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OBM Transplantation

(ISSN 2577-5820)

OBM Transplantation (ISSN 2577-5820) is an international peer-reviewed Open Access journal published quarterly online by LIDSEN Publishing Inc., which covers all evidence-based scientific studies related to transplantation, including: transplantation procedures and the maintenance of transplanted tissues or organs; assimilation of grafted tissue and the reconstitution of removed organs or parts of organs; transplantation of heart, lung, kidney, liver, pancreatic islets and bone marrow, etc. Areas related to clinical and experimental transplantation are also of interest.

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Open Access Review

Pharmacological Strategies to Enhance Bone Graft Integration: Emerging Agents and Molecular Pathways

Garzain Bint e Attar , Mohd. Ashif Khan *

  1. Department of Translational and Clinical Research, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi 110062, India

* Correspondence: Mohd. Ashif Khan

Academic Editor: Eric M. Bluman

Special Issue: Bone Grafting in Trauma and Elective Orthopaedics

Received: May 15, 2025 | Accepted: December 18, 2025 | Published: December 31, 2025

OBM Transplantation 2025, Volume 9, Issue 4, doi:10.21926/obm.transplant.2504262

Recommended citation: Bint e Attar G, Khan MA. Pharmacological Strategies to Enhance Bone Graft Integration: Emerging Agents and Molecular Pathways. OBM Transplantation 2025; 9(4): 262; doi:10.21926/obm.transplant.2504262.

© 2025 by the authors. This is an open access article distributed under the conditions of the Creative Commons by Attribution License, which permits unrestricted use, distribution, and reproduction in any medium or format, provided the original work is correctly cited.

Abstract

Bone grafting remains a cornerstone technique in orthopedic and reconstructive surgery, yet achieving successful graft integration continues to pose significant challenges, particularly in conditions such as osteoporosis, diabetes mellitus, and large bone defects. Traditional graft materials such as autografts, allografts, xenografts, and synthetics, often encounter limitations including immune rejection, poor vascularization, and insufficient osteogenic support. Emerging pharmacological strategies have shown promise in enhancing graft integration by modulating bone-healing pathways, promoting angiogenesis, and regulating inflammatory responses. This review comprehensively explores the biological mechanisms underlying bone repair, including the roles of key molecular pathways such as Wnt/β-catenin, BMP signaling, VEGF-mediated angiogenesis, and the RANK/RANKL/OPG axis. It further examines the therapeutic application of osteoinductive agents (e.g., BMPs, PTH analogs), anti-resorptive drugs (e.g., bisphosphonates, Denosumab), angiogenic modulators (e.g., VEGF, PDGF), and biologics targeting inflammatory cytokines (e.g., TNF-α, IL-6, IL-1β). Innovative approaches such as nanotechnology-based drug delivery, scaffold-based release systems, and gene therapy are also discussed for their potential to achieve localized, controlled, and sustained enhancement of graft performance. While several FDA-approved agents, such as rhBMP-2 and PDGF-BB, have advanced clinical practice, persistent challenges including variability in patient healing, delivery limitations, adverse effects, and regulatory hurdles, highlight the need for continued research. Future directions emphasize the development of multifunctional, personalized therapeutics that actively guide bone regeneration, supported by rigorous translational studies to ensure clinical efficacy and safety.

Graphical abstract

Click to view original image

Keywords

Bone graft integration; pharmacological strategies; osteoinductive agents; angiogenesis; inflammatory cytokines; nanotechnology-based drug delivery

1. Introduction

Bone Grafting is a surgical technique used to replace missing bone tissue through donor-to-recipient transfers of bone cells, employing autogenous, allogeneic, or synthetic materials to both support structure and facilitate bone healing [1]. Orthopedic and reconstructive surgery use this essential procedure to repair skeletal defects that arise from different causes, such as trauma, congenital anomalies, infection, or tumor resection [2]. The main purpose of bone grafting is to promote new bone growth, enabling patients to regain functional bone structure in affected areas. The selection of graft material is a fundamental factor for achieving positive clinical results [3].

Medical practice utilizes various bone grafts, which differ in their biological responses and mechanical properties [4]. Autografts are the preferred choice because they originate from patient tissue, which possesses remarkable osteogenic, osteoinductive, and osteoconductive properties. However, the quantity of available graft tissue, along with donor-site complications, limits the use of autografts [5]. The use of human donor allografts offers practical surgical advantages, although these materials pose risks of immunological reactions and disease transmission [6]. Xenografts that use non-human tissue and synthetic grafts made from ceramics and polymers provide scalable alternatives, though they fail to achieve the same biological activity as autografts [7]. This diversity in graft options highlights a persistent clinical dilemma: graft choice alone cannot consistently ensure reliable integration across all patient populations.

The range of available grafting materials does not resolve the clinical challenge of achieving proper graft integration. The main obstacle to graft success stems from rejection events driven by incompatible immune responses, particularly in allografts and xenografts [8,9]. Additionally, poor vascularization at the graft site impairs nutrient delivery and cellular infiltration, thereby compromising bone regeneration [10]. Tissue damage becomes worse when an immune response becomes too active because it blocks the process of new bone formation [11]. These limitations highlight the need for therapeutic strategies that do not merely replace the defect but actively modulate the biological environment to support integration.

The clinical treatment of bone defects becomes much more challenging when treating patients whose physiological state makes bone healing and repair very difficult [12]. Osteoporosis affects bone density and the balance of bone remodeling, reducing the support required for graft stability and integration [13]. Such bones with limited osteogenic potential tend to heal poorly, delaying bone repair. Diabetes mellitus causes additional complications because elevated blood glucose levels destroy bone-forming cells (osteoblasts) while blocking the development of new blood vessels needed for graft nourishment [14]. The healing process is delayed, and the risk of graft failure increases [15]. Large bone defects exceed the natural healing abilities of human tissues, resulting in an insufficient ability to close gaps. The healing process becomes challenging since these defects need complete cellular activity together with scaffold support and vascularization, yet these elements are often absent.

Given these limitations, there is increasing interest in using pharmacological agents to enhance bone graft success. The agents demonstrate benefit by maintaining cell viability while enhancing bone tissue integration and accelerating tissue repair at implant sites. Growth factors such as BMPs and VEGF drive osteogenic and vascular pathways, while anti-inflammatory biologics may prevent immune-mediated graft damage [16]. Angiogenic modulators improve vascular supply, and osteoinductive compounds accelerate matrix deposition. Importantly, these drugs are increasingly viewed not as standalone solutions but as synergistic adjuncts that can tailor the biological environment to meet the demands of challenging clinical scenarios such as osteoporosis, diabetes, and large bone defects [10].

Thus, this review examines emerging pharmacological agents and molecular pathways that have the potential to enhance bone graft integration, with particular emphasis on their mechanisms of action, clinical evidence, and translational relevance.

2. Mechanisms of Bone Healing and Graft Integration

Bone healing is a coordinated biological process that restores the structural and mechanical integrity of bone following injury or surgical intervention [12]. Successful graft integration similarly depends on the timely orchestration of cellular, molecular, and vascular events that parallel native bone repair [17]. The healing process progresses through overlapping inflammatory, repair, and remodeling phases [18], each governed by specific signaling pathways that regulate cell recruitment, differentiation, and matrix turnover. Understanding these mechanisms is essential because current pharmacological strategies target defined checkpoints within these pathways to optimize graft incorporation.

2.1 Phases of Bone Healing

2.1.1 Inflammatory Phase

The inflammatory phase initiates immediately after injury and establishes the microenvironment required for subsequent repair [19]. Hematoma formation at the fracture site recruits neutrophils, macrophages, and lymphocytes [20], which secrete cytokines such as IL-1, IL-6, TNF-α, and TGF-β, triggering downstream healing cascades [19,21]. These mediators not only clear necrotic tissue but also activate mesenchymal stem cells (MSCs) to commit toward osteogenic lineages [22]. Because early inflammatory signaling influences MSC recruitment and vascular ingrowth, disturbances in this phase can directly compromise graft acceptance.

2.1.2 Repair Phase

Soft callus formation occurs first during the repair phase before the development of a hard callus. The process of mesenchymal stem cell differentiation results in the formation of chondrocytes and osteoblasts, leading to the development of cartilaginous and bony matrices, respectively [23]. Osteoblast activation is the main feature of this phase because it drives bone formation [24]. Concurrently, angiogenesis is stimulated when vascular endothelial growth factor (VEGF) is released into the tissue space, as both processes enable the damaged area to be revascularized and deliver the oxygen and nutrients required for regeneration [25]. The cartilaginous matrix is replaced by mineralized bone through endochondral ossification as the tissue progresses through its structural recovery [26]. The effectiveness of this phase is particularly relevant for graft integration, as insufficient vascularization is a major contributor to graft failure.

2.1.3 Remodeling Phase

The remodeling phase converts immature woven bone into mechanically resilient lamellar bone [27]. This process depends on coordinated osteoclast-mediated resorption and osteoblast-mediated deposition, influenced by mechanical loading and molecular cues [28]. Remodeling can continue for months and is essential for restoring biomechanical strength and long-term graft stability [29]. Modulation of this phase through antiresorptive or osteoanabolic therapies is therefore a key consideration in enhancing graft outcomes.

2.2 Key Molecular Pathways in Bone Regeneration

Several signaling pathways regulate bone healing, and many emerging pharmacological agents modulate these pathways to improve graft incorporation (Figure 1).

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Figure 1 Overview of major molecular pathways involved in bone graft integration and the pharmacological agents targeting them. The flowchart illustrates BMP/SMAD signaling (targeted by rhBMP-2 and rhBMP-7), Wnt/β-catenin activation (enhancing osteoblast differentiation), the RANK/RANKL/OPG axis (targeted by Denosumab), and VEGF-mediated angiogenesis (modulated by PDGF-BB and pro-angiogenic agents).

2.2.1 Wnt/β-Catenin Signaling Pathway

The Wnt/β-catenin pathway plays a central role in osteoblast lineage commitment and bone matrix formation [30,31]. Activation of Wnt ligands stabilizes β-catenin, allowing its nuclear translocation and the subsequent induction of osteogenic genes such as RUNX2 and osterix [32]. Impairment of Wnt signaling disrupts osteoblast maturation and compromises fracture healing and graft integration [33]. Interactions between Wnt and BMP pathways further illustrate the pathway’s importance in coordinated bone regeneration.

2.2.2 Bone Morphogenetic Protein (BMP) Signaling Pathway

BMPs, particularly BMP-2, BMP-4 and BMP-7, form part of the TGF-β superfamily to regulate bone formation as fundamental molecular factors [34]. Cell-surface receptors (BMPRs) bind BMPs, activating signaling that leads to SMAD protein activation and osteogenic gene transcription in the nucleus. The osteoblastic differentiation of mesenchymal stem cells, together with matrix mineralization, results from BMP signaling [35]. Recombinant BMPs have been used clinically to enhance bone healing and graft incorporation [36,37]. However, limitations such as cost and dose-related adverse effects have prompted interest in more targeted osteoinductive therapies.

2.2.3 RANK/RANKL/OPG Axis

Bone resorption, together with osteoclastogenesis, is controlled through the RANK/RANKL/OPG system [38]. Osteoblasts and stromal cells create RANKL to activate RANK on osteoclast precursors, which drives their differentiation and activation process [39]. Osteoprotegerin (OPG) functions as a decoy receptor made by osteoblasts to block RANKL binding to RANK, which prevents osteoclast development and function [40]. Maintaining an appropriate balance between resorption and formation is essential for graft remodeling. This axis also underlies antiresorptive therapies used to stabilize grafted bone.

2.2.4 Vascular Endothelial Growth Factor-Mediated Angiogenesis

The process of angiogenesis serves as a vital support mechanism during bone repair, particularly when treating large defects or inadequate blood supply conditions of grafts [41]. Vascular Endothelial Growth Factor (VEGF) is the main regulatory factor that stimulates endothelial cells to multiply and migrate directionally to form new blood vessels [42]. The newly developed blood vessels provide vital delivery of oxygen, nutrients, and signaling molecules, which support the regeneration of bone tissue. Furthermore, the VEGF signaling pathway operates in concert with Bone Morphogenetic Proteins (BMPs) to promote improved blood vessel development and bone tissue formation [43]. Additionally, under low-oxygen conditions, which are common at the injury site, hypoxia-inducible factors (HIFs) are activated to enhance VEGF expression, thereby strengthening the connection between the bone healing processes of angiogenesis and osteogenesis [44,45].

3. Pharmacological Strategies for Enhancing Bone Graft Integration

Pharmacological agents that enhance bone graft integration modulate osteogenesis, resorption, angiogenesis, and inflammation (Table 1). These strategies target defined molecular pathways involved in graft incorporation, thereby complementing surgical techniques and improving clinical outcomes:

Table 1 Pharmacological Agents Enhancing Bone Graft Integration – Mechanisms and Therapeutic Roles.

3.1 Osteoinductive and Anabolic Agents

Osteoinductive and anabolic agents enhance graft integration by stimulating osteoblast differentiation and matrix deposition. Their efficacy stems from activating specific signaling pathways that replicate or amplify physiological bone regeneration.

3.1.1 Bone Morphogenetic Proteins (BMPs)

BMPs operate as transformative regulators of bone formation and healing within the members of the transforming growth factor-beta (TGF-β) superfamily. The osteoinductive properties of BMP-2 and BMP-7 enable these proteins to trigger the transformation of mesenchymal stem cells into osteoblasts in a highly effective manner [65,66]. This process involves activation of the Smad signaling cascade, and when Smad signaling is activated, it stimulates the expression of osteogenic genes while the cell produces bone matrix components [67]. The clinical use of recombinant human BMPs (rhBMPs) exists for spinal fusion surgeries as well as non-union fracture repair and multiple orthopedic procedures, all of which aim to improve graft incorporation [67]. Nevertheless, the use of mesenchymal stem cell therapy requires careful evaluation because it has been associated with reported complications, which include ectopic bone formation and local inflammatory responses [68,69].

3.1.2 Parathyroid Hormone and Analogs

The administration of parathyroid hormone (PTH), along with its analog teriparatide (PTH 1-34), gives periodic short-term benefits to bone structure through enhanced osteoblast action and expanded cellular survival [70,71]. Through PTH1 receptor activation, cAMP and PKA signaling pathways become activated to mediate these effects. The United States Food and Drug Administration approves PTH analogs for osteoporosis treatment, while ongoing research assesses their potential to accelerate fracture healing and improve bone graft attachment to host tissue [72]. Research indicates that these agents enhance bone quality while accelerating graft-host union, especially in patients with reduced healing capacity [73,74,75,76].

3.2 Anti-Resorptive Agents

Bone graft integration requires a balanced coupling of resorption and formation. Excessive early resorption can destabilize grafts, making anti-resorptive therapies a valuable adjunct in selected scenarios.

3.2.1 Bisphosphonates

The synthetic compounds known as bisphosphonates show a strong attraction to hydroxyapatite in bone, which results in their targeted accumulation at active bone remodeling sites [77] (Figure 2). Osteoclasts absorb bisphosphonates (BPs) during bone resorption, and the drugs disrupt the mevalonate pathway, leading to prenylation defects in small GTPase proteins and, eventually, osteoclast cell death, followed by reduced bone breakdown [78]. Research demonstrates that BPs effectively improve graft survival rates by preventing excessive bone resorption [79,80]. The local application of BPs at low to moderate doses has been shown to be effective in enhancing both graft bone formation and mechanical strength according to research [81]. However, the incorporation of grafts into bone tissue can be compromised when BPs are administered systemically or when high local concentrations are used [80,81]. The therapeutic window for BP use in grafting is narrow; thus, the correct application of BP during grafting requires specialized drug-delivery systems because the effective dosage range is very narrow. Implant coatings that contain BP deliver the drug specifically to target areas to achieve high local impact without causing substantial systemic drug absorption [49].

Click to view original image

Figure 2 Classification of Bisphosphonates for Bone Graft Integration.

3.2.2 Denosumab

Denosumab is a fully human monoclonal antibody that binds to RANKL, preventing its interaction with the RANK receptor on osteoclast precursors [51]. Osteoclast differentiation stops, and their function, along with survival, is inhibited, leading to reduced bone resorption. The suppressive action of Denosumab on osteoclasts makes it an effective bone grafting support, especially for procedures at risk of substantial bone loss [82]. Research findings show that denosumab treatment improves both callus development and fracture gap healing in complex therapeutic situations [52,53]. Moreover, injectable bone graft composites containing this agent demonstrate promising results for controlling bone remodeling balance according to research [83].

The benefits of denosumab treatment for bone resorption control require close monitoring because stopping the medication leads to increased bone turnover [84]. Additionally, potential adverse effects such as hypocalcemia and osteonecrosis of the jaw require vigilance [85].

3.3 Angiogenic and Vascular-Enhancing Agents

Early vascularization is crucial for graft survival, nutrient delivery, and osteogenesis. Agents that promote angiogenesis directly influence graft success.

3.3.1 Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor (PDGF) - Based Therapies

The angiogenic factor VEGF strongly drives endothelial cell growth and migration, leading to the formation of new blood vessels [86]. Bone graft revascularization occurs via VEGF, which enables the transport of essential nutrients and oxygen to the graft site [41]. Scientific investigations have proven that external VEGF treatments improve bone development and blood vessel network growth in laboratory animals with bone injuries [87,88]. During hypoxic conditions, which frequently occur in graft sites, VEGF expression increases to stimulate angiogenesis [89]. Studies have shown that VEGF interacts with the Notch and Noggin signaling pathways, demonstrating its complex role in linking angiogenesis to osteogenesis [90,91].

PDGF functions with VEGF to recruit pericytes and smooth muscle cells to stabilize newly developed blood vessels [55]. The graft site attracts mesenchymal stem cells (MSCs) through PDGF action, which later transform into osteoblasts for bone formation [92]. Research indicates that simultaneous administration of PDGF and VEGF produces concurrent benefits for vascularization and osteogenesis, supporting their joint use as a promising approach to improve bone graft integration [10,93].

3.3.2 Hypoxia-Inducible Factors (HIFs)

Hypoxia-Inducible Factors (HIFs), including HIF-1α, act as transcription factors that detect low oxygen levels to activate genes that control both angiogenesis and metabolic processes [56]. The hypoxic response mechanism in bone tissue depends heavily on HIF-1α functions to adapt to conditions that occur after graft implantation. The hypoxic environment causes HIF-1α to stabilize while it moves to the nucleus to activate VEGF and other target genes [94]. Visualizing the revascularization of the graft site becomes possible through VEGF upregulation because it enhances angiogenesis levels. The protein HIF-1α controls both the differentiation process and activity levels of osteoblasts, which in turn stimulates bone tissue regeneration [95,96]. Research has investigated deferoxamine (DFO) as well as other prolyl hydroxylase inhibitors for their ability to stabilize HIF-1α to promote bone healing [96,97,98]. Experimental research has demonstrated that DFO administration enhances bone regeneration through increased tissue repair because of new blood vessel formation in animal subjects [57]. This pathway represents a promising target for grafts placed in poorly vascularized environments.

3.4 Biologics Targeting Inflammatory Cytokines

Local inflammatory conditions strongly affect bone graft integration because tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6) and interleukin-1 beta (IL-1β) function as vital cytokines in this process. Graft failure becomes more likely when pro-inflammatory cytokines, which promote healing, exceed surpass normal levels, as they then inhibit osteogenesis [99,100,101].

Osteoclastogenesis is enhanced by TNF-α stimulates its development, leading to increased bone resorption [102]. Research shows that increased TNF-α levels create obstacles to both bone repair and implant material incorporation into the bone [103]. The biologic agents etanercept and infliximab show promise in managing TNF-α activity through their TNF-α inhibitory properties to enhance bone regeneration according to research [102,104,105]. Research findings show that inhibitor drugs decrease inflammation and enhance osteoblast differentiation, thereby improving graft integration [104,106,107].

The inflammatory response cytokine IL-6 plays dual functions within bone metabolism [108]. IL-6 supports osteoblast function under certain conditions, but it also drives osteoclast differentiation, leading to bone resorption [109]. Clinical studies have examined the use of the monoclonal antibody tocilizumab to target IL-6 because it aims to control bone resorption while maintaining bone formation [110,111]. Clinical studies show that blocking IL-6 enhances both bone density and graft stability [112,113].

IL-1β functions as a powerful inflammatory mediator that promotes osteoclast cell activity and suppresses osteoblast cell function to lead to bone loss [114]. The inflammatory effects of IL-1 receptor antagonist Anakinra have been shown to reduce these cellular responses [60,115]. The scientific evidence shows that inhibiting IL-1β creates beneficial conditions for bone maintenance and supports essential processes needed for graft integration [116].

The strategic use of biologic agents to control tissue inflammation appears to hold great potential for promoting bone graft integration. These therapies reduce harmful cytokine effects, which help establish a better environment for bone regeneration and graft incorporation.

3.5 Other Potential Pharmacological Strategies

Sclerostin inhibitors such as romosozumab enhance Wnt signaling and stimulate robust osteoblast activity, thereby increasing bone mass and strength [61,117]. These medicines enhance both osteoblast activity and bone formation by blocking sclerostin, resulting in stronger, denser bone. The pharmaceutical company is studying the use of romosozumab locally for bone grafting procedures despite its current systemic administration for osteoporosis treatment [62]. Delivering Wnt signaling stimulants at the implant site would improve graft integration while minimizing systemic drug effects, delivering superior healing results.

The integration of bone grafts requires the successful prevention of infections as a vital component. Preventing infection risks during bone graft integration relies on the widespread use of local antibiotic delivery systems, including polymethyl methacrylate (PMMA) beads and calcium sulfate pellets [63,64]. The traditional use of PMMA beads exists, but they lack resorbable properties, and patients may need surgical removal. The antibiotic release profile of calcium sulfate beads allows for extended drug delivery at therapeutic levels to the graft site as they are biodegradable [118,119]. Studies show that antibiotics-loaded calcium sulfate beads, including vancomycin and tobramycin, can stop bacterial growth and biofilm development that leads to graft failure [120]. Moreover, the resorption of calcium sulfate eliminates the need for further procedures to remove delivery systems, thereby reducing patient morbidity [121].

4. Comparative Insights Across Drug Classes and Key Translational Bottlenecks

Pharmacological agents used to enhance bone graft integration vary widely in their mechanisms, dosing requirements, and translational readiness. Osteoinductive factors such as BMP-2 and BMP-7 provide strong anabolic signals but require high doses and controlled delivery to avoid adverse effects, such as ectopic ossification [122]. Systemic anabolic agents, including intermittent PTH, offer more balanced remodeling support, although their benefits depend heavily on precise dosing schedules [70]. Anti-resorptive therapies (bisphosphonates and Denosumab) help stabilize grafts by reducing excessive osteoclastic activity, yet excessive suppression of turnover can delay long-term graft maturation [123]. Angiogenic agents such as VEGF and PDGF enhance early vascularization but face challenges due to short half-lives and difficulty achieving sustained, physiologic release at the graft site [124]. Immunomodulatory biologics targeting pro-inflammatory cytokines show promise in reducing graft resorption; however, concerns about systemic immunosuppression and optimal timing limit broader application [125]. Across all classes, key translational barriers persist, including narrow and poorly defined dosing windows, uncertainty surrounding the optimal timing of administration relative to graft placement, and ongoing challenges with spatiotemporally controlled delivery. Additionally, long-term safety concerns ranging from aberrant bone formation to immune dysregulation continue to impede routine clinical use. Addressing these limitations is essential to advance pharmacologic strategies that reliably support graft healing in clinical practice.

5. Mechanistic Pathways: Distinguishing Causal Evidence from Correlational Findings

Recent pharmacological approaches to improve bone graft integration act through diverse biological pathways; however, the strength of mechanistic evidence varies considerably. Pathways with clear causal roles are those demonstrated through genetic models, targeted inhibition, or controlled temporal manipulation. BMP-mediated Smad1/5/8 signaling has been directly linked to osteoblast differentiation and new bone formation, with knockout models showing failure of graft incorporation [65]. Similarly, intermittent PTH activation of the Wnt/β-catenin pathway has been shown to have a causal effect on osteoprogenitor expansion and improved graft remodeling [126]. VEGF-driven angiogenesis also has strong causal support, as vascular blockade consistently impairs graft survival in both preclinical and clinical settings [86].

In contrast, several pathways frequently described in the literature remain associative rather than mechanistically proven. Anti-inflammatory cytokine modulation (e.g., TNF-α or IL-6 inhibition) correlates with reduced graft resorption, yet causal links are less definitive because immunosuppression affects multiple downstream processes [127]. Similarly, many nanoparticle- or peptide-based therapies show improvements in bone volume or histology, but their specific intracellular targets remain incompletely elucidated, making the mechanistic relationship more speculative [128].

Overall, differentiating causally validated pathways from correlational findings is essential for translating pharmacologic strategies into predictable clinical interventions. Strengthening mechanistic clarity will also guide drug selection, dosing windows, and combination therapy design in future clinical applications.

6. Emerging Approaches for Targeted Drug Delivery

6.1 Nanotechnology-Based Drug Delivery

Nanotechnology has emerged as a key strategy for enhancing bone graft integration by enabling site-specific, controlled delivery of therapeutic agents while minimizing systemic exposure [129,130]. The nanoscale dimensions and elevated surface area of nanoparticles (NPs) enable engineers to develop therapeutic delivery systems targeting bone graft sites for improved osteointegration while reducing systemic toxicity [129]. NPs designed for drug delivery systems can transport different bioactive molecules, such as growth factors, antibiotics, and genetic material, to create favorable conditions for bone regeneration [131].

Mesoporous silica nanoparticles (MSNs) have been used to deliver combined bone morphogenetic proteins (BMPs) and antibiotics a single system [132]. Core–shell mesoporous silica nanoparticles containing BMP-2 at the core and gentamicin at the shell have shown dual capabilities for both osteogenic regeneration and antibacterial protection according to research [133]. Additionally, chitosan-based nanohybrid hydrogels with dual functionalities as bone regenerative scaffolds and drug delivery platforms for extended drug release capabilities at the treatment area have been developed [134].

Furthermore, titanium dioxide (TiO2) nanostructures have been explored for drug delivery applications because they exhibit superior biocompatibility and effective bone integration [135]. The drug delivery properties of TiO2 nanotubes have been developed to incorporate both antibiotics and growth factors, leading to effective bone healing and infection prevention [129,136]. Similarly, superparamagnetic iron oxide nanoparticles (SPIONs) offer the advantage of magnetic targeting, allowing for the directed delivery of drugs to specific bone sites under an external magnetic field, thereby enhancing the precision of treatment [137,138].

Overall, nanotechnology provides spatiotemporally controlled drug delivery, a feature critical for synchronized bone healing and the reduction of common postoperative complications. Recent AI-driven strategies, including the accelerated discovery of self-assembling peptides, are further expanding the design space for next-generation nanocarriers and enabling more precise control over therapeutic release profiles [139].

6.2 Scaffold-Based Drug Release Systems

Scaffold-based systems integrate mechanical support with localized therapeutic delivery, offering a dual advantage in bone graft procedures [140]. Advances in 3D printing enable fabrication of defect-specific scaffolds with controlled porosity and architecture, improving both tissue integration and drug-loading efficiency [141,142]. Drug molecules can be integrated into scaffolds to enable controlled drug delivery at the implantation site. The integration of scaffolds containing vascular endothelial growth factor (VEGF) with cephalexin antibiotics enables both proangiogenic and antibacterial properties, thereby enhancing bone regeneration while preventing infections [143].

Research has shown extensive use of biodegradable polymers including poly (lactic-co-glycolic acid) (PLGA) and gelatin because they enable the controlled delivery of growth factors [144]. PLGA nanoparticles containing bone morphogenetic protein-2 (BMP-2) have been shown to drive osteogenic stem cell differentiation thus demonstrating utility in bone tissue engineering [145]. Similarly, the release of growth factors through gelatin microparticles enables controlled biochemical delivery systems that enhance calcium deposition, a key indicator of bone healing [146].

These scaffold-based systems both give support to structures while preparing environments that promote bone healing by delivering therapeutic agents to specific treatment locations [147]. Recent advances in musculoskeletal organoid systems provide more physiologically relevant platforms for evaluating scaffold–tissue interactions and may help reduce dependence on animal models in preclinical bone regeneration research [148]. Innovations in hydrogel-based organoid culture further contribute to understanding how advanced biomaterials influence cellular organization and may guide the refinement of scaffold-mediated drug delivery strategies [149]. Such advanced drug delivery systems integrated into bone graft procedures offer the opportunity to enhance clinical outcomes and eliminate systemic drug use while reducing side effects.

6.3 Gene Therapy Approaches

Gene therapy offers a fundamentally different mechanism for promoting bone regeneration by enabling sustained, endogenous production of osteoinductive proteins at the graft site [150,151]. The approaches for delivering genes in bone regeneration can be divided into two main types: in vivo and ex vivo delivery [152]. The direct application of genetic material within the patient's body constitutes in vivo gene therapy because it targets cells at the graft site [153]. Ex vivo gene therapy requires medical professionals to extract patient cells followed by laboratory modification to produce osteoinductive factors before returning the cells to the graft site [153]. Both methods have shown potential in promoting bone healing and integration.

The clinical translation of gene- and biologic-based therapeutics is limited not only by their biological potency but also by delivery feasibility. Viral vectors, particularly adenoviruses, are the primary choice used in gene therapy because of their high transduction efficiency [154]. However, researchers now work on non-viral delivery systems because viral vectors present risks, including immune responses and mutagenicity [155]. Consequently, attention has shifted to non-viral carriers, including liposomes and nanoparticles, which offer safer profiles but lower transfection efficiency [156]. Liposomal delivery of BMP-2 genes has been shown to enhance bone regeneration in animal models [157,158].

Despite the potential benefits, several challenges hinder the clinical translation of gene therapy in bone regeneration [159]. The safety and efficiency of gene delivery vectors, along with potential immune responses and uncontrolled gene expression that can lead to adverse events, represent significant concerns for gene therapy. Moreover, the main challenge in tissue engineering is achieving controlled gene expression at the graft site without harming adjacent tissues. Addressing these challenges requires the development of advanced delivery systems and thorough preclinical studies to ensure safety and efficacy. The increasing integration of AI tools into scientific research is also accelerating biomaterial design, predictive modelling, and literature synthesis, supporting the development of next-generation drug delivery systems and regenerative platforms [160].

7. FDA-Approved Pharmacological Agents for Enhancing Bone Graft Integration

The U.S. Food and Drug Administration (FDA) has approved several pharmacological agents for boosting bone graft integration in orthopedic and dental procedures as listed in Table 2. These include osteoinductive growth factors such as BMPs, angiogenic mediators like PDGF-BB, and synthetic peptides that enhance cell–matrix interactions.

Table 2 FDA-approved agents for bone graft integration.

The FDA approved Recombinant human Bone Morphogenetic Protein-2 (rhBMP-2) as the most popular therapeutic agent for anterior lumbar interbody fusion in 2002, making it the first of its kind [161]. The FDA approved rhBMP-2 for tibial nonunion treatment in 2004 under the commercial name Infuse (Medtronic) and for specific oral and maxillofacial procedures in 2007 [165]. As an osteoinductive agent, rhBMP-2 drives mesenchymal stem cells to differentiate into osteoblasts and accelerates bone formation [166].

The FDA approved recombinant human Bone Morphogenetic Protein-7 (rhBMP-7), known commercially as OP-1 (Stryker), through a Humanitarian Device Exemption (HDE) to treat long bone nonunions in 2001 [46]. The product delivered promising outcomes, but the market withdrew it in 2014 due to both commercial aspects and regulatory modifications [164].

The FDA approved Platelet-Derived Growth Factor-BB (PDGF-BB) because it functions as an essential component for bone repair through its mechanisms of angiogenesis and cellular recruitment [167]. The product received FDA approval in 2005 for the treatment of periodontal defects before gaining clearance in 2015 for use in ankle and hindfoot fusion procedures under the names GEM 21S and Augment [162,163]. PDGF-BB stimulates complete tissue regeneration through dual effects on cell multiplication and matrix development [168].

Furthermore, the P-15 synthetic peptide under the brand name i-Factor (Cerapedics) received FDA approval in 2015 for cervical spine fusion procedures at the C3-C7 levels [164]. While BMP-based therapies remain the most widely studied osteoinductive agents, P-15 represents a different class of bone graft substitute. P-15 is a collagen-mimetic peptide that promotes osteoblast attachment and matrix mineralization through integrin-mediated signaling, thereby improving the early cell–matrix interface essential for graft incorporation [169]. This synthetic peptide mimics the cell-binding domain of type I collagen to promote cellular adhesion and initiate essential osteogenic signaling pathways [169]. Clinical studies demonstrate fusion rates comparable to autograft bone [170,171], although the evidence base remains smaller than for BMP-2 or PDGF-BB. Nevertheless, P-15 offers a promising alternative for spinal and periodontal applications, particularly where osteoconductive support is prioritized.

8. Natural Bioactive Agents in Bone Graft Integration

Natural bioactive compounds have emerged as promising adjuncts for enhancing bone graft integration due to their osteogenic, anti-inflammatory, and pro-angiogenic properties. Compounds such as curcumin, resveratrol, icariin, quercetin, berberine, and osthole promote osteoblast differentiation by activating key pathways, including Wnt/β-catenin, BMP/Smad, and MAPK, while simultaneously inhibiting osteoclastogenesis by downregulating RANKL-mediated signalling [172,173]. Their anti-inflammatory activity, particularly suppression of TNF-α, IL-1β, and IL-6, creates a more favorable microenvironment for graft incorporation [174,175]. Recent research highlights advancements in delivery strategies designed to overcome poor bioavailability and rapid degradation [176]. Curcumin-loaded nanoparticles, icariin-functionalized bioactive scaffolds, and resveratrol-encapsulated hydrogels have demonstrated enhanced bone regeneration, improved vascularization, and superior graft-host integration in preclinical models [177]. Moreover, hybrid systems combining natural compounds with growth factors or ceramic scaffolds show synergistic effects on osteogenesis and mineralization [178]. Despite these promising outcomes, the translational potential of natural agents remains limited by the absence of standardized dosing, variability in compound purity, and insufficient long-term clinical studies. Continued research focusing on optimized delivery systems, pharmacokinetics, and controlled clinical evaluations is necessary to advance these agents toward clinical application in bone grafting.

9. Clinical Applications and Outcomes of Pharmacological Agents in Bone Regeneration and Graft Integration

Table 3 summarizes clinical evidence on the application of rhBMP-2, rhPDGF-BB, and P-15 in bone regeneration and periodontal therapy. Across multiple case reports, rhBMP-2 has demonstrated predictable enhancement of alveolar ridge height, peri-implant bone formation, and maxillofacial defect reconstruction. Reported outcomes include vertical bone gains of 5–5.5 mm [179], improved peri-implant parameters in elderly patients [180], stable supracrestal augmentation [181], and effective reconstruction of atrophic maxillae [182]. Its utility also extends to orthopedic indications, with complete long-bone union in nonunion cases [183] and successful healing of mandibular and humeral defects [184,185,186,187].

Table 3 Summary of Clinical Applications and Outcomes of rhBMP-2, rhPDGF-BB, and P-15 in Bone Regeneration and Periodontal Treatments.

rhPDGF-BB has shown consistent benefit in periodontal and peri-implant regenerative procedures, particularly in defects requiring enhanced angiogenesis. It has enabled successful reconstruction of peri-implantitis-associated ridge defects [188] and complete Grade II furcation closure when combined with FDBA [189].

The biomimetic peptide P-15 supports periodontal regeneration by promoting cell adhesion and matrix formation, with clinical evidence demonstrating regeneration of cementum, bone, and periodontal ligament without adverse effects such as ankylosis or root resorption [190].

10. Challenges and Limitations

Despite major advances in bone grafting and adjunct pharmacological therapies, several biological and translational barriers continue to limit consistent clinical success. Patient-specific variability remains a central challenge; comorbidities such as aging, osteoporosis, diabetes, smoking, and nutritional deficiencies significantly impair osteogenesis and angiogenesis, thereby compromising graft incorporation [191]. Osteoporosis reduces bone mass and remodeling capacity, while diabetes disrupts osteoblast activity and microvascular stability, collectively increasing the risk of delayed union and graft failure [192,193]. Immune-mediated responses further hinder integration, particularly with allografts and xenografts, where inflammatory cytokine release accelerates graft degradation [194]. Although anti-inflammatory therapies may mitigate these effects, systemic administration carries risks including immunosuppression, infection, and delayed wound repair [195]. Different patient populations may respond uniquely to pharmacologic adjuncts due to variations in bone biology and systemic health. Individuals with osteoporosis often exhibit reduced osteogenic potential. They may benefit more from anabolic or anti-resorptive agents, whereas patients with diabetes typically experience impaired angiogenesis and heightened inflammatory responses, requiring therapies that target both vascular and immune pathways. These differences highlight the importance of patient-specific stratification when selecting adjunctive pharmacologic therapies for graft integration.

Insufficient vascularization represents another major limitation, particularly in large defects or regions with compromised perfusion [4]. While angiogenic agents such as VEGF and PDGF show strong experimental efficacy, their clinical translation is constrained by rapid degradation, difficulty in achieving controlled release, and potential toxicity [196]. Drug delivery itself remains problematic: systemic administration often results in low target-site concentrations and off-target effects, whereas local delivery systems face issues of burst release, uneven distribution, and material instability.

Emerging nanotechnology and scaffold-based delivery systems also present notable risks. Nanoparticles may accumulate in off-target tissues, induce oxidative stress, or trigger unintended immune responses due to unpredictable degradation and protein corona formation. Scaffold systems can fail through inconsistent degradation, insufficient mechanical strength, or inflammatory reactions to synthetic polymers. These risks, combined with challenges in reproducibility and regulatory validation, currently limit the clinical readiness of these advanced delivery platforms.

In addition to biological barriers, emerging delivery systems also face significant technical limitations. Nanoparticles may suffer from low loading efficiency, unpredictable in vivo degradation, and rapid clearance by the mononuclear phagocyte system. Scaffold-based systems often struggle with inconsistent pore interconnectivity, inadequate mechanical strength in load-bearing regions, and difficulty achieving uniform drug distribution throughout the matrix. Gene delivery platforms further present risks of uncontrolled expression, genomic integration, and variable transfection efficiency, which can compromise both safety and therapeutic reliability. These technical constraints collectively limit the reproducibility and clinical scalability of advanced delivery technologies.

A major translational limitation across pharmacologic classes is the lack of standardized dosing windows and timing protocols relative to graft placement. Many osteoinductive, angiogenic, and anti-resorptive agents display narrow therapeutic ranges, with early or excessive dosing impairing essential inflammatory and remodeling processes. Furthermore, long-term safety profiles remain incompletely characterized, particularly regarding ectopic ossification with BMPs, rebound bone turnover with Denosumab, immunomodulation-related infection risk with cytokine inhibitors, and delayed adverse events associated with gene or nanoparticle-based therapies.

Beyond biological barriers, regulatory and translational constraints limit the progression of advanced therapies. Gene therapy, nanoparticle-based systems, and bioactive scaffolds require extensive safety testing, long-term data, and substantial financial investment before clinical approval [197,198]. The absence of standardized evaluation metrics for graft performance further complicates comparison across studies. High costs also restrict access, particularly in low-resource healthcare settings.

In addition, several approved pharmacological agents carry clinically significant adverse effects. Bisphosphonates and Denosumab may impair normal bone remodeling and have been associated with osteonecrosis of the jaw and atypical fractures [199,200,201]. Similarly, BMP-based therapies may cause ectopic bone formation or inflammatory reactions when dosing is not well controlled [202]. Finally, the field lacks robust long-term clinical evidence. Most available data originate from preclinical studies or short-duration trials, limiting understanding of graft durability, mechanical stability, and long-time functional outcomes. Much of the available clinical evidence presented in this review consists only of small case series or isolated case reports, which sit at the lowest tier of the evidence hierarchy and cannot establish causality or predict long-term clinical performance. As a result, current conclusions must be interpreted cautiously until supported by larger, rigorously designed clinical trials. This evidence gap continues to delay the development of standardized clinical guidelines and the broad adoption of emerging therapies.

Regulatory experience with bone-related biologics shows that successful translation depends on clear safety profiles and tightly controlled dosing. Agents like BMP-2 and PDGF received restricted clinical indications due to concerns about dose-related adverse events. In contrast, newer options such as gene-based constructs and combination biologic platforms remain in early-phase trials due to complex regulatory pathways and unresolved long-term safety issues. These outcomes help identify which emerging therapies are realistically positioned for future clinical use.

11. Future Directions and Conclusion

Despite advancements in bone grafting techniques, challenges such as immune rejection, poor vascularization, and impaired healing in comorbid conditions persist [203]. Future research should focus on refining osteoinductive agents such as BMPs and PTH analogs, to minimize complications like ectopic bone formation, while ensuring that anti-resorptives such as bisphosphonates and Denosumab are administered with precise control to maintain balanced remodeling.

The clinical application of angiogenic therapies using VEGF, PDGF, and HIF stabilizers demands improved delivery and dosage methods before reaching clinical implementation. The development of immunomodulatory biologics that focus on TNF-α, IL-1β, and IL-6 needs additional research to establish a microenvironment that promotes regeneration instead of inflammatory responses.

Emerging technological developments featuring nanocarriers with bioengineered scaffolds and gene therapy deliver localized medications sustainably for better integration between tissues and reduced systemic effects. These platforms hold a promising clinical future when integrated with practice-based evidence from strong preclinical and clinical studies.

However, several knowledge gaps still limit the predictability of clinical translation. Optimal dosing windows, long-term safety profiles, and comparative effectiveness data remain insufficient across most drug classes. Many agents also present inherent trade-offs between efficacy and risk, particularly when used at higher or prolonged doses. Emerging combination strategies that pair osteoinductive, angiogenic, and immunomodulatory mechanisms may offer a more balanced therapeutic benefit. Still, their advantages over single-agent regimens require systematic evaluation in well-designed clinical studies. Addressing these gaps will be essential for guiding next-generation, evidence-driven bone graft therapeutics.

In conclusion, the future of bone grafting lies in developing multifunctional, personalized, and biologically active systems that not only replace bone but also actively stimulate and guide regeneration. Continued interdisciplinary collaboration and rigorous translational research will be critical for optimizing long-term outcomes and advancing the next generation of bone repair therapies.

Author Contributions

Garzain Bint e Attar conceptualized the review, performed the comprehensive literature search, curated and analyzed the data, and drafted the original manuscript. Dr. Mohd. Ashif Khan contributed to the study design, provided critical intellectual input, supervised the work, and revised the manuscript for important scientific content. Both authors reviewed, edited, and approved the final version of the manuscript.

Competing Interests

The authors have declared that no competing interests exist.

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