Worldwide, knee osteoarthritis represents the most common musculoskeletal disease with significant personal and societal health and financial effects,¹ with disability rates, morbidity, financial costs, and mortality rates rivaling those of rheumatoid arthritis.² The lifetime risk of the development of osteoarthritis is estimated to be greater than 45%, with the knee representing four-fifths of the total osteoarthritis burden.³ The age wave coupled with a rising incidence of obesity is making osteoarthritis a leading cause of disability with profound individual and societal effects.⁴ The etiology of knee osteoarthritis is attributed to many factors including age-related wear; cartilage and subchondral bone overload; joint overuse; acute trauma; congenital and acquired malalignment; metabolic factors such as obesity, chronic inflammation, and diabetes mellitus type 2; and genetic predisposition. Although diagnosis of osteoarthritis can be made via radiographs documenting joint-space narrowing, subchondral sclerosis, bone cysts, or deformity, knee osteoarthritis may present with significant signs and symptoms without substantial radiographic changes. Therefore, diagnosis should include consideration of underlying pathology as well as the clinical picture.⁵,⁶ Surgical intervention with knee arthroplasty is an effective treatment for advanced knee osteoarthritis but is not without financial and personal costs. Nonsurgical pain management uses a spectrum of pharmacologic and lifestyle approaches, but few current therapies address prevention of knee osteoarthritis or halt progression of the disease. Given the high variability of osteoarthritis, new research is focusing on describing osteoarthritis subtypes and designing treatments to prevent onset and progression of specific phenotypes. It is important to be aware of updates in the understanding of knee osteoarthritis pathology, nonsurgical intervention, and technical advances in surgical approaches.

As a pivotal connector of the lower-extremity kinetic chain, the knee serves a central role in overall locomotion and experiences mechanical stressors from functional abnormalities above and below the joint. The most significant synovial joint in the body, the knee complex consists of four unique bony joints connected and covered
by multiple tissue types with diverse functions including bone, cartilage, ligament, tendon, synovium, fat, and skin. Degradation of the joint cartilage, the definition of arthritis, may be caused by a variety of stimuli over time and is generally slowly progressive with increasing symptoms and severity over time.⁷

At a basic level, a diarthrodial joint is composed of two bones, the cartilage layer bone endcap and the layer of synovium serving to seal, feed, and lubricate the joint. Chondrocytes, enveloped in extracellular matrix, are exquisitely sensitive to changes in mechanical microenvironment load and inflammatory state, causing them to upregulate production of matrix metalloproteinase (MMP) including MMP-1 and MMP-13 (important in type II collagen) and MMP-3 (a potent aggrecanase). Production of these cytokines leads to increased proteoglycan degradation and collagen breakdown.⁸ As cartilage degradation progresses with accompanying phenotypic changes to the chondrocytes themselves, subchondral bone remodeling commences leading to a cycle of overload and responsive cytokine production all acting in a paracrine manner furthering cartilage breakdown and the inflammatory processes. In addition, inflammation of the infrapatellar fat pad in an environment of osteoarthritis may contribute to pain in osteoarthritis by secreting increased adipocytokines and inflaming the adjacent synovium.⁹

Multiple risk factors contribute to the onset and progression of knee osteoarthritis. Age and trauma are significant contributors, with traumatic cartilage damage at any age increasing the risk of future knee osteoarthritis nearly fourfold.⁷ Female genetics, weight/joint overload, repetitive overuse, low bone density, and lean muscle mass also contribute to osteoarthritis development and progression. The utilization of total knee arthroplasty (TKA) has increased faster than the utilization of total hip arthroplasty, which is singularly attributed to the increasing obesity rates in the United States.¹⁰ Recently, new research as described in a 2021 study illuminates the importance of estrogen in maintenance of cartilage integrity and points to the loss of estrogen in perimenopause and menopause as a cause of joint pain and progression of frank osteoarthritis.¹¹ Another area of increased exploration into the pathophysiology of osteoarthritis is the rise of senescent cells seen with chronologic aging.

Loss of cartilage, changes in chondrocyte morphology, vascular channel changes in the subchondral bone, and fat pad fibrosis as well as loss of sex hormones and the rise of senescent cells with aging are thought to contribute to the pain pattern associated with osteoarthritis. These heterogeneous pathways to disease progression necessitate reframing knee osteoarthritis from a single entity into a multitude of unique osteoarthritis phenotypes requiring and allowing exploration of each as an opportunity for precision medicine. Osteoarthritis phenotypes may include the synovial inflammatory phenotype, pain-driven phenotypes, cartilage degradation phenotype, systemic metabolic pathway, or osteoporotic overload phenotype, for example.¹²

In patients presenting with pain, stiffness, and swelling, the first step in diagnosis of knee osteoarthritis is often radiographs. Multiple grading scales for diagnosis exist, including the American College of Rheumatology criteria,¹³ the common Kellgren-Lawrence scale,¹⁴ the Ahlbäck classification,¹⁵ or the knee osteoarthritis grading system.¹⁶ Progressive joint-space narrowing, subchondral sclerosis, osteophyte formation, and subchondral cysts are the hallmark radiographic features. Knee osteoarthritis is, however, multifactorial and may exist without significant radiographic evidence. Conversely, significant radiographic findings may exist without pain.

Multiple etiologies are responsible for the development and progression of knee osteoarthritis. This poses a challenge for a one-size-fits-all approach to treatment and mandates consideration of the heterogeneous pathways leading to the disease in designing care. The variety of potential osteoarthritis phenotypes will allow for more precise treatment designs targeting each individual patient’s osteoarthritis profile such as predominant inflammation, cell senescence, cartilage metabolism, and subchondral vascularity. Exponential technology such as artificial intelligence and machine learning and metabolomics may allow expedited understanding of the key differentiators of unique osteoarthritis phenotypes. Current care pathways include lifestyle modification and augmentation, systemic pharmacologics, intra-articular injections including orthobiologics, and surgical realignment or replacement of one or more compartments.

The American Academy of Orthopaedic Surgeons, American College of Rheumatology, and the Osteoarthritis Research Society International have independently evaluated nonsurgical approaches to knee osteoarthritis. Table 1 summarizes their recommendations.¹⁷,¹⁸,¹⁹

Given the complexities of osteoarthritis etiology, any single intervention, whether lifestyle, systemic, or intra-articular, is unlikely to address all facets of osteoarthritis
presentation or progression. It is now recommended that a multimodal intra-articular approach be undertaken, combining several effective treatments.²⁰ Current approaches focus on pain relief and are unable to modify or prevent the disability of long-term osteoarthritis. The FDA has called for a focus on drug development that actually modifies the disease process and underlying pathophysiology to prevent structural damage and disability.²¹ Although there is no currently approved drug in this category, the goal is true disease remission and early intervention before joint-space narrowing, angular deformities, and major structural damage.

Novel investigational drugs targeting inflammatory mediators work to counteract the low-grade chronic sterile inflammation that arises secondary to the immune system dysregulation of aging.²² These may include interleukin 1 inhibitors that prevent the proinflammatory cytokine from mediating the pain response, bone resorption, and ultimate cartilage destruction. Another approach targets tumor necrosis factor alpha production. Tumor necrosis factor alpha functions as a proinflammatory cytokine produced by synoviocytes and chondrocytes in the knee causing pain and structural damage. It also plays a paracrine role in the production of interleukins, MMP, and a variety of other destructive molecules.¹¹