Bone quality and biologic enhancers for spinal fusion in osteoporosis: a narrative review

Study design and rationale

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.

Search strategy and criteria

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.

Inclusion and exclusion criteria

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.

Study selection and data extraction

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.

Fig. 1

Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020 (PRISMA 2020) flow diagram of study selection. This diagram illustrates the systematic search and screening process. A total of 1,247 records were identified across three databases (PubMed/MEDLINE, n=612; EMBASE, n=489; Cochrane Library, n=146). After duplicate removal (n=287), 960 records were screened by title and abstract, with 847 excluded. Of 113 full-text articles assessed, 60 were excluded for: insufficient outcome data (n=18), in vitro only studies (n=15), case reports/conference abstracts (n=12), cervical-only studies (n=9), and duplicate cohorts (n=6). A total of 53 studies were included in the narrative synthesis. RCT, randomized controlled trial.

Risk of bias assessment

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.

Certainty of evidence assessment

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.

Data synthesis

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.

Study selection

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).

Risk of bias assessment

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

Table 1

Risk of bias assessment of key randomized controlled trials (Cochrane RoB 2.0)

Table 2

Risk of bias assessment of key observational studies (Newcastle-Ottawa Scale)

The prevalence and underestimation of compromised bone quality

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].

Table 3

Comprehensive assessment of bone quality in spinal fusion candidates

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].

Pharmacologic optimization of the fusion substrate

Anabolic agents: teriparatide

The strongest evidence for pharmacologic augmentation of spinal fusion pertains to teriparatide (recombinant human PTH 1–34). A pivotal network meta-analysis by He et al. [8] synthesized integrated data from 13 RCTs encompassing multiple antiosteoporotic agents. Teriparatide demonstrated a statistically significant superiority over placebo in promoting spinal fusion, with an OR of 3.2 (95% CI, 1.4–7.8). In the SUCRA ranking, the combination of teriparatide and denosumab demonstrated the highest probability of efficacy (SUCRA=90.9), followed by teriparatide alone (SUCRA=74.0) [8]. Early prospective work by Ohtori et al. [9] demonstrated that daily teriparatide administration accelerated posterolateral fusion in postmenopausal women, achieving significantly higher fusion rates at 10 months compared to bisphosphonate controls. Ebata et al. [10] further established the clinical utility of weekly teriparatide in a multicenter prospective RCT, revealing improved osseous union within six months following lumbar interbody fusion for osteoporosis-related degenerative disorders. Critically, treatment duration has emerged as a significant determinant of teriparatide efficacy. Kim et al. [11] conducted a retrospective study in older adults and discovered that those receiving teriparatide for more than 6 months exhibited a significantly higher 12-month union rate of 87.1% compared to 65.0% in those treated for less than 6 months. Longer treatment was also associated with improved Visual Analog Scale and Oswestry Disability Index scores, without increased mechanical complications [11]. This evidence supports a minimum treatment duration of 6 months for optimal fusion outcomes. The efficacy of key antiosteoporotic agents is summarized in Table 4 [8,11,12,27,28], and comparative fusion rates are illustrated in Fig. 2 [11,12,29].

Table 4

Efficacy of key anti-osteoporotic medications in enhancing spinal fusion

Fig. 2

Comparative efficacy of interventions on spinal fusion rates (separated by evidence type). (A) Clinical studies (human): Teriparatide treatment exceeding 6 months demonstrates the highest union rate (87.1%) at 12 months [11]. Denosumab and bisphosphonates show moderate improvements in early fusion (25%) at 6 months over controls (10.5%) [12]. (B) Preclinical studies (rat model): mesenchymal stem cell (MSC)-derived exosomes show superior fusion efficacy (83.3%) compared to scaffold-only controls (27.3%) [29]. Direct cross-comparison between clinical (Panel A) and preclinical (Panel B) data is not valid due to fundamental differences in study design, species, fusion model, outcome assessment methods, and follow-up duration. Panels are presented separately for descriptive purposes only.

Next-generation biologic enhancers beyond BMP-2

Cell-free therapies: MSC-derived exosomes

Mesenchymal stem cell (MSC)-derived exosomes have emerged as a leading cell-free biologic strategy for bone regeneration. These nanoscale extracellular vesicles (30–150 nm) carry biomolecules, including microRNAs, proteins, and lipids, and mediate intercellular communication that modulates osteogenic, angiogenic, and immunomodulatory pathways [33]. In a seminal preclinical study, Lam et al. [34] demonstrated that MSC-derived exosomes enhanced posterolateral spinal fusion in a rat model, with higher fusion rates than scaffold-only controls. Micro-CT and histological assessment confirmed substantial new bone formation with mature trabecular architecture at the fusion site. Zhang et al. [29] further corroborated these findings, showing that exosomes from human umbilical cord MSCs promoted bone healing through HIF-1alpha-mediated angiogenesis, with increases in trabecular number, thickness, and bone volume fraction and minimal ectopic bone formation. This favorable safety profile contrasts with the well-documented adverse effects of high-dose rhBMP-2, including ectopic ossification and inflammatory seroma development [35,36]. The cell-free nature of exosome therapy also circumvents the regulatory and logistical constraints associated with live cell transplantation. A summary of emerging biologic enhancers and biomaterial technologies is provided in Table 5 [29,34,35,37–43].

Table 5

Emerging biologic enhancers and biomaterial technologies in spinal fusion (preclinical evidence)

Advanced biomaterials and 3D printing

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 imperative of bone health optimization

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 frontier of biologics and biomaterials

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].

An integrated strategy for personalized fusion

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.

Fig. 3

Integrated multimodal framework for personalized spinal arthrodesis. This diagram outlines the proposed clinical workflow. Phase I involves comprehensive bone quality assessment using dual-energy X-ray absorptiometry (DXA), trabecular bone score (TBS), Fracture Risk Assessment Tool (FRAX), vertebral bone quality (VBQ), and metabolic panels. Phase II involves the synergistic application of targeted interventions across three pillars: systemic optimization, advanced biologics, and biomaterial scaffolds. The integration of these elements aims to achieve optimized spinal fusion outcomes. PTH, parathyroid hormone; TPTD, teriparatide; DMAB, denosumab; MSC, mesenchymal stem cell; NELL-1, Nel-like molecule type 1; BMP-2, bone morphogenetic protein-2; 3D, three-dimensional.

Quality of evidence and certainty of recommendations

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.

Table 6

Summary of findings and GRADE certainty assessment for major interventions

Limitations

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.