new information to help understand mechanisms of pain perception in the OA joint. In this section, the evidence from imaging-based studies demonstrating that bone marrow lesions (BMLs) and synovitis mediate pain in OA will be discussed.
MRI is a sensitive technique, which allows the evaluation of several soft tissue structures including synovium, cartilage and subchondral bone. BMLs can often be visualized on MRI in subjects with OA (Fig. 2). For example, in one of the largest studies of its kind, BMLs were found in 272 (77.5%) out of 351 people with painful knees compared with 15 (30%) out of 50 with no knee pain (P < 0.001) [28]. BMLs are alterations in signal intensity, which are adjacent to the subchondral plate [24], and include bone marrow necrosis, bone marrow fibrosis, trabecular abnormalities and bone marrow oedema [25]. BMLs may appear after acute injury as a result of impact collision between the femoral condyle and tibial plateau [26]. However, BMLs can also occur in joint regions, which are subjected to chronic excess focal loading including when joints are malaligned [27]. Felson et al. [28] reported a study of 401 knee OA participants, 50 of whom had no knee pain. Subjects had coronal T2-weighted fat-suppressed MRI scans and BMLs were graded 0–3 according to their size. The frequency of BMLs increased with radiographic grade of OA: 48% of Kellgren–Lawrence (KL) Grade 0 had BMLs compared with 100% of those with KL Grade 4. Additionally, BMLs were found in 78% of painful knee group compared with 30% of the non-painful knee group (P < 0.001). In another study of BMLs in OA subjects analysed by painful and non-painful OA groups, larger lesions (>1 cm2) were more frequent in the painful vs non-painful knee OA group (P < 0.05) [29]. In this study of women with knee OA, the participants with larger BMLs were more likely to have full-thickness cartilage defects, adjacent subcortical bone abnormalities and painful knee OA with an odds ratio of 3.2 [29].
Fig. 2
MRI sagittal knee imaging showing severe OA with cartilage loss and femoral bone oedema (→ in yellow).

Although much attention has been focused on BMLs, MRI studies of subjects with OA also have a number of other joint changes, which include knee effusions, meniscal lesions, hyaline cartilage loss and synovitis, all at the same time (reviewed in [30]). It is, therefore, not entirely clear as to which lesions come first and whether there is a temporal sequence to the development of lesions that influence pain in OA. These issues have been addressed by the Multicenter Osteoarthritis Study (MOST) study [31, 32], which is a large prospective, longitudinal study to assess the temporal relation between MRI-detected BMLs, full-thickness cartilage loss and subchondral cysts (SCs) in the same subregion of the knee, for the evaluation of the pathogenesis of SCs in light of SF intrusion and bone contusion theories. The findings of the MOST study have demonstrated that mensical pathology is strongly associated with incident and enlarging BMLs [32] and BMLs also predict SC formation in the same region [31], thereby supporting the bone contusion theory of SC formation. Previous studies have demonstrated that BMLs and full thickness cartilage loss predict SC formation longitudinally [33]. BMLs appear to represent focal bone remodelling due to overloading, and enlarging BMLs are predictors of pain and progression of cartilage damage in OA [34]. They are, therefore, potential targets for treatment of pain in OA.

Taljanovic et al. [35] compared MRI features with histological findings in 19 subjects after hip replacement, demonstrating microfractures in different stages of healing and bone marrow necrosis in 100% of patients of whom 85% had bone marrow fibrosis. In contrast, only 40% of patients had small amounts of oedema. This study concluded that the amount of bone marrow oedema in the OA hip, as measured by MRI, correlates with the severity of pain, radiographic findings and microfractures.

Synovitis in OA

Synovitis is an under-appreciated phenomenon in OA, which may explain the perception of pain. Various imaging modalities including US (Fig. 3) and MRI have demonstrated that synovitis is a common subclinical phenomenon in OA-affected hands, hips and knees [37–39]. Roemer et al. [37] semi-quantitatively assessed synovitis using contrast-enhanced MRI and showed that 89.2% of OA-affected knees showed Grade >2 synovitis. The most common sites of detection included the posterior cruciate ligament and the suprapatellar region. Synovitis has also been shown to have a strong correlation with knee pain severity [assessed by the Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain scale] in a contrast-enhanced MRI study [39]. For knee pain, synovitis conferred a 9.2-fold increased odds ratio compared with those without synovitis (Table 1).


- BMLs and Synovitis on imaging highly correlated with pain scores.
- Centrally mediated pain processing also likely.  antidepressant = Duloxetine (Cymbalta) used for OA pain.


Calcified Tissue International
, Volume 103, Issue 2, pp 131–143 | Cite as

How Do MRI-Detected Subchondral Bone Marrow Lesions (BMLs) on Two Different MRI Sequences Correlate with Clinically Important Outcomes?

Authors     Siti Maisarah Mattap


The aim of this study is to describe the association of bone marrow lesions (BMLs) present on two different MRI sequences with clinical outcomes, cartilage defect progression, cartilage volume loss over 2.7 years, and total knee replacement (TKR) over 13.3 years. 394 participants (50–80 years) were assessed at baseline and 2.7 years. BML presence at baseline was scored on T1-weighted fat-suppressed 3D gradient-recalled acquisition (T1) and T2-weighted fat-suppressed 2D fast spin-echo (T2) sequences. Knee pain, function, and stiffness were assessed using WOMAC. Cartilage volume and defects were assessed using validated methods. Incident TKR was determined by data linkage. BMLs were mostly present on both MRI sequences (86%). BMLs present on T2, T1, and both sequences were associated with greater knee pain and functional limitation (odds ratio = 1.49 to 1.70; all p < 0.05). Longitudinally, BMLs present on T2, T1, and both sequences were associated with worsening knee pain (β = 1.12 to 1.37, respectively; p < 0.05) and worsening stiffness (β = 0.45 to 0.52, respectively; all p < 0.05) but not worsening functional limitation or total WOMAC. BMLs present on T2, T1, and both sequences predicted site-specific cartilage defect progression (relative risk = 1.22 to 4.63; all p < 0.05) except at the medial tibial and inferior patellar sites. Lateral tibial and superior patellar BMLs present on T2, T1, and both sequences predicted site-specific cartilage volume loss (β = − 174.77 to − 140.67; p < 0.05). BMLs present on T2, T1, and both sequences were strongly associated with incident TKR. BMLs can be assessed on either T2- or T1-weighted sequences with no clinical predictive advantage of either sequence.


Alternative therapies that have some evidence.

Glucosamine and chondroitin.
Studies have been mixed on these nutritional supplements. A few have found benefits for people with osteoarthritis, while most indicate that these supplements work no better than a placebo. Glucosamine and chondroitin can interact with blood thinners such as warfarin and cause bleeding problems.

Avocado-soybean unsaponifiables.
This nutritional supplement — a mixture of avocado and soybean oils — is widely used in Europe to treat knee and hip osteoarthritis. It acts as an anti-inflammatory, and some studies have shown it can slow or even prevent joint damage.
reduces rate of loss of joint space width by 20%
The "unsaponifiables" or unsaponifiable fraction of a fatty substance include all of the components that after a process called alkaline hydrolysis (saponification) are barely soluble in aqueous solutions, but are soluble in organic solvents. More simply, unsaponifiables are the lipid fraction that cannot be transformed into soap. In general, less than 2% of oil’s content is unsaponifiable. Therefore, unsaponifiables consist of all of the non hydrolysable components of the fatty substance as well as those that mainly result from the saponification of fatty esters (sterols esters, waxes, tocopherol esters...).

Omega-3 fatty acids.
Omega-3s, found in fatty fish and fish oil supplements, might help relieve pain and improve function.