Leucine

證據等級: L5

預測適應症: 10 個

Leucine: From Nutritional Supplement Use to Postmenopausal Osteoporosis (Preliminary Signal)

One-Sentence Summary

Leucine is an essential branched-chain amino acid (BCAA) with no formally documented original disease indication in this evidence pack; it is primarily known as a nutritional/dietary supplement supporting muscle protein synthesis. Of 10 TxGNN-predicted indications, the model’s single highest-scoring hit (congenital prothrombin deficiency, ~99% score) has zero supporting trials or literature and is flagged by the source data itself as a likely spurious knowledge-graph pairing. The only candidate with actual human clinical evidence is Postmenopausal Osteoporosis (rank 6, 97.42% score), supported by 1 completed clinical trial and a handful of observational/metabolomics studies — evidence that is suggestive but far from conclusive.

Quick Overview

Item	Content
Original Indication	Not established — no approved/registered indication data available; Leucine is used as an essential amino acid nutritional supplement
Predicted New Indication	Postmenopausal Osteoporosis (best-evidenced of 10 TxGNN candidates)
TxGNN Prediction Score	97.42%
Evidence Level	L3
South Africa Market Status	Not marketed
Number of SAHPRA Registrations	0
Recommended Decision	Hold

Why is This Prediction Reasonable?

Currently, detailed mechanism of action data is not available (Data Gap). Based on known pharmacology, Leucine is a branched-chain amino acid (BCAA) that activates the mTORC1 signalling pathway, its role in promoting skeletal muscle protein synthesis is well established, and mechanistically it may be applicable to postmenopausal osteoporosis through the “muscle-bone unit” — the concept that muscle mass and loading capacity exert anabolic stimulus on bone remodeling.

The rationale is indirect rather than a direct bone-metabolism mechanism: BCAA supplementation could theoretically increase muscle strength and mechanical loading on bone, which secondarily supports bone mineral density, rather than acting on osteoblasts/osteoclasts directly. Because the original MOA field is a data gap, this link cannot be confirmed against an established pharmacological profile and should be treated as a hypothesis rather than a proven mechanism.

It is also important to note that 9 of the 10 TxGNN-predicted indications for Leucine in this evidence pack have essentially no supporting evidence (L5, “Hold”), and several literature hits across candidates (e.g., in acne, bone Paget disease, sclerosing cholangitis) turned out to be false-positive name matches — genes or proteins containing “leucine” in their name (e.g., LRG1, LRRc17, TGF-β1 Leu→Pro polymorphisms) rather than studies of leucine as a therapeutic agent. The postmenopausal osteoporosis candidate is the only one where genuine leucine/BCAA pharmacology appears in the literature.

Clinical Trial Evidence

Trial Number	Phase	Status	Enrollment	Key Findings
NCT01757340	N/A	Completed	43	Calorie Restriction With Leucine Supplementation in Postmenopausal Women — evaluated effects of leucine supplementation during calorie-restriction weight loss on insulin sensitivity, colonocyte proliferation, gut microbiome, muscle mass/function, and bone mineral density in obese postmenopausal women. Bone mineral density was a secondary/exploratory endpoint, not the primary outcome.

No SANCTR or PACTR-registered trials were identified for this indication.

Literature Evidence

PMID	Year	Type	Journal	Key Findings
40023006	2025	Preclinical	J Chromatogr B	Branched-chain amino acid metabolism implicated in the “kidney-bone axis” protective mechanism against postmenopausal osteoporosis in a rat model
37495941	2023	Cohort/Microbiome	BMC Microbiology	Gut microbiota (Klebsiella, Escherichia-Shigella) and amino acid metabolism proposed as monitoring markers for postmenopausal osteoporosis
33293818	2020	Cross-sectional Cohort	Vasc Health Risk Manag	Metabolite profiling linking osteoporosis and atherosclerosis in postmenopausal women, identifying candidate metabolic biomarkers
31141566	2019	Cross-sectional Metabonomics	PLoS One	1H NMR-based metabonomics discriminated osteopenia from osteoporosis in postmenopausal women via metabolite panels
40703670	2025	Cohort/Microbiome	Front Cell Infect Microbiol	Gut microbiota changes in postmenopausal women with low bone density linked to serum amino acid metabolism
23408954	2013	Preclinical (animal)	PLoS One	GC-TOF/MS metabolomic profiling identified metabolic shifts, including amino acid changes, during estrogen deficiency-induced bone loss in rats
35542168	2018	Preclinical (animal)	RSC Advances	LC-MS plasma metabolomics revealed metabolic (including amino acid) variations in ovariectomy-induced osteoporosis in rats

Note: A further ~13 literature hits returned by the search (e.g., TGF-β1 Leu10→Pro polymorphism studies, NPY gene Leu7/Pro7 polymorphism, LRRc17 protein studies, L-carnitine RCT) were excluded from this table — they involve gene/protein names containing “leucine” as an amino-acid residue, or unrelated amino acids/genes, not leucine as a therapeutic supplement, and do not constitute pharmacological evidence.

South Africa Market Information

Leucine currently has no SAHPRA-registered products (0 registrations; market status: Not marketed) in this evidence pack. No dosage forms, brand names, or approved indications are available to report.

Safety Considerations

Please refer to the SAHPRA-approved Professional Information (PI) for safety information. Report adverse drug reactions to SAHPRA.

(Note: This evidence pack flags a Blocking data gap — TFDA/SAHPRA label warnings and contraindications are unavailable, which by itself precludes progression past initial safety screening (S1) regardless of efficacy evidence.)

Conclusion and Next Steps

Decision: Hold

Rationale: The only candidate with any clinical evidence — postmenopausal osteoporosis — is supported by a single completed trial whose primary endpoints were metabolic/body-composition rather than bone-specific, plus observational metabolomics studies that are mechanistically suggestive at best (L3, no controlled bone-outcome RCT). Combined with a Blocking gap in safety/label data and zero SAHPRA registrations, there is currently insufficient evidence to proceed beyond a research question.

To proceed, the following is needed:

SAHPRA/TFDA Professional Information (warnings, contraindications) to complete safety screening (S1) — currently a Blocking gap
Confirmed mechanism of action data from DrugBank or primary literature
A dedicated RCT with bone mineral density / fracture risk as a primary endpoint in postmenopausal women
Clarification of regulatory pathway, since Leucine has no existing SAHPRA-registered product in South Africa

Other TxGNN-Predicted Indications Screened (Not Pursued)

| Rank | Disease | TxGNN Score | Evidence Level | Reason Not Pursued | |——|———|——|——|———| | 1 | Congenital prothrombin deficiency | 98.99% | L5 | No trials/literature; likely spurious structural pairing in knowledge graph | | 2 | Gastroparesis | 98.85% | L5 | No trials/literature; no plausible mechanism identified | | 3 | Acne | 98.42% | L4 | Literature suggests leucine/mTORC1 activation may worsen acne (opposite direction); the one trial found is an unrelated name-match (LRG1 biomarker) | | 4 | Bone Paget disease | 98.00% | L5 | Literature concerns unrelated SQSTM1/VCP gene mutations, not leucine pharmacology | | 5 | Obsolete vitamin D deficiency | 97.67% | L5 | No evidence; disease term itself is an obsolete ontology entry — recommend excluding from future candidate lists | | 7 | Sclerosing cholangitis | 97.18% | L5 | Literature is genetic/immunologic; the one direct leucine-peptide study shows it induces cholangitis in a rat model, contradicting a therapeutic hypothesis | | 8 | Pregnancy-associated osteoporosis | 96.57% | L4 | Only 2 papers; one animal study on a leucine metabolite (HMB), one unrelated genetic case report | | 9 | Albinism-deafness syndrome | 96.43% | L5 | No evidence whatsoever | | 10 | Worth syndrome | 96.33% | L5 | No evidence whatsoever; theoretical bone-metabolism overlap only |

Disclaimer

This content is for research purposes only and does not constitute medical advice. Clinical validation is required before any clinical application.