Pulmonary

Review
doi: 10.1111/joim.13634
Osteoarthritis, part of life or a curable disease? A

bird’s-eye view
Martin Englund
Department of Clinical Sciences Lund, Orthopedics, Clinical Epidemiology Unit, Faculty of Medicine, Lund University, Lund, Sweden
Abstract. Englund M. Osteoarthritis, part of life or cardiovascular disease, and depressive symptoms.
a curable disease? A bird’s-eye view. J Intern Med. The current management and treatments largely
2023;293:681–693. rely on contextual factors, and the actual effects
of the intended therapeutic element of today’s
Osteoarthritis (OA) is a chronic joint disease interventions are minor. The different mechanis-
caused by disruption of joint homeostasis by a tic pathways (endotypes) and clinical character-
variety of systemic and biomechanical factors. The istics (phenotypes) of OA make the development
disease is characterized by degradation of carti- of disease-modifying treatments challenging. Cur-
lage and other joint tissues, and low-grade inflam- rent development of drug candidates, aimed to
mation which may result in pain, reduced func- restore joint homeostasis, is mainly targeting either
tion, and disability. The disease appears to have inhibition of catabolic factors or stimulation of
ancient origins, with findings of OA recognized anabolic factors. However, there is yet no break-
in fossilized bones from birdlike dinosaurs living through in stage III clinical trials. Earlier diagno-
some 130 million years ago. Today, the burden of sis, better knowledge of endotypes—for example,
OA in the world’s population is steadily increas- by new insights into soluble biomarkers, and com-
ing due to aging and often rising rates of obe- positional imaging—and more careful selection of
sity. Structural findings, indicative of the disease, patients into clinical trials are possible tools to aid
are also frequent in asymptomatic persons, which development of future therapies.
make the distinction between disease and nor-
mal aging sometimes challenging. OA is frequently Keywords: epidemiology, etiology, osteoarthritis,
associated with comorbidity in the form of obesity, pain, therapeutics
History and definition The hallmark of OA is the degradation and loss

of articular cartilage, although most tissues of the
Typical findings associated with osteoarthritis (OA)
joint become affected, such as bone, synovium, lig-
have been noted on fossilized bones from birdlike
aments, menisci (knee), labrum (hip), periarticular
dinosaurs living some 130 million years ago [1].
fat, and muscles.
The disease has also been reported in the lower cer-
vical and upper thoracic vertebra of a Neanderthal The most frequently used disease definition for
man from La Chapelle-aux-Saints, France [2]. OA knee OA for epidemiologic study purposes involves
is therefore one of the oldest documented diseases frequent knee pain and radiographic changes on
there is. However, the term “osteoarthritis” was X-rays in the form of doubtful or definite joint
introduced relatively late, documented in 1889, space narrowing and the presence of bony spurs
by John Kent Spender, but was then referring to (osteophytes) [5]. Similar definitions apply for
rheumatoid arthritis [3]. The modern definition of other joint sites. Still, X-ray changes often appear
OA aims to capture the complex molecular events relatively late in the course of the disease when
in its pathogenesis, as well as the multiple mani- substantial loss of joint cartilage has already
festations and the not-always-distinct relationship occurred. Thus, there is potential for substantial
between disease (structure) and illness (symptoms) underestimation of the true proportion of the pop-
(Table 1) [4]. ulation suffering from OA. There is currently an
© 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine. 681
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OA, part of life or a curable disease? / M. Englund
Table 1. Definition of osteoarthritis (OA) according to the reported at about 1%–2.5% of the Gross National
Osteoarthritis Research Society International (OARSI) Product in countries, such as the US, Canada,
…a disorder involving movable joints characterized by United Kingdom (UK), France, and Australia [11].
cell stress and extracellular matrix degradation Indirect costs—such as loss of productivity due
to sick leave and early retirement—are relatively
initiated by micro- and macro-injury that activates
high, even though the peak incidence of OA is after
maladaptive repair responses including
retirement age [12]. Of all sick leave and disabil-
pro-inflammatory pathways of innate immunity. The
ity pensions in Sweden, about 2% of days were
disease manifests first as a molecular derangement attributable to knee OA or associated comorbidi-
(abnormal joint tissue metabolism) followed by ties among patients with knee OA [13]. In general,
anatomic, and/or physiologic derangements much of the societal costs of OA are driven by its
(characterized by cartilage degradation, bone high prevalence, absence of a cure, and limited
remodeling, osteophyte formation, joint inflammation, effective treatment options.
and loss of normal joint function), that can culminate
in illness
Structural alterations and symptoms
There is often discordance between structural find-
ongoing initiative by the Osteoarthritis Research
ings of OA and clinical symptoms [14]. A person
Society International (OARSI) to develop classifi-
with mild or no structural alterations on X-ray
cation criteria for early stage symptomatic knee
may nonetheless experience severe symptoms, and
OA. These criteria are intended to enable clinical
vice versa—for example, a person with massive
observational studies of natural history as well
osteophytes and no joint space left on X-rays but
as randomized clinical trials enrolling patients at
with only relatively mild symptoms. Still, in gen-
an earlier stage of their disease [6]. New criteria
eral there is an association between radiographic
to classify hand OA have also just recently been
severity of the disease and pain [15].
developed by the European Alliance of Associa-
tions for Rheumatology (EULAR), aimed at defining
It is also worth stressing that features indicative
the disease for overall hand OA, interphalangeal
of OA on magnetic resonance imaging (MRI) are
OA, and OA in the base of the thumb [7].
highly frequent findings in asymptomatic joints.
In the knees of persons without any radiographic
Epidemiology and burden
evidence of OA, MRI revealed cartilage damage in
Today, OA is the most prevalent chronic joint dis- 69%, osteophytes in 74%, bone marrow lesions in
ease, with an estimated 530 million people affected 52%, and meniscal lesions in 24%, whereof the
worldwide [8]. Over the last 30 years, estimates vast majority were asymptomatic [16]. This high
suggest an increased absolute number of sufferers frequency of structural findings on MRIs repre-
by 113%, largely explained by increased prevalence sents a gray zone, in which questions remain as to
of obesity and the increased proportion of elderly. what structural changes may be considered part
In the United States (US), the knee alone has a of normal aging of a joint, and what changes are
prevalence of symptomatic disease of about 16% part of osteoarthritic disease processes [17]. Given
above the age of 45 years [9]. In Sweden, periph- this uncertainly, it is imperative to be careful when
eral joint OA that has resulted in a consultation interpreting or communicating results of joint X-
with a medical doctor occurs in about one in four rays or MRI findings to a patient. Use of MRI in
adults in the same age group [10]. The most com- the clinical setting upon suspicion of OA should
mon joint locations for symptomatic disease pre- be restricted, as the risk of incidental findings
senting at health care are knee, hip, finger, and is high—for example, for the knee, a degenera-
spine, although OA is not infrequent in other loca- tive meniscal lesion. These meniscal lesions are
tions, such as toe, jaw, ankle, wrist, acromioclav- unlikely to be the direct cause of the patient’s knee
icular joint, and shoulder. symptoms but may trigger unnecessary meniscal
surgeries [18, 19]. In general, knee pain is more
The societal burden of OA is likely underestimated, likely to originate from other processes also asso-
partly due to the challenges to define the dis- ciated with OA, potentially due to loss of menis-
ease given that radiographic changes appear rela- cus function, such as bone marrow lesions and (or)
tively late. Still, the cost of illness for OA has been low-grade synovitis [20, 21].
682 © 2023 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.
Journal of Internal Medicine, 2023, 293; 681–693
Inflammation and biomechanics

During much of the 20th century, OA was sim-
ply labeled as a “wear and tear” disease, sug-
gesting that further loading of the joint would
be bad. However, the last decades of research
have revealed a much more complex etiology and
pathogenesis. Low-grade inflammation is one of
the features associated with early disease [22].
Pro-inflammatory cytokines have a wide range of
actions and signaling pathways in joints. Some of
these cytokines—such as IL-33, IL-17, IL-6, and
IL-22—have been reported to have a direct asso-
ciation with cartilage degradation, whereas other
cytokines—such as IL-15, IL-1, IL-7, and IL-34—
have been reported to have an indirect relation-
ship [23]. As a consequence, there have been great
hopes that targeting inflammation will be the key to
success in the treatment of OA, similar to the suc-
cess story with biological treatments in rheuma- Fig. 1 Overview of the vicious cycle of osteoarthritis (OA).
toid arthritis. However, such visions have not yet
been fulfilled and are probably unlikely to become
so unless biomechanical factors are taken into the defects, meniscal extrusion, bone shape changes,
equation. The contribution of biomechanical fac- malalignment—will vastly alter the biomechanical
tors to the progression of OA may thus be one of contact stresses, which are likely to propagate fur-
the key reasons as to why the development of treat- ther pathological and inflammatory responses in
ments to modify the course of disease is difficult tissues—a vicious cycle that, once established, is
[24]. challenging to break (Fig. 1).
After all, one main feature that differentiates OA Main systemic and biomechanical risk factors
from the more inflammatory types of arthritis is
The balance to maintain joint homeostasis is deli-
the often critical contribution of chronic joint over-
cate, and aging-related processes as well as other
loading or acute injury to the initiation and pro-
risk factors make that balance more vulnerable. At
gression of the disease [25, 26]. Thus, even if the
some point in time after exposure to risk factors,
phrasing “wear and tear” is inappropriate, biome-
there may be a shift in joint metabolism, leading
chanics cannot simply be ignored. The joint’s tis-
to the initiation of the cascade of events character-
sues are constantly responding and remodeling
istic for OA. This may eventually result in symp-
to loads and friction. As an example, leg length
toms, functional limitations, and disability. Similar
inequality has been reported to be a biomechani-
to many other common chronic diseases, there are
cal risk factor for OA in both the hip and the knee
multiple risk factors that often coexist and increase
of the shorter limb, that is, the limb having the
the risk for OA. The most well-studied ones are as
greater ground reaction force [27]. Such chronic
follows.
biomechanical risk factors, or acute injuries such
as tears in the meniscus or labrum—responsible
Older age
for load distribution and stability of the knee and
hip joint, respectively—may trigger increased local Aging-related processes affect essentially all organs
contact stresses to the hyaline cartilage. This may and structures in the body, and joints are no excep-
trigger responses from chondrocytes which even- tion. OA is relatively rare in younger adults, with
tually lead to an unfortunate shift in the balance increasing incidence after middle age [9]. However,
of catabolic and anabolic factors, where inflam- it is not entirely clear what the risk-factor “age” rep-
matory pathways may play a critical role [28]. resents in terms of disease etiology. Age may simply
In essence, biomechanics and inflammation likely be a stand-in for extent of exposure to other risk
interact: The altered biomechanical properties of a factors, such as time with obesity, time since joint
joint with established OA—for example, cartilage injury, and time with chronic joint overloading.
But aging is also associated with molecular and reported to have greater pain severity [41]. There
cellular changes, including epigenetic changes that is also insufficient knowledge of the role of gut
directly influence the risk of disease [29], for exam- microbiota, which may be associated with chronic
ple, via the complement system [30]. It is likely inflammation in diseases like OA [42].
that both these principal pathways contribute to
the role of “older age” in the development of OA. Acute joint injury
Acute injury is a strong, well-established risk fac-
Female sex
tor, in particular for knee OA [43, 44]. In persons
Female sex is associated with more symptomatic who have experienced injury and surgical treat-
OA in general, especially after menopause [12, 31, ment of the menisci and/or the anterior cruciate
32]. Women appear to have higher OA prevalence, ligament (ACL) of the knee, about 50% of persons
utilize more health care, and suffer from more pain, develop typical signs or symptoms of knee OA after
inflammation, and disability, as compared to men. 10–20 years [45]. The reasons for the increased risk
The mechanisms are not fully elucidated, but hor- are still not fully elucidated, but altered and/or
monal factors and joint laxity may play important increased biomechanical contact stress on carti-
roles [33]. Hormonal replacement therapy in post- lage surfaces is likely the main explanation. Early
menopausal women has, however, not yet provided bone shape changes have been reported just a few
conclusive evidence [34]. months after acute ACL-injury, and these changes
resemble the ones seen in established OA [46]. Sur-
Genes gical reconstruction of the ACL to restore stabil-
As in most chronic diseases, the genetic component ity has not yet been able to reduce the risk of OA,
of OA is relatively strong but also differs between which may indicate that other molecular processes
joint sites [35]. For instance, hand and hip OA have associated with acute trauma—for example, pro-
a stronger genetic component than knee OA [36]. inflammatory cytokine release and disruption of
The genetic contribution to hand OA likely varies joint homeostasis—may also influence the risk of
between 48% and 87% depending on the exact fin- OA development [47]. Interestingly, MRI signs of
ger joint site, with the thumb base having the high- restored continuity of the ACL have recently been
est genetic contribution. The corresponding genetic reported after nonsurgical management of acute
contribution for the risk of knee and hip prosthesis ACL tears and seem to be associated with better
surgery due to OA has been reported to be 45% and patient-relevant outcomes [48]. This finding needs
73%, respectively [37]. For the knee, environmen- to be reproduced but may further motivate rehabil-
tal factors, such as acute knee injury or chronic itative therapies that may facilitate innate tissue
overloading, are likely to play a bigger role. repair, as compared to surgical reconstruction of
the ACL [49].
Obesity
Chronic joint overloading
Obesity is a public health concern affecting popu-
lations in most developed countries. Being obese There is ample epidemiologic evidence that occupa-
substantially increases the risk for OA in the tions with highly physical workloads—for example,
weight-bearing joints, with lifetime risk of symp- within agriculture, fishery, or forestry—involving
tomatic knee OA increasing from 30% to about 60% manual labor, such as lifting and carrying heavy
in those with a body mass index of 30 or higher, as items, climbing stairs, or working in kneeling posi-
compared to having a body mass index below 25 tions, are associated with increased risk for knee
[38]. Obesity is thus one of the strongest poten- OA and hip OA [50].
tially modifiable risk factors for OA yet identified.
Multimorbidity
Although the mechanisms by which obesity drives
OA are largely related to biomechanical overload- OA is often associated with comorbidity, but the
ing, there is also evidence of the involvement of exact nature of these associations is still largely
molecular pathways on cartilage metabolism, for unclear. Register data from the UK have suggested
example, via insulin resistance and metabolic syn- five clusters of comorbidity patterns: relatively
drome, and innate and adaptive immune responses healthy (i.e., little comorbidity), cardiovascular,
that may lead to the initiation and progression of musculoskeletal–mental health, cardiovascular–
OA [39, 40]. The role of obesity is less clear for musculoskeletal, and metabolic [51]. In a corre-
hand OA, but obese hand OA patients have been sponding Spanish population-based dataset, four
similar clusters were reported: Low-morbidity, lage and bone turnover or inflammation, no sin-
back/neck pain plus mental health, metabolic syn- gle biomarker (or set of biomarkers) has yet
drome, and multimorbidity [52]. The comorbid- shown clinical utility for mainstream use [60]. As
ity profiles may differ depending on the joint site an example, one of the most commonly studied
affected—for instance, with knee OA seeming more biomarkers is the C-telopeptide fragment of type II
strongly linked with diabetes mellitus type 2 than collagen degradation (CTX-II), which is an indicator
hip OA [53]. of cartilage degradation.
It is likely that common risk factors such as age For research purposes, a number of new MRI
and obesity often play a major role in comorbidity, sequences and processing techniques have been
but there are also causal links that can be bidirec- developed to determine the changes of joint struc-
tional. For instance, chronic knee pain may lead to tures, including cartilage morphometry [61] and
reduced physical activity and weight gain, which changes to bone shape [62]. In addition, composi-
increase the risk of, for example, cardiovascular tional in vivo imaging techniques with MRI—such
disease, depression, and diabetes mellitus type 2 as T2 and T1rho relaxation time mapping—will
[53]. However, there is also evidence that diabetes provide new insights, in particular into the early
mellitus type 2 is associated with increased risk development of OA, whereas joint structures are
of developing OA [54]. Interestingly, the use of relatively macroscopically intact [63, 64]. These
metformin—a glucose-lowering drug with potential techniques may also serve as potential tools in clin-
chondroprotective, immunomodulating, and pain- ical trials to increase sensitivity to change with
reducing properties—has been reported to be asso- respect to early structural changes. However, there
ciated with less cartilage loss and reduced risk of is not yet sufficient knowledge of their utility in
total knee replacement for OA [55, 56]. clinical practice, and their relationship with symp-
toms is probably weak. Thus, the gold standard
OA—one or several diseases? end point for disease modification in knee OA
remains the prevention or reversal of the loss of
In the future, the term OA may potentially become
joint space on X-rays, as defined by the US Food
an umbrella diagnosis for several closely related
and Drug Administration (FDA) and the European
diseases, differing in their extents of involvement
Medicines Agency (EMA) [65].
of different mechanistic pathways (endotypes) and
clinical presentations (phenotypes) [57]. There are
many suggested OA phenotypes and ways to Brief overview of the management
define them. For instance, one systematic review
has proposed that clinical OA includes at least OA is a disease for which there is a need for
six subgroups: (1) chronic pain phenotype with both improved symptomatic treatments and new
central sensitization; (2) inflammatory phenotype; disease-modifying therapies. In 2005, the best evi-
(3) metabolic syndrome phenotype; (4) bone and dence management of OA was proposed as a pyra-
cartilage metabolism phenotype; (5) mechanical mid (Fig. 2) [66], and there have not been any prin-
(malalignment) phenotype; and (6) minimal joint cipal changes to that strategy in current treatment
disease phenotype [58]. Another example is OA in guidelines from the major organizations in the US
finger joints, which may be classified as either ero- and in Europe [67–69]. Specific recommendations
sive or nonerosive, each with distinct clinical char- may vary depending on joint site, but in principal
acteristics, in which the former has worse progno- they are quite similar for both hip and knee OA,
sis [59]. briefly outlined as follows:
The base of the pyramid—which is currently rec-

The role of soluble biomarkers, quantitative, and
ommended to be offered to essentially all patients—
compositional MRI
involves education and lifestyle advice—including
Over the last decades, there has been much weight management if applicable, as well as exer-
effort to identify soluble biomarkers in synovial cise therapy and/or mind-body programs such as
fluid, blood, or urine to help in the diagnosis of yoga or tai chi—and topical NSAIDs. The middle
OA, the identification of its specific endotypes, of the pyramid has several add-ons in the form of
and the monitoring of its progression and treat- symptomatic treatments, primarily the use of oral
ment. Although there are still a number of can- NSAIDs or Cox-2 inhibitors, and orthoses if appli-
didate biomarkers, for example, targeting carti- cable. If symptom relief is insufficient, the next
Fig. 2 Schematic overview and examples of management of osteoarthritis in peripheral joints. Differences may apply for
type of affected joint, comorbidities, and other patient-specific factors. Source: Adapted from Lohmander et al. [66].
step(s) may encompass intraarticular injectables, the intervention represents only a minor part of
typically corticosteroids, particularly if the symp- the improvement, when the total treatment effect
toms are monoarticular, or, for instance, per oral is already modest. The two main nonspecific fac-
duloxetine, the latter preferably in the case of coex- tors are the placebo effect and the regression-to-
isting depressive symptoms. Opioids including tra- the-mean phenomenon. Although the concept of
madol are unfortunately frequently prescribed for placebo is well-known among both researchers and
OA pain, but these have limited effect and are health professionals [72], the practical implications
associated with several adverse effects and risk of regression to the mean, which is a statistical
of addiction [70]. Thus, opioids should be avoided phenomenon, are less familiar. This phenomenon
unless there is a clear plan for their use and dis- may be strong in OA, where there is often a fluctu-
continuation. The top of the pyramid represents ating natural history of pain [73]. In the clinic, or
surgical treatments in the form of joint replace- in trials and observational studies, patients usu-
ment surgery, or for the knee, in certain cases, ally become enrolled when they are experiencing a
osteotomy. pain flare. The pooling of data to a common starting
point (baseline) during a flare makes them on aver-
age more symptomatic than the source population,
The role of contextual factors in the treatment response
and they are thus likely to improve by the natu-
To understand the limited effect of today’s treat- ral course of the disease itself [74]. Importantly, in
ments, it is important to understand the strong contrast to the placebo effect, which is an effect of
contribution of contextual (nonspecific) factors to the intervention and its context, regression to the
the total treatment effect for OA pain. On average, mean simply creates the illusion of improvement;
nonspecific factors have been reported to explain it represents no effect of the intervention at all
about 75% of the total improvement in pain for (Fig. 3). Still, results in trials are often reported as
a variety of OA treatments [71]. This means that improvement from baseline, inflating the impres-
the actual effect of the therapeutic element(s) of sion of effectiveness in all intervention arms.
in today’s treatment recommendations from the

major organizations [67–69].
Lately, the efficacy of exercise in the manage-

ment of OA has also been questioned, as a well-
known placebo intervention—intraarticular saline
injection—also achieved similar improvement to
education and exercise in a clinical trial [76, 77].
Interestingly, evidence of any treatment effect of
exercise as a therapeutic element of intervention is
lacking [78]. In another recent high-quality study,
investigators reported similar improvement in the
attention control arm, when muscle strengthen-
ing was tested as a treatment for knee OA [79].
There was also no evidence of a dose–response rela-
tionship of muscle strengthening on knee pain or
knee function as outcome, a finding which has
recently been reproduced by others [80]. The over-
interpreted evidence of benefits of exercise ther-
apy for OA pain—essentially all stemming from tri-
als without a placebo-treated group—is likely from
Fig. 3 Schematic illustration of the principal components the contribution of regression to the mean to the
to improvement in pain for patients in a typical trial for
observed improvement as well as the placebo effect
osteoarthritis.
[74]. Reasons why exercise therapy may still be rec-
ommended include its relative low cost, safety, and
Essentially, to provide observational evidence of other benefits for the patients, who are often over-
improvement after an intervention is easy in OA. weight and/or suffer from multimorbidity.
Patients meeting the criteria for a lot of symp-
toms simply need to be recruited, and then, by the
natural history of the disease itself, the patients Surgical treatments
will likely feel better at any follow-up time point. There is a high, unmet need for surgical treatment
In addition, improvement can be gained by the for the many patients with late-stage disease and
placebo effect of the intervention, or the other severe symptoms. Although arthroscopic lavage,
contextual factors associated with the interven- debridement, and resection of torn meniscus have
tion [75]. These nonspecific reasons for improve- been reported to be no more effective that sham
ment make it imperative to base evidence of treat- surgery in knee OA [19], they may still have a role in
ment efficacy in OA on randomized controlled tri- carefully selected patients, for example, those with
als, using a control treatment with known efficacy a loose body (typically a cartilaginous or osteocar-
or preferably a placebo or sham intervention, all tilaginous fragment) causing knee locking or para-
done with adequate blinding. Unless there are very meniscal cysts. There is no evidence of any benefit
specific circumstances or strong treatment effects, of arthroscopic procedures for OA of the hip [81].
such designs are the only way to determine the
effect of the intended therapeutic element of the High tibial osteotomy of the knee is a surgical treat-
intervention. ment to preserve the joint, and the procedure is
typically used for medial compartment disease in
Moreover, patients usually start to self-medicate which the knee joint is then realigned to unload the
when they are in a pain flare, so it may be hard medial compartment. This treatment has been con-
to distinguish what the result of the actual treat- cluded to be effective to reduce pain and increase
ment is, and what is explained by the natural his- function and may also reduce or delay the need for
tory itself. All this likely explains the great pop- total joint replacement [82].
ularity of various nutritional supplements claim-
ing to reduce OA pain, including agents such as Total joint replacement remains the final treat-
glucosamine and chondroitin sulphates, which are ment option when other treatments do not pro-
usually heavily marketed but not recommended vide sufficient pain relief [83]. There are a variety of
technical approaches and components for different eration are briefly outlined in the following sec-
joint sites. The principal joints responsible for the tions.
highest volumes of surgery are the knee and hip.
OA is responsible for about 90% of joint replace-
ments at these sites. Joint replacement surgery is Inhibition of catabolic factors
effective in about 80%–90% of knee and hip OA The Wnt signaling pathway regulates crucial
patients to reduce pain and increase function, but aspects of cell fate determination, cell proliferation,
as with any major procedure, it is associated with and cell migration. The Wnt pathway inhibitor lore-
adverse events including the loosening of implants civivint has been developed to affect chondrocyte,
and infection, which may require revision surgery osteoblast, and synovial cell differentiation. Prelim-
[84]. Today, the 25-year survival of implants is over inary results from the latest phase III study did not
80% for the knee and about 60% for the hip [85, meet its primary end point in pain, comparing the
86]. Joint replacement is also available as treat- treatment with placebo arms [92]. However, there
ment for OA in other joints, for example, the base were indications of an effect in patients with less
of thumb [87]. severe radiographic OA of their knees, suggesting
that intervening at earlier stages may be preferable.
Experimental treatments The trial is still ongoing to evaluate effects of a sec-
ond dose on patient-relevant outcomes as well as
Treatments using stem cells or other regenerative long-term structural progression.
therapies such as platelet-rich plasma (PRP) are
becoming increasingly popular. However, there is Cathepsin K is a cysteine protease that degrades
not yet sufficient evidence to recommend these type I and II collagen and aggrecan, and it is
according to most treatment guidelines. Ongo- involved in bone resorption. MIV-711 is a selec-
ing placebo-controlled trials may hopefully pro- tive cathepsin K inhibitor. Phase II studies have
vide guidance for the efficacy of stem cell ther- indicated bone remodeling and less cartilage loss
apy [88], whereas for PRP, the results from the in the MIV-711 treatment groups compared with
latest placebo-controlled trials for knee and ankle placebo, but there was no effect on pain compared
OA have been disappointing [89–91]. Early indica- with placebo [93].
tions of the effectiveness of these therapies may
partly have stemmed from misinterpretation of IL-1 is a pro-inflammatory cytokine, and there is a
the improvement observed in case-series and low- long and well-documented history of the effective-
quality randomized controlled trials, an improve- ness of IL-1 inhibition in the prevention of RA pro-
ment which may largely be driven by nonspecific gression. IL-1 is known to degrade cartilage. How-
factors including both strong placebo effect and ever, phase II trials of the IL-1 inhibitors anakinra
regression to the mean. and lutikizumab have not been able to demonstrate
any effect on structure modification or symptoms
Development of disease-modifying OA drugs (DMOADs) in knee OA, compared to placebo [94, 95]. Lutik-
izumab has also been evaluated in a phase IIa trial
For disease modification, there is most likely not for erosive hand OA, with no essential difference
going to be one “silver bullet” that targets OA at in pain or imaging outcomes compared to placebo
large. Instead, we are seeing the development of [96].
a wide variety of different strategies to modify the
course of disease. As OA largely is the consequence The enzyme A disintegrin and metalloproteinase
of an imbalance between anabolic and catabolic with thrombospondin motifs 5 (ADAMTS-5) is
molecular processes within the joint, there are involved in the degradation of aggrecan, which is
two main pharmaceutical strategies: inhibition of a critical proteoglycan and building block of car-
catabolic factors and stimulation of anabolic fac- tilage. ADAMTS-5 induces cartilage degradation
tors. Still, these two strategies may be challeng- and has been reported to be highly expressed in
ing if there is too much underlying biomechani- patients with OA [97, 98]. There have been several
cal derangement. Although there are multiple drug attempts in preclinical models to inhibit ADAMTS-
candidates under preclinical development, there 5, but often with safety concerns. Still, one com-
are fewer candidates that have passed phase II clin- pound (GLPG1972/S201086) made it to a rela-
ical trials. Some of the main disease-modifying OA tively large phase II trial [99], but a company
drug (DMOAD) candidates currently under consid- announcement of the study results revealed that
the trial did not meet its end point of reducing the as it has been for hundreds of millions of years, as
rate of cartilage loss. we can see from fossil remains [1]. There is no bio-
logical cure within sight, but deeper understand-
Stimulation of anabolic factors ing of the different OA endotypes will continue to
enable new molecular targets for earlier and more
Sprifermin is a recombinant form of human fibrob- effective interventions. Still, as before, most peo-
last growth factor-18, which showed early promise ple suffering from OA will also in the future need
in clinical trials in increasing cartilage thickness to adapt and cope with mild symptoms, through
on MRI, but was not associated with reduction in education, lifestyle alterations, and weight man-
symptoms [100]. Long-term follow up of the trial agement. Within the next decade, we will likely see
reported that the treatment’s benefit to cartilage an increasing number of disease-modifying can-
thickness was maintained over 3.5 years [101]. didates targeting different joint structures such
as cartilage, bone, or synovium, interventions
Transforming growth factor β1 (TGF-β1) is involved that hopefully will reduce symptoms. In essence,
in several biological processes, including cell pro- any cost-effective and safe intervention that may
liferation, tissue formation, and inflammation. reduce the risk of structural and symptomatic pro-
TissueGene-C is a cell-based gene therapy that gression of OA is welcomed with open arms. More-
aims to improve cartilage function and reduce over, as basic science on aging makes progress,
inflammation by promoting TGF-β1 activity. Ani- completely new treatment strategies may be devel-
mal models have suggested improved structure oped, for example, targeting the loss of epigenetic
and reduction in pain upon this treatment, and information governing aging processes as well as
phase II trials did not suggest any severe adverse chronic diseases strongly associated with aging
events [102]. A small phase III trial suggested [104].
improvements in pain and knee structure com-
pared to placebo [103], and a larger phase III trial
Acknowledgments
is ongoing.
The author acknowledges the funding support from
Examples of challenges in DMOAD development the Swedish Research Council, the Skåne Uni-
versity Hospital, the Österlund Foundation, the
The development of DMOADs for slowly progress- National Health Service (ALF governmental fund-
ing chronic diseases such as knee OA can be ing for clinical research), the Greta and Johan
time- and resource-consuming. One common issue Kock Foundation, the Swedish Rheumatism Asso-
with most trials so far is the relatively late stage ciation, King Gustaf V’s 80-year Birthday Founda-
of OA required for patients to enter a trial, typ- tion, and the Foundation for Movement Disabilities
ically of radiographic severity corresponding to in Skåne.
Kellgren–Lawrence grades 2 and 3. At these stages,
there is often already substantial cartilage loss and Conflict of interest statement
meniscal extrusion, making it plausible that the
biomechanical derangement may already be too The author reports receiving consultancy fees from
severe for pharmaceutical interventions to inter- Cellcolabs AB (Sweden) and Key2Compliance AB
fere effectively. This may partly explain the often- (Sweden).
disappointing trial results. Another challenge is
the typical mixing of different OA endotypes within
trials, due to our current limited understanding References
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Review

Osteoarthritis, part of life or a curable disease? A

History and definition The hallmark of OA is the degradation and loss

Inflammation and biomechanics

The base of the pyramid—which is currently rec-

in today’s treatment recommendations from the

Lately, the efficacy of exercise in the manage-

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