Osteoarthritis, What and What Not to Treat

Osteoarthritis (OA) is the most common form of arthritis, and with the aging of the world population, its significance in terms of health expenditure and quality of life is increasing [1]. Although cartilage destruction is a main pathology of OA, synovial inflammation, subchondral bone sclerosis, osteophyte formation, and changes in periarticular muscles also play important roles [2]. Despite decades of intensive research, the treatment of OA has been unsatisfactory, and not a single disease-modifying OA drug (DMOAD) has been approved, creating a huge unmet need in modern medicine. With this dismal situation, we have to raise questions about whether our current understanding and approaches toward OA are appropriate.

To begin with, the fundamental question is what the distinction between disease and the natural process of aging is for OA. This is a question that has been raised for a long time. Although many researchers simply regard OA as a disease, the distinction is not always clear. The average life expectancy has risen from 47 to 73 years of age in the seven decades spanning 1950–2020 [3]. This rate of increase in life expectancy is unprecedented, considering that the same amount of lifespan expansion occurred spanning thousands of years from the Bronze age to the beginning of the 20th century [4].

Among all the human organs affected by the detrimental effect of aging, human knee joints bear the brunt of yet another evolutionary burden, bipedal walking, which separates hominids from the rest of the four-legged mammals. Quadrupedal laboratory rodents rarely develop OA, even in obese animals; however, obligatory bipedal exercise leads to pathologic changes compatible with human OA cartilage degeneration [5, 6]. This leads us to speculate that OA may be an evolutionary maladaptation; human knee joints may be poorly equipped to sustain such a massive increase in mechanical load occurring during such an abruptly prolonged life span.

Evolutionary maladaptation is reflected in the gap between lifespan, that is, the total life lived, and health span, that is, the period free from disease, which is currently estimated at around 9 years [7]. OA may be a strong driver for increasing this gap considering the strong influence of age on its prevalence. The World Health Organization (WHO) guiding principle of achieving health as “a state of complete physical, mental and social well-being” is not possible through technological advances only [7]. In that regard, OA treatment might better focus on how to protect natural joints for elongated life span by creation of favorable work condition and lifestyle factors.

The second question is whether we are aiming at the right target to alleviate patient suffering. The poor correlation between structural, especially cartilage, damage and patient symptoms is well known. Knee pain due to OA is a key symptom influencing the decision to seek medical attention and a better predictor of disability than radiographic changes [8]. On the other hand, radiographic OA changes are weakly correlated with pain and physical function, and a significant number of subjects with Kellgren-Lawrence grade 4 OA do not report pain [9]. The current therapeutic pipeline for OA, however, focuses on the restoration of damaged cartilage. This tendency became noticeable since the first report of successful autologous chondrocyte transplantation to repair deep cartilage defects in 1994 [10]. Although that study included mostly young patients without OA, and the structural outcome after 10 years is rarely available, the concept of restoring damaged cartilage as the ‘holy grail’ for OA treatment has settled. Not only the technical difficulty of regeneration of damaged cartilage, a tissue with a very low cell proliferation rate and no blood supply, but also the problem of whether it is a proper target for OA treatment is an important issue. A recent meta-analysis of 50 clinical studies and 13 systematic reviews/meta-analyses revealed that stem cell therapy for knee OA relieved pain in patients over time but did not improve knee function [11]. However, the clinical studies included were fraught with limited evidence regarding study objectives, test designs, patient populations, as well as risk of bias assessment, outcome description, and potential conflicts of interest [11]. Long-term preservation of cartilage has not been reported, either [11].

Lorecivivint is a novel OA drug that targets bispecific tyrosine phosphorylation-regulated kinases and cdc2-like kinases, altering the Wnt pathway, which is a key regulator of maintaining normal tissue function. The Phase IIa trial showed that lorecivivint slowed joint space narrowing, a biomarker of OA disease progression, while consistently improving patient pain over a period of more than 1 year [12]. Although this may be the first OA drug effective for both structure and pain, phase 3 study results are needed to confirm these results and to verify whether these benefits can also be seen in the long term.

The last question is if we are not doing harm to our patients. In this era of rapid technological advancement, we sometimes lose the context of the clinical situation and are bewildered in the plethora of information that may be of little significance to patients. For instance, we tend to pay attention only to findings revealed by imaging, the most prominent example of which is the case of meniscal damage. Time and again, meniscal tear/degeneration was observed very frequently among the elderly subjects, and this was not associated with knee pain in OA subjects [13]. It is, thus, of no surprise that a few high-quality randomized controlled trials of arthroscopic meniscectomy (AM) for degenerative meniscal tear did not prove its efficacy [13]. However, the number of knee arthroscopic surgeries has grown rapidly along with the introduction of MRI, which reveals a high prevalence of meniscal tears in OA, and there is a possibility that surgery is performed to resect meniscal lesions that may not be the cause of symptoms. Arthroscopic knee surgery remains the most common type of knee surgery, and the number of AM increased by 12.67% in 8 years in Korea, with the incidence of meniscus surgeries per 100 000 population-year in Korea almost 10-fold higher compared to the United States [14]. In addition to the lack of clinical efficacy, some recent studies raise additional concerns that AM itself may be detrimental to the maintenance of the joint structure. In a 5-year follow-up study from the Meniscal Tear in Osteoarthritis Research (MeTeOR) trial comparing physical therapy vs. AM, 7.1% of individuals randomized to AM underwent total knee replacement (TKR) over 5 years, with a hazard ratio for TKR of 2.0 compared to those randomized to PT [15]. In a Korean study using administrative data, the TKR rate in the AM group was 25% higher than that in the non-AM group 10 years after the surgery [16].

It is not only unnecessary surgical procedures but also ineffective medication that causes harm to patients. We are all aware of the small effect size and adverse effects of long-term use of pharmaceutics for OA. In addition to gastrointestinal and renal side effects, OA patients are not immune to the recent epidemics of opioid addiction. A recent survey study in the US showed that 12.8% of OA patients were prescribed an opioid-based medication, and decreases in traditional opioid prescriptions have been countered by an increase in tramadol prescription [17]. Although tramadol, a weak opioid agonist, has been considered safer than other opioid medications with a lower risk of physical dependence, recent evidence tells a different story. Among patients aged 50 years and older with OA, the initial prescription of tramadol was associated with a significantly higher rate of mortality over 1 year of follow-up compared with commonly prescribed nonsteroidal anti-inflammatory drugs [18]. Atypical withdrawal symptoms after abrupt tramadol discontinuation have been reported, as well [19]. As of February 2023, the Food and Drug Administration (FDA) Center for Drug Evaluation and Research announced safety-related labeling changes to tramadol highlighting the risk of addiction, abuse, or misuse [19].

The origin of OA pain is diverse and differs from patient to patient. In addition to nociceptive pain arising from direct tissue damage, neuroplastic pain also plays a major role [20]. The reason for the unsatisfactory efficacy of pain medication for OA, thus, stems from the fact that treatments such as NSAIDs and intra-articular steroids are not effective for non-nociceptive pain. On the other hand, the positive aspect of pain should also be considered. Despite the promising effect of alleviating pain, tanezumab, a monoclonal antibody that inhibits nerve growth factor, was not approved for use by the FDA because of joint safety events such as rapidly progressive OA [21]. This result is a reminder that, like all types of pain, OA pain may have a beneficial role in protecting the joint from further damage. An animal study using the destabilization of the medial meniscus model showed that pain behavior was delayed by 10 weeks relative to the histologic evidence of tissue damage [22]. In evolutionary terms, local inhibition of pain would allow the animal to continue normal life despite mild tissue damage and would impart an advantage for survival, while after moderate damage has occurred, pain would protect the animal from further damage to the joint.

In conclusion, there is more confusion than magic about current OA treatment. In musculoskeletal health care, overdiagnosis is widespread and leads to unnecessary tests and treatments that do not benefit patients, and OA is no exception [23]. While continued research is essential for the proper management of OA, comprehensive understanding and perspective for its pathogenesis are needed to avoid hype and bring about hope (Figure 1).

Hyun Ah Kim contemplated the subject and wrote the manuscript.

The author declares no conflicts of interest.