Therapeutic potential of Cissus quadrangularis Linn. (Veld Grape) in osteoporosis and arthritis: A scoping review of preclinical evidence

INTRODUCTION

Bone-related disorders encompass a wide spectrum of conditions that significantly impact an individual’s quality of life. These include osteoporosis, arthritis, Paget’s disease, osteonecrosis, bone cancer, rickets, scoliosis, and gout, affecting millions worldwide [1]. In India, osteoporosis and arthritis are the most prevalent, with osteoporosis showing a higher incidence among the elderly and postmenopausal women [2]. According to the World Health Organization, 30% of postmenopausal women globally suffer from osteoporosis. Reports indicate that in India, 61 million individuals are affected, with women comprising 80% of cases. Notably, osteoporosis manifests 10–20 years earlier in the Indian population compared to Western countries, posing a significant public health and economic burden [3]. Osteoporosis, a metabolic bone disorder, is characterized by impaired microarchitecture, reduced bone mineral density (BMD), trabecular thinning, cortical deterioration, and increased porosity [4]. It is classified into primary and secondary forms, with primary osteoporosis further subdivided into age-related and postmenopausal types [5,6]. Secondary osteoporosis, on the other hand, arises from underlying medical conditions or medications that impair bone regeneration [7]. In both sexes, hypogonadism accelerates bone loss and increases fracture risk [8]. Additionally, genetic variations, such as mutations in the vitamin D receptor gene, influence bone metabolism and susceptibility to osteoporosis [9]. The pathophysiology of osteoporosis revolves around dysregulated bone remodeling, a dynamic process essential for maintaining skeletal integrity. Similarly, arthritis, a group of inflammatory conditions primarily affecting the joints, disrupts normal joint homeostasis, leading to pain, stiffness, swelling, and restricted mobility. The most prevalent form is osteoarthritis, characterized by cartilage degeneration, while rheumatoid arthritis represents a secondary autoimmune-driven variant [10,11].

Psoriatic arthritis is associated with the skin disorder psoriasis [12], whereas gout results from uric acid crystal deposition in joints [13]. Juvenile idiopathic arthritis manifests as chronic arthritis in young individuals [14]. Furthermore, obesity has been strongly correlated with the onset and progression of arthritis, particularly osteoarthritis [15]. In addition, smoking has been identified as a significant risk factor for the development and progression of rheumatoid arthritis [16]. It is fundamental to possess a more profound understanding of the pathophysiology of arthritis so as to develop targeted treatment methods. When the immune system attacks the synovium, B cells and T cells become activated, and enzymatic mediators like cyclooxygenase and 5-lipoxygenase (5-LOX) are elevated in the inflammatory synovium [11]. The bone is renovated, and osteophytes appear as a result of the cartilage’s degradation, which reveals the underlying bone [17]. The management of osteoporosis remains challenging due to underdiagnosis, inadequate risk assessment, and high treatment costs, which limit accessibility to effective therapies [18]. While rheumatoid arthritis and gout are less common, osteoarthritis affects approximately 22% of the population. The lack of awareness, delayed diagnosis, and absence of standardized treatment protocols further hinder arthritis management [19]. Existing pharmacological interventions, such as bisphosphonates and hormone replacement therapy, have potential adverse effects, underscoring the need for alternative therapeutic strategies. Traditional medicinal plants with pharmacological properties may serve as promising interventions for bone health [20].

One such plant is Cissus quadrangularis Linn (CQ), which features four-winged internodes on a fleshy, fibrous stem. Known for its antioxidant and antibacterial properties, CQ is rich in calcium, phosphorus, and anabolic steroidal compounds, contributing to bone metabolism and regeneration [21].

Numerous phytochemical investigations of CQ have identified a wide spectrum of bioactive constituents, including carbohydrates, proteins, lipids, ascorbic acid, alkaloids, saponins, glycosides, triterpenoids, phytosterols, tannins, and flavonoids. The aerial stem has been reported to contain both primary metabolites (cyclic and acyclic fatty acids, methyl esters, iridoids, amino acids, gums, and mucilages) and secondary metabolites (alkaloids, flavones, saponins, steroids, stilbenes, cardiac glycosides, carotene, and ascorbic acid). The underground parts share many of these compounds, though typically lack vitamins, proteins, and fatty acids. Traditionally, CQ is known for its fracture-healing and analgesic properties. Additionally, its extracts exhibit antioxidant, antibacterial, antifungal, and anti-hemorrhoidal activities [22]. This review aims to critically evaluate the therapeutic potential of CQ in the management of osteoporosis and arthritis, with a focus on its mechanisms of action, effective dosage ranges, and long-term efficacy as evidenced by in vivo studies.

Addressing osteoporosis and arthritis, especially within the Indian context, is critical. Given CQ’s multifaceted benefits—enhanced bone regeneration, improved fracture healing, reduced fracture risk, joint tissue protection, and alleviation of pain and inflammation—its integration into mainstream healthcare warrants exploration. This review seeks to bridge the gap between traditional medicine and modern therapeutic strategies by elucidating CQ’s medicinal properties and potential clinical applications with the aim of understanding CQ’s role in bone health, highlighting its potential as a natural therapeutic agent for osteoporosis and arthritis management.

The phytochemicals present in CQ demonstrate significant therapeutic potential in managing bone-related disorders. Understanding the mechanisms by which these phytonutrients influence bone metabolism is critical, predominantly their interaction with key cellular signaling pathways. These include RANKL-OPG, estrogen, MAPK, inflammatory response, Wnt, calcium, and bone morphogenetic protein (BMP) pathways, all of which regulate gene expression essential for bone remodeling. Vital to this process is the NF-κB pathway, comprising RANK, its ligand RANKL, and the decoy receptor OPG, which together maintain bone homeostasis. Osteoblast differentiation is principally governed by RUNX2, a transcription factor that modulates osteogenic markers such as collagen type I, alkaline phosphatase (ALP), osteopontin, osteocalcin, and bone sialoproteins. RUNX2 expression is, in turn, upregulated by BMP, TGF-β, IGF, and Wnt signaling, promoting osteoblast maturation. Increased ALP activity during this process further reflects active bone metabolism [23].

Osteoporosis results from excessive bone resorption surpassing bone formation, principally driven by RANKL-RANK interactions that stimulate osteoclast activity and pro-inflammatory cytokine release tumor necrosis factor-alpha (TNF-α, IL-1, and IL-7), along with OPG downregulation. Osteoblast differentiation is regulated by signaling pathways such as Wnt, PTH, BMPs, and FGF. In postmenopausal women, estrogen deficiency disturbs bone homeostasis, further aggravated by oxidative stress, raised homocysteine, and reduced folate and SOD levels. Conventional therapies (e.g., bisphosphonates, PTH analogs, and calcitonin) stimulate bone formation but carry risks of adverse effects and cost-related barriers. In contrast, herbal medicines offer a promising, potentially safer alternative for managing osteoporosis and osteoarthritis [24].

Figure 1 presents a schematic representation of bone remodeling, highlighting key regulatory mechanisms [25]. The RANK/RANKL/OPG signaling pathway, which governs osteoclast differentiation and activation, is disrupted in osteoporosis, leading to excessive bone resorption. Additionally, impairment of the β-catenin signaling pathway compromises optimal osteoblast function, further contributing to bone loss [8].

Figure 1. Schematic representation of bone remodelling cycle. [Click here to view]

Botanical profile and traditional uses of CQ

CQ, or Veldt grape, belongs to the Vitaceae family. Table 1 depicts the scientific classification of CQ [26]. It is an uncultivated and fast-growing succulent plant with tendrils. It is native to India, Bangladesh, and Sri Lanka, and is found in Africa. Figure 2 shows the distribution of CQ based on data from the CABI Digital Library, indicating its native regions in green and countries of introduction in pink.

Table 1. Scientific classification of CQ. [Click here to view]

Figure 2. Geographical distribution of CQ, showing its native range (green) and introduced regions (pink). Source: CABI Digital Library [28] . [Click here to view]

The name “quadrangularis” is owing to the distinctive characteristic quadrangular shape of the stem, which is visible in Figure 3, which shows the foliage and stem of CQ [27,28]. It belongs to arid habitats and subtropical areas with low rainfall and high temperatures. Its common English name is ‘Veldt grape’. Different parts of the CQ plant are used as medicines. Traditionally, CQ is known as a bonesetter, and is used for bone regeneration and for skin infections [29]. Every part of the plant has its own unique therapeutic analgesic, antioxidant, anti-inflammatory, and anti-microbial applications. As a general tonic, it was used in folk medicine for joint pain, fractures, and osteoporosis [29,30].

Figure 3. Foliage and stem of CQ. Source: CABI Digital Library [27] . [Click here to view]

METHODOLOGY

Data screening and extraction

Data screening and selection were conducted using a systematic approach that ensured a streamlined and transparent review process. Two authors independently screened the abstracts, followed by a full-text evaluation of studies that met the inclusion criteria. A PRISMA flow diagram was used to depict study selection, illustrating the number of records identified, screened, included, and excluded at each stage. Key variables, including dosage, administration route, and outcome measures, were extracted and synthesized to assess CQ efficacy in bone health management. This approach ensured a structured evaluation of the available evidence, highlighting gaps and future research directions. Figure 4 displays the PRISMA flow diagram of the study selection process.

Figure 4. PRISMA flow diagram of the study selection process. [Click here to view]

RESULTS

A total of 294 studies were initially identified through database searches. After the removal of 142 duplicates, 151 unique studies remained for screening. Following a title and abstract assessment, 113 studies proceeded to full-text review. Based on the predefined selection criteria, 28 studies were included, while 72 were excluded. Among the selected studies, 18 focused on osteoporosis, and 10 specifically addressed arthritis. The subsequent tables synthesize the extracted data to align with the objectives of this review. Table 2 provides a detailed analysis of osteoporosis studies, including those that evaluate long-term effects. While, Table 3 summarizes the therapeutic effects of CQ on arthritis, detailing its mechanisms of action, effective dosages, long-term impacts, and comparative efficacy with standard treatments.

Table 2. Effects of CQ on osteoporosis: dosages, mechanism, impact, and long-term outcomes. [Click here to view]

Table 3. Summary of CQ effects on arthritis: mechanisms, dosages, long-term impact, and comparisons with standard treatments. [Click here to view]

Table 4 outlines the pharmacological activities of CQ emphasizing its bioactive components and their therapeutic roles. Complementing this, Figures 5–7 illustrates the chemical structures of these key bioactive compounds, providing a visual representation of their molecular composition [60–62]. Additionally, Table 5 presents the classical formulations of CQ highlighting its traditional medicinal applications.

Table 4. Pharmacological activities of CQ: bioactive components, mechanisms and therapeutic implications. [Click here to view]

Figure 5. Chemical structure of bioactive component of CQ: ascorbic acid. [Click here to view]

Figure 6. Chemical structure of bioactive component of CQ: Lupeol. [Click here to view]

Figure 7. Chemical structure of bioactive component of CQ: beta-sitosterol. [Click here to view]

Table 5. Classical and contemporary formulations of CQ: therapeutic potential and pharmacological insights. [Click here to view]

DISCUSSION

CQ has been shown through a literature review to possess anti-inflammatory, bone-healing, and bone-mineral density properties that help manage bone illnesses like osteoporosis and arthritis [49]. The anabolic steroid from the CQ plant showed a marked influence on the rate of fracture healing by the early generation of all connective tissue [67].

The therapeutic effects of CQ in treating bone diseases have been well-recognized in ancient Indian traditional medicine [68]. Traditionally, in folk as well as Ayurvedic medicine, its extracts were used as oral and topical applications to treat fractures and sprains, to speed up the healing process. The studies brief in Table 2 provide substantial evidence for the anti-osteoporotic potential of CQ through several mechanisms of action. The therapeutic effects of CQ cannot solely be attributed to individual phytoconstituents but are likely a result of synergistic interactions among flavonoids, triterpenoids, and steroidal compounds, enhancing bioavailability and biological activity beyond what isolated constituents achieve. The extracts of CQ, prepared using diverse solvents such as acetone, ethanol, ethyl acetate, butanol, hexane, and petroleum ether, have been examined for their impact on bone health. CQ has confirmed its efficacy in osteoporosis management by inhibiting osteoclastogenesis, reducing bone resorption, and stimulating osteoblast differentiation and mineralization. The acetone extract demonstrated anti-inflammatory effects through COX-2 and LOX-5 inhibition, while ethanolic and ethyl acetate extracts efficiently inhibited osteoclastogenesis and enhanced osteoblast activity, assisting bone regeneration. Predominantly, the petroleum ether extract showed steroid-like phytoestrogenic activity, which amended bone mineralization and strength, similar to the standard anti-osteoporotic drug raloxifene. Likewise, a phytoestrogen-rich fraction (IND-HE) improved estrogen levels, mirroring the beneficial effects of estradiol on bone density and thickness. Prominently, the long-term safety of CQ was emphasized in select studies, where no cytotoxic effects or conflicting changes in body weight were observed, indicating its potential as a safe therapeutic intervention [52]. The downregulation of osteoclast markers and the modulation of key signaling pathways, such as BMP and Wnt, further back its role in bone healing and protection. However, some studies lacked data on long-term effects and standard drug comparisons, necessitating further investigation into CQ’s sustained efficacy and clinical significance. The fundamental concept of these research studies is that the plant contains unidentified anabolic steroids that work by binding to the bone’s estrogenic receptor. The plant’s ability to promote early bone ossification and remodeling can also improve metabolism and osteoblasts’ rapid uptake of minerals such as calcium, sulfur, and strontium [22].

Overall, the findings strengthen CQ’s potential as a natural alternative for osteoporosis management. Upcoming studies should focus on clinical trials to establish optimal dosages, long-term effects, and comparative efficacy besides the conventional osteoporosis treatments. The studies summarized in Table 3 highlight the credibility of CQ in managing arthritis through various bioactive extracts. The ethanol, methanol, and aqueous extracts of CQ demonstrated significant anti-arthritic activity by inhibiting protein denaturation and regulating autoantigen production. Notably, CQ showed a higher inhibition rate (98.44%) compared to diclofenac sodium (94.22%), signifying its robust anti-inflammatory potential. Furthermore, CQ stem extract (CQSE) and hydroalcoholic extract (CQHE) contributed to osteoarthritis management by conserving collagen and proteoglycan stability in cartilage, suppressing matrix metalloproteinase (MMP-2 and MMP-9), and encouraging cartilage regeneration. CQSE displayed better cartilage remodeling compared to naproxen, suggesting its therapeutic advantage. Moreover, long-term administration of CQHE did not modify physiological parameters in animal models, reinforcing its safety for sustained use [59]. Overall, these findings suggest that CQ holds anti-inflammatory and chondroprotective properties, making it a likely natural alternative for arthritis management. Further clinical studies are essential to establish its optimal dosage, long-term efficacy, and comparative benefits over standard pharmacological treatments. The pharmacological activities of CQ are accredited to its bioactive components, which play a crucial role in bone health and arthritis management. For osteoporosis, β-Sitosterol has established significant osteoprotective properties by enhancing bone formation, exerting estrogenic effects, and inhibiting bone resorption [33,63]. These mechanisms contribute to enhanced BMD, making it beneficial for osteoporosis prevention and management. Additionally, vitamin C plays a critical role in bone metabolism by supporting collagen synthesis and promoting mineral deposition in the bone matrix, further reinforcing its anti-osteoporotic potential. Regarding arthritis, Lupeol, a key bioactive compound, has revealed strong anti-inflammatory effects by effectively binding to TNF receptors, which are involved in the inflammatory response. It also provides cartilage protection and reduces oxidative stress, thereby preventing the progression of arthritis. Overall, the presence of these bioactive components in CQ highlights its therapeutic potential in managing osteoporosis and arthritis [41]. More in-depth studies are required to discover their precise mechanisms, clinical efficacy, and long-term benefits in human populations. Various formulations have been developed, integrating CQ with other bioactive herbal components to enhance its efficacy.

These bone-strengthening formulations, incorporate CQ along with a combination of herbal and mineral ingredients traditionally used to support bone health. These include Hen Eggshell Ash—rich in calcium carbonate, Lac Resin, Indian Bdellium, and Arjuna Tree Bark (Terminalia arjuna) among others. These formulations have demonstrated osteoprotective effects, particularly in postmenopausal osteoporosis, by enhancing bone remineralization and density [63]. The sustained-release tablet (SRT) formulation, which includes CQ along with Water chestnut, Cassia uniflora, and Boswellia serrata, has been developed to provide prolonged anti-inflammatory and anti-arthritic effects. This formulation efficiently reduces inflammation, making it a promising option for arthritis management [59]. Likewise, there are polyherbal preparations that combine CQ with Lac resin, Indian Ginseng, Country Mallow, and Arjun Tree Bark, all known for their bone-strengthening properties. Such formulations have shown efficacy in improving BMD, reinforcing its role in osteoporosis and arthritis treatment [56]. Furthermore, the dried CQSE has demonstrated anti-arthritic activity by decreasing pro-inflammatory cytokines, supporting its use in inflammatory joint conditions [66]. These formulations underline the pharmacological versatility of CQ in skeletal health and inflammatory disorders. Future research should focus on clinical validation, optimized dosages, and long-term safety to enhance its therapeutic applications.

The literature has suggested CQ’s effectiveness in bone regeneration and pain alleviation as a valuable remedy in traditional medical practices [57]. To enhance the exploration and integration of traditional knowledge concerning CQ into clinical practice, its standardized plant extracts are being incorporated into formulations for nutraceuticals and dietary supplements that target bone health [68]. It clearly shows the potential to enhance bone formation, implying that it might prevent the loss of bone mass and the possibility of fractures. In line with a collaborative study of results focusing on both diseases, CQ has shown effects similar to those of typical synthetic medicines in terms of efficacy [48]. Furthermore, one research study on CQ-fortified raw rice and rice flour demonstrated promising effects on osteoporosis and osteoarthritis that have been documented. The increased content of CQ fortificant in the products enhanced BMD, decreased systemic inflammation, and averted articular degeneration and micro-architectural damages in experimental models of osteoporosis and osteoarthritis. The results imply that dietary modifications can be vital in preventing and managing bone-related disorders [68].

Although CQ is linked to therapeutic benefits through compounds like β-sitosterol, lupeol, and vitamin C, its precise molecular mechanisms remain inadequately understood. Most studies lack dose-response data and direct validation of these bioactives in bone or joint tissues, highlighting a major gap in phytopharmacological evidence.

Key knowledge gaps include the absence of standardized phytochemical profiling, limited pharmacokinetic and pharmacodynamics data, inadequate dose-response and long-term safety evidence, and few comparative studies with standard treatments like bisphosphonates or NSAIDs. Future research should focus on isolating active constituents via bioassay-guided fractionation and validating mechanisms using pathway-specific models while also conducting clinical trials to assess efficacy, safety, and dosing. Until more robust evidence emerges, CQ should be viewed as a complementary therapy. Its use in functional foods or nutraceuticals such as CQ-fortified rice may offer preventive benefits in bone health, as early in vivo studies indicate.

CONCLUSION

In conclusion, this review revealed the potential pharmacological actions of CQ for its diverse bioactive components, classical formulations, mechanisms of action, dosages, and impacts in managing osteoporosis and arthritis. Vitamin C and β-sitosterol prevent osteoporosis by promoting bone formation and inhibiting resorption. Lupeol’s anti-arthritic qualities include reduced inflammation, cartilage protection, and immune regulation. Bone-strengthening herbal supplements containing CQ, SRT, polyherbal formulations, and Stem Powder have all been shown to promote joint health and lower pro-inflammatory cytokines.

In animal models, the CQ dosage of 200 mg/kg body weight to 400 mg/kg body weight was found effective in managing the ailments.

Despite its promising pharmacological profile, further clinical studies are necessary to establish standardized dosages, evaluate long-term effects, and ensure safety for therapeutic use. Future research should focus on clinical validation, mechanistic insights, and formulation optimization to fully harness the medicinal potential of CQ in musculoskeletal disorders.

ACKNOWLEDGMENT

The authors would like to thank Ms. Anushthi Singh and Ms. Surabhi Singh Yadav for their support during the preparation of the manuscript.

AUTHOR CONTRIBUTIONS

All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; took part in drafting the article or revising it critically for important intellectual content; agreed to submit to the current journal; gave final approval of the version to be published; and agree to be accountable for all aspects of the work. All the authors are eligible to be an author as per the International Committee of Medical Journal Editors (ICMJE) requirements/guidelines.

FINANCIAL SUPPORT

There is no funding to report.

CONFLICT OF INTEREST

The authors report no financial or any other conflicts of interest in this work.

ETHICAL APPROVALS

This study does not involve experiments on animals or human subjects.

DATA AVAILABILITY

All data generated and analyzed are included in this research article.

PUBLISHER’S NOTE

All claims expressed in this article are solely those of the authors and do not necessarily represent those of the publisher, the editors and the reviewers. This journal remains neutral with regard to jurisdictional claims in published institutional affiliation.

USE OF ARTIFICIAL INTELLIGENCE (AI)-ASSISTED TECHNOLOGY

The authors declares that they have not used artificial intelligence (AI)-tools for writing and editing of the manuscript, and no images were manipulated using AI.

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