Ketosterones

Ketosterones (Ketosteroids from Cissus quadrangularis): A Comprehensive Reference

1. Identity and Nomenclature

Chemical Definition

"Ketosteroids" — also spelled "ketosterones" in the supplement industry — are a subclass of steroids that contain a ketone group (a carbonyl group, C=O) at one or more positions in the steroid skeleton. The steroid skeleton, known as the sterane core, is a tetracyclic structure consisting of three six-membered rings (A, B, and C) and one five-membered ring (D). The positions at which the ketone group can be located include carbons 1, 2, 3, 4, 6, 7, 11, 12, 15, 16, 17, and 20. The presence of a ketone group at these positions can significantly alter the biological activity of the steroid molecule. More precisely, a ketosteroid (or oxosteroid) is a steroid in which a hydrogen atom has been replaced with a ketone (C=O) group.

In the context of dietary supplements and nutraceuticals, the term "ketosterones" (or "3-ketosteroids") refers specifically to the phytosterol fraction found in Cissus quadrangularis that is standardized and quantified for commercial extract preparations. Ketosterones are plant sterols, a type of phytochemical. The primary compound of commercial interest is designated 3-ketosterone (also written 3-ketosteroid), reflecting the position of the carbonyl group at carbon-3 of the sterane skeleton.

Botanical Source

Cissus quadrangularis is extracted from a vine in the grape family that grows in Africa, Southeast Asia, and India. Cissus quadrangularis (synonyms: Vitis quadrangularis Wall. ex Wight; family: Vitaceae) is a long fleshy climber with jointed stem, leaf, and tendrils. It is a succulent plant that grows in tropical and subtropical xeric forests.

The plant is known by numerous common and regional names: Adamant creeper, Square-stalked vine, Veldt grape, Devil's backbone, Asthisamharaka, Hadjod, Pirandai, Sannalam, Nalleru, Vajravelli, and Mangara valli. It is native to India, Bangladesh, and Sri Lanka, and is also found in Africa and Southeast Asia, with importation to Brazil and the southern United States.

The Cissus quadrangularis plant reaches a height of about 1.5 m and has quadrangular-sectioned branches with internodes approximately 8 to 10 cm long and 1.2 to 1.5 cm wide. Along each angle is a leathery edge.

Part of Plant Used

The stem and leaf of Cissus quadrangularis L. (Vitaceae), indigenous to Asia and Africa, are used for medicinal and dietary purposes. The stem, roots, and shoots are the most important plant parts used medicinally. In commercial extract preparations, aerial parts — especially the stem — are the primary source.

Commercial Forms and Standardization

Cissus quadrangularis extract standardized to 40% ketosterones, derived from the Cissus quadrangularis plant, is a botanical ingredient increasingly recognized in food products and dietary supplements for its potential health benefits. Commercial extracts are typically standardized to ketosterone levels ranging from 2.5% to 40%. The maximum ketosterone content in laboratory extraction studies was observed in 90% methanolic extract, followed by ethyl acetate and water extracts, at 6.2%, 2.46%, and 0.10%, respectively. Commercial forms include powder (churna), capsules/extracts, decoctions/teas, and external oils/liniments.

2. Traditional and Historical Use

Ayurvedic Medicine (India)

Hadjod (Cissus quadrangularis), also called asthisamharaka or "bone setter" in Ayurveda, has a long history of traditional use for bone and joint health. The plant's Sanskrit name Asthisamharaka literally translates to "that which strengthens bones." Hadjod, also known as Hadjora or Vajravalli, is one of Ayurveda's most respected herbs, mentioned in ancient texts for its rejuvenating and restorative properties.

The plant finds references in the ancient Sushruta Samhita (circa 600–800 BCE) as "Asthisamharaka," literally meaning "that which unites bones." In these early surgical texts, healers advocated its use as a decoction post-fracture. Hadjod also appears in classical texts like the Vangasena Samhita (circa 12th century CE) and the Bhaishajya Ratnavali, where it is praised as Asthishrinkhala ("chain of bones"). Early Sanskrit manuscripts describe its use for fractures, sprains, and arthritic stiffness. Ayurvedic scholars Charaka and Sushruta highlight Cissus quadrangularis for its rasa (taste) of tikta-kashaya and its Kapha-Pitta balancing properties.

In Ayurveda, Hadjod is classified as a "Rasayana" herb, believed to promote longevity and overall well-being. It is traditionally used for supporting bone health, healing fractures, and strengthening the skeletal system, and for alleviating joint pain, inflammation, and stiffness associated with conditions like arthritis. Additional traditional Ayurvedic applications include treatment of loss of appetite, indigestion, hemorrhoids, intestinal worms, gout, internal bleeding, and leucorrhea.

In Ayurveda, the fresh juice of the Cissus quadrangularis plant in a dosage of 20 ml twice daily is used to accelerate fracture healing and restore bone mass. External application of a paste prepared from Hadjod powder and warm water is also used for the same purposes.

Traditionally, village healers in central India powdered the dried vine and combined it with herbal decoctions, applying poultices directly to broken limbs. By the 17th–18th century, Unani practitioners had adopted it for joint ankylosis, and Siddha texts recommended it for toothache when mixed with clove oil.

In Ayurveda, it is used as Pachan dravya (digestive aid), Sara (relieves constipation), Athiyuk (strengthening bones), and Vrushya (aphrodisiac). In Unani medicine, it is used to treat gastritis.

African and Other Traditional Systems

Cissus quadrangularis has a long history of use in traditional medicine; it has been valued for centuries in Ayurveda, the ancient Indian system of healing. Traditional uses include stimulating bone growth. In Africa, the plant has been used to treat various ailments, with traditional healers relying on its stems and leaves to address health issues.

Modern Resurgence and Supplement Industry

Modern scientific resurgence began in the 1970s at India's National Institute of Nutrition, where preliminary animal studies validated bone-healing efficacy, setting the stage for decades of research and commercial supplements worldwide. Several dietary supplements in the USA contain C. quadrangularis extract standardized to ketosteroid content.

3. Key Constituents and Phytochemistry

Phytochemical Profile

Cissus quadrangularis contains a wide variety of chemical constituents, including steroids, flavonoids, stilbenes, iridoids, triterpenes, and gallic acid derivatives. The plant contains chemicals including flavonoids, indanes, phytosterols, ketosteroids, vitamin C, and beta-carotene. These chemicals are reported to be strong antioxidants.

Phytochemical constituents that have been isolated from the plant — playing a major role in its bioactivity — include gallic acid derivatives, steroids, iridoids, flavonoids, stilbenes, and triterpenes, possessing activities such as anti-inflammatory, anti-tumor, gastroprotective, antioxidant, and antimicrobial properties. Identified polyphenolic compounds include catechin, epicatechin, quercetin-3-O-β-glucopyranoside, kaempferol-3-O-β-glucoside, quercetin-3-O-β-rhamnoside, leachianol F, amurensin A, pallidol, resveratrol, and quadrangularin A.

Early attempts to isolate anabolic steroidal substances from static tissue cultures of C. quadrangularis resulted in the isolation of β-sitosterol and stigmasterol. Ketosteroids and β-sitosterol in C. quadrangularis are noted to exhibit estrogenic action relevant for bone metabolism, and to modulate bone remodeling by stimulating osteoblasts via estrogen receptors.

The 3-Ketosteroid Fraction: Identity and Measurement Challenges

Cissus quadrangularis (CQ) is reported to contain 3-ketosteroids and to have bone health benefits. The "ketosterones" label used in supplement standardization refers to this 3-ketosteroid fraction. Studies indicate, however, that claims of ketosteroid content need not necessarily correlate to biological effects, warranting extensive phytochemical characterization of biologically active principles from C. quadrangularis. In other words, the conventional quantification of ketosteroids used to standardize commercial extracts has not been demonstrated to directly predict biological potency, a critical limitation acknowledged in the peer-reviewed literature.

There has been positive regulation by ethanolic extract of CQ on the proliferation, differentiation, and matrix mineralization of human osteoblast-like SaOS-2 cells. The anabolic actions of the ethanolic extract are mediated through increased mRNA and protein expression of Runx2, a key transcription factor involved in the regulation of bone matrix proteins.

Cissus quadrangularis is a Vitaceae-derived medicinal plant rich in flavonoids, phytosterols, triterpenoids, vitamins, and bone-relevant minerals, conferring combined antioxidant, anti-inflammatory, phytoestrogenic, and osteoanabolic properties that modulate key pathways involved in bone remodeling.

4. Mechanisms of Action

Osteoblast Stimulation and Bone Matrix Protein Upregulation

The plant's active constituent, 3-ketosteroid, is anabolic in nature. This phytogenic steroid stimulates osteoblastogenesis by acting on the estrogenic receptors of bone cells. The underlying mechanism has been found to involve the MAPK-dependent pathway. As alkaline phosphatase (ALP) and TRAP represent osteoblast and osteoclast cells respectively, CQ extract increases the extent of mineralized nodules along with ALP expression.

Differentiation and mineralization studies on MC3T3-E1 pre-osteoblast cell lines with CQ fractions revealed early and enhanced mineralization in cultures treated with the hexane fraction (CQ-H), as indicated by Von Kossa staining and expression profiles of osteoblast marker genes including osterix, Runx2, alkaline phosphatase (ALP), collagen (Col1a1), integrin-related bone sialoprotein (IBSP), osteopontin (OPN), and osteocalcin (OCN).

Anti-Osteoclastogenic Effects

CQ, popularly known as Hadjod, is a traditional medicinal herb exhibiting osteoprotective potential in various bone diseases, especially osteoporosis and fractures. A 2023 study published in Cells investigated the osteoprotective and immunoporotic potential of CQ in preventing inflammatory bone loss under estrogen-deficient conditions. CQ extract showed anti-osteoporotic activity in ovariectomized mice by increasing bone mineral density, restoring trabecular bone, and decreasing serum osteocalcin and TRAP5b levels without toxicity.

Anti-Inflammatory Mechanisms

Research has demonstrated that CQ inhibits key pro-inflammatory mediators. CQ's ability to inhibit key enzymes of metabolism, such as pancreatic lipase, α-amylase, and α-glucosidase in vitro, could contribute to weight reduction. Studies have also examined inhibition of cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways as potential anti-inflammatory mechanisms.

Adipocyte Browning and Metabolic Modulation

In human white adipocyte (hWA) browning experiments, CQ extract treatment at 10, 100, and 1000 ng/ml significantly enhanced UCP1 mRNA expression in a dose-dependent manner when compared to pioglitazone treatment (p < 0.001). The plant is known for its rich phytochemical profile, including ketosteroids and flavonoids that enhance osteoblast activity and accelerate fracture healing.

5. Scientific Evidence by Area of Use

5.1 Bone Health and Fracture Healing

Traditional and Preclinical Background: Cissus quadrangularis (CQ), a traditional medicinal plant, is increasingly recognized for its potential benefits in promoting bone health, including effects on bone-related biomarkers promoting bone healing and bone density improvement.

Preclinical Evidence: Animal and in vitro studies provide support for the use of Cissus in promoting bone fracture healing and as an anti-osteoporotic agent. In an orchidectomized (ORX) rat model, the increase in absolute weight was appreciable in the CQ aqueous extract-treated group. With respect to bone parameters, a similar trend was seen; the mean bone density, strength, and calcium content were found to be highest in the group treated with CQ aqueous extract compared to groups treated with other extracts.

Human Clinical Evidence — Fracture Healing: Numerous clinical studies have reported that treatment with CQ at a dose of 1.2–10 g/day for 4–12 weeks accelerated bone fracture healing without any severe adverse events.

A pilot study published in the AYU journal evaluated CQ as an osteogenic agent in maxillofacial fracture. All patients were treated by open reduction internal fixation method and postoperative management with antibiotics and analgesics. Patients were divided into two groups; in Group 1, one capsule of C. quadrangularis (500 mg) was administered three times a day for 6 weeks (n = 5). The investigators concluded that C. quadrangularis helps in reducing pain, swelling, and fracture mobility and accelerates the healing of fracture jaw bones. This was a small pilot study and its findings require confirmation in larger controlled trials.

Systematic Review and Meta-Analysis (2025): A systematic search of PubMed, Embase, Scopus, and the Cochrane Library databases conducted up to April 2025 included randomized controlled trials in human participants receiving CQ and reporting bone biomarkers, with no restrictions on age, sex, disease severity, or administration route. The CQ intervention was significantly associated with increased serum parathyroid hormone levels, with no significant effects on other bone-related biomarkers. Although there were a limited number of studies, these findings suggest its potential for modulating bone health; however, further research is needed to confirm these results and explore its clinical applications. This most recent systematic review represents the highest level of available evidence and reflects the current state of the literature.

Postmenopausal Bone Loss: This evidence highlights CQ as a potential alternative intervention for the prevention of bone loss. However, a clinical study of CQ determining its effect on bone density and safety in a target group of low-bone mass patients had not previously been performed, leading to a randomized placebo-controlled trial examining the effect of 24 consecutive weeks of oral CQ administration on delaying bone loss in postmenopausal women with osteopenia.

Evidence Strength: Bone healing evidence is supported by multiple small clinical trials and a 2025 systematic review. The overall picture suggests biological plausibility and some clinical signal for fracture-healing acceleration and parathyroid hormone modulation, but the body of randomized controlled trial evidence in humans remains limited in scale and methodological rigor. Claims about ketosteroid content being the singular driver of these effects are disputed by the Himalaya Drug Company research group's own findings.

5.2 Joint Health and Exercise-Induced Pain

CQ has been reported to have anti-inflammatory activity. Bloomer et al. (2013) at the University of Memphis examined the therapeutic effects of CQ supplementation in healthy, exercise-trained men with joint-specific pain, noting that strenuous high-volume exercise is often associated with inflammation and joint pain.

Twenty-nine men between the ages of 20 and 46 years, who reportedly experienced chronic joint pain as a result of strenuous exercise, participated in the pilot study. All men received CQ 3,200 mg daily for 8 weeks. Before and after the 8-week intervention period, subjects completed the Western Ontario and McMaster Universities Index of Osteoarthritis (WOMAC) questionnaire to determine their degree of joint pain. Clinical measures including heart rate, blood pressure, and blood biomarkers were also collected.

An 8-week course of supplementation with CQ reduced joint pain in the sample of 29 young, otherwise healthy, exercise-trained men with joint-specific pain.

Evidence Strength: This was an uncontrolled pilot study (no placebo group), conducted in a single, highly specific population. The results are preliminary. While the finding is consistent with the anti-inflammatory pharmacology of CQ constituents, it cannot be generalized without larger, properly controlled trials.

5.3 Weight Management and Metabolic Syndrome

In a clinical study by Oben et al., 92 obese (BMI >30) participants were randomized into three groups: placebo, formulation/no diet, and formulation/diet (2,100–2,200 calories/day). Thirty-one overweight participants (BMI 25–29) formed a fourth (no diet) treatment group.

At the end of the trial period, statistically significant net reductions in weight and central obesity, as well as in fasting blood glucose, total cholesterol, LDL-cholesterol, triglycerides, and C-reactive protein were observed in participants who received the formulation, regardless of diet. The authors concluded that the CQ formulation appeared to be useful in the management of weight loss and metabolic syndrome.

In a second human trial, supplementation of 300 mg/day CQ extract (CQR-300) with no dietary restriction for 8 weeks in obese and overweight Cameroonians decreased body weight, waist circumference, blood glucose levels, and LDL cholesterol levels — but not body fat percentage — when compared to baseline values.

A 2021 randomized trial published in Scientific Reports by Chatree et al. investigated white adipocyte browning. CQ treatment in obese humans significantly decreased waist circumference at week 4 and week 8 when compared with baseline values (p < 0.05), and significantly decreased hip circumference at week 8 when compared with baseline and week 4 values (p < 0.05). Serum leptin levels of the CQ-treated group were significantly higher at week 8 compared to baseline levels. CQ extract treatment on human white adipocytes at 10, 100, and 1,000 ng/ml significantly enhanced UCP1 expression in a dose-dependent manner when compared to pioglitazone treatment (p < 0.001 for all doses).

A double-blind placebo-controlled study combining CQ with Irvingia gabonensis was also conducted. Seventy-two obese or overweight subjects were recruited for a 10-week study. All diabetics as well as pregnant and lactating women were excluded. None of the participants took any weight-reducing medication nor followed any specific diet. Of the 72 subjects, 33 (45.8%) were male and 39 (54.2%) were female; the mean BMI was >26 kg/m², and the age range was 21–44 (mean age 29.3). This double-blind placebo-controlled study reported a reduction in weight of 11.3 ± 0.8% in the obese group and 8.4 ± 1.1% in the overweight group compared with placebo groups after 8 weeks of trial.

Evidence Strength: Several human studies support the use of Cissus extracts in weight management. However, many of these trials share a common investigator group (Oben et al.), are primarily conducted in Cameroonian populations, and some have used a proprietary preparation (CQR-300) in combination with other botanicals, limiting attribution of effects to CQ or its ketosteroid fraction alone. Independent replication is limited.

5.4 Antioxidant Activity

The plant contains chemicals including flavonoids, phytosterols, ketosteroids, vitamin C, and beta-carotene, which are reported to be strong antioxidants. Preclinical studies have supported antioxidant roles for CQ, particularly its polyphenolic fraction. Evidence in humans for antioxidant outcomes specifically attributable to the ketosteroid fraction is not clearly established in the available literature.

5.5 Anti-Osteoporotic Effects

CQ exhibits promising anti-osteoporotic and anti-arthritic effects in preclinical models. However, well-designed clinical trials are necessary to confirm its efficacy and safety in humans for potential therapeutic applications. A systematic literature search across PubMed, SCOPUS, JSTOR, and Web of Science focused on English-language animal studies from 2003 to 2024 for osteoporosis and 2010–2024 for arthritis supported this preclinical case.

5.6 Claimed Anabolic / Bodybuilding Activity

No studies have been conducted demonstrating that Cissus exhibits anabolic and bodybuilding activities. Based on studies to date, Cissus extracts appear to be exceedingly safe and free of adverse effects at the doses commonly used. Furthermore, no study has been carried out in the past that demonstrates its anabolic and body-building activities. Despite marketing of ketosterone-standardized CQ extracts as anabolic supplements, the existing peer-reviewed literature does not support this use.

6. Body Systems and Health Areas

Based on available peer-reviewed evidence and documented traditional use, Cissus quadrangularis and its ketosteroid fraction have been associated with the following body systems and health areas:

• Skeletal System: Bone fracture healing, bone mineral density, anti-osteoporotic activity, osteoblast differentiation and mineralization, inhibition of osteoclastogenesis. The ketosteroids and flavonoids in CQ enhance osteoblast activity and accelerate fracture healing.
• Musculoskeletal / Joint System: Joint pain reduction in exercise-trained individuals, anti-arthritic activity in animal models, anti-inflammatory effects at joints.
• Metabolic / Adipose System: Cissus may help prevent weight gain by reducing waist circumference and affecting adiponectin levels.
• Cardiovascular / Lipid Metabolism: Reductions in LDL-cholesterol, total cholesterol, and triglycerides reported in human clinical trials involving metabolic syndrome populations.
• Glycemic Regulation: Reductions in fasting blood glucose reported in clinical trials.
• Gastrointestinal System: Traditional use as digestive aid; gastroprotective properties investigated preclinically.
• Immune System: Osteoprotective and immunoporotic potential of CQ has been investigated, demonstrating effects via modulating the host immune system under estrogen-deficient conditions.

7. Dosage Forms and Reported Dosages

The following dosages are reported in peer-reviewed human studies only:

• In the Bloomer et al. (2013) pilot study for joint pain, 29 exercise-trained men received CQ 3,200 mg daily for 8 weeks.
• Multiple clinical studies have reported CQ at a dose of 1.2–10 g/day for 4–12 weeks for the context of bone fracture healing.
• In the Oben et al. (2007) obesity trial, 300 mg/day of CQ extract (CQR-300) was administered for 8 weeks with no dietary restriction.
• In the Oben et al. (2006) metabolic syndrome study, 92 obese (BMI >30) participants were randomized across formulation/no diet and formulation/diet groups (2,100–2,200 calories/day), alongside 31 overweight participants.
• In the maxillofacial fracture pilot study, patients in the treatment group received one 500 mg capsule of C. quadrangularis three times a day for 6 weeks.
• Traditional Ayurvedic dosage: The fresh juice of the plant at 20 ml twice daily is traditionally used to accelerate fracture healing and restore bone mass.

The wide range of dosages (from 300 mg/day of standardized extract to 10 g/day of crude powder) across studies reflects differences in extract concentration and standardization levels, making direct comparisons difficult.

8. Safety Considerations

General Tolerability

Cissus quadrangularis is taken for a variety of reasons including bone health, metabolic health, arthritis, and hemorrhoids; however, its benefits for any use are not well defined. The plant seems to be well tolerated when taken by mouth, but it may cause gas, trouble sleeping, dry mouth, headaches, or diarrhea.

Subchronic Toxicology and Mutagenicity

In a subchronic toxicology study, Sprague Dawley rats (20/sex/group) were administered (by gavage) CQ extract (CQR-300) at dose levels of 0, 100, 1,000, and 2,500 mg/kg body weight per day for 90 days. No treatment-related clinical signs of toxicity, mortality, or changes in body weights, body weight gain, or food consumption were noted. Functional observation tests and ophthalmological examination did not reveal any changes. No toxicologically significant treatment-related changes in hematological, clinical chemistry, urinalysis parameters, or organ weights were noted.

No treatment-related macroscopic and microscopic abnormalities were noted at the end of the treatment period. The results of mutagenicity studies as evaluated by the Ames assay, in vitro chromosomal aberration test, and in vivo micronucleus assay did not reveal any genotoxicity of CQR-300. Based on the subchronic study, the no-observed-adverse-effect level (NOAEL) for CQ extract (CQR-300) was determined at 2,500 mg/kg bw/day, the highest dose tested.

Combined Toxicological-to-Clinical Assessment

The cell culture studies and the three clinical studies in humans taken together with the long history of traditional medicinal use indicate that Cissus stem powder and dried extracts given daily for extended periods of time (up to 10 weeks in humans and 90 days in rats) do not produce serious adverse events.

In a systematic review and meta-analysis of randomized controlled trials, no serious adverse effects were reported.

Hepatotoxicity Considerations

The liver is a principal target organ of metabolic disorders, and recent studies have focused on exploring the efficacy of CQ extract against various metabolic disorders involving the liver as the prime target organ, suggesting a considerable potential for hepatotoxicity. A study aimed to assess the mutagenic, cytotoxic, mitochondrial dysfunction, and apoptotic activity of CQ extract in HepG2 cells. MTT, SRB, trypan blue dye exclusion, and lactate dehydrogenase (LDH) assays were performed in HepG2 cell lines to determine cytotoxicity; mutagenic potential was assessed by the Ames test using various strains of Salmonella typhimurium. MTT and SRB cytotoxicity assays demonstrated dose-dependent cytotoxicity of the extract; however, the three highest non-cytotoxic doses investigated by trypan blue dye exclusion and LDH assay did not reveal cytotoxicity. The hepatic risk at doses used in human studies has not been clinically demonstrated, but this area warrants attention in future long-duration trials.

Potential Drug Interactions

Cissus quadrangularis may increase the levels of medications metabolized by the liver, potentially leading to toxicity. This is a pharmacokinetic concern relating to hepatic enzyme modulation that has been flagged in the literature but has not been systematically characterized in clinical interaction studies.

9. Evidence Gaps, Limitations, and Research Outlook

Studies indicate that claims of ketosteroid content obtained by conventional standardization methods need not necessarily correlate to biological effects, and hence warrant extensive phytochemical characterization of the biologically active principles from Cissus quadrangularis. This is perhaps the most consequential scientific limitation in the field: the "ketosteroid" marker used to standardize and label dietary supplements is not validated as the sole or primary driver of the plant's observed biological effects.

Comprehensive clinical validation remains limited. Most studies to date are either small-scale, preclinical, or use extracts rather than isolated ketosterones, making it challenging to attribute effects to ketosterones alone.

While CQ exhibits promising anti-osteoporotic and anti-arthritic effects in preclinical models, well-designed clinical trials are necessary to confirm its efficacy and safety in humans for potential therapeutic applications.

References

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