This study is a comprehensive narrative review conducted employing a systematic search methodology. Given the broad scope encompassing bone quality assessment, pharmacological optimization, and emerging biologics/biomaterials—domains that span heterogeneous study designs, populations, and outcome measures—a narrative synthesis approach was undertaken rather than a conventional meta-analytic systematic review based on a single, narrowly defined PICO (Population, Intervention, Comparison, Outcome) question. This approach enables integration of evidence across multiple interconnected research domains while preserving the transparency and reproducibility of a systematic search. The review was not registered in the PROSPERO registry.

A comprehensive systematic literature search was conducted in PubMed/MEDLINE, EMBASE, and the Cochrane Library databases for articles published through September 2025. The search strategy primarily combined medical subject headings and free-text terms across the following domains: (1) spinal fusion, spinal arthrodesis, lumbar fusion; (2) bone quality, osteoporosis, bone mineral density, dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS), Fracture Risk Assessment Tool (FRAX), vertebral bone quality (VBQ); (3) antiosteoporotic agents, teriparatide, parathyroid hormone (PTH), denosumab, bisphosphonates, romosozumab; (4) biologics, exosomes, Nel-like molecule type 1 (NELL-1), gene therapy, bone morphogenetic protein (BMP); and (5) biomaterials, 3D printing, scaffold. Boolean operators (AND/OR) were applied to combine search domains. Reference lists of included articles and relevant systematic reviews were manually screened for identifying additional eligible studies.

Studies were included if they comprised (1) randomized controlled trials (RCTs), prospective or retrospective cohort studies, and meta-analyses evaluating the effect of bone quality on spinal fusion outcomes; (2) clinical trials assessing the efficacy of antiosteoporotic pharmacotherapy (anabolic, antiresorptive, or combination) on spinal fusion or union rates; (3) preclinical studies (in vivo animal models) investigating emerging biologic enhancers (exosomes, novel growth factors, gene therapy) for spinal fusion; (4) studies evaluating advanced biomaterials and 3D-printed scaffolds for spinal fusion applications; and (5) publications in English. Exclusion criteria were (1) case reports, editorials, letters, and conference abstracts without full text; (2) in vitro studies without in vivo validation; (3) studies limited to cervical spine fusion without extrapolation to general fusion biology; and (4) studies with insufficient outcome data.

The study selection process is depicted in the PRISMA 2020 flow diagram (Fig. 1). Titles and abstracts of all identified records were screened independently by two reviewers, followed by full-text assessment against predefined eligibility criteria. Disagreements were resolved by consensus. Data extraction was performed independently by two reviewers using a standardized form. Extracted variables included study design, sample size, patient characteristics, intervention details, comparison groups, primary outcomes (fusion/union rate), secondary outcomes (functional scores, complication rates), and follow-up duration. For network meta-analyses, odds ratios (ORs), surface under the cumulative ranking curve values, and confidence intervals (CIs)were documented.

The risk of bias was assessed independently by two reviewers. Randomized controlled trials were evaluated using the Cochrane Risk of Bias 2.0 (RoB 2.0) tool (Cochrane, London, UK) across five domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in measurement of the outcome, and bias in selection of the reported result. Observational cohort studies were assessed using the Newcastle-Ottawa Scale (NOS), which evaluates selection (four stars), comparability (two stars), and outcome (three stars) domains, with a maximum score of 9. Studies scoring 7–9 were considered high quality, 4–6 moderate quality, and 0–3 low quality. Disagreements in the risk of bias assessment were resolved through discussion.

The certainty of evidence for major clinical recommendations was assessed using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework and was rated as high, moderate, low, or very low based on five domains: risk of bias, inconsistency, indirectness, imprecision, and publication bias. RCT evidence was rated as “high” certainty at baseline and was downgraded as appropriate; observational evidence was rated “low” at baseline, and preclinical evidence was rated as “very low” by default. A “summary of findings” table was constructed for key intervention–outcome pairings.

Given the heterogeneity of study designs, interventions, and outcomes across the included topics, a narrative synthesis approach was adopted in lieu of a pooled meta-analysis. Data were synthesized thematically based on the review objectives: bone quality assessment, pharmacological optimization, biologic enhancers, and biomaterial innovations. Quantitative data from included meta-analyses and RCTs were extracted and reported descriptively with appropriate effect estimates.

The systematic search identified 1,247 records across PubMed/MEDLINE (n=612), EMBASE (n=489), and the Cochrane Library (n=146) databases. After eliminating 287 duplicate records, 960 records were screened by title and abstract. Of these, 847 were excluded for not meeting inclusion criteria (irrelevant topic, non-English articles, inappropriate study design). The remaining 113 full-text articles were assessed for eligibility. Of these, 60 were excluded for the following reasons: insufficient outcome data (n=18), lack of in vivo validation (n=15), case reports or conference abstracts (n=12), cervical spine-limited studies without relevance to general fusion biology (n=9), and duplicate cohorts (n=6). Ultimately, 53 studies were included in the narrative synthesis. The complete study selection process is presented in the PRISMA 2020 flow diagram (Fig. 1).

The risk of bias assessment results for key RCTs and observational studies are presented in Tables 1 and 2 [5–14], respectively.

Anderson et al. [15] highlighted that optimizing bone health for orthopedic surgery requires a broad-based strategy beyond calcium and vitamin D supplementation. Studies have demonstrated that using DXA alone classifies approximately 26.6% of spinal surgery candidates as osteoporotic (T-score ≤−2.5), whereas incorporating TBS and FRAX increased the proportion identified with impaired bone quality or high fracture risk to 37.5% [15]. This finding underscores the significant underestimation of bone fragility when relying on DXA alone. Vitamin D deficiency (serum 25(OH)D <20 ng/mL) and insufficiency (<30 ng/mL) are highly prevalent among spinal fusion candidates. Stoker et al. [16] reported that among 313 patients undergoing spinal fusion, 27% were vitamin D deficient and 57% had suboptimal levels (<30 ng/mL), with younger age, obesity, and lack of supplementation identified as key risk factors. A subsequent meta-analysis of 1,142 spinal fusion patients reported a pooled vitamin D deficiency prevalence of 38.9% [16]. This has profound implications for bone healing and fusion biology, given the essential role of vitamin D in calcium absorption, osteoblast function, and prevention of pseudoarthrosis. Importantly, TBS is minimally affected by lumbar spine osteoarthritis, making it a reliable indicator in older adults [17]. A summary of bone quality assessment modalities and their relevance to spinal fusion is presented in Table 3 [5,6,15–20].

Beyond DXA and TBS, opportunistic imaging modalities have gained attention. The VBQ score, an magnetic resonance imaging (MRI)-based parameter, employs vertebral body signal intensity on standard T1-weighted sequences to estimate bone quality [5]. VBQ has been shown to predict fragility fractures independently of bone mineral density (BMD) [18] and can be regionalized to assess segmental bone quality, which is valuable for surgical planning [6]. While VBQ offers a practical, cost-neutral screening tool based on routinely acquired preoperative MRIs, its moderate specificity warrants confirmation with DXA-based methods [5,19].

The clinical consequences of unaddressed poor bone quality in spinal surgery are well recognized. Reduced pedicle screw purchase in osteoporotic bone is associated with increased rates of screw loosening [21]. Cage subsidence is more prevalent in patients with low BMD, compromising interbody fusion [22]. Furthermore, in long-segment constructs for adult spinal deformity, osteoporosis is a significant risk factor for proximal junctional kyphosis (PJK) and adjacent segment fractures [23–25]. A recent systematic review and meta-analysis by Nakarai et al. [7] demonstrated that low Hounsfield unit (HU) values at the upper instrumented vertebra were strongly associated with PJK/proximal junctional failure after adult spinal deformity surgery. A cutoff HU value of approximately 120 yields a pooled diagnostic odds ratio of 7.01, underscoring the clinical utility of computed tomography (CT)-based bone quality assessment in surgical planning. These complications often require revision surgery, significantly increasing patient morbidity and healthcare costs [26].

3D printing technology has established a new paradigm in spinal fusion scaffold design by enabling patient-specific implants with precisely controlled macro- and micro-architectures [42,45]. Principal advantages include the following: (1) geometry tailored to the patient’s anatomy and defect size; (2) optimized porosity and pore inter-connectivity to promote vascular ingrowth and nutrient diffusion critical for osteogenesis; and (3) adjustable degradation kinetics synchronized with the rate of new bone formation [43]. Hybrid scaffolds integrating biocompatible metals (e.g., titanium) for mechanical support with bioactive ceramics (e.g., hydroxyapatite and tricalcium phosphate) or polymers for biologic integration represent a particularly promising strategy [43,46]. These scaffolds can also serve as controlled-release platforms for biologic agents, including growth factors and exosomes, creating a localized osteoinductive microenvironment that sustains biologic delivery throughout the critical healing period [39,42]. A comprehensive review by Kim et al. [47] outlined the evolution of bone fusion materials from traditional autografts and allografts to emerging technologies, including demineralized bone matrix, ceramics, synthetic peptides, and cellular bone allografts, as well as recent advancements in hydrogels, nanomaterials, and 3D-printed biomaterials. The review highlights the ongoing search for ideal graft substitutes with optimal osteogenic, osteoinductive, and osteoconductive properties. The integration of patient-specific 3D-printed scaffolds with advanced biologic loading represents a novel frontier in personalized spinal fusion technology.

The findings of this review underscore the critical importance of proactive assessment and optimization of bone health in spinal fusion candidates. As noted by Anderson et al. [15], DXA alone is a suboptimal screening tool for orthopedic surgical candidates, failing to identify a significant proportion of patients with impaired bone quality. A comprehensive preoperative protocol integrating DXA with TBS, FRAX, VBQ (where available from preoperative MRI), and metabolic panels (vitamin D, calcium, and PTH) should be considered the standard of care [20,48,49]. Early identification of at-risk patients enables timely initiation of targeted pharmacological interventions preoperatively, allowing for meaningful bone quality improvement before fusion surgery. A large-scale nationwide study by Tanaka et al. [14] confirmed osteoporosis as an independent risk factor for perioperative complications in patients undergoing lumbar spinal stenosis surgery. Furthermore, the study revealed that osteoporotic patients exhibited significantly higher complication rates, increased blood transfusion requirements, and prolonged anesthesia durations, further underscoring the need for systematic preoperative screening and optimization. Moderate-certainty evidence from a network meta-analysis of 13 RCTs [8] strongly supports teriparatide as the first-line anabolic agent for fusion enhancement in patients with impaired bone quality, ideally for a duration exceeding six months [8–11]. The combination with denosumab offers the highest potential efficacy and may be considered in high-risk cases [8]. However, key considerations include treatment cost, patient adherence to injectable therapies, and the need for carefully planned transition strategies after denosumab discontinuation to avoid rebound bone loss [50,51]. Prevention of surgical site infection remains a major consideration in spinal fusion procedures, particularly in patients with impaired bone quality and metabolic comorbidities [52].

The emergence of MSC-derived exosomes as potent cell-free biologic enhancers represents one of the most promising advances in this field. The preclinical data demonstrating fusion rates exceeding 83% in animal models, along with a favorable safety profile (minimal ectopic bone), positions exosome therapy as a potential successor to high-dose rhBMP-2 [29,34]. However, this evidence is currently considered as very low certainty under the GRADE framework, as it is derived solely from preclinical animal models without human clinical validation. Significant translational hurdles remain, including standardization of exosome isolation, characterization, and potency assays, as well as defining optimal dosing, carrier systems, and delivery strategies for clinical application [33]. NELL-1 and gene therapy-based techniques offer additional avenues for localized biologic enhancement, with potentially improved safety profiles compared to BMP-2 [37,38,40]. However, these findings are currently supported by very low to low certainty evidence, pending completion of ongoing human trials. The ongoing clinical trial of NELL-1 (NB1) will be critical in determining its safety and efficacy in humans [39]. 3D-printed scaffolds provide an optimal platform for the localized delivery of these emerging biologics, enabling precise control over the spatial and temporal release of therapeutic agents at the fusion site [42,43,45].

Drawing on the evidence consolidated in this review, we propose an integrated, multimodal framework for personalized spinal arthrodesis (Fig. 3). Phase I involves comprehensive assessment of bone quality employing a multi-tool panel (DXA, TBS, FRAX, VBQ, and metabolic labs). Phase II comprises the combined application of interventions across three complementary domains: (1) systemic optimization—primarily teriparatide-based anabolic therapy, combined with vitamin D/calcium supplementation; (2) advanced biologics—localized delivery of next-generation enhancers (exosomes, NELL-1, or low-dose BMP-2 combinations) tailored to the patient’s risk profile; and (3) biomaterial scaffolds—3D-printed, patient-specific constructs engineered for optimal porosity, mechanical stability, and controlled biologic release. This framework acknowledges that spinal fusion is not a singular biological event but a complex process influenced by systemic metabolic status, local biologic signaling, and the biomechanical milieu. Sagittal balance is an important determinant of lumbar spinal loading and overall surgical outcomes [53]. A personalized approach that addresses all three domains concurrently offers the greatest potential for achieving consistent and durable arthrodesis, particularly in the increasing population of older adults with impaired bone quality.

The GRADE framework-based assessment of the key clinical recommendations in this review is summarized in Table 6 (summary of findings) [8,11,12,27,29,34,37–39,42,43,45]. Overall, the evidence supporting systemic pharmacological optimization for spinal fusion is of moderate certainty, derived predominantly from RCTs with certain limitations regarding blinding and heterogeneity. Evidence supporting teriparatide as first-line anabolic therapy is rated as moderate certainty, based on a network meta-analysis of 13 RCTs, with downgrading due to some concerns regarding risk of bias (including open-label designs in some trials) and imprecision. The combination of teriparatide and denosumab achieved the highest SUCRA ranking; however, the certainty of evidence is low due to the limited number of direct comparison trials. Evidence for antiresorptive agents (bisphosphonates and denosumab) as fusion enhancers is of low certainty owing to inconsistency across studies and minimal benefit over placebo for fusion promotion. Emerging biologic enhancers, including MSC-derived exosomes, NELL-1, and gene therapy approaches, are uniformly rated as having very low certainty evidence, as findings are derived largely from preclinical animal models. While preclinical results are highly promising, clinical translation has not yet been validated. Similarly, evidence for 3D-printed scaffolds is deemed as very low certainty due to the lack of comparative clinical trials. These GRADE ratings should inform clinical decision-making and emphasize the urgent need for well-designed prospective clinical trials, particularly for emerging biologic interventions.

This review has several limitations. First, the broad scope of this narrative review enables a comprehensive synthesis across multiple interconnected domains but limits focused, quantitative pooling typical of a conventional systematic review with meta-analysis. Second, the evidence for next-generation biologics (exosomes, NELL-1, and gene therapy) is predominantly preclinical, with uncertain clinical translation; accordingly, all related recommendations are rated as very low certainty under the GRADE framework. Third, the heterogeneity of study designs, patient populations, fusion techniques, and outcome measures across the included pharmacological studies limits direct comparability. Fourth, the network meta-analysis data are derived from RCTs with variable inclusion criteria and follow-up durations [8]. Fifth, the long-term safety and cost-effectiveness of the proposed multimodal approach remain untested in prospective studies. Sixth, the risk of bias assessment identified concerns in several included studies, particularly due to lack of blinding in open-label pharmacological trials, which may have influenced reported outcomes. Seventh, publication bias may influence the available evidence, as negative findings are less likely to be published; formal assessment using funnel plots was not feasible given the narrative synthesis approach. Finally, the review was not prospectively registered, introducing a potential risk of reporting bias. Future large-scale, prospective, multicenter RCTs are required to corroborate the clinical efficacy and safety of emerging biologic enhancers and the proposed integrated framework.