Machine learning reconstruction of digit bone Raman spectra enables noninvasive transcutaneous detection of systemic osteoporosis.

Osteoporosis, a major global epidemic, often goes undetected until a fracture occurs, largely due to poor access to screening using gold standard methods, such as dual-energy X-ray absorptiometry (DXA). As a potential nonionizing radiation alternative, we present a transcutaneous spatially offset Raman spectroscopy (SORS) approach combined with machine learning (ML) to recover bone spectra through overlying soft tissue and extract diagnostic information. In a human cadaveric study spanning normal, osteopenic, and osteoporotic donors, we acquired paired Raman measurements from transcutaneous fingers at multiple spatial offsets (0, 3, and 6 mm) and from the corresponding exposed finger bones. Using this paired dataset, supervised machine-learning models were trained to reconstruct exposed-bone Raman spectra from transcutaneous measurements, enabling direct recovery of bone biochemical signatures from transcutaneous tissue. The ML-predicted bone spectra preserved physiologically meaningful Raman features and demonstrated statistically significant differences between normal and osteoporotic groups across four key Raman-derived metrics (p ≤ 0.05), representing, to our knowledge, the first demonstration of transcutaneous Raman discrimination between clinically established bone-health categories in a human cadaveric study. The ML-predicted spectra further correlated with distal-radius DXA T-scores (r = 0.73, RMSECV ≈ 1.4), approaching the performance achieved using exposed-bone measurements (r = 0.9, RMSECV ≈ 0.8). Finally, preliminary in vivo measurements from two volunteers revealed clear bone-related transcutaneous spectral features consistent with cadaveric data, supporting translational feasibility. Together, these results establish a foundation for nonionizing radiation, transcutaneous Raman assessment of bone health using supervised spectral extraction from accessible measurement sites.