The Growing Case for Suboptimal Muscle and Muscle Mechanisms as Possible Osteoarthritis Mediators or Moderators: 25 Year Scoping Update and Commentary

Osteoarthritis, a disabling joint disease with no known cause may have a strong muscle based etiology, rather than an age associated ‘wear and tear’ etiology. Herein we review and present a snapshot of 25 years of current and prior research in this respect. As such, peer reviewed data published from 2000-2025 imply a possible role for suboptimal muscular contractile forces, as well as the presence of disordered muscle physiology and temporal functioning as significant disease mediators and moderators. Indeed, while not definitive, it appears more research as well as clinical applications in this realm are not only indicated, but could prove highly insightful and fruitful.

Keywords:Aging; Etiology; Muscle; Osteoarthritis; Pain; Prevention; Treatment

What causes osteoarthritis, a major functional disabler of the older population, and is there more to this disease than its explanation as an inevitable outcome of age related ‘wear and tear’ processes? For more than 100 years researchers have sought to establish the precise pathogenic pathway leading to osteoarthritis. Indeed, this widespread heterogeneous disease that quite readily impacts freely moving joints such as the knee, is of great current concern because once the disease process is present, it is currently largely incurable and often progressive. However, over time, diverse studies have pointed to multiple factors other than aging alone as potential pathogenic osteoarthritis determinants, including diverse intrinsic muscle abnormalities and responses in the neuromotor system and others [1-3].

This possibility is of immense import in the disease amelioration context because not only does osteoarthritis commonly only manifest in its later stages where there is presently a limited ability to effectively treat its multiple disabling manifestations, but it is the most prevalent joint disorder, and leading cause of joint pain and joint disability throughout the world [4, 5]. Hence, recognizing and appreciating that perhaps a variety of muscle mechanisms may underpin this disease in some cases as well as the degree to which treatment is effective or not, tentatively opens a window for at least some safe cost effective preventive opportunities. Unfortunately, despite a large amount of related research, and the possibility that pathology of the neuromotor system is one factor promoting joint dysfunction [1, 2], this idea is not pursued to any meaningful degree in the realm of mainstream osteoarthritis understandings and intervention recommendations. Additionally, although supported by many diverse ‘acute’ animal model studies of simulated osteoarthritis to a high degree, muscle mechanisms studied clinically are largely non uniform and often hard to differentiate as far as having any tangible or distinct disease modifier or mediator impact or potential. There is also a marked lack of well-designed longitudinal clinical studies [6] and very few that study vantage points other than muscle mass and strength when muscle is studied. Even here, less than desirable information is forthcoming here because researchers generally fail to examine the underlying origins of any observed muscle deficit, including those most commonly observed and it is challenging to aggregate so many differing findings [7].

Indeed, while every clinician recognizes symptomatic osteoarthritis when they see it, the precise explanation for the underlying causes of these symptoms remains obscure. There is also a limited ability to accurately predict the natural course of the disease and hence what therapy is desirable and what is undesirable remains as unclear in 2025 as it was in 2000 or before that time despite almost three decades of specific inquiry. Nonetheless, over time, a growing body of data has suggested some forms of muscle-related loading outcomes arising from subnormal muscle balances and dysfunctional temporal responses and suboptimal joint stresses and strains may be harmful to its key tissue, articular cartilage [8-11]. This includes the derangement of cartilage collagen and proteoglycans matrix contents and their vital water attracting properties and extent, and may occur consequent to both excessive focally directed muscle impacts or a failure thereof [12-14]. As well, various forms of subnormal intrinsic muscle contractile dysfunction, muscular atrophy, quality, fiber type alterations and volume declines, plus muscle mitochondrial and lipid content abnormalities along with poorly modulated muscle reflex responses may play an independent or cumulative pathogenic role [15-20].

Other abnormalities may involve a combination of untimely or reactive muscle contraction forces and a retarded rate of force development as well as magnitude, alterations in muscle fiber fast and slow ratios, morphology, and groupings, plus neuromuscular junction changes that lead to chondrocyte death, cartilage loss and eventual loss of the joint’s load bearing surface [21-24]. As well, possible muscle mass losses and their influence on muscle pain, spasm, intrinsic bio-molecular processes [23] and ion channel alterations may underpin an array of diverse overlapping physiological and pathological processes associated with osteoarthritis [21, 25]. That is, alone, or in combination, it is clear diverse inherent or reactive muscle adaptations or responses that persistently impinge or strain on one or more joint structures [26] may affect multiple cartilage biochemical, metabolic, and signaling pathways as well as cartilage molecular processes detrimentally and progressively [26, 27]. However, this set of findings and others is highly non uniform and challenging to unify or verify. For example, in some cases, one set of muscles, but not others appear to prevail in the presence of osteoarthritis [17, 28], while novel attention to averting muscle aging and degeneration processes currently implicate a role for extracellular vesicle extrusion in the osteoarthritis derangement syndrome cycle that warrants attention [29]. However, it appears the fact osteoarthritis when present in not uniform either from joint to joint within one individual, or across individuals with the same diagnosis [30] speaks to etiological factors other than age in our view, and possible muscle as a key support and mobility correlate [eg., 31-35]. The same arguments can also be applied against most genetic and systemic explanations of osteoarthritis where muscle is not directly implicated.

This brief focuses on cumulative evidence, which reflects this aforementioned viewpoint as published in a sample of peer reviewed journals over the last 20-25 years.

Using the PUBMED, Google Scholar, and PubMedCentral databases and the terms: muscle and osteoarthritis, muscle fatigue and osteoarthritis, muscle pathology and osteoarthritis, muscle dysfunction and osteoarthritis articles cited between 2000 and 2025 were eligible if they addressed the theme of this overview and line of inquiry. In general, foreign language publications, proposals for study, or those published in conference proceedings were excluded. Only a narrative perspective of selected sources is provided, and no specific muscle form or joint was examined. The article quality of those highlighted is assumed in each case to be valid. No formal analysis was possible or plausible to conduct.

Rationale

Given its role as both an afferent and efferent neuromotor transmitter, muscles not only produce movement voluntarily or reflexively, but relay various modes of proprioceptive information that promote function, joint stability, joint protection, and shock absorption functions.

Significance

Despite years of study, osteoarthritis remains an increasing disabling condition that is rising steadily as population’s age. This line of inquiry was specifically sought and extended following a previous review, so as to advance the hope that osteoarthritis as suffered by increasing numbers of aging adults is not inevitable. The topic appears a worthy one to pursue however as it seems likely this knowledge is absolutely essential to improving our present limited ability to not only effectively initiate preventative strategies against the disease, as well as the ability to foster rehabilitation in general, and specifically after surgery. Moreover, averting its progression which might considerably reduce the magnitude as well as the economic and social costs of this disabling disease is another reason for pursuing all avenues of inquiry that may be fruitful.

Key Findings

As can be discerned clearly on PUBMED, it is only after many years of studying osteoarthritis where almost no muscle related study was published, it is clear that since the late 1990s at least 600 related articles with more being posted each year have emerged. Many however, still remain less than focused on any single topic, or a specific set of joint problems or emergent disease indicators other than the knee and hip and aspects of pain and muscle strength. Most currently conclude though that regardless of what muscle variable is examined there is room for as well as promise that further study will prove insightful, but the research as a whole remains of poor quality as acknowledged by multiple authors. However, what is clear is that very few articles where some aspect of muscle and its relevance to osteoarthritis that are published would refute some form of beneficial or harmful muscle osteoarthritis joint linkage. Indeed, as time has evolves, there is also an array of novel approaches that increased the strength of a possible muscle joint coupling that is affected or can affect a healthy joint at any age.

As such, although no systematic analysis is possible, multiple past studies and new modes of investigation support a possible contributing factor of muscle to the development, manifestations, and progression of osteoarthritis as follows though it is impossible to truly aggregate the data in our view with any degree of confidence. Indeed, based on an array of past studies it appears plausible to infer that osteoarthritis damage can be caused, anticipated, or magnified by a variety of muscular mechanisms, including exposure to abnormal or excessive muscular forces, as well as inadequate muscle forces. It also appears that the characteristic focal areas of cartilage damage occurring in osteoarthritis joints may reflect site specific cartilage damage consequent to subnormal muscle forces placed on cartilage, for example by imbalanced muscle agonist/ antagonist force generation processes. Others imply the presence of an intricate array of signaling pathways linking muscle and cartilage may be involved and activated in the face of muscle dysfunction, muscle injury and muscle spasm, muscular contractures, muscle weakness leading to abnormal movement patterns and joint reaction forces, muscle inflammation and sorenss, plus impaired muscle afferent activity and muscle strength declines [36-40].

Yet others suggest poor muscular coordination, especially a reduced ability to generate eccentric muscle forces in a timely manner, changes in motor unit physiology, skeletal mal-alignments and related abnormal muscular force adaptations, pre-existing muscle pathology and alterations in afferent input to the central nervous system associated with proprioceptive acuity and muscular effectors that provide muscle strength and capacity to stabilize the joint may be subnormal. As well, related muscle cross-sectional area declines may further impair the efficiency of joint loading both before or after the onset of osteoarthritis joint manifestations [38-45]. It also appears that the presence of any inter-limb asymmetries generated during walking and other weight bearing functions, coupled with persistent differential intra-limb muscle force generating capacity and muscle size declines [17, 41] can predictably foster abnormal joint forces that lead to disruptions of both cartilage physiology and its structure at one or more joints and others [17, 42].

Although no cause effect relationship is often discussed when reporting on osteoarthritis and muscle, it was recently shown that people with patella-femoral osteoarthritis as a whole have tended to present with lower strength and volume of the hip and quadriceps muscles as well as altered muscle activation of the vastus medialis and lateralis and hip abductors during ascending and descending stairs when compared to asymptomatic controls [46]. Shorter et al. [47] who conducted a systematic review proposed there may be a possible impact of muscle wasting in this regard as far as osteoarthritis progression is concerned that could directly affect both muscle force capacity as well as joint stability and mobility, thus impairing cartilage nutrition as well as cartilage shock absorption and thus potentially playing a significant role in osteoarthritis development and/or its progression and osteoarthritis symptoms. Others recently echoed and focused on highlighting the observable association of osteoarthritis and its impact on declining function in the context of declines in muscle mass, and strength [27, 48], and the possible encroachment of muscle adipose tissue to replace muscle tissues in this regard [49].

Sherman et al. [50] proposed dysfunction in efferent pathways following the onset of knee pathology may play a further role in fostering long-term impairments in quadriceps and hamstrings muscle performances, daily function, and health-related quality of life. As per Wu et al. [51] it appears weight-bearing activity is associated with incident knee osteoarthritis in people with low levels of lower-limb muscle mass, while Khali et al. [52] acknowledge the importance of continuing to restore muscle composition, architecture, and mass even after hip joint replacement surgery. This is because their cumulative findings have shown factors such as obesity, and muscle atrophy, often exacerbated by aging, may increase the risk of joint instability and falls that can lead to further joint based problems, as well as delayed healing even if not a disease precursor. To counter this adverse cycle of possible events a role for increasing muscle protein after surgery has been duly advocated and holds some promise for reducing muscle atrophy.

There also appears to be relatively unexplored linkages between articular cartilage and muscle degeneration that may have a bearing on both treatment as well as the pathology of articular cartilage [38]. Another common finding is that osteoarthritis and sarcopenia may be associated [53, 54]. Moreover, a role for pathogenic muscle strength declines should not be ignored [55], as this may have a bearing on the synthesis and release of muscle myokines or biological messengers that are produced and exuded to impact bone and cartilage microstructure [56, 57]. This is consistent with observations that quadriceps muscle atrophy can trigger subchondral bone abnormalities and cartilage degeneration, which would be a risk factor for development of osteoarthritis, while anti atrophy exercise approaches would likely prove beneficial [57]. In a study conducted by Tuna et al. [58] this group showed that femoral cartilage thickness was reduced, and knee osteoarthritis prevalence increased in cases deemed sarcopenic, pointing to a role for muscle fat mass in this disease cycle. Additionally, decreased medial femoral cartilage thickness predicted sarcopenia, while another found associations between osteoarthritis biomarkers and muscle fat fraction measures [59].

A recent report further shows the existence of correlations among muscle morphology changes, cervical degeneration, and its clinical features in cases with non specific neck pain that warrants attention [60]. Another indicated a role for muscle anatomy and its bearing on chondral lesion development is hard to dispute [61], while Liu et al. [62] also imply a role for muscle activation pattern changes or variations in muscle amplitude, contraction duration, muscle synergy, and co contraction abnormalities and others in this regard that can presumably affect intra as well as intermuscular stabilization and neuromotor strategies, joint structural integrity, pain, joint range of movement, effusion and stiffness [63-67]. Other problems such as the presence and severity of muscle inflammation [68], and/or muscle fiber and collagen content alterations [54] may explain findings of consistent muscle power alterations in cases suffering from osteoarthritis. In addition, regardless of pain status, subnormal muscle mitochondrial energetic and the presence of excess muscle fat mass, in addition to muscle strength declines, impaired satellite cell density, high profibrotic gene expression, and a slow-to-fast fiber type transition may play a role [69-72].

Indeed, in addition to joint malalignment and muscle asymmetries [73], and diverse insights from pre clinical lab based studies [eg., 16, 74], the clinical impact of muscle including changes in aging muscle energy metabolism and homeostasis [75], and the potential failure of the muscle to contract in both a coordinated, well modulated, and timely fashion [76] are specifically noteworthy. Also warranting attention in this regard are: 1) the presence and origins of deficient muscle volumes [77, 78], 2) muscle weakness and inflammation [68], 3) remediable morphologic muscle fiber type changes [76], 4) subnormal muscle contractile patterns [76, 79]. Indeed, data from a host of cartilage studies show that it is highly likely that the osteoarthritis manifestations mentioned above involve muscle loading effects on cartilage electromechanical properties, fluid and ion flow. Moreover, even if muscle alterations are solely reactionary in osteoarthritis [80], the aforementioned findings alone may lead us to conclude that chondrocytes and myoblasts share common pathological targets and pathways, and that muscle is an intricate determinant of physical and signals pathways that mediate cartilage structure in this respect. Thus unsurprisingly, when injured directly muscle trauma may yet induce a cycle of events that underpin the onset of osteoarthritis [80]. In addition, the finding of differences in the organization of the motor cortex in adults with and without osteoarthritis suggests some adults will be more vulnerable in this regard than others [81]. Muscle responses to joint derangement [82] may also be implicated. As a result, unless this is acknowledged, it may be difficult to anticipate the immediate functional restoration of muscle structure and function after corrective joint surgery in all cases especially in the face of prevailing or possible muscle inflammation susceptibility [83].

Can a case be made for a consistently influential role of muscle in osteoarthritis and its pain cycle? In this overview, that is emergent rather than definitive it is clear the array of publications on this theme shows muscle factors that may well interact negatively as far as joint status is concerned as well as reactively in response to joint destruction. Despite its shortcomings it remains clear this avenue of investigation is noteworthy especially as far as advancing efforts towards reducing the osteoarthritis burden substantively as well as its costs. It also conveys the idea that aging adults do not need to be fearful of their joints wearing out as muscle factors rather than age may be implicated. While hard to differentiate as far as their possible temporal and pathogenic features are concerned, weakness of muscle at any age, muscle inhibition, muscle inflammation and oxidative stress [79], altered muscle architecture [84], muscle atrophy, muscle protein degradation and low degrees of skeletal muscle mass may all play a role [85-87].

However this cannot be established in our view until future carefully designed and controlled longitudinal efforts to examine the state of the musculature in this respect more closely, including that of the unaffected side in unilateral cases of osteoarthritis are forthcoming. Also what muscle attributes should be targeted specifically is not known and warrants study. However, as per Yang et al. [88] sarcopenia-implying age related bone and muscle mass declines- may be helpful to intervene upon to some degree as this state may well contribute quite markedly and commonly to osteoarthritis progression through its impact on joint reaction forces, local and systemic inflammation, and muscle-derived stimulatory and sensory impairments [89, 90]. Conversely, intervention approaches applied individually or collectively as indicated as well as sooner rather than later may prove beneficial at all disease stages if adhered to in the long term.

In the interim, we agree with Rauhansalo et al. [30] that an advanced understanding of osteoarthritis in its own right will be especially useful in developing evidence based osteoarthritis management practices in this regard, including the correction of unhelpful misconceptions, such as nothing can be done for osteoarthritis, joint injections of various sorts are safe with no side effects, and all exercise is beneficial even in the face of inflammation and instability, excessive joint loading, and joint effusion. In addition, if an individual client is not responding to conservative treatment after several weeks of intensive continuous treatment or is showing declining function assessments should be conducted to eliminate the possibility that this is due to irreversible damage in the neuromotor system.

If so, applications to counter this may need to include:
• Active range of motion exercises.
• Daily gentle controlled antagonist muscle stretches.
• Efforts to minimize joint impact, effusion, inflammation.
• Electrical muscle stimulation.
• Endurance exercises.
• Modalities that minimize pain and muscle spasm.
• Biofeedback [91]
• Electroacupuncture [92]
• Ice packs/heat
• Kinesiotaping [93]
• Manipulation with movement [94]
• Massage [96]
• Muscle energy applications [94]
• Muscle vibration.
• Protein supplements [52].
• Sensori-motor/targeted neuromuscular exercise training [95, 97].
• Strength training [65, 71, 97].
• Vitamin D supplements or exposure [98].
• Weight loss or weight control

In addition, if our hypothesis is supported in the future, as appears it may according to current observations [99, 100] it would, at least, provide a possible avenue for more preventive approaches to counter osteoarthritis, and to assure optimal surgical outcomes as well as non surgical outcomes for people with osteoarthritis are the rule not the exception. As is presently observed in this regard there is increasing support for aging adults to persist in partaking in healthy exercise, a situation that must surely engender hope for an aging adult that the disease can actually be prevented or attenuated to a high degree and is not inevitable. However, even though Aleem et al. [85] noted asymmetric glenoid wear and humeral-head subluxation in osteoarthritis were associated with asymmetric atrophy within the rotator cuff transverse plane, and increased posterior rotator cuff muscle area compared with anterior rotator cuff muscle area was associated with greater posterior glenoid wear and subluxation it was impossible to discern if the results were causative or associative. Consequently, having a better understanding of all the mechanisms that might contribute to the manifestations of osteoarthritis, especially those that may underlie causative motor abnormalities found in osteoarthritis may provide hope for minimizing the immense burden of this prevalent disorder, as well as for improving outcomes. In particular, the ability to both intervene as early as possible and to apply well-founded evidence based specific approaches rather than broad generic solutions, is likely to prove highly efficacious in ameliorating this disabling health condition. Since different muscles may undergo different types of pre-or post-arthritic change, different treatment approaches may be desirable at different time periods for minimizing problems at a single joint site and at distant joint sites.

As well as more sophisticated clinical examinations that can guide the clinician more ably, the ability of clinicians to better understand how to intervene to foster optimal muscle is desirable. Imparting these understandings to their osteoarthritis patients may also help to secure more successful outcomes in the long run, as well as their heightened cooperation to pursue the long and continuous rehabilitation commonly required, particularly in those with mild to moderate osteoarthritis who desire a high life quality and degree of independence. Encouraging those at risk for the disease to be equally compliant is also highly recommended, as care must be taken against doing more harm than good due to excessive exercise or joint use and injury exposure at all ages.

Even though there is no clear consistent body of literature, a temporal link between muscle and joint structural interactions in osteoarthritis continues to hold great promise for understanding its pathology and support for continuing to examine the importance of muscle in the osteoarthritic disease process in the future. In particular, based on recent data, intrinsic muscle properties and composition, muscle fat mass, muscle mass declines, fiber specific muscle atrophy, fatigue and muscle weakness, muscle as an entity is increasingly accepted as one topic of major importance in efforts to uncover potential modifiable correlates of osteoarthritis at any age. Moreover, it appears the exploration of various muscle and other important correlates of the disease including inflammation, joint alignment, joint stability, joint loading, muscle volume declines can help avert or counter various degrees of joint attrition at all ages. Careful neuromuscular assessments and subsequent interventions that target muscle will greatly alleviate the osteoarthritis disease burden and/or the extent of any ensuing additional joint involvement and deterioration, suffering and untold public health costs at all ages.

To better discern what intervention strategies are indicated several measures may prove helpful to ascertain:
1. The extent and type of any general functional impairments;
2. The degree of pain intensity and emotional health status;
3. Muscle fat mass estimates;
4. Stability and limb alignment measures;
5. Muscle EMG and reflex responsiveness estimates;
6. Muscle mass, and proprioception acuity;
7. Bilateral as well as proximal and distal muscle properties and imbalances;
8. Measures of muscle quality;
9. Muscle swelling and inflammation;
10. Muscle strength and endurance.

None.

None.

No conflict of interest.