Novel therapeutic approaches targeting biomechanical pathway alterations in bone diseases

1 Introduction

The bone structure is not a static framework but a highly dynamic, load-bearing tissue that is continuously renewed throughout life (Kaur et al., 2020). This renewal occurs through bone remodelling, a tightly regulated process in which aged or micro-damaged bone is resorbed by osteoclasts (osteolysis) and subsequently replaced by newly formed bone through osteoblast-driven formation (osteogenesis). This ongoing cycle enables the skeleton to adapt to changing mechanical demands imposed by daily activities, growth, aging, and physical loading (Lynch and Fischbach, 2014). A key regulatory concept governing this adaptive process is the mechanostat, a biological feedback system that senses mechanical strain within bone and modulates bone mass and architecture accordingly. Within a normal physiological strain range, bone remodelling remains balanced, thereby maintaining structural integrity without excessive bone accumulation. When mechanical loading is reduced—such as during prolonged bed rest, immobilization, or in bones that have already attained high mass or mechanically efficient architecture—bone resorption is favored, leading to gradual bone loss. In contrast, increased mechanical stimulation, as observed with regular physical activity or athletic training, promotes bone formation and skeletal strengthening. Importantly, both physiological and pathological bone remodelling occur predominantly at bone surfaces rather than within the bulk tissue. Consequently, remodelling rates are substantially higher in cancellous (trabecular) bone, which possesses a large surface-to-volume ratio and is located in regions such as the vertebrae and the ends of long bones, compared with cortical bone, which is denser and remodels more slowly. This differential remodelling behavior explains why trabecular-rich skeletal sites are particularly sensitive to alterations in mechanical loading and are often the first to exhibit structural changes associated with bone disorders (Pagnotti et al., 2012). At the molecular and cellular levels, mechanical stimuli further regulate the organization of bone matrix components, including collagen and hydroxyapatite, as well as the behavior of osteocytes, osteoblasts, and osteoclasts embedded within the matrix. Through this integrated mechanobiological response, mechanical loading governs reciprocal interactions between bone cells and the extracellular matrix, ultimately determining bone strength, quality, and long-term skeletal adaptation (Ma et al., 2022). In addition to matrix deformation, fluid shear stress (FSS) affects both the bone matrix and resident cells by acting on the surfaces of the lacunar–canalicular network, where it is sensed by osteocytes through deformation of canalicular walls and direct stimulation of cell membranes. Shear forces are also transmitted to the endosteal surface, influencing surface-lining cell activity. Moreover, collagen within newly formed osteoid, as well as collagen fibers lining the bone surface, may be directly exposed to interstitial fluid flow, enabling mechanical cues to be conveyed to both cells and the extracellular matrix (Shuai et al., 2018; Niu et al., 2023). Physiological bone strain varies with skeletal location and loading history, with routine activities generating low-magnitude cyclic strains, while intense movements such as running or jumping impose infrequent but substantially higher strain levels that are believed to exert a dominant influence on adaptive remodeling (Cullen et al., 2001). Although bone tissue undergoes plastic deformation only at relatively low strain limits, in vitro studies indicate that cells require much larger deformations to initiate intracellular signaling (Fritton and Weinbaum, 2009; Cai et al., 2025). This apparent discrepancy suggests that macroscopic tissue strains are locally amplified at the reduced anabolic signalling and compromised regulation of remodeling cellular scale, likely through microstructural features of bone and fluid-mediated forces acting at cell–matrix adhesion sites (Lu et al., 2012). In parallel, load-induced pressure gradients drive interstitial fluid flow within bone and marrow spaces, producing shear stresses that modulate the behavior of osteocytes, osteoblasts, and mesenchymal progenitor cells. The bone marrow, as a fluid-filled porous compartment, is particularly sensitive to such pressure-driven flows, which can influence cellular function under both physiological and pathological conditions. While direct characterization of marrow physicochemical properties remains limited, evidence from pressure-modulation studies indicates that changes in intramedullary pressure and associated fluid movement play a meaningful role in regulating cellular activity within the skeletal microenvironment (Haessler et al., 2012; Robling et al., 2006).

2 Mechanotransduction pathways in bone

Bone health and structural integrity are maintained through tightly regulated mechanotransduction pathways that allow skeletal cells to sense, interpret, and respond to mechanical forces. These pathways do not operate in isolation but interact with metabolic, inflammatory, and survival signaling networks to coordinate bone formation and resorption. When mechanical sensing or signal integration is disrupted, this balance is lost, contributing to the development and progression of skeletal disorders such as osteoporosis, osteoarthritis, and bone malignancies. Understanding the overarching framework of bone mechanotransduction therefore, provides a conceptual foundation for the detailed cellular and molecular mechanisms discussed in subsequent sections and highlights its relevance as a therapeutic target for restoring physiological bone adaptation (Spyropoulou et al., 2015). Table 1 comprises of various bone cells that exhibit stimulus-specific mechanobiological responses which are essential for skeletal adaptation and remodeling. Cyclic stretch primarily acts on MSCs and favors osteogenic commitment, whereas fluid shear stress is mainly detected by osteoblasts and osteocytes, stimulating their proliferation and differentiation. Also, Table 2 outlines the effects of different loading conditions on bone homeostasis by linking specific mechanical environments with characteristic cellular responses and remodeling outcomes. Figure 1 shows the integrated framework of load dependent bone Mechanotransduction and homeostasis which signify the mechanical forces acting on bone are sensed by osteocytes and osteoblasts through specialized cellular structures, including integrins, ion channels, the cytoskeleton, and the primary cilium. These cues converge on intracellular signaling hubs that integrate biophysical inputs into biochemical responses. Biophysical–biochemical coupling across molecular, cellular, and tissue scales ensures context-specific signal interpretation, ultimately regulating load-dependent bone remodeling and skeletal homeostasis. Table 3 summarizes representative experimental studies investigating mechanotherapeutic strategies for targeting bone mechanosignaling pathways across diverse biological models.

TABLE 1. Mechanical stimuli and cell- specific responses in bone.

TABLE 2. Effects of mechanical loading on bone homeostasis.

TABLE 3. Summary of experimental studies for targeting approaches mechanosignaling pathways, highlighting study models, mechanotherapeutic strategies, and key osteogenic outcomes.

2.1 Cellular sensors and signal transduction of mechanical stimuli in bone

Bone cells possess specialized sensing mechanisms that enable them to detect mechanical loading and initiate intracellular signaling required for skeletal adaptation. Mechanical forces generated by tissue deformation and interstitial fluid flow are primarily perceived by osteocytes and osteoblasts at the cell surface. Structures such as the glycocalyx, membrane microdomains (including lipid rafts and caveolae), and cell–matrix adhesion sites serve as initial mechanosensors that transmit external forces to the cytoskeleton (Duncan and Turner, 1995). Force transmission through the cytoskeleton enables the conversion of mechanical cues into intracellular signals by activating adhesion-associated complexes. Mechanical loading enhances signaling at focal adhesions and promotes the activation of early mechanosensitive mediators, including focal adhesion kinase and downstream kinases, which relay information to the nucleus and influence gene regulation (Liedert et al., 2005; Liu et al., 2023). In parallel, mechanically stimulated bone cells release rapid signaling molecules such as nitric oxide and prostaglandins, facilitating communication across the osteocyte network and coordinating multicellular responses. Together, these sensing and early transduction events establish the foundation for downstream signaling cascades that regulate bone remodeling. By integrating surface mechanosensing, cytoskeletal force transmission, and paracrine signaling, bone cells effectively translate physical loading into coordinated biological responses that maintain skeletal structure and function (Hu et al., 2025).

2.2 Force-induced signaling pathways in bone cells

Force-induced signaling in bone cells is mediated by distinct yet overlapping pathways depending on the type of mechanical stimulus. Mechanical cyclic stretch promotes early osteogenic commitment of mesenchymal stromal cells through activation of NGF–TrkA, NOTCH, and PERK–eIF2α–ATF4 pathways, leading to upregulation of key osteogenic markers such as RUNX2, osteocalcin, and type I collagen. Fluid shear stress primarily stimulates osteoblast proliferation and differentiation via Ca²⁺ influx through TRPV4 channels and downstream ERK5 and AMPK signaling, while also modulating calcium oscillations in a stage-dependent manner. In contrast, compressive forces preferentially regulate osteoclastogenesis and bone resorption by enhancing RANKL signaling, TNF-α expression, and osteoclast-specific gene activation, with effects strongly dependent on force magnitude. Additional mechanical stimuli, including vibration and ultrasound, further influence bone cell fate and remodeling by modulating prostaglandin-mediated signaling and mineral density, highlighting the diverse mechanobiological responses governing skeletal adaptation (Wang et al., 2018; Chen et al., 2015). Previous studies showed that deletion of the mechanosensitive ion channel Piezo1 in Dmp1-Cre–targeted cells, encompassing both osteoblasts and osteocytes, leads to reduced bone mass and impaired skeletal responses to mechanical stimuli. To specifically define the role of Piezo1 in osteocytes, Piezo1 was selectively deleted in mature osteocytes using Sost-Cre mice. These mice displayed reduced bone mineral density, decreased cancellous bone mass, and diminished cortical thickness accompanied by reduced periosteal expansion. Notably, despite these structural deficits, their skeletal response to mechanical loading remained intact. Collectively, these findings indicate that Piezo1 in mature osteocytes is important for maintaining bone mass under physiological conditions but is not essential for load-induced bone adaptation (Li S. et al., 2025).

2.3 Integration of mechanical cues into bone remodelling pathways

Mechanical stimuli do not directly control the behavior of bone cells, but are converted into biochemical signals, which converge on a specific number of intracellular regulatory pathways that regulate bone remodeling (Sen et al., 2008). It is a step in the integration of initial mechanosensing signals and downstream responses, such as gene expression responses, cell fate decisions, and the functional activity of osteoblasts, osteocytes, and osteoclasts. Mechanical-induced signals are incorporated at the molecular level via kinase-dependent cascades, G-protein-dependent pathways, and intracellular stores of second messengers such as calcium ions and cyclic nucleotides (Rubin et al., 2006). These signaling centers serve as convergence points with the transcriptional and metabolic regulators via which mechanical signals can be received to ensure that the anabolic and catabolic processes are synchronized to match the current mechanical forces (Mehreen et al., 2025; Nikitovic et al., 2016). Mechanical signaling at the cell surface is transduced through this coordinate signaling system into tissue-level remodeling responses. This type of integration helps to maintain the structural integrity and respond dynamically to the ongoing changes in the loading conditions by ensuring that local mechanical cues cause a balance between bone formation and resorption (Keightley et al., 2014; Kaveh et al., 2020; Wang et al., 2022).

2.4 Biophysical and biochemical coupling in bone mechanotransduction

Although the result of remodeling is defined by signaling integration, physical force-biochemical coupling is an essential requirement to generate effective bone mechanotransduction. Mechanical stimuli, including the mechanical strength of the matrix, tensile stress, and osmotic stress, change the biophysical characteristics of bone cells by modulating cytoskeletal tension, cellular geometry, and force distribution (Chen et al., 2018). These bodily alterations form the setting where biochemical signaling is triggered and controlled. The effect of force on cytoskeletal organization modulates the accessibility of molecules, spatial proximity, and interaction of signaling proteins, thus modulating signal strength, duration, and specificity (Yu et al., 2017). This biophysical-biochemical interdependence is important to make sure that mechanical stimuli are coded into context-dependent, graded biochemical responses as opposed to pathway promiscuity. These kinds of coupling can be used to coordinate cellular responses throughout interconnected networks of bone cells at the tissue level, and can be used to coordinate remodelling both locally and globally. The impairment of this coupling affects the mechanosensitivity and adaptive remodeling, which are the causes of skeletal fragility and degenerative bone diseases. It is important to understand this mechanistic framework, thus to help us decode the normal skeletal mechanism and devise mechanoresponsive therapeutic systems of bone repair and regeneration (Putra et al., 2023).

2.5 Load-dependent signaling pathways in bone homeostasis

Bone homeostasis is strongly governed by mechanical loading, with osteocytes acting as the primary coordinators of load-dependent remodeling. Adequate mechanical stimulation favors bone formation, whereas reduced or absent loading shifts remodeling toward resorption (Kaur et al., 2023). Osteocytes integrate strain and fluid shear signals and relay this information to osteoblasts and osteoclasts, thereby adjusting bone mass and architecture to match functional demands. Load-dependent signaling regulates bone turnover by modulating key regulatory balances rather than activating isolated pathways (Kim et al., 2020). Mechanical loading suppresses the expression of sclerostin, relieving inhibition of osteogenic programs and promoting bone formation. In parallel, loading influences osteoclast activity by adjusting the relative levels of pro-resorptive and anti-resorptive cues, ensuring that bone resorption is app5ropriately restrained under physiological conditions. Through these coordinated responses, mechanical loading aligns cellular activity with structural requirements, preserving skeletal strength and integrity. Disruption of load-dependent signaling—such as during immobilization, aging, or disease—compromises this balance and contributes to progressive bone loss. Understanding how bone cells integrate mechanical demand into homeostatic signaling provides a critical foundation for developing strategies that restore physiological loading responses and prevent skeletal degeneration (Wu et al., 2024).

3 Dysregulation of biomechanical signaling in bone diseases

Although healthy bone continuously adapts to mechanical loading through well-coordinated mechanotransduction, this responsiveness deteriorates in various pathological conditions. Mechanosensitive cells such as osteocytes and osteoblasts rely on structural and molecular cues to translate physical stimuli into anabolic signals that sustain bone formation and suppress excessive resorption, as shown in Figure 2. In common skeletal disorders, these processes become compromised, leading to disrupted load responsiveness and imbalanced remodeling. In osteoporosis, impaired mechanotransduction contributes to diminished bone formation and accelerated resorption. Mechanosensing elements including integrins, ion channels, connexins, and primary cilia show altered expression or function, weakening the ability of osteocytes to sense and transmit mechanical cues to effector cells. This results in reduced anabolic signaling and compromised regulation of remodeling, ultimately driving skeletal fragility and reduced mechanical integrity (Chen et al., 2025). Age-related changes further exacerbate this dysregulation. With aging, osteocytes exhibit morphological and functional decline, leading to a reduced capacity to respond to mechanical stimuli. Alterations in osteocyte lacunar structure and decreased mechanosensitive ion channel activity have been linked to lower bone adaptive responses and increased susceptibility to osteoporosis (Feng et al., 2024). Beyond osteoporosis, imbalances in mechanical signaling are implicated in osteoarthritis and other degenerative conditions where subchondral bone experiences abnormal loading patterns, reinforcing maladaptive cellular behavior and disease progression (Zhang et al., 2025a). Collectively, these alterations in biomechanical signaling diminish the skeleton’s ability to adapt to mechanical demand and underscore the need for therapeutic strategies that restore or compensate for impaired mechanosensitivity.

4 Novel therapeutic approaches targeting biomechanical pathway alterations in bone diseases

4.1 Mechanotherapy and load-mimetic interventions

Mechanotherapy refers to therapeutic strategies that deliberately apply controlled mechanical forces to activate biological repair and regeneration pathways. Unlike conventional physical therapy, mechanotherapy is grounded in mechanobiology, recognizing that tissues actively sense and respond to mechanical stimuli through cellular signaling rather than behaving as passive structures. By delivering carefully timed and tissue-specific mechanical cues, mechanotherapy aims to restore physiological signaling disrupted in disease or injury (Thompson et al., 2016). At the cellular level, mechanical forces regulate proliferation, differentiation, and matrix synthesis through mechanotransduction, the process by which physical stimuli are converted into biochemical responses (McCarthy and Camci-Unal, 2021). Central to this process is the extracellular matrix–integrin–cytoskeleton axis, which transmits externally applied forces to the nucleus and alters gene expression via cytoskeletal reorganization and force-sensitive signaling pathways. The nature of the biological response depends on force magnitude, frequency, duration, and the mechanical properties of the surrounding matrix. In bone and musculoskeletal tissues, mechanotherapy exploits the inherent load responsiveness of osteocytes, osteoblasts, and mesenchymal stem cells (Zong et al., 2025). Modalities such as low-intensity vibration, low-intensity pulsed ultrasound, dynamic compression, and controlled loading have been shown to stimulate osteogenic differentiation, enhance matrix deposition, and accelerate fracture healing. These approaches partially replicate the anabolic effects of physical exercise, making them particularly valuable in conditions where normal loading is limited, such as immobilization, aging, or post-surgical recovery. Clinically, mechanotherapy is increasingly integrated into rehabilitation and regenerative medicine. Early mobilization, targeted loading, and load-mimetic stimulation improve tissue integration, reduce disuse-induced bone loss, and enhance functional recovery. Importantly, mechanotherapy does not merely compensate for reduced mechanical activity but actively re-engages mechanosensitive pathways to promote adaptive remodeling. As such, it represents a promising non-pharmacological strategy to restore bone homeostasis by harnessing the body’s intrinsic responsiveness to mechanical cues (Thomas, 2024). In one of the study, researchers reported that daily low-magnitude vibration therapy exerts osteogenic effects and may serve as a non-pharmacological intervention for degenerative bone disease. In a randomized, double-blind, placebo-controlled trial involving postmenopausal women with low to moderate bone mineral density, 1 year of brief daily vibration exposure significantly improved distal tibial mechanical stiffness compared with placebo. The intervention was also associated with a reduction in vertebral marrow adiposity and favorable changes in trabecular microarchitecture and volumetric bone density. These findings support the concept that cyclic mechanical stimulation can preserve bone strength and limit the shift of mesenchymal stem cell differentiation toward adipogenesis, highlighting mechanotherapy as a viable strategy for maintaining skeletal integrity in postmenopausal bone loss (Rajapakse et al., 2020). In another study, researchers reported that in postmenopausal women with osteopenia, a 12-month intervention using either vibration training or resistance training did not significantly increase bone mineral density compared with a non-training control group. However, BMD was maintained across all groups over the study period. Notably, resistance training led to significant improvements in muscle strength, postural control, and health-related quality of life, whereas vibration training showed limited functional benefits. These findings suggest that while load-based interventions may not substantially increase BMD in osteopenic women, regular mechanical loading—particularly through resistance exercise—contributes significantly to musculoskeletal function and fracture risk reduction (Kienberger et al., 2022). Such opposing results are probably indicative of inherent weaknesses in BMD as an endpoint measurement of mechanotherapy effectiveness. The effect of mechanical interventions might selectively enhance bone quality, microarchitecture and neuromuscular functionality instead of causing significant shifts in mineral density, which could be detected by DXA. Also, the results of vibration are highly sensitive to loading conditions (frequency, magnitude, duration), skeletal location, baseline bone condition, and patient compliance which makes inter-trial comparisons more difficult. In this respect, the inability to see an elevation in BMD does not automatically denote a biological inefficacy but, instead, provides a reminder of the necessity to use more suitable functional and structural outcome measures.

It is reported that low-intensity pulsed ultrasound (LIPUS) enhanced fracture healing in racehorses with proximal sesamoid bone fractures. Following 4 weeks of daily LIPUS treatment, affected horses showed improved lameness scores, radiographic signs of callus formation, and favorable hematological changes, including increased serum alkaline phosphatase activity and elevated calcium and phosphorus levels. Pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), which were elevated during early fracture stages, gradually normalized with treatment, indicating resolution of inflammation. These findings suggest that LIPUS promotes bone repair by improving local microcirculation, reducing inflammation, and accelerating callus maturation, supporting its clinical utility as a non-invasive mechanotherapy for fracture management (Zhang et al., 2025b).

4.2 Pharmacological targeting of mechanosensitive pathways

Better understanding of bone remodeling has clarified why some current drugs cause predictable side effects and has also revealed new intervention points across osteoclast formation, osteoblast activity, and osteocyte-driven coupling. Therapeutic strategies now focus on (i) reducing excessive resorption, (ii) boosting formation, and (iii) correcting cell-to-cell “coupling” signals that coordinate both processes (Xu et al., 2023).

4.2.1 Established drug targets

• RANKL (Denosumab): Blocking RANKL strongly suppresses osteoclast formation, improves BMD, and can reduce cortical porosity. A key limitation is rebound bone turnover after stopping therapy, because osteoclast lineage precursors can rapidly reactivate once RANKL signaling returns; follow-on antiresorptive therapy is often used to reduce fracture risk after withdrawal (Price, 2010). Denosumab suppresses bone resorption by neutralizing RANKL but is associated with rapid rebound osteoclast activation after treatment withdrawal. Using in situ hybridization across species and skeletal sites, recent studies demonstrate that this rebound is driven by localized changes in the RANKL/OPG axis. In mice, OPG:Fc treatment selectively increased RANKL expression in trabecular bone surface cells while reducing OPG expression in both osteocytes and surface-lining cells; similar but stronger effects were observed following acute PTH exposure. These findings indicate that osteocytes and osteoprogenitors jointly create focal osteoclastogenic niches during anti-RANKL therapy, which remain primed for rapid osteoclast recruitment upon treatment cessation. Single-cell RNA sequencing further identifies RANKL-expressing cells as osteoprogenitors characterized by high Mmp13 expression, confirming their role as the principal cellular source of osteoclastogenic signals under both physiological and therapeutic conditions (El-Masri et al., 2024). The study evaluated the effectiveness of denosumab in patients with osteoporotic vertebral compression fractures (OVCFs) and compared outcomes between individuals with and without a prior history of osteoporotic fractures. Seventy patients undergoing percutaneous vertebroplasty received standard calcium–vitamin D supplementation plus denosumab (60 mg every 6 months) for 1 year. Post-treatment analysis showed significant increases in lumbar spine and hip bone mineral density (BMD) across all patients, accompanied by improvements in pain (VAS), functional disability (ODI), vertebral height restoration, and sagittal alignment. Notably, patients experiencing their first osteoporotic fracture demonstrated greater BMD gains than those with previous fractures, indicating that denosumab may be particularly effective when initiated early in the osteoporotic disease course (Jiang et al., 2025). Bisphosphonates (BPs) suppress resorption mainly by disrupting osteoclast function and survival. Nitrogen-containing BPs inhibit the mevalonate pathway, preventing prenylation of small GTPases needed for cytoskeletal organization and ruffled border formation; other BPs generate cytotoxic ATP-like metabolites. Their skeletal retention helps maintain antiresorptive effects but also contributes to long exposure (Ebetino et al., 2011). A large meta-analysis of 47 placebo-controlled randomized trials involving over 59,000 patients showed that bisphosphonates do not reduce all-cause mortality in osteoporosis, despite their proven ability to lower fracture risk. This finding was consistent across different bisphosphonate drugs, regions, populations, and study durations, supporting their use primarily for fracture prevention rather than survival benefit (Lan et al., 2022). In a large real-world cohort of treatment-naïve postmenopausal women, denosumab was associated with significantly lower fracture risk than alendronate across all major skeletal sites. Fracture risk reduction increased with longer treatment duration, indicating sustained and superior protection with denosumab (Curtis et al., 2024).
• Sclerostin (Romosozumab and other anti-SOST agents): Sclerostin inhibits Wnt/β-catenin signaling; neutralizing it produces a strong anabolic response and lowers fracture risk. However, concerns about cardiovascular adverse events limit use in some patients. Newer concepts aim for more selective interference with sclerostin functional regions to preserve skeletal benefit while reducing systemic risk. Vinculin, a focal adhesion protein, is reduced in osteocytes during age-related osteoporosis and is essential for osteocyte adhesion and mechanosensitivity. Osteocyte-specific vinculin loss causes bone loss in load-bearing bones by impairing osteoblast formation and blunting the anabolic response to mechanical loading. Mechanistically, vinculin restrains Mef2c nuclear activity, thereby suppressing sclerostin expression; its loss enhances Mef2c-driven Sost transcription and reduces bone formation. Deletion of Sost rescues the bone phenotype, identifying vinculin as a key mechanoregulator of osteocyte-mediated bone formation (Wang et al., 2025). Neutralizing sclerostin antibodies (Scl-Ab) are clinically used to reduce fracture risk in postmenopausal osteoporosis, yet their optimal timing and dosing remain unclear. This study evaluated early intermittent low-dose Scl-Ab administration in ovariectomized rats. Monthly low-dose treatment enhanced bone formation, suppressed osteoclastogenesis, and reduced catabolic gene expression. It improved osteocyte survival, evidenced by fewer empty lacunae and reduced perilacunar remodeling, while attenuating secondary mineralization and osteocyte mechanosensitivity. These findings indicate that early low-exposure Scl-Ab therapy favors surface bone formation while limiting osteocyte-driven secondary mineralization following early bone loss (Naqvi et al., 2024).
• PTH1R (Teriparatide, Abaloparatide): PTH1R activation can be anabolic only with intermittent exposure; sustained signaling increases resorption. Differences in receptor signaling duration (especially cAMP kinetics) help explain why dosing pattern matters. Next-step efforts include pathway-biased modulation to keep formation benefits while lowering hypercalcemia and resorptive spillover (Beaudart et al., 2025). Abaloparatide and teriparatide are PTH1R-targeting osteoanabolic therapies used in patients at high fracture risk. In a large retrospective claims analysis of women aged ≥50 years, abaloparatide initiation was associated with significantly lower rates of hip and nonvertebral fractures compared with teriparatide over 18 months of follow-up. These benefits were consistent across age, prior fracture, and prior antiresorptive subgroups. Cardiovascular event rates were comparable between treatments, indicating similar safety profiles (Tabatabai et al., 2025).

4.2.2 Emerging and next-generation targets

• LGR4 as an alternative RANKL receptor: LGR4 competes with RANK for RANKL and can dampen osteoclastogenic transcriptional programs (e.g., NFATc1). Soluble or engineered LGR4-based approaches may neutralize pathological excess RANKL while potentially reducing rebound risk (Takegahara et al., 2024). RANK–RANKL interaction is a central driver of osteoclast differentiation and a key therapeutic target in osteoporosis. LGR4 functions as an alternative RANKL receptor that negatively regulates canonical RANK signaling during osteoclastogenesis. Using bone marrow–derived macrophages and a mouse model of RANKL-induced bone loss, this study demonstrated that a mutant RANKL (MT-RANKL) preferentially binds LGR4 rather than RANK. MT-RANKL activated GSK-3β signaling independently of AKT, inhibited NFATc1 nuclear translocation, and reduced osteoclast formation. In vivo, MT-RANKL colocalized with LGR4 and suppressed bone resorption, highlighting LGR4-dependent signaling as a promising anti-resorptive therapeutic strategy (Jang et al., 2023). LGR4 acts as an alternative RANKL receptor that suppresses RANK-mediated osteoclastogenesis. A structure-guided mutant RANKL selectively activates LGR4 signaling, enhances GSK-3β phosphorylation, inhibits NFATc1 nuclear translocation, and reduces osteoclast formation and bone resorption in RANKL-induced models, highlighting LGR4-biased RANKL modulation as a potential anti-resorptive strategy for osteoporosis (Jang et al., 2021). Osteoclast precursors (OPs) have been identified as active components of the premetastatic niche that facilitate early-stage breast cancer bone metastasis. RSPO2 and RANKL derived from breast cancer cells signal through the receptor LGR4 to promote OP recruitment and niche formation by modulating DKK1 via Gαq/β-catenin signaling. DKK1 suppresses LRP5-dependent WNT signaling, enhancing Rnasek expression and OP accumulation. Clinically, elevated RSPO2–LGR4–DKK1 expression correlates with bone metastasis, while therapeutic blockade using soluble LGR4 extracellular domain reduces osteolytic lesions, highlighting LGR4 signaling as a potential target to inhibit breast cancer bone metastasis (Yue et al., 2022).
• Selective targeting of soluble RANKL: Because membrane-bound RANKL participates in immune-linked reverse signaling, selectively inhibiting soluble RANKL is being explored as a way to reduce bone resorption while minimizing immune disruption. Selective inhibition of soluble RANKL–RANK interaction represents a promising strategy to suppress pathological osteoclast activation while preserving immune function. Using molecular dynamics simulations, a druggable binding pocket unique to soluble RANKL was identified, enabling the development of the small-molecule inhibitor S3-15. This compound selectively disrupts soluble RANKL–RANK binding without affecting membrane-bound RANKL signaling. In vitro and in vivo studies demonstrated that S3-15 effectively reduces osteoclastogenesis and bone loss without inducing immunosuppression, highlighting structure-guided targeting of soluble RANKL as a novel anti-osteoporotic approach (Huang et al., 2022). A structure-modified RANKL variant selectively inhibits RANK signaling while activating LGR4–GSK3β pathways, suppressing NFATc1-driven osteoclastogenesis. The variant also induces anti-RANKL antibodies that block osteoclast formation, resulting in reduced bone loss in ovariectomized mice and supporting a dual-action immunotherapeutic strategy for osteoporosis (Ko et al., 2021).
• CSF1R (M-CSF axis): CSF1R supports osteoclast precursor survival and primes RANK expression. Inhibiting this axis can reduce osteoclastogenesis; dual-target designs are being investigated to avoid excessive suppression of formation (Irvine et al., 2009). Osteoclast activity depends on integrin-mediated attachment and sealing zone formation, making integrins attractive antiresorptive targets. The challenge is that integrins also contribute to MSC behavior and osteogenic signaling, so selectivity and timing are essential. Estrogen deficiency–induced bone loss is driven by excessive osteoclast activity and chronic inflammation. Bisabolangelone significantly inhibited osteoclast formation and bone resorption by suppressing inflammatory and oxidative signaling while enhancing antioxidant responses. It directly targets CSF1R, and restoring CSF1R reversed its anti-osteoclast effects. In ovariectomized mice, Bisabolangelone protected against bone loss by reducing osteoclast activity and inflammation, highlighting its potential as a CSF1R-mediated osteoprotective agent (Mo et al., 2025). Disulfiram reduced estrogen deficiency–induced bone loss in ovariectomized mice by suppressing early osteoclast formation without affecting osteoblast activity. It decreased CCR2- and CCR5-positive osteoclast precursors and downregulated Tnfrsf11a expression, indicating inhibition of osteoclastogenesis at an early stage. These findings support Disulfiram’s potential as a repurposed therapeutic agent for osteoporosis (Fukui et al., 2025).
• S1P receptors (S1PR1/2),: S1P gradients regulate osteoclast precursor trafficking between blood and marrow. Modulating S1PR signaling can alter recruitment and fusion of precursors at remodeling sites—an indirect but potentially powerful route to control resorption. Semaphorins and Ephrin–Eph pathways coordinate osteoclast–osteoblast communication. Certain semaphorin and ephrin interactions suppress formation or restrain resorption depending on receptor context, offering a route to restore balanced coupling rather than simply “switching off” resorption (Tsourdi et al., 2021). Bone cells exchange regulatory RNAs via EVs; disease states can amplify pathogenic miRNAs that worsen remodeling or osteochondral degeneration. Blocking EV release or neutralizing specific miRNAs shows promise in preclinical work, but clinical translation hinges on safe, cell-selective delivery. Targets that maintain osteocyte connectivity (Sp7-linked dendrite programs) and regulate osteoblast differentiation (Runx2-centered regulation) are biologically compelling, but require precision targeting to avoid off-target effects due to broad roles in development and tissue homeostasis. In a prospective study of 826 older men followed for 8 years, low vitamin D levels and elevated parathyroid hormone were associated with faster deterioration of bone microarchitecture and estimated bone strength at the distal radius and tibia. Vitamin D deficiency was linked to greater loss of cortical and trabecular bone and reduced mechanical strength, while higher PTH levels were associated with accelerated cortical thinning and trabecular expansion. These findings indicate that vitamin D deficiency and secondary hyperparathyroidism contribute to accelerated bone loss in older men (Bobillier et al., 2020).

4.3 Mechanoresponsive biomaterials and smart implants

Mechanoresponsive biomaterials and smart implants represent an advanced strategy for bone repair that moves beyond passive fixation toward active regulation of the osteogenic microenvironment. Bone is inherently a dynamic, load-bearing tissue, and mechanical cues strongly govern its regeneration (Fowler et al., 2021). Accordingly, modern smart implants are designed as three-dimensional (3D) constructs with precisely controlled stiffness, porosity, surface characteristics, and degradation profiles, enabling them to sense and respond to mechanical stimuli such as stress and strain (Li X. et al., 2025; Montoya et al., 2021). Through the activation of mechanotransduction pathways, these materials directly influence the behavior of stem and progenitor cells, enhance osteogenic differentiation, and promote extracellular matrix deposition, thereby supporting functional bone regeneration. In addition to mechanical adaptability, smart implants increasingly incorporate multifunctional properties to better mimic native bone tissue. These include modulation of osteoblast–osteoclast balance, promotion of vascularization, antibacterial functionality, and osteoimmunomodulatory effects that collectively support long-term implant integration and tissue healing (Golebiowska and Nukavarapu, 2022). Despite significant progress, the complex interactions between material physicochemical properties, intracellular signaling networks, stem-cell niches, and tissue regeneration are not yet fully understood, limiting the rational design of ideal implants. Ongoing research on multifunctional and synergistic mechanoresponsive platforms, including emerging concepts such as neurogenic bone repair, is expected to enable more adaptive, patient-specific implant strategies and improved clinical outcomes in bone defect reconstruction (Intravaia et al., 2023).

Focal adhesion kinase (FAK) is a key mechanosensitive regulator in distraction osteogenesis (DO), a widely used but slow process for repairing large bone defects. In this study, the FAK activator (ZINC40099027, 2025) was shown to enhance both blood vessel formation and bone regeneration. ZN27 promoted endothelial cell migration and angiogenesis, while also stimulating osteogenic differentiation of mesenchymal stem cells, as reflected by increased mineralization and osteogenic marker expression. These effects were mediated through activation of the FAK–ERK1/2 signaling pathway. In a rat DO model, ZN27 increased vascularization in the distraction area and accelerated new bone formation. Overall, the findings suggest that ZN27 supports bone repair by coupling angiogenesis and osteogenesis, highlighting its potential as a mechanobiology-driven therapy for large bone defects (Li et al., 2024). ZINC40099027 (2025), a focal adhesion kinase activator, enhanced bone regeneration during distraction osteogenesis by promoting angiogenesis and osteogenic differentiation through FAK–ERK1/2 signaling. In a rat tibial model, ZN27 increased vascularization in the distraction zone and accelerated new bone formation, highlighting its potential to improve mechanically driven bone repair (Yang et al., 2025).

4.4 Stem cell–based and mechanically guided regenerative therapies

Stem cell–based regenerative medicine aims to restore bone structure and function without scar formation by harnessing the self-renewal, differentiation, and paracrine properties of stem cells (Gómez-Barrena et al., 2011). Mesenchymal stem cells (MSCs) and human pluripotent stem cells (hPSCs) have emerged as key therapeutic candidates for bone regeneration. MSCs derived from bone marrow, adipose tissue, and umbilical cord have demonstrated strong osteogenic and angiogenic potential, particularly when combined with biomaterial scaffolds (Hoang et al., 2022). Mechanical cues and biomimetic environments play a critical role in directing stem cell fate and enhancing functional bone repair (Zhang et al., 2021). Although autologous bone grafting remains the clinical gold standard, its limitations have accelerated the development of stem cell–based alternatives. Scaffold-assisted and mechanically guided strategies improve cell survival, integration, and structural stability at defect sites. Recent studies emphasize the importance of MSC tissue origin in determining therapeutic outcomes, supporting personalized regenerative approache (Fisher et al., 2016). Stem cells also promote bone healing through the secretion of bioactive factors that regulate host cell behavior (Zhang et al., 2024). Despite promising preclinical and early clinical results, large-scale clinical translation remains limited. Advances in regulatory frameworks, standardized cell characterization, and biomarker-guided patient selection are expected to improve trial quality. Overall, stem cell–based and mechanically guided therapies represent a promising and evolving strategy for bone regeneration (Iaquinta et al., 2019; Deschaseaux et al., 2009). The integration of tissue engineering and cell therapy represents an effective approach for bone regeneration. Human mesenchymal stem cells (hMSCs) are attractive for this purpose due to their low immunogenicity, high proliferative ability, and osteogenic potential. In this study, hMSCs seeded on scaffolds showed good cell viability and maintained osteogenic differentiation. Their regenerative efficacy was evaluated in a calvarial bone defect model using micro-CT, histological analysis, and osteogenic marker expression. The hMSC–scaffold construct significantly enhanced new bone formation compared with scaffold-only and untreated groups. These findings suggest that hMSC-loaded scaffolds can effectively stimulate bone regeneration in critical-sized defects (Im et al., 2013). This study evaluated an elastin/polycaprolactone/nano-hydroxyapatite (PCL/nHA) nanofibrous scaffold combined with mesenchymal stem cells (MSCs) for bone regeneration. In vitro analyses confirmed good cytocompatibility, supporting cell attachment, migration, and proliferation. An ovariectomized rat model with critical-sized femoral defects was used to assess in vivo efficacy. Rats were divided into control, scaffold-only, and scaffold + BM-MSC groups. After 30 days, stereological analysis and gene expression studies showed significantly increased bone regeneration, along with higher Bmp-2 and Vegf expression in treated groups. These findings suggest that 3D PCL/nHA scaffolds combined with MSCs can effectively accelerate fracture healing in osteoporotic conditions (Hejazi et al., 2021). Recent advances suggest that scaffold-free mesenchymal stem cell (MSC) sheet technology may offer an effective alternative for bone tissue engineering. In this study, bone marrow–derived MSC (BMSC) sheets were evaluated in a weight-bearing rat femoral defect model. BMSC sheets were generated using temperature-responsive culture surfaces and implanted into critical bone defects stabilized with internal fixation. Radiographic, micro-CT, and histological analyses demonstrated significantly greater new bone formation, higher bone volume fraction, and improved histological scores compared with untreated controls. These findings indicate that scaffold-free BMSC sheets can effectively enhance bone regeneration in large, load-bearing defects and may serve as a complementary or standalone regenerative strategy, although further validation is required (Mito et al., 2024). Bioactive glass was incorporated into a gelatin/nano-hydroxyapatite scaffold to enhance bone regeneration through improved osteoinductive and angiogenic properties. In vitro and in vivo analyses showed that the G/nHAp/BG scaffold significantly increased osteogenic and angiogenic marker expression, especially when seeded with bone marrow–derived mesenchymal stem cells (BMSCs). In a rat critical-sized bone defect model, BMSC-seeded G/nHAp/BG scaffolds promoted superior bone formation and structural recovery compared with cell-free scaffolds. Notably, the regenerative outcomes were comparable to autografts. These results highlight the synergistic effect of bioactive scaffolds and MSCs in accelerating bone regeneration (Oryan et al., 2018).

4.5 Targeting osteocyte-centered mechanosignaling

Osteocytes are the primary mechanosensors of bone and serve as master regulators of bone remodeling by coordinating osteoblast and osteoclast activity. Embedded within the mineralized matrix, they integrate mechanical cues and biochemical signals to maintain skeletal homeostasis and regulate both local bone remodeling and systemic mineral metabolism. Mechanical loading is essential for preserving bone mass, whereas unloading or reduced mechanical stimulation leads to bone loss and fragility (Choi et al., 2022). Osteocytes detect mechanical forces through multiple mechanosensors, including the cytoskeleton, dendritic networks, integrin-based focal adhesions, connexins, primary cilia, ion channels, and the extracellular matrix. Disruption of osteocyte function, as demonstrated in genetic ablation models, results in impaired bone quality, increased porosity, and altered mechanoadaptive responses. These findings highlight osteocyte-centered mechanosignaling pathways as critical regulators of skeletal integrity and promising therapeutic targets for the treatment of osteoporosis and other bone-related disorders (Qin et al., 2020; Tatsumi et al., 2007). One of the study showed that loss of the mechanosensor Piezo1 in late osteoblasts and osteocytes leads to reduced bone mass and impaired osteocyte maturation, characterized by disrupted dendrite number, length, and connectivity. These defects are associated with reduced YAP activity and altered Wnt/β-catenin signaling, and can be largely reversed by intermittent YAP activation. The study further identifies CCN1/2 as key downstream mediators linking Piezo1 to YAP signaling. Restoring CCN1/2 expression rescues osteocyte network formation and bone defects by activating Src and promoting cytoskeletal organization. Overall, the Piezo1–YAP–CCN1/2 axis emerges as a critical regulator of osteocyte mechanotransduction and a potential therapeutic target for bone disorders (Hu et al., 2025). In another study, researchers compared osteogenic induction by targeting key mechanoreceptors—Piezo1, Fzd1, Fzd2, and integrin α5—using different agonists. The binding efficiency of antibodies versus aptamers was evaluated, along with optimization of aptamer concentration for effective bone formation. Mechanoactivation of integrin α5 (CD49e) produced the strongest osteogenic response, significantly upregulating RUNX2 and LEF1 expression compared with other receptors. Notably, magnetic nanoparticles (MNPs) conjugated with aptamers induced greater LEF1 activation than antibody-conjugated MNPs, highlighting the superior efficacy of aptamers. Osteogenic signaling was also found to be highly dependent on aptamer concentration. Overall, the findings demonstrate that aptamer-mediated mechanoactivation using MNP platforms offers a promising and tunable strategy for enhancing bone regeneration (Hajiali et al., 2023).

Although rodent and large-animal models have strong mechanistic insights, they have significant drawbacks to their predictive value in humanity. The variability in bone turnover, bone loading between animals and humans, longevity, and pathology of diseases implies that mechanically induced changes may be more effective than therapeutic agents in the human body than in animals, especially in chronic diseases like postmenopausal osteoporosis. Despite the success of pharmacological intervention based on the target of mechanosensitive pathways, most of them indicate trade-offs between skeletal advantage and systemic danger, and the problem of rebound effects and safety. These problems reinforce the idea that the control of the mechanosignaling pathways in vitro alone might not recapitulate mechanosignaling-mediated load-dependent regulation observed in physiological bone remodeling.

5 Translational challenges and future directions

Despite substantial advances in understanding bone mechanobiology, translating mechanosignaling-based strategies into routine clinical practice remains challenging. One of the primary limitations lies in the complexity of bone as a multiscale, dynamic tissue where mechanical forces, cellular responses, and biochemical signaling are tightly interwoven. Current experimental models often simplify loading conditions or isolate single pathways, which may not fully capture the spatial and temporal complexity of mechanical stimuli experienced in vivo. This limits the predictive value of preclinical findings and underscores the need for more physiologically relevant models that integrate realistic loading environments with cellular and molecular readouts. Another major challenge is the heterogeneity of patient populations and disease states (Choi et al., 2022). Bone mechanosensitivity varies with age, sex, metabolic status, hormonal milieu, and disease severity, making it unlikely that a single mechanotherapeutic approach will be universally effective (Chen et al., 2025). Inter-individual differences in osteocyte function, stem cell responsiveness, and mechanosensor expression further complicate treatment outcomes. Future strategies must therefore move toward personalized mechanomedicine, where mechanical interventions, biomaterials, or pharmacological agents are tailored based on patient-specific biomechanical and biological profiles (Cai et al., 2025). Clinical translation is also constrained by difficulties in controlling and standardizing mechanical stimuli. While mechanotherapy modalities such as vibration, ultrasound, and controlled loading show promise, defining optimal dosing parameters—including magnitude, frequency, duration, and timing—remains an ongoing challenge. Inconsistent protocols across studies hinder reproducibility and slow regulatory approval. The development of smart, feedback-controlled systems capable of adapting mechanical input in real time may help overcome these limitations and improve therapeutic precision (Liedert et al., 2005). From a therapeutic development perspective, targeting mechanosensitive pathways requires careful balance. Excessive activation or prolonged inhibition of key signaling nodes may disrupt physiological remodeling and produce unintended effects in non-skeletal tissues. Achieving spatial and temporal specificity—particularly when modulating osteocyte-centered signaling—will be critical for ensuring safety and efficacy. Advances in targeted delivery systems, mechanoresponsive biomaterials, and pathway-biased ligands offer promising avenues to address these concerns. Looking ahead, the integration of bone mechanobiology with emerging technologies such as bioengineered models, digital twins, and artificial intelligence–driven optimization may accelerate discovery and translation. Collaborative efforts spanning basic science, engineering, and clinical research will be essential to bridge existing gaps. By aligning mechanistic insights with patient-centered design and regulatory considerations, mechanobiology-based therapies hold strong potential to reshape the prevention and treatment of bone disorders in the coming years (Di et al., 2023).

6 Conclusion

Bone is a living, mechanically responsive tissue that continuously adapts to its functional environment. Disruption of biomechanical signaling—at the level of mechanosensors, intracellular pathways, or load-dependent remodeling—plays a key role in the development of bone disorders such as osteoporosis, impaired fracture healing, and degenerative skeletal conditions. Growing insights into bone mechanotransduction have shifted therapeutic thinking beyond conventional antiresorptive or anabolic drugs toward strategies that actively restore physiological load responsiveness. Emerging approaches, including mechanotherapy, targeted modulation of mechanosensitive pathways, mechanoresponsive biomaterials, smart implants, and mechanically guided stem-cell therapies, aim to re-engage the skeleton’s intrinsic adaptive capacity. By influencing osteocyte-centered signaling and bone cell communication, these strategies offer more balanced and durable regulation of bone remodeling. Nevertheless, clinical translation remains challenging due to biological heterogeneity, difficulties in standardizing mechanical interventions, and the need for precise control of signaling pathways. Future progress will rely on personalized, load-informed therapeutic designs supported by advances in biomaterials, targeted drug delivery, and integrative mechanobiology. Overall, therapies targeting biomechanical pathway alterations represent a promising shift toward dynamic, regenerative, and patient-specific management of bone diseases.

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Footnotes

Edited by: Ya-Ping Xiao, Wuhan Third Hospital, China

Reviewed by: Kenda Jawich, International University for Science and Technology, Syria

Mikhail Artamonov, Penn Medicine, United States