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Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review)

  • Authors:
    • Qi Xiao
    • Haimin Zeng
    • Ruhui Yang
    • Yuxin Zhan
    • Fangzhen Lin
    • Bofan Chen
    • Xiang Chen
  • View Affiliations / Copyright

    Affiliations: Department of Rehabilitation Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China, Department of Rehabilitation Medicine, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
    Copyright: © Xiao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 35
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    Published online on: December 2, 2025
       https://doi.org/10.3892/ijmm.2025.5706
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Abstract

Branched‑chain amino acids (BCAAs) are biologically active amino acids with branched carbon chains, recognized for their diverse biological functions and therapeutic potential. BCAAs have demonstrated promising effects in the prevention and treatment of various conditions, including muscle growth disorders, cardiovascular diseases and cancer. Despite extensive research confirming their targeted therapeutic effects in multiple domains, the mechanisms of action and therapeutic range of BCAAs remain incompletely understood. Osteoporosis, a metabolic bone disease, is a global public health issue characterized by an imbalance between osteoblast‑mediated bone formation and osteoclast‑induced bone resorption, resulting in fragile bones and an elevated risk of fractures. Given the well‑documented therapeutic roles of BCAAs, their potential link to osteoporosis has been explored, emphasizing the influence of BCAA metabolism on bone metabolism. The present review aims to summarize findings on the relationship between BCAA metabolism and osteoporosis, and to investigate the mechanisms by which BCAA metabolism may exert anti‑osteoporotic effects. The review first outlines the fundamental processes and key factors influencing bone metabolism, BCAA metabolism and osteoporosis. It then examines the interactions between these processes and the effects of BCAA metabolism on bone health. Finally, it explores the potential of targeting BCAA metabolic pathways as a future therapeutic strategy for osteoporosis, highlighting BCAAs as a promising target for treating this condition.
View Figures

Figure 1

Bone metabolism process. Apoptotic
osteocytes release ATP via PANX1 channels, activating P2Y1
receptors on neighboring osteocytes, which upregulate RANKL through
cyclooxygenase-dependent pathways. Simultaneously, DAMPs from
apoptotic cells engage macrophage PRRs, triggering the release of
proinflammatory cytokines (such as TNFα and IL-6) that further
enhance osteoblastic RANKL production. The RANKL-RANK interaction
promotes osteoclast differentiation, with cathepsin K facilitating
bone resorption. In parallel, osteocyte bone-lining syncytium
activates Wnt/β-catenin signal: Wnt ligand binds to the receptor on
the membrane to stabilize β-catenin, driving osteoblast
differentiation and OPG production. This dual regulatory mechanism
ensures a balance between bone resorption (RANKL-driven) and
formation (Wnt-mediated) during remodeling. ATP, adenosine
triphosphate; OPG, osteoprotegerin; P2Y, purinergic receptor P2Y;
PANX1, Pannexin 1; PRR, pattern recognition receptor; RANK, RANKL,
receptor activator of NF-κB; RANKL, RANK ligand; DAMP,
damage-associated molecular pattern. Created in BioRender. zhan, a.
(2025) https://BioRender.com/7e0mcn5.

Figure 2

Key regulators of bone metabolism.
Calcium-phosphate homeostasis factors (blue): PTH/PTHrP modulates
calcium-phosphate metabolism through the PTH1R/cAMP/PKA pathway;
1,25 (OH)2D3 promotes intestinal calcium and
phosphate absorption; calcitonin suppresses osteoclast activity.
Osteocyte network factors (green): Connexin 43 mediates
intercellular communication; degeneration of the dendritic network
of bone cells leads to a decline in bone function; TGF-β1 regulates
the integrity of the intrinsic regulatory network. Bone formation
and balance factors (yellow): GH/IGF-1 drives bone remodeling;
estrogen promotes bone cell survival; osteocalcin maintains bone
metabolism homeostasis; irisin protects the bone-muscle axis. cAMP,
cyclic adenosine monophosphate; GH, growth hormone; IGF-1,
insulin-like growth factor-1; PKA, protein kinase A; PTH,
parathyroid hormone; PTH1R, PTH1 receptor; PTHrP, PTH-related
protein; TGF-β, transforming growth factor-β. Created in BioRender.
zhan, a. (2025) https://BioRender.com/cgf8v8x.

Figure 3

Role of BCAAs in bone metabolism.
BCAAs (leucine, isoleucine and valine) undergo deamination to
produce α-ketoacids (KIC, KIV and KMV), which are then oxidatively
decarboxylated by BCKDH. The resulting metabolites are further
processed through enzymatic reactions to generate acetyl-CoA (from
leucine and isoleucine) and succinyl-CoA (from valine and
isoleucine). Acetyl-CoA and succinyl-CoA enter the TCA cycle,
influencing mitochondrial function and oxidative stress. BCAA
metabolites, including 3-HIB and BAIBA, regulate trans-endothelial
fatty acid transport, white adipose tissue browning and osteoclast
precursor differentiation. mTORC1 signaling, activated by BCAAs,
modulates osteoclastogenesis and bone resorption, while insulin
resistance linked to BCAA dysregulation impairs osteoblast function
and exacerbates bone cell damage. 3-HIB, 3-hydroxyisobutyric acid;
α-KG, α-ketoglutarate; ATP, adenosine triphosphate; BAIBA,
β-aminoisobutyric acid; BCAA, branched-chain amino acid; BCKDH,
branched-chain α-ketoacid dehydrogenase; mTORC, mechanistic target
of rapamycin complex; KIC, α-ketoisocaproate; KIV,
α-ketoisovalerate; KMA, α-ketomethylvalerate; TCA, tricarboxylic
acid; R-CoA, acyl-CoA. Created in BioRender. zhan, a. (2025)
https://BioRender.com/9461i1f.

Figure 4

Mechanisms of bone metabolism
dysregulation in osteoporosis pathogenesis. Estrogen deficiency
triggers immune activation (IL-15 and IL-7) in BMDCs, promoting the
differentiation of TM cells into TEM cells,
which secrete TNFα and IL-17A to synergize with RANKL in
osteoclastogenesis. Increased intestinal permeability and mucosal
inflammation amplify Th17 cell-derived IL-17A, exacerbating
osteoclast activity. Vitamin D deficiency and dietary
calcium/phosphate insufficiency impair mineralization. Cellular
senescence in BMSCs elevates SASP factors (IL-6 and IL-8),
inhibiting osteoblast differentiation through epigenetic
suppression. Dysregulated pathways (RANKL/RANK/OPG, Wnt/β-catenin,
BMP-Smad and PI3K/Akt/mTOR) disrupt osteoblast-osteoclast coupling,
while estrogen loss reduces osteocyte survival and
mechanotransduction. PTH imbalance disrupts calcium-phosphate
homeostasis, collectively driving bone resorption over formation.
These factors ultimately exacerbate osteoporosis development. BMDC,
bone marrow dendritic cell; BMSC, bone marrow mesenchymal stem
cell; mTOR, mechanistic target of rapamycin; NAP1L2, nucleosome
assembly protein 1 like 2; OPG, osteoprotegerin; PTH, parathyroid
hormone; RANK, receptor activator of NF-κB; RANKL, RANK ligand;
SASP, senescence-associated secretory phenotype; TEM,
effector TM; Th17, T helper 17; TM, memory T.
Created in BioRender. zhan, a. (2025) https://BioRender.com/3k6hy0g.
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Copy and paste a formatted citation
Spandidos Publications style
Xiao Q, Zeng H, Yang R, Zhan Y, Lin F, Chen B and Chen X: Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review). Int J Mol Med 57: 35, 2026.
APA
Xiao, Q., Zeng, H., Yang, R., Zhan, Y., Lin, F., Chen, B., & Chen, X. (2026). Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review). International Journal of Molecular Medicine, 57, 35. https://doi.org/10.3892/ijmm.2025.5706
MLA
Xiao, Q., Zeng, H., Yang, R., Zhan, Y., Lin, F., Chen, B., Chen, X."Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review)". International Journal of Molecular Medicine 57.2 (2026): 35.
Chicago
Xiao, Q., Zeng, H., Yang, R., Zhan, Y., Lin, F., Chen, B., Chen, X."Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 35. https://doi.org/10.3892/ijmm.2025.5706
Copy and paste a formatted citation
x
Spandidos Publications style
Xiao Q, Zeng H, Yang R, Zhan Y, Lin F, Chen B and Chen X: Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review). Int J Mol Med 57: 35, 2026.
APA
Xiao, Q., Zeng, H., Yang, R., Zhan, Y., Lin, F., Chen, B., & Chen, X. (2026). Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review). International Journal of Molecular Medicine, 57, 35. https://doi.org/10.3892/ijmm.2025.5706
MLA
Xiao, Q., Zeng, H., Yang, R., Zhan, Y., Lin, F., Chen, B., Chen, X."Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review)". International Journal of Molecular Medicine 57.2 (2026): 35.
Chicago
Xiao, Q., Zeng, H., Yang, R., Zhan, Y., Lin, F., Chen, B., Chen, X."Branched‑chain amino acid metabolism and bone metabolism: Implications for osteoporosis pathogenesis and therapeutic strategies (Review)". International Journal of Molecular Medicine 57, no. 2 (2026): 35. https://doi.org/10.3892/ijmm.2025.5706
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