Journal of Ayurveda and Integrated Medical Sciences

Introduction

Osteoarthritis is the most prevalent form of arthritis, affecting millions of people worldwide. It is a degenerative joint disease characterized by the breakdown of articular cartilage and subchondral bone, leading to pain, stiffness and decreased mobility. This chronic condition primarily impacts the knees, hips, hands and spine; and its incidence increases with age.^[1] Several risk factors contribute to the development and progression of osteoarthritis:

Age: The risk of osteoarthritis increases with age due to cumulative joint wear and tear.

Gender: Women are more likely to develop osteoarthritis, particularly after menopause, suggesting a hormonal component.

Genetics: Family history and genetic predisposition play crucial roles in susceptibility to osteoarthritis.

Obesity: Excess body weight increases mechanical stress on weight-bearing joints and contributes to systemic inflammation.

Joint Injury: Previous joint injuries, such as fractures or ligament tears, can lead to secondary osteoarthritis.

Repetitive Stress: Occupations or activities involving repetitive joint stress can accelerate cartilage wear.

Epidemiology

Osteoarthritis most frequently occurs after age 30 years and prevalence increases steeply with age. Globally, 595 million people had osteoarthritis in 2020, equal to 7.6% of the global population. Compared with 2020, cases of osteoarthritis are projected to increase 74.9% for knee, 48.6% for hand, 78.6% for hip, and 95.1% for other types of osteoarthritis by 2050.^[2]

About 73% of people living with osteoarthritis are older than 55 years and 60% are females. With a prevalence of 365 million, the knee is the most frequently affected joint, followed by the hip and the hand. 344 million people living with osteoarthritis experience moderate or severe symptoms. With ageing populations and increasing rates of obesity and injury, the prevalence of osteoarthritis is expected to continue to increase globally.^[3]

Non-pharmacologic Therapies: Physical therapy, weight management and assistive devices.

Pharmacologic Therapies: Analgesics, nonsteroidal anti-inflammatory drugs (NSAIDs), COX-2 inhibitors and intra-articular corticosteroid injections.

Surgical Interventions: In advanced cases, joint replacement surgery may be considered.

In general, oral and topical NSAIDs, including COX-2 inhibitors, are strongly recommended first-line treatments for osteoarthritis due to their ability to improve pain and function but are associated with increased risks in patients with certain comorbidities (e.g., heightened cardiovascular risks). Intra-articular corticosteroid injections are generally recommended for osteoarthritis management and have relatively minor adverse effects. Other treatments, such as capsaicin, tramadol, and acetaminophen, are more controversial, and many updated guidelines offer differing recommendations.^[4]

Patients with osteoarthritis do not have access to a remedy that cures the degenerative changes to stop the recurrence of pain. Current therapeutics possess certain drawbacks, including the frustration of the patients due to the intolerance, non-adherence, ineffectiveness of drugs and possible side-effects. Studies have suggested a link between NSAIDs administration and inhibition of bone healing. NSAIDs seem to affect the transition phase of mesenchymal stem cells towards functional chondrocytes by inhibiting the expression of key molecules like TGF-β3.^[5]

There is a lack of an effective and long-term treatment plan in the fight against osteoarthritis. There is a great need for the continuous development of new, safe and effective treatment of osteoarthritis. Among the many active compounds that have been studied for the treatment of osteoarthritis, extracts from plants and specific phyto-chemicals from natural resources have been of great interest in recent decades. Several studies evaluating osteoarthritis therapy based on natural sources revealed potential activity, especially in reduction of pain, stiffness and cartilage loss as well as improvement in physical function. Natural substances, in comparison with medicament, do not cause such adverse effects, which is the positive side of their use.

individuals who are unlikely to comply with study protocols or follow-up visits were excluded. Individuals with any other condition or circumstance that, in the judgment of the investigator, would make the participant unsuitable for participation in the study were excluded. Patients could be withdrawn from the study at their own request or if they experience intolerable adverse events, show insufficient therapeutic effect, or needed deviations from the protocol at the discretion of the investigator.

Study Design

A non-randomized phase 4, prospective open label clinical trial in 70 patients diagnosed with osteoarthritis was planned following required GCP guidelines. After careful selection in terms of the eligibility criteria, screened subjects willing to enroll after explaining the clinical study procedure were requested to sign the Patient Consent Form.

At baseline visit (0 day), Patient information sheet was provided to each subject in their language of preference. Case record form (CRF) was filled by the attending physician with complete medical history and required personal details of the subject at the start of the study. A thorough physical examination and necessary laboratory investigations were carried at baseline (0 day) and after completion of treatment (90 days).

Safety and efficacy evaluation of patients' clinical response to treatment was monitored from baseline till end of 90 days. All data were carefully entered in the Case Record Form provided. Side-effects were closely monitored in all patients. All adverse events were recorded by the investigator, and rated for severity and relationship to the study medication.

Clinical assessments

The patients were evaluated at baseline and 90 days after onset of treatment. Efficacy was evaluated on the basis of improvement in knee flexion, quadriceps and hamstring muscle strength, 6-minute walk test score, European Q5D quality of life; reduction in knee swelling, pain intensity, WOMAC-pain, stiffness and physical function score and VAS pain scale. The Physician global assessment and Patient’s global assessment (at end of the study) on efficacy and tolerability were made on a scale of 1- 5, namely, Excellent = 5, Good = 4, Fair = 3, Poor = 2 and Very Poor = 1.

Table 3 & 4 shows laboratory findings and vital parameters of patients before and after treatment, respectively. Treatment with the Rymanyl Tablets did not lead to any abnormalities in the laboratory investigations and vital parameters as compared to the baseline values, reflecting its safety in knee osteoarthritis. Patients tolerated Rymanyl Tablets without any adverse events that needed discontinuation.

Table 3: Laboratory Safety Parameters

Table 4: Vital Parameters

Table 5 shows Global assessment of response by Physicians and Patients respectively after 90 days of treatment with Rymanyl Tablets.

These findings confirm the efficacy of Rymanyl Tablets in the study population during the study period.

Discussion

Chronic pain is a major concern among people with osteoarthritis and can hinder a patient's quality of life, physical function and mental well-being. While no approved disease modifying therapies exist,

pain management for individuals with OA is an evolving field. The management of osteoarthritis mostly involves targeting matrix-degrading proteases or senescent chondrocytes, promoting cartilage repair or limiting bone remodelling and local lowgrade inflammation.^[6]

Notably, while many commonly administered NSAIDs have low rates of toxicity in controlled clinical trials, the strength of associations with adverse events are typically larger in observational studies. Oral NSAIDs are associated with toxicity involving gastro-intestinal, cardio-vascular and renal systems. Despite their potential for toxicity, oral NSAIDs remain the most frequently used pharmaceutical treatment for OA-related pain.^[7]

The ongoing development of new agents, especially from natural plant/phyto source will provide additional management options, which in turn motivates discussion on how best to incorporate them into current treatment algorithms. Diverse approaches are recommended to manage osteoarthritis such as lifestyle modifications, diet intervention and pharmacotherapy. Despite the worldwide use of NSAIDs, their long-term efficacy is still questionable.

Consequences of these drugs are arguable, due to their numerous adverse effects. Traditional herbal medicine represents an alternative and complementary approach for managing osteoarthritis because of its low toxicity and beneficial effects, such as anti-inflammatory and antioxidant effects. Recently, there is a tremendous awareness in patients and physicians to manage osteoarthritis with natural extracts. Large number of studies performed on the efficacy and safety of natural products, showed significant improvement in osteoarthritis outcomes. Medicinal formulations have shown promising effects in reducing pain and consequently improving function, making them new therapeutic options.^[8]

Agnuside (AGN), a nontoxic, natural small molecule isolated from the extract of Vitex negundo L. (Verbenaceae), has been demonstrated to have antioxidant, anti-inflammatory, analgesic and many other properties. AGN alleviates synovitis and fibrosis in experimental KOA through the inhibition of HIF-1α accumulation and NLRP3 inflammasome activation.^[13]

communis is widely distributed globally and is rich in bioactive phytoconstituents with multifaceted therapeutic roles. It modulates numerous inflammatory and biochemical markers and highlights its potential in the management of nociception and inflammation.^[14]

Root extracts of Withania somnifera are known to possess analgesic, anti-inflammatory and chondro-protective effects. A study evaluated efficacy and tolerability of a standardized aqueous extract of roots plus leaves of W. somnifera in patients with knee joint pain and discomfort. At the end of 12 weeks, compared to baseline and placebo, significant reductions were observed in mean Modified WOMAC and Knee Swelling Index (KSI) with W. somnifera (250 and 125 mg) groups. Visual Analogue Scale (VAS) scores for pain, stiffness and disability were significantly reduced in W. somnifera (250 and 125 mg) groups. W. somnifera 250 mg group showed earliest efficacy at 4 weeks.^[15]

Conclusion

The present interventional study indicates that Rymanyl Tablets are effective and safe in controlling signs and symptoms of knee osteoarthritis. There were no clinically significant adverse events either reported or observed during the entire study period. The overall compliance with the treatment was good and no treatment discontinuations were reported. Rymanyl Tablets typically improve knee flexion, quadriceps and hamstring muscle strength, walking capacity, overall physical function and quality of life as well as reduce knee swelling, intensity of pain and stiffness. Rymanyl Tablets aim at reducing the symptoms of osteoarthritis with an alternative approach to reduce further cartilage damage.

Cost of Study: All medications required during the 90 days of trial were provided by the sponsor. Charak Pharma Pvt. Ltd. reserves all rights over any publications of the study during the course and post completion.

9. Kalpana Patel, SVVS Ravi Mangu, Shinde Vijay Sukhdeo, Kunal Sharan, Ethanolic extract from the root and leaf of Sida cordifolia promotes osteoblast activity and prevents ovariectomy-induced bone loss in mice, Phytomedicine, Volume 99, 2022, 154024, ISSN 0944-7113, https://doi.org/10.1016/j.phymed.2022.154024.

10. Pallavi S. Nirmal, Suresh D. Jagtap, Prasad P. Devarshi, Aarti N. Narkhede, Soumya J. Koppikar, Dhanashri R. Ingale, Abhay M. Harsulkar; Cartilage protective effect of Sida cordifolia L. and Piper longum L. is through modulation of MMPs and TIMP; International Journal of Advanced Research (2015), Volume 3, Issue 11, 480 – 488

11. Nirmal, P.S., Jagtap, S.D., Narkhede, A.N. et al. New herbal composition (OA-F2) protects cartilage degeneration in a rat model of collagenase induced osteoarthritis. BMC Complement Altern Med 17, 6 (2017). https://doi.org/10.1186/s12906-016-1535-9

12. Ban, Y., Wang, Y., Qiao, L., Zhang, C., Wang, H., He, X., Jia, D., & Zheng, C. (2023). Total lignans from Vitex negundo seeds attenuate osteoarthritis and their main component vitedoin A alleviates osteoclast differentiation by suppressing ERK/NFATc1 signaling. Phytotherapy Research, 37(4), 1422–1434. https://doi.org/10.1002/ptr.7750

13. Zhang, Li, Li, Xiaochen, Zhang, Haosheng, Huang, Zhengquan, Zhang, Nongshan, Zhang, Li, Xing, Runlin, Wang, Peimin, Agnuside Alleviates Synovitis and Fibrosis in Knee Osteoarthritis through the Inhibition of HIF-1α and NLRP3 Inflammasome, Mediators of Inflammation, 2021, 5534614, 11 pages, 2021. https://doi.org/10.1155/2021/5534614

14. Gupta, R., Chaudhary, A.K. & Sharma, R. Analgesic and Anti-inflammatory Potential of Ricinus communis: Evidence from Pharmacology to Clinical Studies. Curr. Pharmacol. Rep. 10, 27–67 (2024). https://doi.org/10.1007/s40495-023-00347-7

15. G.S.H. Ramakanth, C. Uday Kumar, P.V. Kishan, P. Usharani; A randomized, double blind placebo controlled study of efficacy and tolerability of Withaina somnifera extracts in knee joint pain; Journal of Ayurveda and Integrative Medicine; Volume 7, Issue 3, 2016, Pages 151-157; ISSN 0975-9476; https://doi.org/10.1016/j.jaim.2016.05.003.