The interrelationship between prostate cancer and osteoporosis: new perspectives on shared molecular pathways and treatment strategies.

Introduction

Osteoporosis and its associated fractures have become a prominent global public health issue. The global prevalence of osteoporosis has been reported as 23.1% in women and 11.7% in men, with an upward trend increasingly evident among individuals diagnosed with cancer [ 1 , 2 ] . Prostate cancer constitutes the second most commonly diagnosed malignancy in men, with tumor progression largely reliant on androgen presence. Androgen deprivation therapy (ADT) is regarded as the primary treatment modality for advanced prostate cancer and is also employed as an adjuvant approach in cases of early high-risk prostate cancer. Evidence suggests that individuals undergoing ADT exhibit a 28% reduction in bone mineral density (BMD) compared to age-matched control groups over a 10-year period, with the incidence of osteoporosis reaching 81% [ 3 ] . Osteoporosis frequently contributes to skeletal-related events (SRE), such as pathological fractures, severe pain, and bone instability. Among prostate cancer patients, the overall fracture risk is elevated by 1.9-fold, accompanied by a 9% increase in absolute fracture risk [ 4 , 5 ] . Pathological fractures are linked to more than a 20% rise in mortality risk in this population [ 5 ] . As a result, osteoporosis has been extensively recognized as a significant complication in the treatment of prostate cancer.

However, patients with prostate cancer exhibit increased susceptibility to osteoporosis even in the absence of ADT. A study conducted by Hussain et al [ 4 ] revealed that 42% of individuals with advanced prostate cancer presented with osteoporosis prior to the initiation of ADT, a prevalence significantly higher than that observed in age-matched control groups. Signaling pathways such as RANKL/RANK/OPG, Wnt, and CXCL12/CXCR4 are involved in both prostate cancer progression and bone metabolic disorders (e.g., osteoporosis). Factors such as TGF-β and IGF-1 are also important factors that cannot be ignored. This suggests that osteoporosis should not be regarded merely as a consequence of prostate cancer treatment. Rather, it may be a condition potentially linked to prostate cancer through overlapping molecular mechanisms, thereby offering possible therapeutic targets for concurrent management of both diseases.

The RANKL, Wnt, CXCL12/CXCR4, TGF-β, and IGF-1 pathways are key pathways that have attracted considerable attention in various diseases, including prostate cancer and osteoporosis. ADT is indispensable in the treatment of prostate cancer. As a result, many reviews have been published on them. However, existing reviews typically focus only on prostate cancer or osteoporosis as individual diseases, or cover only partial pathways, failing to fully explore the crosstalk between these pathways in both prostate cancer and osteoporosis [ 3 , 6 , 7 ] . This review aims to fill this gap by providing a comprehensive analysis of the mechanistic connections between osteoporosis and prostate cancer, with an in-depth discussion of the common signaling pathways involved. We discuss the potential benefits, clinical limitations, safety issues, and clinical translation challenges of these targets from the perspective of both diseases, and evaluate the feasibility of dual-target therapies. Furthermore, we summarize key points from current clinical guidelines regarding skeletal health management for prostate cancer patients. Therefore, this review not only seeks to provide a comprehensive overview of the potential molecular connections between prostate cancer and osteoporosis but also summarizes existing therapeutic strategies, explores potential therapeutic targets, and provides valuable references and guidance for researchers in this field. No AI was utilized in the manuscript development [ 8 ] .

Osteoporosis

Osteoporosis can be categorized into two primary types according to etiology: primary osteoporosis and secondary osteoporosis [ 9 ] . Primary osteoporosis predominantly comprises postmenopausal osteoporosis, senile osteoporosis, and idiopathic osteoporosis. In contrast, secondary osteoporosis arises from a more intricate set of causes, including endocrine disorders (e.g., hyperthyroidism), connective tissue diseases (e.g., rheumatoid arthritis), and pharmacologically induced osteoporosis. Drug-induced osteoporosis is commonly attributed to prolonged administration of agents that disrupt calcium-phosphorus metabolism or impair bone remodeling. Frequently implicated medications include long-term glucocorticoid therapy and osteoporosis secondary to ADT in prostate cancer patients [ 10 ] . Under physiological conditions, bone metabolism is maintained as a dynamic equilibrium governed primarily by osteoclast-mediated bone resorption and osteoblast-mediated bone formation [ 11 ] . A disturbance of this homeostatic process may lead to the onset of osteoporosis. A common method for diagnosing osteoporosis is dual-energy X-ray absorptiometry (DXA) [ 12 ] . DXA scans can accurately measure BMD at sites such as the spine, hip, and forearm. Due to its simplicity, non-invasiveness, and ability to provide quantitative data, it is widely considered the gold standard for diagnosing osteoporosis [ 13 ] . In clinical research, the Fracture Risk Assessment Tool (FRAX) is also extensively used. The FRAX model combines a patient’s clinical characteristics (such as age, sex, weight, and previous fracture history) with bone mineral density data to assess the risk of fractures occurring over the next 10 years [ 14 ] . Furthermore, by measuring bone resorption and formation biomarkers, physicians and researchers can gain dynamic information about bone metabolism [ 15 , 16 ] . This helps to identify osteoporosis risk earlier, particularly in cases of mild bone loss that may not be detectable by DXA.

HIGHLIGHTS Shared pathways : The RANKL, Wnt, CXCL12/CXCR4, TGF-β, and IGF-1 pathways are key in both prostate cancer and osteoporosis, making them potential therapeutic targets for managing both conditions. Literature gap addressed : Unlike previous reviews that focus solely on either prostate cancer or osteoporosis, this review uniquely provides an integrated perspective on the mechanistic overlap between the two diseases. Dual-disease analysis : This review explores both conditions simultaneously, emphasizing the role of shared molecular mechanisms in developing effective dual-purpose therapeutic strategies. Therapeutic potential and limitations : This review discusses both the therapeutic potential and safety challenges of targeting shared pathways, and assesses whether dual-target therapies are feasible. Future directions and research implications : This review serves as a valuable resource for guiding future research and improving patient management strategies in both diseases. Guideline summary : This review summarizes key recommendations from current clinical guidelines on skeletal health management in prostate cancer patients, providing practical value for clinicians.

The dysregulation of the RANKL/RANK/OPG pathway is regarded as one of the central molecular mechanisms contributing to the development of osteoporosis. RANKL, secreted by osteoblasts, binds to RANK receptors on the surface of osteoclast precursor cells, thereby facilitating the differentiation, activation, and survival of osteoclasts and ultimately enhancing bone resorption [ 17 ] . OPG mitigates bone resorption by binding to RANKL and preventing its interaction with RANK receptors on osteoclast precursor cells, thereby suppressing osteoclast activity [ 18 ] (Fig. 1 ). Moreover, the Wnt signaling pathway and the CXCL12/CXCR4 axis have also been identified as significant regulators of bone metabolism. Activation of the Wnt/β-catenin pathway induces the differentiation of mesenchymal stem cells into osteoblasts by upregulating osteoblast-specific genes (e.g., Runx2 and Osterix) [ 19 ] . The CXCL12/CXCR4 pathway has been implicated in promoting the proliferation, migration, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) [ 20 ] . TGF-β and IGF-1 also associated with osteogenesis. TGF-β promotes osteogenic differentiation by activating the Smad2/3 signaling pathway. Specifically, TGF-β promotes osteoblasts to release OPG and inhibit RANKL expression [ 21 ] . In addition, TGF-β promotes β-catenin stability, while β-catenin enhances Smad-mediated transcription, together driving osteoblast differentiation and bone matrix mineralization [ 22 , 23 ] . However, Liu et al [ 24 ] revealed that the synergistic interaction between TGF-β and Wnt signaling can also act on non-osteoblastic cells within bone tissue, leading to an upregulation of RANKL expression, which in turn facilitates the differentiation and activation of osteoclasts. IGF-1 promotes the differentiation of MSCs into osteoblasts by activating mTOR through the PI3K-Akt pathway [ 25 ] . Figure 1. The RANK/RANKL/OPG signaling axis in bone homeostasis. Osteoblasts release RANKL and OPG. RANKL binds to the RANK receptor on the surface of osteoclast precursor cells, thereby promoting osteoclastogenesis and activation. OPG can competitively inhibit the binding of RANKL to RANK, thereby regulating osteoclast formation and function. This figure was drawn by Figdraw.

Osteoporosis and prostate cancer

The influence of prostate cancer on bone metabolism is primarily reflected in alterations in hormonal levels and the occurrence of bone metastasis.

First, both the treatment and progression of prostate cancer have been shown to alter systemic hormone levels, frequently increasing the risk of bone loss. Among therapeutic approaches, ADT exerts the most pronounced effect on bone metabolism. ADT substantially suppresses testosterone levels either surgically (e.g., bilateral orchiectomy) or pharmacologically (e.g., luteinizing hormone-releasing hormone analogues or antagonists), thereby inhibiting the androgen receptor (AR) signaling pathway and suppressing prostate cancer cell proliferation [ 26 ] . The consequent decline in testosterone leads to reduced estrogen levels generated via aromatization. Estrogen deficiency, in turn, results in downregulated OPG expression and elevated RANKL levels, thereby promoting osteoclast differentiation while impairing osteoblast activity [ 27 ] . Clinical studies have demonstrated that patients undergoing ADT experience an annual decrease in lumbar spine and hip BMD of approximately 2–10%. Following long-term therapy, BMD levels in these patients are reported to be 6.5–28% lower than those in age-matched, untreated individuals [ 3 , 28 ] . The rate of bone loss is most rapid during the initial phase of treatment. Although it subsequently decelerates, the loss remains progressive [ 29 ] . Approximately 50% of patients receiving ADT develop osteoporosis within 5 years, and this prevalence increases to 81% after 10 years [ 3 ] .

Second, bone metastasis represents a frequent complication of prostate cancer, with over 80% of patients with advanced disease developing skeletal involvement [ 30 ] . Prostate cancer-associated bone metastases exhibit mixed lesion characteristics, wherein osteoblastic and osteolytic processes coexist within metastatic foci [ 31 ] . This leads to a state of elevated bone turnover. In metastatic sites, the interaction between prostate cancer cells and the bone matrix establishes a self-perpetuating “vicious cycle” of prostate cancer bone metastasis [ 32 ] (Fig. 2 ). Upon migration to bone tissue, prostate cancer cells secrete various factors (e.g., PTHrP, PGE2) that induce osteoblasts to express RANKL. In concrete terms, PTHrP activates RANKL expression through dual signaling pathways involving Gαs and Gαq, which respectively depend on the cAMP–PKA–CREB and PLC–PKC–AP-1 signaling cascades. RANKL functions as a “soil factor” in bone metastasis by recruiting RANK-expressing prostate cancer cells to colonize bone tissue [ 33 ] . RANKL further engages RANK receptors on osteoclast precursors, promoting osteoclastogenesis, intensifying bone resorption, and accelerating bone degradation. The resorption process subsequently releases growth factors embedded within the bone matrix, such as TGF-β1 and IGF-1 [ 34 ] . IGF-1 enhances prostate cancer cell proliferation, survival, and adaptability within the bone microenvironment by activating the MAPK and PI3K-AKT-mTOR signaling pathways, thereby contributing to the progression of bone metastasis [ 34 , 35 ] . Following receptor binding on prostate cancer cells, TGF-β1 initiates activation of the SMAD2/3 complex, which translocates into the nucleus to regulate downstream gene transcription, thereby promoting cancer cell proliferation, survival, and invasiveness [ 36 ] . Concurrently, RANKL has been shown to significantly upregulate MMP-1 expression in prostate cancer cells such as PC-3 [ 37 ] . MMP-1, a collagenase, degrades type I collagen – the primary structural component of the bone matrix – thereby compromising the physical barrier of the bone microenvironment and facilitating prostate cancer cell migration and invasion [ 38 , 39 ] . Collectively, these molecular events intensify prostate cancer bone metastasis, reinforcing a pathological cycle that fosters both tumor progression and bone destruction. Figure 2. The RANK/RANKL “vicious cycle” in bone metastasis. Upon migration to bone tissue, prostate cancer cells secrete various factors (e.g., PTHrP, PEG2) that induce osteoblasts to express RANKL, which functions as a “soil factor” in bone metastasis by recruiting RANK-expressing prostate cancer cells to colonize bone tissue. RANKL further engages RANK receptors on osteoclast precursors, promoting osteoclastogenesis, intensifying bone resorption, and accelerating bone degradation. This figure was drawn by Figdraw.

However, even in the absence of bone metastasis and ADT, the incidence of osteoporosis among prostate cancer patients remains markedly elevated [ 3 ] . Studies have shown that 42% of men with prostate cancer exhibited osteoporosis prior to the initiation of treatment, in contrast to 27% in age-matched control groups [ 4 ] . Research conducted by Mistry et al [ 40 ] revealed that 45–61% of men presented with at least one grade 2 vertebral fracture before the administration of ADT. Furthermore, it has been demonstrated that prostate cancer cells are capable of secreting specific factors, including RANKL, IL-6, and PTHrP, which interfere with normal bone metabolism and consequently induce bone loss [ 41 , 42 ] .

Therefore, the influence of prostate cancer on bone metabolism is multifactorial, and the relationship between prostate cancer and osteoporosis cannot be regarded merely as a treatment-induced causal association. Conversely, these conditions may be interconnected through overlapping molecular mechanisms. A comprehensive understanding of these shared mechanisms may facilitate the development of more effective therapeutic strategies for prostate cancer patients, thereby reducing the risk of osteoporosis and enhancing overall quality of life.

Shared molecular pathways between prostate cancer and osteoporosis

RANKL/RANK/OPG signaling pathway

RANKL, a member of the tumor necrosis factor superfamily 11, exists in both membrane-bound and soluble forms, being expressed by T cells, osteoblasts, tumor cells, and other cell types [ 43 ] . RANK, classified under the tumor necrosis factor receptor superfamily member 11A, is predominantly expressed in osteoclast precursors, mature osteoclasts, dendritic cells, and certain tumor cells [ 44 ] . OPG serves as a decoy receptor that competitively inhibits the interaction between RANKL and RANK. A reduction in OPG levels or an elevated RANKL/RANK ratio facilitates increased osteoclast activity, thereby accelerating bone resorption and ultimately contributing to the progression of osteoporosis [ 45 ] .

RANKL is markedly expressed in prostate cancer tissues [ 46 ] . Elevated RANKL expression has been correlated with prostate cancer progression, a heightened risk of bone metastasis, and reduced survival rates [ 47 ] . Upon binding of RANKL to its receptor RANK on the cellular membrane, downstream activation of IκB kinase α (IKKα) is initiated, involving its phosphorylation and subsequent translocation into the nucleus. Once translocated, the activated IKKα engages with the promoter region of the human Maspin gene, resulting in transcriptional repression [ 48 ] . Maspin, a serine protease inhibitor, suppresses prostate cancer cell migration and invasion; its loss compromises adhesion to the basement membrane and facilitates the induction of epithelial-mesenchymal transition (EMT) [ 49 ] . Moreover, the RANKL-RANK signaling axis activates the NF-κB pathway via the IKK complex, which includes IKKα and associated subunits. This activated NF-κB modulates transcription factors such as Snail and Twist, suppresses epithelial markers like E-cadherin, and enhances mesenchymal markers including vimentin and N-cadherin, collectively promoting EMT [ 50 ] . EMT induces a reduction in intercellular adhesion among prostate cancer cells and augments their motility [ 51 ] . The concurrent influence of EMT and Maspin dysregulation accelerates the detachment of prostate cancer cells from the primary tumor, facilitates intravasation, and promotes colonization of distant organs, including the bone.

Wnt/β-catenin signaling pathway

The Wnt signaling pathway preserves tissue homeostasis by orchestrating stem cell self-renewal and cellular differentiation processes [ 52 ] . The canonical pathway stabilizes β-catenin to activate transcription of growth-related genes, while the non-canonical pathway regulates cell polarity and calcium signaling independently of β-catenin [ 53 ] (Fig. 3 ). Figure 3. Diagram of canonical and non-canonical Wnt signaling pathways. Activation of the canonical Wnt pathway recruits DVL to the membrane, disrupting the destruction complex (AXIN1/2, APC, GSK3β, CK1α). Stabilized β-catenin accumulates in the cytoplasm and translocates to the nucleus to regulate gene transcription. Binding of DKK1 to LRP inhibits Wnt signaling by preventing Wnt ligand–receptor interaction, resulting in β-catenin phosphorylation and subsequent proteasomal degradation. The non-canonical Wnt pathway activates cytoskeletal remodeling and gene transcription via the PCP (ROCK/JNK) and Ca 2+ (PKC/NFAT) signaling branches. This figure was drawn by Figdraw.

The Wnt signaling pathway is fundamentally involved in the pathogenesis and therapeutic modulation of osteoporosis. Activation of the Wnt/β-catenin signaling cascade facilitates the differentiation of BMSCs into osteoblasts while concurrently suppressing their adipogenic differentiation [ 54 ] . In addition, Wnt signaling enhances the maturation and survival of osteoblasts and indirectly attenuates osteoclast activity through the upregulation of OPG expression and suppression of RANKL production [ 55 ] . However, the study conducted by Maeda et al [ 56 ] indicated that specific non-canonical Wnt pathways, such as the Wnt5a/ROR2 axis, may stimulate RANK expression in osteoclast precursor cells via activation of the JNK signaling pathway, thereby contributing to bone resorption. Collectively, the Wnt signaling pathway predominantly acts to suppress osteoclastogenesis and facilitate osteogenesis.

In prostate cancer, activation of the Wnt pathway has been associated with elevated Gleason scores, increased prostate-specific antigen (PSA) levels, earlier disease onset (diagnosed before age 50), and a heightened risk of recurrence following radical prostatectomy [ 57 , 58 ] . Canonical Wnt signaling supports the self-renewal capacity of prostate cancer stem cells by inducing the expression of downstream target genes such as LGR5, CD44, and NANOG [ 59 ] . Activation of the canonical pathway results in the nuclear accumulation of β-catenin, which forms complexes with the AR to promote the transcription of AR target genes (e.g., PSA), thereby enhancing prostate cancer cell resistance to ADT [ 60 ] . Non-canonical Wnt pathways, including Wnt5A, are activated through FZD2 and ROR2 receptors and trigger the Ca 2 ⁺/CaMKII signaling axis, leading to cytoskeletal reorganization and increased migratory capacity of prostate cancer cells [ 61 , 62 ] . Concurrently, Wnt5A may act synergistically with the TGF-β signaling cascade to upregulate EMT markers such as N-cadherin and Vimentin via the SMAD pathway, thereby facilitating EMT progression and promoting prostate cancer metastasis [ 34 , 63 ] . In addition, non-canonical Wnt signaling (e.g., Wnt11) can regulate prostate cancer cell growth independently of AR signaling, enhancing cell survival and resistance to therapeutic interventions following castration [ 59 ] . The study by Vela et al [ 62 ] demonstrated that expression of the non-canonical Wnt target gene PITX2 was 2252-fold higher in bone metastatic lesions than in normal prostate tissue, suggesting a potential role of non-canonical Wnt signaling in driving bone metastasis. The Wnt and RANKL/RANK/OPG pathways can form a positive feedback loop within bone metastatic lesions. Aberrant activation of the Wnt signaling pathway in prostate cancer cells can facilitate the osteogenic differentiation of BMSCs, which subsequently results in elevated secretion of RANKL [ 64 ] . This increase in RANKL further amplifies Wnt signaling in prostate cancer cells, thereby enhancing their invasiveness and metastatic potential, and accelerating the progression of bone metastasis [ 47 ] . In summary, although Wnt pathway activation contributes to osteogenesis in bone metabolism, it also facilitates the proliferation and metastatic dissemination of prostate cancer cells.

CXCL12/CXCR4

Chemokines are signaling molecules responsible for regulating cellular migration and adhesion. CXCL12, also referred to as SDF-1, functions as a homeostatic CXC chemokine [ 65 ] . The signaling axis constituted by CXCL12 and its receptor CXCR4 has been implicated in a wide range of physiological and pathological processes, including bone metabolism, embryonic development, tissue repair, angiogenesis, tumor progression, and cellular proliferation [ 66 , 67 ] (Fig. 4 ). Figure 4. Schematic representation of the CXCR12/CXCR4 signaling pathway. Upon CXCL12 binding, CXCR4 activates G protein–dependent signaling pathways including PI3K/AKT, Ras/RAF/ERK, PLC/Ca 2+ /PKC, and Rho GTPases (Rac, Rho, Cdc42), regulating cell survival, migration, and chemotaxis. It also inhibits adenylate cyclase (AC) to reduce cAMP. CXCR4 can additionally signal via G protein–independent pathways such as JAK/STAT and GRK/β-arrestin. This figure was drawn by Figdraw.

The CXCL12/CXCR4 axis exerts multifaceted regulatory effects on bone metabolism. This axis facilitates the proliferation, migration, and osteogenic differentiation of BMSCs by activating downstream signaling cascades such as PI3K/Akt and MAPK pathways [ 66 ] . With advancing age, expression levels of CXCL12 and its receptors, including CXCR4, in muscle and bone tissues are reduced, leading to impaired migratory capacity and diminished osteogenic differentiation potential of BMSCs, thereby compromising bone formation and repair processes [ 68 ] . Conversely, circulating CXCL12 levels have been shown to increase progressively with aging and are associated with the recruitment of osteoclasts [ 69 , 70 ] . Studies have shown that CXCL12 establishes a concentration gradient that directs the migration of CXCR4-expressing osteoclast precursors toward specific sites poised for bone resorption [ 71 ] . The CXCL12/CXCR4 signaling axis also augments RANK expression in osteoclast precursors, thereby increasing their responsiveness to RANKL stimulation [ 72 ] . Furthermore, CXCR4 signaling can activate critical molecules such as NF-κB and ERK, which intersect with the downstream pathways of RANKL. These signals promote the differentiation and activation of osteoclasts. A cohort study involving 1536 elderly individuals revealed a negative correlation between plasma CXCL12 levels and hip BMD [ 69 ] . Moreover, plasma CXCL12 levels were found to be positively correlated with TNF-α and CTX-1 expression [ 70 ] . TNF-α has been demonstrated to promote osteoclastogenesis under both in vitro and in vivo conditions [ 73 ] . CTX-1 serves as a sensitive biochemical marker of bone turnover, and elevated serum CTX-1 levels indicate enhanced bone resorption in individuals presenting with vertebral or hip fractures [ 74 ] . In conclusion, increased plasma CXCL12 concentrations are strongly associated with elevated osteoclast activity, although the precise mechanisms involved remain incompletely understood.

In prostate cancer, elevated CXCR4 protein expression has been significantly associated with tumor metastasis, though no correlation has been observed with Gleason score or T staging [ 51 ] . The CXCL12/CXCR4 axis has been found to upregulate the expression of migration-associated proteins, such as MMP-9, by activating downstream signaling cascades, including PI3K/Akt and ERK pathways, thereby enhancing prostate cancer cell adhesion to vascular endothelium and promoting their invasive behavior [ 75 ] . The CXCL12/CXCR4 axis is also involved in the recruitment of immune cells. CXCL12 can attract monocytes, which subsequently differentiate into tumor-associated macrophages or myeloid-derived suppressor cells (MDSCs), thereby promoting the formation of an immunosuppressive microenvironment [ 76 ] . This enables prostate cancer cells to evade immune surveillance, thereby facilitating their local growth and invasion. In the bone metastatic stage, the role of the CXCL12/CXCR4 axis becomes more complex. The axis not only serves as a signal guiding cancer cells to migrate to the bone marrow but also acts as an amplifier of immune suppression. Specifically, CXCL12, highly expressed by bone marrow stromal cells, attracts CXCR4-positive prostate cancer cells to the bone microenvironment in a directional manner [ 77 ] . After being recruited to the bone microenvironment, prostate cancer cells can induce the expression of integrin αvβ3, thereby augmenting their adhesive capacity [ 75 ] . Concurrently, CXCL12/CXCR4 signaling indirectly upregulates RANKL expression in prostate cancer cells, promoting osteoclast differentiation and consequently driving bone destruction and tumor progression [ 78 ] . The CXCL12/CXCR4 pathway also facilitates the activation of the β-catenin/TCF/LEF transcriptional complex, leading to the upregulation of Wnt target genes, including CXCL12 itself. This establishes a positive feedback loop that further amplifies the signaling [ 19 ] . Meanwhile, immune cells recruited by CXCL12 may interact with osteoclasts and cancer cells, contributing to the formation of a more complex immunosuppressive network [ 79 ] . Sun et al [ 80 , 81 ] shown that inhibition of CXCR4 – through the administration of neutralizing antibodies or the antagonist AMD3100 – leads to a marked reduction in both bone metastases and prostate cancer tumor burden in murine models. Similarly, Cordier et al [ 82 ] demonstrated that combined inhibition of CXCR4 and TRPV6, a calcium channel involved in prostate cancer progression, significantly can suppress bone metastasis.

TGF-β and IGF-1

TGF-β and IGF-1 facilitate osteogenesis and also drive prostate cancer progression through separate molecular mechanisms. High circulating IGF-1levelshave have been associated with an increased risk of prostate cancer, particularly in cases of low-grade prostate cancer [ 83 ] . IGF-1 receptor is consistently overexpressed in metastatic prostate cancer and is associated with poor prognosis [ 22 ] . IGF-1 promotes prostate cancer progression by activating the IGF-1 receptor, which then activates multiple signaling pathways, including the PI3K and MAPK pathways [ 22 , 84 ] .

TGF-β appeared to play a dual role in prostate cancer proliferation. In the early stages of prostate cancer, TGF-β acts as a tumor suppressor. It maintains tissue homeostasis by inhibiting cell proliferation and inducing cell-cycle arrest, such as G1 phase arrest, in normal prostate epithelial cells and early-stage prostate cancer cells [ 85 ] . As prostate cancer progresses, cancer cells develop resistance to the growth-inhibitory effects of TGF-β, enabling TGF-β to switch toward promoting disease progression. TGF-β enhances the invasive properties and migratory of prostate cancer cells by inducing EMT [ 86 ] . Meanwhile, it inhibits the functions of immune effector cells, including T cells and NK cells, thereby establishing an immunosuppressive microenvironment that facilitates the evasion of immune surveillance by prostate cancer cells [ 87 ] . In addition, TGF-β acts synergistically with multiple pathways, including the CXCL12/CXCR4, RANKL/RANK/OPG, and Wnt signaling pathways. Research indicates that TGF-β increases CXCR4 expression, boosting prostate cancer cells’ response to CXCL12 and aiding their migration and bone metastasis [ 88 ] . In the tumor-bone microenvironment, TGF-β indirectly prompts prostate cancer cells to express RANKL, fueling the vicious cycle of prostate cancer bone metastasis [ 78 ] . TGF-β is also capable of activating non-Smad signaling pathways, including the PI3K/AKT and Rho GTPases pathways, which interact synergistically with the Wnt signaling pathway to facilitate EMT [ 87 ] . A study has shown that targeting TGF-β signaling, such as through the use of TGF-β inhibitors, may slow the progression of prostate cancer, particularly in metastatic castration-resistant prostate cancer (CRPC) [ 89 ] .

Current treatment strategies and dual-action drugs development

Basic supportive care

Bone health management remains a challenge in men with prostate cancer. The new guidelines from the American Urological Association (AUA/SUO) and the National Comprehensive Cancer Network (NCCN) recommend routine BMD assessment in patients, particularly those receiving long-term ADT [ 90 , 91 ] . Specific methods include baseline measurement performed using dual-energy X-ray absorptiometry and assessment of the 10-year fracture risk using the FRAX tool [ 92 ] . Lifestyle interventions have been established as an important strategy for managing osteoporosis in patients with prostate cancer. The NCCN guidelines (v2.2025) and European Association of Urology guidelines (EAU, 2025) strongly recommend that all prostate cancer patients are strongly advised to supplement with calcium and vitamin D (1000–1200 mg of calcium daily and maintain serum vitamin D levels at 30–50 ng/ml), while also implementing lifestyle interventions including weight-bearing exercise, smoking cessation, and limiting alcohol consumption [ 46 , 91 ] . Although current clinical evidence has not consistently demonstrated that exercise training significantly increases BMD in patients with prostate cancer, numerous studies have highlighted its important role in promoting bone-related health. Cormie et al [ 93 ] demonstrated that a 12-week resistance training program could be safely implemented even in prostate cancer patients with bone metastases. The intervention led to approximately an 11% increase in muscle strength, a 5% improvement in endurance, a 12% enhancement in walking ability, and a 24% increase in physical activity levels. Similarly, the study by Winters-Stone et al [ 94 ] showed that regular resistance and impact training significantly improved muscle strength, self-reported physical function, and reduced functional disability in prostate cancer survivors.

In addition, differences in patient age and ethnicity should not be overlooked. Elderly patients experience age-related bone loss at an average rate of 1–2% per year, and this rate may double following ADT compared to younger individuals [ 46 ] . BMD tends to be higher and osteoporosis less prevalent in Blacks than in Whites [ 95 ] . Among patients with prostate cancer receiving ADT, Black individuals also show higher BMD and lower fracture risk compared to Whites [ 96 ] . For patients at high risk of bone-related events, a combination of drug therapy and lifestyle interventions is recommended. Table 1 summarizes the bone-protective interventions recommended for prostate cancer in recent guidelines issued by the AUA/SUO, NCCN, EAU, European Society for Medical Oncology (ESMO), and the Advanced Prostate Cancer Consensus Conference (APCCC, 2024). Table 1 Bone protection strategies for prostate cancer patients. Medicines Mechanism Target audience Dosage regimen Contraindication Adverse reactions Guideline support Zoledronic acid Inhibiting osteoclast activity 1. Patients accepting ADT prevention of bone loss 1. Prevention of bone loss: 5 mg IV once a year 1. Severe renal insufficiency (creatinine clearance <30 ml/min) 1. Acute phase reactions: fever, muscle pain (20–30% incidence) NCCN (Version.2.2025 ): A recommended IV bisphosphonate for mCRPC. APCCC (2024) : Supported in high SRE-risk patients. 2. Patients with mCRPC (Bone metastasis): prevention of SREs 2. Hypocalcemia (requires calcium and vitamin D supplementation) EAU (2025 ): Strongly recommended for mCRPC; not recommended in mHSPC unless osteoporosis. 2. Prevention of SREs: 4 mg IV every 3–4 weeks 3. Renal toxicity AUA/SUO (2023 ): Moderate recommendation for mCRPC. 4. Osteonecrosis of the Jaw (1–2% incidence) 2. Uncorrected hypocalcemia ESMO (2020 ): Recommended for mCRPC. 5. Atypical femoral fractures Alendronate Inhibiting osteoclast activity Prevention/treatment of ADT-related bone loss; not for bone metastases. 70 mg PO once weekly 1. Esophageal motility disorders (e.g., esophageal stricture, achalasia) 1. Oesophagitis/gastrointestinal ulcer NCCN (Version.2.2025) : Oral alternative for ADT-related bone loss. 2. Hypocalcemia (low risk) ESMO (2020) : Option for patients who avoid injections. 3. Osteonecrosis of the Jaw (<1%, rare) EAU (2025 ): Recommended for ADT-induced bone loss; not for metastatic disease. 2. Inability to remain in an upright position 4. Atypical femoral fractures 3. Severe renal insufficiency (creatinine clearance <30 ml/min) Denosumab RANKL inhibitor, blocking osteoclast activation 1. Patients accepting ADT prevention of bone loss 1. Prevention of bone loss: 60 mg SC every 6 months 1. Uncorrected hypocalcemia 1. Hypocalcaemia (highest risk, requires strict monitoring) NCCN (Version.2.2025) : Strongly recommended for ADT-related bone loss; preferred option for preventing SREs in mCRPC (superior to zoledronic acid). 2. Allergy to any ingredient 2. Osteonecrosis of the Jaw (1.8%–3.7% incidence) 2.Patients with mCRPC (Bone metastasis): prevention of SREs 3. Atypical femoral fractures 4. Risk of rebound fractures after discontinuation of medication AUA/SUO (2023 ): Moderately recommended for mCRPC (similar to zoledronic acid), with no distinction in priority. 2. Prevention of SREs: 120 mg SC every 4 weeks EMSO (2020 ): Strongly recommended for mCRPC based on high‑quality evidence; superior to zoledronic acid in delaying first SRE. EAU (2025 ): Strong recommendation for mCRPC; recommended for ADT bone loss; not recommended for SRE prevention in non-metastatic CRPC. APCCC (2024 ): Supported as an option in ADT-related bone loss and bone-metastatic mCRPC; no formal consensus. 92% of experts favored tapering or stopping after 2 years. Radium-223 Alpha particle radiotherapy, targeting bone metastases, inducing double-strand DNA breaks. Patients with symptomatic bone metastases from mCRPC (without visceral metastases) 55 kBq/kg IV, once a month for 6 cycles. 1. Visceral metastasis or large lymph node metastases 1. Bone marrow suppression (anemia, thrombocytopenia) NCCN (Version.2.2025)/ EAU (2025)/ ESMO (2020 ): Recommended for symptomatic bone-metastatic mCRPC (without visceral metastases). 2. Diarrhoea (25%) 3. Hypocalcemia 2. Insufficient bone marrow reserve: Platelets <100,000/μl, Neutrophils < 1,500/μl, Hemoglobin < 10.0 g/dl AUA/SUO (2023 ): Strongly recommended for symptomatic bone-metastatic mCRPC (without visceral metastases or lymphadenopathy >3 cm). 3. Contraindicated for use in combination with abiraterone and prednisone ADT, androgen deprivation therapy; APCCC, Advanced Prostate Cancer Consensus Conference; AUA/SUO, American Urological Association/ Society of Urologic Oncology; EAU, European Association of Urology; ESMO, European Society for Medical Oncology; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; NCCN, National Comprehensive Cancer Network; SRE, skeletal-related event.

Bisphosphonates

Bisphosphonates preserve bone structural integrity by suppressing osteoclast activity and decelerating bone resorption. Alendronate and risedronate have been clinically validated for maintaining BMD in patients undergoing ADT. In a randomized trial involving 104 non-metastatic prostate cancer patients, those treated with risedronate maintained lumbar spine BMD over a 24-month period, whereas the placebo group exhibited a substantial reduction (13.6% decrease at 24 months) [ 97 ] . Oral formulations, including risedronate (35 mg weekly) and alendronate, have been approved by the European Medicines Agency for the management of male osteoporosis [ 98 ] . Intravenous zoledronic acid is also frequently administered for the treatment of osteoporosis, typically at a dose of 5 mg annually via intravenous infusion. In contrast, for patients with bone metastases, a dosage of 4 mg every 3–4 weeks is recommended. Several studies have demonstrated that zoledronic acid can reduce the incidence of SREs by 30–50%. However, no significant improvement in overall survival has been observed among prostate cancer patients [ 99 , 100 ] .

Denosumab

In patients with prostate cancer, denosumab is employed for the management of osteoporosis and bone metastases to delay and reduce SREs, enhance quality of life, and extend survival. The mechanism of action of denosumab involves high-affinity binding to RANKL, thereby inhibiting the RANKL-RANK signaling pathway [ 101 ] . Significant increases in BMD and reductions in fracture risk have been demonstrated in pivotal clinical trials. In a randomized, double-blind study involving 734 prostate cancer patients receiving ADT, those treated with denosumab (60 mg subcutaneously every 6 months) exhibited lumbar spine BMD increases of 6.7% at 1 year and 8.9% at 2 years, significantly exceeding those observed in the placebo group [ 102 ] . In the context of prostate cancer bone metastases, denosumab not only suppresses osteoclast-mediated bone destruction but also indirectly diminishes the survival and invasiveness of prostate cancer cells within the bone microenvironment, thereby contributing to delayed onset of SREs, particularly pathological fractures [ 103 , 104 ] . In terms of SRE prevention, denosumab has demonstrated greater efficacy than zoledronic acid and does not require dose modification based on renal function [ 105 – 107 ] . Among patients with metastatic CRPC, administration of denosumab (120 mg every 4 weeks) significantly prolonged the time to first SRE compared to zoledronic acid (20.7 months vs 17.1 months) [ 106 ] . Additionally, denosumab has been shown to extend bone metastasis-free survival. A study by Smith et al [ 103 ] reported that denosumab delayed the time to first bone metastasis by 4.2 months in patients with CRPC. However, its use has been associated with relatively high incidences of osteonecrosis of the jaw (1.8–3.7%) and hypocalcemia (up to 13%), necessitating a careful risk-benefit evaluation. Currently, there is no supporting evidence that combination therapy with bisphosphonates enhances therapeutic efficacy. According to the 2024 APCCC, 92% of experts endorsed either discontinuation or reduced frequency of bone-targeted agents (e.g., denosumab) after 2 years of administration [ 29 ] . Nonetheless, rebound bone resorption following denosumab discontinuation may elevate the risk of vertebral fractures, thereby supporting a transition to bisphosphonates (e.g., alendronate or zoledronic acid) to stabilize bone metabolism.

Radium-223

To date, radium-223 is the only bone-seeking radiopharmaceutical shown to prolong overall survival and prevent symptomatic skeletal events in men with metastatic CRPC and bone metastases [ 91 ] . It is a targeted alpha therapy that induces localized cytotoxicity in bone metastases [ 108 ] . In the ALSYMPCA trial, radium-223 significantly improved median overall survival (14.9 vs 11.3 months); and delayed the time to first symptomatic skeletal event (15.6 vs 9.8 months) compared with placebo [ 109 ] . To reduce the risk of fractures, bone protectors should be used in combination with radium-223, and combination with abiraterone is prohibited [ 46 ] . Guidelines consistently recommend radium-223 for patients with symptomatic bone metastases and no visceral disease [ 46 , 91 , 110 ] .

Dickkopf-1: a shared target for prostate cancer and osteoporosis treatment

The majority of patients with advanced prostate cancer eventually progress to CRPC following prolonged endocrine therapy [ 111 ] . For individuals with CRPC, few effective treatment options currently exist beyond chemotherapy, and CRPC has emerged as the predominant cause of mortality in this population. Genetic mutations have been identified in approximately 10–20% of patients with advanced prostate cancer, resulting in aberrant activation of the Wnt signaling pathway [ 112 , 113 ] . Consequently, the combination of Wnt pathway-targeted agents with endocrine therapy or other treatment strategies has become increasingly necessary and may enhance therapeutic efficacy across diverse prostate cancer subtypes.

Within the Wnt signaling pathway, Dickkopf-1 (DKK1) has been identified as a highly promising target for the concurrent treatment of prostate cancer and osteoporosis. Among the DKK family members, DKK1 is the most extensively studied and has been recognized as one of the most potent extracellular inhibitors of Wnt signaling [ 114 ] . It functions by binding to the Wnt co-receptors LRP5/6, thereby preventing the formation of the FZD-LRP complex and subsequently inhibiting β-catenin accumulation. However, emerging evidence suggests that elevated DKK1 expression, particularly in serum, paradoxically facilitates prostate cancer progression and is associated with poor prognosis, bone metastases, and therapeutic resistance [ 53 , 115 ] . This paradoxical effect is thought to involve the activation of non-canonical Wnt pathways (e.g., Wnt/PCP or Wnt/JNK), which may be triggered by DKK1-mediated inhibition of the canonical Wnt pathway, ultimately contributing to bone metastasis [ 116 ] . Additionally, DKK1 may interact with the CKAP4 receptor, subsequently activating the PI3K/AKT signaling cascade. Its specific manifestations are a reduction in NK cells and CD8 + T cells, accompanied by an increase in M2 macrophages and resting NK cells, resulting in impaired immune surveillance that may indirectly promote androgen resistance [ 117 , 118 ] . DKK1 secreted by prostate cancer cells has also been shown to inhibit osteoblast differentiation and activity, thereby enhancing bone resorption. Simultaneously, it upregulates RANKL, a key osteoclast-activating factor, contributing to the formation of osteolytic lesions in bone metastases [ 119 ] .

Current evidence suggests that inhibition of DKK1 effectively suppresses prostate cancer progression. In the study conducted by Hall et al [ 120 ] , the knockout of DKK1 in osteolytic prostate cancer cells was shown to delay the development of both soft tissue and bone tumors. In a study by Rinella et al [ 121 ] , silencing or knockout of DKK1 significantly inhibited the growth, migration, and expression of metastasis-related genes in metastatic CRPC cells. Subsequent in vivo experiments in mice further demonstrated that DKK1 deficiency slowed prostate cancer growth and inhibited lung metastasis. Research by Wise et al [ 122 ] demonstrated that monoclonal antibodies targeting DKK1 (e.g., DKN-01) reduced tumor burden in prostate cancer mouse models, with therapeutic effects dependent on NK cell activity. Subsequently, Wise et al [ 123 ] initiated a phase 1/2 clinical trial to evaluate the efficacy of DKN-01 as monotherapy or in combination with docetaxel in patients with metastatic CRPC. However, patient recruitment for this trial was slow, as it required the enrollment of individuals with high DKK1 expression or specific Wnt signaling pathway mutations. Despite the eventual inclusion of patients with treatment-emergent neuroendocrine prostate cancer and aggressive variant prostate cancer, enrollment remained limited, with only 18 participants – 10 assigned to monotherapy and 8 to combination therapy. The results showed that the combination of DKN-01 and docetaxel demonstrated a partial response rate of 71%. Only three patients experienced a durable response, while the others failed to maintain a significant therapeutic effect during follow-up. The median progression-free survival in the combination therapy group was 5.7 months, which is slightly higher than the expected outcomes of docetaxel monotherapy reported in the literature. This modest improvement still falls short of the durable efficacy required to meet the therapeutic needs of patients with metastatic CRPC. Ultimately, the trial was terminated early.

The suboptimal outcomes of the trial may be partly attributed to the selection of patients with a predisposition toward Wnt signaling pathway mutations. This is because the antitumor effects of DKK1 inhibition may, in part, be mediated through suppression of the DKK1/CKAP4 axis. DKK1/CKAP4 axis markedly related to tumor-immune microenvironment and immune infiltration [ 117 , 124 , 125 ] . DKK1 may drive the accumulation of suppressive myeloid populations, ultimately reducing T cell and NK cell responses in prostate cancer [ 22 , 122 ] . Research indicates that prostate cancer exhibiting elevated DKK1 expression demonstrates diminished infiltration of CD8 + T cells and reduced levels of activated NK cells. Furthermore, inhibition of DKK1 restores the antitumor activity of NK cells in prostate cancer models [ 122 ] . Comparable mechanisms have undergone more extensive validation in the contexts of breast cancer, melanoma, and colorectal cancer [ 126 – 128 ] .

DKK1 has been extensively investigated in the context of osteoporosis. Elevated serum DKK1 levels have been reported in patients experiencing long-term immobilization or disuse-induced bone loss [ 129 ] . In a study of Mediterranean anemia-related osteoporosis, serum DKK1 concentrations were found to be elevated prior to treatment and significantly reduced following zoledronic acid administration, accompanied by concurrent improvements in BMD [ 130 ] . In both ovariectomized mice and rhesus macaques, subcutaneous administration of the anti-DKK1 antibody RH2-18 resulted in a significant enhancement of bone mineral density, with particularly notable improvements in the trabecular compartment [ 131 ] . A preclinical investigation targeting multiple myeloma employed the anti-DKK1 antibody BHQ-880 in mouse models, with results indicating markedly increased osteoblast numbers, elevated serum human osteocalcin levels, and enhanced trabecular bone formation [ 132 ] . The proposed mechanism involves activation of the Wnt signaling pathway following DKK1 inhibition, thereby enhancing osteoblast function [ 55 ] .

CXCR4 antagonist: dual targeting of osteoporosis and prostate cancer

Multiple studies have confirmed that CXCR4 antagonists are capable of effectively inhibiting prostate cancer progression. For example, Sun et al [ 81 ] demonstrated that CXCR4 antagonists (e.g., anti-CXCR4 antibodies or the peptide antagonist TN14003) significantly suppressed prostate cancer bone tumor growth and reduced levels of the bone resorption marker pyridinoline. Benslimane-Ahmim et al [ 67 ] demonstrated that OPG activates the CXCL12/CXCR4 signaling axis in prostate cancer. In vitro, conditioned medium from OPG-pretreated endothelial colony-forming cells significantly enhanced the chemotactic response of prostate cancer cells, and this effect was partially blocked by the CXCR4 antagonist AMD3100. Additionally, Domanska et al [ 133 ] found that the CXCR4 antagonist AMD3100 enhanced the sensitivity of prostate cancer cells to docetaxel chemotherapy, an effect validated through both in vitro and in vivo (mouse model) experiments. The underlying mechanism is believed to involve AMD3100-mediated blockade of the CXCL12/CXCR4 axis. This disruption interferes with the interaction between prostate cancer cells and the bone marrow microenvironment, thereby reducing resistance to chemotherapeutic agents.

In the context of bone metabolism, CXCR4 antagonists have been shown to suppress osteoclast formation via a distinct mechanism while preserving osteogenic function. For instance, AMD3100 directly inhibits CXCL12/CXCR4 interactions within the bone marrow, thereby facilitating the mobilization of hematopoietic stem cells into the circulation and indirectly reducing osteoclast numbers at bone surfaces [ 134 ] . In ovariectomized animal models simulating osteoporosis, blockade of the CXCR4 signaling pathway (e.g., through AMD3100 administration) has been associated with reductions in bone resorption markers and increases in BMD [ 135 ] . Although AMD3100 mobilizes hematopoietic stem and progenitor cells in healthy mice, it does not exert a significant effect on BMD, indicating that its action may depend on the pathological hyperactivity of osteoclasts observed in osteoporosis. In a separate study on diabetic osteoporosis, the CXCR4 antagonist AMD3465 was reported to reverse osteoblast apoptosis and downregulate matrix metalloproteinase expression, thereby attenuating the degradation of the bone matrix [ 136 ] .

Overall, CXCR4 antagonists exhibit potential as dual-function agents for the treatment of both osteoporosis and prostate cancer. In patients with early-stage prostate cancer, these compounds may reduce the risk of bone metastasis and delay the decline in BMD. In advanced-stage prostate cancer patients receiving chemotherapy, CXCR4 antagonists may also enhance tumor responsiveness to docetaxel.

Challenges in the clinical application of CXCR4 antagonists and anti-DKK1 antibodies

Although CXCR4 antagonists and anti-DKK1 antibodies hold therapeutic potential, they still face significant translational and clinical challenges before being widely applied in the management of prostate cancer and osteoporosis. Anti-DKK1 therapy may paradoxically activate the canonical Wnt pathway, which is closely associated with the proliferation and metastasis of prostate cancer cells. Signaling redundancy among the Wnt, CXCR4, and TGF-β axes may enable cancer cells to bypass the blockade of a single pathway, thereby limiting therapeutic efficacy. Moreover, the role of DKK1 in immune regulation may be modulated by the functional status of the host immune system [ 137 ] . In hosts lacking functional NK cells, the therapeutic efficacy of anti-DKK1 strategies may be limited. Similarly, CXCR4 antagonists such as AMD3100 and AMD3465 may alter the migration of immune cells [ 138 ] . They may alter the infiltration pattern of immune cells within the prostate cancer microenvironment, thereby potentially affecting antitumor immune responses. More importantly, the CXCL12/CXCR4 pathway intersects with the PI3K-Akt and TGF-β pathways, both of which play critical roles in the immunosuppressive microenvironment of bone metastases. This suggests that inhibiting CXCR4 may trigger unpredictable immunological effects.

Therapeutic efficacy may vary dramatically depending on different subtypes of prostate cancer. For instance, neuroendocrine CRPC is independent of androgen receptor signaling and driven by complex mutations. In this subtype, anti-DKK1 therapy may offer limited benefit or even pose a risk, since activation of the Wnt pathway could synergize with non–androgen receptor pathways to promote tumor progression. In contrast, patients with bone metastasis-dominant CRPC may benefit the most from anti-DKK1 treatment. By inhibiting DKK1, it may be possible to restore osteoblast function, reduce skeletal-related events, and potentially impair tumor–bone microenvironment interactions that support metastatic growth. Similarly, the effectiveness of CXCR4 antagonists may differ across subtypes due to variations in prostate cancer homing dependence and immune microenvironment composition.

From a clinical perspective, the monoclonal antibody DKN-01, which targets DKK1, has shown some promise in early-phase studies with prostate cancer. However, its phase I/II trials were prematurely terminated due to limited durable responses and unclear biomarker-based patient selection. This underscores the need for more effective stratification strategies, particularly for patients with CKAP4 positivity or high DKK1 expression. Although DKK1 blockade has demonstrated therapeutic potential, its selectivity remains uncertain due to the expression of DKK1 in normal tissues; systemic inhibition may disrupt bone homeostasis or immune tolerance. Similarly, CXCR4 is broadly expressed in hematopoietic and endothelial cells, raising concerns about off-target effects and hematologic toxicity. High doses of CXCR4 antagonists have been associated with leukocytosis, gastrointestinal symptoms, and immunosuppression. Despite encouraging results from preclinical studies, clinical efficacy has remained limited and inconsistent. For example, CXCR4 antagonists have demonstrated anti-metastatic activity in preclinical studies using prostate cancer models; however, clinical data in humans remain scarce, and these agents have not yet been approved for the treatment of this indication.

Dual-target therapies often face pharmacokinetic challenges, including mismatched half-lives, inconsistent bioavailability, overlapping toxicities, and complex dosing schedules that hinder clinical translation. These issues are well illustrated by inhibitors targeting the Wnt and CXCL12/CXCR4 pathways. Wnt signaling typically requires sustained suppression to affect transcriptional programs and the tumor–bone microenvironment, whereas CXCL12 signaling is rapid and dynamic, responding to chemokine gradients that regulate immune cell trafficking and prostate cancer cells homing. As a result, Wnt inhibitors such as anti-DKK1 antibodies usually exhibit longer half-lives and delayed effects, while CXCR4 antagonists like AMD3100 are rapidly cleared and demand frequent dosing or continuous infusion. This pharmacokinetic mismatch complicates co-administration, increasing the risk of subtherapeutic exposure or cumulative toxicity. Moreover, because both pathways intersect in the bone marrow niche, simultaneous inhibition may disrupt bone remodeling, hematopoiesis, or immune surveillance. These challenges underscore the importance of innovative strategies – such as advanced drug delivery systems or sequential dosing regimens – to optimize therapeutic synergy while minimizing adverse effects.

Therefore, the clinical translation of CXCR4 antagonists and anti-DKK1 antibodies for the treatment of prostate cancer and osteoporosis reveals several key gaps. A primary challenge is the complex interplay of their mechanisms, as anti-DKK1 therapy may inadvertently activate the canonical Wnt pathway associated with cancer cell proliferation, while CXCR4 signaling intersects with immunosuppressive pathways, potentially leading to unpredictable immune responses. Furthermore, clinical trial designs have proven inadequate, with premature terminations due to unclear biomarker selection and limited durable responses. Safety concerns arise from the non-selective inhibition of DKK1 and CXCR4, risking disruption of bone homeostasis and immune tolerance. Additionally, pharmacokinetic mismatches complicate co-administration, increasing the risk of suboptimal dosing and cumulative toxicity. These challenges emphasize the need for innovative strategies to optimize therapeutic efficacy while mitigating adverse effects.

Future directions and translational outlook

Alghamri et al [ 139 ] developed synthetic protein nanoparticles by polymerizing human serum albumin and modifying them with the tumor-penetrating peptide internalizing RGD, enabling targeted encapsulation and systemic delivery against the CXCL12/CXCR4 signaling axis. This delivery system improved the pharmacokinetic properties of the therapeutic agents (e.g., half-life and bioavailability) and significantly reduced the intratumoral infiltration of CXCR4 + monocytic MDSCs in glioblastoma model, thereby promoting immune microenvironment remodeling and inducing immunogenic cell death. This system shows promise for future use in prostate cancer and osteoporosis. Such a platform holds promise for the co-delivery of anti-DKK1 agents and CXCR4 antagonists, enabling simultaneous targeting of bone metabolic dysregulation and disease progression, while overcoming challenges related to pharmacokinetic mismatch and off-target risks. Moreover, after the pharmacokinetic challenges are resolved, the combination of anti-DKK1 and CXCR4 inhibitors with ADT will represent a promising yet underexplored area of research.

Bispecific therapies (e.g., sclerostin–DKK1 bispecific antibodies) represent a promising yet underexplored avenue. Sclerostin is a secreted factor produced by osteocytes [ 75 ] . Similar to DKK1, it blocks Wnt signaling by binding to LRP5 and LRP6 [ 140 ] . The combination of anti-DKK1 antibodies and anti-sclerostin antibodies can completely relieve the inhibition of the Wnt pathway, maximizing bone formation and overcoming the limitations of monotherapy, such as the compensatory upregulation of DKK1 caused by anti-sclerostin monotherapy [ 141 ] . Animal model data show that combination therapy is superior to monotherapy in increasing bone mass and improving bone biomechanical strength, making it particularly suitable for patients with severe osteoporosis and those who do not respond well to single-agent treatments [ 142 ] . Meng et al [ 143 ] developed a targeted antibody payload platform that enables simultaneous neutralization of SOST and DKK1 via a single engineered dual-specific antibody. This bispecific molecule exhibited markedly enhanced bone anabolic activity compared to monotherapy in preclinical models. A phase II clinical trial evaluating AGA-2118, a bispecific antibody targeting both DKK1 and SOST, is currently in the patient recruitment stage for the treatment of osteoporosis. However, the role of anti-sclerostin antibodies in prostate cancer remains unclear, and future research should first clarify their specific effect on prostate cancer. The RANKL vaccine shows potential in preventing bone metastasis and treating bone-related diseases. This vaccine works by inducing a specific immune response to block the binding of RANKL to RANK, thereby inhibiting osteoclast activity, reducing bone resorption, and preventing the occurrence of bone metastasis [ 144 ] . By enhancing the immune system’s recognition and neutralization of RANKL, the RANKL vaccine holds promise in slowing the progression of bone lesions. However, its research is still in the early stages, and more clinical studies are needed to further validate its safety, efficacy, and long-term effects.

Patient stratification will play a crucial role in future treatments and clinical trials. By stratifying patients based on specific biomarkers, such as the expression levels of CXCR4 or DKK1, treatments can be made more personalized and precise. This approach can significantly improve treatment outcomes and reduce unnecessary side effects. Currently, there is a gap in the research on biomarkers for osteoporosis in prostate cancer patients. Future studies should focus on identifying predictive biomarkers to provide more accurate treatment strategies (e.g., gene therapies) for clinical practice. A deeper understanding of the tumor–immune–bone axis is also crucial. For example, DKK1 blockade may elicit distinct immunological effects depending on the composition of immune cells within the bone marrow microenvironment. Similarly, CXCR4 inhibition also alter the recruitment of MDSCs and the mechanisms underlying their interactions with the stroma and prostate cancer cells. These immunological consequences should be systematically evaluated in future trials.

Conclusions

The association between prostate cancer and osteoporosis cannot be attributed solely to treatment-related causal factors. Signaling pathways – such as the RANKL/RANK/OPG, Wnt, CXCL12/CXCR4, TGF-β, and IGF-1 – form a complex regulatory network between prostate cancer and bone metabolism. Given the involvement of these signaling pathways in both the progression of prostate cancer and the regulation of bone metabolism, the development of therapeutic agents targeting these pathways may represent a promising strategy for the simultaneous treatment of prostate cancer and osteoporosis (Fig. 5 ). For instance, anti-DKK1 antibodies (e.g., DKN-01 and BHQ880) have demonstrated anti-prostate cancer activity in preclinical models and early-phase clinical trials. In osteoporotic animal models, anti-DKK1 antibodies have been shown to increase bone mineral density. Dual-target therapies, including those directed at DKK1 and CXCR4, demonstrate substantial therapeutic potential by potentially enhancing efficacy through synergistic effects and mitigating the risk of drug resistance. At present, our comprehension of the intricate mechanisms underlying the actions of these drugs is inadequate. Achieving precise drug delivery to both prostate cancer cells and the bone microenvironment continue to pose a significant challenge. Moreover, well-designed clinical trials are needed to evaluate the safety and therapeutic efficacy of these agents in humans. Figure 5. Key roles of the RANKL/RANK/OPG, Wnt, and CXCL12/CXCR4 pathways in prostate cancer and bone metabolism. Activation of the Wnt pathway promotes osteoblast differentiation. DKK1 is highly expressed in advanced prostate cancer, where it inhibits the canonical Wnt pathway, potentially activating the non-canonical pathway and thereby driving prostate cancer progression. DKK1 interacts with CKAP4, further promoting prostate cancer progression. Anti-DKK1 antibodies represent potential therapeutic agents targeting these pathways. The RANKL/RANK/OPG pathway promotes osteoclast differentiation and accelerates prostate cancer progression. Corresponding therapeutic agents, such as the RANKL inhibitor denosumab, have been developed. CXCL12/CXCR4 activation enhances osteoclast activity and promotes prostate cancer progression. CXCR4 antagonists, such as AMD3100 and AMD3465, are potential therapeutic agents targeting this pathway. This figure was drawn by Figdraw.

Acknowledgements

Not applicable.

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

Published online 12 January 2026

Ethical approval

Not applicable.

Consent

Not applicable.

Conflicts of interest declaration

None.

Sources of funding

This research was funded by Guangdong Basic and Applied Basic Research Foundation (2020A1515110946), Research Fund for Academician LinHe New Medicine (JYHL2022FMS09), Project of Medical and Health Technology Development Program in Shandong Province (202204050782), Jining Key Research and Development Foundation (2022YXNS006), The Tai Shan Young Scholar Foundation of Shandong Province (tsqn202408394), and Shandong Postdoctoral Innovation Project (SDCX-ZG-202400011).

Author contributions

Z.Z.: and L.Z.: conception and design of the study; Z.J.: and Z.Z.: literature research and writing – first draft; J.Z., Z.Q., and Z.L.: review, rewriting, and revision – manuscript. All authors read and approved the final manuscript.

Research registration unique identification number (UIN)

Not applicable.

Guarantor

Zhiguo Zhu.

Provenance and peer review

Not commissioned, externally peer-reviewed.

Data availability statement

Not applicable.

References

[1] Wang CC Liu HC Lin WL . Osteosarcopenia in patients with cancer: a systematic review and meta-analysis . Medicine . 2024 ; 103 : e40476 . 39533564 10.1097/MD.0000000000040476 PMC11557054

[2] Salari N Ghasemi H Mohammadi L . The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis . J Orthopaedic Surg Res . 2021 ; 16 : 609 . 10.1186/s13018-021-02772-0 PMC8522202 34657598

[3] Tuck SP Hanusch B Walker J Datta HK . Prostate cancer and osteoporosis . Curr Osteoporosis Rep 2013 ; 11 : 11–20 . 10.1007/s11914-012-0131-2 23355097

[4] Hussain SA Weston R Stephenson RN George E Parr NJ . Immediate dual energy X-ray absorptiometry reveals a high incidence of osteoporosis in patients with advanced prostate cancer before hormonal manipulation . BJU Int 2003 ; 92 : 690–94 . 14616447 10.1046/j.1464-410x.2003.04471.x

[5] Melton LJ,3 Lieber MM Atkinson EJ . Fracture risk in men with prostate cancer: a population-based study . J Bone Miner Res . 2011 ; 26 : 1808–15 . 21520274 10.1002/jbmr.405 PMC3321611

[6] Adejuyigbe B Kallini J Chiou D Kallini JR . Osteoporosis: molecular Pathology, diagnostics, and therapeutics . Int J Mol Sci 2023 ; 24 : 14583 . 37834025 10.3390/ijms241914583 PMC10572718

[7] Foessl I Dimai HP Obermayer-Pietsch B . Long-term and sequential treatment for osteoporosis . Nat Rev Endocrinol 2023 ; 19 : 520–33 . 37464088 10.1038/s41574-023-00866-9

[8] Agha RA Mathew G Rashid R . Transparency in the reporting of Artificial Intelligence – the TITAN guideline . Prem J Sci . 2025 ; 2025 : 100082 .

[9] Guo W Jin P Li R . Dynamic network biomarker identifies cdkn1a-mediated bone mineralization in the triggering phase of osteoporosis . Exp Mol Med . 2023 ; 55 : 81–94 . 36599933 10.1038/s12276-022-00915-9 PMC9898265

[10] Molagoda IMN Athapaththu A Park EK . Fermented oyster (Crassostrea gigas) extract cures and prevents prednisolone-induced bone resorption by activating osteoblast differentiation . Foods (Basel, Switzerland) 2022 ; 11 : 678 . 35267311 10.3390/foods11050678 PMC8909515

[11] Zheng ZG Cheng HM Zhou YP . Dual targeting of SREBP2 and ERRα by carnosic acid suppresses RANKL-mediated osteoclastogenesis and prevents ovariectomy-induced bone loss . Cell Death Differ . 2020 ; 27 : 2048–65 . 31907393 10.1038/s41418-019-0484-5 PMC7308277

[12] Skrabal F Heymsfield SB Skrabal K . Sizing and mending of appendicular muscle mass for hydration during the 12-lead electrocardiogram: true incidence of sarcopenia in heart failure . J Cachexia, Sarcopenia and Muscle . 2024 ; 15 : 575–86 . 38275200 10.1002/jcsm.13423 PMC10995443

[13] Vendrami C Shevroja E Gonzalez Rodriguez E . Muscle parameters in fragility fracture risk prediction in older adults: a scoping review . J Cachexia, Sarcopenia and Muscle . 2024 ; 15 : 477–500 . 38284511 10.1002/jcsm.13418 PMC10995267

[14] Kanis JA Johansson H Harvey NC McCloskey EV . A brief history of FRAX . Arch Osteoporos 2018 ; 13 : 118 . 30382424 10.1007/s11657-018-0510-0 PMC6290984

[15] Kuo TR Chen CH . Bone biomarker for the clinical assessment of osteoporosis: recent developments and future perspectives . Biomarker Res 2017 ; 5 : 18 . 10.1186/s40364-017-0097-4 PMC5436437 28529755

[16] Lara JPN Mayerson E Gertz E . Bone biomarkers and subsequent survival in men with hormone-sensitive prostate cancer: results from the SWOG S1216 phase 3 trial of androgen deprivation therapy with or without orteronel . Europ Urol . 2024 ; 85 : 171–76 . 10.1016/j.eururo.2023.03.036 PMC10662935 37085425

[17] Urabe F Kosaka N Yamamoto Y . Metastatic prostate cancer-derived extracellular vesicles facilitate osteoclastogenesis by transferring the CDCP1 protein . J Extracell Vesicles . 2023 ; 12 : e12312 . 36880252 10.1002/jev2.12312 PMC9989745

[18] Yahiro Y Maeda S Morikawa M . BMP-induced Atoh8 attenuates osteoclastogenesis by suppressing Runx2 transcriptional activity and reducing the Rankl/Opg expression ratio in osteoblasts . Bone Res . 2020 ; 8 : 32 . 32923015 10.1038/s41413-020-00106-0 PMC7463266

[19] Ben-Ghedalia-Peled N Vago R . Wnt signaling in the development of bone metastasis . Cells 2022 ; 11 : 3934 . 36497192 10.3390/cells11233934 PMC9739050

[20] Sanghani-Kerai A Coathup M Samazideh S . Osteoporosis and ageing affects the migration of stem cells and this is ameliorated by transfection with CXCR4 . Bone Jt Res . 2017 ; 6 : 358–65 . 10.1302/2046-3758.66.BJR-2016-0259.R1 PMC5492335 28576885

[21] Wu M Wu S Chen W Li YP . The roles and regulatory mechanisms of TGF-β and BMP signaling in bone and cartilage development, homeostasis and disease . Cell Res 2024 ; 34 : 101–23 . 38267638 10.1038/s41422-023-00918-9 PMC10837209

[22] Liu G Zhu M Zhang M Pan F . Emerging role of IGF-1 in prostate cancer: a promising biomarker and therapeutic target . Cancers 2023 ; 15 : 5228 . 36831629 10.3390/cancers15041287 PMC9954466

[23] Zhong M Xu W Tian P . An inherited allele confers prostate cancer progression and drug resistance via RFX6/HOXA10-orchestrated TGFβ signaling . Adv Sci (Weinheim, Baden-Wurttemberg, Germany) . 2024 ; 11 : e2401492 . 10.1002/advs.202401492 PMC11348203 38932472

[24] Liu Y Zhao L Li M . Osteocytes Produces RANKL Via Wnt-TGFβ Signaling Axis for Osteoclastogenesis . Int J Bio Sci . 2025 ; 21 : 5821–41 . 41079923 10.7150/ijbs.117481 PMC12509901

[25] Park J Yan G Kwon KC . Oral delivery of novel human IGF-1 bioencapsulated in lettuce cells promotes musculoskeletal cell proliferation, differentiation and diabetic fracture healing . Biomaterials . 2020 ; 233 : 119591 . 31870566 10.1016/j.biomaterials.2019.119591 PMC6990632

[26] Choi E Buie J Camacho J Sharma P de Riese WTW . Evolution of androgen deprivation therapy (ADT) and its new emerging modalities in prostate cancer: an update for practicing urologists, clinicians and medical providers . Res Rep Urol 2022 ; 14 : 87–108 . 35386270 10.2147/RRU.S303215 PMC8977476

[27] Dhabhar B . Cancer treatment-induced bone loss: role of denosumab in non-metastatic breast cancer . Breast cancer (Dove Medical Press) 2022 ; 14 : 163–73 . 35860287 10.2147/BCTT.S353332 PMC9292456

[28] Alibhai SM Gogov S Allibhai Z . Long-term side effects of androgen deprivation therapy in men with non-metastatic prostate cancer: a systematic literature review . Crit Rev Oncol/hematol 2006 ; 60 : 201–15 . 16860998 10.1016/j.critrevonc.2006.06.006

[29] Gillessen S Turco F Davis ID . Management of patients with advanced prostate cancer. report from the 2024 advanced prostate cancer consensus conference (APCCC) . Europ Urol . 2025 ; 87 : 157–216 . 10.1016/j.eururo.2024.09.017 39394013

[30] Lee S Mendoza TR Burner DN . Novel dormancy mechanism of castration resistance in bone metastatic prostate cancer organoids . Int J Mol Sci 2022 ; 23 : 3203 . 35328625 10.3390/ijms23063203 PMC8952299

[31] Roodman GD . Mechanisms of bone metastasis . New Engl J Med 2004 ; 350 : 1655–64 . 15084698 10.1056/NEJMra030831

[32] Nakai Y Okamoto K Terashima A . Efficacy of an orally active small-molecule inhibitor of RANKL in bone metastasis . Bone Res . 2019 ; 7 : 1 . 30622830 10.1038/s41413-018-0036-5 PMC6315020

[33] Jones DH Nakashima T Sanchez OH . Regulation of cancer cell migration and bone metastasis by RANKL . Nature . 2006 ; 440 : 692–96 . 16572175 10.1038/nature04524

[34] Zhang X . Interactions between cancer cells and bone microenvironment promote bone metastasis in prostate cancer . Cancer Commun (London, England) 2019 ; 39 : 76 . 10.1186/s40880-019-0425-1 PMC6873445 31753020

[35] Shorning BY Dass MS Smalley MJ Pearson HB . The PI3K-AKT-mTOR Pathway and Prostate Cancer: at the Crossroads of AR, MAPK, and WNT Signaling . Int J Mol Sci 2020 ; 21 : 4507 . 32630372 10.3390/ijms21124507 PMC7350257

[36] Fournier PG Juárez P Jiang G . The TGF-β Signaling Regulator PMEPA1 Suppresses Prostate Cancer Metastases to Bone . Cancer Cell . 2015 ; 27 : 809–21 . 25982816 10.1016/j.ccell.2015.04.009 PMC4464909

[37] Pulukuri SM Rao JS . Matrix metalloproteinase-1 promotes prostate tumor growth and metastasis . Int J Oncol 2008 ; 32 : 757–65 . 18360703 PMC2292413

[38] Sabbota AL Kim HR Zhe X . Shedding of RANKL by tumor-associated MT1-MMP activates Src-dependent prostate cancer cell migration . Cancer Res . 2010 ; 70 : 5558–66 . 20551048 10.1158/0008-5472.CAN-09-4416 PMC2896434

[39] Zhang T Wang Y Xie M . HGF-mediated elevation of ETV1 facilitates hepatocellular carcinoma metastasis through upregulating PTK2 and c-MET . J Exp Clin Cancer Res . 2022 ; 41 : 275 . 36109787 10.1186/s13046-022-02475-2 PMC9479266

[40] Mistry R Hughes D Wadhwa V Parr N . Lateral spine radiographs before androgen deprivation treatment detect a high incidence of undiagnosed vertebral fragility fractures in men with advanced prostate cancer . J Urol 2011 ; 186 : 474–80 . 21705031 10.1016/j.juro.2011.03.149

[41] Li B Wang P Jiao J . Roles of the RANKL-RANK axis in immunity-implications for pathogenesis and treatment of bone metastasis . Front Immunol . 2022 ; 13 : 824117 . 35386705 10.3389/fimmu.2022.824117 PMC8977491

[42] Chaudagar K Hieromnimon HM Khurana R . Reversal of Lactate and PD-1-mediated macrophage immunosuppression controls growth of PTEN/p53-deficient prostate cancer . Clin Cancer Res . 2023 ; 29 : 1952–68 . 36862086 10.1158/1078-0432.CCR-22-3350 PMC10192075

[43] Honma M Ikebuchi Y Suzuki H . RANKL as a key figure in bridging between the bone and immune system: its physiological functions and potential as a pharmacological target . Pharmacol Ther 2021 ; 218 : 107682 . 32956720 10.1016/j.pharmthera.2020.107682

[44] Rao S Cronin SJF Sigl V Penninger JM . RANKL and RANK: from mammalian physiology to cancer treatment . Trends Cell Biol 2018 ; 28 : 213–23 . 29241686 10.1016/j.tcb.2017.11.001

[45] El-Masri BM Andreasen CM Laursen KS . 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 . 39424806 10.1038/s41413-024-00362-4 PMC11489716

[46] EAU Guidelines . EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Limited update March 2025 (presented at EAU Annual Congress Madrid 2025) . Arnhem, The Netherlands : EAU Guidelines Office ; 2025 . Available from : https://uroweb.org/guideline/prostate-cancer/

[47] Park M Cho YJ Kim B . RANKL immunisation inhibits prostate cancer metastasis by modulating EMT through a RANKL-dependent pathway . Sci Rep . 2021 ; 11 : 12186 . 34108600 10.1038/s41598-021-91721-2 PMC8190078

[48] Colomer C Pecharroman I Bigas A Espinosa L . Targeting IKKα kinase to prevent tumor progression and therapy resistance . Cancer Drug Resist (Alhambra, Calif) 2020 ; 3 : 482–90 . 10.20517/cdr.2019.104 PMC8992499 35582445

[49] Luo JL Tan W Ricono JM . Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin . Nature . 2007 ; 446 : 690–94 . 17377533 10.1038/nature05656

[50] Liaghat M Ferdousmakan S Mortazavi SH . The impact of epithelial-mesenchymal transition (EMT) induced by metabolic processes and intracellular signaling pathways on chemo-resistance, metastasis, and recurrence in solid tumors . Cell Commun Signaling . 2024 ; 22 : 575 . 10.1186/s12964-024-01957-4 PMC11610171 39623377

[51] Mirzaei S Paskeh MDA Okina E . Molecular Landscape of LncRNAs in Prostate Cancer: a focus on pathways and therapeutic targets for intervention . J Exp Clin Cancer Res . 2022 ; 41 : 214 . 35773731 10.1186/s13046-022-02406-1 PMC9248128

[52] Liu J Xiao Q Xiao J . Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities . Signal Transduct Target Ther . 2022 ; 7 : 3 . 34980884 10.1038/s41392-021-00762-6 PMC8724284

[53] Murillo-Garzón V Kypta R . WNT signalling in prostate cancer . Nat Rev Urol 2017 ; 14 : 683–96 . 28895566 10.1038/nrurol.2017.144

[54] Shen G Ren H Shang Q . Foxf1 knockdown promotes BMSC osteogenesis in part by activating the Wnt/β-catenin signalling pathway and prevents ovariectomy-induced bone loss . EBioMedicine . 2020 ; 52 : 102626 . 31981979 10.1016/j.ebiom.2020.102626 PMC6992955

[55] Gao Y Chen N Fu Z Zhang Q . Progress of Wnt Signaling Pathway in Osteoporosis . Biomolecules 2023 ; 13 : 483 . 36979418 10.3390/biom13030483 PMC10046187

[56] Maeda K Kobayashi Y Udagawa N . Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis . Nature Med . 2012 ; 18 : 405–12 . 22344299 10.1038/nm.2653

[57] Patel R Brzezinska EA Repiscak P . Activation of β-catenin cooperates with loss of pten to drive AR-Independent castration-resistant prostate cancer . Cancer Res . 2020 ; 80 : 576–90 . 31719098 10.1158/0008-5472.CAN-19-1684

[58] Wang L Dehm SM Hillman DW . A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone . Ann Oncol . 2018 ; 29 : 352–60 . 29069303 10.1093/annonc/mdx689 PMC6304474

[59] Verras M Sun Z . Roles and regulation of Wnt signaling and beta-catenin in prostate cancer . Cancer Lett 2006 ; 237 : 22–32 . 16023783 10.1016/j.canlet.2005.06.004

[60] Hou Y Zhao Z Li P . Combination therapies with Wnt signaling inhibition: a better choice for prostate cancer treatment . Biochim Biophys Acta, Rev Cancer . 2024 ; 1879 : 189186 . 39332651 10.1016/j.bbcan.2024.189186

[61] Ren D Dai Y Yang Q . Wnt5a induces and maintains prostate cancer cells dormancy in bone . J Exp Med . 2019 ; 216 : 428–49 . 30593464 10.1084/jem.20180661 PMC6363426

[62] Vela I Morrissey C Zhang X . PITX2 and non-canonical Wnt pathway interaction in metastatic prostate cancer . Clin Exp Metastasis . 2014 ; 31 : 199–211 . 24162257 10.1007/s10585-013-9620-7

[63] Zhang X Li H Wang Y . Nuclear receptor NURR1 functions to promote stemness and epithelial-mesenchymal transition in prostate cancer via its targeting of Wnt/β-catenin signaling pathway . Cell Death Dis . 2024 ; 15 : 234 . 38531859 10.1038/s41419-024-06621-w PMC10965960

[64] Ye S Lin Q Deng M . Crosstalk between OPG/RANKL/RANK in bone marrow mesenchymal stem cells and Wnt/b-catenin pathway in prostate cancer cells regulates bone metastasis of prostate cancer . POL J PATHOL . 2025 ; 76 : 25–37 . 40755328 10.5114/pjp.2025.150029

[65] Luo H Chen D Li R . Genetically engineered CXCR4-modified exosomes for delivery of miR-126 mimics to macrophages alleviate periodontitis . J Nanobiotechnol . 2023 ; 21 : 116 . 10.1186/s12951-023-01863-w PMC10061745 36991451

[66] Periyasamy-Thandavan S Herberg S Arounleut P . Caloric restriction and the adipokine leptin alter the SDF-1 signaling axis in bone marrow and in bone marrow derived mesenchymal stem cells . Mol Cell Endocrinol . 2015 ; 410 : 64–72 . 25779533 10.1016/j.mce.2015.03.001 PMC4706462

[67] Benslimane-Ahmim Z Pereira J Lokajczyk A . Osteoprotegerin regulates cancer cell migration through SDF-1/CXCR4 axis and promotes tumour development by increasing neovascularization . Cancer Lett . 2017 ; 395 : 11–19 . 28263839 10.1016/j.canlet.2017.02.032

[68] Luo F Su Y Zhang Z Li J . Bone marrow mesenchymal stem cells promote the progression of prostate cancer through the SDF-1/CXCR4 axis in vivo and vitro . Clin Transl Oncol 2022 ; 24 : 892–901 . 34855138 10.1007/s12094-021-02740-4

[69] Carbone LD Bůžková P Fink HA . Association of Plasma SDF-1 with bone mineral density, body composition, and hip fractures in older adults: the cardiovascular health study . Calcif Tissue Int . 2017 ; 100 : 599–608 . 28246930 10.1007/s00223-017-0245-8 PMC5649737

[70] Yang XW Huang HX Wang F . Elevated plasma CXCL12/SDF-1 levels are linked with disease severity of postmenopausal osteoporosis . Innate Immun . 2020 ; 26 : 222–30 . 31640442 10.1177/1753425919883365 PMC7144032

[71] Nugraha AP Kitaura H Ohori F . C-X-C receptor 7 agonist acts as a C-X-C motif chemokine ligand 12 inhibitor to ameliorate osteoclastogenesis and bone resorption . Mol Med Rep 2022 ; 25 : 78 . 35014674 10.3892/mmr.2022.12594 PMC8778739

[72] Brylka LJ Schinke T . Chemokines in physiological and pathological bone remodeling . Front Immunol 2019 ; 10 : 2182 . 31572390 10.3389/fimmu.2019.02182 PMC6753917

[73] Ding P Tan Q Wei Z . Toll-like receptor 9 deficiency induces osteoclastic bone loss via gut microbiota-associated systemic chronic inflammation . Bone Res . 2022 ; 10 : 42 . 35624094 10.1038/s41413-022-00210-3 PMC9142495

[74] Kawana K Takahashi M Hoshino H Kushida K . Comparison of serum and urinary C-terminal telopeptide of type I collagen in aging, menopause and osteoporosis . Int J Clin Chem 2002 ; 316 : 109–15 . 10.1016/s0009-8981(01)00742-2 11750280

[75] Wang M Xia F Wei Y Wei X . Molecular mechanisms and clinical management of cancer bone metastasis . Bone Res 2020 ; 8 : 30 . 32793401 10.1038/s41413-020-00105-1 PMC7391760

[76] Li K Shi H Zhang B . Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer . Signal Transduct Target Ther . 2021 ; 6 : 362 . 34620838 10.1038/s41392-021-00670-9 PMC8497485

[77] Conley-lacomb MK Semaan L Singareddy R . Pharmacological targeting of CXCL12/CXCR4 signaling in prostate cancer bone metastasis . Mol Cancer . 2016 ; 15 : 68 . 27809841 10.1186/s12943-016-0552-0 PMC5093938

[78] Jiang H . Prostate cancer bone metastasis: molecular mechanisms of tumor and bone microenvironment . Cancer Manage Res 2025 ; 17 : 219–37 . 10.2147/CMAR.S495169 PMC11796448 39912095

[79] Kohli K Pillarisetty VG Kim TS . Key chemokines direct migration of immune cells in solid tumors . Cancer Genet Ther 2022 ; 29 : 10–21 . 10.1038/s41417-021-00303-x PMC8761573 33603130

[80] Sun YX Wang J Shelburne CE . Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo . J Cell Biochem . 2003 ; 89 : 462–73 . 12761880 10.1002/jcb.10522

[81] Sun YX Schneider A Jung Y . Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo . J Bone Miner Res . 2005 ; 20 : 318–29 . 15647826 10.1359/JBMR.041109

[82] Cordier C Haustrate A Mihalache A . Targeting TRPV6/CXCR4 complexes prevents castration-resistant prostate cancer metastasis to the bone . Signal Transduct Target Ther . 2025 ; 10 : 287 . 40908300 10.1038/s41392-025-02376-8 PMC12411641

[83] Ravi P Wang V Fichorova RN . IGF-1 axis changes with ADT and docetaxel in metastatic prostate cancer . Endocr Relat Cancer 2023 ; 30 : e230241 . 37671811 10.1530/ERC-23-0241 PMC11304032

[84] Feng Z Levine AJ . The regulation of energy metabolism and the IGF-1/mTOR pathways by the p53 protein . Trends Cell Biol 2010 ; 20 : 427–34 . 20399660 10.1016/j.tcb.2010.03.004 PMC2921989

[85] Thompson-Elliott B Johnson R Khan SA . Alterations in TGFβ signaling during prostate cancer progression . Am J Clin Exp Urol 2021 ; 9 : 318–28 . 34541030 PMC8446771

[86] Sun Y Schaar A Sukumaran P Dhasarathy A Singh BB . TGFβ-induced epithelial-to-mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression . Mol Carcinog 2018 ; 57 : 752–61 . 29500887 10.1002/mc.22797 PMC5947546

[87] Deng Z Fan T Xiao C . TGF-β signaling in health, disease, and therapeutics . Signal Transduct Target Ther . 2024 ; 9 : 61 . 38514615 10.1038/s41392-024-01764-w PMC10958066

[88] Zhang B Li Y Wu Q . Acetylation of KLF5 maintains EMT and tumorigenicity to cause chemoresistant bone metastasis in prostate cancer . Nat Commun . 2021 ; 12 : 1714 . 33731701 10.1038/s41467-021-21976-w PMC7969754

[89] Narayan V Barber-Rotenberg JS Jung IY . PSMA-targeting TGFβ-insensitive armored CAR T cells in metastatic castration-resistant prostate cancer: a phase 1 trial . Nature Med . 2022 ; 28 : 724–34 . 35314843 10.1038/s41591-022-01726-1 PMC10308799

[90] Lowrance W Dreicer R Jarrard DF . Updates to Advanced Prostate Cancer: AUA/SUO Guideline . J Urol . 2023 ; 209 : 1082–90 . 37096583 10.1097/JU.0000000000003452

[91] National Comprehensive Cancer Network (NCCN) . NCCN Clinical Practice Guidelines in Oncology: prostate Cancer. Version 2.2025 . Plymouth Meeting, PA : NCCN ; 2025 . Available from : https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf .

[92] Herath M Cohen A Ebeling PR Milat F . Dilemmas in the management of osteoporosis in younger adults . JBMR Plus 2022 ; 6 : e10594 . 35079682 10.1002/jbm4.10594 PMC8771004

[93] Cormie P Newton RU Spry N . Safety and efficacy of resistance exercise in prostate cancer patients with bone metastases . Prostate Cancer Prostatic Dis . 2013 ; 16 : 328–35 . 23917308 10.1038/pcan.2013.22

[94] Winters-Stone KM Dobek JC Bennett JA . Resistance training reduces disability in prostate cancer survivors on androgen deprivation therapy: evidence from a randomized controlled trial . Arch Phys Med Rehabil . 2015 ; 96 : 7–14 . 25194450 10.1016/j.apmr.2014.08.010 PMC4433162

[95] Campoverde Reyes KJ Stanford FC Singhal V . Bone density, microarchitecture and strength estimates in white versus African American youth with obesity . Bone . 2020 ; 138 : 115514 . 32622072 10.1016/j.bone.2020.115514 PMC7423738

[96] Morgans AK Hancock ML Barnette KG . Racial differences in bone mineral density and fractures in men receiving androgen deprivation therapy for prostate cancer . J Urol . 2012 ; 187 : 889–93 . 22245322 10.1016/j.juro.2011.10.136 PMC3671868

[97] Choo R Lukka H cheung P . Randomized, double-blinded, placebo-controlled, trial of risedronate for the prevention of bone mineral density loss in nonmetastatic prostate cancer patients receiving radiation therapy plus androgen deprivation therapy . Int J Radiat Oncol Biol Phys 2013 ; 85 : 1239 – 45 . 23265571 10.1016/j.ijrobp.2012.11.007

[98] Graham LS Lin JK Lage DE . Management of Prostate Cancer in Older Adults . Am Soc Clin Oncol Edu Book Am Soc Clin Oncol Ann Meet 2023 ; 43 : e390396 . 10.1200/EDBK_390396 37207299

[99] Jakob T Tesfamariam YM Macherey S . Bisphosphonates or RANK-ligand-inhibitors for men with prostate cancer and bone metastases: a network meta-analysis . Cochrane Database Syst Rev . 2020 ; 12 : Cd013020 . 33270906 10.1002/14651858.CD013020.pub2 PMC8095056

[100] James ND Sydes MR Clarke NW . Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial . Lancet (London, England) . 2016 ; 387 : 1163–77 . 26719232 10.1016/S0140-6736(15)01037-5 PMC4800035

[101] Jakob T Monsef I Kuhr K . Bone-modifying agents for the prevention of bone loss in women with early or locally advanced breast cancer: a systematic review and network meta-analysis . Cochrane Database Syst Rev 2019 ; 2019 : CD013451 . 10.1002/14651858.CD013451.pub2 PMC11232105 38979716

[102] Smith MR Egerdie B Hernández Toriz N . Denosumab in men receiving androgen-deprivation therapy for prostate cancer . New Engl J Med . 2009 ; 361 : 745–55 . 19671656 10.1056/NEJMoa0809003 PMC3038121

[103] Smith MR Saad F Coleman R . Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial . Lancet (London, England) . 2012 ; 379 : 39–46 . 22093187 10.1016/S0140-6736(11)61226-9 PMC3671878

[104] Lu J Hu D Zhang Y . 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 . 36860316 10.3389/fonc.2023.1133828 PMC9969102

[105] Henry DH Costa L Goldwasser F . Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma . J Clin Oncol Off J Am Soc Clin Oncol . 2011 ; 29 : 1125–32 . 10.1200/JCO.2010.31.3304 21343556

[106] Fizazi K Carducci M Smith M . Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study . Lancet (London, England) . 2011 ; 377 : 813–22 . 21353695 10.1016/S0140-6736(10)62344-6 PMC3090685

[107] Stopeck AT Lipton A Body JJ . Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study . J Clin Oncol Off J Am Soc Clin Oncol . 2010 ; 28 : 5132–39 . 10.1200/JCO.2010.29.7101 21060033

[108] Yang Y Alencar LMR Pijeira MSO . [(223)Ra] RaCl(2) nanomicelles showed potent effect against osteosarcoma: targeted alpha therapy in the nanotechnology era . Drug Delivery . 2022 ; 29 : 186–91 . 35191342 10.1080/10717544.2021.2005719 PMC8741223

[109] Parker C Nilsson S Heinrich D . Alpha emitter radium-223 and survival in metastatic prostate cancer . New Engl J Med . 2013 ; 369 : 213–23 . 23863050 10.1056/NEJMoa1213755

[110] Parker C Castro E Fizazi K . Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up . Ann Oncol . 2020 ; 31 : 1119–34 . 32593798 10.1016/j.annonc.2020.06.011

[111] Kim WK Buckley AJ Lee D-H . Androgen deprivation induces double-null prostate cancer via aberrant nuclear export and ribosomal biogenesis through HGF and Wnt activation . Nat Commun . 2024 ; 15 : 1231 . 38336745 10.1038/s41467-024-45489-4 PMC10858246

[112] Pal SK Swami U Agarwal N . Characterizing the Wnt pathway in advanced prostate cancer: when, why, and how . Europ Urol 2020 ; 77 : 22–23 . 10.1016/j.eururo.2019.06.029 31300236

[113] Kulac I Roudier MP Haffner MC . Molecular pathology of prostate cancer . Surg Pathol Clin 2021 ; 14 : 387–401 . 34373091 10.1016/j.path.2021.05.004

[114] Chu HY Chen Z Wang L . Dickkopf-1: a Promising Target for Cancer Immunotherapy . Front Immunol . 2021 ; 12 : 658097 . 34093545 10.3389/fimmu.2021.658097 PMC8174842

[115] Yuan S Hoggard NK Kantake N Hildreth BE,3 Rosol TJ . Effects of Dickkopf-1 (DKK-1) on Prostate Cancer Growth and Bone Metastasis . Cells 2023 ; 12 : 2695 . 38067123 10.3390/cells12232695 PMC10705757

[116] Koushyar S Meniel VS Phesse TJ Pearson HB . Exploring the Wnt Pathway as a Therapeutic Target for Prostate Cancer . Biomolecules 2022 ; 12 : 309 . 35204808 10.3390/biom12020309 PMC8869457

[117] Kikuchi A Matsumoto S Sada R . Dickkopf signaling, beyond Wnt-mediated biology . Semin Cell Dev Biol 2022 ; 125 : 55–65 . 34801396 10.1016/j.semcdb.2021.11.003

[118] Rachner TD Göbel A Benad-Mehner P Hofbauer LC Rauner M . Dickkopf-1 as a mediator and novel target in malignant bone disease . Cancer Lett 2014 ; 346 : 172–77 . 24462802 10.1016/j.canlet.2014.01.010

[119] Lehmann J Thiele S Baschant U . Mice lacking DKK1 in T cells exhibit high bone mass and are protected from estrogen-deficiency-induced bone loss . iScience . 2021 ; 24 : 102224 . 33748710 10.1016/j.isci.2021.102224 PMC7961106

[120] Hall CL Zhang H Baile S . p21CIP-1/WAF-1 induction is required to inhibit prostate cancer growth elicited by deficient expression of the Wnt inhibitor Dickkopf-1 . Cancer Res . 2010 ; 70 : 9916–26 . 21098705 10.1158/0008-5472.CAN-10-0440 PMC3059079

[121] Rinella L Fiorentino G Compagno M . Dickkopf-1 (DKK1) drives growth and metastases in castration-resistant prostate cancer . Cancer Genet Ther . 2024 ; 31 : 1266–79 . 10.1038/s41417-024-00783-7 38740881

[122] Wise DR Schneider JA Armenia J . Dickkopf-1 can lead to immune evasion in metastatic castration-resistant prostate cancer . JCO Precis Oncol 2020 ; 4 : 1167 – 79 . 10.1200/PO.20.00097 PMC7529521 33015525

[123] Wise DR Pachynski RK Denmeade SR . A Phase 1/2 multicenter trial of DKN-01 as monotherapy or in combination with docetaxel for the treatment of metastatic castration-resistant prostate cancer (mCRPC) . Prostate Cancer Prostatic Dis 2024;28:363–9. 10.1038/s41391-024-00798-z 38341461

[124] Jaschke N Hofbauer LC Göbel A Rachner TD . Evolving functions of Dickkopf-1 in cancer and immunity . Cancer Lett 2020 ; 482 : 1–7 . 32251706 10.1016/j.canlet.2020.03.031

[125] Doucet D Brubaker C Turner D Gregory CA . Factors affecting the role of canonical Wnt inhibitor Dickkopf-1 in cancer progression . Front Oncol 2023 ; 13 : 1114822 . 37007131 10.3389/fonc.2023.1114822 PMC10050559

[126] Haas MS Kagey MH Heath H . mDKN-01, a Novel Anti-DKK1 mAb, enhances innate immune responses in the tumor microenvironment . Mol Cancer Res . 2021 ; 19 : 717–25 . 33443105 10.1158/1541-7786.MCR-20-0799

[127] Lee S Ricci B Tran J . Stroma-derived Dickkopf-1 contributes to the suppression of NK cell cytotoxicity in breast cancer . Nat Commun . 2025 ; 16 : 1183 . 39885132 10.1038/s41467-025-56420-w PMC11782527

[128] Sui Q Liu D Jiang W . Dickkopf 1 impairs the tumor response to PD-1 blockade by inactivating CD8+ T cells in deficient mismatch repair colorectal cancer . J Immunother Cancer . 2021 ; 9 : e001498 . 33782107 10.1136/jitc-2020-001498 PMC8009229

[129] Baron R Gori F . Targeting WNT signaling in the treatment of osteoporosis . Curr Opin Pharmacol 2018 ; 40 : 134–41 . 29753194 10.1016/j.coph.2018.04.011

[130] Voskaridou E Christoulas D Xirakia C . Serum Dickkopf-1 is increased and correlates with reduced bone mineral density in patients with thalassemia-induced osteoporosis. Reduction post-zoledronic acid administration . Haematologica . 2009 ; 94 : 725–28 . 19407319 10.3324/haema-tol.2008.000893 PMC2675686

[131] Glantschnig H Scott K Hampton R . A rate-limiting role for Dickkopf-1 in bone formation and the remediation of bone loss in mouse and primate models of postmenopausal osteoporosis by an experimental therapeutic antibody . J Pharmacol Exp Ther . 2011 ; 338 : 568–78 . 21531794 10.1124/jpet.111.181404

[132] Fulciniti M Tassone P Hideshima T . Anti-DKK1 mAb (BHQ880) as a potential therapeutic agent for multiple myeloma . Blood . 2009 ; 114 : 371–79 . 19417213 10.1182/blood-2008-11-191577 PMC2714212

[133] Domanska UM Timmer-Bosscha H Nagengast WB . CXCR4 inhibition with AMD3100 sensitizes prostate cancer to docetaxel chemotherapy . Neoplasia (New York, NY) . 2012 ; 14 : 709–18 . 10.1593/neo.12324 PMC3431178 22952424

[134] De Clercq E . The AMD3100 story: the path to the discovery of a stem cell mobilizer (Mozobil) . Biochem Pharmacol 2009 ; 77 : 1655–64 . 19161986 10.1016/j.bcp.2008.12.014

[135] Im JY Min WK Park MH . AMD3100 improves ovariectomy-induced osteoporosis in mice by facilitating mobilization of hematopoietic stem/progenitor cells . BMB Reports . 2014 ; 47 : 439–44 . 24314140 10.5483/BMBRep.2014.47.8.159 PMC4206715

[136] Zhang Z Wu H Huang S . AMD3465 (hexahydrobromide) rescues the MG63 osteoblasts against the apoptosis induced by high glucose . Biomed Pharmacothe . 2021 ; 138 : 111476 . 10.1016/j.biopha.2021.111476 33773470

[137] Malladi S Macalinao DG Jin X . Metastatic latency and immune evasion through autocrine inhibition of WNT . Cell . 2016 ; 165 : 45–60 . 27015306 10.1016/j.cell.2016.02.025 PMC4808520

[138] Liu Q Li Z Gao JL . CXCR4 antagonist AMD3100 redistributes leukocytes from primary immune organs to secondary immune organs, lung, and blood in mice . Eur J Immunol . 2015 ; 45 : 1855–67 . 25801950 10.1002/eji.201445245 PMC4461468

[139] Alghamri MS Banerjee K Mujeeb AA . Systemic Delivery of an Adjuvant CXCR4-CXCL12 Signaling inhibitor encapsulated in synthetic protein nanoparticles for glioma immunotherapy . ACS Nano . 2022 ; 16 : 8729–50 . 35616289 10.1021/acsnano.1c07492 PMC9649873

[140] Suen PK Qin L . Sclerostin, an emerging therapeutic target for treating osteoporosis and osteoporotic fracture: a general review . J Orthop Transl 2016 ; 4 : 1–13 . 10.1016/j.jot.2015.08.004 PMC5987014 30035061

[141] Holmes D . Dual sclerostin–DKK1 antibody outperforms monotherapy . Nat Rev Endocrinol 2016 ; 12 : 435–435 . 10.1038/nrendo.2016.99 27312866

[142] Florio M Gunasekaran K Stolina M . A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair . Nat Commun . 2016 ; 7 : 11505 . 27230681 10.1038/ncomms11505 PMC4894982

[143] Meng S Liu Q Dai R . Development of a novel macroscopic regulation and microscopic intervention mode nanosystem for osteoporosis treatment . Mater Today Bio . 2025 ; 32 : 101829 . 10.1016/j.mtbio.2025.101829 PMC12139015 40475860

[144] Ko YJ Sohn HM Jang Y . A novel modified RANKL variant can prevent osteoporosis by acting as a vaccine and an inhibitor . Clin Transl Med . 2021 ; 11 : e368 . 33784004 10.1002/ctm2.368 PMC7967917