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

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.

Keywords: BCAA metabolism; BCAAs; bone metabolism; osteoporosis; therapeutic target.

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 T_M cells into T_EM 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; T_EM, effector T_M; Th17, T helper 17; T_M, memory T. Created in BioRender. zhan, a. (2025) https://BioRender.com/3k6hy0g.