Osteoarthritis is a chronic joint disease that in 2020 affected 7.6% of the world’s population — about 595 million people — according to the Global Burden of Disease Study 2021.

The World Health Organization includes it among the leading causes of disability because of its impact. In Spain, the prevalence of osteoarthritis was 29.35% according to the EPISER 2016 study, considering cervical, lumbar, hip, knee, and hand osteoarthritis.

Multifactorial Disease Model

Osteoarthritis is a degenerative disease characterized by pain, stiffness, reduced joint mobility, joint instability, swelling, muscle weakness, and loss of joint function. Pain may initially be associated with specific activities and, in more advanced stages, become less predictable and occur at rest. Severe cases involve a substantial loss of quality of life, need for specialized care, and significant healthcare costs, and may lead to total joint replacement.

For a long time, it was considered a mechanically caused disease associated with joint wear from trauma, overuse, excess weight, or aging. However, it has become increasingly clear that it involves systemic changes, comorbidities, and a variety of interrelated factors. Osteoarthritis is now more often viewed as a multifactorial disease.

Francisco Castro Domínguez , MD, head of Rheumatology at Teknon Medical Center, Barcelona, Spain, told Univadis Spain, part of the Medscape Professional Network, that “Today the word osteoarthritis is better understood as an umbrella term that covers different pathways leading to the end state of cartilage loss or destruction rather than a single disease. It has multiple risk factors, and they overlap to differing degrees throughout its progression.”

Cartilage degradation is usually accompanied by synovial hyperplasia, increased vascularization of the synovium and subchondral bone, and osteophyte formation at the joint margins, along with subchondral bone sclerosis. Synovial membrane inflammation (synovitis), low-grade systemic inflammation, local disturbances in immune regulation, oxidative stress, and mitochondrial dysfunction in chondrocytes and synovial cells are also present. Furthermore, the immune system contributes to maintaining inflammation and disease progression.

Inflammation: Crossroads

Osteoarthritis is not limited to effects in the affected joint; it is accompanied by a low-grade systemic inflammatory state and an imbalance in the immune response. There is a close interaction among systemic inflammation, metabolic alterations, cellular aging, and gut dysbiosis, with these factors influencing and reinforcing one another.

Castro illustrated: “Today we know that for many patients, osteoarthritis is driven by chronic low-grade inflammation linked to metabolism, not only by mechanical wear and tear. Osteoarthritis is increasingly approached as a disease of the entire joint and the body, together with its comorbidities which differ for each patient, and not just the cartilage. Inflammation is a continuum, not simply a binary ‘present or absent’ state.”

Although osteoarthritis is not classified as an autoimmune disease, there is clear evidence of immune system participation in its initiation and progression. Persistent inflammation maintained by cytokines and immune cells plays a key role in structural joint damage. This affects not only cartilage but also the synovial membrane and subchondral bone. Both innate and adaptive immune cells have been identified in the affected joints, participating in the process and influencing its course and severity. They also affect processes such as angiogenesis, chondrocyte activation, and subchondral bone remodeling, contributing to progressive structural damage.

Other phenomena can also modulate inflammation. These include meta-inflammation associated with obesity and metabolic syndrome and inflammaging, linked to chronic inflammation resulting from cellular aging. Dysbiosis may also play a role as microbial products and metabolites released by an imbalanced microbiota can activate inflammatory pathways and contribute to a proinflammatory systemic state.

Finally, while chronic low-grade inflammation and metabolic factors are receiving increasing attention, Castro noted, “Despite this, there is still a gap between current pathophysiological knowledge and its systematic implementation in daily practice.”

Treatment and Segmentation

Treatments for osteoarthritis have traditionally focused on relieving symptoms, improving mobility, and slowing progression of joint damage while maintaining joint function. Pharmacotherapy will continue to play a key role in symptom control, especially pain and inflammation.

More broadly, Castro said, “Until recently, patients were treated according to a stepwise symptomatic logic — analgesics, nonsteroidal anti-inflammatory drugs, intraarticular injections, exercise — often without formally identifying whether a metabolic-inflammatory component, the metabolic phenotype, or a mechanoinflammatory component due to overload or biomechanical alteration predominated. However, this concept is gradually gaining importance.”

“For example, in the metabolic phenotype, the target is not only pain but the biology of adipose tissue — including adipokines, chronic low-grade inflammation — and its interaction with the joint. Practically, this translates into prioritizing interventions with metabolic and systemic anti-inflammatory impact, such as sustained weight loss, structured exercise, glycemic and lipid control, sleep optimization, and mental health support, while reserving some intraarticular therapies for moments or subgroups in which local biology is more clearly predominant.”

He added, “It is increasingly clear that not all patients with osteoarthritis follow the same trajectory, nor should they all be included in the same clinical trials or receive the same therapeutic sequence. Not all patients progress the same way or by the same mechanisms, and that’s where stratification becomes crucial.”

Physical and Surgical Treatment

Often used alongside pharmacologic approaches, functional rehabilitation programs focus on strengthening periarticular muscles and improving stability and can play a key role in reducing pain, increasing function, and preventing relapses.

Weight loss alone can significantly reduce pain and improve mobility, especially in knee and hip osteoarthritis. In cases such as knee or hip osteoarthritis associated with axis deviations or load displacement, orthopedic devices like insoles, braces, canes, or walkers can be helpful. These address postural and/or mechanical load issues. Additional physical therapies such as ultrasound, pulsed electromagnetic fields, or electrotherapy may be used complementarily to relieve pain in certain cases. However, the evidence for their efficacy is limited and inconsistent.

More advanced cases of osteoarthritis may require surgical intervention. Among the most common procedures are total knee or hip arthroplasty and patellofemoral arthroplasty. Other interventions include shoulder, elbow, or ankle arthroplasties, arthroscopic debridement, which removes loose fragments or inflamed tissue, and, in some cases, arthrodesis or joint fusion.

One potential complication of joint replacement is infection of the prosthesis. Bacterial biofilms can form on prosthetic surfaces and are difficult to eradicate. Infection may cause septic arthritis or osteomyelitis and could necessitate complete prosthesis replacement. Research is underway into the use of antibacterial coatings to prevent this.

Regenerative Medicine Overview

Regenerative medicine is one of the most promising fields. It seeks to restore damaged cartilage by harnessing the body’s own repair capacities. In addition to biomaterials, approaches include therapies based on mesenchymal stem cells and the use of autologous chondrocytes to regenerate cartilage tissue. One example is autologous chondrocyte implantation, in which chondrocytes are taken from the patient, expanded in the laboratory, and reimplanted into the defect with the help of a biological membrane or biomaterial.

Another example is cartilage bioengineering, which aims to repair cartilage by integrating autologous cells with biomaterials into the joint. Using “seed” cells that can grow and differentiate into cartilage tissue on a three-dimensional biocompatible scaffold — for example, collagen, hyaluronic acid, or biodegradable polymers — could create new cartilage. This can be done in two ways: ex vivo cultivation of tissue before implantation, or directly in situ (potentially less invasive).

Castro cautioned against excessive short-term optimism: Regenerative medicine in osteoarthritis has a potentially very relevant role and is a promising research avenue; however, scientific rigor is necessary. Today, although there are encouraging signs, significant limitations persist that, for now, prevent widespread adoption.

At the pharmacologic level, another notable recent preclinical advance in regenerative medicine — though in mouse models — cartilage regeneration was achieved using a drug that inhibits 15-hydroxyprostaglandin dehydrogenase.

These results are scientifically very interesting because they suggest reprogramming of preexisting chondrocytes; however, until robust validation and guarantees of translational safety exist, they should be regarded as a preclinical promise. Certainly, clinical translation in osteoarthritis is a real challenge precisely because of the complexity described earlier.

Precision Medicine Approach

While emphasizing the importance of precision medicine, Castro pointed to a more coherent and realistic present-day approach: therapeutic sequences that include control of synovitis and the inflammatory environment, metabolic optimization, modulation of cartilage repair in appropriate subgroups, and restoration of biomechanics and the joint microenvironment.

He also stresses the importance of early intervention. The potential for improvement and disease reversal, he said, is greatest in early stages and decreases as the joint progresses to advanced structural damage. He added that it is in these initial stages that the joint retains a greater capacity for adaptation, and the inflammatory and metabolic environment, as well as synovitis, are more amenable to modulation. The balance between anabolism and catabolism can still be shifted back toward homeostasis.

The propensity to reach less reversible situations, however, depends on the patient and will vary according to the dominant endotype, the rate of progression, the synovitis pattern, the biomechanical state, and the pain-sensitization component. Therefore, a realistic future approach involves stratifying and subdividing the disease according to its trajectory and defining clinically useful osteoarthritis subgroups to optimize treatment and outcomes.

Conclusions

The understanding of osteoarthritis has evolved profoundly, making clear its multifactorial nature with inflammatory, immunometabolic, and systemic components. As Castro said, “Osteoarthritis is not a single disease but a set of biological and clinical trajectories that culminate in degeneration of articular cartilage as the central element. The future is not about doing more of the same, but about advancing subdivision and stratification — for example, identifying who will progress and who will not, and why — early intervention and the development of targeted therapies whether immunometabolic or regenerative for defined patient subgroups.”

Castro concluded by noting the critical difference among symptomatic improvement like pain and function, structural modification like cartilage measurable by imaging techniques and functional biological regeneration-like tissue with properties comparable to healthy cartilage, with durability and clinical correlation. Many interventions stop at the first level; some begin to show signals at the second; and the third remains, to this day, a true challenge. Regenerating cartilage is not just creating tissue, but achieving tissue that is functional, durable, and clinically impactful.

Castro declared having no conflict of interest affecting his statements on the subject of this article.

This article was translated from Univadis Spain.