Immune-neural regulatory mechanism of osteoporosis induced by androgen deficiency

Literature search strategy

This systematic review employed a comprehensive search strategy across electronic databases including PubMed, Web of Science, and Scopus to identify relevant studies published between January 2000 and May 2025. Search terms combined Medical Subject Headings (MeSH) and free-text keywords related to four core themes: (1) androgen signaling (e.g., “androgen deficiency,” “testosterone,” “androgen receptor,” “hypogonadism”); (2) bone metabolism (e.g., “osteoporosis,” “osteoblast,” “RANKL”); (3) mechanistic pathways (e.g., “immune regulation,” “macrophage polarization,” “neuro-skeletal axis”); and (4) signaling systems (e.g., “erythropoietin and erythropoietin receptor (EPO/EPOR) signaling,” “HPA axis”). Boolean operators (AND/OR) were utilized to link concepts, such as pairing androgen deficiency with osteoporosis while integrating immune or nervous system components. To ensure literature saturation, reference lists of included articles were manually screened for additional studies.

Inclusion and exclusion criteria

Studies were selected based on their focus on molecular pathways linking androgen deficiency to bone loss through immune or neural mechanisms. Inclusion encompassed original research (animal models, in vitro experiments, clinical trials) and reviews reporting key pathways such as RANKL/OPG, Janus kinase 2/Signal transducer and activator of transcription 5 (JAK2/STAT5), or neuropeptide interactions. Publications were restricted to English language. Exclusion criteria eliminated studies unrelated to bone metabolism or androgen signaling, along with case reports and conference abstracts lacking full datasets.

Quality assessment and data synthesis

Two authors independently screened titles/abstracts and reviewed full texts, resolving discrepancies through consensus. Data extraction captured study design, model systems, mechanistic insights, and key findings. Methodological rigor was evaluated using AMSTAR-2 for systematic reviews and ARRIVE 2.0 guidelines for animal studies, ensuring robust evidence synthesis.

Data availability

As a review synthesizing published literature, no new raw data were generated. All extracted information is fully referenced within the manuscript. Detailed search strategies are provided in File S1. The key molecules discussed in this review are summarized in Table 1.

Interplay of androgens and erythropoietin in bone metabolism via immune regulation

EPO is a critical hormone produced by fetal liver cells and adult kidneys that plays an essential role in stimulating erythropoiesis through its interaction with the EPOR. Clinically, EPO is utilized to address anemia associated with chronic kidney disease, myelodysplastic syndromes, and various cancers. The binding of EPO to EPOR facilitates the formation of a homodimer, which is capable of activating several downstream signaling pathways, including JAK2, mitogen-activated protein kinase (MAPK), and PI3K, culminating in the phosphorylation of STAT5 (Cantarelli, Angeletti & Cravedi, 2019). Recent studies indicate that EPO’s effects extend beyond erythropoiesis, with significant implications for bone metabolism and homeostasis (Rauner et al., 2021).

In the context of bone tissue, EPO and its receptor play a fundamental role by directly influencing osteoblasts and osteoclasts in a dose-dependent manner. Osteoclast precursors express elevated levels of EPOR, in contrast to mature osteoclasts that exhibit minimal expression. EPO activates the JAK2/STAT5 pathway within these precursors, promoting their differentiation into mature osteoclasts (Rauner et al., 2021). Moreover, osteoprogenitor cells and mature osteoblasts also express EPOR, which may exacerbate bone resorption through modulation of the RANKL/OPG axis (Awida et al., 2022). Interestingly, low doses of EPO do not significantly increase the number of osteoclast precursors but inhibit osteoblast precursor proliferation and mineralization capacity. Conversely, high doses of EPO notably boost osteoclast precursor numbers, while neither stimulating osteoblast precursors nor prominently altering the RANKL/OPG ratio (Kolomansky et al., 2020). In young murine models, physiological levels of EPO may enhance osteoblast differentiation and promote bone formation through several signaling pathways, including mTOR and Ephrin B2/EphB4, while also stimulating endothelial cells to enhance vascularization, thereby supporting bone repair (Suresh, Lee & Noguchi, 2020).

The clinical application of local EPO has demonstrated efficacy in promoting fracture healing, suggesting potential benefits in bone formation at physiological doses. These findings underscore the notion that the role of EPO in bone metabolism is nuanced and context-dependent, necessitating a careful assessment of its clinical use against the backdrop of potential pro-hematopoietic effects and risks for bone loss (Suresh, Lee & Noguchi, 2020). Androgens, particularly testosterone, exert significant regulatory effects on the EPO/EPOR system. In vitro investigations suggest that testosterone may enhance EPO bioactivity by elevating EPOR expression rather than directly increasing EPO levels. Membrane-active androgens can modulate EPOR transcription, thereby amplifying the efficacy of EPO signaling (Maggio et al., 2013). Additionally, some evidence suggests that supraphysiologic doses of anabolic androgenic steroids, particularly testosterone, may elevate serum EPO levels by inhibiting hepatic clearance or directly stimulating renal EPO production (Heiland et al., 2023). EPOR is not limited to osteoblasts and osteoclasts; it is also expressed on a variety of immune cells, including monocyte-macrophages, B cells, T cells, neutrophils, mast cells, and dendritic cells, suggesting the potential for androgens to influence the EPO/EPOR system and its impact on bone homeostasis, either directly or indirectly via immune modulation (Cantarelli, Angeletti & Cravedi, 2019; Wiedenmann et al., 2015). For instance, EPO has been shown to alter macrophage polarization, reducing the recruitment and differentiation of pro-inflammatory M1-like macrophages while promoting the characteristic anti-inflammatory M2 macrophages (Horwitz et al., 2022; Yang et al., 2021). Furthermore, EPO enhances the secretion of pro-angiogenic factors from bone marrow macrophages, ultimately affecting the bone marrow microenvironment (Eggold & Rankin, 2019). B cells also contribute significantly to bone homeostasis through EPOR signaling. EPO stimulation facilitates the upregulation of RANKL expression in B cells, fostering osteoclast differentiation and enhancing bone resorption. Notably, B cells, especially Pro-B cell subpopulations, have the ability to transdifferentiate into functional osteoclasts in vitro and in vivo, a process dependent on CD115 expression, which is upregulated by EPOR. Bone loss is significantly mitigated in conditional knockout models of EPOR in B cells, underscoring the critical regulatory role of B-cell-mediated EPO/EPOR signaling in bone remodeling (Deshet-Unger et al., 2020).

EPO exerts primarily quantitative and indirect anti-inflammatory effects on neutrophils while demonstrating a bidirectional regulatory function on T cells, suppressing effector T-cell activity to mitigate inflammation and promoting regulatory T cells to enhance immune tolerance (Cantarelli, Angeletti & Cravedi, 2019). Additionally, while mouse bone marrow-derived mast cells express EPOR, most cell-surface receptors are under-expressed, resulting in EPO conveying anti-inflammatory signals without impacting mast cell differentiation, proliferation, or apoptosis (Wiedenmann et al., 2015). EPO further targets immature dendritic cells via EPOR, enhancing their immunostimulatory capacity and amplifying the inflammatory response in conjunction with TLR-4 signaling (Rocchetta et al., 2011).

In conclusion, the EPO/EPOR system serves a multifaceted role in bone homeostasis, its actions meticulously governed by androgens while establishing a dynamic interplay with the immune system. Future research endeavors may aim to explore intervention strategies targeting the EPO/EPOR system, potentially paving the way for innovative therapeutic approaches to address metabolic bone diseases such as osteoporosis.

The role of androgens in regulating osteoclast activity via RANKL expression by immune cells

Androgens modulate osteoclast activity primarily by regulating RANKL production from various immune cells, as summarized in Fig. 1. RANKL, also referred to as tumor necrosis factor superfamily member 11 (TNFSF11), is a critical component of the tumor necrosis factor (TNF) superfamily. In conjunction with osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB (RANK), which belong to the TNFR superfamily, RANKL plays a significant role in bone physiology. RANKL forms a homotrimer that binds to the RANK receptor, whereas RANK and OPG are monomers and homodimers, respectively (Ono et al., 2020).

The RANK/RANKL/OPG signaling pathway plays a crucial role in the regulation of osteoporosis and bone metabolism. When RANK, which is expressed on osteoclast precursors, binds to RANKL, it induces trimerization and activation of the RANK receptor. The intracellular domains of RANK contain binding sites for the bridging protein TNF receptor-associated factor (TRAF), which is instrumental in the signaling cascade that follows RANK activation. Upon activation of RANK, several signaling complexes are recruited, particularly TRAF6. This recruitment focuses on activating various kinases, leading to the nuclear translocation and activation of key transcription factors, including nuclear factor of activated T-cells 1 (NFATc1), c-fos, and nuclear factor κ B (NF-κB). These factors are essential regulators of the osteoclast-specific transcriptional program, driving the differentiation and activity of osteoclasts (Takegahara, Kim & Choi, 2022). Excessive RANKL expression can result in heightened osteoclast activity, resulting in an imbalance between bone resorption and formation, which ultimately contributes to bone loss. Recent studies have highlighted new insights into this pathway and its implications for therapeutic strategies in osteoporosis management.

Furthermore, the immune system plays a pivotal role in the regulation of bone metabolism through the actions of cytokines and the secretion of RANKL by immune cells. Certain immune cell types, including specific T-lymphocyte subtypes, B-lymphocytes, M1 macrophages, mast cells, and neutrophils, have been shown to secrete RANKL, influencing bone metabolism. Additionally, ARs present in the cellular matrix or on immune cell surfaces may mediate the effect of androgens on RANKL secretion, thus indirectly affecting bone mass (Fischer & Haffner-Luntzer, 2022; Gubbels Bupp & Jorgensen, 2018).

Androgens also serve as crucial immunomodulatory factors by binding to the AR, which is expressed in various immune cells, including macrophages and neutrophils, as well as in bone marrow stromal cells (Mantalaris et al., 2001). Through genomic pathways, androgens regulate immune cell function by inducing a conformational change in the AR, allowing it to translocate into the nucleus. Within the nucleus, AR binds to the ARE in target genes, thus regulating gene transcription and influencing immune cell activity (Li & Al-Azzawi, 2009; Mantalaris et al., 2001). Additionally, androgens can exert rapid non-genomic effects that activate traditional second messenger signaling pathways, including increased intracellular calcium concentrations and the activation of kinases, including kinase A (PKA), protein kinase C (PKC), and MAPK. These events occur within seconds and do not require transcription and translation processes (Li & Al-Azzawi, 2009).

Overall, androgens and their receptors exhibit distinct regulatory mechanisms that significantly affect immune cell behavior. Notably, in male mice, androgens inhibit the generation of B lymphocytes in the bone marrow by acting on the AR present in osteoblast lineage cells (Wilhelmson et al., 2015). The proper balance of androgens is essential for maintaining bone homeostasis; deficiencies or abnormalities in AR function can lead to bone loss and osteoporosis. The potential of selective androgen receptor modulators (SARMs) for the treatment of osteoporosis and related disorders presents a promising avenue for future research and therapeutic intervention (Xie et al., 2022).

Hypothalamic-pituitary-gonadal (HPG) axis

The HPG axis plays a crucial role in the regulation of bone metabolism in females. This regulatory pathway begins with the hypothalamus, which secretes gonadotropin-releasing hormone (GnRH) to control the activity of the pituitary gland. When there is a state of androgen deficiency, feedback mechanisms are activated, leading to an increased release of GnRH. In response to GnRH stimulation, the anterior pituitary gland releases oxytocin (OT), prolactin (PRL), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). The action of FSH and LH on the ovaries stimulates the secretion of various sex hormones, including estrogens, progestins, androgens, and inhibins (Kauffman, 2024; Nicks, Fowler & Gaddy, 2010).

Androgen deficiency, particularly among hypopituitary women, can vary in its impact on bone density; however, current evidence regarding the significance of androgens in women and the effects of hormone replacement therapy remains limited (Esposito et al., 2024). Beyond their essential involvement in reproductive function, this intricate regulatory network is closely linked to bone metabolism. Disruption at any point within this system can adversely affect the normal progression of bone metabolism, potentially leading to a variety of related disorders. Recent studies have demonstrated that FSH can stimulate osteoclast activity, negatively influencing bone mass. Furthermore, FSH has been found to positively impact adipocyte function, and the blockade of FSH using antibodies against the FSH receptor has resulted in increased bone mass and decreased body fat (Bergamini et al., 2024). Additionally, LH and FSH exert indirect control over bone development by encouraging the ovary to produce sex hormones (Nicks, Fowler & Gaddy, 2010). Oxytocin contributes to bone dynamics by attaching to receptors on bone cells, regulating the function of bone marrow mesenchymal stem cells, osteoblasts, osteoclasts, and other cellular components, thereby stimulating bone formation and inhibiting bone resorption (Wang et al., 2024). Nevertheless, prolactin has detrimental effects on osteoporosis; its multifaceted mechanisms contribute to increased bone resorption and decreased bone formation, reducing bone mineral density and a heightened risk of fractures (di Filippo et al., 2020).

The role of progesterone in bone metabolism remains less well-defined; it may operate through distinct receptors on osteoblasts or by modulating the expression of TGF-beta. Inhibins have been shown to suppress the differentiation of both osteoblasts and osteoclasts, consequently lowering bone turnover and correlating with menopausal bone loss, while activins promote the differentiation of osteoblasts. Estrogen has a significant impact on both osteoblasts and osteoclasts, regulating their proliferation, differentiation, and activity, as well as influencing bone remodeling through the modulation of cytokine production (Nicks, Fowler & Gaddy, 2010).

In summary, the HPG axis plays a delicate and integral role in maintaining the balance of bone formation and resorption through the antagonistic and synergistic interactions of various hormones, a balance that can be disrupted by androgen deficiency. Abnormalities within any component of this system may lead to disorders of bone metabolism, such as osteoporosis. Therefore, a thorough investigation into the individual and collective effects of these hormones is essential to advance our understanding of the mechanisms underlying bone diseases and to develop personalized treatment strategies.

Hypothalamic-pituitary-adrenal (HPA) axis

Androgens bind to pituitary and hypothalamic ARs, exerting significant regulatory effects on the HPA axis. At the hypothalamic level, the activation of the HPA axis is reduced when androgens like testosterone inhibit the production of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP) within small cell neuroendocrine neurons located in the dorsal medial section of the paraventricular nucleus (PVN) (Zuloaga, Lafrican & Zuloaga, 2024). There is a negative correlation between testosterone levels and stress-induced responses involving adrenocorticotropic hormone (ACTH) and corticosterone, as androgens suppress ACTH release in a dose-dependent manner at the pituitary level. When androgen levels drop, the HPA axis gets activated via feedback mechanisms, leading to the release of ACTH from the pituitary gland due to increased CRH and AVP secretion, which then stimulates the adrenal glands to produce high levels of cortisol, such as GCs (Williamson, Bingham & Viau, 2005).

Glucocorticoid-induced osteoporosis (GIO) represents a prevalent form of secondary osteoporosis, contributing to increased morbidity and mortality. The pathogenesis of GIO involves decreased bone formation and increased bone resorption (Wang et al., 2020b). Elevated GCs influence bone formation in two ways: under normal physiological conditions, endogenous GCs support bone formation, while excessive GCs inhibit the PI3K/Akt pathway by downregulating Sema3A expression, hindering osteoblast differentiation (Xing, Feng & Zhang, 2021). Androgens are crucial for maintaining bone health by regulating GC levels and preventing hyperactivation of the HPA axis, thereby protecting bone density. Conversely, when there is a deficiency of androgens, the HPA axis becomes overactive, leading to increased GC levels and consequent bone loss. Interestingly, a retrospective study indicated that androgen excess might protect bone density in women suffering from classical congenital adrenocortical hyperplasia (CAH) who have been exposed to high cumulative doses of GCs (Lee et al., 2022). This body of evidence underscores the pivotal role of androgens in the neuroendocrine-skeletal regulatory system, highlighting their mechanisms as potential key targets in developing therapeutic strategies for bone metabolic disorders.

Regulation of neurotransmitters

Androgens significantly influence bone metabolic balance by modulating the activity of dopaminergic neurons within the central nervous system. The mechanisms through which androgens affect dopamine secretion are characterized by bidirectional regulation and changes in neuronal populations. Specifically, androgens play a crucial role in regulating the burst firing of dopamine neurons by inhibiting prefrontal glutamatergic neurons from projecting to the ventral tegmental area (VTA) and by reducing NMDA receptor-mediated inhibitory control. This regulatory action helps maintain dopamine levels in the prefrontal cortex within an optimal range (Kritzer, Adler & Locklear, 2025). At the structural level, supplementation with testosterone or its metabolite, dihydrotestosterone (DHT), can reverse the effects of androgens that increase neuronal numbers following denervation, thereby preventing the survival of dopamine neurons located in the substantia nigra pars compacta (SNpc) and VTA (Johnson et al., 2010). These processes indicate that androgens dynamically modulate both the activity and survival of dopamine neurons, thereby influencing the functional equilibrium of the dopamine system.

Disruptions in the central dopamine system can significantly impact the processes of bone remodeling through the actions of dopamine receptors expressed in bone tissue. All subtypes of dopamine receptors (D1–D5) are expressed by human monocyte-derived osteoclast precursor cells. In patients with rheumatoid arthritis, stimulation of D2-like receptors has been shown to significantly enhance osteoblast mineralization and promote the formation of bone matrix. Activation of D2-like receptors (D2–D4) dramatically suppresses RANKL-induced osteoclast differentiation and bone resorption by lowering intracellular cAMP levels, thereby reducing TRAP-positive cell numbers, Cathepsin K expression, and the area of bone resorption (Schwendich et al., 2022; Wang et al., 2021). In contrast, D1-like receptors (D1/D5) may indirectly contribute to inflammatory bone loss by influencing Th17 cell differentiation while simultaneously promoting osteoblast function; however, they do not directly impact osteoclast differentiation (Feng et al., 2023a; Schwendich et al., 2022). Additionally, osteoblasts possess the ability to synthesize dopamine independently and utilize both autocrine and paracrine pathways to influence local dopamine receptor activity, creating an autoregulatory network that is integral to bone metabolism (Schwendich et al., 2022).

Through the regulation of dopamine neuron numbers and activity, androgens appear to indirectly support the homeostasis of bone metabolism. These findings underscore the role of the dopamine system in promoting bone formation through receptor-mediated signaling pathways, thereby establishing a novel regulatory network involving the androgen-dopamine-skeletal axis. This framework provides a molecular basis for understanding the mechanisms associated with neuroendocrine-related osteoporosis and the protective effects of androgen replacement therapy on bone health.

Sensory nerve fibers and neuropeptides

Sensory nerves, which are extensively distributed throughout the periosteum—especially in areas of active bone metabolism—play a crucial role in osteogenesis through the secretion of neuropeptides, including CGRP, SP, and Sema3A (Chen et al., 2024). These neuropeptides can significantly influence the equilibrium of bone remodeling by directly interacting with various bone cells, including osteoblasts, MSCs, and chondrocytes, via specific receptors, or by modulating local inflammation and angiogenesis (Chen et al., 2024; Steverink et al., 2021). The regulation of bone homeostasis by sensory nerves occurs through the secretion of neuropeptides that inhibit osteoclast activity while promoting osteoblast differentiation. CGRP is known to reduce osteoclastogenesis through the inhibition of the RANKL signaling pathway, as well as activate the cAMP/PKA/CREB pathway in osteoblasts to enhance bone formation. Low concentrations of SP increase the proliferative capacity of BMSCs and promote their differentiation into osteoblasts via the Wnt/β-catenin pathway, while also facilitating angiogenesis while high concentrations of over-activated NK1 receptors, triggering the release of pro-inflammatory factors (e.g., IL-6, TNF-alpha), exacerbated local inflammatory responses, and indirectly enhanced osteoclast activity through the up-regulation of RANKL signaling, leading to pathological bone resorption (Chen et al., 2024; Stöckl et al., 2025). Meanwhile, Sema3A serves a vital role in maintaining bone homeostasis by binding to the Nrp1 receptor present on both osteoblasts and osteoclasts, thereby facilitating a dual effect of promoting osteoblast differentiation and inhibiting RANKL-induced osteoclast differentiation (Xu, 2014). Importantly, osteoblasts can also secrete Sema3A; however, the expression of Sema3A originating from osteoblasts is not influenced by androgen signaling (Yamashita et al., 2022).

Research involving a conditional knockout mouse model (SLICK-AR), which specifically deletes the DNA-binding domain of the AR in neurons, has demonstrated that the AR in these neurons directly facilitates sensory neuron axon regeneration through a DNA-binding domain-dependent genomic signaling pathway. It is noteworthy that this action exhibits sex-differentiated characteristics, with female subjects potentially compensating for AR deficiency through non-neuronal AR signaling mechanisms (e.g., glial cells) or ER pathways. Furthermore, aging or decreased testosterone levels may result in reduced nerve regeneration (Ward et al., 2021). Thus, strategically targeting AR signaling may provide synergistic benefits in promoting peripheral nerve regeneration, enhancing functional recovery, and supporting the maintenance of bone metabolic homeostasis.

Synovial tissue plays a critical role by lining the noncartilaginous surfaces of synovial joints, serving to nourish these avascular structures, which are vital for bone formation. Prolonged inflammation within the synovial tissue can result in bone destruction as well as periarticular and systemic osteoporosis (Tanaka, 2019). Androgens have been found to modulate the distribution and activity of sensory nerves through synovial AR, which influences the release of neuropeptides, thereby regulating the equilibrium between bone formation and resorption. An elevated ratio of estrogen to androgen can suppress AR signaling. This suppression may lead to the growth of sensory nerve fibers from inflamed tissue, disrupting the release of neuropeptides such as SP and subsequently amplifying inflammation and exacerbating bone destruction (Liu et al., 2023).

Furthermore, androgens are recognized for their anti-inflammatory effects. Inflammation can alter bone structure through modified usage and the production of various inflammatory mediators. It is also worth noting that the peripheral nervous system may assume a sensory role in responding to mechanical and inflammatory influences on bone structure (Straub et al., 2013). Targeting the androgen-sensory neuraxis presents a promising avenue for novel therapeutic strategies aimed at treating rheumatoid arthritis and related bone metabolic disorders. It is essential to pursue further research to explore the underlying molecular mechanisms and assess the clinical translational potential of this approach.

Neuromuscular junction

Bone possesses the ability to sense mechanical signals and convert them into biochemical signals, which are crucial for maintaining bone homeostasis (Mei et al., 2024). The neuromuscular junction (NMJ), as a specialized synapse between motor neurons and skeletal muscle fibers, is central to this process. It facilitates the release of acetylcholine (ACh), which activates the postsynaptic membrane acetylcholine receptor (AChR). This activation generates an endplate potential (EPP), leading to action potentials in muscle fibers that enable contractile functions. In recent years, accumulating evidence has highlighted the crosstalk between muscle and bone, with a pooled analysis indicating that osteomuscular dystrophy is associated with an increased risk of fractures, falls, and mortality (Teng et al., 2021). The modulation of muscle contractile activity may significantly influence the pathophysiology of osteoporosis, indirectly affecting bone metabolism. Mechanical stress from muscle activity initiates strain production in bone through mechanical loading, thereby enhancing the osteogenic response. This occurs through the stimulation of nitric oxide (NO) and prostaglandins (PGE2) release from osteoblasts, which synergizes with hormone therapy and promotes the secretion of myofactors (such as FGF-2 and IGF-1) and bone-derived factors (such as osteocalcin). Collectively, these factors regulate the processes of bone formation and resorption (Li et al., 2019; Notelovitz, 2002).

Impairments in the structure or function of the NMJ frequently lead to decreased efficiency in neuromuscular transmission. Such dysfunction can result in reduced mechanical loads on bone, ultimately diminishing the activation of bone formation signaling and increasing bone resorption. Moreover, NMJ dysfunction may contribute to decreased endocrine hormone release, exacerbating the neural-skeletal connection and potentially accelerating bone loss and the development of osteoporosis (Iyer, Shah & Lovering, 2021; Kaji, 2024). Studies indicate that following gonadectomy in adult male rats, testosterone deficiency results in a significant reduction of nicotinic-type AChR tropism, with a 70% decrease in the amplitude of neurally evoked endplate currents and a 1.8-fold reduction in maximal AChR binding in rat aponeurotic muscles, although receptor-binding rate constants remain unaffected. These observations suggest that testosterone is vital for modulating neuromuscular transmission by maintaining the density of postsynaptic membrane AChRs without altering their binding properties (Souccar et al., 1991). Furthermore, androgens have been shown to enhance muscle mass and strength, stimulate bone through mechanical loading, and promote bone formation (Chang et al., 2013; Notelovitz, 2002).

Sex differences in immune responses

Sex hormones are key regulators of immune system and skeletal function, and alterations in their levels—such as age-related declines—constitute major risk factors for osteoporosis. In males, androgens influence immune responses through AR signaling or aromatization into estrogens, thereby maintaining bone homeostasis. Overall, declining androgen levels activate the immune system, thereby driving bone resorption. In women, skeletal immune regulation is more complex, involving a sharp drop in estrogen and relative changes in androgen levels. Together, these factors induce a chronic, low-grade inflammatory state that drives bone loss. Sex hormones (estrogens, progestogens, and androgens) act as key immunomodulators, regulating innate immune cell functions through their nuclear receptors and inducing epigenetic remodeling, thereby participating in the regulation of sexual dimorphism in bone metabolism. Androgens exert overall anti-inflammatory and immunosuppressive effects, indirectly inhibiting osteoclast activity by suppressing macrophage cytokine release, downregulating TLR4 expression, and reducing leukotriene synthesis, thereby protecting male bones. Similarly, progesterone exhibits potent immunosuppressive properties, which contribute to maintaining bone immune homeostasis. Estrogen’s effects are more complex and concentration-dependent: At physiological levels, it moderately enhances immune responses. At high concentrations, it exhibits anti-inflammatory effects by suppressing Th1/Th17 cells and enhancing Treg function, potentially providing indirect skeletal protection. Postmenopausal estrogen decline leads to increased inflammation, contributing to osteoporosis. These sex hormone-mediated differences in the immune microenvironment partially explain why postmenopausal women, whose immune state shifts toward pro-inflammation, are more susceptible to osteoporosis. In contrast, men enjoy relative bone protection due to the sustained immunosuppressive effects of androgens, highlighting the central role of immune mechanisms in sex hormone-related bone metabolic disorders (Forsyth et al., 2024; Shepherd et al., 2020). Androgens regulate Tregs by directly acting on the Foxp3 gene. Within Treg cells, upon activation, androgen receptors bind directly to this specific region of the Foxp3 gene, thereby initiating gene transcription. This effect exhibits specificity in terms of gender and physiological state: androgens significantly increase Foxp3+ Treg numbers only in female T cells during the ovulatory phase, with no such effect observed in male T cells or female T cells in other menstrual cycle phases. Tregs are potent immunosuppressive cells that effectively inhibit the activation and function of effector T cells, macrophages, and osteoclast precursors. By upregulating Tregs, androgens indirectly suppress osteoclast generation and activity, thereby reducing bone resorption and providing protective effects for maintaining bone density. Persistently elevated androgen levels in males may keep the Treg-skeleton axis in a stable, “locked-in” protective state over the long term, contributing to the generally lower incidence of osteoporosis in men compared to women of the same age. The androgen surge during female ovulation may dynamically maintain immune and skeletal homeostasis throughout the reproductive cycle by transiently and potently expanding Tregs to counterbalance the pro-inflammatory tendencies potentially induced by estrogen at this time. Postmenopausally, with declines in both androgen and estrogen, this dynamic protective mechanism of Tregs weakens, potentially exacerbating bone loss (Walecki et al., 2015).

Sex differences in neuroendocrine regulation

Beyond immune regulation, the nervous system’s control over bone metabolism also exhibits significant sex differences, with androgens playing distinct roles in males and females. In males, high levels of androgens exert a direct effect via AR on corticotropin-releasing factor (CRF) neurons widely distributed throughout the limbic system (e.g., bed nucleus of the stria terminalis, amygdala). This action constitutes a potent “tonic inhibition” of the CRF system, stably reducing the basal activity and stress responsiveness of the HPA axis, thereby maintaining GCs at physiologically low levels. When androgen deficiency occurs (e.g., castration, aging), this inhibition is lifted. This leads to excessive activation of neural circuits involved in stress and anxiety—particularly CRF neurons in the bed nucleus of the stria terminalis and amygdala—which ultimately drives increased release from CRF neurons in PVN via not-yet-fully-elucidated neural connections. This results in HPA axis hyperactivation and pathologically elevated GCs levels. Persistently elevated GCs then reduce bone formation by inhibiting osteoblast activity and promoting osteoblast apoptosis, ultimately triggering or exacerbating osteoporosis. This pathway is particularly pronounced in males, as their CRF neurons express AR at significantly higher levels than females, constituting a key mechanism for the neuroendocrine regulation of osteoporosis gender dimorphism (Rybka et al., 2023).