Accepted Manuscript

Title: Clinical settings in knee osteoarthritis: Pathophysiology

guides treatment

Author: Gabriel Herrero-Beaumont Jorge A. Roman-Blas

Olivier Bruyère Cyrus Cooper John Kanis Stefania Maggi
René Rizzoli Jean-Yves Reginster

PII: S0378-5122(16)30304-8
DOI: http://dx.doi.org/doi:10.1016/j.maturitas.2016.11.013
Reference: MAT 6731

To appear in: Maturitas

Received date: 25-10-2016

Accepted date: 14-11-2016

Please cite this article as: Herrero-Beaumont Gabriel, Roman-Blas Jorge A,

Bruyère Olivier, Cooper Cyrus, Kanis John, Maggi Stefania, Rizzoli René,
Reginster Jean-Yves.Clinical settings in knee osteoarthritis: Pathophysiology guides
treatment.Maturitas http://dx.doi.org/10.1016/j.maturitas.2016.11.013

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Clinical settings in knee osteoarthritis: Pathophysiology guides treatment

Gabriel Herrero-Beaumont1, Jorge A. Roman-Blas1, Olivier Bruyère2, Cyrus Cooper3,

John Kanis4, Stefania Maggi5, René Rizzoli6, Jean-Yves Reginster7

1
Joint and Bone Research Unit, Rheumatology Department, Fundación Jiménez Díaz,
Autonomous University of Madrid, Madrid, Spain.
2
Support Unit in Epidemiology and Biostatistics, Department of Public Health, Epidemiology
and Health Economics, University of Liège, Liège, Belgium.
3
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK; NHIR
Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.
4
WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield, UK.
5
Aging Program, National Research Council, Padova, Italy.
6
Service of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva,
Switzerland.
7
Department of Public Health, Epidemiology and Health Economics, University of Liège, Liège,
Belgium.

Corresponding author:

Dr. Gabriel Herrero-Beaumont.

Bone and Joint Research Unit.

Fundación Jiménez Díaz.

Av. Reyes Católicos 2.

28040 Madrid. Spain.

Tel: +34-91-550 49 18.

Fax: +34-91-544-2636.

E-mail: gherrero@fjd.es

1
Highlights
• Osteoarthritisis the most common chronic joint disorder and its
prevalence increases rapidly during midlife.
 The complex nature of the relationships between numerous factors
involved in the etiopathogenesis makes difficult the identification of
osteoarthritisis phenotypes.
• An adequate stratification of patients with osteoarthritisis into particular
phenotypes could optimize the design of individualized treatments.
• Four well-defined clinical phenotypes are proposed in osteoarthritisis:
biomechanical, osteoporotic, metabolic and inflammatory.

ABSTRACT

Osteoarthritis (OA) is the most common chronic joint disorder and its prevalence increases
rapidly during midlife. Complex interactions of genetic alterations, sex hormone deficit, and
aging with mechanical factors and systemic inflammation-associated metabolic syndrome lead
to joint damage. Thus, the expression of a clinical phenotype in the early stages of OA relies on
the main underlying pathway and predominant joint tissue involved at a given time. Moreover,
OA often coexists with other morbidities in the same patient, which in turn condition the OA
process. In this scenario, an appropriate identification of clinical phenotypes, especially in the
early stages of the disease, may optimize the design of individualized treatments in OA. An
ESCEO-EUGMS (European Union Geriatric Medicine Society) working group has recently
suggested possible patient profiles in OA. Hereby, we propose the existence of 4 clinical
phenotypes – biomechanical, osteoporotic, metabolic and inflammatory – whose
characterization would help to properly stratify patients with OA in clinical trials or studies.
Further research in this field is warranted.

Keywords: osteoarthritis, phenotypes, etiopathogenesis, clinical manifestations, treatment

2
1. Introduction

Osteoarthritis (OA) is a main cause of disability worldwide and even more, aging
population and increasing obesity rates are expected to further rise its burden on the
population and health systems (1). OA is a multifactorial disease where genetic, hormonal,
aging, mechanical and metabolic factors interact by complex molecular mechanisms regulating
the biology of joint tissues, and finally the articular cartilage.

2. OA: from molecular physiopatology to clinical settings

In recent years, relevant evidence has led to a better understanding of the

physiopathology of OA. Thus, three main biological processes: genetic alterations, sex hormone
deficit, and aging have been proposed to induce crucial changes in joint tissues originating
preliminary osteoarthritic changes (2). Moreover, the intricate interplay between mechanical
stress and these processes notably influences the structure and function of joint tissues in OA.
Indeed, abnormal loading originates extracellular matrix (ECM splitting, increased cellular
activity and tissue hydration in the articular cartilage, as well as increased remodeling of the
subchondral bone in early stages of OA (3).
Not only mechanical overload, but also components of the metabolic syndrome
(MetS) are involved in the development and progression of OA (4-6). Dysregulation of adipose
tissue-derived inflammatory cytokines, including IL-1, IL-6, TNF-α, and particularly adipokines
induce the expression of proinflammatory mediators and degradative enzymes that inhibit
cartilage matrix synthesis and stimulate subchondral bone remodeling. In turn, subchondral
ischemia with subsequent impairment of nutrient exchange into the articular cartilage can
occur in hypertension (7). Hyperlipidemia-induced lipid deposition in joint tissues, particularly
in chondrocytes, might trigger OA development (8). Finally, hyperglycemia boosts the local
formation of oxidative stress and advanced glycation products in joint tissues, as well as
induces low-grade systemic inflammation (9).
The interactions of genetic alterations, sex hormone deficit, and aging with mechanical
factors and systemic inflammation-associated metabolic syndrome could give defined OA
phenotypes with specific therapeutic targets (2). Since OA may affect any joint tissue, the
expression of a clinical phenotype in early stages relies on the main underlying pathway and
predominant joint tissue involved at a given time. Thus, the predominant manifestation will be
nonspecific bone pain when the main event is subchondral bone injury and joint swelling when
the main target is the synovial membrane. These clinical phenotypes are interchangeable

3
during early stages of the disease, while, advanced OA shows common pathogenic, clinical and
imaging manifestations in late stages becoming a generalized joint disorder (10). Furthermore,
OA often coexist with other morbidities in the same patient, which in turn, condition the OA
process. The variety of all these factors contributes importantly to the difficulties for an
appropriate classification and identification of phenotypes in clinical studies or trials in OA.

3. Clinical phenotypes in OA

The identification of distinct clinical phenotypes, especially in the early stages of the
disease may be of vital importance in the management of OA since it could optimize the design
of individualized treatments. Hereby, we propose the existence of 4 clinical phenotypes whose
characterization would help to obtain relevant progress in the management of OA.

3.1. Biomechanical OA: Mechanical stress is one of the major factors involved in the
development and progression of OA, particularly in weight-bearing joints. High dynamic load,
particularly the knee adduction moment impulse, was related with great loss of medial tibial
cartilage volume (11). Medial knee joint load during walk may be particularly increased in
individuals with varus malalignment and/or medial meniscal damage. Notably, significant
relationships were found between physical activity and cartilage volume loss along 2.4 years,
varying in accordance with baseline cartilage volume (12).
Overweight itself clearly possesses a harmful biomechanical effect on the knee,
although proinflammatory adipokines partially mediate the association between elevated body
mass index (BMI) and knee OA (13). Surrogates for mechanical stress such as weight and fat-
free mass have been strongly associated with knee OA in population-based cohort studies,
even after adjustment for metabolic factors (14-16). A linear relationship has been
demonstrated between weight change and change in tibial cartilage volume and symptoms in
obese adults at 2.3 years follow-up (17). Likewise, weight loss was associated with
improvement of proteoglycan content and reduction of cartilage thickness loss of medial
articular cartilage over 1 year (18). Weight gain was associated with greater cartilage loss,
whilst weight loss was associated with the converse in subjects with meniscal tears, but not in
the larger subgroup without meniscal lesions (19). Patients with a biomechanical profile may
benefit from non-pharmacology therapy (i.e. load-modifying approaches), hyaluronic acid, etc.

3.2. Osteoporotic OA: The marked rise in the prevalence of OA in women around
menopause and the presence of estrogen receptors in joint tissues stimulated an interest in

4
the role of estrogen deficiency in OA (20). In this sense, increasing experimental evidence has
improved our knowledge on the role of estrogen in joint homeostasis. Estrogens beneficially
regulate important cellular events at articular tissues by acting through several complex
molecular mechanisms at multiple levels (20). Different experimental models of OA have
shown that increased remodeling and impaired structure of subchondral bone aggravate
cartilage damage (21,22). In addition, association of single nucleotide polymorphisms in
estrogen receptor alpha with OA has been reported in different populations (23).
Epidemiological and clinical studies have supported a relationship between OA and
estrogen deficiency (20). Beneficial structural effects of therapy with estrogen and particularly
with some SERMs have been reported in several animal models of OA (24). In patients, 50%
inhibition of biomarkers levels of cartilage degradation was described in women with OA
receiving estrogen therapy (25). Recently, population studies have shown that women taking
estrogens had significantly less joint replacement (26), and moreover, estrogen therapy
reduced by almost 40% the revision rates after knee or hip arthroplasty (27). Together, these
data indicate that estrogen deficiency may induce deleterious effect on all joint tissues,
particularly at the subchondral bone where high remodeling may lead to the development of
osteoporotic OA in early postmenopause (28). Patients with this profile potentially may be
particularly responsive to bone active drugs.

3.3. Metabolic OA: Beyond the relationship between metabolic factors and knee OA, the
associations between obesity as well as the metabolic syndrome and its components with
increased hand OA (29), a non weight-bearing joint per se, emphasize the presence of a
specific clinical subtype, metabolic OA. Metabolic factors including high abdominal
circumference, hypertension, high fat consumption, and self-reported diabetes mellitus were
associated with early cartilage degradation measured with T2 relaxation times at the knee in
middle-aged subjects (30). Moreover, the accumulation of MetS components was significantly
associated with the incidence of knee OA (5). The presence of hypertension and diabetes
mellitus was associated with bone loss at subchondral plate in knee OA (31).
Leptin levels were found to explain almost half of the association between elevated body
weight and knee OA (13). Both baseline leptin and change in leptin levels were correlated with
longitudinal cartilage thinning (32). Furthermore, baseline leptin levels were associated with
the presence of osteophytes, synovitis and effusion, cartilage defects, bone marrow lesions
and meniscal tears assessed by MRI 10 years later in middle-aged women (33). In addition,
statin use was related with reduced incidence and progression of knee OA (34). For these
reasons, metabolic OA has been recently proposed as a discrete OA phenotype and fifth

5
component of Metabolic Syndrome (4). In the same line, diabetes has been regarded as a
causative factor for a new OA phenotype (9). Thus, patients with metabolic OA may potentially
benefit from anti-lipidemic drugs, caloric restriction, etc.

3.4. Inflammatory OA: OA has traditionally been regarded as a degenerative disease,

however it is well established nowadays that local as well as chronic systemic low grade
inflammation are important features of OA. Synovial inflammation contributes to the
pathophysiology and symptoms of OA, through an increased local production of
proinflammatory cytokines and mediators of joint tissue damage (35-37). OA inflammation is
typically mild, chronic, mediated by the innate immune system, and without a marked systemic
acute phase response. Significant inflammatory and fibrotic findings are observed in the
synovium of OA patients in advanced stages, but also in early cases (35-38). OA synovitis is
characterized by macrophage infiltration and activation rather than specific immune
responses, and by the presence of associated anabolic events (e.g. osteoblast activation and
fibrosis) rather than unique catabolic biochemical pathways.
OA synovitis predicts structural progression (39), and varies in parallel with changes in
pain (40). It shows different distribution with a patched pattern and more confined to the areas
adjacent to damaged cartilage. A synovitis pattern affecting patellar sites was associated with
pain, in contrast than other patterns with different locations (37). Synovial inflammation is
particularly pronounced in a subset of knee OA patients, even from early stages. Thus, it has
become an attractive therapeutic target to alter the development and progression of OA.
Patients with inflammatory profile may respond to NSAIDs, methotrexate, biologics, etc.

4. Conclusions

Based on the etiopathogenesis of the disease, we propose the presence of four clinical
phenotypes in OA: biomechanical, osteoporotic, metabolic and inflammatory. The recognition
of well-designed phenotypes should help to better orientate research, facilitate trial design,
and define which OA patients are the most likely to benefit from specific treatments. More
research into this field is necessary for a proper design of individualized treatments in OA.

5. Practice points
•The complex nature of the relationships between numerous factors involved in the
etiopathogenesis makes difficult the identification of OA phenotypes.

6
•An adequate stratification of OA patients into particular phenotypes could optimize the
design of individualized treatments.
•Four well-defined clinical phenotypes are proposed in OA: biomechanical, osteoporotic,
metabolic and inflammatory.

6. Research agenda
•To improve our understanding of the intricate mechanisms involved in the development and
progression of OA.
• To develop an adequate stratification of OA patients into particular clinical phenotypes,
according to the etiopathogenesis of the disease.
•To conduct clinical studies that optimize the design of phenotype-based treatments in OA.

Contributors
All authors were involved in drafting the article or revising it critically for important intellectual
content, and all authors approved the final version.

Conflict of interest
The authors declare they have no conflicts of interest.

Funding
This work was partially supported by research grants from the Instituto de Salud Carlos III
(PI13/00570, PI16/00065) and co-funded by European Regional Development Fund (ERDF).

Provenance and peer review

This article has undergone peer review.

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