Osteocytes in the Metastatic Bone Niche: Mechanistic Pathways and Therapeutic Targets.

1. Introduction

Traditionally, bone biology research took an osteoclast-centric perspective of bone resorption and metastasis, with osteoclasts being believed to be the main offenders of the skeletal destruction in metastatic disease. This osteoclast-focused “vicious cycle” model explained the interaction between tumor cells and osteoclasts. It suggested that tumor cells increase the differentiation and activity of osteoclasts, which results in bone degradation and the release of growth factors from the matrix that, in turn, promote tumor growth, thus providing a clear mechanistic link between resorption and metastatic progression [ 1 ]. However, this view does not fully capture the cellular complexity of the metastatic bone microenvironment.

Osteocytes, the most abundant cells in bone and the principal cells embedded within the mineralized matrix, are increasingly recognized as active organizers of bone homeostasis rather than passive bystanders [ 2 ]. Because of their unique anatomical position and extensive communication network within bone, osteocytes are well placed to integrate local and systemic cues and to coordinate interactions among tumor cells, osteoblast-lineage cells, osteoclasts, stromal cells, and immune components of the bone niche [ 2 , 3 ]. Emerging evidence suggests that osteocytes influence multiple stages of metastatic progression, from early niche conditioning to later remodeling of established lesions, thereby shaping both tumor behavior and skeletal response.

This review argues that osteocytes are not passive bystanders in metastatic bone disease but integrative regulators of niche state. We therefore organize the literature around how osteocytes influence metastatic stages, the major signaling axes through which they act, and the translational implications of targeting osteocyte-driven remodeling, mechanosensation, senescence, and immune crosstalk. Figure 1 summarizes the major signaling axes involved in octeocyte-tumor interactions.

2. Osteocyte Biology

Osteocytes are the mature bone cells that reside in the mineralized matrix. They communicate with each other through a highly organized lacunocanalicular network (LCN) that also facilitates nutrient exchange and enables interaction with the surrounding extracellular matrix [ 4 ]. It is a misconception to think that osteocytes are merely metabolically inactive cells; as they actually have the capability to alter their immediate surroundings through perilacunar/canalicular remodeling (PLR), which is a key factor for the quality and mechanical properties of bone [ 4 ]. Osteocytes achieve that by synthesizing enzymes that facilitate both matrix degradation and renewal. Among the secreted enzymes that break down collagen and other organic materials are matrix metalloprotease 13 (MMP13) and cathepsin K (CTSK), while carbonic anhydrase 2 (CA2) helps create an acidic environment in the perilacunar area, thus allowing mineral dissolution. If such enzymatic processes do not function properly, this leads to the disintegration of the LCN, alterations in bone material properties, and increased bone fragility; therefore, osteocytes are key to matrix turnover and skeletal homeostasis [ 4 ].

Beyond their role in maintaining and remodeling mineralized bone, osteocytes act as endocrine and paracrine regulators that coordinate bone remodeling and systemic mineral metabolism [ 5 ]. Through the RANKL/Osteoprotegrin (OPG) pathway, osteocytes regulate osteoclast formation and bone resorption. Additionally, they precisely regulate bone formation by the release of sclerostin (SOST) and Dickkopf-1 (DKK1), which are very efficacious inhibitors of Wnt/β-catenin signaling [ 6 ]. Furthermore, osteocytes produce several signaling molecules, including interleukin 6 (IL-6), ATP, prostaglandin E 2 (PGE 2 ), and CXCL chemokines, which, in addition to modulating osteoblast–osteoclast coupling, also regulate immune–bone interactions in the skeletal microenvironment. Consequently, osteocytes become major regulators of mineral balance, both locally in the bones and at the whole-body level [ 5 ].

A significant aspect of PLR and osteocyte signaling is the ability of osteocytes to sense and respond to mechanical forces. Osteocytes act as the primary mechanosensors within bone [ 7 ]. Mechanical loading results in fluid shear stress within the LCN that is detected by mechanosensitive pathways with Piezo1 and Piezo2 ion channels’ involvement, leading to calcium influx and the activation of downstream anabolic signaling pathways [ 7 ]. Furthermore, mechanical stimulation leads to connexin-43 (Cx43) hemichannels’ opening, which in turn releases ATP and PGE 2 , leading to amplification of mechanotransduction as well as bone remodeling [ 7 ]. These mechanical forces are integrated into the transcriptional factors YAP and TAZ, which translocate into the nucleus on loading to modulate gene expressions linked to survival signaling, differentiation, and bone formation of osteocytes. Essentially, these mechanosensory inputs endow osteocytes with the capability to transduce these mechanical forces into bioactive signals that are fundamental to the skeletal strength maintenance [ 7 ].

3. Osteocytes Across the Metastatic Cascade

Osteocytes influence the metastatic process at multiple temporal stages, from early niche conditioning to late-stage remodeling and skeletal-related events. Framing osteocyte functions along the metastatic cascade helps distinguish stage-specific mechanisms (e.g., dormancy maintenance versus osteoclast-driven reactivation) and clarifies which therapeutic strategies are most plausible for prevention, containment, or treatment of established lesions. This cascade-based structure also provides a rationale for combining standard antiresorptives with osteocyte-targeted interventions and for embedding osteocyte-centric biomarkers into clinical trial endpoints ( Figure 2 ).

3.1. Homing, Seeding, and Early Colonization

At the beginning of bone metastasis, tumor cells that spread reach the bone marrow and the endosteal niche, where they are trafficked and retained by chemokine gradients, especially the CXCL12–CXCR4 axis, thus mimicking hematopoietic stem cell homing [ 8 ]. Whilst osteoblasts and stromal cells constitute the main sources of CXCL12 in this niche, osteocytes are gaining recognition as a significant part of the endosteal microenvironment that influences chemokine fields indirectly through the control of bone remodeling and niche architecture [ 1 ] ( Figure 2 A). There is increasing evidence that osteocytes respond to tumor-induced changes by altering their secretory and signaling profiles. In this way, they affect tumor cell survival, dormancy, and the first colonization of tumor cells in the bone marrow [ 1 ]. During this phase of tumor-bone interaction, there is also activation of the Notch signaling pathway via tumor-bone cell crosstalk. Specifically, tumor-expressed Jagged1 (JAG1) binds Notch receptors on bone-resident cells, thus promoting a pro-metastatic niche with increased osteoclastogenic and inflammatory signaling [ 9 ]. While it has been a common theme in most mechanistic studies to limit their focus to osteoblasts and stromal cells, recent studies have concluded that dysregulated Notch signaling can induce osteocyte apoptosis and thus disrupt bone homeostasis. This finding strengthens the idea that osteocytic Notch activation may be a factor in remodeling the early metastatic niche [ 10 ].

3.2. Dormancy vs. Reactivation

Osteocytes play a role in maintaining the equilibrium between dormancy and reactivation of tumor cells that have spread to bone by influencing the production of factors that lead to osteoclast formation and the bone remodeling environment where dormant tumor cells (DTCs) are located [ 11 ]. They express both RANKL and OPG; therefore, they are capable of influencing the RANKL/OPG ratio, favoring increased RANKL to promote osteoclast formation and bone resorption, which has been linked to dormancy escape of DTCs [ 11 ]. Osteocytes produce other molecules that antagonize Wnt signaling, such as sclerostin and DKK1m, which have been shown to inhibit osteoblast activity and alter the bone microenvironment. Modulation of these Wnt antagonists may affect the niche, favoring maintenance of dormancy or escape [ 11 ]. Different mechanical inputs are detected by osteocytes, which then regulate the secretion of signaling molecules that influence the activities of both osteoblasts and osteoclasts. Additionally, changes in mechanical signaling have been associated with modifications in the RANKL/OPG system and their consequent impact on the bone remodeling niche [ 12 ]. Physiological mechanical loading increases the opening of Cx43 hemichannels in osteocytes and the extracellular release of ATP, which can decrease osteoclast activity, thereby helping maintain a more quiescent niche. On the other hand, a loss of these signals can contribute to osteoclast activation and DTC reactivation [ 11 ]. When combined, these signals that sustain bone cells (changes in RANKL/OPG, alterations of Wnt antagonists, and mechanically regulated ATP release through Cx43) essentially form a live microenvironment that may limit DTCs to dormancy or facilitate their reactivation and progression to dissemination in bone ( Figure 2 B).

3.3. Progression to Osteolysis and Osteosclerosis

As bone metastasis progresses to form osteolytic lesions, a rise in osteocyte apoptosis seems to be localized with the increased expression of osteoclastogenic signals such as RANKL, which not only attracts osteoclast precursors but also promotes their differentiation and resorptive activity, thus increasing the well-known “vicious cycle” of bone destruction that tumor growth in bone feeds on [ 1 ]. By releasing RANKL, osteocytes can control osteoclastogenesis as well as change the structure of their surrounding perilacunar and pericanalicular matrix, as well, which is a process similar to that of osteoclastic resorption in that it requires acidification and the use of matrix-degrading enzymes such as MMP13 and CTSK, which are capable of releasing more matrix components and thus contributing to bone loss [ 1 , 13 ]. In metastatic microenvironments, there is an increase in Wnt antagonists from osteocytes, such as sclerostin and DKK1 that inhibit osteoblast differentiation, tipping the balance towards bone resorption over formation, therefore, synergizing with tumor-secreted factors to aggravate osteolysis [ 1 , 14 ]. Osteocyte apoptosis, together with the action of perilacunar bone-resorbing enzymes such as MMP13 and CTSK, and the upregulation of sclerostin and DKK1, propels the microenvironment away from new-bone formation towards resorption, thereby directly linking osteocyte function to the establishment of osteolytic lesions and the therapeutic strategy in anti-RANKL treatment ( Figure 2 C).

4. Mechanistic Axes: Osteocytes Interface with Tumor and Stroma

4.1. RANKL/OPG Control by Osteocytes

The role of osteocytes on RANKL/OPG balance has been the subject of much interest. Much of the literature points towards the possibility of osteocytes being a major source of RANKL in the bone environment [ 15 ]; however, a recent paper published in 2024 has demonstrated the possibility that osteocytes act as a major producer of OPG, while different osteoprogenitor cells are the major producers of RANKL [ 16 ]. The initial belief came from studies on knockout mouse models, such as the Dmp1-cre;Tnfsf11 fl/fl and Sost-cre;Tnfsf11 fl/fl models, where Tnfsf11 is the gene encoding for RANKL [ 15 , 17 ]. The results of these studies collectively pointed to osteocytes as the major source of RANKL, as it was believed that only osteocytes were targeted by both transgenes [ 15 ]. However, multiple studies since then have revealed that other non-osteocytic cell populations are targeted by the Dmp1 and Sost promoters, calling into question the validity of the prior conclusions [ 18 , 19 , 20 ]. El-Masri et al. argue that it is, in fact, osteoprogenitor cells, not osteocytes, that were the main target in these previous knockout studies, and they supported this with scRNAseq data from enriched bone marrow stroma isolated from mice. This data showed that the most abundant RANKL+ cells also expressed high levels of MMP13, a marker that is highly expressed on osteoprogenitor cells on bone surfaces [ 16 , 21 ]. This balance between RANKL and OPG is disrupted in the presence of denosumab, a RANKL-antibody used to reduce fracture risk and increase bone mass [ 22 ]. Studies on patients treated with denosumab have shown an elevated RANKL/OPG ratio in their blood [ 19 , 23 ], with a drop in OPG production that may be due to loss of surface osteoblasts that are later converted into osteocytes, 2 major sources of OPG production [ 16 ]. This elevated ratio may explain why many of these patients develop accelerated bone loss on denosumab discontinuation [ 24 ]. This phenomenon may also be relevant to increased metastatic risk, as many studies have shown that osteolysis is a major promoter of bone metastasis [ 25 ].

Taken together, the current evidence no longer supports the unqualified statement that osteocytes are the sole or universal dominant source of RANKL in vivo. Rather, osteocytes remain central regulators of the RANKL/OPG axis and may be particularly important for OPG production. In contrast, osteoprogenitor populations may account for a substantial fraction of RANKL in some settings. The translational implication is that therapeutic strategies should focus on the functional balance of the axis and the disease context, rather than assuming a single cellular source across all models of metastatic bone disease

4.2. Mechanotransduction

Physical exercise has been theorized to have a protective effect against cancer progression and spread. In bones, the most abundant mechanosensitive ion channel is known as Piezo1. Recent studies have explored the effects of Piezo1 stimulation on bone metastasis. Multiple studies used low-magnitude, high-frequency (LMHF) vibration as an alternative to exercise to assess its effects on bone metastasis and to compare them with those of Yoda1, a chemical Piezo1 activator. These studies revealed that the combination of LMHF and Yoda1 treatment significantly suppresses the effect on osteoclastogenesis and breast cancer cells’ extravasation and migration, as well as has a positive effect on nuclear translocation of YAP in osteocytes [ 26 , 27 ]. Another demonstrated effect of Piezo1 stimulation is the phosphorylation and activation of Akt, which suppresses SOST expression and reduces sclerostin, a crucial inhibitor of cancer metastasis [ 28 ]. Connexin channels are another class of ion channels that play a crucial role in cell communication. Connexin 43 (Cx43) is the most abundant and studied connexin in bone tissue [ 29 ]. Cx43 forms hemichannels that, when mechanically stimulated, serve as a direct portal for releasing prostaglandin E 2 (PGE 2 ) as well as ATP, as mentioned prior [ 30 ] ( Figure 1 ). The released PGE2 increases β-catenin expression and decreases sclerostin expression within osteocytes, simultaneously inducing osteoblast activity while reducing osteoclast activity [ 30 , 31 ]. On the other hand, released ATP assists in killing tumor cells by activating the purinergic receptor P2X7 on dendritic cells, thereby activating the inflammasome pathway [ 32 ]. Recent preclinical studies have also found that antibodies targeting Cx43 and activating these hemichannels in osteocytes reduce cell growth in breast cancer and osteosarcoma, as well as improve survival rates, making them a potential therapeutic strategy for preventing cancer spread [ 33 ].

4.3. Cell-Fate Programs

Osteocytes can influence bone cells even after death, as apoptotic osteocytes have been shown to affect osteoclastogenesis significantly. These osteocytes show an increased secretion of RANKL, TNF-α, IL-6, VEGF, and ICAMs, among other osteoclastogenic factors. All of these factors can promote osteoclast differentiation and maturation in both direct and indirect ways [ 34 ]. Similarly, necrotic osteocytes release damage-associated molecular patterns (DAMPs) that bind to pattern recognition receptors on immune cells like dendritic cells, leading to the production of pro-inflammatory cytokines that further induce the expression of RANKL, which in turn leads to the promotion of osteoclastogenesis [ 34 , 35 ]. Additionally, a recent study on mice has shown that osteocytes in bones affected by breast cancer are induced into a premature form of senescence with a unique senescence-associated secretory profile (SASP) that favors osteoclastogenesis [ 36 ]. These senescent osteocytes become a major source of factors such as RANKL, MMP13, and IL-6, all of which amplify lytic potential in the bone and lead to cancer-induced bone loss [ 36 ].

4.4. Osteocyte-Derived Extracellular Vesicles

The role of extracellular vesicles (EVs) in intercellular communication has garnered much attention in the literature. Among bone cells, osteocytes have been most associated with EV secretion in cases of mechanical stimulation [ 37 ]. These mechanically stimulated osteocytes release EVs that carry cargo like RANKL, OPG, sclerostin, and different microRNAs (miRNAs) that have been shown to promote bone formation as well as play a role in cancer metastasis to the bone [ 38 ]. However, the evidence remains sparse, and this field requires further exploration.

4.5. Tumor-Driven Reprogramming of Osteocytes

Just as osteocytes have a large influence on the bone microenvironment, osteocytes themselves can be influenced by tumor-derived factors. One very significant factor is the transmembrane receptor NOTCH, which plays a pivotal role in cell differentiation and function, and is constitutively active in certain types of cancer, like breast cancer and multiple myeloma [ 39 , 40 ], as well as promotes tumor development and skeletal metastasis in cancers like breast and prostate cancer [ 41 ]. Jagged1 (JAG1), a major ligand of NOTCH, is expressed abundantly on osteocytes, revealing a crucial mechanism for interaction between osteocytes and tumor cells expressing NOTCH receptors [ 42 ]. The activation of osteocytes through JAG1-NOTCH interactions increases the production of RANKL, resulting in osteoclast differentiation and increased osteolysis [ 43 ]. A recent study examined melanoma cells’ ability to convert osteocytes into pro-tumorigenic cells. In this study, osteocytes exposed to conditioned media from melanoma cells exhibited high CXCL5 expression, a chemokine that promotes melanoma cell migration and invasion [ 44 ]. Such a mechanism may be present in other types of cancer and warrants further investigation.

5. Osteocytes and Immuno-Skeletal Crosstalk

The skeletal and immune systems interact in many ways, with recent studies showing that osteocytes play a major role in these interactions.

5.1. Osteoimmunology: Definition and Scope

The term osteoimmunology has been coined by Dr. Yongwon Choi to describe the science that studies the interactions between the immune system and bone and its influence on disease [ 45 ]. The cells at the center of interest for this science have traditionally been osteoblasts and osteoclasts, as their interactions with the immune system have been studied quite extensively [ 46 ], while the role of osteocytes, the most abundant and widespread cells in bone, in influencing the immune system has remained elusive for a long time [ 46 ]. However, the role of osteocytes as an immunoregulatory node has been attracting more attention recently as more interactions between osteocytes and immune processes are being explored, from the secretion of cytokines like TNF-α and RANKL, to the alteration of myeloid cell differentiation [ 47 , 48 ]. The unique position of osteocytes between the bone matrix, stromal cells, and immune cells, both figuratively and literally, makes them a key point of interest in the context of bone metastasis. As the immune system’s influence as a key regulator of tumor spread becomes more apparent, the importance of immunoregulatory nodes such as osteocytes and their role in cancer spread becomes clearer.

5.2. Osteocytes in Immune Crosstalk in Metastasis

Many features of osteocytes make them a centerpiece in the crosstalk between the immune system and bone metastasis ( Figure 1 ). Osteocytes are not only the most abundant cells in bone, but the lacunocanalicular network they inhabit pervades the bone and forms a wide network for these cells to interact [ 49 ]. They serve a variety of roles in different processes within the bone, from mechanosensation to inflammation, and produce factors that influence these processes, like cytokines and chemokines [ 44 , 50 , 51 , 52 ]. Additionally, their ability to influence the recruitment and differentiation of immune cells allows them to alter the interactions between the immune system and bone metastasis, both in the bone marrow and endosteal spaces [ 47 , 53 , 54 ].

Among the changes osteocytes induce in immune cells are alterations in myeloid cell composition and differentiation [ 47 ]. One study revealed that mice with reduced osteocytes have an altered myeloid lineage differentiation with expanded myeloid progenitors, neutrophils, and monocytes, and impaired lymphopoiesis, especially B cells [ 47 ]. These changes were attributed to the acquisition of SASP in both osteogenic and myeloid lineage cells [ 47 ]. Another type of immune cell affected by osteocytes is the antigen-presenting cell, such as a dendritic cell or macrophage. These cells’ activities are induced and amplified by the increase in extracellular ATP triggered by mechanical stimulation of Cx43 on osteocytes, which activates the P2X7 receptor on antigen-presenting cells [ 33 ]. These effects ultimately facilitate the recruitment and activation of CD8+ T cells and reduce the differentiation of CD4+ T cells into regulatory T cells (Treg). This elevation in extracellular ATP can also promote tissue-resident memory T cells (CD8+ Trm), which have been shown to correlate positively with tumor growth in both mouse models and human patients [ 55 , 56 , 57 ]. These various mechanisms of interaction serve to either amplify or dampen the immune system’s function within bone, either supporting anti-tumor immunity or contributing to the formation of immunosuppressive niche states. The major osteocyte signaling pathways implicated in metastatic progression and their effects on the bone niche are summarized in Table 1 .

6. Clinical and Translational Targets

6.1. Denosumab (Anti-RANKL)

Therapies for metastatic bone disease, such as bisphosphonates and denosumab, target the bone microenvironment to prevent skeletal-related events (SREs) [ 59 ]. In a systematic review based on 4 randomized clinical trials, denosumab has demonstrated a consistent ability to delay the first SRE as well as alleviate bone pain in a manner similar to zoledronic acid [ 60 ]. However, risks such as hypocalcemia and osteonecrosis of the jaw are higher with denosumab, and cost-effectiveness may favor zoledronic acid in some settings [ 61 , 62 ]. Extended dosing intervals for denosumab in early phase II trials show promise in reducing toxicities and costs but lack extensive supporting data, as clinical endpoints may not always correlate with outcomes [ 63 ].

Mechanistically, RANKL inhibition by denosumab prevents skeletal events, yet its impact on osteocyte-driven tumor dormancy and persistence is poorly understood [ 64 , 65 ]. Osteocytes regulate bone remodeling via the RANKL–OPG pathway, and experimental data suggest metastatic breast cancer cells disrupt osteocyte viability and mechanotransduction, including RANKL/OPG dysregulation [ 66 ]. Osteocyte apoptosis, induced by tumor-derived factors like BIGH3/TGFBI, impairs network communication by reducing Cx43, contributing to bone breakdown independent of osteoclast activity [ 67 ].

Dormant tumor cells (DTCs) in the bone marrow persist under quiescent conditions, with their detection serving as an early marker of metastasis and prognostic indicator [ 68 ]. The bone microenvironment plays a critical role in metastasis dynamics, with osteoblast activity promoting dormancy and osteoclast-driven bone resorption reactivating DTCs through TGF-β, Wnt, and Notch pathways [ 65 , 69 ]. While denosumab targets RANKL signaling, its influence on osteocyte apoptosis and the dormancy niche remains unclear, highlighting a key research gap [ 64 , 66 , 69 ].

6.2. Sclerostin and Wnt Modulation

Romosozumab, a monoclonal antibody targeting sclerostin, enhances bone formation and reduces resorption via activation of the Wnt signaling pathway, making it a candidate therapy for bone diseases associated with malignancies that require validation [ 70 , 71 ]. Its primary osteoanabolic effects have drawn attention for treating bone loss and weakness in cancer; however, concerns arise regarding systemic Wnt/β-catenin pathway activation, which is frequently dysregulated in tumors and may influence tumor–bone interactions [ 70 , 72 ]. Preclinical evidence suggests that in Wnt-responsive tumors, altered osteocyte signaling via Wnt activation could either promote tumor adaptation within the bone or facilitate metastasis [ 70 , 72 ]. This underscores the need for further studies to evaluate the safety and efficacy of anti-sclerostin therapies in metastatic bone disease, particularly in combination with anti-resorptives like bisphosphonates or denosumab, to optimize outcomes [ 70 , 71 , 72 ].

DKK1 inhibitors, such as BHQ880, offer a complementary approach to treating cancers like multiple myeloma, in which bone disease is characterized by increased osteoclast activity and suppressed osteoblast function [ 73 , 74 ]. DKK1-mediated Wnt inhibition plays a central role in osteoblast suppression and residual bone destruction, making anti-DKK1 strategies a rational choice for addressing the mixed osteolytic and osteoblastic states seen in myeloma bone disease [ 73 , 74 , 75 ]. By reversing Wnt pathway impairment, anti-DKK1 agents promote bone formation and repair while disrupting the vicious cycle of tumor–bone marrow niche interactions that drive both bone destruction and tumor progression. However, questions remain about how bone formation alone influences disease behavior and how to integrate anti-DKK1 therapies into standard regimens alongside anti-resorptives [ 74 , 76 , 77 ]. Further research is necessary to understand their impact on the tumor–bone interface and optimize their clinical application [ 73 , 74 , 75 ].

6.3. Mechanotherapy and Mechanosensors

6.3.1. Pizeo1 Agonism and LMHF Vibration

Piezo1, a key mechanosensor in bone physiology, plays an essential role in osteocyte mechanotransduction by converting mechanical signals into biochemical responses critical for bone remodeling and homeostasis [ 50 , 78 , 79 ]. Recent proof-of-concept preclinical studies suggest that enhancing osteocyte mechanosensation via Piezo1 agonism, such as the tool compound Yoda1, combined with low-magnitude, high-frequency (LMHF) vibration, can restrain metastatic behavior in bone-related cancers. For example, Yoda1 and LMHF vibration have been shown to regulate osteocyte signaling, reducing MDA-MB-231 breast cancer cell migration and extravasation, which are critical steps in metastasis [ 26 , 27 ]. Preclinical data also suggest that vibration-based interventions can influence the metastatic bone microenvironment, with in vivo studies demonstrating reduced breast cancer bone metastasis and vascularization [ 80 ].

The translational roadmap for Piezo1-based therapies includes developing safer pharmacological modulators and personalized mechanical loading prescriptions, such as LMHF vibration, to enhance osteocyte mechanosensation without adverse effects [ 81 , 82 , 83 , 84 , 85 ]. While not yet clinically established, these approaches hold promise not only for preventing bone loss in mechanical unloading or age-related osteoporosis but also for mitigating metastatic progression by targeting the bone microenvironment [ 26 , 27 , 80 , 86 , 87 ].

6.3.2. Cx43 Hemichannel Activation

Cx43 hemichannels are critical mediators of osteocyte communication and play a key role in bone remodeling and metastatic progression. Activation of Cx43 hemichannels using targeted peptides (e.g., Cx43-M1/M2) or antibodies has emerged as a novel osteocyte-centric therapy class with the potential to curb bone metastases and warrants further clinical testing. Preclinical animal studies using monoclonal Cx43-M2 antibodies have shown an effective ability to inhibit the growth of breast cancer in mouse breast carcinoma in wild-type mice, as well as human breast cancer in immunocompromised mice in vivo [ 33 ]. These strategies reduce osteocyte apoptosis, suppress osteoclast activity, and promote osteoblast-mediated bone formation, helping to maintain bone integrity in metastatic disease contexts. By restoring osteocyte functionality and reducing pathological bone resorption, Cx43-based therapies may also prevent the vicious cycle of tumor–bone interactions, where bone-derived factors promote tumor survival and progression [ 87 ]. Further research is needed to refine the application of Cx43-targeted interventions, including their integration with Piezo1-based therapies and anti-resorptive agents, as part of a comprehensive strategy to address bone loss and metastasis in cancer [ 78 , 86 , 87 ].

6.4. PLR Enzymes and Acidification

Osteocytes play an active role in bone microenvironment remodeling through perilacunar remodeling (PLR), a process that involves localized matrix degradation and mineral mobilization. This capability becomes particularly relevant in cancer-associated bone diseases, where tumors can exploit osteocyte-driven remodeling to support skeletal colonization and growth [ 88 , 89 ]. Osteocytes employ molecular pathways overlapping with classical bone resorption mechanisms, including enzymes such as MMP13, CTSK, and CA2, which drive PLR and acidification of the lacunar microenvironment [ 90 , 91 ]. Acidification is a central mechanism enabling osteocytes to dissolve mineral components and modify matrix biochemistry, thereby influencing cancer cell behavior within the bone niche [ 91 , 92 ].

Targeting PLR-associated enzymes like MMP13, CTSK, and CA2 offers a therapeutic approach to blunt osteocyte-driven matrix mobilization near tumor foci. However, systemic inhibition of these pathways raises safety concerns, such as the increased stroke risk observed in preclinical animal trials with the cathepsin K inhibitor odanacatib, emphasizing the need for local or cell-targeted strategies [ 93 ]. Localized modulation of PLR could limit tumor-favorable remodeling while reducing systemic adverse effects, particularly in metastatic bone disease, where osteocyte activity contributes to the permissive microenvironment for tumor progression [ 88 , 90 , 91 ].

Future therapeutic efforts should focus on targeted delivery of inhibitors to osteocytes or the tumor-bone interface to mitigate osteocyte-driven matrix degradation while minimizing systemic risks. This approach aligns with the emerging recognition of osteocyte PLR as a clinically relevant contributor to cancer-induced bone remodeling, offering a path to reduce osteocyte-mediated tumor progression in the bone microenvironment [ 88 , 89 , 90 , 91 , 92 , 94 ].

6.5. Purinergic Signaling

Osteocytes actively regulate bone remodeling through purinergic signaling, in which extracellular ATP (eATP) acts as a key messenger. Under mechanical loading or stress, osteocytes can release ATP into the microenvironment via Cx43 hemichannels, a process linked to mechanosensitive inputs such as Piezo1, providing a direct route by which mechanical cues drive eATP signaling [ 7 , 95 ].

This eATP signal is then transduced through purinergic receptors on surrounding cells, with P2X7 standing out as a clinically relevant target because it is directly activated by eATP and implicated in inflammation and bone remodeling [ 96 ]. In osteoclast biology specifically, accumulating evidence connects P2X7 signaling to osteoclast differentiation and resorption; P2X7 knockdown suppresses osteoclastogenesis via autophagy and Ca 2+ /calcineurin-associated pathways, supporting the concept that modulating P2X7 can blunt osteoclast function and limit osteolysis in disease [ 58 , 97 ]. Since osteoclast-driven osteolysis also sustains tumor–bone feedback loops, dampening osteoclast activity via eATP→P2 receptor signaling is positioned as a translational strategy to protect bone integrity in malignant settings [ 98 ].

Beyond bone resorption, eATP signaling can also influence tumor behavior in the bone niche. ATP has been shown to inhibit breast cancer cell migration and bone metastasis through purinergic receptor signaling (via P2Y11 in that model), underscoring that extracellular purines can directly modulate metastatic traits rather than acting only as generic “stress” signals [ 32 ]. In parallel, P2X7 biology has been linked to cancer progression and bone metastasis in prostate cancer contexts, further supporting purinergic receptors as actionable nodes at the tumor–bone interface [ 99 ]. Current and emerging therapeutic strategies targeting osteocyte-regulated pathways, including their mechanisms, evidence level, and major limitations, are summarized in Table 2 .

Together, these findings support a focused, testable axis: leverage osteocyte Cx43 hemichannel–mediated eATP release to engage P2X pathways, particularly pharmacologic modulation of P2X7, to inhibit osteoclast differentiation/resorption and, in turn, dampen tumor-promoting dynamics in bone [ 7 , 58 , 95 , 96 , 97 , 98 ].

6.6. Senolytics/Senomorphics

Evidence is increasingly linking osteocyte senescence to the biology of metastatic bone disease. In breast cancer bone metastasis, single-cell and functional data indicate osteocytes can undergo premature senescence associated with altered signaling and bone destruction, implicating senescent osteocytes as modifiable niche regulators rather than passive bystanders [ 36 , 54 ]. Senescence may drive niche “permissiveness” via the SASP—pro-inflammatory and tissue-remodeling factors that can promote osteoclast activity, suppress osteoblast function, and alter immune regulation [ 36 , 54 , 100 ].

Translationally, this motivates senescence-targeting strategies to remodel the metastatic niche. Senolytics that eliminate senescent cells have proof-of-concept in marrow-associated microenvironments; navitoclax (ABT-263) has been used in preclinical trials to reduce senescent niche components, supporting pharmacologic tractability [ 101 ]. Human data also support the clinical feasibility of intermittent senolytic regimens with bone-metabolism outcomes [ 102 ]. In parallel, senomorphic/SASP-directed approaches aim to blunt harmful secretory outputs; a cited example is liposome-encapsulated fisetin reducing SASP cytokines (including IL-6 and IL-8) without clear senolysis, supporting the broader rationale for SASP-targeted agents (e.g., IL-6–axis interventions) as a niche-modifying strategy [ 103 ].

Finally, the observation of senescent stromal populations in pre-metastatic bone marrow in advanced breast cancer suggests senescence may contribute early to a permissive environment, strengthening the case for testing senolytic (e.g., navitoclax) and SASP-suppressing approaches in dedicated bone metastasis models to determine whether targeting osteocyte/stromal senescence can reduce niche permissiveness and metastatic progression [ 36 , 54 , 104 ].

6.7. EV-Directed Strategies

6.7.1. EV Biogenesis and Uptake Inhibitors

Extracellular vesicles (EVs), particularly exosomes, are critical mediators of tumor–bone crosstalk, enabling cancer cells to condition the bone microenvironment for metastasis. Inhibiting EV biogenesis and uptake offers possible therapeutic strategies to disrupt this communication and reduce metastatic progression [ 105 ]. Tumor EV biogenesis depends on regulated pathways, such as those involving neutral sphingomyelinase 2 (nSMase2) and Rab proteins, which are viable targets for pharmacological inhibition. nSMase2 inhibitors, for instance, show potential to reduce EV secretion and weaken tumor-driven remodeling of the bone niche, offering a more targeted alternative to nonspecific interventions [ 106 , 107 , 108 ]. Additionally, blocking EV uptake via mechanisms such as micropinocytosis could prevent functional delivery of EV cargo to bone-resident and stromal cells, thereby interrupting pro-metastatic signaling cascades [ 109 , 110 ].

6.7.2. Engineered Exosomes with Bone Tropism for Drug Delivery

Beyond EV inhibition, engineered exosomes with bone tropism offer an early proof-of-concept approach for therapeutic delivery. Unlike tumor-derived EVs, non-bone-derived engineered vesicles may offer superior targeting capabilities, enabling precise delivery of therapeutics to osteocytes and other bone-resident cells. This strategy leverages the natural ability of exosomes to transport molecular cargo, while modifying their tropism to enhance specificity toward skeletal tissues [ 105 , 111 ]. Such vesicles could be used to deliver EV inhibitors or other drugs directly to the bone microenvironment, reducing systemic toxicity and maximizing therapeutic efficacy.

6.8. Systemic Modulators Impacting Osteocytes

Accumulating evidence highlights the role of β2-adrenergic receptor (β2AR) signaling in promoting bone metastasis by modulating host bone cells, including osteoclasts and stromal cells. Sympathetic nervous system (SNS) activation and downstream adrenergic signaling have been shown to enhance metastatic progression by reshaping the bone microenvironment, supporting tumor colonization, and altering bone remodeling dynamics [ 112 , 113 ]. In particular, β2AR activation has been associated with increased osteoclast activity, directly linking adrenergic tone to pro-metastatic bone remodeling processes [ 113 ].

Pharmacological β-blockade, a well-established approach to tamp down sympathetic tone, offers a promising strategy to disrupt these tumor-promoting pathways. β-blockers could mitigate β2AR-driven enhancement of bone metastasis by modulating both tumor behavior and the bone microenvironment. Preclinical and mechanistic studies support the potential of β-blockers to influence immune remodeling, stromal conditioning, and bone niche permissiveness, providing a strong translational rationale for their use in bone-metastatic disease [ 112 , 113 , 114 , 115 , 116 ].

While preclinical evidence is compelling, prospective clinical data are needed to validate the efficacy of β-blockers in mitigating metastasis-associated bone disease. Observational studies have suggested potential benefits in certain cancer settings, but robust trials are necessary to confirm their utility and identify specific patient populations most likely to benefit [ 112 , 117 , 118 ].

Adrenergic signaling may also intersect with osteocyte biology, as osteocytic cells have been reported to express β-adrenergic receptors and to alter RANKL/OPG signaling in response to β-adrenergic stimulation. However, direct evidence linking osteocytic β-adrenergic signaling to metastatic bone progression remains limited, so this pathway is best viewed as a contextual rather than a core osteocyte-targeted axis.

Overall, targeting β2AR signaling through β-blockade represents a rational systemic strategy to address the adrenergic contributions to bone metastasis, with the potential to reduce metastatic progression by interfering with tumor–bone cell interactions and remodeling dynamics [ 112 , 113 ].

7. Biomarkers and Imaging Readouts of Osteocyte Activity in Metastasis

Osteocytes are emerging as key regulators of bone remodeling and metastatic bone disease, making their secretory outputs and structural changes clinically relevant for monitoring skeletal metastases. Serum biomarkers such as sclerostin (SOST) and DKK1 represent mechanistically significant readouts of osteocyte activity. Sclerostin, a Wnt signaling antagonist, reflects osteocyte mechanotransduction and remodeling dynamics, whereas DKK1 has been implicated in Wnt pathway dysregulation in osteolytic metastases, particularly in cancers such as NSCLC [ 38 , 119 , 120 ]. These biomarkers, along with bone turnover markers such as NTX and bone-specific alkaline phosphatase (BAP), support dynamic monitoring of bone remodeling and metastatic burden across cancer types [ 121 , 122 , 123 ].

Imaging also plays a pivotal role in capturing osteocyte-related structural changes. High-resolution microCT enables visualization of lacunar-canalicular network (LCN) integrity and perilacunar remodeling (PLR), with altered lacunar density and morphology serving as proxies for osteocyte network disruption in metastatic bone [ 124 , 125 ]. These imaging-derived metrics complement serum biomarker data by providing lesion-specific insights into osteocyte-driven remodeling.

Mechanistic studies further highlight osteocyte signaling pathways, such as ATP and prostaglandin E 2 (PGE 2 ) release mediated by connexin 43 (Cx43) activation, as contributors to osteocyte remodeling and metastatic niche evolution. Additionally, single-cell and spatial profiling in human metastatic bone lesions have revealed osteocyte senescence, linking cellular aging to disrupted bone remodeling and metastatic progression [ 10 , 38 , 92 , 126 ].

By combining serum biomarkers (e.g., sclerostin, DKK1), turnover markers (e.g., NTX, BAP), imaging proxies for LCN integrity, and mechanistic insights into osteocyte signaling and senescence, a comprehensive framework can be developed for diagnosing, stratifying, and monitoring metastatic bone disease [ 92 , 119 , 120 , 124 , 125 ]. These integrated approaches improve upon traditional imaging alone, offering a multi-layered strategy to better understand and manage tumor–bone interactions.

8. Conflicting Data and Nuances

8.1. Tumor Context

Anti-sclerostin drugs augment bone mass by disinhibiting canonical Wnt/β-catenin signaling in osteoblast-lineage cells; nevertheless, Wnt also plays a crucial role in promoting tumor growth and stemness in various malignancies. The existing findings indicate a context-dependent “double-edged” phenomenon in skeletal metastasis that correlates closely with the tumor’s responsiveness to Wnt ligands.

A study on breast cancer in mice revealed that sclerostin antibody or Sost deficiency significantly enhanced bone metastases of MDA MB 231 cells, which exhibit a strong response to Wnt3a, but did not affect Wnt-responsive cell lines. Anti-sclerostin elevated the Wnt target gene AXIN2 and nuclear β-catenin in bone-colonized tumor cells, signifying direct stimulation of canonical Wnt signaling in metastases [ 127 ]. Anti-sclerostin promoted tumor sphere development, indicative of a stem-like characteristic, without augmenting two-dimensional proliferation or migration, implying the expansion of a stem-like subpopulation rather than overall growth [ 127 ]. Anti-sclerostin elevated the number of osteoclasts and their precursors in metastatic bone, perhaps exacerbating the “vicious cycle” of osteolytic metastasis [ 127 ]. Inhibition of sclerostin enhances systemic bone development; nevertheless, in Wnt ligand-responsive breast cancer cells located in bone, the same Wnt activation may promote tumor stemness and increase metastatic burden.

In multiple myeloma, where Wnt activation is important in pathogenesis, many models demonstrate that sclerostin inhibition restores bone integrity without promoting tumor development. Neutralizing sclerostin reinstates osteoblast functionality, repairs lytic lesions, and enhances bone mass; however does not promote multiple myeloma tumor proliferation in several preclinical models or ex vivo human bone organ cultures [ 128 , 129 ]. In combined therapy, the sclerostin antibody did not diminish the efficacy of a potent anti-multiple myeloma Notch inhibitor, and tumor burden was only influenced by the anti-cancer medication, rather than by the co-administration of the sclerostin antibody [ 128 ]. A restricted retrospective cohort of multiple myeloma patients in remission, treated with Scl ab for bone repair, demonstrated enhanced bone mass without any recorded disease relapse during a brief follow-up period, but the sample size and length were constrained [ 128 ]. Narrative and mechanistic assessments consistently indicate that in multiple myeloma and several breast cancer models, sclerostin inhibition either exerts no effect or diminishes tumor growth in bone, concurrently enhancing bone strength [ 129 , 130 ].

The primary differentiator in the breast cancer study is the tumor’s susceptibility to Wnt ligands. Wnt-responsive metastases (e.g., MDA MB 231) exhibited significant responsiveness to Wnt3a in TOPFLASH/AXIN2 tests, wherein sclerostin inhibition resulted in enhanced beta-catenin signaling inside the tumor, augmented tumor sphere development, and an increase in metastases [ 127 ]. Conversely, Wnt unresponsive or weakly responsive metastases exhibited negligible Wnt3a response in vitro, and anti-sclerostin did not enhance bone metastases of these lines [ 127 ].

In multiple myeloma, tumor cells may respond to Wnt under certain conditions; however, sclerostin inhibition primarily reactivates osteoblasts and mitigates Wnt antagonism in the niche, without triggering a proliferative Wnt transcriptional program in multiple myeloma cells [ 128 ]. Consequently, the identical systemic intervention may be mostly osteoanabolic and anti-resorptive, with Wnt activation restricted to the osteoblast/osteocyte compartment, encompassing PDGFR–M CSF regulation and diminished osteoclastogenesis [ 131 ]. Conversely, in instances when tumor cells are receptive to Wnt ligands and exist within a Wnt-abundant bone microenvironment, the intervention may also stimulate beta-catenin in metastases, hence augmenting stemness and metastatic load [ 127 ].

In general, anti-sclerostin therapy seems to be safer in contexts where tumor cells are either Wnt-unresponsive or absent (such as multiple myeloma in deep remission or non-malignant osteoporosis); nonetheless, it may pose a potential metastatic risk in the presence or suspicion of Wnt ligand-sensitive tumors with a propensity for bone involvement.

8.2. Cell Stage and Load Regime

Piezo1 is expressed throughout the osteoblast lineage, but its prevalence and functional significance vary with maturation: it facilitates osteocyte differentiation and dendrite development during the late osteoblast-to-osteocyte transition, whereas Piezo1 in fully mature osteocytes is less essential for adaptive loading responses. The absence of Piezo1 in late osteoblasts and osteocytes impairs osteocyte differentiation and diminishes both the number and length of dendrites, underscoring the essential function of Piezo1 in the maturation process [ 132 ].

Osteoblast-lineage cells express piezo1, which facilitates mechanosensitive transcriptional responses in whole-animal models and cultured osteocyte-lineage cells when bone mass is decreased by lineage deletion [ 132 ]. Despite being reduced, Piezo1 is functionally retained in mature osteocytes, as the targeted deletion in these cells modifies steady-state bone mass and microstructure, indicating its expression and physiological significance in mature cells [ 133 ]. Intermittent stimulation of downstream effectors (YAP) or systemic overexpression of CCN1/2 mitigated dendritic and bone abnormalities resulting from Piezo1 deficiency, hence endorsing a differentiation-stage role facilitated by Piezo1-mediated signaling [ 132 ].

Pharmacologic Piezo1 (Yoda1) activation can restore glucocorticoid-suppressed differentiation and mechanosensitivity in periosteal/osteoprogenitor contexts and replicate flow-induced gene responses in cultured osteocyte-lineage cells, which is consistent with its function in promoting or restoring differentiation-linked mechanisms [ 132 , 134 ]. In models of glucocorticoid-induced osteoporosis, the expression of Piezo1 is modulated by HES1, and the activation of Piezo1 promotes the phosphorylation of CaMKII and Akt, thereby reinstating mechanosensitive responses and lacunocanalicular integrity [ 134 ].

Piezo1-induced Ca 2+ signals activate Cx43 hemichannels through the PI3K-Akt pathway and initiate ATP–P2X signaling and Panx1 to maintain intracellular Ca 2+ responses to mechanical stress in osteocytes [ 135 ]. The conditional deletion of Piezo1 from the osteoblast/osteocyte lineage (Dmp1-Cre) disrupts the bone anabolic response to mechanical loading, while deletion limited to mature osteocytes (Sost-Cre) reduces bone mass without inhibiting the skeletal loading response. This suggests that mechanosensory dependence is more pronounced in earlier and late-differentiating lineage cells than in fully mature osteocytes [ 133 ]. In MLO-Y4 cells, fluid shear enhances Piezo1 and modifies OPG/RANKL expression through NOTCH3, suggesting that Piezo1-dependent mechanosensing affects osteoclastogenic signaling in osteocyte-like cells [ 136 ]. One model showed unanticipated Wnt/β-catenin activation when Piezo1 was lost in the lineage, indicating a possible interaction between Piezo1-driven mechanotransduction and the normal bone anabolic pathways during differentiation [ 132 ].

Extensive deletions in osteoblast/osteocyte lineages (Dmp1 Cre, Prx1 Cre, Runx2 Cre) result in osteoporosis due to modified osteoblast–osteoclast interactions and heightened resorption, highlighting Piezo1 as a pivotal mechanosensor in the skeleton [ 135 , 137 , 138 , 139 , 140 , 141 , 142 ]. Although these models demonstrate significant alterations in the bone microenvironment, metastasis is not yet explicitly studied. Microfluidic and in vitro studies demonstrate that Yoda1 or Piezo1-mediated osteocyte activation under low magnitude high frequency vibration can: Reduce MDA MB 231 breast cancer cell migration through osteoclast-dependent pathways [ 27 ]; increase nuclear YAP in osteocytes and inhibit osteoclastogenesis; decrease breast cancer cell extravasation into bone mimetic settings; Piezo1 activation amplifies this inhibitory impact [ 26 ]. These findings suggest that osteocytes’ functioning of Piezo1 contributes to the formation of a microenvironment that inhibits the initial stages of bone metastasis [ 26 , 27 ]. No in vivo models have directly tested bone metastasis burden in Piezo1-deficient mature osteocyte backgrounds [ 26 , 27 ]. It is unknown whether osteocyte-specific Piezo1 loss alone, without systemic bone loss, is sufficient to alter metastatic seeding, dormancy, or outgrowth.

8.3. Tumor Type Heterogeneity in Engaging Osteocytes

Single-cell profiling among various cancers reveals a minimum of three “ecosystem archetypes” of bone metastasis, characterized by macrophages/osteoclasts, Treg/exhausted T cells, or monocytes, with only a modest correlation to the tissue of origin, highlighting both convergent and divergent pathways to bone colonization [ 143 ].

Bone metastases from breast cancer are primarily osteolytic and characterized by a macrophage/osteoclast (Mφ OC) archetype, triggered by the typical “vicious cycle”: tumor-derived substances promote osteoclastogenesis and bone resorption, which in turn releases growth factors that further boost tumor proliferation. Single-cell findings indicate that breast bone lesions predominantly cluster within the Mφ OC archetype, characterized by robust osteoclast programs and estrogen-responsive macrophages [ 143 ].

Breast metastases exhibit microenvironmental variability across different sites: bone lesions demonstrate increased neutrophil infiltration relative to primary tumors, while lymph node metastases exhibit reduced macrophage presence [ 144 , 145 ]. In scRNA sequencing of primary tumors, lymph nodes, brain, and bone metastases, bone lesions are distinguished by elevated levels of proliferative cancer-associated fibroblasts (pCAFs) interacting with malignant epithelial cells, which are associated with an unfavorable prognosis [ 144 ]. Tumor cells co-cultured with cancer-associated fibroblasts (CAFs) exhibit increased expression of IL-6 and IL-8, hence augmenting invasiveness and angiogenesis [ 144 ]. Marrow adipocytes facilitate breast and melanoma bone metastases by supplying lipids and pro-inflammatory mediators (e.g., PPARγ, IL-1β, IL-6, FABP4, CXCL1/2) that enhance tumor proliferation and osteolysis [ 146 ].

Prostate cancer bone metastases are often osteoblastic, though frequently mixed; there is considerable molecular and stromal heterogeneity. Transcriptomic profiling identifies three molecular subtypes (MetA–C); MetB exhibits elevated proliferation, diminished PSA levels, and a suboptimal response to androgen restriction therapy [ 147 ]. Histologically, the majority of metastases contain several epithelial subclones exhibiting diverse morphologies and are situated within a heterogeneous stroma characterized by varying bone content, vascular density, and fibroblast markers [ 147 ]. Two stromal subtypes are identified: one characterized by high bone density, reduced vascularity, and a favorable prognosis, and another marked by increased proliferation, greater vascularity, and poorer results [ 147 ].

Chemokine signaling influenced by the microenvironment modulates prostate bone disease. Prostate cancer cells that metastasize to bone stimulate mesenchymal stem cells (MSCs) to produce CXCL8 and its murine counterpart Cxcl1; MSC-derived Cxcl1 inhibits osteoblast development, fosters a pro-tumoral immunological environment characterized by immature neutrophils, and facilitates tumor proliferation [ 148 ]. The genetic deletion of Cxcl1 in mesenchymal stem cells (MSCs) promotes osteogenesis, modifies immunological composition (resulting in a reduction in immature neutrophils and an increase in monocytes), and significantly inhibits prostate tumor growth in bone [ 148 ]. Previous research also associates CXCL8 family chemokines with osteolytic bone metastases in breast cancer and multiple myeloma, where they promote osteoclastogenesis and tumor viability [ 148 ].

Heterogeneity in kinase signaling further differentiates bone from other metastatic locations. In PTEN-deficient mice, bone metastases, unlike those in the lung or liver, demonstrate heightened PI3K/mTOR signaling and c MET expression; suppression of c MET selectively disrupts bone lesions [ 145 ]. EpCAM high epithelial cells exhibiting elevated PI3K/mTOR activity coexist with EpCAM low mesenchymal cells displaying reduced kinase activity, resulting in varied susceptibility to PI3K/mTOR inhibitors [ 145 ].

Multiple myeloma results in characteristic widespread osteolytic bone disease accompanied by significant skeletal consequences. Although the included publications exhibit limited representation of precise molecular variability, numerous consistent features are evident throughout preclinical models. Multiple myeloma bone disease has clinical endpoints analogous to those of solid bone metastases, including fractures, pain, and diminished quality of life. It is often replicated in conjunction with breast and prostate bone metastasis using intratibial systems that replicate osteolytic lesions and pain behaviors [ 149 , 150 ].

The activation of osteoclasts induced by chemokines is fundamental. CXCL8 is increased in bone stromal cells in multiple myeloma and facilitates both myeloma survival and tumor-associated osteolysis, mirroring the activities of the CXCL8 family in osteolytic breast cancer and in the MSC-mediated regulation of prostate bone metastases [ 148 ]. Increased osteocyte apoptosis has been observed in multiple myeloma lytic lesions, signifying a significant role of osteocyte death in bone degradation, a phenomenon that is now also mechanistically elucidated in melanoma [ 151 ]. Bone marrow adipocytes seem to significantly facilitate multiple myeloma and prostate bone disease, followed by breast cancer and melanoma, via metabolic and cytokine interactions; nevertheless, clinical data are limited [ 146 ].

Bone metastases from melanoma are less prevalent than visceral or cerebral metastases but are associated with significant morbidity due to osteolytic lesions and skeletal-related complications. Lesions are predominantly osteolytic and mediated by osteoclasts via both RANKL-dependent and independent mechanisms [ 152 ]. Tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, and cancer-associated fibroblasts establish an immunosuppressive tumor microenvironment that facilitates osteoclastogenesis through cytokines such as IL-6 and CXCL8, which activate the JAK/STAT3, NF-κB, and MAPK pathways in osteoclast precursors and melanoma cells [ 152 ]. In addition to immune cells, systemic variables influence melanoma formation in bone. The depletion of the gut microbiome due to broad-spectrum antibiotics accelerates intraosseous melanoma proliferation and osteolysis by hindering the expansion of NK and Th1 cells in the intestine and their CXCR3/CXCL9-mediated migration to tumor-infiltrated bone marrow; obstructing lymphocyte egress or CXCR3/CXCL9 signaling replicates this acceleration [ 153 ].

Recent elucidations at the level of bone resident cells have identified two osteocyte-centered processes that underscore distinctive melanoma-bone interactions: ferroptotic osteocyte death and CXCL5-mediated tumor support. Melanoma bone metastases induce significant osteocyte mortality mostly through ferroptosis, rather than apoptosis or necroptosis. RNA sequencing of osteocyte-enriched calcified bone demonstrates an enrichment of ferroptosis pathways and signatures associated with “response to iron ion”, characterized by the downregulation of GPX4 and upregulation of HMOX1 [ 151 ]. Mechanistically, HIF1α functions upstream of HMOX1, promoting excessive autophagy-mediated ferritin breakdown (ferritinophagy), resulting in iron overload and lipid peroxidation, ultimately leading to osteocyte ferroptosis [ 151 ]. The suggested loss of osteocytes is believed to contribute to further bone loss and remodeling in melanoma tumors [ 151 ].

A separate and complementary route entails osteocyte-derived CXCL5 as a prometastatic signal exclusively induced by melanoma cells. Through RNA sequencing and chemokine analysis, osteocytes exposed to melanoma cells significantly upregulate and release CXCL5 [ 44 ]. This activation is not merely basal chemokine production but rather a tumor-conditioned response that reprograms osteocytes into active facilitators of metastatic development.

Osteocyte-derived CXCL5 functionally promotes melanoma cell motility and invasion in vitro through the CXCR2 receptor on melanoma cells [ 44 ]. Silencing of CXCR2 in melanoma significantly diminishes their migratory response to osteocytes, indicating that the communication between osteocytes and tumors occurs via a CXCL5–CXCR2 axis. In vivo, melanoma cells expressing lower levels of CXCR2 produce fewer bone metastases and result in reduced bone loss in murine models [ 44 ].

Importantly, simultaneous targeting of CXCL5 in osteocytes and CXCR2 in melanoma cells nearly entirely halts melanoma growth in bone in vivo. This bilateral necessity emphasizes CXCL5 induction as a point of reciprocal interaction rather than a unidirectional tumor-intrinsic program [ 44 ]. In melanoma, CXC chemokines such as CXCL1, CXCL5, and CXCL8 are overexpressed in skin tumors and linked with prognosis and inflammation; however, the unexpected result is that osteocytes, rather than melanoma cells alone, are the primary source of CXCL5 in the metastatic niche [ 44 , 154 ].

9. Knowledge Gaps and Future Experiments

9.1. Causal Mapping of LCN Topology Changes vs. DTC Fate

In murine osteotropic breast and prostate cancer, cortical regions with tumors exhibit enlarged lacunae, compromised canalicular connection, and localized alterations in vascular canal density in comparison to controls, signifying significant LCN remodeling at metastatic sites [ 3 , 155 ]. The structural alterations are associated with osteolytic and osteosclerotic areas, as well as initial declines in bone mechanical competence, indicating that tumor–osteocyte interactions modify the LCN and bone strain perception [ 3 , 155 ]. Osteocyte network density and structure fluctuate with mineral content and across cortical areas in robust bone, influencing mechanosignaling capability [ 156 , 157 ].

Numerous studies indicate that signals originating from osteocytes, particularly under mechanical pressure, play a role in either sustaining or disrupting tumor dormancy. The transfer of osteocyte mitochondria can activate STING-dependent antitumor immunity, hence restricting metastatic development in bone [ 158 ].

Reviews highlight osteocytes as essential regulators of metastatic niche signaling (cytokines, EVs, mechanotransduction), although they fail to specify certain LCN network features (degree, path length, clustering) as factors influencing DTC dormancy versus outgrowth [ 3 , 10 , 159 , 160 ].

Recent results indicate that osteocytes and their mechanosensitive signaling, partially reliant on the LCN, can facilitate tumor dormancy or inhibit metastatic advancement in bone. Nonetheless, no research currently establishes that the spatial architecture of the LCN serves as a causal regulator that determines DTC dormancy vs. metastatic expansion, rather than merely acting as a consequence or modification of larger osteocyte-tumor interactions.

9.2. In Vivo Dissection of Osteocyte EV Cargo on Tumor Dormancy/Full Outgrowth

The sole directly pertinent in vivo research linking osteocyte-derived sEVs, miRNA cargo, and cancer cell activity is the recent study on NSCLC bone metastases conducted by Xie et al. [ 161 ]. Other sEV–miRNA studies elucidate pathways of miRNA-mediated tumor suppression or bone remodeling; however, they are either not obtained from osteocytes or not conducted in bone metastasis models [ 162 , 163 , 164 , 165 ].

In a model of bone metastases in non-small cell lung cancer (NSCLC), osteocytes detecting mechanical stimulation (by tibial loading or treadmill exercise) released small extracellular vesicles (sEVs) enriched in tumor suppressor microRNAs, particularly miR 99b 3p [ 161 ]. Gain and loss of function experiments identified miR 99b 3p as the principal mediator, directly targeting the E3 ligase MDM2 through its 3′ UTR, thereby functionally alleviating p53 from MDM2-mediated repression and restricting NSCLC proliferation [ 161 ].

Although not based on bone osteocytes, numerous in vivo investigations corroborate the overarching notion that sEV-supplied tumor suppressor microRNAs can inhibit metastatic proliferation. Intraperitoneal delivery of miR–29 b–loaded bone marrow MSC sEVs inhibited peritoneal metastases of gastric cancer by counteracting TGFβ-induced mesothelial epithelial–mesenchymal transition-like alterations and diminishing tumor adherence and colonization [ 165 ]. The fate of disseminated tumor cells within the bone microenvironment is governed by microenvironmental stress, TGFβ–p38–mediated dormancy programs [ 166 ], immune surveillance [ 167 , 168 ], and the nature of the pre-metastatic niche [ 169 , 170 , 171 ].

9.3. Trials That Embed Osteocyte-Centric Endpoints (SOST/DKK1 Dynamics; Cx43-HC Activity; Senescence Markers) into Standard Anti-Resorptive Regimens

Osteocytes modulate bone formation and resorption through Wnt antagonists (sclerostin, DKK1) and connexin 43 hemichannels (Cx43 HC). These signals are more closely associated with alterations in bone microarchitecture than traditional resorption indicators such as CTX, which just indicate collagen degradation.

Sclerostin and DKK1 are primarily released by osteocytes, directly inhibiting Wnt/β-catenin signaling, which suppresses osteoblast development and promotes osteoblast death, therefore leading to increased osteoclastogenesis and bone resorption [ 172 , 173 , 174 ]. Increased sclerostin has been associated with diminished bone formation, enhanced resorption, and decreased bone mineral density in osteoporosis, chronic kidney disease, metabolic bone disorders, Gaucher disease, and diabetes-related bone fragility [ 172 , 173 , 174 , 175 , 176 , 177 ]. CTX indicates present osteoclast activity; nevertheless, it fails to account for osteocyte-mediated alterations in remodeling set point or cortical porosity, which are essential factors influencing bone quality.

In multiple myeloma, sclerostin and DKK1 levels correlated with bone lesion burden and therapeutic response; reductions during treatment coincided with enhancements in myeloma bone disease, indicating their utility for monitoring treatment-induced alterations in bone integrity, particularly when CTX is influenced by disease activity [ 178 ]. In Gaucher disease, increased sclerostin is significantly correlated with bone pain, marrow infiltration, Erlenmeyer deformity, and osteopenia/osteoporosis, as the usual sclerostin–DKK1 equilibrium is disrupted with declining bone mineral density, thereby directly connecting these osteocyte markers to structural pathology and symptoms [ 177 ]. A case–control study on osteoporosis indicated significantly elevated serum sclerostin levels in osteoporotic participants compared to controls, demonstrating strong diagnostic sensitivity and specificity for osteoporosis status [ 179 ].

In postmenopausal osteoporosis treated with romosozumab, CTX decreases and BMD increases; nonetheless, Dkk1 progressively rises and is inversely correlated with P1NP, reflecting the diminished anabolic response despite ongoing CTX suppression [ 180 ]. DKK1 effectively encapsulates compensatory osteocyte responses and forecasts the decline in bone-forming ability that CTX fails to predict. Preclinical and clinical studies targeting Wnt demonstrate that anti-sclerostin therapy enhances bone mineral density (BMD) and reduces fracture incidence, while also altering both C-terminal telopeptide (CTX) and formation indicators; the Wnt inhibitors are pivotal in this mechanism [ 174 , 181 , 182 ]. Assessing sclerostin/DKK1 in these trials directly evaluates target engagement and aids in interpreting paradoxical changes in CTX levels.

Sclerostin and DKK1 serve as upstream regulators of cortical porosity, trabecular thickness, and turnover equilibrium; their levels closely correlate with variations in bone volume and structure across various disorders and therapies [ 172 , 175 , 176 , 177 , 178 , 182 ]. CTX is unable to differentiate between high turnover with maintained structure and high turnover accompanied by significant microarchitectural degradation. Sclerostin is influenced by mechanical stress, diabetes, chronic kidney disease, inflammatory conditions, and malignant bone disorders, positioning it as a systemic integrator of variables that compromise bone quality beyond mere resorption [ 172 , 173 , 174 , 177 , 183 ]. Data from CKD biopsies and transplant bone histomorphometry directly associate sclerostin/DKK1 with turnover category and bone volume, which are the gold standards for assessing bone quality, whereas CTX demonstrates little predictive capability at the individual histological level [ 172 , 175 ].

9.4. Mechanotherapy Dosing and Piezo-Safe Agonists Translation

Existing research suggests a mechanistically credible additive or synergistic interaction between mechanical dosage (vibration/loading) and Piezo1 agonists in promoting bone growth, along with nascent evidence on their impact on bone metastasis.

Moderate tibial loading combined with Yoda1 in approximately 50-week-old mice resulted in superior cortical and trabecular protection compared to either intervention alone, demonstrating enhanced cortical polar moment of inertia and a greater proportion of mice exhibiting beneficial structural modifications, indicative of at least additive effects. The identical loading profile combined with Yoda1 effectively reduced age-related bone loss more than individual treatments; however, it could not completely reverse severe damage generated by doxorubicin, suggesting that synergy has limitations under extreme cytotoxic stress [ 184 ]. In 22-month-old mice, tibial loading with an adjusted waveform that increases fluid flow while maintaining modest strain, in conjunction with Yoda2 injections, synergistically enhanced cortical parameters; in vivo Ca 2+ imaging validated osteocyte Piezo1 activation by Yoda2 during loading [ 185 ]. Whole body vibration combined with Yoda1 in young mice approximately doubled bone growth compared to controls, while in mature mice, the combination (with a reduced duration of 15 min vibration) mitigated cortical polar moment loss, where individual treatments were predominantly ineffective, suggesting an age-dependent synergy [ 186 ].

Mechanistically, Piezo1 serves as a pivotal mechanostat in osteoblasts, osteocytes, and BMSCs: mechanical stress or vibration activates Piezo1, resulting in Ca 2+ influx, thereby promoting osteoblast differentiation and inhibiting osteoclastogenesis [ 135 , 137 , 138 , 139 , 187 ]. Yoda1/Yoda2 or more recent agonists replicate or enhance these pathways and can repair osteoporosis caused by disuse, glucocorticoids, and age in preclinical animals [ 135 , 139 , 187 , 188 , 189 ]. Reviews explicitly indicate that Piezo1 agonists exhibit synergy with vibration and emphasize the necessity to adjust vibration frequency and intensity as a formal “dose” variable [ 187 ].

Certain studies indicate that moderate loading alone can safeguard against breast cancer-induced osteolysis, while Piezo1 activation in osteoclast lineage cells inhibits NFATc1 and osteoclastogenesis, even in models of inflammatory bone loss. This underscores a convergent pathway through which mechanical load and agonists may collaboratively mitigate resorption and the formation of metastatic niches [ 137 , 184 , 190 ].

Elevated frequencies (vibration, ultrasound) predominantly stimulate interstitial fluid movement and Piezo1 activation in osteocytes and osteoblasts, while moderate frequency dynamic loading (approximately 4 Hz) induces tissue-level strains alongside fluid flow; optimized low strain, high flow profiles appear especially efficacious when paired with agonists in aged bone [ 185 , 186 ]. Prolonged or excessive activation of Piezo1 (e.g., large systemic doses of Yoda1) can lead to cortical perforation and detrimental remodeling, especially in diseased or metastatic bone, indicating that safe synergy necessitates submaximal mechanical and chemical dosages [ 184 , 187 ]. Piezo1 in osteocytes, osteoblasts, bone marrow stem cells, macrophages, and pre-osteoclasts integrates mechanical and pharmacological stimuli to promote osteogenesis, diminish marrow adipogenesis, facilitate M2 macrophage polarization, and decrease osteoclastogenesis, thereby enhancing bone rigidity and potentially rendering it a less conducive environment for metastasis [ 137 , 184 , 187 , 188 , 189 , 191 ].

Optimal frequency/amplitude-drug dosing regimens and long-term safety require further dedicated studies, but current evidence supports a mechanistically grounded, context-dependent synergy between carefully dosed Piezo1 agonists and mechanotherapy for bone anabolism and partial protection against metastatic osteolysis.

Among these priorities, osteocyte-centric biomarkers and trial endpoints are the most immediately tractable because they can be embedded in ongoing bone metastasis studies using serum markers, imaging, and correlative tissue analyses. EV cargo mapping is likely the next most actionable area, particularly if lineage-resolved approaches can distinguish osteocyte-derived vesicles from other bone and tumor sources. By contrast, LCN topology is arguably of the highest mechanistic interest but remains the least clinically tractable in the near term because of technical constraints in resolving osteocyte network architecture in vivo in patients.

10. Clinical Perspective and Trial Design

10.1. Combine Denosumab with Cx43-HC Activators or Mechanotherapy

Denosumab effectively inhibits RANKL-mediated osteoclastogenesis and osteolysis, enhancing bone mass and diminishing the risk of skeletal-related events and bone metastases in high RANKL environments [ 192 , 193 , 194 , 195 ]. Independently, the activation of osteocytic Cx43 hemichannels (Cx43 HC), whether through pharmacological means or mechanical loading, promotes anabolic remodeling and anti-tumor signaling from osteocytes [ 7 , 30 , 33 , 196 , 197 ]. Current findings indicate robust molecular complementarity; however, there are no published trials that directly integrate denosumab with Cx43 HC activators or structured mechanotherapy.

Activation of Cx43 M2 in osteocytes diminishes TRAP + osteoclasts at the endosteal surface, decreases bone resorption during unloading, and enhances cortical and trabecular mass in aged and unused bone [ 196 ]. Mechanical loading that activates Cx43 HCs diminishes SOST, amplifies β-catenin signaling, and redirects remodeling towards creation; conversely, when Cx43 HCs are compromised, loading unexpectedly elevates endosteal osteoclast activity [ 197 ]. Combined denosumab with Cx43 HC activation and mechanotherapy may offer dual anti-resorptive control through systemic RANKL inhibition and localized osteocyte-mediated suppression of osteoclastogenesis, achieved by reduced SOST levels, modified RANKL/OPG ratios, and maintained osteocyte survival [ 30 , 196 , 197 ].

Cx43 M2 modifies anti-tumor immunity by augmenting tumor-infiltrating effector T cells and diminishing regulatory T cells, transforming the bone-tumor niche from supportive to suppressive. Mechanical loading initiates the pathway Piezo1→Ca 2+ →PI3K–Akt→Cx43 HCs, resulting in prolonged Ca 2+ and ATP signaling that promotes bone anabolism [ 7 ]. Reviews highlight the significance of Cx43 HCs and PGE 2 in transducing mechanical stimuli into anabolic and potentially protective signals within bone [ 30 , 197 ]. In a skeleton treated with denosumab, where osteoclast-mediated “vicious cycle” signaling is diminished [ 192 , 193 , 194 ], the application of Cx43 HC activators or mechanotherapy may establish an osteocyte-driven microenvironment rich in ATP/PGE 2 that is directly tumor-suppressive and immunostimulatory [ 7 , 30 , 33 ].

The discontinuation of denosumab leads to a significant resurgence in bone resorption, attributed to the accumulation of osteoclast precursors/osteomorphs and elevated RANKL levels, along with reduced OPG at bone surfaces and within osteocytes [ 16 , 198 ]. Activation of osteocytic Cx43 HCs diminishes osteocyte apoptosis and SOST during unloading, hence maintaining a more anabolic and less osteoclastogenic milieu [ 196 , 197 ]. Maintaining Cx43 HC activation and mechanical loading during transitions of denosumab may potentially mitigate rebound osteoclastogenesis; however, this has not been empirically verified.

Cx43 signaling is contingent upon context: osteocytic Cx43 can facilitate osteoclastogenesis through JAK–STAT pathways and oxidative stress in wear particle osteolysis [ 199 ], while abnormal hemichannel opening may exacerbate inflammatory conditions [ 200 ]. Consequently, indiscriminate activation of Cx43 HCs may be detrimental in certain microenvironments. Denosumab’s immunological effects, mediated by RANKL on immune cells, connect with Cx43 HC-driven ATP and cytokine signaling.

10.2. If Contemplating Anti-Sclerostin, Stratify by Tumor Wnt Dependency

Anti-sclerostin antibodies (e.g., romosozumab, Scl ab) significantly stimulate canonical Wnt signaling in bone and serve as powerful osteoanabolics; however, Wnt is also a critical oncogenic pathway, and sclerostin plays context-dependent cardiovascular protective roles, resulting in a limited safety margin for patients with bone-tropic cancers [ 181 , 201 , 202 , 203 , 204 , 205 ]. In a breast cancer model, the inhibition of sclerostin specifically augmented bone metastases of Wnt-responsive MDA MB 231 cells, characterized by β-catenin accumulation in bone-colonized cells, improved tumorsphere formation indicative of stem-like properties, and an increase in osteoclasts and precursors inside the lesions [ 127 ]. This indicates that in Wnt ligand-responsive breast cancer, systemic suppression of sclerostin can expedite skeletal colonization and increase tumor burden in bone [ 127 ].

Multiple myeloma (MM) typically exhibits Wnt inhibition within the microenvironment, characterized by elevated levels of DKK1 and sclerostin. Neutralizing sclerostin reinstates osteoblasts and osteo CAR cells, and ameliorates lytic lesions without inducing multiple myeloma growth in various murine and ex vivo human bone models [ 75 , 206 ]. Preclinical models of multiple myeloma and breast cancer often demonstrate no effect or diminished tumor growth with sclerostin inhibition; however, the Hiraga study emphasizes that this is specific to cell lines and Wnt-dependent [ 70 , 75 , 127 , 206 ]. Reviews highlight that osteoanabolic Wnt stimulation in patients with a history of, or active, bone tropic malignancies poses a theoretical oncogenic risk, and existing preclinical and clinical data are inadequate for conclusive safety assessments [ 70 , 202 , 205 ].

In multiple myeloma models, the combination of anti-sclerostin monoclonal antibodies with zoledronic acid is suggested as a rational dual strategy to avert bone loss and multiple myeloma-related bone disease [ 75 ].

Notch serves as a crucial mediator of the interaction between multiple myeloma and the bone niche. The bone-targeted γ-secretase inhibitor (BT GSI) decreased multiple myeloma load and osteolysis more efficiently than systemic GSI, while circumventing gastrointestinal effects [ 206 ]. In multiple myeloma mice, the combination of Scl ab and BT GSI maintained the anti-tumor transcriptional program of BT GSI (upregulating apoptosis, downregulating proliferation and Notch targets), did not provoke pro-proliferative alterations in multiple myeloma cells, and facilitated bone healing without undermining tumor control [ 128 , 206 ].

In Wnt-driven metastasis, tumor cells utilize several converging pathways (Wnt, RANKL, Notch/Jagged1) to restructure the bone niche. The concurrent stimulation of bone formation (via anti-sclerostin) and targeted Notch inhibition within bone (e.g., BT GSI) may: restore normal osteoblast and osteo CAR cell function (bone-forming and immune-modulatory stromal cells) [ 128 ], inhibit tumor-promoting Notch signals and osteoclastogenesis [ 206 , 207 , 208 ], and diminish pro-metastatic Wnt effects by attenuating complementary niche signals.

Anti-sclerostin therapy for Wnt-dependent bone metastases poses significant risks of increasing skeletal colonization in Wnt-responsive malignancies and potential cardiovascular damage. Rational trial designs must focus on tumor Wnt biology, incorporate ongoing anti-resorptive or bone-targeted Notch suppression, and rigorously restrict exposure and eligibility to safeguard the bone niche without promoting tumor growth.

Given the context-dependent tumor effects of sclerostin blockade, any translational application should be interpreted in light of the Wnt-responsiveness framework summarized in Section 8.1 .

10.3. Senolytics for Osteocyte SASP in Metastatic Niches

Therapy-induced senescence (TIS) resulting from chemotherapy, radiotherapy, PARP/CDK4/6 inhibitors, and certain antibodies generates a diverse population of senescent tumor and stromal cells that may exhibit acute immunostimulatory properties but are chronically driven by the senescence-associated secretory phenotype (SASP), leading to immunosuppression, resistance, relapse, and systemic toxicity [ 209 , 210 , 211 , 212 , 213 , 214 , 215 ]. “One-two punch” techniques combine a senescence-inducing primary drug with a secondary senolytic or SASP modulator to eliminate TIS cells and restructure the tumor microenvironment (TME) [ 209 , 210 , 212 , 213 , 216 , 217 ].

Senescent osteocytes in bone develop a pro-inflammatory, pro-osteoclastogenic secretory profile (SASP) that alters bone remodeling and the marrow immune niche. Crucial SASP elements, such as RANKL and IL-6, connect senescence to osteoclast activation, bone degradation, and an inflammatory, myeloid-biased microenvironment that could possibly promote metastasis. Senescent osteocytes significantly enhance osteoclastogenesis and bone resorption; the elimination of senescent cells using senolytics mitigates bone loss in metastatic models [ 36 , 54 ].

Osteocyte-induced senescence propagates to mesenchymal and myeloid progenitors, elevating SASP scores and systemic levels of TNF-α, IL-1β, and IL-6. The bone marrow transitions towards myelopoiesis, characterized by an increase in myeloid progenitors, neutrophils, and monocytes, while B-cell lymphopoiesis diminishes, resulting in a chronically inflamed, myeloid-dominant microenvironment [ 47 ].

TIS can initially enhance cGAS STING/type I IFN-mediated T cell recruitment and create “hot” tumor microenvironments (TMEs), but prolonged SASP leads to the predominance of tired CD8 + T cells, dysfunctional NK cells, and M2-like macrophages, thereby diminishing the efficacy of immune checkpoint inhibitors (ICIs) [ 210 , 214 , 218 , 219 , 220 ]. In murine models, the increase in senescent cells directly induces resistance to immune checkpoint inhibitors; pre-immunotherapy senolysis with navitoclax (ABT 263) reinstates CD8 + T cell infiltration, normalizes myeloid compartments, and enhances survival [ 221 ].

In various TIS situations, reliance on BCL xL represents a consistent vulnerability; BCL xL BH3 mimetics exhibit senolytic properties even when overall “mitochondrial priming” does not increase compared to proliferating cells [ 216 ]. Chronic SASP stimulates systemic senescent cell anti-apoptotic pathways (SCAPs) and induces secondary senescence in stromal and immunological cells; prolonged delays exacerbate off-tumor senolytic targets.

In “senescence-driven ICI resistance,” navitoclax administered prior to anti-PD-1/PD-L1 therapy eradicates senescent and senescence-conditioned myeloid cells, normalizes the tumor microenvironment, enhances CD8 + T cell proliferation, and reinstates ICI responsiveness [ 221 ]. Reviews indicate that pre-ICI senolysis can eliminate chronic SASP-mediated immunosuppressive niches (Tregs, MDSCs, M2 macrophages), thereby enhancing the eventual efficacy of checkpoint blockade. Inhibition of PARP and CDK4/6 in colorectal cancer elicits a pronounced tumor-intrinsic signature (TIS) and a type I interferon-rich senescence-associated secretory phenotype (SASP), which enhances CD8 + and natural killer (NK) cell infiltration while reducing granulocytic myeloid-derived suppressor cells (G MDSCs); the addition of αPD-L1 eradicates TIS cells and extends survival [ 219 ]. In this context, the “second punch” refers to immunotherapy rather than a traditional small-molecule senolytic, using immune-mediated elimination of senescent cells.

Most scheduling insights originate from preclinical models; comprehensive human pharmacodynamic data on senescence and SASP kinetics across various regimens are missing [ 209 , 210 , 211 , 214 , 216 , 217 ]. In vivo direct characterization of naïve and memory T cell sensitivity to clinical senolytics is limited; existing recommendations for safeguarding naïve T cells are predominantly inferential [ 214 , 218 , 222 , 223 ]. The heterogeneity of senescence (tumor, stromal, and immunological) indicates that senolysis at a single time point may be inadequate; dynamic, biomarker-guided approaches utilizing single-cell and spatial omics are recommended but have not yet become standard practice [ 209 , 211 , 214 , 218 , 224 ].

In the context of metastatic bone disease, the most compelling rationale for senescence-directed therapy is not senolysis in oncology at large, but the specific contribution of senescent osteocytes and adjacent stromal populations to a pro-resorptive, immunomodulatory bone niche. Thus, future work should prioritize bone-metastasis models that directly test whether osteocyte-targeted senolytic or senomorphic strategies reduce SASP output, preserve bone integrity, and limit metastatic outgrowth, rather than extrapolating broadly from non-skeletal tumor systems.

11. Conclusions

Osteocytes are no longer tenable as passive bystanders in metastatic bone disease; rather, the literature now supports their role as master integrators that translate mechanical strain, mineral demands, immune cues, and tumor-derived signals into coordinated remodeling outputs that can either constrain or enable metastatic success. Their embedded position within the lacunocanalicular network gives them unique access to sense altered loading and matrix microdamage, and to couple these inputs to endocrine/paracrine programs that shape osteoclastogenesis and osteoblast function (e.g., RANKL/OPG control, Wnt inhibition via sclerostin/DKK1), as well as to matrix turnover through perilacunar/canalicular remodeling (PLR) enzymes and acidification pathways [ 3 , 4 , 6 , 7 , 45 ]. In metastatic settings, osteocyte apoptosis and senescence-associated secretory programs amplify osteoclastogenic and inflammatory signaling, functionally linking osteocyte cell-fate decisions to osteolysis and tumor-supportive niche remodeling [ 1 , 31 , 36 , 51 ]. Mechanotransduction nodes such as Piezo1 and Cx43 hemichannels further position osteocytes as signal routers that convert mechanical inputs into ATP/PGE 2 -linked outputs with downstream effects on osteoclast activity, immune activation, and even direct tumor cell behavior [ 8 , 27 , 29 , 30 , 46 , 75 ]. Together, these advances shift the conceptual center of the “vicious cycle” from an osteoclast-centric loop to a broader osteocyte-governed systems framework in which osteocytes set the remodeling gain, sculpt niche architecture, and modulate immuno-skeletal tone across the metastatic cascade [ 1 , 2 , 3 , 61 , 62 ].

This reframing has immediate translational implications: osteocyte-directed therapies must be pursued with precision and context awareness—defined by tumor intrinsic signaling dependencies, lesion phenotype (osteolytic vs. osteoblastic/mixed), disease stage (seeding/dormancy/outgrowth), and host factors that alter mechanobiology and immune states [ 61 , 62 , 139 ]. Emerging modalities—mechanotherapy and Piezo1/Cx43 axis manipulation, purinergic signaling leverage, and senolytics/senomorphics targeting osteocyte/stromal SASP—are best viewed not as one-size-fits-all add-ons, but as niche-reprogramming tools whose benefit/risk profiles depend on dosing, timing, and microenvironmental state [ 75 , 77 , 78 , 79 , 83 , 84 , 91 , 92 , 93 , 94 , 95 , 96 , 98 , 99 , 127 ].

Ultimately, repositioning osteocytes as integrative regulators of mechanics, metabolism, immunity, and tumor ecology provides a coherent rationale for next-generation, osteocyte-informed trial designs that aim to preserve skeletal integrity while actively destabilizing the metastatic niche—by tailoring interventions to the biology of both the tumor and the osteocyte network that it attempts to co-opt [ 2 , 3 , 36 , 61 , 62 , 86 , 88 , 154 , 156 ].

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Author Contributions

Conceptualization, K.S.M. and A.D.; writing—original draft preparation, A.D., M.B. and K.S.M.; writing—review and editing, A.D., M.B., L.F., M.A. and K.S.M.; supervision, K.S.M.; project administration, K.S.M. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

References

1. Riquelme M.A. Cardenas E.R. Jiang J.X. Osteocytes and Bone Metastasis Front. Endocrinol. 2020 11 567844 10.3389/fendo.2020.567844 PMC7591672 33162934

2. Wu Y. Gan D. Liu Z. Qiu D. Tan G. Xu Z. Xue H. Osteocytes: Master Orchestrators of Skeletal Homeostasis, Remodeling, and Osteoporosis Pathogenesis Front. Cell Dev. Biol. 2025 13 1670716 10.3389/fcell.2025.1670716 41081044 PMC12508660

3. Verbruggen S.W. Role of the Osteocyte in Bone Metastasis—The Importance of Networking J. Bone Oncol. 2024 44 100526 10.1016/j.jbo.2024.100526 38304485 PMC10831278

4. Yee C.S. Schurman C.A. White C.R. Alliston T. Investigating Osteocytic Perilacunar/Canalicular Remodeling Curr. Osteoporos. Rep. 2019 17 157 168 10.1007/s11914-019-00514-0 31227998 PMC7202397

5. Michigami T. Paracrine and Endocrine Functions of Osteocytes Clin. Pediatr. Endocrinol. 2023 32 1 10 10.1297/cpe.2022-0053 36761497 PMC9887291

6. Delgado-Calle J. Bellido T. The Osteocyte as a Signaling Cell Physiol. Rev. 2022 102 379 410 10.1152/physrev.00043.2020 34337974 PMC8858675

7. Zeng Y. Riquelme M.A. Hua R. Zhang J. Acosta F.M. Gu S. Jiang J.X. Mechanosensitive Piezo1 Calcium Channel Activates Connexin 43 Hemichannels through PI3K Signaling Pathway in Bone Cell Biosci. 2022 12 191 10.1186/s13578-022-00929-w 36457052 PMC9716748

8. Kondo K. Matsushita Y. Skeletal Stem Cell Lineages in Osteosarcoma and Bone Metastasis J. Bone Miner. Metab. 2026 44 1 9 10.1007/s00774-026-01700-8 41711876

9. Sethi N. Dai X. Winter C.G. Kang Y. Tumor-Derived Jagged1 Promotes Osteolytic Bone Metastasis of Breast Cancer by Engaging Notch Signaling in Bone Cells Cancer Cell 2011 19 192 205 10.1016/j.ccr.2010.12.022 21295524 PMC3040415

10. Anloague A. Delgado-Calle J. Osteocytes: New Kids on the Block for Cancer in Bone Therapy Cancers 2023 15 2645 10.3390/cancers15092645 37174109 PMC10177382

11. Zarrer J. Taipaleenmäki H. The Osteoblast in Regulation of Tumor Cell Dormancy and Bone Metastasis J. Bone Oncol. 2024 45 100597 10.1016/j.jbo.2024.100597 38550395 PMC10973597

12. Chen N. Danalache M. Liang C. Alexander D. Umrath F. Mechanosignaling in Osteoporosis: When Cells Feel the Force Int. J. Mol. Sci. 2025 26 4007 10.3390/ijms26094007 40362247 PMC12071322

13. Hajjawi M.O.R. MacRae V.E. Huesa C. Boyde A. Millán J.L. Arnett T.R. Orriss I.R. Mineralisation of Collagen Rich Soft Tissues and Osteocyte Lacunae in Enpp1 Mice Bone 2014 69 139 147 10.1016/j.bone.2014.09.016 25260930 PMC4228085

14. Lungu O. Toscani D. Giuliani N. Mechanistic Insights into Bone Destruction in Multiple Myeloma: Cellular and Molecular Perspectives J. Bone Oncol. 2025 51 100668 10.1016/j.jbo.2025.100668 40124903 PMC11928850

15. Xiong J. Piemontese M. Onal M. Campbell J. Goellner J.J. Dusevich V. Bonewald L. Manolagas S.C. O’Brien C.A. Osteocytes, Not Osteoblasts or Lining Cells, Are the Main Source of the RANKL Required for Osteoclast Formation in Remodeling Bone PLoS ONE 2015 10 e0138189 10.1371/journal.pone.0138189 26393791 PMC4578942

16. El-Masri B.M. Andreasen C.M. Laursen K.S. Kofod V.B. Dahl X.G. Nielsen M.H. Thomsen J.S. Brüel A. Sørensen M.S. Hansen L.J. Mapping RANKL- and OPG-Expressing Cells in Bone Tissue: The Bone Surface Cells as Activators of Osteoclastogenesis and Promoters of the Denosumab Rebound Effect Bone Res. 2024 12 62 10.1038/s41413-024-00362-4 39424806 PMC11489716

17. Nakashima T. Hayashi M. Fukunaga T. Kurata K. Oh-Hora M. Feng J.Q. Bonewald L.F. Kodama T. Wutz A. Wagner E.F. Evidence for Osteocyte Regulation of Bone Homeostasis through RANKL Expression Nat. Med. 2011 17 1231 1234 10.1038/nm.2452 21909105

18. Lim J. Burclaff J. He G. Mills J.C. Long F. Unintended Targeting of Dmp1-Cre Reveals a Critical Role for Bmpr1a Signaling in the Gastrointestinal Mesenchyme of Adult Mice Bone Res. 2017 5 16049 10.1038/boneres.2016.49 28163952 PMC5282469

19. Fu Q. Bustamante-Gomez N.C. Reyes-Pardo H. Gubrij I. Escalona-Vargas D. Thostenson J.D. Palmieri M. Goellner J.J. Nookaew I. Barnes C.L. Reduced Osteoprotegerin Expression by Osteocytes May Contribute to Rebound Resorption after Denosumab Discontinuation JCI Insight 2023 8 e167790 10.1172/jci.insight.167790 37581932 PMC10561722

20. Matic I. Matthews B.G. Wang X. Dyment N.A. Worthley D.L. Rowe D.W. Grcevic D. Kalajzic I. Quiescent Bone Lining Cells Are a Major Source of Osteoblasts During Adulthood Stem Cells 2016 34 2930 2942 10.1002/stem.2474 27507737 PMC5450652

21. Andersen T.L. Jensen P.R. Sikjaer T.T. Rejnmark L. Ejersted C. Delaisse J.-M. A Critical Role of the Bone Marrow Envelope in Human Bone Remodeling J. Bone Miner. Res. 2023 38 918 928 10.1002/jbmr.4815 37038371

22. Kendler D.L. Cosman F. Stad R.K. Ferrari S. Denosumab in the Treatment of Osteoporosis: 10 Years Later: A Narrative Review Adv. Ther. 2022 39 58 74 10.1007/s12325-021-01936-y 34762286 PMC8799550

23. Cawley K.M. Bustamante-Gomez N.C. Guha A.G. MacLeod R.S. Xiong J. Gubrij I. Liu Y. Mulkey R. Palmieri M. Thostenson J.D. Local Production of Osteoprotegerin by Osteoblasts Suppresses Bone Resorption Cell Rep. 2020 32 108052 10.1016/j.celrep.2020.108052 32905775 PMC7493998

24. Sølling A.S. Tsourdi E. Harsløf T. Langdahl B.L. Denosumab Discontinuation Curr. Osteoporos. Rep. 2023 21 95 103 10.1007/s11914-022-00771-6 36564572

25. Yuan X. Qian N. Ling S. Li Y. Sun W. Li J. Du R. Zhong G. Liu C. Yu G. Breast Cancer Exosomes Contribute to Pre-Metastatic Niche Formation and Promote Bone Metastasis of Tumor Cells Theranostics 2021 11 1429 1445 10.7150/thno.45351 33391543 PMC7738874

26. Song X. Lin C.-Y. Mei X. Wang L. You L. Reduction of Breast Cancer Extravasation via Vibration Activated Osteocyte Regulation iScience 2022 25 105500 10.1016/j.isci.2022.105500 36419845 PMC9676352

27. Lin C.-Y. Song X. Ke Y. Raha A. Wu Y. Wasi M. Wang L. Geng F. You L. Yoda1 Enhanced Low-Magnitude High-Frequency Vibration on Osteocytes in Regulation of MDA-MB-231 Breast Cancer Cell Migration Cancers 2022 14 3395 10.3390/cancers14143395 35884459 PMC9324638

28. Sasaki F. Hayashi M. Mouri Y. Nakamura S. Adachi T. Nakashima T. Mechanotransduction via the Piezo1-Akt Pathway Underlies Sost Suppression in Osteocytes Biochem. Biophys. Res. Commun. 2020 521 806 813 10.1016/j.bbrc.2019.10.174 31708103

29. Zhang Y. Acosta F.M. Jiang J.X. Connexin 43 Hemichannels and Related Diseases Antib. Ther. 2024 7 361 369 10.1093/abt/tbae024 39678258 PMC11646280

30. Zhao D. Wu J. Acosta F.M. Xu H. Jiang J.X. Connexin 43 Hemichannels and Prostaglandin E2 Release in Anabolic Function of the Skeletal Tissue to Mechanical Stimulation Front. Cell Dev. Biol. 2023 11 1151838 10.3389/fcell.2023.1151838 37123401 PMC10133519

31. Kitase Y. Barragan L. Qing H. Kondoh S. Jiang J.X. Johnson M.L. Bonewald L.F. Mechanical Induction of PGE2 in Osteocytes Blocks Glucocorticoid-Induced Apoptosis through Both the β-Catenin and PKA Pathways J. Bone Miner. Res. 2010 25 2657 2668 10.1002/jbmr.168 20578217 PMC3179278

32. Liu X. Riquelme M.A. Tian Y. Zhao D. Acosta F.M. Gu S. Jiang J.X. ATP Inhibits Breast Cancer Migration and Bone Metastasis through Down-Regulation of CXCR4 and Purinergic Receptor P2Y11 Cancers 2021 13 4293 10.3390/cancers13174293 34503103 PMC8428338

33. Riquelme M.A. Wang X. Acosta F.M. Zhang J. Chavez J. Gu S. Zhao P. Xiong W. Zhang N. Li G. Antibody-Activation of Connexin Hemichannels in Bone Osteocytes with ATP Release Suppresses Breast Cancer and Osteosarcoma Malignancy Cell Rep. 2024 43 114377 10.1016/j.celrep.2024.114377 38889005 PMC11380445

34. Zhao W. Qian J. Li J. Su T. Deng X. Fu Y. Liang X. Cui H. From Death to Birth: How Osteocyte Death Promotes Osteoclast Formation Front. Immunol. 2025 16 1551542 10.3389/fimmu.2025.1551542 40165960 PMC11955613

35. Gkouveris I. Hadaya D. Elzakra N. Soundia A. Bezouglaia O. Dry S.M. Pirih F. Aghaloo T. Tetradis S. Inhibition of HMGB1/RAGE Signaling Reduces the Incidence of Medication-Related Osteonecrosis of the Jaw (MRONJ) in Mice J. Bone Miner. Res. 2022 37 1775 1786 10.1002/jbmr.4637 35711109 PMC9474692

36. Kaur J. Adhikari M. Sabol H.M. Anloague A. Khan S. Kurihara N. Diaz-delCastillo M. Andreasen C.M. Barnes C.L. Stambough J.B. Single-Cell Transcriptomic Analysis Identifies Senescent Osteocytes That Trigger Bone Destruction in Breast Cancer Metastasis Cancer Res. 2024 84 3936 3952 10.1158/0008-5472.CAN-24-0857 39312185 PMC11611663

37. Morrell A.E. Brown G.N. Robinson S.T. Sattler R.L. Baik A.D. Zhen G. Cao X. Bonewald L.F. Jin W. Kam L.C. Mechanically Induced Ca 2+ Oscillations in Osteocytes Release Extracellular Vesicles and Enhance Bone Formation Bone Res. 2018 6 6 10.1038/s41413-018-0007-x 29581909 PMC5859015

38. Yan Y. Wang L. Ge L. Pathak J.L. Osteocyte-Mediated Translation of Mechanical Stimuli to Cellular Signaling and Its Role in Bone and Non-Bone-Related Clinical Complications Curr. Osteoporos. Rep. 2020 18 67 80 10.1007/s11914-020-00564-9 31953640

39. Choy L. Hagenbeek T.J. Solon M. French D. Finkle D. Shelton A. Venook R. Brauer M.J. Siebel C.W. Constitutive NOTCH3 Signaling Promotes the Growth of Basal Breast Cancers Cancer Res. 2017 77 1439 1452 10.1158/0008-5472.CAN-16-1022 28108512

40. Delgado-Calle J. Anderson J. Cregor M.D. Hiasa M. Chirgwin J.M. Carlesso N. Yoneda T. Mohammad K.S. Plotkin L.I. Roodman G.D. Bidirectional Notch Signaling and Osteocyte-Derived Factors in the Bone Marrow Microenvironment Promote Tumor Cell Proliferation and Bone Destruction in Multiple Myeloma Cancer Res. 2016 76 1089 1100 10.1158/0008-5472.CAN-15-1703 26833121 PMC4775415

41. Yu J. Canalis E. Notch and the Regulation of Osteoclast Differentiation and Function Bone 2020 138 115474 10.1016/j.bone.2020.115474 32526405 PMC7423683

42. Canalis E. Notch in Skeletal Physiology and Disease Osteoporos. Int. 2018 29 2611 2621 Correction in Osteoporos. Int. 2019 , 30 , 251. https://doi.org/10.1007/s00198-018-4742-z 10.1007/s00198-018-4694-3 30194467 PMC6494455

43. Canalis E. Yu J. Schilling L. Yee S.-P. Zanotti S. The Lateral Meningocele Syndrome Mutation Causes Marked Osteopenia in Mice J. Biol. Chem. 2018 293 14165 14177 10.1074/jbc.RA118.004242 30042232 PMC6130932

44. Jia Y. Zhang F. Meng X. Andreev D. Lyu P. Zhang W. Lai C. Schett G. Bozec A. Osteocytes Support Bone Metastasis of Melanoma Cells by CXCL5 Cancer Lett. 2024 590 216866 10.1016/j.canlet.2024.216866 38589005

45. Schett G. Takayanagi H. Editorial Overview: Osteoimmunology Bone 2022 162 116466 10.1016/j.bone.2022.116466 35688362

46. Okamoto K. Nakashima T. Shinohara M. Negishi-Koga T. Komatsu N. Terashima A. Sawa S. Nitta T. Takayanagi H. Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems Physiol. Rev. 2017 97 1295 1349 10.1152/physrev.00036.2016 28814613

47. Ding P. Gao C. Gao Y. Liu D. Li H. Xu J. Chen X. Huang Y. Zhang C. Zheng M. Osteocytes Regulate Senescence of Bone and Bone Marrow eLife 2022 11 e81480 10.7554/eLife.81480 36305580 PMC9678362

48. Yang N. Liu Y. The Role of the Immune Microenvironment in Bone Regeneration Int. J. Med. Sci. 2021 18 3697 3707 10.7150/ijms.61080 34790042 PMC8579305

49. van Tol A.F. Schemenz V. Wagermaier W. Roschger A. Razi H. Vitienes I. Fratzl P. Willie B.M. Weinkamer R. The Mechanoresponse of Bone Is Closely Related to the Osteocyte Lacunocanalicular Network Architecture Proc. Natl. Acad. Sci. USA 2020 117 32251 32259 10.1073/pnas.2011504117 33288694 PMC7768754

50. Li X. Kordsmeier J. Xiong J. New Advances in Osteocyte Mechanotransduction Curr. Osteoporos. Rep. 2021 19 101 106 10.1007/s11914-020-00650-y 33420631 PMC8168381

51. Ohori F. Kitaura H. Marahleh A. Ma J. Miura M. Ren J. Narita K. Fan Z. Lin A. Mizoguchi I. Osteocyte Necroptosis Drives Osteoclastogenesis and Alveolar Bone Resorption during Orthodontic Tooth Movement Sci. Rep. 2025 15 19413 10.1038/s41598-025-04697-8 40461721 PMC12134139

52. Giraldo-Osorno P.M. Wirsig K. Asa’ad F. Omar O. Trobos M. Bernhardt A. Palmquist A. Macrophage-to-Osteocyte Communication: Impact in a 3D in Vitro Implant-Associated Infection Model Acta Biomater. 2024 186 141 155 10.1016/j.actbio.2024.08.005 39142531

53. Nookaew I. Xiong J. Onal M. Bustamante-Gomez C. Wanchai V. Fu Q. Kim H.-N. Almeida M. O’Brien C.A. Refining the Identity of Mesenchymal Cell Types Associated with Murine Periosteal and Endosteal Bone J. Biol. Chem. 2024 300 107158 10.1016/j.jbc.2024.107158 38479598 PMC11007436

54. Frieling J.S. Lynch C.C. Tales of Cancer-Induced Bone Disease from the Senescent Osteocyte Crypt Cancer Res. 2024 84 3917 3918 10.1158/0008-5472.CAN-24-3611 39618247

55. Borges da Silva H. Peng C. Wang H. Wanhainen K.M. Ma C. Lopez S. Khoruts A. Zhang N. Jameson S.C. Sensing of ATP via the Purinergic Receptor P2RX7 Promotes CD8+ Trm Cell Generation by Enhancing Their Sensitivity to the Cytokine TGF-β Immunity 2020 53 158 171 158–171.e6 10.1016/j.immuni.2020.06.010 32640257 PMC8026201

56. Schenk U. Frascoli M. Proietti M. Geffers R. Traggiai E. Buer J. Ricordi C. Westendorf A.M. Grassi F. ATP Inhibits the Generation and Function of Regulatory T Cells through the Activation of Purinergic P2X Receptors Sci. Signal. 2011 4 ra12 10.1126/scisignal.2001270 21364186

57. Wanhainen K.M. Peng C. Zhou M.H. Macedo B.d.G. O’Flanagan S. Yang T. Kelekar A. Burbach B.J. Borges da Silva H. Jameson S.C. P2RX7 Enhances Tumor Control by CD8+ T Cells in Adoptive Cell Therapy Cancer Immunol. Res. 2022 10 871 884 10.1158/2326-6066.CIR-21-0691 35588154 PMC9250641

58. Lu J. Shi X. Fu Q. Han Y. Zhu L. Zhou Z. Li Y. Lu N. New Mechanistic Understanding of Osteoclast Differentiation and Bone Resorption Mediated by P2X7 Receptors and PI3K-Akt-GSK3β Signaling Cell. Mol. Biol. Lett. 2024 29 100 10.1186/s11658-024-00614-5 38977961 PMC11232284

59. Schwartz E. Reichert Z. Van Poznak C. Pharmacologic Management of Metastatic Bone Disease Bone 2022 158 115735 10.1016/j.bone.2020.115735 33171313

60. Widyadharma I.P.E. Tertia C. Vania A. Tiffani P. Wiratnaya I.G.E. The Effect of Denosumab vs. Zoledronic Acid in Preventing Skeletal-Related Events, Including Pain-Related Bone Metastasis: A Systematic Review Postep. Psychiatr. Neurol. 2024 33 172 177 10.5114/ppn.2024.144603 39678460 PMC11635426

61. Chen J. Zhou L. Liu X. Wen X. Li H. Li W. Meta-Analysis of Clinical Trials to Assess Denosumab over Zoledronic Acid in Bone Metastasis Int. J. Clin. Pharm. 2021 43 2 10 10.1007/s11096-020-01105-1 32964403

62. Wadhwa R. Gupta N. Dixit J. Malhotra P. Lakshmi P. Prinja S. Cost-Effectiveness Analysis of Denosumab in the Prevention of Skeletal-Related Events Among Patients with Breast Cancer with Bone Metastasis in India JCO Glob. Oncol. 2024 10 e2300396 10.1200/GO.23.00396 38452304 PMC10939583

63. Keisner S.V. Prevention of Skeletal-Related Events with Extended-Interval Denosumab: A Review of the Literature Ann. Pharmacother. 2024 58 174 184 10.1177/10600280231168456 37131302

64. Clézardin P. Coleman R. Puppo M. Ottewell P. Bonnelye E. Paycha F. Confavreux C.B. Holen I. Bone Metastasis: Mechanisms, Therapies, and Biomarkers Physiol. Rev. 2021 101 797 855 10.1152/physrev.00012.2019 33356915

65. Hofbauer L.C. Bozec A. Rauner M. Jakob F. Perner S. Pantel K. Novel Approaches to Target the Microenvironment of Bone Metastasis Nat. Rev. Clin. Oncol. 2021 18 488 505 10.1038/s41571-021-00499-9 33875860

66. Sarazin B.A. Liu B. Goldman E. Whitefield A.N. Lynch M.E. Bone-Homing Metastatic Breast Cancer Cells Impair Osteocytes’ Mechanoresponse in a 3D Loading Model Heliyon 2023 9 e20248 10.1016/j.heliyon.2023.e20248 37767467 PMC10520780

67. Pan T. Liu F. Hao X. Wang S. Wasi M. Song J.H. Lewis V.O. Lin P.P. Moon B. Bird J.E. BIGH3 Mediates Apoptosis and Gap Junction Failure in Osteocytes during Renal Cell Carcinoma Bone Metastasis Progression Cancer Lett. 2024 596 217009 10.1016/j.canlet.2024.217009 38849015 PMC11964150

68. Wang Y. Liu J. Gong Y. Hu B. Xie J. Cheng J. Huang Q. Bone Marrow Disseminated Tumor Cell Detection Is Beneficial for the Early Finding of Bone Metastasis and Prognosis Diagnostics 2024 14 1629 10.3390/diagnostics14151629 39125505 PMC11311593

69. Dai R. Liu M. Xiang X. Xi Z. Xu H. Osteoblasts and Osteoclasts: An Important Switch of Tumour Cell Dormancy during Bone Metastasis J. Exp. Clin. Cancer Res. CR 2022 41 316 10.1186/s13046-022-02520-0 36307871 PMC9615353

70. Chukir T. Taipaleenmäeki H. Cheung M. Farooki A. Bone Health in Cancer: Perspective on the Use of Osteoanabolic Agents Ther. Adv. Endocrinol. Metab. 2025 16 20420188251367252 10.1177/20420188251367252 40904745 PMC12402605

71. Anastasilakis A.D. Tsourdi E. Τhe Story of Sclerostin Inhibition: The Past, the Present, and the Future Hormones 2025 24 41 58 10.1007/s42000-023-00521-y 38170438

72. Craig S.E.L. Michalski M.N. Williams B.O. Got WNTS? Insight into Bone Health from a WNT Perspective Curr. Top. Dev. Biol. 2023 153 327 346 10.1016/bs.ctdb.2023.01.004 36967199

73. Gau Y.-C. Yeh T.-J. Hsu C.-M. Hsiao S.Y. Hsiao H.-H. Pathogenesis and Treatment of Myeloma-Related Bone Disease Int. J. Mol. Sci. 2022 23 3112 10.3390/ijms23063112 35328533 PMC8951013

74. Zhang F. Zhuang J. Pathophysiology and Therapeutic Advances in Myeloma Bone Disease Chronic Dis. Transl. Med. 2022 8 264 270 10.1002/cdt3.35 36420171 PMC9676126

75. Harada T. Hiasa M. Teramachi J. Abe M. Myeloma–Bone Interaction: A Vicious Cycle via TAK1–PIM2 Signaling Cancers 2021 13 4441 10.3390/cancers13174441 34503251 PMC8431187

76. Lu H. Pundole X. Lee H.C. The Role of Bone-Modifying Agents in Myeloma Bone Disease JBMR Plus 2021 5 e10518 10.1002/jbm4.10518 34368608 PMC8328802

77. Abduh M.S. An Overview of Multiple Myeloma: A Monoclonal Plasma Cell Malignancy’s Diagnosis, Management, and Treatment Modalities Saudi J. Biol. Sci. 2024 31 103920 10.1016/j.sjbs.2023.103920 38283805 PMC10818257

78. Rolvien T. Amling M. Disuse Osteoporosis: Clinical and Mechanistic Insights Calcif. Tissue Int. 2022 110 592 604 10.1007/s00223-021-00836-1 33738515 PMC9013332

79. Xu X. Liu S. Liu H. Ru K. Jia Y. Wu Z. Liang S. Khan Z. Chen Z. Qian A. Piezo Channels: Awesome Mechanosensitive Structures in Cellular Mechanotransduction and Their Role in Bone Int. J. Mol. Sci. 2021 22 6429 10.3390/ijms22126429 34208464 PMC8234635

80. Matsumoto T. Mukohara A. Effects of Whole-Body Vibration on Breast Cancer Bone Metastasis and Vascularization in Mice Calcif. Tissue Int. 2022 111 535 545 10.1007/s00223-022-01009-4 35896728

81. Kinsella J.A. Debant M. Parsonage G. Morley L.C. Bajarwan M. Revill C. Foster R. Beech D.J. Pharmacology of PIEZO1 Channels Br. J. Pharmacol. 2024 181 4714 4732 10.1111/bph.17351 39402010 PMC7618196

82. Lei L. Wen Z. Cao M. Zhang H. Ling S.K.-K. Fu B.S.-C. Qin L. Xu J. Yung P.S.-H. The Emerging Role of Piezo1 in the Musculoskeletal System and Disease Theranostics 2024 14 3963 3983 10.7150/thno.96959 38994033 PMC11234281

83. Dhandapani R. Sathyanarayanan K. Pradhan S. Translating Structural Hierarchy and Mechanobiology of Bone in Microphysiological Systems Small 2026 22 e09536 10.1002/smll.202509536 41474030

84. Thien N.D. Hai-Nam N. Anh D.T. Baecker D. Piezo1 and Its Inhibitors: Overview and Perspectives Eur. J. Med. Chem. 2024 273 116502 10.1016/j.ejmech.2024.116502 38761789

85. Liu Y. Xu Y.-Q. Long Y.-Y. Xiao H. Ma Y.-Y. Li Y.-W. Mechanosensitive Channel Piezo1 in Calcium Dynamics: Structure, Function, and Emerging Therapeutic Strategies Front. Mol. Biosci. 2025 12 1693456 10.3389/fmolb.2025.1693456 41195420 PMC12582999

86. Shoaib Z. Fan T.M. Irudayaraj J.M.K. Osteosarcoma Mechanobiology and Therapeutic Targets Br. J. Pharmacol. 2022 179 201 217 10.1111/bph.15713 34679192 PMC9305477

87. Lin Y. Makkar H. Zhang S. Chen B. Zhan C. Vining K. Mechanical Cues Orchestrate Monocyte Behavior in Immune Regulation and Disease APL Bioeng. 2025 9 021506 10.1063/5.0268234 40584818 PMC12205964

88. Pin F. Prideaux M. Bonewald L.F. Bonetto A. Osteocytes and Cancer Curr. Osteoporos. Rep. 2021 19 616 625 10.1007/s11914-021-00712-9 34773212 PMC8963429

89. Briggs E.N. Lynch M.E. The Role of Osteocytes in Pre-Metastatic Niche Formation Curr. Osteoporos. Rep. 2024 22 105 114 10.1007/s11914-023-00857-9 38198034

90. Pin F. Prideaux M. Huot J.R. Essex A.L. Plotkin L.I. Bonetto A. Bonewald L.F. Non-Bone Metastatic Cancers Promote Osteocyte-Induced Bone Destruction Cancer Lett. 2021 520 80 90 10.1016/j.canlet.2021.06.030 34233150 PMC8440379

91. Davey R.A. Clarke M.V. Golub S.B. Russell P.K. Zajac J.D. The Calcitonin Receptor Regulates Osteocyte Lacunae Acidity during Lactation in Mice J. Endocrinol. 2021 249 31 41 10.1530/JOE-20-0599 33638943

92. Ikezaki-Amada K. Miyamoto Y. Sasa K. Yamada A. Kinoshita M. Yoshimura K. Kawai R. Yano F. Shirota T. Kamijo R. Extracellular Acidification Augments Sclerostin and Osteoprotegerin Production by Ocy454 Mouse Osteocytes Biochem. Biophys. Res. Commun. 2022 597 44 51 10.1016/j.bbrc.2022.01.111 35123265

93. Yee C.S. Meliadis C. Kaya S. Chang W. Alliston T. The Osteocytic Actions of Glucocorticoids on Bone Mass, Mechanical Properties, or Perilacunar Remodeling Outcomes Are Not Rescued by PTH(1-34) Front. Endocrinol. 2024 15 1342938 10.3389/fendo.2024.1342938 PMC11291448 39092287

94. Adhikari M. Delgado-Calle J. Role of Osteocytes in Cancer Progression in the Bone and the Associated Skeletal Disease Curr. Osteoporos. Rep. 2021 19 247 255 10.1007/s11914-021-00679-7 33818732 PMC8486016

95. Cliff C.L. Williams B.M. Chadjichristos C.E. Mouritzen U. Squires P.E. Hills C.E. Connexin 43: A Target for the Treatment of Inflammation in Secondary Complications of the Kidney and Eye in Diabetes Int. J. Mol. Sci. 2022 23 600 10.3390/ijms23020600 35054783 PMC8776095

96. Huang H. He Y.-M. Lin M.-M. Wang Y. Zhang X. Liang L. He X. P2X7Rs: New Therapeutic Targets for Osteoporosis Purinergic Signal. 2023 19 207 219 10.1007/s11302-021-09836-0 35106736 PMC9984661

97. Ma Y. Di R. Zhao H. Song R. Zou H. Liu Z. P2X7 Receptor Knockdown Suppresses Osteoclast Differentiation by Inhibiting Autophagy and Ca 2+ /Calcineurin Signaling Mol. Med. Rep. 2022 25 160 10.3892/mmr.2022.12677 35266012 PMC8941524

98. Agrawal A. Jørgensen N.R. Extracellular Purines and Bone Homeostasis Biochem. Pharmacol. 2021 187 114425 10.1016/j.bcp.2021.114425 33482152

99. Song H. Arredondo Carrera H.M. Sprules A. Ji Y. Zhang T. He J. Lawrence E. Gartland A. Luo J. Wang N. C-Terminal Variants of the P2X7 Receptor Are Associated with Prostate Cancer Progression and Bone Metastasis—Evidence from Clinical and Pre-Clinical Data Cancer Commun. 2023 43 400 404 10.1002/cac2.12391 36582013 PMC10009667

100. Feng T. Xie F. Lee L.M.Y. Lin Z. Tu Y. Lyu Y. Yu P. Wu J. Chen B. Zhang G. Cellular Senescence in Cancer: From Mechanism Paradoxes to Precision Therapeutics Mol. Cancer 2025 24 213 10.1186/s12943-025-02419-2 40781676 PMC12333312

101. Hellmich C. Wojtowicz E. Moore J.A. Mistry J.J. Jibril A. Johnson B.B. Smith J.G.W. Beraza N. Bowles K.M. Rushworth S.A. p16INK4A-Dependent Senescence in the Bone Marrow Niche Drives Age-Related Metabolic Changes of Hematopoietic Progenitors Blood Adv. 2023 7 256 268 10.1182/bloodadvances.2022007033 35622970 PMC9840237

102. Farr J.N. Atkinson E.J. Achenbach S.J. Volkman T.L. Tweed A.J. Vos S.J. Ruan M. Sfeir J. Drake M.T. Saul D. Effects of Intermittent Senolytic Therapy on Bone Metabolism in Postmenopausal Women: A Phase 2 Randomized Controlled Trial Nat. Med. 2024 30 2605 2612 10.1038/s41591-024-03096-2 38956196 PMC11705617

103. Henschke A. Grześkowiak B. Ivashchenko O. Sánchez-Cerviño M.C. Coy E. Moya S. Targeting Cellular Senescence with Liposome-Encapsulated Fisetin: Evidence of Senomorphic Effect Int. J. Mol. Sci. 2025 26 7489 10.3390/ijms26157489 40806616 PMC12347707

104. Borzone F.R. Giorello M.B. Martinez L.M. Sanmartin M.C. Feldman L. Dimase F. Batagelj E. Yannarelli G. Chasseing N.A. Senescent Mesenchymal Stem/Stromal Cells in Pre-Metastatic Bone Marrow of Untreated Advanced Breast Cancer Patients Oncol. Res. 2023 31 361 374 10.32604/or.2023.028104 37305388 PMC10229310

105. Dabaliz A. Mahmoud H. AlMutawa R. Mohammad K.S. Sending the Signal to Bone: How Tumor-Derived EVs Orchestrate Pre-Metastatic Niche Formation and Skeletal Colonization Biomedicines 2025 13 1640 10.3390/biomedicines13071640 40722712 PMC12292996

106. Krylova S.V. Feng D. The Machinery of Exosomes: Biogenesis, Release, and Uptake Int. J. Mol. Sci. 2023 24 1337 10.3390/ijms24021337 36674857 PMC9865891

107. Rezaie J. Akbari A. Rahbarghazi R. Inhibition of Extracellular Vesicle Biogenesis in Tumor Cells: A Possible Way to Reduce Tumorigenesis Cell Biochem. Funct. 2022 40 248 262 10.1002/cbf.3695 35285964

108. Tallon C. Hollinger K.R. Pal A. Bell B.J. Rais R. Tsukamoto T. Witwer K.W. Haughey N.J. Slusher B.S. Nipping Disease in the Bud: nSMase2 Inhibitors as Therapeutics in Extracellular Vesicle-Mediated Diseases Drug Discov. Today 2021 26 1656 1668 10.1016/j.drudis.2021.03.025 33798648 PMC8364476

109. Bhadresha K. Upadhyay V. Brahmbhatt J. Mughal M.J. Jain N. Rawal R. In Vitro Model of Predicting Metastatic Ability Using Tumor Derived Extracellular Vesicles; beyond Seed Soil Hypothesis Sci. Rep. 2022 12 20258 10.1038/s41598-022-24443-8 36424413 PMC9691738

110. Zhao M. Zhou L. Zhai Y. Sun A. Shao G. Lin Q. Macropinocytosis: Both a Target and a Tool for Cancer Therapy Biomolecules 2025 15 936 10.3390/biom15070936 40723808 PMC12292500

111. Giannandrea D. Citro V. Lesma E. Bignotto M. Platonova N. Chiaramonte R. Restoring Tissue Homeostasis at Metastatic Sites: A Focus on Extracellular Vesicles in Bone Metastasis Front. Oncol. 2021 11 644109 10.3389/fonc.2021.644109 33869035 PMC8044846

112. Madel M.-B. Elefteriou F. Mechanisms Supporting the Use of Beta-Blockers for the Management of Breast Cancer Bone Metastasis Cancers 2021 13 2887 10.3390/cancers13122887 34207620 PMC8228198

113. Conceição F. Sousa D.M. Tojal S. Lourenço C. Carvalho-Maia C. Estevão-Pereira H. Lobo J. Couto M. Rosenkilde M.M. Jerónimo C. The Secretome of Parental and Bone Metastatic Breast Cancer Elicits Distinct Effects in Human Osteoclast Activity after Activation of Β2 Adrenergic Signaling Biomolecules 2023 13 622 10.3390/biom13040622 37189370 PMC10135909

114. Conceição F. Sousa D.M. Loessberg-Zahl J. Vollertsen A.R. Neto E. Søe K. Paredes J. Leferink A. Lamghari M. A Metastasis-on-a-Chip Approach to Explore the Sympathetic Modulation of Breast Cancer Bone Metastasis Mater. Today Bio 2022 13 100219 10.1016/j.mtbio.2022.100219 PMC8857466 35243294

115. Lourenço C. Conceição F. Jerónimo C. Lamghari M. Sousa D.M. Stress in Metastatic Breast Cancer: To the Bone and Beyond Cancers 2022 14 1881 10.3390/cancers14081881 35454788 PMC9028241

116. Conceição F. Sousa D.M. Paredes J. Lamghari M. Sympathetic Activity in Breast Cancer and Metastasis: Partners in Crime Bone Res. 2021 9 9 10.1038/s41413-021-00137-1 33547275 PMC7864971

117. Posielski N.M. Richards K.A. Liou J.-I. Borza T. Abel E.J. Downs T.M. Jarrard D.F. Beta-Adrenergic Antagonists and Cancer Specific Survival in Patients with Advanced Prostate Cancer: A Veterans Administration Cohort Study Urology 2021 155 186 191 10.1016/j.urology.2021.02.008 33587939

118. Mellgard G. Patel V.G. Zhong X. Joshi H. Qin Q. Wang B. Parikh A. Jun T. Alerasool P. Garcia P. Effect of Concurrent Beta-Blocker Use in Patients Receiving Immune Checkpoint Inhibitors for Advanced Solid Tumors J. Cancer Res. Clin. Oncol. 2023 149 2833 2841 10.1007/s00432-022-04159-y 35788726 PMC10739778

119. Chen M. Li W. Lei L. Zhang L. Role of SOST in Response to Mechanical Stimulation in Bone and Extraosseous Organs Biomolecules 2025 15 856 10.3390/biom15060856 40563496 PMC12190277

120. Qiao R. Zhong R. Chang Q. Teng J. Pei J. Han B. Chu T. Serum Dickkopf-1 as a Clinical and Prognostic Factor in Non-Small Cell Lung Cancer Patients with Bone Metastases Oncotarget 2017 8 79469 79479 10.18632/oncotarget.18446 29108326 PMC5668059

121. Li L. Shen X. Liang Y. Li B. Si Y. Ma R. N-Telopeptide as a Potential Diagnostic and Prognostic Marker for Bone Metastasis in Human Cancers: A Meta-Analysis Heliyon 2023 9 e15980 10.1016/j.heliyon.2023.e15980 37215848 PMC10199183

122. Wang H. Hong M. Ding L. Song B. Serum Cross-Linked N-Telopeptide of Type I Collagen as a Potential Diagnostic Marker for Bone Metastasis in Lung Cancer: An Updated Meta-Analysis Thorac. Cancer 2023 14 787 793 10.1111/1759-7714.14808 36717764 PMC10040280

123. Jiang C. Hu F. Xia X. Guo X. Prognostic Value of Alkaline Phosphatase and Bone-Specific Alkaline Phosphatase in Breast Cancer: A Systematic Review and Meta-Analysis Int. J. Biol. Markers 2023 38 25 36 10.1177/03936155231154662 36775971

124. Moreno-Jiménez I. Heinig S. Heras U. Maichl D.S. Strifler S. Leich E. Blouin S. Fratzl P. Fratzl-Zelman N. Jundt F. 3D Osteocyte Lacunar Morphometry of Human Bone Biopsies with High Resolution microCT: From Monoclonal Gammopathy to Newly Diagnosed Multiple Myeloma Bone 2024 189 117236 10.1016/j.bone.2024.117236 39151745

125. Eltit F. Wang Q. Jung N. Munshan S. Xie D. Xu S. Liang D. Mojtahedzadeh B. Liu D. Charest-Morin R. Sclerotic Prostate Cancer Bone Metastasis: Woven Bone Lesions with a Twist JBMR Plus 2024 8 ziae091 10.1093/jbmrpl/ziae091 39224570 PMC11365963

126. Maroni P. Bendinelli P. Bone, a Secondary Growth Site of Breast and Prostate Carcinomas: Role of Osteocytes Cancers 2020 12 1812 10.3390/cancers12071812 32640686 PMC7408809

127. Hiraga T. Horibe K. Koide M. Yamashita T. Kobayashi Y. Sclerostin Blockade Promotes Bone Metastases of Wnt-responsive Breast Cancer Cells Cancer Sci. 2023 114 2460 2470 10.1111/cas.15765 36840409 PMC10236625

128. Sabol H.M. Anloague A. Kaur J. Bustamante-Gomez C. Khan S. Paxton B.C. Nester M.R. Hackney J. Diaz-delCastillo M. Mann D. Healing of Lytic Lesions and Restoration of Bone Health in Multiple Myeloma through Sclerostin Inhibition Exp. Hematol. Oncol. 2025 14 108 10.1186/s40164-025-00699-4 40847323 PMC12372396

129. Vasiliadis E.S. Evangelopoulos D.-S. Kaspiris A. Benetos I.S. Vlachos C. Pneumaticos S.G. The Role of Sclerostin in Bone Diseases J. Clin. Med. 2022 11 806 10.3390/jcm11030806 35160258 PMC8836457

130. Ideta H. Yoshida K. Okamoto M. Sasaki J. Kito M. Aoki K. Yoshimura Y. Suzuki S. Tanaka A. Takazawa A. Antitumor Effect of Sclerostin against Osteosarcoma Cancers 2021 13 6015 10.3390/cancers13236015 34885123 PMC8656567

131. Thouverey C. Apostolides P. Brun J. Caverzasio J. Ferrari S. Sclerostin Blockade Inhibits Bone Resorption through PDGF Receptor Signaling in Osteoblast Lineage Cells J. Clin. Investig. 2024 9 e176558 10.1172/jci.insight.176558 PMC11141910 38713511

132. Li X. Zhang C. Vail C.E. Sherrill J.T. Xiong J. Piezo1 Expression in Mature Osteocytes Is Dispensable for the Skeletal Response to Mechanical Loading Bone 2025 190 117276 10.1016/j.bone.2024.117276 39389439 PMC11611638

133. Hu Y.J. Wu X. Wang F. Jin Y. Jin Y. Liu Y. Cong Q. Yang Y. Piezo1-Mediated Mechanotransduction Controls Osteocyte Maturation and Dendrite Development via a YAP-CCN-Src Signaling Axis Nat. Commun. 2025 16 10859 10.1038/s41467-025-65636-9 41315189 PMC12675637

134. Liu Z. Tang Y. He L. Geng B. Lu F. He J. Yi Q. Liu X. Zhang K. Wang L. Piezo1-Mediated Fluid Shear Stress Promotes OPG and Inhibits RANKL via NOTCH3 in MLO-Y4 Osteocytes Channels 2022 16 127 136 10.1080/19336950.2022.2085379 35754337 PMC9721416

135. Li X. Han L. Nookaew I. Mannen E. Silva M.J. Almeida M. Xiong J. Stimulation of Piezo1 by Mechanical Signals Promotes Bone Anabolism eLife 2019 8 e49631 10.7554/eLife.49631 31588901 PMC6779475

136. Ochiai N. Etani Y. Noguchi T. Miura T. Kurihara T. Fukuda Y. Hamada H. Uemura K. Takashima K. Tamaki M. The Pivotal Role of the Hes1/Piezo1 Pathway in the Pathophysiology of Glucocorticoid-Induced Osteoporosis JCI Insight 2024 9 e179963 10.1172/jci.insight.179963 39641269 PMC11623955

137. Wang L. You X. Lotinun S. Zhang L. Wu N. Zou W. Mechanical Sensing Protein PIEZO1 Regulates Bone Homeostasis via Osteoblast-Osteoclast Crosstalk Nat. Commun. 2020 11 282 10.1038/s41467-019-14146-6 31941964 PMC6962448

138. Sun W. Chi S. Li Y. Ling S. Tan Y. Xu Y. Jiang F. Li J. Liu C. Zhong G. The Mechanosensitive Piezo1 Channel Is Required for Bone Formation eLife 2019 8 e47454 10.7554/eLife.47454 31290742 PMC6685704

139. Zhou T. Gao B. Fan Y. Liu Y. Feng S. Cong Q. Zhang X. Zhou Y. Yadav P.S. Lin J. Piezo1/2 Mediate Mechanotransduction Essential for Bone Formation through Concerted Activation of NFAT-YAP1-ß-Catenin eLife 2020 9 e52779 10.7554/eLife.52779 32186512 PMC7112954

140. Hendrickx G. Fischer V. Liedert A. Von Kroge S. Haffner-Luntzer M. Brylka L. Pawlus E. Schweizer M. Yorgan T. Baranowsky A. Piezo1 Inactivation in Chondrocytes Impairs Trabecular Bone Formation J. Bone Miner. Res. 2020 36 369 384 10.1002/jbmr.4198 33180356

141. Nottmeier C. Lavicky J. Gonzalez Lopez M. Knauth S. Kahl-Nieke B. Amling M. Schinke T. Helms J. Krivanek J. Koehne T. Mechanical-Induced Bone Remodeling Does Not Depend on Piezo1 in Dentoalveolar Hard Tissue Sci. Rep. 2023 13 9563 10.1038/s41598-023-36699-9 37308580 PMC10261143

142. Li X. Zhang C. Bowman H.H. Stambough J.B. Stronach B.M. Mears S.C. Barnes L.C. Ambrogini E. Xiong J. Piezo1 Opposes Age-associated Cortical Bone Loss Aging Cell 2023 22 e13846 10.1111/acel.13846 37147884 PMC10265162

143. Liu F. Ding Y. Xu Z. Hao X. Pan T. Miles G. Wang S. Wu Y.-H. Liu J. Bado I.L. Single-Cell Profiling of Bone Metastasis Ecosystems from Multiple Cancer Types Reveals Convergent and Divergent Mechanisms of Bone Colonization Cell Genom. 2025 5 100888 10.1016/j.xgen.2025.100888 40412393 PMC12278635

144. Zhu L. Liu M. Shang Y. Cheng J. Zhao H. Zhang J. Shen D. Single-Cell Profiling Transcriptomic Reveals Cellular Heterogeneity and Cellular Crosstalk in Breast Cancer Lymphatic Node, Bone, and Brain Metastases Sci. Rep. 2025 15 2217 10.1038/s41598-025-85531-z 39820531 PMC11739685

145. Karabacak N.M. Zheng Y. Dubash T.D. Burr R. Micalizzi D.S. Wittner B.S. Lin M. Wiley D.F. Comaills V. Emmons E. Differential Kinase Activity Across Prostate Tumor Compartments Defines Sensitivity to Target Inhibition Cancer Res. 2022 82 1084 1097 10.1158/0008-5472.CAN-21-2609 35045985 PMC8930560

146. Salamanna F. Contartese D. Errani C. Sartori M. Borsari V. Giavaresi G. Role of Bone Marrow Adipocytes in Bone Metastasis Development and Progression: A Systematic Review Front. Endocrinol. 2023 14 1207416 10.3389/fendo.2023.1207416 37711896 PMC10497772

147. Halin Bergström S. Semenas J. Nordstrand A. Thysell E. Wänman J. Crnalic S. Widmark A. Thellenberg-Karlsson C. Andersson P. Gidlund S. Morphological Heterogeneities in Prostate Cancer Bone Metastases Are Related to Molecular Subtypes and Prognosis Clin. Exp. Metastasis 2025 42 49 10.1007/s10585-025-10365-y 40841830 PMC12370827

148. Johnson C.S. Costanzo-Garvey D. Valencia J.C. Rajgopal S. Reed T. Brannon E.R. Frieling J.S. Mosley D.D. Wyatt T.A. Edmondson E.F. Targeted Deletion of Cxcl1 in MSCs Regulates Osteogenesis and Suppresses Bone-Metastatic Prostate Cancer Mol. Cancer Res. 2025 23 739 758 10.1158/1541-7786.MCR-24-0672 40298918 PMC12319404

149. Kähkönen T.E. Wen J. Yang R. Xu Y. Zhang M. Halleen J.M. Abstract 3927: Bone Metastasis Technology Platform: Establishing Clinically Relevant Bone Metastasis Models for Breast and Prostate Cancer and Multiple Myeloma Cancer Res. 2025 85 3927 10.1158/1538-7445.AM2025-3927

150. Kähkönen T.E. Wen J. Yang R. Halleen J. Abstract C122: Effects of Standard-of-Care Therapies on Tumor Growth, Tumor-Induced Bone Loss and Bone Pain in Preclinical Models of Breast and Prostate Cancer Bone Metastasis and Multiple Myeloma Bone Disease Mol. Cancer Ther. 2025 24 C122 10.1158/1535-7163.TARG-25-C122

151. Jia Y. Li R. Li Y. Kachler K. Meng X. Gießl A. Qin Y. Zhang F. Liu N. Andreev D. Melanoma Bone Metastasis-Induced Osteocyte Ferroptosis via the HIF1α-HMOX1 Axis Bone Res. 2025 13 9 10.1038/s41413-024-00384-y 39814705 PMC11735842

152. Ma Y. Zhang L. Liu W. Immunosuppressive Tumor Microenvironment and Advance in Immunotherapy in Melanoma Bone Metastasis Front. Immunol. 2025 16 1608215 10.3389/fimmu.2025.1608215 40936894 PMC12420609

153. Pal S. Perrien D.S. Yumoto T. Faccio R. Stoica A. Adams J. Coopersmith C.M. Jones R.M. Weitzmann M.N. Pacifici R. The Microbiome Restrains Melanoma Bone Growth by Promoting Intestinal NK and Th1 Cell Homing to Bone J. Clin. Investig. 2022 132 e157340 10.1172/JCI157340 35503658 PMC9197523

154. Zhou X. Peng M. He Y. Peng J. Zhang X. Wang C. Xia X. Song W. CXC Chemokines as Therapeutic Targets and Prognostic Biomarkers in Skin Cutaneous Melanoma Microenvironment Front. Oncol. 2021 11 619003 10.3389/fonc.2021.619003 33767987 PMC7985846

155. Hemmatian H. Conrad S. Furesi G. Mletzko K. Krug J. Faila A.V. Kuhlmann J.D. Rauner M. Busse B. Jähn-Rickert K. Reorganization of the Osteocyte Lacuno-Canalicular Network Characteristics in Tumor Sites of an Immunocompetent Murine Model of Osteotropic Cancers Bone 2021 152 116074 10.1016/j.bone.2021.116074 34174502

156. Chen J. Aido M. Roschger A. Van Tol A. Checa S. Willie B.M. Weinkamer R. Spatial Variations in the Osteocyte Lacuno-Canalicular Network Density and Analysis of the Connectomic Parameters PLoS ONE 2024 19 e0303515 10.1371/journal.pone.0303515 38743675 PMC11093372

157. Jones C.E. Blouin S. Raguin E. Weinkamer R. Berzlanovich A. Fratzl P. Hartmann M.A. The Human Osteocyte Lacunocanalicular Network Structure in Osteons of the Iliac Crest of Elderly Women Depends on Mineral Content but Not Individual Age Acta Biomater. 2026 209 493 503 10.1016/j.actbio.2025.11.036 41274619

158. Zhou H. Zhang W. Li H. Xu F. Yinwang E. Xue Y. Chen T. Wang S. Wang Z. Sun H. Osteocyte Mitochondria Inhibit Tumor Development via STING-Dependent Antitumor Immunity Sci. Adv. 2024 10 eadi4298 10.1126/sciadv.adi4298 38232158 PMC10793952

159. Kreps L.M. Addison C.L. Targeting Intercellular Communication in the Bone Microenvironment to Prevent Disseminated Tumor Cell Escape from Dormancy and Bone Metastatic Tumor Growth Int. J. Mol. Sci. 2021 22 2911 10.3390/ijms22062911 33805598 PMC7998601

160. Smith J.T. Chai R.C. Bone Niches in the Regulation of Tumour Cell Dormancy J. Bone Oncol. 2024 47 100621 10.1016/j.jbo.2024.100621 39157742 PMC11326946

161. Xie J. Xu Y. Liu X. Long L. Chen J. Huang C. Shao Y. Cai Z. Zhang Z. Zhou R. Mechanically Stimulated Osteocytes Maintain Tumor Dormancy in Bone Metastasis of Non-Small Cell Lung Cancer by Releasing Small Extracellular Vesicles eLife 2024 12 RP89613 10.7554/eLife.89613.3 38547196 PMC10977966

162. Kim D.-K. Bandara G. Cho Y.-E. Komarow H.D. Donahue D.R. Karim B. Baek M.-C. Kim H.M. Metcalfe D.D. Olivera A. Mastocytosis-Derived Extracellular Vesicles Deliver miR-23a and miR-30a into Pre-Osteoblasts and Prevent Osteoblastogenesis and Bone Formation Nat. Commun. 2021 12 2527 10.1038/s41467-021-22754-4 33953168 PMC8100305

163. Hajivalili M. Hosseini M. Niknam B. Baghaei K. Mosaffa N. Pouyani M.R. Amani D. Tumor-Derived Small Extracellular Vesicles Loaded with Functionally Active miR-34a Mimic Can Modify the Anti-Tumor Response in 4T1 Breast Cancer Animal Model Cancer Cell Int. 2025 25 352 10.1186/s12935-025-03994-6 41088222 PMC12523053

164. Li X. Chen R. Li Y. Wang P. Cui Y. Yang L. Zhu X. Zhang R. miR-27a-5p—Abundant Small Extracellular Vesicles Derived from Epimedium-Preconditioned Bone Mesenchymal Stem Cells Stimulate Osteogenesis by Targeting Atg4B-Mediated Autophagy Front. Cell Dev. Biol. 2021 9 642646 10.3389/fcell.2021.642646 34621733 PMC8491742

165. Kimura Y. Ohzawa H. Miyato H. Kaneko Y. Kuchimaru T. Takahashi R. Yamaguchi H. Kurashina K. Saito S. Hosoya Y. Intraperitoneal Transfer of microRNA-29b-containing Small Extracellular Vesicles Can Suppress Peritoneal Metastases of Gastric Cancer Cancer Sci. 2023 114 2939 2950 10.1111/cas.15793 36939028 PMC10323101

166. Bragado P. Estrada Y. Sosa M.S. Schewe D.M. Capobianco C. Moore K. Farina H.G. Aguirre-Ghiso J. Abstract 5234: Microenvironmental Signals Dictate Disseminated Tumor Cells (DTCs) Fate through Regulation of TGFβII and P38α Cancer Res. 2012 72 5234 10.1158/1538-7445.AM2012-5234

167. Eyles J. Puaux A.-L. Wang X. Toh B. Prakash C. Hong M. Tan T.G. Zheng L. Ong L.C. Jin Y. Tumor Cells Disseminate Early, but Immunosurveillance Limits Metastatic Outgrowth, in a Mouse Model of Melanoma J. Clin. Investig. 2010 120 2030 2039 10.1172/JCI42002 20501944 PMC2877955

168. Hu J. Sánchez-Rivera F.J. Wang Z. Johnson G.N. Ho Y. Ganesh K. Umeda S. Gan S. Mujal A.M. Delconte R.B. STING Inhibits the Reactivation of Dormant Metastasis in Lung Adenocarcinoma Nature 2023 616 806 813 10.1038/s41586-023-05880-5 36991128 PMC10569211

169. Carpenter R.A. Kwak J.-G. Peyton S.R. Lee J. Implantable Pre-Metastatic Niches for the Study of the Microenvironmental Regulation of Disseminated Human Tumour Cells Nat. Biomed. Eng. 2018 2 915 929 10.1038/s41551-018-0307-x 30906645 PMC6424369

170. Foster B.M. Shi L. Harris K.S. Patel C. Surratt V.E. Langsten K.L. Kerr B.A. Bone Marrow-Derived Stem Cell Factor Regulates Prostate Cancer-Induced Shifts in Pre-Metastatic Niche Composition Front. Oncol. 2022 12 855188 10.3389/fonc.2022.855188 35515124 PMC9063312

171. Shimizu H. Takeishi S. Nakatsumi H. Nakayama K.I. Prevention of Cancer Dormancy by Fbxw7 Ablation Eradicates Disseminated Tumor Cells JCI Insight 2019 4 e125138 10.1172/jci.insight.125138 30830867 PMC6478422

172. Magalhães J. Quelhas-Santos J. Pereira L. Neto R. Castro-Ferreira I. Martins S. Frazão J.M. Carvalho C. Could Bone Biomarkers Predict Bone Turnover after Kidney Transplantation?—A Proof-of-Concept Study J. Clin. Med. 2022 11 457 10.3390/jcm11020457 35054152 PMC8780588

173. Li Y. Luo Y. Huang D. Peng L. Sclerostin as a New Target of Diabetes-Induced Osteoporosis Front. Endocrinol. 2024 15 1491066 10.3389/fendo.2024.1491066 PMC11666367 39720253

174. Rodríguez-Ortiz M.E. Díaz-Tocados J.M. Torralbo A.I. Valdés-Díaz K. Rivas-Domínguez A. Guerrero F. Reina-Alfonso I. Naves-Díaz M. Alonso-Montes C. Rodelo-Haad C. Impact of Elevated Sclerostin Levels on Bone Resorption: Unravelling Structural Changes and Mineral Metabolism Disruption Bone Jt. Res. 2025 14 448 462 10.1302/2046-3758.145.BJR-2024-0227.R1 PMC12068932 40355125

175. Neto R. Pereira L. Magalhães J. Quelhas-Santos J. Martins S. Carvalho C. Frazão J.M. Sclerostin and DKK1 Circulating Levels Associate with Low Bone Turnover in Patients with Chronic Kidney Disease Stages 3 and 4 Clin. Kidney J. 2021 14 2401 2408 10.1093/ckj/sfab081 34754436 PMC8572981

176. Chen L. Gao G. Shen L. Yue H. Zhang G. Zhang Z. Serum Sclerostin and Its Association with Bone Turnover Marker in Metabolic Bone Diseases Dis. Markers 2022 2022 7902046 10.1155/2022/7902046 36124027 PMC9482545

177. Ivanova M.M. Dao J. Kasaci N. Friedman A. Noll L. Goker-Alpan O. Wnt Signaling Pathway Inhibitors, Sclerostin and DKK-1, Correlate with Pain and Bone Pathology in Patients with Gaucher Disease Front. Endocrinol. 2022 13 1029130 10.3389/fendo.2022.1029130 PMC9730525 36506070

178. Gerov V. Gerova D. Micheva I. Nikolova M. Mihaylova G. Galunska B. Dynamics of Bone Disease Biomarkers Dickkopf-1 and Sclerostin in Patients with Multiple Myeloma J. Clin. Med. 2023 12 4440 10.3390/jcm12134440 37445475 PMC10342782

179. Al-Masoody A.K.H. Naser S.A. AL-Khafaji M.N. Al-Fahham A.A. Evaluation of Sclerostin as a New Biomarker in the Diagnosis of Osteoporosis Genij Ortop. 2025 31 625 631 10.18019/1028-4427-2025-31-5-625-631

180. Adami G. Montanari F. Fassio A. Pollastri F. Piccinelli A. Benini C. Pasetto E. Tugnolli M. Gatti D. Rossini M. Increase in Serum DKK1 Levels Attenuates the Anabolic Response to Romosozumab in Postmenopausal Osteoporosis J. Bone Miner. Res. 2026 41 143 149 10.1093/jbmr/zjaf110 40827677 PMC12865849

181. Yu S. Li D. Zhang N. Ni S. Sun M. Wang L. Xiao H. Liu D. Liu J. Yu Y. Drug Discovery of Sclerostin Inhibitors Acta Pharm. Sin. B 2022 12 2150 2170 10.1016/j.apsb.2022.01.012 35646527 PMC9136615

182. Choi R.B. Hoggatt A.M. Horan D.J. Rogers E.Z. Hong J.M. Robling A.G. Targeting Sclerostin and Dkk1 at Optimized Proportions of Low-Dose Antibody Achieves Similar Skeletal Benefits to Higher-Dose Sclerostin Targeting in the Mature Adult and Aged Skeleton Aging Dis. 2022 13 1891 10.14336/AD.2022.0315 36465166 PMC9662273

183. Shi T. Shen S. Shi Y. Wang Q. Zhang G. Lin J. Chen J. Bai F. Zhang L. Wang Y. Osteocyte-Derived Sclerostin Impairs Cognitive Function during Ageing and Alzheimer’s Disease Progression Nat. Metab. 2024 6 531 549 10.1038/s42255-024-00989-x 38409606

184. Wasi M. Chu T. Guerra R.M. Kooker R. Maldonado K. Li X. Lin C.-Y. Song X. Xiong J. You L. Mitigating Aging and Doxorubicin Induced Bone Loss in Mature Mice via Mechanobiology Based Treatments Bone 2024 188 117235 10.1016/j.bone.2024.117235 39147353 PMC11475016

185. Meslier Q.A. Oehrlein R. Shefelbine S.J. Combined Effects of Mechanical Loading and Piezo1 Chemical Activation on 22-Months-Old Female Mouse Bone Adaptation Aging Cell 2025 24 e70087 10.1111/acel.70087 40410950 PMC12341773

186. Chu T. Wasi M. Guerra R.M. Song X. Wang S. Sims-Mourtada J. You L. Wang L. Skeletal Response to Yoda1 and Whole-Body Vibration in Mice Varied with Animal Age, Bone Compartment, Treatment Duration, and Radiation Exposure Bone 2025 198 117525 10.1016/j.bone.2025.117525 40389188 PMC12184667

187. Liu C. Yang J. Dong Z. Zhao S. Tian Z.-H. Li Y.-Y. Hao Y.-K. Wang M. The Central Mechanotransducer in Osteoporosis Pathogenesis and Therapy Front. Endocrinol. 2025 16 1658967 10.3389/fendo.2025.1658967 PMC12500442 41064361

188. Hu Y. Tian H. Chen W. Liu Y. Cao Y. Pei H. Ming C. Shan C. Chen X. Dai Z. The Critical Role of The Piezo1/Β-catenin/ATF4 Axis on The Stemness of Gli1 + BMSCs During Simulated Microgravity-Induced Bone Loss Adv. Sci. 2023 10 2303375 10.1002/advs.202303375 PMC10646271 37759400

189. Wang B. Liu J. Wang Q. Arhatte M. Cheong L.Y. Glogowska E. Jiang X. Chung S.K. Jin L. Hu Q. Piezo1 Activation Suppresses Bone Marrow Adipogenesis to Prevent Osteoporosis by Inhibiting a Mechanoinflammatory Autocrine Loop Signal Transduct. Target. Ther. 2025 10 357 10.1038/s41392-025-02455-w 41145414 PMC12559722

190. Shindo S. Nakamura S. Hawthorne A. Heidari A. Pastore M.R. Okamoto M. Suzuki M. Salinas M. Memida T. Minond D. Piezo1 Protects against Inflammatory Bone Loss via a Unique Ca 2+ -Independent Mechanism in Osteoclasts Front. Immunol. 2025 16 1661538 10.3389/fimmu.2025.1661538 41080556 PMC12507952

191. Cai G. Lu Y. Zhong W. Wang T. Li Y. Ruan X. Chen H. Sun L. Guan Z. Li G. Piezo1-mediated M2 Macrophage Mechanotransduction Enhances Bone Formation through Secretion and Activation of Transforming Growth Factor-β1 Cell Prolif. 2023 56 e13440 10.1111/cpr.13440 36880296 PMC10472522

192. Lu J. Hu D. Zhang Y. Ma C. Shen L. Shuai B. Current Comprehensive Understanding of Denosumab (the RANKL Neutralizing Antibody) in the Treatment of Bone Metastasis of Malignant Tumors, Including Pharmacological Mechanism and Clinical Trials Front. Oncol. 2023 13 1133828 10.3389/fonc.2023.1133828 36860316 PMC9969102

193. Yao Z. Getting S.J. Locke I.C. Regulation of TNF-Induced Osteoclast Differentiation Cells 2021 11 132 10.3390/cells11010132 35011694 PMC8750957

194. Li B. Wang P. Jiao J. Wei H. Xu W. Zhou P. Roles of the RANKL–RANK Axis in Immunity—Implications for Pathogenesis and Treatment of Bone Metastasis Front. Immunol. 2022 13 824117 10.3389/fimmu.2022.824117 35386705 PMC8977491

195. De Leon-Oliva D. Barrena-Blázquez S. Jiménez-Álvarez L. Fraile-Martinez O. García-Montero C. López-González L. Torres-Carranza D. García-Puente L.M. Carranza S.T. Álvarez-Mon M.Á. The RANK–RANKL–OPG System: A Multifaceted Regulator of Homeostasis, Immunity, and Cancer Medicina 2023 59 1752 10.3390/medicina59101752 37893470 PMC10608105

196. Zhao D. Tu C. Zhang L. Guda T. Gu S. Jiang J.X. Activation of Connexin Hemichannels Enhances Mechanosensitivity and Anabolism in Disused and Aged Bone JCI Insight 2024 9 e177557 10.1172/jci.insight.177557 39641271 PMC11623949

197. Zhao D. Riquelme M.A. Guda T. Tu C. Xu H. Gu S. Jiang J.X. Connexin Hemichannels with Prostaglandin Release in Anabolic Function of Bone to Mechanical Loading eLife 2022 11 e74365 10.7554/eLife.74365 35132953 PMC8824479

198. Kim A.S. Girgis C.M. McDonald M.M. Osteoclast Recycling and the Rebound Phenomenon Following Denosumab Discontinuation Curr. Osteoporos. Rep. 2022 20 505 515 10.1007/s11914-022-00756-5 36201122 PMC9718877

199. Ouyang J. Chai H. Sun C. Wang S. She C. Geng D. Xu W. Titanium Particles Activate Osteocytic Connexin 43 to Induce Oxidative Stress and Osteoclastogenesis Through the JAK-STAT Pathway Antioxid. Redox Signal. 2025 43 215 238 10.1089/ars.2024.0894 40207369

200. Zhang J. Riquelme M.A. Hua R. Acosta F.M. Gu S. Jiang J.X. Connexin 43 Hemichannels Regulate Mitochondrial ATP Generation, Mobilization, and Mitochondrial Homeostasis against Oxidative Stress eLife 2022 11 e82206 10.7554/eLife.82206 36346745 PMC9642995

201. Liu J. Xiao Q. Xiao J. Niu C. Li Y. Zhang X. Zhou Z. Shu G. Yin G. Wnt/β-Catenin Signalling: Function, Biological Mechanisms, and Therapeutic Opportunities Signal Transduct. Target. Ther. 2022 7 3 10.1038/s41392-021-00762-6 34980884 PMC8724284

202. Elahmer N.R. Wong S.K. Mohamed N. Alias E. Chin K.-Y. Muhammad N. Mechanistic Insights and Therapeutic Strategies in Osteoporosis: A Comprehensive Review Biomedicines 2024 12 1635 10.3390/biomedicines12081635 39200100 PMC11351389

203. Yu Y. Wang L. Ni S. Li D. Liu J. Chu H.Y. Zhang N. Sun M. Li N. Ren Q. Targeting Loop3 of Sclerostin Preserves Its Cardiovascular Protective Action and Promotes Bone Formation Nat. Commun. 2022 13 4241 10.1038/s41467-022-31997-8 35869074 PMC9307627

204. Langdahl B.L. Hofbauer L.C. Forfar J.C. Cardiovascular Safety and Sclerostin Inhibition J. Clin. Endocrinol. Metab. 2021 106 1845 1853 10.1210/clinem/dgab193 33755157

205. Ahamad S. Saquib M. Hussain M.K. Bhat S.A. Targeting Wnt Signaling Pathway with Small-Molecule Therapeutics for Treating Osteoporosis Bioorg. Chem. 2025 156 108195 10.1016/j.bioorg.2025.108195 39864370

206. Sabol H.M. Ferrari A.J. Adhikari M. Amorim T. McAndrews K. Anderson J. Vigolo M. Lehal R. Cregor M. Khan S. Targeting Notch Inhibitors to the Myeloma Bone Marrow Niche Decreases Tumor Growth and Bone Destruction without Gut Toxicity Cancer Res. 2021 81 5102 5114 10.1158/0008-5472.CAN-21-0524 34348968 PMC8488008

207. Kuek V. Hughes A.M. Kotecha R.S. Cheung L.C. Therapeutic Targeting of the Leukaemia Microenvironment Int. J. Mol. Sci. 2021 22 6888 10.3390/ijms22136888 34206957 PMC8267786

208. Zerlotin R. Oranger A. Pignataro P. Dicarlo M. Sanesi L. Suriano C. Storlino G. Rizzi R. Mestice A. Di Gioia S. Irisin Prevents Trabecular Bone Damage and Tumor Invasion in a Mouse Model of Multiple Myeloma JBMR Plus 2024 8 ziae066 10.1093/jbmrpl/ziae066 38855797 PMC11162589

209. Luo J. Sun T. Liu Z. Liu Y. Liu J. Wang S. Shi X. Zhou H. Persistent Accumulation of Therapy-Induced Senescent Cells: An Obstacle to Long-Term Cancer Treatment Efficacy Int. J. Oral Sci. 2025 17 59 10.1038/s41368-025-00380-w 40750580 PMC12317027

210. Chibaya L. Snyder J. Ruscetti M. Senescence and the Tumor-Immune Landscape: Implications for Cancer Immunotherapy Semin. Cancer Biol. 2022 86 827 845 10.1016/j.semcancer.2022.02.005 35143990 PMC9357237

211. Dong Z. Luo Y. Yuan Z. Tian Y. Jin T. Xu F. Cellular Senescence and SASP in Tumor Progression and Therapeutic Opportunities Mol. Cancer 2024 23 181 10.1186/s12943-024-02096-7 39217404 PMC11365203

212. Chambers C.R. Ritchie S. Pereira B.A. Timpson P. Overcoming the Senescence-associated Secretory Phenotype (SASP): A Complex Mechanism of Resistance in the Treatment of Cancer Mol. Oncol. 2021 15 3242 3255 10.1002/1878-0261.13042 34137158 PMC8637570

213. Jin P. Duan X. Li L. Zhou P. Zou C. Xie K. Cellular Senescence in Cancer: Molecular Mechanisms and Therapeutic Targets MedComm 2024 5 e542 10.1002/mco2.542 38660685 PMC11042538

214. Lam Y. Gu J. Yin P. Cellular Senescence in Cancer: Unveiling Dual Roles, Tumor Microenvironment Dynamics and Therapeutic Innovations (Review) Oncol. Lett. 2025 30 592 10.3892/ol.2025.15338 41158311 PMC12557303

215. Cao L. Li K. Li Q. Tong Q. Wang Y. Huang L. The Controversial Role of Senescence-Associated Secretory Phenotype (SASP) in Cancer Therapy Mol. Cancer 2025 24 283 10.1186/s12943-025-02475-8 41204284 PMC12595836

216. López J. Llop-Hernández À. Verdura S. Serrano-Hervás E. Martinez-Balibrea E. Bosch-Barrera J. Teixidor E. López-Bonet E. Martin-Castillo B. Sardanyés J. Mitochondrial Priming and Response to BH3 Mimetics in “One-Two Punch” Senogenic-Senolytic Strategies Cell Death Discov. 2025 11 91 10.1038/s41420-025-02379-y 40055336 PMC11889205

217. Malayaperumal S. Marotta F. Kumar M.M. Somasundaram I. Ayala A. Pinto M.M. Banerjee A. Pathak S. The Emerging Role of Senotherapy in Cancer: A Comprehensive Review Clin. Pract. 2023 13 838 852 10.3390/clinpract13040076 37489425 PMC10366900

218. Sun W. Targeting the Senescent Tumor Microenvironment to Sensitize Immunotherapy Highlights Sci. Eng. Technol. 2025 139 260 271 10.54097/te6m0d54

219. Wang T. Liu W. Shen Q. Tao R. Li C. Shen Q. Lin Y. Huang Y. Yang L. Xie G. Combination of PARP Inhibitor and CDK4/6 Inhibitor Modulates C GAS/STING- Dependent Therapy-induced Senescence and Provides “One-two Punch” Opportunity with ANTI -PD-L1 Therapy in Colorectal Cancer Cancer Sci. 2023 114 4184 4201 10.1111/cas.15961 37702298 PMC10637067

220. Xiong L. Cheng J. Cellular Senescence and Immunosenescence in Melanoma: Insights from the Tumor Microenvironment Cancer Med. 2025 14 e71223 10.1002/cam4.71223 40926366 PMC12420674

221. Maggiorani D. Le O. Lisi V. Landais S. Moquin-Beaudry G. Lavallée V.P. Decaluwe H. Beauséjour C. Senescence Drives Immunotherapy Resistance by Inducing an Immunosuppressive Tumor Microenvironment Nat. Commun. 2024 15 2435 10.1038/s41467-024-46769-9 38499573 PMC10948808

222. Admasu T.D. Yu J.S. Harnessing Immune Rejuvenation: Advances in Overcoming T Cell Senescence and Exhaustion in Cancer Immunotherapy Aging Cell 2025 24 e70055 10.1111/acel.70055 40178455 PMC12073907

223. Liu Q. Li J. Sun X. Lin J. Yu Z. Xiao Y. Li D. Sun B. Bao H. Liu Y. Immunosenescence and Cancer: Molecular Hallmarks, Tumor Microenvironment Remodeling, and Age-Specific Immunotherapy Challenges J. Hematol. Oncol. 2025 18 81 10.1186/s13045-025-01735-w 40846970 PMC12374445

224. Deng Y. Kumar A. Xie K. Schaaf K. Scifo E. Morsy S. Li T. Ehninger A. Bano D. Ehninger D. Targeting Senescent Cells with NKG2D-CAR T Cells Cell Death Discov. 2024 10 217 10.1038/s41420-024-01976-7 38704364 PMC11069534