Bone health in neuroendocrine tumors and prognostic implications beyond skeletal metastases

Background: The potential impact of NET (neuroendocrine tumor)-related disease burden on musculoskeletal health remains inconclusive. Aim: To assess the musculoskeletal status, its prognostic relevance and association with tumor aggressiveness in NET patients. Materials and methods: This cross-sectional study included 41 patients with grade (G) 1, 2, or 3 gastroenteropancreatic (GEP) and lung NETs. Among them, 38 were selected for comparison with 47 healthy controls matched for age, sex and body mass index (BMI). The musculoskeletal health was assessed by dual-energy X-ray absorptiometry (DXA) scan. Results: Within the NET group (median age=72 years old, 46% women), degraded TBS (trabecular bone score) was found in 71% of patients, with osteopenia affecting up to 59% at the femoral neck. The prevalence of hypovitaminosis D was 68%, whereas of low RSMI (relative skeletal muscle index) suggestive of sarcopenia 37%. Patients with advanced-stage NETs showed significantly lower L1-L4 BMD (bone mineral density), L1-L4 T-score, L1-L4 Z-score, 25-hydroxyvitamin D [25(OH)D] levels and BMI than those with earlier-stage disease. G2 NETs were associated with worse L1-L4 BMD, L1-L4 T-score, total hip T-score and diaphysis BMD than G1 NETs. In multivariate analysis, higher 25(OH)D levels and BMI were independently associated with longer progression-free survival (PFS), whereas higher Ki-67 was associated with shorter PFS. Correlation analyses showed inverse associations between Ki-67 and total hip T-score (rho = -0.314, p=0.048) and diaphysis BMD (rho = -0.354, p=0.025); age at NET diagnosis correlated with poorer bone parameters, whereas higher BMI was associated with better bone indices and RSMI. Compared with healthy controls, NET patients had significantly lower TBS, regardless of BMD, T-score or Z-score. Conclusion: NET patients showed a substantial burden of musculoskeletal impairment, with trabecular microarchitecture deterioration detectable despite BMD versus healthy controls. Advanced disease stage, higher grade and systemic treatment were associated with poorer bone health. Increased vitamin D levels and BMI were independently associated with longer PFS, supporting a potential relationship between nutritional-metabolic status and oncological outcomes. Low muscle mass was also frequent, although not significantly associated with tumor aggressiveness. These exploratory findings highlight the need for structured musculoskeletal assessment in NET patients and require validation in larger prospective studies.