Estrogen deficiency is a key upstream driver of PMOP, and its classic mechanism can be summarized as an imbalance in bone remodeling. This imbalance involves enhanced osteoclast activity while osteoblast function is suppressed, leading to long-term bone resorption exceeding bone formation, which results in decreased bone mass and destruction of bone microstructure (17, 18). In the classic model of the “osteocyte center,” the RANK/RANKL/OPG axis dominates the differentiation and activation intensity of osteoclasts, while the Wnt/β-catenin pathway determines osteogenic differentiation and bone formation capacity; both together maintain the homeostasis of bone remodeling (19). Estrogen can inhibit bone resorption and promote bone formation by lowering the RANKL/OPG ratio and maintaining Wnt/β-catenin activity. However, the postmenopausal decline of estrogen leads to an increase in the RANKL/OPG ratio and a weakening of Wnt/β-catenin signaling, thus forming the classic pathological picture of PMOP (20–23). It is noteworthy that the local signaling imbalance in osteocytes alone cannot fully explain the persistent bone loss in PMOP. Estrogen deficiency can also be accompanied by elevated pro-inflammatory cytokines and immune cell profile shifts, and these changes are coupled with the RANK/RANKL/OPG and Wnt/β-catenin pathways, further amplifying bone resorption signals and reinforcing the bias in bone remodeling (24). Additionally, abnormalities in immune-related pathways such as the NLRP3 inflammasome and ANXA1/FPR2 in bone remodeling-related cells also suggest that the bone metabolism process is deeply embedded in the immune regulation network (25). Therefore, in the subsequent chapters of this review, we emphasize the upgrade from this “classic osteocyte model” to the “bone immune model.” Under the background of estrogen deficiency, RANK/RANKL/OPG and Wnt/β-catenin are no longer just local signaling axes between osteocytes but are co-opted and reprogrammed by bone marrow immune cells, cytokine networks, and inflammation-aging signals. These changes thus drive the persistent bone loss in PMOP.

Bone marrow is not only the site of generation and renewal of immune cells but also a key microenvironment where bone cells and immune cells coexist and regulate each other (26, 27). In this microenvironment, immune cells influence the processes of bone resorption and osteogenesis through cytokine networks and direct cell contact. The synergy of proinflammatory effectors and RANKL signaling is considered an important mechanistic basis driving enhanced bone resorption (28–31). Meanwhile, the metabolic state of immune cells and changes related to bone marrow fat can further shape the inflammatory phenotype and influence bone remodeling, forming a coupling network of “immune-metabolism-bone remodeling” (32–35). Therefore, examining PMOP from the perspective of the bone marrow microenvironment helps establish a more direct mechanistic bridge between “systemic inflammation/immune drift” and “local bone metabolic imbalance,” providing a conceptual basis for subsequent discussions on immune cell reprogramming, key signaling network elucidation, and immune-targeted intervention strategies (36).

In summary, bone loss in PMOP can be explained by the imbalance of the two major axes of RANK/RANKL/OPG and Wnt/β-catenin, and its persistence is likely amplified by inflammation-immune changes induced by estrogen deficiency and remodeling of the bone marrow microenvironment, providing a theoretical basis for precision interventions based on bone immunology.

The bone immune microenvironment refers to the dynamic regulatory network formed by immune cells and stromal cells within the bone marrow, through the interaction of cytokines and receptor-ligand interactions. It serves as a key hub connecting immune homeostasis and the balance of bone remodeling (37–39). In PMOP, hormonal changes not only affect osteoblasts and osteoclasts themselves but also accompany the reprogramming of bone marrow immune cell functions and enhanced inflammatory states. These changes promote bone resorption, inhibit bone formation, and accelerate bone loss (40–42). In addition, BMSCs play a dual role in bone regeneration and immune regulation, and their phenotypic changes may further affect bone immune homeostasis, providing a basis for potential intervention targets (43). From a therapeutic perspective, current clinical interventions mainly focus on inhibiting bone resorption or promoting bone formation, such as anti-RANKL antibodies and bisphosphonates. However, incorporating immune cells and their inflammatory networks into the framework of bone metabolism regulation can provide new entry points for combined strategies aimed at immune regulation and restoration of bone remodeling balance. These strategies include regulating macrophage polarization; inhibiting key inflammatory factors and inflammasome pathways; and promoting the formation of an immunotolerant microenvironment (44, 45). Furthermore, the concept of dynamic regulation of the bone immune microenvironment provides theoretical support for bone regeneration materials and bone defect repair, that is, promoting bone healing and integration by optimizing immune responses (46, 47). In summary, research on the bone immune microenvironment not only deepens the understanding of the immunopathological mechanisms of PMOP but also offers a more translational theoretical framework for immune-targeted therapies and bone tissue engineering strategies (Figure 1).

The occurrence of PMOP is accompanied by significant changes in the structure and cellular lineage composition of the bone marrow microenvironment, which involves aging and phenotypic remodeling of HSCs/HSPCs and MSCs, a fundamental process that drives the imbalance of the bone immune microenvironment (7). First, hematopoietic stem cells exhibit typical functional decline and lineage bias after menopause. In aging and menopause-related models, the total number of bone marrow HSCs does not necessarily decrease significantly, but their self-renewal capacity and long-term hematopoietic potential weaken, showing a tendency to differentiate toward the myeloid lineage, while lymphoid generation is relatively suppressed, leading to an imbalance in immune cell generation (48). This “myeloid skewing” is specifically manifested as an increase in the proportion of myeloid cells such as monocytes/macrophages and neutrophils, while the generation of lymphocytes such as B cells and T cells decreases. This shift not only weakens adaptive immune responses but also lays the cellular foundation for the formation of a pro-inflammatory environment in the bone marrow.

MSCs, as key supporting cells for HSCs and precursors of osteoblasts, also profoundly affect the bone marrow microenvironment through their aging and phenotypic remodeling (49). In postmenopausal and aging bone marrow, the proliferation capacity of MSCs decreases, their colony-forming ability weakens, and their osteogenic differentiation potential significantly declines, while the tendency to differentiate into adipocytes increases, leading to the accumulation of bone marrow adipose tissue (BMAT) and a reduction in bone mass (50). During this process, the expression of key receptors such as CXCR4 in aged MSCs is downregulated, weakening their supportive capacity for HSPCs and disrupting the homeostasis maintenance of the “MSC–HSC” axis. Co-culture experiments show that co-culturing aged MSCs with young HSPCs can induce premature aging and myeloid skewing phenotypes in the latter, suggesting that MSC dysfunction directly reshapes HSC fate determination through intercellular signaling (51).

At the transcriptional and signaling pathway levels, multiple pathways regulating lineage differentiation undergo reprogramming in aged MSCs. For example, the transcription factor EBF1 plays a key role in maintaining the osteogenic capacity and immune homeostasis of MSCs, and its absence can lead to impaired MSCs proliferation, decreased osteogenic capacity, and upregulation of inflammation-related gene expression in the bone marrow microenvironment, thereby promoting myeloid skewing and hematopoietic abnormalities in HSCs (52). In addition, the secretion profile of aged MSCs also changes, regulating the cell cycle and colony-forming ability of HSPCs through the secretion of cytokines and extracellular vesicles (EVs), with changes in the composition of miRNA within EVs being considered one of the important mechanisms mediating the functional imbalance of the MSCs–HSPCs axis (53). In the context of PMOP, the disruption of the osteogenic–adipogenic differentiation balance of MSCs not only directly leads to insufficient bone formation but also indirectly affects the spatial distribution and activation state of bone marrow immune cells by promoting BMAT expansion. The adipokines and inflammatory mediators secreted by BMAT can further alter the lineage composition and activation thresholds of bone marrow immune cells, making “MSCs aging–lineage skewing–BMAT increase” a structural hub connecting abnormal bone metabolism and immune reprogramming (54).

In summary, the functional decline and myeloid skewing of bone marrow HSCs after menopause, along with the aging of MSCs, decreased osteogenic potential, and reprogramming towards the adipocyte lineage, collectively reshape the cellular lineage composition and spatial structure of the bone marrow. This provides a “platform” for subsequent immune reprogramming, chronic inflammation maintenance, and bone loss. It should be noted that the aging-related secretory phenotype (SASP) and chronic low-grade inflammation (inflammaging) mechanisms derived from the aforementioned changes will be systematically elaborated in sections 5.4 and 6.2 from the perspectives of “local bone marrow aging” and “systemic inflammatory aging,” respectively. It should be emphasized that most evidence regarding the mechanisms related to HSC/HSPC aging and their association with BMAT expansion mainly comes from aging/castrated animal models and studies related to bone marrow aging. Furthermore, there is still a lack of systematic human data on the fine structure and functional changes of the bone marrow niche in typical PMOP patients. Therefore, the pathological framework of “MSC aging–lineage skewing–BMAT increase” outlined in this section is more of an analogical integration based on related osteoporosis and aging research, and its specific mechanisms in the PMOP population require further validation. The specific molecular and signaling interactions with the BMAT–immune–bone axis will be further elaborated in section 3.3.

Under normal physiological conditions, bone remodeling alternates between the bone resorption phase mediated by osteoclasts and the bone formation phase dominated by osteoblasts. Osteoclasts dissolve minerals and degrade the organic bone matrix by secreting acidic substances and proteases, while releasing growth factors stored in the bone matrix. Subsequently, these signals can recruit and activate osteoblasts to complete the refilling and reconstruction of bone, thus forming a tightly coupled “resorption–formation” cycle (55, 56). In this process, osteoblasts originate from BMSCs, whose differentiation and function are finely regulated by various signaling pathways and transcription factors to ensure the continuous repair of local micro-damage and the long-term maintenance of bone microstructure (57, 58).

Osteocytes, as the most numerous and longest-lived cells in bone tissue, are embedded in the lacunae and canaliculi of the bone matrix, and interconnected by their dendritic processes to form a dense “osteocyte network” (LCN), which is the core mechanosensor and signaling hub of bone tissue (59). Osteocytes can sense mechanical stress and metabolic changes, communicating with neighboring osteocytes, osteoblasts, and osteoclast precursors on the bone surface through gap junctions and EVs (60). The OPG, RANKL, and various factors they produce can directly regulate osteoclast differentiation and activity, and provide feedback to modulate the differentiation and mineralization capacity of osteoblasts, thus coordinating bone resorption and bone formation in both spatial and temporal dimensions (61). In a healthy bone environment, osteocytes, osteoblasts, and osteoclasts form a dynamically balanced “osteocyte–bone remodeling coupling unit.”

In the context of PMOP, the combined effects of estrogen deficiency and chronic inflammation in the bone marrow microenvironment disrupt this coupling systemically. On the one hand, the differentiation and mineralization capacity of osteoblasts decline, with the upstream MSC osteogenic potential weakening and shifting towards the adipogenic lineage, leading to insufficient new bone formation. On the other hand, both the number and function of osteoclasts are enhanced, with bone resorption continuously dominating, presenting a typical “bone resorption > bone formation” imbalance (62). From the perspective of signaling pathways, estrogen deficiency and pro-inflammatory cytokines can inhibit the expression of osteogenic-related genes by activating pathways such as NF-κB and STAT3, weakening the synthesis of bone matrix proteins (such as osteocalcin and osteopontin) and bone morphogenetic proteins, further amplifying osteogenic defects (63, 64). In this context, some natural products or Chinese medicine compounds (such as deer antler extract) with both immune and metabolic regulatory effects can inhibit osteoclasts and promote osteoblasts, providing preliminary pharmacological evidence for integrating bone immune regulation (65–67).

At the same time, the osteocyte network itself also undergoes structural damage in PMOP: increased osteocyte apoptosis, destruction of the LCN structure, and weakened mechanosensing and signal transmission capabilities, leading to impaired adaptive remodeling of bone tissue to mechanical stimuli and metabolic signals (68). The EVs secreted by osteocytes play an important role in regulating communication between osteoblasts, osteoclasts, and immune cells, and their dysfunction further weakens local bone repair capacity, amplifying the osteoclast/osteoblast imbalance (69–71). Overall, in PMOP, the combination of “decreased osteoblast number and function + increased osteoclast activity + structural damage to the osteocyte network and weakened mechanosensing” constitutes the cellular basis for the deterioration of bone microstructure and bone mass loss (72, 73). (Figure 2). It should be noted that many detailed mechanisms regarding the imbalance of osteoblast/osteoclast coupling and the destruction of the osteocyte network are still mainly based on castrated animal models, bone defect repair models, and some other basic research on bone metabolic diseases (such as RA-related bone destruction), and the high-resolution structural and functional verification of human PMOP bone specimens is relatively limited. Therefore, the description of the imbalance of “osteoblasts–osteoclasts–osteocytes” in this section can be seen more as a pathological framework extrapolated from related models to PMOP, and the specific degree and population differences still need to be clarified by further clinical and translational research.

In summary, this section primarily outlines the morphological and cellular basis of the imbalance in osteoblast-osteoclast coupling in PMOP with respect to “bone structure and osteocyte network.” Specific cytokine networks, RANKL signaling activation, and their cascading effects with immune cells will be elaborated in subsequent sections 4.3 and 5.1, and will not be discussed here again.

BMAT plays an important role in the bone marrow microenvironment, with its quantity and function undergoing dynamic changes under various physiological and pathological conditions (74). BMAT is not only an energy-storing fat depot but also an active tissue involved in endocrine and immune regulation, participating in the modulation of bone metabolism and immune response. Particularly in diseases associated with reduced bone mass, such as PMOP, the increase in bone marrow adipocytes is considered one of the important factors for bone loss (75). This section focuses on the mechanisms by which the increase in bone marrow adipocytes regulates immune response and bone metabolism through the secretion of adipokines. It also examines how the interaction between adipose tissue and immune cells promotes inflammatory states and inhibits the osteogenic process. Firstly, the increase in bone marrow adipocytes is accompanied by changes in the secretion of adipokines (such as adiponectin, leptin, inflammatory cytokines, etc.), which regulate the metabolic balance of bones through paracrine and endocrine pathways (76). Studies have shown that the expansion of bone marrow adipose tissue is closely related to the decline in bone mass. Pro-inflammatory factors produced by adipocytes can activate immune cells in the bone marrow, inducing local chronic low-grade inflammation, thereby promoting bone resorption and inhibiting bone formation (77). For example, leptin secreted by bone marrow adipocytes not only regulates systemic energy metabolism but also exerts signaling effects through its receptors on bone marrow immune cells and osteocytes, affecting the inflammatory state of the bone marrow microenvironment and the dynamics of bone metabolism (78).

Secondly, there exists a complex interaction between adipose tissue and immune cells. Bone marrow adipocytes secrete various pro-inflammatory cytokines and chemokines, attracting and activating macrophages, T cells, and other immune cells in the bone marrow, which prompts their polarization toward pro-inflammatory phenotypes, thus forming a chronic inflammatory microenvironment (79). This inflammatory state not only inhibits the differentiation and function of osteoblasts but also activates osteoclasts, increasing bone resorption activity, leading to the occurrence and progression of osteoporosis (80). Moreover, fatty acids and related proteins (such as FABP4) in adipose tissue participate in lipid metabolism and inflammatory signal transduction, further exacerbating the immune imbalance in the bone marrow microenvironment (81). Moreover, the metabolic state of bone marrow adipocytes and their interactions with immune cells are regulated by endocrine factors and external environments. For instance, postmenopausal estrogen deficiency promotes the accumulation of bone marrow adipose tissue and activates immune cells through inflammatory factors secreted by adipocytes, forming a pro-inflammatory microenvironment that leads to bone loss (82). Certain receptors on adipocytes, such as the activation or inhibition of the CD40 signaling pathway, can also regulate the function of bone marrow immune cells, affecting bone metabolism and the state of adipocytes (83). Additionally, bone marrow adipose tissue interacts with BMSCs and other bone marrow stromal cells to regulate their differentiation towards adipocytes or osteoblasts, thereby influencing bone repair and remodeling (84).

In summary, the increase in bone marrow adipose tissue is not only a phenotypic marker of bone metabolic diseases such as osteoporosis but also regulates the activity and inflammatory state of immune cells in the bone marrow through the secretion of various adipokines, forming a complex regulatory network of fat–immune–bone. The interaction between adipose tissue and immune cells promotes the inflammatory state of the bone marrow microenvironment, inhibits osteoblast activity, enhances bone resorption, ultimately leading to bone loss. In animal models related to PMOP and clinical observations, the expansion of BMAT is highly correlated with bone loss and fracture risk, suggesting that bone marrow fat is not only a passive marker of bone marrow aging but also an important “amplifier” of immune reprogramming and inflammatory bone loss. A deeper understanding of the mechanisms by which bone marrow adipose tissue functions in the bone immune microenvironment is expected to provide new therapeutic strategies and intervention targets for diseases such as PMOP (Figure 3). This subsection focuses on the expansion of BMAT and its role as a structural and endocrine hub of “fat–immune–bone”; the specific immune lineage changes driven by adipokines and the remodeling of cytokine networks will be elaborated in Sections 4 and 5 from the perspectives of “immune phenotype” and “signaling pathways,” respectively.

The remodeling of the bone marrow microenvironment constitutes a key link in the pathogenesis of osteoporosis, where the interactions among blood vessels, nerves, and matrix components form a complex regulatory network. The impairment of bone marrow angiogenesis plays a crucial role in the pathological process of osteoporosis. Under normal circumstances, bone marrow blood vessels not only provide essential nutrients and oxygen to osteocytes but also provide channels for the migration and distribution of immune cells (85). However, in obesity and aging models induced by a high-fat diet, dysfunction of bone marrow blood vessels leads to reduced angiogenesis in the bone marrow microenvironment, which in turn affects the directional migration and activity of immune cells, decreases immune defense efficiency, and weakens the metabolic support for osteocytes. This abnormal angiogenesis not only limits the rate of cellular renewal within the bone marrow but also promotes the accumulation of adipocytes in the bone marrow, creating a microenvironment conducive to bone resorption, ultimately leading to reduced bone mass and structural damage (86).

Secondly, nerve signals play an important role in bone immune regulation. The abundant nerve fibers within the bone marrow regulate the functional state of immune cells and bone metabolism processes by releasing neurotransmitters and neuropeptides. The conduction of nerve signals regulates the activation and secretion functions of immune cells such as bone marrow macrophages and T cells, influencing the balance of bone remodeling (36). In the pathological state of osteoporosis, the dysregulation of the nerve-immune axis can exacerbate the inflammatory response in the bone marrow, enhance the activity of bone resorption cells, and inhibit the function of osteoblasts (87). Furthermore, nerve signals may mediate the interaction between the bone marrow and the central nervous system, forming a systemic regulatory network that modulates the dynamic changes in the bone immune microenvironment (88).

Additionally, the ECM of the bone marrow serves as an important “scaffold” for maintaining the structure and signal transduction of the bone marrow, and changes in its components and physical properties profoundly affect cell behavior (89). After menopause, the imbalance of ECM components such as type I collagen and proteoglycans, as well as changes in matrix stiffness, can directly regulate the adhesion, migration, and colonization of HSCs/HSPCs and MSCs, thereby influencing their differentiation tendencies between osteogenic/adipogenic lineages. At the same time, ECM remodeling alters the spatial presentation of adhesion molecules and chemokines, reshaping the distribution patterns of immune cells such as T cells and macrophages within the bone marrow cavity. Increasing evidence suggests that abnormal ECM remodeling after menopause is closely related to immune cell activation and inflammation amplification, maintaining a low-grade chronic inflammatory state in the bone marrow by promoting the sustained release of pro-inflammatory factors, thereby further exacerbating the bone loss process (90). However, current direct evidence regarding the abnormal vascular-nerve-matrix pathway in PMOP mainly comes from studies on bone biopsies of castrated/aged animal models, obesity-related models, and some other bone disease patients, lacking systematic human data on the fine structure and mechanical characteristics of the bone marrow niche in typical PMOP patients. Therefore, this section provides more of a “pathological framework based on related models” rather than definitive conclusions fully validated in the PMOP population.

In summary, the vascular-nerve-matrix pathway collaborates in the remodeling of the bone marrow microenvironment: impaired angiogenesis limits the migration of immune cells and the nutritional supply to osteocytes; meanwhile, the abnormal remodeling of ECM components and matrix stiffness alters the adhesion, migration, and spatial distribution of HSCs/MSCs and maintains chronic inflammation; additionally, nerve signals participate in the pathological process of osteoporosis by regulating immune cell functions. This section focuses on the remodeling at the “structural and niche” level, providing space and contextual background for the subsequent discussions on immune lineage changes (Section 4) and chemotactic axes (Section 5.3), avoiding repetitive mechanistic elaboration on the same group of cells and factors at different levels. A deeper understanding of these mechanisms provides new perspectives for the study of the bone immune microenvironment in PMOP and lays the foundation for the development of future therapeutic strategies targeting the bone marrow microenvironment (Figure 3).

The functions and phenotypes of innate immune cells in the bone marrow microenvironment are regulated by various internal and external environmental factors, especially under the pathological state of PMOP, where their immune reprogramming exhibits significant characteristics. Bone marrow macrophages polarize towards the pro-inflammatory M1 type, becoming a key factor in the progression of osteoporosis (91). In this process, the output of inflammatory factors from M1 macrophages is enhanced (such as TNF-α, IL-1β, and IL-6). To avoid elaborating on the detailed mechanisms of the cytokine network in different sections, this section only emphasizes the phenotypic characteristics of “pro-inflammatory polarization + enhanced osteoclast activity.” The specific positions and synergistic effects in the cytokine network will be integrated and elaborated in section 4.3. M1 macrophages enhance osteoclast activity, speeding up the absorption of bone matrix and bone loss (92). This polarization shift is driven not only by the enhancement of inflammatory signals in the bone marrow microenvironment but also closely related to the remodeling of HSCs/HSPCs functions.

The recently proposed concept of “trained immunity” provides a new theoretical framework for understanding the reprogramming of innate immunity in the bone marrow. Brief microbial or inflammatory stimuli (such as BCG or β-glucan) can induce HSPCs and their progeny myeloid cells to acquire a long-term “memory-like” enhanced response capability through metabolic and epigenetic remodeling, resulting in a stronger inflammatory response upon re-encountering stimuli (93, 94). This mechanism has protective significance in anti-infection and anti-tumor contexts, but in chronic bone metabolic diseases, it may manifest as the maintenance of persistent low-grade inflammation. In the context of PMOP, factors such as estrogen deficiency, bone marrow aging, and BMAT expansion overlap, making “trained immunity” more likely to solidify towards a pro-inflammatory phenotype, forming what is known as “trained inflammatory marrow,” providing a long-term drive for inflammatory bone loss (95). This part mainly supplements the “immune consequences” of HSC myeloid bias described in section 3.1 at the level of immune function and memory-like reprogramming, without repeating the structural details of cell lineages and ecological niches.

Monocytes and dendritic cells (DCs) also undergo significant phenotypic and functional remodeling, participating in the formation and maintenance of the inflammatory environment. Studies have found that inflammatory and metabolic reprogramming can induce monocytes to transition to a pro-inflammatory phenotype, with the cytokines and chemokines they secrete further exacerbating the inflammatory microenvironment in the bone marrow (96). As a bridge connecting innate and adaptive immunity, the functions of DCs are regulated by the skeletal metabolic environment, which may manifest as a decline in antigen presentation capacity and abnormal release of inflammatory signals in osteoporosis, leading to impaired immune surveillance and imbalanced bone remodeling (97). Additionally, metabolites in the bone marrow microenvironment, such as lactate, can also regulate the signaling pathways of macrophages and dendritic cells, affecting their polarization states and functional activities, further promoting pro-inflammatory responses (98). This reprogramming of innate immune cells is not limited to the local bone marrow but interacts with systemic inflammatory responses and the bone-immune axis. Recent studies have shown that hematopoietic stem cells in the bone marrow undergo metabolic and epigenetic reprogramming under external stimuli, forming a trained immunity state, which is beneficial for anti-infection and anti-tumor responses but may also become the pathological basis for chronic inflammation and diseases such as osteoporosis (99, 100). In PMOP, this trained immunity is more inclined to maintain a low but persistent pro-inflammatory environment, keeping osteoclast signaling in a mildly activated state, becoming a “hard-to-turn-off engine” for bone loss (101).

In summary, the reprogramming of bone marrow innate immune cells in PMOP is characterized by the polarization shift of macrophages towards the pro-inflammatory M1 type, enhancing osteoclast activity; at the same time, the phenotypic and functional changes of monocytes and dendritic cells collectively shape a stable pro-inflammatory bone immune microenvironment. These changes are maintained through complex metabolic and epigenetic mechanisms and are highly consistent with the concept of trained immunity. Future research should focus on precisely regulating the states of these immune cells, especially in the context of estrogen deficiency and bone marrow aging, in order to restore bone marrow immune homeostasis and thus slow down the progression of osteoporosis.

Adaptive immune cells play a key role in the bone marrow microenvironment, and changes in their lineage and function are closely related to osteoporosis, especially PMOP. The decline in estrogen levels after menopause leads to complex reprogramming of the immune system, affecting the homeostasis of the bone immune microenvironment and the balance of bone metabolism (102). Firstly, the imbalance of Th17/Treg cells is a core link in the changes of adaptive immune cell lineages. Th17 cells are a type of helper T cell that promotes inflammatory responses, and the IL-17 they secrete can significantly promote the differentiation and activity of osteoclasts, thereby enhancing bone resorption and leading to a decrease in bone mass. In contrast, Treg primarily suppress immune responses, maintain immune tolerance, and protect bone tissue from excessive destruction (103). After menopause, due to estrogen deficiency, the suppressive function of Treg cells weakens, while the number and activity of Th17 cells increase, leading to an imbalance between the two, resulting in a pro-resorptive inflammatory environment that facilitates the onset and progression of osteoporosis (104). Relevant studies suggest that regulating the Th17/Treg balance is a potential therapeutic strategy to alleviate PMOP (105). Secondly, the activation of T follicular helper cells (Tfh) and CD8⁺ T cells also participates in bone immune regulation and the process of inflammatory aging. Tfh cells mainly support the maturation of B cells and antibody production. Their activation affects the composition and function of B cell subsets in the bone marrow microenvironment, thereby indirectly regulating bone metabolism (106, 107). At the same time, CD8⁺ T cells, as a type of cytotoxic T lymphocyte, participate not only in immune surveillance within the bone marrow but also influence the function of osteoclasts and osteoblasts by secreting cytokines. With aging and menopause, the functional state of CD8⁺ T cells changes, exhibiting characteristics of inflammatory aging, which may exacerbate the pathological process of osteoporosis (108).

Moreover, changes in B cell subsets are also crucial in the bone immune environment. Regulatory B cells (Breg) have immunosuppressive effects and can secrete anti-inflammatory cytokines such as IL-10 to inhibit excessive immune activation and maintain immune balance in the bone marrow (109). After menopause, the number of Breg cells decreases, and their immunosuppressive ability weakens, making pro-inflammatory T cells and osteoclast-related signals more dominant (110). In contrast, the number of age-related B cells (ABCs) significantly increases. These B cells exhibit a strong pro-inflammatory phenotype and significantly upregulate RANKL expression, which can directly promote osteoclast differentiation and bone resorption (111, 112). Therefore, the transition of B cell subsets from “Breg dominance” to “ABCs dominance” constitutes a typical adverse reprogramming of the adaptive immune system to the skeletal environment (113). However, current associations between Th17/Treg imbalance, Breg/ABCs reconstruction, and PMOP are mainly based on small-scale clinical studies of peripheral blood/limited bone marrow samples from postmenopausal osteoporosis patients; some mechanistic understandings of Tfh, CD8⁺ T cells, and ABCs are more derived from other chronic immune diseases such as rheumatoid arthritis. Therefore, the inferences in this section under the context of PMOP still have certain analogical and exploratory nature (105, 114).

In summary, in the bone marrow immune microenvironment of PMOP, significant changes occur in the lineage of adaptive immune cells. The imbalance of Th17/Treg cells promotes inflammation and bone resorption; the activation of Tfh and CD8⁺ T cells participates in bone immune regulation and inflammatory aging; and the reconstruction of B cell subsets regulates bone metabolism through RANKL. More importantly, the changes in the aforementioned T/B cell axis synergize with RANKL upregulation and NLRP3 inflammasome activation, forming a key node of inflammatory bone loss in the PMOP bone immune microenvironment, laying an immunological foundation for the subsequent discussion on cytokine networks and signaling pathways.

The remodeling of the cytokine network in the bone marrow immune microenvironment is an important aspect of the pathogenesis of PMOP. After menopause, due to the decline in estrogen levels, the activity of immune cells in the bone marrow increases, and the expression of pro-inflammatory cytokines is significantly upregulated, resulting in increased osteoclast activity, aggravated bone resorption, and significant bone loss (115). In this process, the increased ratio between RANKL and its inhibitor OPG is a direct manifestation of enhanced bone resorption signaling (116, 117). Centered on this “core of bone resorption signaling,” various pro-inflammatory cytokines such as TNF-α, IL-6, IL-17, and IFN-γ form a synergistic amplification network (118). Considering that these factors have been elaborated from the “cellular origin” perspective in sections 4.1 (M1 polarization) and 4.2 (Th17/Treg imbalance, B cell subset reconstruction), this section will not repeat the discussion by cell type, but rather emphasize their common effects: Immune lineage reprogramming is “translated” into a persistent osteoclastic signal perceivable by the skeletal system through upregulating RANKL, downregulating OPG, and directly or indirectly enhancing osteoclast differentiation and survival (119, 120).

In addition, the activation of inflammasomes such as NLRP3 is closely related to inflammatory bone loss. The NLRP3 inflammasome senses intracellular danger signals, activating the maturation and release of IL-1β and IL-18, promoting local inflammatory responses (121). Studies have shown that the NLRP3 inflammasome is activated in osteoporosis models, promoting the formation of a bone marrow inflammatory environment, exacerbating osteoclast-mediated bone resorption, and synchronously upregulating the expression of pro-inflammatory factors such as TNF-α and IL-6 (122). From a hierarchical perspective, the NLRP3–IL-1β/IL-18 axis can be viewed as an “amplifier”: on one hand, it deepens the pro-inflammatory phenotype of immune cells, and on the other hand, it strengthens the coupling of the cytokine cluster with the RANKL axis, providing upstream driving forces for pathway-level imbalance.

In summary, the bone immune microenvironment of PMOP is characterized by an “immune-bone interface” mediating layer, centered on the imbalance of RANKL/OPG and represented by a cluster of pro-inflammatory factors such as TNF-α, IL-6, IL-17, IFN-γ, and NLRP3–IL-1β/IL-18. This mediating layer connects the structural remodeling and immune lineage changes described in sections 3–4 above, and below, it coordinates the terminal effects of osteogenesis/resorption through RANK and related signaling pathways, thus completing the logical closed loop of “immune reprogramming → bone metabolism imbalance” without repeating the cellular and factor backgrounds (Figure 4).

The RANK/RANKL/OPG axis is a key regulatory system for maintaining skeletal homeostasis, which plays a central role in the pathological process of PMOP. RANKL is secreted by various cells in the bone marrow microenvironment (including osteoblasts, osteocytes, B cells, and some T cells), and can bind to its receptor RANK, promoting the differentiation and activation of osteoclasts, thereby enhancing bone resorption function (123, 124). In contrast, OPG, as a soluble RANKL “decoy” receptor, can competitively bind to RANKL, blocking its interaction with RANK. This inhibits the generation and activity of osteoclasts, maintaining the balance of bone remodeling (125, 126). Under normal circumstances, the dynamic balance between RANKL and OPG ensures the coordination of bone resorption and bone formation, maintaining the homeostasis and health of bone tissue (127).

In postmenopausal women, this balance is disrupted due to a significant decrease in estrogen levels (128). As described in section 4.3, various pro-inflammatory cytokines (including TNF-α, IL-6, IL-17, etc.) promote an increase in the RANKL/OPG ratio by upregulating RANKL and downregulating OPG. To avoid repetitive explanations of the same group of factors and their general inflammatory effects in different sections, this section will not elaborate on their immunological background but will focus on the integration and amplification function of this axis on the “osteocyte side.” Once the RANKL/OPG ratio crosses a critical threshold, osteoclast precursors are continuously activated through RANK-mediated NF-κB, MAPK, and other pathways, promoting their differentiation into mature osteoclasts and extending their lifespan, resulting in a long-term imbalance of “bone resorption > bone formation” (129–131). Furthermore, the expression of OPG is regulated by multiple factors including estrogen, mechanical load, and local microenvironment, and its downregulation not only weakens the buffering capacity against RANKL but also indirectly affects the initiation of the osteogenic process, as excessive bone resorption inhibits the recruitment and activation of osteoblasts (132–134). Therefore, in the PMOP bone immune microenvironment, the RANK/RANKL/OPG axis can be viewed as a signal hub that translates the “structural remodeling + immune reprogramming” described in sections 3–4 into signals for bone loss.

Recent studies have also found that some natural compounds, such as flavonoids, can inhibit osteoclast activity and promote bone formation by regulating the RANKL/RANK/OPG axis, providing new ideas for the treatment of PMOP (135). For example, the flavonoid rutin can regulate the signaling pathways related to this axis, alleviate inflammatory responses and oxidative stress, and restore bone metabolic homeostasis, showing potential therapeutic value (136). From the perspective of bone immunology, such interventions can be understood as downstream rebalancing acting on the “osteocyte-signal hub”: without the need to directly reverse the entire immune lineage reprogramming, by reshaping the response threshold and output intensity of the RANK axis, partially severing the pathway of “immune inflammation leading to osteoclast dominance,” providing actionable targets for the precise prevention and treatment of PMOP.

The Wnt/β-catenin signaling pathway is a key regulatory mechanism in the process of bone formation, widely involved in the proliferation and differentiation of bone cells, and the maintenance of bone tissue homeostasis. This pathway promotes the differentiation of bone marrow mesenchymal stem cells into osteoblasts through the activation of β-catenin, enhancing the synthesis and mineralization of the bone matrix. This thus promotes bone formation (137). Conversely, inhibitors of the Wnt signaling pathway, such as Sclerostin and Dickkopf-1 (DKK1), prevent the accumulation of β-catenin by blocking the binding of Wnt ligands to receptors, reducing osteogenic activity and leading to impaired bone formation (138, 139).

Immune cells regulate the Wnt/β-catenin pathway by secreting various cytokines, thereby affecting the dynamic balance of bone formation. For example, the polarization state of macrophages has a significant impact on Wnt signaling (140). Based on the overall characteristics of M1/M2 polarization clarified in section 4.1, this section will only supplement parts directly related to the Wnt axis without repeating its general inflammatory effects. Studies have shown that pro-inflammatory M1 macrophages can activate the Wnt/β-catenin pathway by releasing IL-17A, promoting the inflammatory response while inhibiting the polarization of M2 macrophages; moderate activation of the Wnt/β-catenin signaling can inversely inhibit IL-17A-induced M1 polarization and promote M2 polarization, thus playing a dual regulatory role in immune-osteogenesis during bone repair (141). In addition, the Wnt signaling pathway also regulates the autophagic activity of macrophages, maintaining their immune regulatory function, which is beneficial for bone tissue regeneration (142).

Regarding inhibitors, DKK1, as a classic Wnt antagonist, also plays an important role in immune regulation. Research on tumors and the bone microenvironment suggests that DKK1 can promote the formation of an immunosuppressive microenvironment by affecting the phenotype of macrophages and other immune cells, and inhibit immune responses related to bone repair (143). Some studies indicate that DKK1 can activate downstream signals such as PI3K–AKT after binding to immune cell surface receptors (e.g., CKAP4), inducing an immunosuppressive phenotype and hindering tissue repair, suggesting that the “DKK1–immune–bone” axis may be a noteworthy negative regulatory pathway in osteoporosis and bone injury; correspondingly, blocking DKK1 is expected to restore Wnt-dependent osteogenic capacity and may indirectly improve the bone immune microenvironment (143). Sclerostin is primarily secreted by osteocytes and serves as another important inhibitory factor of the Wnt pathway, maintaining bone mass balance in bone metabolism. Sclerostin not only directly inhibits osteoblast function but also participates in the regulation of the immune system, affecting the development and differentiation of B cells (95). It reduces osteoblast activity by lowering Wnt/β-catenin signaling, promoting bone resorption, thereby affecting the stability of the bone immune microenvironment (144). Clinical studies have found that elevated levels of DKK1 and Sclerostin in the plasma of PMOP patients are closely related to decreased bone density and increased fracture risk (145). Meanwhile, activating the Wnt/β-catenin signaling pathway can promote bone repair and formation while improving the polarization state of immune cells, becoming an important target for the treatment of osteoporosis and bone injury (146). However, it should be noted that much of the existing mechanistic evidence regarding the fine associations between the Wnt/β-catenin–Sclerostin/DKK1 axis and immunological aspects such as macrophage polarization and B cell development largely comes from models of rheumatoid arthritis, tumor bone microenvironments, and bone defect repair rather than PMOP models. Therefore, the discussion of the “Wnt–immune–osteogenesis” interactive network’s role in PMOP in this section should be understood more as an integrated mechanism across diseases and models, and its specific effects in the typical PMOP bone marrow microenvironment still require further verification in subsequent studies.

Currently, there is still limited direct evidence regarding the CXCL12–CXCR4 and S1P chemotactic axes in the context of PMOP. The following primarily draws on research findings from bone marrow-related diseases such as AML, MM, and WHIM syndrome, as a technical and research paradigm that can be transferred to PMOP. The chemokine CXCL12 and its receptor CXCR4 axis play a core role in the migration and localization of immune cells in the bone marrow. HSCs in the bone marrow rely on the support of cytokines and signaling molecules in the local microenvironment. The CXCL12/CXCR4 axis not only directly promotes the quiescent state of HSCs, but is also responsible for guiding HSCs into the stem cell “niche” in the bone marrow, achieving their correct localization and long-term maintenance (147, 148). Bone marrow stromal stem cells and endothelial cells (ECs) are the main constituent cells of these niches, secreting CXCL12 to provide directional migration signals for HSCs and their progeny blood cells (149). In addition, the CXCL12/CXCR4 axis is also involved in regulating the maintenance of immune memory cells, such as memory T cells and plasma cells, which rely on this axis to migrate to the bone marrow and interact with niche cells, ensuring their survival and functional continuity (150). In summary, the CXCL12/CXCR4 axis coordinates the generation of various blood and immune cells in the bone marrow and the maintenance of immune memory by mediating cell recruitment and subsequent maintenance signals. This reflects the key position of this chemotactic axis in stabilizing the bone immune microenvironment. Furthermore, the dysfunction of the CXCR4 receptor can lead to abnormal localization of immune cells and dynamic disturbances of cells in the bone marrow, with typical diseases such as WHIM syndrome, whose etiology is caused by mutations in the CXCR4 gene that lead to receptor endocytosis blockage, resulting in an excessive response to CXCL12 signals, causing mature neutrophils to be abnormally retained in the bone marrow, manifested as neutropenia and recurrent infections. This pathological mechanism further confirms the importance of the CXCL12/CXCR4 axis in regulating the localization of immune cells in the bone marrow (151, 152). Different mutation types have varying impacts on CXCR4 signaling, leading to diversity in clinical manifestations and signaling pathway activities, which also suggests that treatment strategies targeting CXCR4 need to consider the complexity of its signaling regulation (153). In addition to CXCL12/CXCR4, sphingosine-1-phosphate (S1P) axis is also an important regulatory factor for immune cell migration. S1P regulates the circulation of lymphocytes and their homing to the bone marrow by binding to its receptors, maintaining the spatial distribution balance of immune cells (154). Although the specific mechanisms of S1P are not detailed in this review, in the bone marrow and immune microenvironment, S1P interacts with the CXCL12/CXCR4 axis to jointly regulate the migration, localization, and functional status of immune cells, thereby affecting bone immune homeostasis.

In the tumor microenvironment, especially in multiple myeloma, the CXCL12/CXCR4 axis is exploited by malignant plasma cells to evade immune surveillance, promote the localization of tumor cells in the bone marrow, and cause bone destruction. This suggests that this axis not only maintains the normal distribution of immune cells under physiological conditions but may also be pathologically regulated under disease conditions, becoming a potential therapeutic target (155). Existing CXCR4 antagonists such as plerixafor have been used clinically for stem cell mobilization and cancer treatment, demonstrating the feasibility of intervening in this chemotactic axis to regulate the bone marrow immune microenvironment (156). Additionally, the exosome-mediated chemokine delivery mechanism also reveals the extensive role of the CXCL12/CXCR4 axis in tissue regeneration and immune cell recruitment (157). For example, Schwann cell-derived exosomes promote the migration of endogenous stem cells to the injury site by carrying CXCL12 signals, facilitating tissue repair and regeneration, indicating that this chemotactic axis also plays an important role in intercellular communication and regulation in the bone immune microenvironment (158).

In summary, the CXCL12–CXCR4 and S1P chemotactic axes play pivotal roles in the recruitment, migration, and localization of immune cells in the bone marrow. These axes ensure the dynamic balance and functional stability of the bone immune microenvironment. They coordinate the maintenance of hematopoietic stem cells, the preservation of immune memory, and the spatial distribution of immune cells through complex signaling networks, thereby affecting bone metabolism and bone immune homeostasis, and serve as important entry points for studying the pathological mechanisms of PMOP and developing new therapeutic strategies. Currently, direct mechanistic studies on the CXCL12–CXCR4 and S1P axes in the context of PMOP are still relatively limited, with existing evidence mostly coming from bone marrow-related diseases such as AML, MM, and WHIM syndrome, as well as the field of stem cell mobilization. The role of these axes in potentially participating in the localization of immune cells and maintaining low-grade inflammation in PMOP is primarily based on cross-disease and cross-model analogical inference, and lacks systematic verification at the bone marrow level in PMOP. Combining existing evidence regarding HSC aging, MSC senescence, and increased BMAT, it is speculated that the remodeling of these chemotactic axes is involved in the changes in immune cell localization in the bone marrow and the maintenance of low-grade chronic inflammation in PMOP.

The previous sections 3.1–3.3 have described HSC/MSC aging, myeloid bias, and BMAT expansion from the perspective of structure and cell lineage, while sections 4.1–4.3 discuss the reprogramming of innate/adaptive immune lineages and the imbalance of cytokine networks. This section, without repeating the structural and lineage details mentioned above, specifically organizes how bone marrow aging and the SASP continuously drive this multi-layered imbalance from a “temporal dimension,” thereby placing PMOP within the broader framework of inflammaging.

As a microenvironment that is crucial to both hematopoiesis and the skeletal system, the cellular population of bone marrow, particularly MSCs and HSCs, undergoes significant aging changes with increasing age. Cell aging refers to the irreversible growth arrest that cells experience, accompanied by a specific secretory phenotype, namely SASP. SASP mainly includes various pro-inflammatory cytokines, chemokines, and proteases, and the continuous release of these factors not only disrupts local tissue homeostasis but also triggers a chronic low-grade inflammatory state known as “inflammaging” (159–161). Bone marrow aging leads to the accumulation of SASP factors, maintaining a chronic, low-grade but persistent inflammatory state, which plays an important role in the development of osteoporosis (162).

More specifically, the shift in osteogenic-adipogenic differentiation of MSCs described in 3.1 and the expansion of BMAT in 3.3 can be seen as the terminal phenotype of bone marrow aging at the structural and lineage levels; while in the temporal dimension, SASP continuously releases factors such as IL-6, IL-1β, and TNF-α, which simultaneously provide sustained stimulation for the pro-inflammatory polarization of macrophages, the imbalance of Th17/Treg, and the reconstruction of B cell subsets described in 4.1–4.2, while reinforcing the RANKL/OPG imbalance and the cytokine cluster amplification effect summarized in 4.3, ultimately leading to a resettlement of osteoclast-dominant homeostasis at the signaling pathway level, such as the RANK axis described in 5.1 (163). In other words, bone marrow aging and its accompanying SASP are not a single pathological link but a “slow but constant” driving force that runs through multiple levels of sections 3–5.

The composition of SASP factors is complex, including various pro-inflammatory cytokines such as IL-6, IL-1β, and TNF-α, which promote the sustained presence of inflammatory responses by activating signaling pathways like NF-κB, interfere with the function of BMSCs, and induce more cells into a state of senescence, forming a self-reinforcing feedback loop (164, 165). In this context, the regenerative potential of bone marrow stromal cells is continuously interfered with by SASP, and bone remodeling is gradually reset to a “new homeostasis” dominated by bone resorption, which also explains why, clinically, even if some reversible risk factors are corrected in the short term, the improvement in bone mass and bone microstructure in PMOP patients remains limited—the “chronic driving force” maintained by bone marrow aging and SASP has not been fundamentally reversed.

Currently, research on bone marrow aging and SASP is gradually deepening, and exploring their regulatory mechanisms and intervention methods has become a new direction for the prevention and treatment of osteoporosis. Some anti-aging strategies, such as drugs targeting apoptotic senescent cells (senolytics) and drugs modulating SASP (senomorphics), show potential application value, as they can alleviate chronic inflammation in the bone marrow microenvironment and improve the bone metabolic environment by clearing senescent cells or inhibiting the secretion of SASP factors, thereby promoting skeletal health (166, 167). In addition, a combination of various strategies such as lifestyle interventions, drug treatments, and molecular targeted therapy is expected to mitigate the negative impacts of bone marrow aging and delay the progression of osteoporosis (168).

In summary, bone marrow aging maintains and exacerbates a chronic low-grade inflammatory state through the secretion of SASP factors, becoming an important mechanism driving osteoporosis, especially PMOP. A deeper understanding of the interaction between bone marrow aging and SASP and their impact on the bone immune microenvironment is of great significance for developing targeted therapeutic strategies and improving the prognosis of osteoporosis patients (Figure 5). From a broader systemic perspective, local bone marrow aging and SASP are also important components of inflammaging, and their systemic effects will be further discussed in section 6.2.

Estrogen exerts a key regulatory role in the bone marrow microenvironment through its receptors (ER), directly affecting immune cell function and bone metabolic balance (169). Estrogen receptors are classified into two subtypes, ERα and ERβ, which mediate the activation state and phenotypic changes of immune cells by regulating downstream gene transcription and multiple signaling pathways (170, 171). For example, estrogen can regulate the metabolic state and secretion of inflammatory factors by T cells and macrophages, promoting the maintenance of an anti-inflammatory phenotype. This indirectly regulates the balance between osteoclasts and osteoblasts and maintains bone homeostasis (172).

After menopause, estrogen levels significantly decline, leading to an imbalance in immune regulation mediated by ER, making immune cells more prone to reprogramming toward a pro-inflammatory phenotype. Studies have shown that estrogen deficiency not only induces immune cells to produce more pro-inflammatory cytokines (such as TNF-α, IL-1β, IL-6), but also promotes the activation of bone-resorbing cells (osteoclasts), enhancing the bone resorption process and causing osteoporosis (21, 173). In addition, the dysbiosis of gut microbiota associated with estrogen deficiency also exacerbates bone loss through the interaction between the immune system and bone metabolism; changes in microbial composition and impaired intestinal barrier can promote the entry of microbe-associated molecular patterns (MAMPs) into the bloodstream, activating innate immune cells in the bone marrow and maintaining low-grade chronic inflammation (174). The specific characteristics of macrophage M1/M2 polarization, Th17/Treg imbalance, and changes in B cell lineages have been detailed in sections 4.1–4.2; therefore, this section emphasizes the upstream triggering role of “estrogen–ER–immune reprogramming” without repeating the mechanisms at the cellular lineage level.

The regulation of immune cell metabolism and function by estrogen also involves endoplasmic reticulum stress (ERS)-related pathways. ERS affects the phenotype and inflammatory state of immune cells by regulating their metabolic reprogramming and secretory profiles (175). Under conditions of estrogen deficiency, ERS-related signals such as the IRE1α/XBP1 pathway are activated, promoting the abnormal expression of pro-inflammatory factors and immune-suppressive factors, further exacerbating the imbalance of the immune microenvironment and osteoporosis (176, 177). It should be noted that current evidence regarding ER-mediated estrogen–immune–bone axis reprogramming mainly comes from animal models and in vitro cell experiments. Direct validation in PMOP patients remains limited. This limited clinical validation indicates that the mechanistic inferences discussed in this review should be considered as a framework of hypotheses rather than definitive conclusions confirmed in clinical settings.

In summary, estrogen plays a pivotal regulatory role in immune cell function and bone metabolism through ER-mediated signaling pathways. After menopause, estrogen deficiency leads to weakened ER signaling, which causes immune cells to shift towards a pro-inflammatory phenotype. This shift enhances osteoclast activity, promotes bone resorption, and ultimately results in osteoporosis.

Inflammaging is a chronic low-grade systemic inflammatory state that occurs with aging and is one of the important upstream driving forces affecting the bone immune microenvironment (178, 179). In postmenopausal women, the decline in estrogen levels, combined with age-related immune senescence, makes key immune cell subpopulations such as bone marrow macrophages and osteal macrophages (bone-resident macrophages) more prone to acquiring pro-inflammatory and senescence-associated transcriptional profiles, thereby amplifying the existing baseline of bone marrow inflammation (180). The continuously released pro-inflammatory mediators (such as IL-6, TNF-α, and others) not only directly damage osteogenic-related cells (such as MSCs and osteoblasts) but also induce a persistent shift in bone metabolism towards bone resorption surpassing bone formation by promoting osteoclast generation and activity (162). In the PMOP model, the clearance of senescent cells or oxidative stress-related subpopulations of bone marrow macrophages can partially alleviate bone loss. This further supports that inflammaging is one of the key pathological bases of PMOP (181, 182).

Unlike Section 5.4, which focuses on “local bone marrow senescence and SASP,” this section emphasizes the systemic level of inflammaging. The impact of inflammaging on the bone immune microenvironment is not limited to the local bone marrow. The SASP factors released by senescent MSCs, T cells, and other immune subpopulations enter circulation and maintain low-grade inflammation throughout the body. This persistent inflammation promotes imbalance in the gut-bone-immune axis and forms a pathological loop of “systemic inflammaging – bone marrow inflammation – bone loss” (183, 184). Furthermore, estrogen deficiency also increases intestinal permeability and microbial displacement by affecting gut microbiome and barrier function, which further amplifies the systemic inflammatory response (185).

From a clinical perspective, multiple cohort studies have observed that systemic inflammatory indicators such as the systemic immune-inflammation index (SII) and C-reactive protein (CRP) are positively correlated with the occurrence of PMOP and fracture risk, suggesting that these inflammatory markers can serve as auxiliary indicators for assessing osteoporosis risk and disease progression (186, 187).Notably, intervention strategies targeting inflammaging are emerging as a new direction in the field of PMOP. In addition to senolytics and senomorphics—agents that selectively eliminate or modulate senescent cells—some active ingredients of traditional Chinese medicine and plant extracts have also shown potential in modulating inflammaging (188). For example, Icariin can promote the recovery of osteoblast function by activating autophagy and inhibiting the inflammatory senescence phenotype of bone marrow macrophages, thereby alleviating bone loss (189). Extracts of Cimicifuga racemosa have been confirmed to reshape macrophage immune metabolism and inhibit proinflammatory signals, exhibiting potential anti-inflammatory aging effects (190). These strategies provide new ideas for comprehensive intervention in PMOP, by regulating the bone immune microenvironment from the perspective of systemic inflammaging. However, current evidence regarding the association between inflammaging and PMOP risk is supported by several large-sample epidemiological studies based on inflammatory indicators such as CRP and SII. Mechanistic evidence targeting specific senescent immune cell subpopulations and their SASP mainly comes from animal models and in vitro experiments. At the same time, research on the intervention effects of natural products like Icariin and Cimicifuga racemosa on inflammaging is still largely in the preclinical stages. Therefore, the relevant content of this section is more suitably understood as mechanistic integration and intervention ideas with clinical relevance, rather than a validated standard treatment pathway.

In summary, inflammaging exacerbates the process of bone loss in PMOP by maintaining chronic low-grade systemic inflammation, altering the composition and function of bone marrow and systemic immune cells, and promoting the continuous release of proinflammatory factors. Compared to the emphasis on local bone marrow senescence mechanisms and the connotation of SASP in Section 5.4, this section supplements the upstream background from the perspectives of systemic inflammaging, clinical inflammatory indicators, and systemic intervention strategies, logically connecting the two perspectives rather than simply repeating them.

The imbalance of the gut microbiome has a profound impact on systemic immune responses and bone metabolism. The surfaces exposed to the external environment in mammals are covered by a large number of symbiotic microorganisms; the gut microbiome is one of the richest ecosystems which regulate the activity of important endocrine hormones related to bone development and metabolism, such as parathyroid hormone (PTH) (191, 192). Studies have shown that gut microorganisms mediate the effects of PTH on bone resorption and bone formation through their metabolites, such as short-chain fatty acids (SCFAs), and through the migration of immune cells; this reveals the communication mechanism between gut microorganisms and bone marrow cells (193). Furthermore, changes in the gut microbiome or antibiotic-induced depletion of the microbiome can weaken the migration of natural killer (NK) cells and Th1 cells from the gut to the bone marrow, leading to accelerated tumor growth in bone tissue. This indicates that the migration of gut immune cells plays a key role in maintaining immune homeostasis in the bone marrow and bone metabolism (194). With aging, both the gut microbiome and the hematopoietic system undergo changes. Gut microorganisms influence the regulation of HSCs and the generation of immune cells through various mechanisms, including their metabolites, MAMPs, and Toll-like receptor (TLR) signaling pathways. These mechanisms indirectly regulate the immune environment of the bone marrow (195). These findings suggest that postmenopausal women with gut microbiome–SCFAs imbalance may amplify the preferential effects of PTH and other endocrine factors on bone resorption, thereby increasing the risk of bone loss.

The impairment of gut barrier function is a critical factor facilitating the entry of pro-inflammatory factors into circulation within the gut-bone-immune axis. Patients with PMOP often exhibit gut microbiome dysbiosis accompanied by gut barrier disruption. This leads to the translocation of bacteria and their products, such as lipopolysaccharides (LPS), across the gut barrier into the bloodstream; this triggers systemic chronic low-grade inflammation, promoting bone resorption and bone loss (196). The expression of tight junction proteins in the gut barrier is reduced, accompanied by increased gut permeability, which promotes inflammatory responses and abnormal activation of immune cells, further affecting the immune microenvironment of the bone marrow (197). Additionally, damage to the gut barrier results in a reduction of beneficial bacteria and their metabolites, such as butyrate, which affects the function of Treg and promotes an increase in inflammatory Th17 cells in the bone marrow, thereby activating the bone resorption process (198, 199). Studies have found that gut microbiota, such as Akkermansia muciniphila, have a protective effect on osteoporosis by regulating the gut barrier and immune responses, with their abundance closely related to bone metabolic status (200). These results collectively point to a potential closed loop related to PMOP. Specifically, the imbalance of gut microbiota and barrier damage not only triggers systemic inflammation but can also directly reprogram the immune status of the bone marrow through specific immune axes.

The imbalance of gut microbiota not only affects local gut immunity but also mediates immune reprogramming of the gut-bone axis through the migration of immune cells and the circulation of metabolic products. Gut immune cells, such as bone marrow-derived dendritic cells and macrophages, undergo phenotypic changes under the influence of gut microorganisms. These changes regulate the immune microenvironment of the bone marrow and affect the bone remodeling process (201). Furthermore, gut microbial metabolites can act on the bone marrow through the bloodstream, regulating the differentiation and function of immune cells within the bone marrow and maintaining skeletal homeostasis (202). Therefore, regulating the gut microbiome and maintaining gut barrier function have become potential strategies for improving osteoporosis and related bone immune diseases. In recent years, treatment research targeting the gut-bone-immune axis has gradually increased, based on probiotics, prebiotics, dietary interventions, and fecal microbiota transplantation, showing good bone protective effects and immune regulatory potential (203, 204). From the perspective of PMOP prevention and treatment, intervention in the gut-bone-immune axis is particularly suitable as a systemic, long-term auxiliary strategy. On one hand, by reconstructing the microbiota-barrier-metabolite network, it alleviates immune imbalance against the background of inflammatory aging. On the other hand, it complements anti-bone resorption and anabolic drugs, with the potential to achieve three-dimensional coordinated regulation involving endocrine, immune, and metabolic systems (205, 206). However, it should be emphasized that much of the evidence regarding the “microbiota-barrier-LPS-Th17/Treg-bone loss” loop and the role of specific strains (such as A. muciniphila) in bone protection still comes from animal models and small exploratory studies. Large-scale prospective cohort and interventional trials specifically targeting postmenopausal osteoporosis/PMOP women are still lacking. Therefore, the discussion of the potential role of the gut-bone-immune axis in PMOP in this section is more of a comparative inference and intervention hypothesis based on cross-disease and cross-model evidence, awaiting further validation and refinement through high-quality clinical and translational research in the future.

In summary, the imbalance of the gut microbiome affects bone metabolism and bone health by influencing gut barrier function and promoting the translocation of inflammatory factors and microbial products into the bloodstream. It also regulates the immune microenvironment of the bone marrow. The gut-bone-immune axis serves as a key regulatory network for immune-related bone diseases such as osteoporosis, providing new therapeutic targets and strategies for clinical practice. To advance this field, future efforts should further deepen the understanding of its molecular mechanisms and promote the development of precision medicine and personalized treatment approaches (Figure 6).

The therapeutic mechanisms of existing anti-osteoporosis drugs are not limited to their direct effects on bone cells; an increasing number of studies reveal their regulatory roles in the bone immune microenvironment, emphasizing the central position of the immune system in the bone remodeling process. Immune cells and the cytokines they secrete regulate the activity of osteoclasts and osteoblasts, affecting the balance of bone metabolism and forming the basis of bone immunology.

Bisphosphonates, the widely used anti-osteoporosis drugs in clinical practice, primarily exert their anti-osteoporosis effects by inducing osteoclast apoptosis and inhibiting bone resorption (207). Recent studies have shown that bisphosphonates also have the potential to regulate the bone immune microenvironment. Firstly, bisphosphonates can reduce the activity of osteoclasts and decrease the release of pro-inflammatory factors related to bone resorption, thereby alleviating the inflammatory state of the bone microenvironment (208). On the other hand, bisphosphonates affect immune cell function by inhibiting the activation of pro-inflammatory macrophages and promoting the increase of Treg. This regulation of immune balance helps protect and repair bone quality (209). In addition, the antigen fragments released from osteoclast apoptosis induced by bisphosphonates can be taken up by antigen-presenting cells, activating specific immune responses and further regulating the activity of immune cells, thus influencing bone remodeling and metabolism (210). These mechanistic insights provide a new immunological perspective on the bone protective effects of bisphosphonates, suggesting that they are not merely simple bone resorption inhibitors. Transitioning to another class of drugs, Denosumab is a humanized monoclonal antibody that specifically targets RANKL (receptor activator of nuclear factor κB ligand). It blocks the binding of RANKL to the RANK receptor and inhibits the formation and function of osteoclasts (211, 212). RANKL is not only a key factor in osteoclast differentiation but also an important signaling molecule for various immune cells such as T cells, B cells, and dendritic cells (213). Denosumab indirectly regulates the activity of immune cells and their communication with bone cells by inhibiting RANKL, restoring balance within the bone immune microenvironment (214). Studies show that Denosumab treatment can reduce the production of pro-inflammatory cytokines, inhibit immune-related bone resorption processes, and improve bone density and bone quality. Furthermore, the application of Denosumab in immune-mediated bone diseases such as rheumatoid arthritis further confirms its mechanism of regulating immune-bone cell interactions (215). However, Denosumab has a minimal impact on the gastrointestinal microbiota, suggesting that its immunomodulatory effects are primarily limited to the local immune environment of the bone (216). Selective estrogen receptor modulators (SERMs) regulate bone metabolism and the immune response by mimicking the bone-protective effects of estrogens. Estrogen deficiency is a major trigger for PMOP, leading to an increase in pro-inflammatory cytokines such as TNF-α and IL-6 in the immune system, promoting osteoclast activity and bone resorption (217). SERMs inhibit the expression of these pro-inflammatory factors by activating estrogen receptors, alleviating the inflammatory state of the bone, while promoting the activity of regulatory immune cells to balance the bone immune microenvironment (206). PTH and its analogs, such as Teriparatide, promote bone formation by directly activating osteoblasts and regulating the release of cytokines from immune cells, such as increasing the anti-inflammatory cytokine IL-10 and IFN-γ. These actions promote bone regeneration and inhibit bone resorption (218, 219). These immunomodulatory effects help restore the dynamic balance of bone metabolism and improve the bone microenvironment. Romosozumab is a monoclonal antibody against sclerostin that promotes bone formation and inhibits bone resorption. Sclerostin, which is secreted not only by osteoblasts, also participates in regulating immune cell function (220, 221). Romosozumab regulates the Wnt signaling pathway, thus affecting the activity of immune cells, improving the inflammatory state, and promoting the repair of the bone immune microenvironment (222). Through these mechanisms, the bidirectional regulatory effects of Romosozumab make it a powerful drug for the treatment of osteoporosis in bone immunology (223).

In summary, existing anti-osteoporosis drugs not only inhibit osteoclast activity and promote osteoblast function but also influence the overall balance of bone metabolism by regulating immune cells and the cytokines they secrete within the bone immune microenvironment. In-depth research on these bone immunological mechanisms provides a theoretical basis and practical guidance for developing more precise and effective treatment strategies for osteoporosis. It also offers important evidence for reinterpreting the mechanisms of action of anti-RANKL drugs such as Denosumab from the perspective of bone immunology. Future drug development should pay greater attention to the cross-regulation between the immune system and bone metabolism, thereby promoting innovative advances in the field of bone immunology.

In recent years, research on the imbalance of the bone marrow immune microenvironment in osteoporosis, especially in PMOP, has driven the development of various emerging immune-targeted therapeutic strategies. The occurrence of PMOP is closely related to inflammatory responses, with inflammatory cytokines such as TNF, IL-6, and IL-17 playing key roles in the imbalance between bone resorption and bone formation. Therefore, interventions targeting these inflammatory pathways show potential for bone protection.

Firstly, treatments targeting inflammatory cytokines such as anti-TNF, anti-IL-6, and anti-IL-17 have been shown to effectively regulate the bone marrow immune microenvironment in osteoporosis (224). TNF, as a pro-inflammatory factor, promotes the differentiation and activity of osteoclasts, exacerbating bone resorption. Inhibiting its signaling pathway using anti-TNF antibodies not only reduces bone resorption but also improves bone metabolic balance (225). Similarly, IL-6 and IL-17 promote bone loss in the bone marrow by activating osteoclast precursors and inducing the release of pro-inflammatory cytokines. Inhibiting these pathways can alleviate inflammatory responses and suppress excessive activation of osteoclasts, thereby exerting bone-protective effects (226). It is important to emphasize that current clinical evidence regarding these biologic agents in directly improving the bone marrow immune microenvironment and reversing bone loss in PMOP patients is still limited. However, the inflammatory pathways they target highly overlap with the immune networks that have been proven to be abnormally activated in the bone marrow of PMOP patients. This overlap provides valuable insights and directions for future exploration of immune-targeted therapeutic strategies for osteoporosis (136). Furthermore, recent studies have shown that the regulation of inflammatory pathways also involves the metabolic and phenotypic reprogramming of myeloid cells and lymphocytes in the bone marrow, offering a new perspective for immune therapies targeting metabolic pathways (227).

Secondly, regulating the functions of immune regulatory cells such as Treg and Breg is an important strategy for restoring the balance of the bone marrow immune microenvironment (228). Treg and Breg cells play central roles in maintaining immune tolerance and suppressing inflammatory responses. Their dysfunction can lead to the excessive activation of pro-inflammatory T cell and B cell subpopulations that promote bone resorption, further exacerbating bone loss. Studies have found that both the quantity and function of Treg cells are impaired in PMOP patients, while promoting the expansion and activation of Treg cells helps to inhibit osteoclast formation and reduce bone resorption (229). Similarly, Breg cells maintain bone immune homeostasis by secreting anti-inflammatory cytokines, including IL-10, which inhibit the activity of pro-inflammatory cells. Immune therapies targeting the regulation of these cell subpopulations, using small molecule drugs or cell therapies, have shown potential bone-protective effects (230). However, current evidence regarding Treg/Breg-related cell therapies or small molecule interventions in the context of PMOP remains largely at the stage of conceptual extrapolation and early experimentation. Existing data are primarily derived from studies on rheumatoid arthritis, osteoarthritis, or tumor immunology, which necessitates more targeted validation in models of estrogen deficiency and postmenopausal populations (231).

In addition, the metabolic reprogramming of immune cells in the bone marrow immune microenvironment has become a new therapeutic target as well. For example, the metabolic status of MDSCs and macrophages derived from bone marrow affects their immunosuppressive functions and bone resorptive effects. Regulating the metabolic pathways of these cells can modulate the immune microenvironment by enhancing anti-inflammatory responses and inhibiting pro-resorptive immune activity, thereby slowing down bone loss (232, 233). The combination of nanotechnology and genetic engineering approaches, such as the intra-bone marrow injection of engineered probiotics or genetically modified hematopoietic stem cells, can precisely regulate the bone marrow immune microenvironment, enhance the activity of anti-inflammatory cells, and suppress bone resorptive immune cells (234, 235). For PMOP, these metabolic reprogramming and nano/gene engineering strategies are currently mostly in the conceptual exploration and early experimental stages, and they theoretically align well with the “trained inflammatory bone marrow” hypothesis, possessing strong translatability and research value (236).

In summary, anti-TNF and anti-IL-6/IL-17 treatments targeting inflammatory pathways, combined with the regulation of Treg/Breg cell functions and suppression of bone resorptive T/B cell subpopulations, constitute emerging directions for immune therapy in PMOP. Additionally, immune intervention strategies based on metabolic reprogramming represent a promising avenue. These strategies rely on key immune pathways, such as TNF-α, IL-6, IL-17 signaling, and regulatory T/B cell modulation, which have been partially validated in rheumatoid arthritis, tumors, and other immune-mediated diseases. They also significantly overlap with the key cell populations and signaling networks involved in the immune reprogramming of PMOP bone marrow, providing a reference path for the future development of truly targeted immune intervention plans for PMOP. Based on rigorous disease-specific validation, integrating molecular targeting, cell therapy, and multi-level immune regulation through nanotechnology is expected to significantly enhance the therapeutic effects of PMOP and improve patients’ bone health and quality of life.

Comprehensive intervention strategies targeting the bone marrow microenvironment show significant potential. They regulate the bone immune microenvironment in PMOP. The aging and inflammatory state of the bone marrow microenvironment not only affects the function of HSCs but also disrupts the balance of bone remodeling, leading to the occurrence and progression of osteoporosis. These intervention measures mainly include the application of senolytics and antioxidants, regulation of bone marrow fat content, promotion of angiogenesis, and the synergistic effects of lifestyle and nutritional interventions (237, 238). Firstly, senolytics and antioxidants restore homeostasis within the bone marrow microenvironment by alleviating aging and chronic inflammation. With age, the bone marrow experiences a decline in cell function, an increase in inflammatory factor levels, and changes in the extracellular matrix. These changes lead to immune cell dysfunction and bone metabolic disorders (239, 240). Senolytics can target senescent cells and promote their clearance. They also reduce the release of pro-inflammatory cytokines such as TNF-α, IL-1β, and IL-6; thereby, they diminish the negative impact of the inflammatory microenvironment on hematopoiesis and bone immunity in the bone marrow (241, 242). Antioxidants help restore immune regulatory functions and bone-forming capacity within the bone marrow by clearing excess reactive oxygen species, alleviating oxidative stress, and protecting the function of BMSCs and immune cells (243). Moreover, nanocomposite materials with stimuli-responsive release systems offer new approaches for the targeted delivery of senolytics and antioxidants to the bone marrow, potentially achieving multi-target regulation of the microenvironment (244).

Secondly, regulating bone marrow fat content and promoting angiogenesis are key factors in improving the bone immune microenvironment. BMAs not only occupy space in the bone marrow but also influence bone metabolism and immune cell function by secreting fatty acids, cytokines, and chemokines (245). Increased bone marrow fat content is closely associated with osteoporosis, as it promotes bone resorption while inhibiting bone formation. By regulating adipocyte differentiation and metabolism, reducing bone marrow fat accumulation can improve the bone immune microenvironment. Furthermore, promoting angiogenesis in the bone marrow helps provide nutrients and oxygen to bone immune cells and hematopoietic stem cells, maintaining their function and activity (246, 247). For example, strategies using bioactive materials to promote vascular and nerve regeneration, combined with endogenous or externally applied immune regulatory mechanisms, can achieve overall optimization of the bone marrow microenvironment. Furthermore, specific probiotics and their metabolites (such as butyrate) can influence the immune microenvironment of the bone marrow by regulating the gut-bone axis, promoting bone development and delaying bone loss (248).

Finally, lifestyle and nutritional interventions play a synergistic role in regulating the bone immune microenvironment. Regular physical exercise not only increases bone mineral density but also activates immune cells in the bone marrow, promoting the functional recovery of key immune subpopulations such as T cells, thereby improving the bone immune microenvironment (249). In terms of nutrition, optimizing the intake of calcium, vitamin D, and nutrients with anti-inflammatory properties helps maintain bone immune homeostasis and skeletal health (250). Additionally, a diet rich in antioxidants and anti-inflammatory components can alleviate inflammation in the bone marrow and, when combined with lifestyle adjustments, is expected to delay the progression of osteoporosis (251).

In summary, comprehensive interventions targeting the bone marrow microenvironment alleviate aging and inflammation through senolytics and antioxidants. They also regulate bone marrow fat and promote angiogenesis to improve immune and bone metabolic environments. These approaches achieve multi-layered, multi-target synergistic regulation in conjunction with lifestyle and nutritional interventions. These strategies not only help restore the balance of the bone immune microenvironment but also provide a new theoretical basis and therapeutic approaches for the prevention and treatment of PMOP. In the future, these strategies, combined with smart materials and precision medicine technologies, are expected to promote the development of clinical translation and personalized treatment (Table 1).

Currently, multi-omics research on the bone marrow immune microenvironment of PMOP is still limited. Therefore, this section mainly uses bone marrow-related diseases such as AML and MM as examples to illustrate the technical pathways and analytical paradigms that can be transferred to PMOP, rather than a simple cross-disease translation of conclusions. With the development of high-throughput sequencing technology and multi-dimensional data integration analysis, multi-omics approaches have become key tools for elucidating the complexity of the bone marrow immune microenvironment. The bone immune microenvironment contains various immune cell subpopulations and their dynamic interactions. The traditional methods struggle to comprehensively reveal their spatiotemporal characteristics and balance states. In contrast, multi-omics approaches systematically depict the overall picture of cellular heterogeneity and functional states by integrating genomic, transcriptomic, epigenomic, and spatial omics data, providing strong technical support for the study of immune reprogramming.

Single-cell RNA sequencing (scRNA-seq) technology can accurately capture the gene expression profiles of immune cells at the single-cell level, revealing the identities and functional states of different cell subpopulations (252). For example, in MM, single-cell sequencing analysis has found the presence of tumor-associated special immune cell populations in the bone marrow, such as distinct NK cells and macrophages, as well as local immune cell aggregation zones. The functional states of these cells are closely related to the genomic evolution of tumor cells, suggesting that dynamic changes in immune cells are key factors in tumor progression (253). Additionally, in the study of AML, single-cell sequencing combined with multi-omics analyses have revealed differences in gene signatures among different immune cell subpopulations. Based on this, a prognostic prediction model was constructed using immune-related genes. This model shows significant differences in patient prognosis between immune-rich and immune-deficient subpopulations (254). These studies indicate that single-cell sequencing can not only finely characterize the diversity of immune cells but also dynamically track their functional transitions during disease progression.

Although single-cell sequencing can reveal cell types and states, its lack of spatial location information limits the understanding of intercellular interactions. Spatial omics technology addresses this limitation by revealing the spatial distribution of cell populations and their signaling communication networks through the combination of gene expression information with the spatial locations of tissues. In the study of AML patients receiving immune therapy, the combination of single-cell RNA sequencing and spatial transcriptomics technology precisely analyzed the spatial distribution of immune cells in the bone marrow and their proximity to leukemia cells. The study found that the local enrichment of immune cells around tumor cells is closely related to treatment response. Additionally, ligand-receptor analysis revealed potential changes in signaling pathways after immune therapy (255). In the bone marrow breakthrough lesions of multiple myeloma, spatial multi-omics revealed the complex spatial structures and diverse interactions between tumor cells and immune cells, suggesting that breakthrough lesions are key sites for the diversification of tumor-immune cell interactions. Furthermore, the combination of spatial omics and single-cell sequencing data helps establish intercellular communication network models, providing in-depth analysis of signaling transmission and immune regulation mechanisms in the bone marrow immune microenvironment (256, 257).

In summary, multi-omics technology reveals the heterogeneity and dynamic changes of immune cells through single-cell sequencing, while spatial omics technology complements this by providing spatial relationships and signaling network information between cells. The two approaches complement each other and jointly promote the in-depth development of research on the bone marrow immune microenvironment. Currently, single-cell and spatial omics research on the bone marrow immune microenvironment of PMOP is still in its early stages. However, the research paradigms mentioned above in diseases such as AML and MM have already provided a reference technical route and analytical framework for constructing the PMOP bone immune map. In the future, applying similar strategies in ovarian removal animal models and postmenopausal female bone marrow samples is expected to finely characterize the cellular lineages and signaling networks of “trained inflammatory bone marrow,” laying the foundation for immune stratification and individualized intervention (Figure 7).

In the field of PMOP, there are still limited animal models and clinical cohort studies that truly focus on “bone marrow immune reprogramming” as the core endpoint. Therefore, this section mainly refers to studies on bone tumors, AML, MM, and other related diseases as methodological and conceptual references, rather than directly extrapolating their pathological conclusions. Constructing a detailed bone immune microenvironment map is a key step in understanding the pathogenesis of PMOP and screening potential therapeutic targets. Currently, research strategies that combine animal models and clinical cohort data provide strong support for this field. First, using transgenic and aging animal models is an effective approach to simulate immune reprogramming in PMOP. Traditional osteoporosis animal models often use specific pathogen-free (SPF) mice; however, the immune systems of SPF mice are relatively immature compared to those of adult humans, making it difficult to fully replicate the immune maturation state. Recent studies suggest using “dirty mouse” models—mice exposed to various microorganisms that develop a more human-like immune system—allowing for a more realistic reflection of the interactions between the immune system and bone tissue, especially regarding immune regulatory mechanisms in osteoporosis and aging-related diseases (258). In addition to “dirty mouse” models, transgenic mice generated through gene knockout technology have been utilized in studies targeting the bone immune microenvironment. For example, in mice with the Skp2 gene knocked out, significant increases in immune cell infiltration were observed in their bone tumor microenvironment. This finding indicates a close relationship between gene regulation and immune rejection, which has implications for the immune regulation of osteoporosis (259). Aging animal models are equally important. For instance, Zmpste24-deficient progeroid mice exhibit delayed fracture healing accompanied by immune system disturbances, such as reduced lymphocyte generation in the bone marrow and increased activation of myeloid cells. These changes demonstrate the impact of the immune microenvironment on bone repair (260). Through these models, the polarization state of immune cells—especially macrophages of the M1 and M2 types—can be dynamically monitored. This monitoring helps regulate bone metabolism and the remodeling process of the bone immune microenvironment, thereby revealing the molecular mechanisms underlying immune reprogramming (261).

Secondly, clinical cohort studies provide practical evidence validating the correlation between immune markers discovered in animal models and the severity of osteoporosis. For example, in analyzing the bone marrow immune microenvironment of patients with AML and MM, researchers found that specific immune gene expression and the abundance of immune cell subpopulations (such as CD8+ T cells, regulatory T cells, and myeloid-derived suppressor cells) closely correlate with disease progression and prognosis (262, 263). Similarly, in patients with osteosarcoma, prognosis models based on immune-related genes indicated that the degree of immune infiltration significantly associates with patient survival rates, highlighting the importance of the immune microenvironment in bone tumors and osteoporosis (264). Furthermore, single-cell RNA sequencing technology combined with spatial transcriptomics provides technical support for constructing the bone immune microenvironment map. Through high-resolution analysis of immune cells in bone tissue and bone marrow, the complex interactions between immune cells and bone metabolic cells—such as MSCs, osteoblasts, and osteoclasts—have been revealed (265). This technological approach helps identify key cell subpopulations and signaling pathways related to immune reprogramming, providing a molecular basis for validating immune markers in clinical cohorts. Finally, combining animal models with clinical cohort data establishes a comprehensive bone immune microenvironment map. For example, the single-cell immunogenomics map of multiple myeloma reveals the heterogeneity of bone marrow immune cells and their association with clinical prognosis, offering important references for the immune regulation of osteoporosis (266, 267). In bone metastatic tumor models, the role of immunosuppressive cells—such as myeloid-derived suppressor cells—in the bone immune microenvironment has also been observed. This observation suggests that immune reprogramming is not limited to osteoporosis but also involves regulation of the bone tumor microenvironment (268, 269).

Overall, the field of PMOP can fully utilize an integrated methodological approach combining transgenic, aging, and ovariectomized animal models with single-cell and spatial omics technologies, alongside clinical bone marrow cohorts, to construct a bone immune microenvironment map specifically for PMOP. This approach not only systematically characterizes the lineage bias of HSCs and MSCs, the reprogramming of innate and adaptive immune cells, and the remodeling of cytokine networks, but also provides a solid translational basis for precise immune stratification and targeted interventions.

With the in-depth understanding of the role of the bone marrow immune microenvironment in the pathogenesis of PMOP, precision stratification and individualized intervention strategies have become important directions in current research and clinical applications. Classifying patients based on the characteristics of the immune microenvironment helps reveal the differences in immune status among different patients, thereby guiding the formulation of more precise treatment plans (270). By integrating single-cell and bulk transcriptome data, studies have found that PMOP patients can be divided into two molecular subtypes based on immune-related differentially expressed genes (IR-DEGs). Subtype 1 shows a higher proportion of M1 macrophage infiltration, indicating a more significant immune activation state (271). In addition, key immune genes such as JUN are significantly overexpressed in M1 macrophages, while HMOX1 is mainly elevated in endothelial cells and M2 macrophages. These immune cells and their interactions constitute a complex network of the PMOP bone immune microenvironment. The diagnostic models constructed based on these immune markers show high accuracy; they provide a powerful tool for early clinical diagnosis and patient classification (272). In terms of individualized treatment, precise immune typing can not only predict the immune status of the disease but also guide the development of innovative drugs targeting immune reprogramming (273). Furthermore, current research indicates that gut microbiota and their metabolites play a key regulatory role in the bone immune microenvironment. Short-chain fatty acids and tryptophan derivatives influence bone metabolism by regulating immune signaling pathways, inflammatory responses, and endocrine networks (274). These effects are concentration-dependent and vary according to specific physiological contexts; they can promote bone formation but may also exacerbate bone resorption. This suggests that precise dosage control and selection of appropriate patient populations are necessary when developing microbiota-targeted therapeutic strategies. Based on this, microbial intervention methods such as probiotics, prebiotics, and fecal microbiota transplantation are being actively explored as emerging directions for the treatment of osteoporosis, especially for elderly patients with impaired immune function. In such cases, personalized risk assessment and safety monitoring of potential adverse effects are particularly important (274).

In the future, the integration of multi-omics data and machine learning algorithms will enable a deeper exploration of key immune regulatory factors in the bone marrow immune microenvironment, facilitating precise patient stratification and the design of individualized treatment plans for PMOP patients. Additionally, developing drugs that target specific immune cell subpopulations or signaling pathways can effectively modulate immune responses within the bone marrow microenvironment, promote bone remodeling, enhance therapeutic effects, and reduce side effects, thereby bringing new breakthroughs to the clinical treatment of PMOP. In summary, the integration of precise immune typing and personalized immune regulation strategies not only enriches the understanding of the pathological mechanisms of osteoporosis but also provides practical, novel therapeutic strategies for clinical practice (Figure 8).