CC BY
31Research Results in Pharmacology
Research Results in Pharmacology 8(4): 167-174
UDC: 616.72-002 DOI 10.3897/rrpharmacology. 8.84951
Recent advances in the pharmacotherapy of osteoarthritis
Muthu Meera1
1 Velammal Medical College Hospital andReasearch Institute, Anuppanadi, Madurai-625009, Tamilnadu, India Corresponding author: Muthu Meera ([email protected])
Academic editor: Tatyana Pokrovskaia ♦ Received 6 April 2022 ♦ Accepted 24 November 2022 ♦ Published 22 December2022
Citation: Meera M (2022) Recent advances in the pharmacotherapy of osteoarthritis. Research Results in Pharmacology 8(4): 167-174. https://doi.org/10.3897/rrpharmacology.8.84951
Introduction: Osteoarthritis (OA) is a common debilitating disease affecting the geriatric population. Management of osteoarthritis is a challenge for orthopedicians because till date there has been no such drug that can completely cure the disease or at least retard/arrest the disease progression. In addition to the currently available treatment options for OA like NSAIDs, opioids, nutraceuticals (glucosamine sulphate and chondroitin sulphate), many new drugs are being discovered or repurposed for use in osteoarthritis. Most of these recent drugs aim at retarding the disease progression rather than providing just a symptomatic relief.
Materials and methods: All relevant articles regarding approved new drugs and pipeline drugs for osteoarthritis published between 2012-2021 were analysed. Those included animal studies as well as clinical trials. Some older articles were also referred to, provided they highlighted any significant data. The obtained data were analysed and compiled.
Results and discussion: Broadly the recent drugs for OA can be classified based upon their site of action as (i) drugs targeting articular cartilage, (ii) drugs targeting inflammation, (iii) drugs targeting the subchondral bone, and (iv) drugs for relieving pain. Ranging from in vitro studies to clinical trials, these drugs are in various phases of drug discovery. Early diagnosis of OA and its management with a drug that retards disease progression rather than prescribing just a symptom reliever is very much necessary in the current situation.
Conclusion: Need for new drugs for OA is increasing day by day. More number of clinical trials with larger sample sizes alone can satisfy the need of disease modifying drugs for OA. This review provides a deep insight into all the recent advances in the pharmacotherapy of osteoarthritis.
Graphical abstract:
Abstract
Copyright Meera M. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC-BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Keywords
osteoarthritis, pharmacotherapy, new drugs.
Introduction
Osteoarthritis (OA) is a degenerative disease of joints. In fact, it is the most common arthritis. It mainly affects the joints that have been continuously stressed upon, such as the hip joint, the knee joint, and small joints of hands and feet. According to the WHO, it is one of the ten most disabling diseases in developed countries. It produces a significant impact on people's physical health as well as mental health. By affecting mental health, it increases the risk of suicidal tendency among affected individuals. It has become one of the leading causes of hospitalization among elderly individuals. Worldwide, 9.6% of men aged over 60 years and 18% of women aged over 60 years are suffering from symptomatic osteoarthritis. In India, the prevalence of osteoarthritis is about 28.7% (Pal et al. 2016). As the proportion of geriatric population as well as proportion of obese individuals continues to increase, the burden of osteoarthritis is increasing every year.
Because of the mutifactorial etiology of the disease, there is variation in the clinical presentation as well as variation in treatment response of affected individuals. Because of these factors, it makes it difficult or almost impossible to find an effective cure for OA. Researchers around the world are putting in lots of efforts in discovering new drugs and repurposing the already approved ones so as to find a permanent solution to this problem, the magnitude of which has increased out of proportion in the recent years.
Risk factors for development of osteoarthritis
The risk factors for the development of OA include (Bor-toluzzi et al. 2018):
i. Age: The risk of developing OA increases as age advances. The peak incidence of OA is in the age group of 55 to 64 years.
ii. Gender: The prevalence of OA is greater among women. This can be explained based on the fact that estrogen promotes the formation of proteoglycans by chondrocytes and regulates osteoblastic activity in the subchondral bone. In postmenopausal women, as the estrogen levels decline, the above functions get disrupted placing women at an increased risk of developing OA.
iii.Obesity: As body weight increases, there is greater stress upon the weight-bearing joints, thus increasing the damage of these joints.
iv. Genetic factors may also predispose an individual to develop OA.
v. Excessive manual labour is another important risk factor.
Etiopathogenesis of osteoarthritis
Osteoarthritis is a wear and tear disease. It may be primary (with no obvious underlying cause) or secondary OA (with a known underlying cause). Secondary OA may be due to any previous trauma to joints, connective tissue disorder, etc. The most commonly affected joints include hip joint, knee joint and the small joints of the hands and feet.
The articular cartilage of a joint consists of extracellular matrix (ECM), which is composed of water, collagen, proteoglycans and chondrocytes. Chondrocytes play a major role in the synthesis of the ECM components whereas proteolytic enzymes degrade them. When there is an imbalance between the synthesis and degradation triggered by trauma or inflammation or any other factor, then it ultimately results in osteoarthritis (Man and Mologhianu 2014).
Schema 1. Current treatment options for Osteoarthritis (Sinusas 2012).
Materials and methods
We made a thorough search of literature to obtain all published information regarding recent advances in the pharmacotherapy of osteoarthritis. All relevant articles regarding new drugs and pipeline drugs published between 2012-2021 were analysed. Some older articles were also referred, provided they highlight any significant data. All obtained data were analysed, compiled and the newer agents were categorized into four groups and discussed in detail.
Results and discussion
The recent drugs for the management of OA can be broadly classified depending upon their target of action as follows:
I. Agents targeting articular cartilage
II. Agents targeting inflammation
III. Agents targeting subchondral bone
IV. Agents targeting pain
Agents targeting articular cartilage
It is a well-known fact that articular cartilage is composed of collagen and cartilage specific proteoglycan (also known as aggrecan). Collagen is degraded by matrix metalloproteinase (MMP) whereas aggrecan is degraded by aggrecanases. So, if these degrading enzymes are inhibited, it is possible to stop progression of OA.
MMP inhibitors
Out of all matrix metalloproteinases, MMP-13 is specifically found in degenerated cartilage of OA patients (Wang et al. 2004) and absent in normal healthy cartilage. Initially broad spectrum MMPs were tried for OA, which produced adverse effects in the form of joint stiffening and pain (musculoskeletal syndrome) (Wojtowicz-Praga et al. 1998).
Aflapin
It is an MMP-3 inhibitor. It is obtained from Boswellia serrata gum resin. It was found to decrease pain and improve physical function in OA patients (Sengupta et al. 2010).
Pycnogenol
It is an MMP-3 and MMP-13 inhibitor. It is obtained from maritime pine bark extract. It had been in use already as a herbal medication with anti-inflammatory property. It was found to reduce pain and joint stiffness in OA patients (Belcaro et al. 2008).
ADAMTS inhibitors
ADAMTS inhibitors inhibit the enzyme aggrecanase. ADAMTS-4 is another name for aggrecanase-1 and ADAMTS-5 is another name for aggrecanase-2. Out of the
two, aggrecanase-2 (ADAMTS-5) is specifically involved in cartilage degradation in OA patients (Larkin et al. 2015).
GSK2394002
It is a humanized monoclonal antibody that selectively inhibits ADAMTS-5. In vitro, ex vivo and animal studies have shown that GSK2394002 modifies the disease structure and causes alleviation of pain-related behaviour in OA (Larkin et al. 2015).
Growth factors
Growth factors are known to have anabolic effect on articular cartilage and they also promote cartilage repair.
Sprifermin
Sprifermin is a recombinant human FGF18 (Fibroblast Growth Factor 18). In preclinical studies, FGF 18 was found to stimulate chondrogenesis (Moore et al. 2005). Phase 1 trial showed that sprifermin not only promotes cartilage thickness, but also reduces cartilage loss in OA (Eckstein et al. 2015).
GEC-TGF-p
GEC-TGF-p stands for 'Genetically Engineered Chondrocytes expressing TGF-P'. Phase 2 trial with this drug showed that GEC-TGF-p produced more positive responses on IKDC (International Knee Documentation Committee Questionnaire, a knee-specific patient-reported outcome measure) and VAS (Visual Analog Scale for pain) scores (Cherian et al. 2015).
BMP
Bone Morphogenetic Protein (BMP) belongs to the TGF-p family. It plays an important role in bone cartilage ho-meostasis. Animal studies have demonstrated that osteo-chondral defects in rabbit knee can be repaired by BMP-2 delivered via viral vectors (Betz et al. 2017). But human studies lack to demonstrate the efficacy of this agent.
Cathepsin K inhibitors
Cathepsin K is an enzyme secreted by osteoclast. It is involved in bone and cartilage degradation. Thus inhibiting this enzyme can prevent the degradation process. MIV-711 is a novel cathepsin K inhibitor. Phase 2 trial showed that the drug causes significant reduction in disease progression. But it failed to produce a significant pain reduction (Conaghan et al. 2018a).
Wnt/p-catenin signalling pathway inhibitors
Wnt/p-catenin signalling pathway is involved in the pathogenesis of OA. SM04690, an inhibitor of this pathway, proved its potential as a DMOAD (Disease Modifying Osteoarthritis Drug) in phase 2 trial (Yazici et al. 2018).
VEGF inhibitors
Elevated levels of VEGF (Vascular Endothelial Growth Factor) are associated with OA progression and inhibition of VEGF and its receptors can prove as a potential treatment for OA (Hamilton et al. 2016).
In rabbit models of OA, intra-articular administration of bevacizumab (VEGF inhibitor) reduced degeneration of articular cartilage and also decreased osteophyte formation. Also, the intra-articular route of administration of bevacizumab was compared with an intravenous route, and the intra-articular route was found to have greater advantage (Nagai et al. 2014).
Diacerein
Diacerein is a semi-synthetic anthraquinone derivative. It inhibits the synthesis of bone resorptive enzymes and reduces osteoclast survival (Boileau et al. 2008). It has anti-inflammatory, anti-catabolic and pro anabolic effects on articular cartilage. It was designated as SYSA-DOA (Symptomatic Slow Acting Drug for Osteoarthritis) (Pavelka et al. 2016). Other SYSADOA include chon-droitin sulphate, glucosamine sulphate, hyaluronate, etc. The adverse effects of diacerin include soft stools, diarrhoea, skin reactions, etc.
NO inhibitors
Nitric Oxide is a pro-inflammatory cytokine. It is a mediator of cartilage destruction in OA. Cindunistat (SD-6010) is an oral selective inducible NO synthase inhibitor. It was proposed to reduce joint space narrowing in OA patients; but phase 2 trial to evaluate this effect failed to show positive results (Hellio le Graverand et al. 2013).
COX-2 inhibitors
COX-2 inhibitors have not only analgesic and anti-inflammatory properties, but also protective effects on cartilage. An animal study demonstrated that the COX-2 inhibitor celecoxib has beneficial effects in OA (Ou et al. 2012). Another COX-2 inhibitor, etoricoxib, was found to reduce pain and improve physical function in knee OA patients in phase 4 trial (Moss et al. 2017).
Agents targeting inflammation
Both local and systemic inflammation plays a pivotal role in the pathogenesis of OA. Thus agents that have been proven to have anti-inflammatory effect have been tried for pharmacotherapy of OA.
TNF-a inhibitors
TNF-a is a pro-inflammatory cytokine released at the site of articular cartilage degradation that further accelerates the damage process. Thus TNF-a inhibitors can slow down this process.
Adalimumab
Among the monoclonal antibodies that inhibit TNF-a, adalimumab was the first to be discovered. In a RCT conducted by Wang et al. (2018), it was found that in-tra-articular injection of adalimumab was well-tolerated and more effective in decreasing the VAS pain score and WOMAC-Western Ontario and McMaster Universities Osteoarthritis Index pain score, in comparison to hyaluronic acid (Wang 2018).
Infliximab
Following evidence from preclinical studies that suggested that infliximab can slow down cartilage degradation (Zhang et al. 2012), a pilot study was conducted in patients with erosive hand OA (Fioravanti et al. 2009), and it was found that infliximab has symptom relieving and disease modifying effects.
DLX105
DLX105 is an antibody against TNF-a. Phase 2a trial with DLX105 was conducted in knee OA patients (ClinicalTrials.gov Identifier: NCT00819572). But the results are yet to be released.
IL-1 inhibitors
IL-1 induces expression of MMP enzyme, thereby promoting inflammation. It also suppresses synthesis of cartilage components like collagen and proteoglycans (Goldring et al. 1988). Thus inhibition of IL-1 can retard OA progression.
Canakinumab
It is a monoclonal antibody that blocks IL-1 receptors. Invitro and preclinical studies were conducted to find the effect of canakinumab on human osteoarthritic chon-drocytes and it was found that the drug counteracts IL-1 and has chondroprotective action (Cheleschi et al. 2015). Later phase 2 trial was conducted to evaluate safety and efficacy of canakinumab in knee OA patients, but results are yet to be released (ClinicalTrials.gov Identifier: NCT01160822).
Anakinra
Anakinra is another IL-1 receptor antagonist proven to have positive outcomes in OA patients (Chevalier et al. 2005; Kraus et al. 2012).
Gevokizumab
This drug neutralises IL-ip. Phase 1 trial to evaluate effect of gevokizumab in erosive hand OA was conducted, but the results are yet to be released (ClinicalTrials.gov Identifier: NCT01882491).
ABT-981
ABT-981 is an immunoglobulin that neutralises both IL-1a and IL-ip. Phase I trial demonstrated that the drug significantly reduced ANC (Absolute Neutrophil Count) and serum levels of IL-1a,IL-ip and C-reactive protein in knee OA patients (Wang et al. 2017b), thus proving its anti-inflammatory and disease modifying effects.
Methotrexate
Methotrexate is a well known DMARD (Disease Modifying Antirheumatic Drug). It reduces both local and systemic inflammation. A phase 3 trial named PROMOTE (Pain Reduction with Oral Methotrexate) was conducted to evaluate efficacy of methotrexate in knee OA patients (Kingsbury et al. 2015), but the results are yet to be released.
Polyphenols
Among the polyphenols that are being tried for OA management, the popular ones include EGCG (Epigallocat-echin gallate) found in green tea and curcumin found in turmeric. EGCG slowed the progression of OA in a post traumatic OA mouse model, thereby demonstrating its chondroprotective and anti-inflammatory properties (Leong et al. 2014). In another study conducted by Zhang et al (2016) in the post-traumatic OA mouse model, oral curcumin reduced OA disease progression and topical curcumin application relieved OA-related pain.
Limonene and Myrcene
Both limonene and myrcene are terpenes found in essential oils. Limonene is found in the peels of citrus fruits. Myrcene is a component of cannabis, cardamom, etc. In vitro study with these compounds showed that both myrcene and limonene prevent inflammatory and catabol-ic responses in human chondrocytes (Rufino et al. 2015).
Agents targeting subchondral bone
Bisphosphanates
Bisphosphanates are the drugs of choice for postmeno-pausal osteoporosis. It is a matter of controversy whether these drugs can retard progression of OA or not. Studies have demonstrated that the bisphosphanates, risedronate (Spector et al. 2005), clodronate (Saviola et al. 2017), alendronate (Nishii et al. 2013) have beneficial effect in OA patients. However, a recent meta analysis (Vaysbrot et al. 2018) concluded that bisphosphanates neither provide symptomatic relief nor retard disease progression. Further studies are required to find out if these drugs actually have any beneficial effect or not.
Strontium ranelate
Strontium ranelate is already approved for osteoporosis. Phase 3 trial to evaluate the efficacy of this drug in OA revealed that the drug has a structure-modifying effect in knee OA and also provides symptomatic relief (Reginster et al. 2013).
SERMs (Selective Estrogen Receptor Modulators)
Osteoarthritis is common in postmenopausal women. SERMs are already in use for postmenopausal osteoporosis. Hence SERMs was tried for use in OA as well and it was found that levormeloxifine and raloxifine have beneficial effects in postmenopausal women with OA and that these drugs are particulary useful in postmenopausal women with osteoporotic OA (Lugo et al. 2014). Osteo-porotic OA is associated with reduced bone mineral density and excessive remodeling of subchondral bone.
Agents targeting pain
Pain is the ultimate problem faced by all OA patients. It severely affects their quality of life and limits their daily
activities. The agents to combat pain in current practice include acetaminophen, NSAIDs and opioids. But because of the adverse effects that occur upon the chronic use of these agents, the need to search for new alternatives has come up.
Nerve growth factor (NGF) inhibitors
NGF is a neurotrophin whose expression is increased in inflamed tissue (Lane et al. 2010). It causes sensitization of pain receptors, thereby modulating pain perception in OA patients. Thus NGF inhibitors have been tried for pain relief in OA.
Tanezumab
Tanezumab is an NGF inhibitor. In a recent meta analysis of 10 RCTs (Chen et al. 2017), it was found that tanezumab (in doses of 2.5 mg, 5 mg, and 10 mg) provides greater pain relief and improvement in physical function when compared to placebo. Adverse effects of the drug include peripheral neuropathy, peripheral oedema, etc.
Previously, FDA imposed a partial clinical hold on non-cancer pain-related studies with tanezumab because of serious adverse effects like osteonecrosis reported with the use of tanezumab in some studies. However, this me-ta-analysis concluded that the occurrence of osteonecrosis is dose dependent and low doses of tanezumab (2.5 mg, 10-25 ^g/kg) is well tolerated with acceptable adverse effects only.
Duloxetine
Duloxetine is a selective serotonin norepinephrine re-uptake inhibitor used as an antidepressant. Duloxetine is approved for the management of fibromyalgia pain. Phase 3 trial with the drug suggested that duloxetine is efficacious for the treatment of pain in OA as well (Wang et al. 2017a).
FX006
Currently intra-articular injection of corticosteroids is widely being used to provide pain relief in chronic OA patients. One such corticosteroid used for intra-articular injection in OA is triamcinolone acetonide (TA). But rapid absorption of this drug into the systemic circulation limits its efficacy as a pain reliever.
FX006 is a novel microsphere-based extended release formulation of triamcinolone acetonide. It ensures that TA remains confined to the joint space for a longer time and also minimizes systemic exposure (Conaghan et al. 2018b). Phase 3 trial showed that FX006 provides long lasting and clinically meaningful pain reduction in moderate to severe OA.
Tapentadol
Opioid analgesics are already in use to relieve pain in severe OA. Tapentadol is a relatively novel opioid analgesic with dual mechanism of action. It is a mu opioid receptor agonist as well as noradrenaline reuptake inhibitor. It has a better side effect profile when compared to the conventional opioids (Merker et al. 2012). It is associated with
Table 1. Summary of recent drugs for OA
SUMMARY
Target Drugs Current status with respect to OA
Articular Aflapin Dietary supplement
cartilage Pycnogenol Dietary supplement
GSK2394002 Pre clinical studies - positive outcome
Sprifermin Phase 1 trial - positive outcome
GEC-TGF ß Phase 2 trial - positive outcome
BMP Pre clinical studies - positive outcome
MIV-711 Phase 2 trial - positive outcome
SM04690 Phase 2 trial - positive outcome
Bevacizumab Animal study - positive outcome
Diacerein Dietary supplement
Cindunistat Phase 2 trial - failed to show
positive outcome
Celecoxib Animal study - positive outcome
Etoricoxib Phase 4 trial - positive outcome
Inflammation Adalimumab Pilot study-positive outcome
Infliximab Pilot study-positive outcome
DLX105 Phase 2a trial - result yet to be published
Canakinumab Phase 2 trial - result yet to be published
Anakinra Phase 2 trial - positive outcome
Gevokizumab Phase 1 trial - result yet to be published
ABT-981 Phase 1 trial - positive outcome
Methotrexate Phase 3 trial - result yet to be published Polyphenols(EGCG, Animal studies - positive outcome curcumin)
Limonene, Myrcene In vitro studies-positive outcome Doubtful efficacy Phase 3 trial - positive outcome In vitro and Animal studies - positive outcome. May be particularly useful in osteoporotic OA
Pain Tanezumab Phase 3 trial - positive outcome
Duloxetine Phase 3 trial - positive outcome
FX006 Phase 3 trial - positive outcome
Tapentadol Phase 3 trial - positive outcome
Cannabidiol Animal study - positive outcome
Note: GEC-TGF ß - Genetically Engineered Chondrocytes expressing TGF-ß; BMP - Bone Morphogenic Protein; SERMs - Selective Estrogen Receptor Modulators; EGCG - Epigallocatechin gallate.
References
■ Belcaro G, Cesarone MR, Errichi S, Zulli C, Errichi BM, Vinci-guerra G, Ledda A, Di Renzo A, Stuard S, Dugall M, Pellegrini L, Errichi S, Gizzi G, Ippolito E, Ricci A, Cacchio M, Cipollone G, Ruffini I, Fano F, Hosoi M, Rohdewald P (2008) Treatment of osteoarthritis with Pycnogenol. The SVOS (San Valentino Osteo-arthrosis Study). Evaluation of signs, symptoms, physical performance and vascular aspects. Phytotherapy Research 22(4): 518-523. https://doi. org/10.1002/ptr.2376 [PubMed]
■ Bennell KL, Paterson KL, Metcalf BR, Duong V, Eyles J, Kasza J, Wang Y, Cicuttini F, Buchbinder R, Forbes A, Harris A, Yu SP, Con-nell D, Linklater J, Wang BH, Oo WM, Hunter DJ (2021) Effect of intra-articular platelet-rich plasma vs placebo injection on pain and medial tibial cartilage volume in patients with knee osteoarthritis: The restore randomized clinical trial. JAMA 326(20): 2021-2030. https://doi.org/10.1001/jama.2021.19415 [PubMed] [PMC]
■ Betz VM, Keller A, Foehr P, Thirion C, Salomon M, Rammelt S, Zwipp H, Burgkart R, Jansson V, Müller PE, Betz OB (2017) BMP-2 gene activated muscle tissue fragments for osteochondral defect regeneration in the rabbit knee. The Journal of Gene Medicine 19(9-10): e2972. https://doi.org/10.1002/jgm.2972 [PubMed]
lesser risk of constipation, somnolence and abuse liability. Phase 3 trial showed that tapentadol provides more superior pain relief for OA in comparison to oxycodone (Lange et al. 2017).
Cannabidiol (CBD)
A recent animal study investigated the safety and therapeutic potential of CBD for relieving arthritic pain and positive results were obtained. It was found that CBD significantly reduced the production of pro-inflammatory cytokines IL-6 and TNF-a while increasing the levels of anti-inflammatory cytokine, IL-10 (Verrico et al. 2020).
Platelet rich plasma
A recent trial evaluated the efficacy of intra-articular injection of platelet-rich plasma in osteoarthritis, but no satisfactory results were obtained with regard to improvement of knee pain or reduction of cartilage volume loss (Bennell et al. 2021). Novel drug delivery systems, like dendrimers, microspheres and solid lipid nanoparticles that ensure efficient intra-articular drug delivery, are now being investigated (Mao et al. 2021).
Conclusion
The need for new drugs that alter the disease progression of OA is increasing day by day. All investigational drugs for OA have been summarized in Table 1. Early diagnosis of OA and its management with a drug that retards disease progression rather than prescribing just a symptom reliever is very much necessary in the current situation. More clinical trials with larger sample sizes alone can satisfy the need of disease modifying drugs for OA.
■ Boileau C, Tat SK, Pelletier JP, Cheng S, Martel-Pelletier J (2008) Diacerein inhibits the synthesis of resorptive enzymes and reduces osteoclastic differentiation/survival in osteoarthritic subchondral bone: a possible mechanism for a protective effect against subchondral bone remodelling. Arthritis Research & Therapy 10(3): R71. https://doi.org/10.1186/ar2444 [PubMed] [PMC]
■ Bortoluzzi A, Furini F, Scirè CA (2018) Osteoarthritis and its management - Epidemiology, nutritional aspects and environmental factors. Autoimmunity Reviews 17(11): 1097-1104. https://doi. org/10.1016/j.autrev.2018.06.002 [PubMed]
■ Cheleschi S, Cantarini L, Pascarelli NA, Collodel G, Lucherini OM, Galeazzi M, Fioravanti A (2015) Possible chondroprotective effect of canakinumab: an in vitro study on human osteoarthritic chondrocytes. Cytokine 71(2): 165-172. https://doi.org/10.1016/j. cyto.2014.10.023 [PubMed]
■ Chen J, Li J, Li R, Wang H, Yang J, Xu J, Zha Z (2017) Efficacy and safety of tanezumab on osteoarthritis knee and hip pains: a meta-analysis of randomized controlled trials. Pain Medicine 18(2): 374-385. https://doi.org/10.1093/pm/pnw262 [PubMed]
Subchondral Bisphosphanates bone Strontium ranelate
SERMs
■ Cherian JJ, Parvizi J, Bramlet D, Lee KH, Romness DW, Mont MA (2015) Preliminary results of a phase II randomized study to determine the efficacy and safety of genetically engineered allogeneic human chondrocytes expressing TGF-ß1 in patients with grade 3 chronic degenerative joint disease of the knee. Osteoarthritis Cartilage 23(12): 2109-2118. https://doi.org/10.1016/jjoca.2015.06.019 [PubMed]
■ Chevalier X, Giraudeau B, Conrozier T, Marliere J, Kiefer P, Goupille P (2005) Safety study of intraarticular injection of inter-leukin 1 receptor antagonist in patients with painful knee osteoarthritis: a multicenter study. The Journal of Rheumatology 32(7): 1317-1323. https://pubmed.ncbi.nlm.nih.gov/15996071/ [PubMed]
■ Conaghan PG, Bowes MA, Kingsbury SR, Brett A, Guillard G, Jansson A (2018a) Six months' treatment with Miv-711, a novel cathepsin k inhibitor demonstrates evidence of osteoarthritis structure modification: results from a 6 month randomized double-blind placebo-controlled phase IIA trial. Osteoarthritis Cartilage 26: S25-S26. https://doi.org/10.1016/jjoca.2018.02.066
■ Conaghan PG, Hunter DJ, Cohen SB, Kraus VB, Berenbaum F, Lieberman JR, Jones DG, Spitzer AI, Jevsevar DS, Katz NP, Burgess DJ, Lufkin J, Johnson JR, Bodick N (2018b) Effects of a single in-tra-articular injection of a microsphere formulation of triamcinolone acetonide on knee osteoarthritis pain: a double-blinded, randomized, placebo-controlled, multinational study. Journal of Bone and Joint Surgery American Volume 100(8): 666-677. https://doi.org/10.2106/ jbjs.17.00154 [PubMed] [PMC]
■ Eckstein F, Wirth W, Guermazi A, Maschek S, Aydemir A (2015) Brief report: intraarticular sprifermin not only increases cartilage thickness, but also reduces cartilage loss: location-independent post hoc analysis using magnetic resonance imaging. Arthritis & Rheumatology 67(11): 2916-2922. https://doi.org/10.1002/art.39265 [PubMed] [PMC]
■ Fioravanti A, Fabbroni M, Cerase A, Galeazzi M (2009) Treatment of erosive osteoarthritis of the hands by intra-articular infliximab injections: a pilot study. Rheumatology International 29(8): 961-965. https://doi.org/10.1007/s00296-009-0872-0 [PubMed]
■ Goldring MB, Birkhead J, Sandell LJ, Kimura T, Krane SM (1988) Interleukin 1 suppresses expression of cartilage-specific types II and IX collagens and increases types I and III collagens in human chondrocytes. The Journal of Clinical Investigation 82(6): 2026-2037. https://doi.org/10.1172/jci113823 [PubMed] [PMC]
■ Hamilton JL, Nagao M, Levine BR, Chen D, Olsen BR, Im HJ (2016) Targeting VEGF and its receptors for the treatment of osteoarthritis and associated pain. The Journal of Bone and Mineral Research 31(5): 911-924. https://doi.org/10.1002/jbmr.2828 [PubMed] [PMC]
■ Hellio le Graverand MP, Clemmer RS, Redifer P, Brunell RM, Hayes CW, Brandt KD, Abramson SB, Manning PT, Miller CG, Vignon E (2013) A 2-year randomised, double-blind, placebo-controlled, multicentre study of oral selective iNOS inhibitor, cindunistat (SD-6010), in patients with symptomatic osteoarthritis of the knee. Annals of Rheumatic Diseases 72(2): 187-195. https://doi.org/10.1136/ann-rheumdis-2012-202239 [PubMed]
■ Kingsbury SR, Tharmanathan P, Arden NK, Batley M, Birrell F, Cocks K, Doherty M, Edwards CJ, Garrood T, Grainger AJ, Green M, Hewitt C, Hughes R, Moots R, O'Neill TW, Roddy E, Scott DL, Watt FE, Torgerson DJ, Conaghan PG (2015) Pain reduction with oral methotrexate in knee osteoarthritis, a pragmatic phase iii trial of treatment effectiveness (PROMOTE): study protocol for a randomized controlled trial. Trials 16: 77. https://doi.org/10.1186/ s13063-015-0602-8 [PubMed] [PMC]
■ Kraus VB, Birmingham J, Stabler TV, Feng S, Taylor DC, Moorman CT 3rd, Garrett WE, Toth AP (2012) Effects of intraarticular IL1-Ra for acute anterior cruciate ligament knee injury: a randomized controlled pilot trial (NCT00332254). Osteoarthritis Cartilage 20(4): 271-278. https://doi.org/10.1016/jjoca.2011.12.009 [PubMed]
■ Lane NE, Schnitzer TJ, Birbara CA, Mokhtarani M, Shelton DL, Smith MD (2010) Tanezumab for the treatment of pain from osteoarthritis of the knee. The New England Journal of Medicine 363(16): 1521-1531. https://doi.org/10.1056/nejmoa0901510 [PubMed] [PMC]
■ Lange B, von Zabern D, Elling C, Dubois C (2017) Efficacy and safety of tapentadol prolonged release for moderate-to-severe chronic osteoarthritis knee pain: a pooled analysis of two double-blind, randomized, placebo- and oxycodone controlled release-controlled studies. Current Medical Research and Opinion 33(8): 1413-1422. https://doi.org/10.1080/03007995.2017.1335188 [PubMed]
■ Larkin J, Lohr TA, Elefante L, Shearin J, Matico R, Su JL, Xue Y, Liu F, Genell C, Miller RE, Tran PB, Malfait AM, Maier CC, Matheny CJ (2015) Translational development of an ADAMTS-5 antibody for osteoarthritis disease modification. Osteoarthritis Cartilage 23(8): 12541266. https://doi.org/10.1016/jjoca.2015.02.778 [PubMed] [PMC]
■ Leong DJ, Choudhury M, Hanstein R, Hirsh DM, Kim SJ, Majeska RJ, Schaffler MB, Hardin JA, Spray DC, Goldring MB, Cobelli NJ, Sun HB (2014) Green tea polyphenol treatment is chondroprotec-tive, anti-inflammatory and palliative in a mouse post-traumatic os-teoarthritis model. Arthritis Research & Therapy 16(6): 508. https:// doi.org/10.1186/s13075-014-0508-y [PubMed] [PMC]
■ Lugo L, Villalvilla A, Largo R, Herrero-Beaumont G, Roman-Blas JA (2014) Selective estrogen receptor modulators (SERMs): new alternatives for osteoarthritis? Maturitas 77(4): 380-384. https://doi. org/10.1016/j.maturitas.2014.01.016 [PubMed]
■ Man GS, Mologhianu G (2014) Osteoarthritis pathogenesis - a complex process that involves the entire joint. Journal of Medicine and Life 7(1): 37-41. https://pubmed.ncbi.nlm.nih.gov/24653755/ [PubMed] [PMC]
■ Mao L, Wu W, Wang M, Guo J, Li H, Zhang S, Xu J, Zou J (2021) Targeted treatment for osteoarthritis: drugs and delivery system. Drug Delivery 28(1): 1861-1876. https://doi.org/10.1080/1071754 4.2021.1971798 [PubMed] [PMC]
■ Merker M, Dinges G, Koch T, Kranke P, Morin AM (2012) Unde-sired side effects of tapentadol in comparison to oxycodone. A me-ta-analysis of randomized controlled comparative studies. Schmerz 26(1): 16-26. https://doi.org/10.1007/s00482-011-1132-2 [PubMed]
■ Moore EE, Bendele AM, Thompson DL, Littau A, Waggie KS, Rear-don B, Ellsworth JL (2005) Fibroblast growth factor-18 stimulates chondrogenesis and cartilage repair in a rat model of injury-induced osteoarthritis. Osteoarthritis Cartilage 13(7): 623-631. https://doi. org/10.1016/j.joca.2005.03.003 [PubMed]
■ Moss P, Benson HAE, Will R, Wright A (2017) Fourteen days of etoricoxib 60 mg improves pain, hyperalgesia and physical function in individuals with knee osteoarthritis: a randomized controlled trial. Osteoarthritis Cartilage 25(11): 1781-1791. https://doi. org/10.1016/j.joca.2017.07.009 [PubMed]
■ Nagai T, Sato M, Kobayashi M, Yokoyama M, Tani Y, Mochida J (2014) Bevacizumab, an anti-vascular endothelial growth factor antibody, inhibits osteoarthritis. Arthritis Research & Therapy 16(5): 427. https://doi.org/10.1186/s13075-014-0427-y [PubMed] [PMC]
■ Nishii T, Tamura S, Shiomi T, Yoshikawa H, Sugano N (2013) Alendronate treatment for hip osteoarthritis: prospective randomized
2-year trial. Clinical Rheumatology 32(12): 1759-1766. https://doi. org/10.1007/s10067-013-2338-8 [PubMed]
■ Ou Y, Tan C, An H, Jiang D, Quan Z, Tang K, Luo X (2012) Selective COX-2 inhibitor ameliorates osteoarthritis by repressing apoptosis of chondrocyte. Medical Science Monitor 18(6): BR247-BR52. https://doi.org/10.12659/msm.882901 [PubMed] [PMC]
■ Pal CP, Singh P, Chaturvedi S, Pruthi KK, Vij A (2016) Epidemiology of knee osteoarthritis in India and related factors. Indian Journal of Orthopaedics 50(5): 518-522. https://doi.org/10.4103/0019-5413.189608 [PubMed] [PMC]
■ Pavelka K, Bruyère O, Cooper C, Kanis JA, Leeb BF, Maheu E, Martel-Pelletier J, Monfort J, Pelletier JP, Rizzoli R, Reginster JY (2016) Diacerein: Benefits, risks and place in the management of osteoarthritis. An opinion-based report from the ESCEO. Drugs & Aging 33(2): 75-85. https://doi.org/10.1007/s40266-016-0347-4 [PubMed] [PMC]
■ Reginster JY, Badurski J, Bellamy N, Bensen W, Chapurlat R, Chevalier X, Christiansen C, Genant H, Navarro F, Nasonov E, Sambrook PN, Spector TD, Cooper C (2013) Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: results of a double-blind, randomised placebo-controlled trial. Annals of the Rheumatic Diseases 72(2): 179-186. https://doi.org/10.1136/ann-rheumdis-2012-202231 [PubMed] [PMC]
■ Rufino AT, Ribeiro M, Sousa C, Judas F, Salgueiro L, Cavaleiro C, Mendes AF (2015) Evaluation of the anti-inflammatory, anti-catabolic and pro-anabolic effects of E-caryophyllene, myrcene and limonene in a cell model of osteoarthritis. European Journal of Pharmacology 750: 141-150. https://doi.org/10.1016/j.ejphar.2015.01.018 [PubMed]
■ Saviola G, Abdi-Ali L, Povino MR, Campostrini L, Sacco S, Dalle Carbonare L, Carbonare LD (2017) Intramuscular clodronate in erosive osteoarthritis of the hand is effective on pain and reduces serum COMP: a randomized pilot trial-The ER.O.D.E. study (ERosive Osteoarthritis and Disodium-clodronate Evaluation). Clinical Rheumatology 36(10): 2343-2350. https://doi.org/10.1007/s10067-017-3681-y [PubMed]
■ Sengupta K, Krishnaraju AV, Vishal AA, Mishra A, Trimurtulu G, Sarma KV, Raychaudhuri SK, Raychaudhuri SP (2010) Comparative efficacy and tolerability of 5-loxin (R) and aflapin (R) against osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. International Journal of Medical Sciences 7(6): 366-377. https://doi.org/10.7150/ijms.7.366 [PubMed] [PMC]
■ Sinusas K (2012) Osteoarthritis: diagnosis and treatment. American Family Physician 85(1): 49-56. https://pubmed.ncbi.nlm.nih. gov/22230308/ [PubMed]
■ Spector TD, Conaghan PG, Buckland-Wright JC, Garnero P, Cline GA, Beary JF, Valent DJ, Meyer JM (2005) Effect of risedronate on joint structure and symptoms of knee osteoarthritis: results of the BRISK randomized, controlled trial [ISRCTN01928173]. Arthritis Research & Therapy 7(3): R625-R633. https://doi.org/10.1186/ ar1716 [PubMed] [PMC]
■ Vaysbrot EE, Osani MC, Musetti MC, McAlindon TE, Bannuru RR (2018) Are bisphosphonates efficacious in knee osteoarthritis? A me-ta-analysis of randomized controlled trials. Osteoarthritis Cartilage 26(2): 154-164. https://doi.org/10.1016/jjoca.2017.11.013 [PubMed]
■ Verrico CD, Wesson S, Konduri V, Hofferek CJ, Vazquez-Perez J, Blair E, Dunner Jr K, Salimpour P, Decker WK, Halpert MM (2020) A randomized, double-blind, placebo-controlled study of daily can-nabidiol for the treatment of canine osteoarthritis pain. Pain 61(9): 2191-2202 https://doi.org/10.1097Zj.pain.0000000000001896 [PubMed] [PMC]
■ Wang G, Bi L, Li X, Li Z, Zhao D, Chen J, He D, Wang CN, Dueñas H, Skljarevski V, Yue L (2017a) Efficacy and safety of duloxetine in Chinese patients with chronic pain due to osteoarthritis: a randomized, double-blind, placebo-controlled study. Osteoarthritis Cartilage 25(6): 832-838. https://doi.org/10.1016/jjoca.2016.12.025 [PubMed]
■ Wang J (2018) Efficacy and safety of adalimumab by intra-articular injection for moderate to severe knee osteoarthritis: an open label randomized controlled trial. Journal of International Medical Research 46(1): 326-334. https://doi.org/10.1177/0300060517723182 [PubMed] [PMC]
■ Wang SX, Abramson SB, Attur M, Karsdal MA, Preston RA, Lozada CJ, Kosloski MP, Hong F, Jiang P, Saltarelli MJ, Hendrickson BA, Medema JK (2017b) Safety, tolerability, and pharmacodynamics of an anti-interleukin-1a/ß dual variable domain immunoglobu-lin in patients with osteoarthritis of the knee: a randomized phase 1 study. Osteoarthritis cartilage 25(12): 1952-1961. https://doi. org/10.1016/j.joca.2017.09.007 [PubMed]
■ Wang X, Manner PA, Horner A, Shum L, Tuan RS, Nuckolls GH (2004) Regulation of MMP-13 expression by RUNX2 and FGF2 in osteoarthritic cartilage. Osteoarthritis Cartilage 12(12): 963-973. https://doi.org/10.1016/jjoca.2004.08.008 [PubMed]
■ Wojtowicz-Praga S, Torri J, Johnson M, Steen V, Marshall J, Ness E, Dickson R, Sale M, Rasmussen HS, Chiodo TA, Hawkins MJ (1998) Phase I trial of Marimastat, a novel matrix metalloproteinase inhibitor, administered orally to patients with advanced lung cancer. Journal of Clinical Oncology 16(6): 2150-2156. https://doi.org/10.1200/ jco.1998.16.6.2150 [PubMed]
■ World Health Organization (2016) World Health Organization. http://www.who.int/chp/topics/rheumatic/en/
■ Yazici Y, McAlindon TE, Gibofsky A, Lane NE, Clauw DJ, Armas E (2018) Results from a 52-week randomized, double-blind, placebo-controlled, phase 2 study of a novel, intra-articular wnt pathway inhibitor (SM04690) for the treatment of knee osteoarthritis. Osteoarthritis Cartilage 26: S293-S294. https://doi.org/10.1016/j. joca.2018.02.589
■ Zhang Q, Lv Hh, Chen A, Liu F, Wu X (2012) Efficacy of inflix-imab in a rabbit model of osteoarthritis. Connective Tissue Research 53(5): 355-358. https://doi.org/10.3109/03008207.2012.661001 [PubMed]
■ Zhang Z, Leong DJ, Xu L, He Z, Wang A, Navati M, Kim SJ, Hirsh DM, Hardin JA, Cobelli NJ, Friedman JM, Sun HB (2016) Curcum-in slows osteoarthritis progression and relieves osteoarthritis-associ-ated pain symptoms in a post-traumatic osteoarthritis mouse model. Arthritis Research & Therapy 18(1): 128. https://doi.org/10.1186/ s13075-016-1025-y [PubMed] [PMC]
Author contributions
■ Muthu Meera, Assistant Professor, Department of Pharmacology, Velammal Medical College Hospital and Rease-arch Institute, e-mail: [email protected], ORCID ID https://orcid.org/0000-0002-7971-0528. The author came up with the idea of doing this review, collected all relevant articles, summarized and interpreted their findings.
