




































_____________________________________________________________________________________________________ 
 
*Corresponding author: E-mail: elmafary@gmail.com; 
 
 
 

Asian Journal of Immunology 
 
3(1): 223-232, 2020; Article no.AJI.57637 
 

 
 

 

 

Molecular Pathogenesis, Clinical Efficacy and Safety 
of Therapeutics Used in the Treatment of 

Osteoarthritis 
 

Shaayau Shehu1*, Abdulaziz Umar Kurya2, Kamal Murtala Farouq3 
and Abdulhakim Umar Toro2 

 
1
Department of Biochemistry, Usmanu Danfodiyo University, Sokoto, Nigeria. 

2
School of Life and Allied Health Sciences, Glocal University, Saharanpur, Uttar Pradesh, India. 

 3
Department of Genetic Engineering, Sharda University, Greater Noida, Uttar Pradesh, India. 

 
Authors’ contributions 

 
This work was carried out in collaboration among all authors. Author SS designed and supervised the 

study, Author AUK wrote the first draft of the manuscript, outline the protocol and performed the 
statistical analysis while Authors KMF and AUT managed the literature search and analyses of the 

study. All authors read and approved the final manuscript. 
 

Article Information 
 

Editor(s): 
(1) Dr. Cynthia Aracely Alvizo Báez, Autonomous University of Nuevo Leon, Mexico. 

Reviewers: 
(1) M.K. Jayalakshmi, Rajiv Gandhi University of Health Science, India. 

(2) Vanessa de Melo Cavalcanti Dantas, Instituto de Pesquisa Aggeu Magalhães, Brazil. 
(3) Marcello Zaia Oliveira, Federal University of Parana, Brazil. 

Complete Peer review History: http://www.sdiarticle4.com/review-history/57637 

 
 
 
 

Received 01 April 2020 
Accepted 07 June 2020 
Published 20 June 2020 

 
 

ABSTRACT 
 

Osteoarthritis (OA) also known as degenerative joint disease, is the most common form of arthritis 
which affects all the tissues of the joint, including the cartilage, bone, ligaments, and muscles. It 
can develop in any number of joints, but most commonly affects the knees, hands, and hips. OA is 
characterized by progressive cartilage deterioration, subchondral bone remodeling, loss of joint 
space, marginal osteophytosis, and loss of joint function. The prevalence rate is estimated to about 
242 million people in the world. OA results from the disruption of the balance between synthesis 
and degradation of extracellular matrix components by the chondrocyte in combination with 
increased uncompensated chondrocyte apoptosis. It is increasingly understood that ageing 
contributes to the development of osteoarthritis by working in conjunction with a variety of other 
factors, both intrinsic and extrinsic to the joint. Several abnormalities in components of the healthy 

Review Article 



 
 
 
 

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224 

 

joints such as meniscus, articular cartilage, subchondral bone and synovial membrane results to 
manifestation the disease. In an attempt to discover new emerging therapeutic target, certain 
diagnostic strategies are applied such as X-ray, Ultrasonography, Anthroscopy and Magnetic 
resonance imaging to have a deep insight on its effect and monitor the progression of the disease. 
Interestingly, many clinical researches proved efficacy of Therapeutics such as Adamulimab which 
block TNF-α and plays significant role in the pathogenesis of the disease, Diacerein which inhibit 
interleukin- 1 β, natural anti-inflammatory compound such as curcumin, bisphosphonate drugs such 
as alendronate and risedronate and anti-osteoporotic drugs such as strontium ranelate, chondroitin 
sulfate, intraarticular hyaluronic acids and glucosamine sulfate are reported to be effective and safe 
in the management of the disease. 

 

 
Keywords: Osteoarthritis; degenerative joint disease; pathogenesis and therapeutics. 
 

1. INTRODUCTION 
 
Osteoarthritis (OA) also known as degenerative 
joint disease is the most common form of arthritis 
which affects all the tissues of the joint, including 
the cartilage, bone, ligaments, and muscles. It 
can develop in any number of joints, but most 
commonly affects the knees, hands, and hips [1]. 
OA typically occurs later in life, usually after age 
50, although may start earlier in the case of joint 
injury but symptoms may vary in severity, 
whereby OA in its severe forms restricts mobility, 
interrupts sleep, and interferes with the sufferer’s 
enjoyment of life [2].  
 
The disease has precisely no cure. However, 
some of the therapeutics mainly aimed at 
reducing the pain, improving the joint function, 
and in some instances delay the progression                 
of the disease [3]. OA occurs when the protective 
cartilage that cushions the ends of two      
opposing bones wears down over time,              
although the articular cartilage and subchondral 
bone often show the most prominent changes 
[4]. OA is primarily characterized by progressive 
cartilage deterioration, marginal osteophytosis, 
subchondral bone remodeling, loss of                        
joint space, and ultimately loss of joint function 
[5]. 
 
OA is also characterized by a degeneration of 
articular cartilage whereby the breakdown leads 
to matrix fibrillation, fissure appearance, gross 
ulceration, and full thickness loss of the joint 
surface which is accompanied by hypertrophic 
changes of bone with osteophyte formation and 
subchondral bone plate thickening. At the early 
stage of the disease, there are changes in the 
synovial membrane together with an 
inflammatory reactions while at advanced stages, 
joint contractures, muscles atrophy and limb 
deformity are commonly observed [6]. 

2. MATERIALS AND METHODS 
 
Using online databases, we conducted a 
literature review of Molecular pathogenesis and 
novel therapeutic potentials of osteoarthritis. The 
key articles used were retrieved predominantly 
from NCBI, Google Scholar, MEDLINE, 
UpToDate, using the terms ‘Osteoarthritis, 
degenerative joint disease, Therapeutics of 
osteoarthritis as keywords for our search. We 
included scientific publications from 1

st
 January 

2010 to 15
th
 December 2018 Articles focusing on 

clinical characteristics, epidemiology, symptoms, 
diagnosis and treatments for Osteoarthritis were 
eligible for selection. 
 

3. EPIDEMIOLOGY OF OSTEOARTHRITIS 
 
The prevalence of OA is break down based on 
different demographic criteria. The Age-related 
demographics shows that Primary osteoarthritis 
is mostly common in elderly and majority of the 
patients are often asymptomatic. Approximately 
80-90% of individuals older than 65 years have 
evidence of radiographic primary osteoarthritis. 
 
However looking at the gender variations women 
are at high risk of the infection than men, this 
also varies with age where as women older than 
55 years have high prevalence rate. OA is a 
major cause of disability in older adults 
worldwide, according to World Health 
Organization (WHO) 9.6% of men and 18.0% of 
women aged 60 years and above has 
symptomatic osteoarthritis worldwide, this lead to 
restriction of movement in 80% of those with 
osteoarthritis and incapable of performing major 
daily activities of life in 20% of OA patients [7]. 
 
In the United States of America, Knee OA 
accounts for more than 80% of the disease’s 
total burden and affects at least 19% of      



 
 
 
 

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225 

 

American adults aged 45 years and older [8,9]. 
According to data produced by the Dutch 
Institute for Public Health, the prevalence of knee 
OA in individuals of 55 years and above is 
reported as 15.6% in men, 30.5% in women, and 
that of hips OA is 4.4% in men and 7.6% in 
women [10]. Recent study of individual’s ≥60 
years of age living in Spain documented a 
prevalence of 6.7% in men and 8.0% in      
women having OA [9]. A review of several 
investigations in Canada has reported the overall 
prevalence ranges between 7.5 and 14.7%    
[11]. 

 

In addition, the North and East regions of China 
had the lowest prevalence of symptomatic knee 
OA 5.4% and 5.5%, respectively, followed by the 
North-East 7.0%, South-Central 7.8%, and 
North-West 10.8% regions. Surprisingly, the 
prevalence was highest 13.7% in subjects living 
in the South-West region [12]. Furthermore, 
prevalence of 22% to 39% was reported in India; 
however it is more common in women than men, 
whereby approximately 45% of women over the 
age of 65 years have symptoms while 70% of 
those over 65 years show radiological evidence 
of OA [7]. 

 

 

 

 

Fig. 1. Prevalence of OA in the united states of 
America showing the disease burden, adult 

infected, men and women [8,9] 

 

Fig. 2. Shows Spain and Canada infection rate 
in men and women [9,11] 

 

 
 

 
Fig. 3. Shows overall prevalence rate for different region in china regardless of gender 

variation [12] 
 
 

80% 

19% 

7.6% 
4.4% 

0 

20 

40 

60 

80 

100 

Disease 

burden 

 adults 

affected 

 women  men 

Knee OA 

Hip OA 
6.7% 

8% 7.5% 

14.7% 

0 

2 

4 

6 

8 

10 

12 

14 

16 

men  women  men  women 

Spain 

Canada 

5.4% 5.5% 

7% 
7.8% 

10.8% 

13.7% 

0 

2 

4 

6 

8 

10 

12 

14 

16 

China 



 
 
 
 

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226 

 

4. DEVELOPMENT OF OSTEOARTHRITIS 
 

There is strong correlation between ageing and 
development of osteoarthritis where it is 
increasingly understood that ageing contributes 
to the development of osteoarthritis by      
working in conjunction with a variety of other 
factors, both intrinsic and extrinsic to the joint.            
It has become distinct that changes that               
results due to aging in the musculoskeletal 
system contribute to the development of 
osteoarthritis by working in conjunction with other 
factors, both intrinsic (e.g., alignment, 
overloading) and extrinsic (e.g., genetics) to the 
joint [13]. The primary changes with osteoarthritis 
occur in the articular cartilage, followed by 

associated changes in the subchondral bone 
[14]. 
 
Recently, more focus has been placed on the 
subchondral bone as the primary cause of 
symptomatic disease. Understanding of changes 
at early stages that lead to development of 
osteoarthritis is important, since these changes 
could still be reversible, and therefore, preventive 
treatment could be initiated to halt or reverse 
further progression of the disease. 
Biomechanical factors in OA play an important 
role in the health of diarthrodial joints. Altered 
joint loading associated to obesity, malalignment, 
trauma, or joint instability are most common 
critical risk factor for joint degeneration [15]. 

 
 

 
 
 
 
 

 

 
Fig.  4. Shows cartilage breakdown on healthy joint which progresses to several stages of OA 
development; stage 1 involves minimum disruption accompanied by 10% cartilage lost, Stage 

2 involve joint space narrowing where cartilage breakdown begins and characterized by 
osteophytes formation, in Stage 3 there is moderate joint reduction where gaps in the cartilage 

expand until they reach bone and lastly stage four which involves 60% cartilage lost and is 
characterized by large osteophytes [16,17] 



 
 
 
 

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5. PATHOGENESIS OF OSTEOARTHRITIS 
 
OA results from the disruption of the balance 
between synthesis and breakdown of 
extracellular matrix components by the 
chondrocyte in addition with increased 
uncompensated chondrocyte apoptosis [18]. In 
the young patient, the pathogenesis of knee 
osteoarthritis is predominantly related to an 
unfavorable biomechanical environment at the 
joint, which results in mechanical demand that 
exceeds the ability of a joint to repair and 
maintain itself thereby predisposing the articular 
cartilage to premature degeneration [19]. The 
pathophysiology of the process by which joint 
degeneration leads to the clinical syndrome of 
osteoarthritis remains poorly understood. 

 
However OA mostly involves degeneration of 
cartilage, abnormal bone remodeling, osteophyte 
formation and joint inflammation [20]. In healthy 
joint several components facilitate the proper 
functioning of joints such as, meniscus (shock 
absorber) a fibrocartilage which disperse the 
weight of the body and reduce friction during 
movement and mainly composed of water, type I 
collagen, and proteoglycans in its extra cellular 
matrix [21]. 
 
The articular cartilage a hyaline cartilage which 
decreases friction and distributes loads and 
mainly composed of water, 90% type II collagen 
and proteoglycans in the matrix [22]. The 
subchondral bone which attenuates forces 
generated through locomotion, with the compact 
subchondral bone plate providing firm support to 
the joint and mainly composed of type I collagen. 
The synovium which produces synovial fluids 
that functions in reducing friction by lubricating 
the joint, absorbing shocks, supplying oxygen, 
nutrients and removing carbon dioxide and 
metabolic wastes from the chondrocytes within 
articular cartilage [23]. Synovial membrane 
composed of two synoviocytes; synovial 
fibroblast and synovial macrophages. The 
synovial fibroblast produces the extracellular 
matrix components of the synovial fluid and thus 
is important for cartilage integrity and lubrication 
of the joint, while the synovial macrophages 
remain relatively quiescent in the healthy joint; 
they become activated in the inflamed joint and, 
along with infiltrating monocytes/macrophages, 
regulate secretion of pro-inflammatory cytokines 
[24,25]. 
 
Several abnormalities such as Mechanical 
abrasion in the knee have been found to promote 

OA, which is mostly seen in the older age and 
can ultimately leads to the progressive 
degenerative changes in the proper functioning 
of the joints. Furthermore, the innate immune 
system plays a role in OA progression through 
the activation of both the complement and 
alternative pathways of inflammation, once 
activated; it leads to an inflammatory response 
that is a major driver of the disease [25]. 
 

6. DIAGNOSIS OF OSTEOARTHRITIS 
 

 X-ray of affected joints will show a loss of the 
joint space. In more advanced cases, there 
may be bone spurs or evidence of worn-down 
ends of the bones in the affected joint [26]. 

 Magnetic resonance imaging (MRI) has a 
tomographic viewing perspective and thus 
provides cross-sectional images of the 
anatomy free of the projectional limitations of 
radiography, the technique is uniquely able to 
depict all the components of the joint, their 
pathologies, articular cartilage, meniscus, 
intraarticular ligaments, synovium, effusion, 
bone attrition, bone marrow lesions, 
subchondral cysts, and intra- and periarticular 
cystic lesions [27]. 

 Arthroscopy: Is a is a surgical procedure 
orthopedic surgeons use to visualize, 
diagnose, and treat problems inside a joint by 
inserting a narrow tube attached to a fiber-
optic video camera through a small incision 
which gives a clear view of the pathological 
changes inside the joint [28]. 

 Ultrasonography is a modern ultrasound 
technique which uses high-frequency sound 
waves to produce images of internal organs 
and other tissue [29].  

 

7. THERAPEUTIC TARGETS OF 
OSTEOARTHRITIS 

 

7.1 TNF-α Blockers 
 

TNF-α is an inflammatory cytokine produced            
by monocytes/macrophages during acute 
inflammation, it plays significant role in the 
pathogenesis of OA. Adalimumab is a human 
monoclonal antibody bioengineered to prevent 
the binding of TNF-α to its receptor and inhibit 
the progression of osteoarthritis. A 12-month 
randomised, double-blind, placebo-controlled trial 
evaluate subcutaneous administration of 40 mg 
adalimumab every two weeks in 60 patients with 
erosive hand OA, however the tolerability and 
safety profiles of adalimumab on those patients 
were very good and resulting to successful 



 
 
 
 

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neutralization of the TNFα there by slowing the 
progression of structural damage in erosive 
interphalangeal finger joint osteoarthritis [30]. 
Anti-TNF-α therapy with infliximab (a chimeric 
monoclonal antibody) was reported to yield 
effective treatment and reduce the incident of 
secondary OA via other pathways [31]. 
 

7.2 IL-1β Inhibitor 
 
IL-1β also known as leukocytic pyrogen, is a key 
pathogenic factor in OA. Hence use of Diacerein 
which is an IL-1β inhibitor, reduces the number 
of IL-1 receptors, thereby resulting to reduction in 
functional IL-1 heterodimer receptor complexes 
and ultimately lowers the disease progression 
[32]. A study of a symptomatic slow‐acting OA 

drug which accesses the primary outcome for 2 
months after the end of a 3 month treatment 
period shows that diacerein is safe and has a 
significant effective for the treatment of knee OA 
[33]. Another study confirmed that symptomatic 
benefit provided by diacerein in terms of pain 
reduction is minimal; the small changes observed 
in the joint space narrowing is of questionable 
clinical relevance and was observed only for OA 
of the hip [34]. In vitro and experimental models 
showed a reduction in cartilage destruction with 
IL-1 by IL-1 receptor antagonists [35]. One of 
recent articles shows a possible benefit in using 
higher doses of Kineret (150-200 mg) in the 
treatment of osteoarthritis of large joints and 
suggest it alternativeness to IA steroid [36]. 
 

7.3 Curcumin 
 
Clinical trials shows similar efficacy of curcuma 
formulation with NSAIDS and glucosamine for 
treatment of osteoporosis [37]. A multicenter 
study reveal the efficacy and safety of Curcuma 
domestica extracts in pain reduction and 
functional improvement and further shows it 
effectiveness, similar to that of ibuprofen [38]. 
The adjuvant therapy of curcumin with diclofenac 
has more potential and beneficial effect than 
individual effect of diclofenac alone [39]. A 
randomized, double-blind, placebo-controlled, 
prospective clinical study of a highly bioavailable 
form of curcumin (theracurmin) in patients with 
osteoarthritis reveal significant effect of the 
compound in deceasing pain and its potential in 
the treatment of human knee osteoarthritis in the 
future [40]. Meriva (a Curcumin-
phosphatidylcholine Complex) is also referred as 
effective and safe agent for the complementary 
management of osteoarthritis, leading to better 
disease control, a decreased use of NSAIDs, and 

overall improvement in the quality of life [41]. 
Another study shows that formulation of 500 mg 
Curcuma longa and Boswellia serrate extract 
(CB) administered twice daily demonstrated a 
greater improvement in the treatment of OA than 
100 mg of celecoxib administered twice a day in 
the scores for pain, walking distance and joint 
line tenderness. The CB formulation was equally 
effective as celecoxib in alleviating crepitus, and 
increasing the range of joint movements with no 
dose-related toxicity and ultimately the 
formulation was termed superior to celecoxib 
(NSAIDs) for the treatment of active OA [42]. 
 

7.4 Bisphosphonates  
 
Bisphosphonates are a group of medicines that 
slow down or prevent bone loss, strengthening 
bones. They work by inhibiting osteoclasts which 
are responsible for breaking down and 
reabsorbing minerals such as calcium from bone. 
Meta-analysis showed that bisphosphonates 
therapy is effective in relieving pain and 
accelerating functional recovery for patients with 
OA [43]. In another clinical studies, administering 
alendronate sodium (a bisphosphonate drug) for 
patients with OA has clinical efficacy in reducing 
joint complications with significant structural 
improvement of the joints, and may delay and 
prevent further disease progression probably 
through inhibition of leptin activity [44]. 
Risedronate a bisphosphonate drug in 
comparison with placebo did not improve signs 
or symptoms of OA, nor did it alter progression of 
OA, only reduction in the level of marker of 
cartilage degradation was observed However 
sustained clinically relevant improvement in signs 
and symptoms was observed in all treatment and 
placebo groups [45]. In a one-year, placebo-
controlled trial that included 59 patients with knee 
OA treated with zoledronic acid 5 mg 
intravenously as a single infusion, a significant 
reduction in visual analogue pain scores versus 
placebo was seen after six months [46]. 
 

7.5 Strontium Ranelate 
 
Strontium ranelate (SR) is an anti-osteoporotic 
drug responsible for balance between bone 
resorption and bone formation [47]. Clinical trial 
reveals that treatment with 1 or 2 g of strontium 
ranelate per day is associated with significant 
structural changes in patients with knee 
osteoarthritis; furthermore, there is a beneficial 
effect on the symptoms specifically at dosage of 
2 g/day [48]. Another study shows that dose of 
1800 mg/kg/day of SR significantly attenuated 



 
 
 
 

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cartilage matrix and chondrocyte loss, and 
decreased chondrocyte apoptosis, in a medial 
meniscal tear model using Sprague–Dawley rats 
[49]. 
 

7.6 Chondroitin Sulfate 
 
A 1 Year, Randomized, Double-Blind, Multicenter 
Clinical Study in Japan, shows that treatment 
with sodium chondroitin sulfate at a 
dose of 1560 mg/d is more effective  than 260 
mg/d more resultant to pain relief in patients with 
knee OA [50]. However, a 2-year multicentre 
exploratory study on efficacy of Chondroitin 
sulfate versus celecoxib on knee osteoarthritis 
structural changes concluded that chondroitin 
sulphate is more superior over celecoxib at 
reducing cartilage volume loss in knee OA 
patients [51]. Meta-analysis of randomized 
controlled trials demonstrated that oral 
chondroitin is more effective than placebo on 
relieving pain and improving physical function. 
Although glucosamine showed positive effect on 
stiffness outcome, further studies are requested 
to investigate the accurate effectiveness of both 
the two drugs [52]. 
 

7.7 Intra Articular Hyaluronic Acids 
 
A Canadian evidence-based perspective 
demonstrated that treatment with Intra articular 
hyaluronic acids is well tolerated, with 
significantly improved pain, function and stiffness 
outcomes compared with placebo or 
noninterventional controls in patients with mild-
to-moderate knee OA [53]. Multi-center open 
perspective study suggests the clinical efficacy of 
a single intra-articular injection of 3 mL intra-
articular hyaluronic acid solution containing 75 
mg high molecular weight (>2 MDa) native 
hyaluronic acid [54]. 
 

7.8 Glucosamine Sulfate 
 

Evidence from a real life setting trials and 
surveys shows that different therapeutic effect 
are obtained with different formulation of 
glucosamine. Therefore, not all formulation of 
glucosamine should be afforded same level of 
recommendation [55]. Glucosamine supplements 
composed of different chemical components and 
have become a mainstay in management of OA 
due to their symptom-relieving effects, cost 
effectiveness, important structure-preserving and 
relatively non-toxic adverse effect profiles. 
However, researches are required to fully 
understand the concept [56]. 

8. CONCLUSION 
 
Many studies on osteoarthritis gave more insight 
on the inflammatory processes, biochemical 
changes and abnormalities in some of the 
component of healthy joint. In this review we 
have highlighted clinical efficacy and safety of 
some therapeutics used in the treatment of OA. 
However, extensive clinical trials should be taken 
to critically elucidate the efficacy of the 
therapeutics. 
 

CONSENT 

 
It is not applicable. 

 
ETHICAL APPROVAL 
 
It is not applicable. 
 

ACKNOWLEDGEMENTS 
 
We appreciate the effort of Usmanu Dandodiyo 
University, Glocal University, Sharda University, 
and Mewar University for their esteemed support 
and guidance towards completion of this review 
article. 
 

COMPETING INTERESTS 
 
Authors have declared that no competing 
interests exist. 
 

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