Bone quality, biology, and next-generation enhancers for spinal fusion in osteoporosis: a comprehensive narrative review with systematic search methodology.

Abstract

Comprehensive narrative review with systematic search methodology. To consolidate current evidence on the influence of bone quality on spinal fusion outcomes and investigate the efficacy of systemic pharmacotherapies as well as emerging biologic and biomaterial enhancements. Impaired bone quality is common among spinal fusion candidates yet frequently remains underdiagnosed. Conventional dual-energy X-ray absorptiometry (DXA) alone underestimates bone fragility. However, novel assessment modalities, systemic pharmacotherapies, and advanced biologics and biomaterials are emerging to address this gap. A systematic search of PubMed, EMBASE, and the Cochrane Library databases was conducted through September 2025 in accordance with the PRISMA 2020 (Preferred Reporting Items for Systematic reviews and Meta-Analyses 2020) guidelines. Search terms included spinal fusion, osteoporosis, bone quality assessment (DXA, trabecular bone score [TBS], vertebral bone quality), antiosteoporotic medications, exosomes, Nel-like molecule type 1, gene therapy, and three-dimensional-printed scaffolds. Clinical trials, meta-analyses, and key preclinical studies were included. Of the 1,247 records identified, 53 met the inclusion criteria. Due to the broad thematic scope encompassing bone quality assessment, pharmacological optimization, and emerging biologics/biomaterials, a narrative synthesis was performed. Risk of bias was assessed employing the Cochrane Risk of Bias 2.0 tool for randomized controlled trials (RCTs) and the Newcastle-Ottawa Scale for observational studies. The certainty of evidence for major clinical recommendations was evaluated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) framework. Comprehensive assessment using TBS and Fracture Risk Assessment Tool identified impaired bone quality in 37.5% of surgical candidates, with vitamin D deficiency or insufficiency present in up to 57%. A network meta-analysis of 13 RCTs found teriparatide as significantly superior to placebo (odds ratio, 3.2; moderate certainty), while teriparatide plus denosumab exhibited the highest efficacy (surface under the cumulative ranking curve [SUCRA]=90.9). Extended teriparatide treatment (>6 months) increased union rates to 87.1%. In preclinical models, mesenchymal stem cell-derived exosomes achieved 83.3% fusion in preclinical models versus 27.3% in controls (very low certainty evidence). Overall risk of bias across included RCTs was low to moderate, while most observational studies were of moderate quality per the Newcastle-Ottawa Scale. A multimodal approach combining comprehensive bone quality assessment, systemic anabolic optimization (moderate certainty evidence), and targeted novel biologics delivered via advanced biomaterial scaffolds (very low certainty evidence) is proposed for optimized spinal arthrodesis outcomes. However, large-scale clinical trials are required to validate these emerging biologic enhancers.