The ability of bone to resist fracture is dependent on the composite nature of its mineral and organic matrix content. Teriparatide (TPTD) and zoledronic acid (ZOL) are approved anabolic and antiresorptive therapies, respectively, to reduce fracture risk in women with postmenopausal osteoporosis. In the SHOTZ study, postmenopausal women with osteoporosis were treated with TPTD (20 μg daily, subcutaneous) or ZOL (5 mg/year, intravenous infusion) for 24 months. Iliac crest biopsies were obtained at 6 months and again at 24 months from approximately one third of the original study cohort. To investigate the early effects of these two drugs on the quality of newly formed bone, we used vibrational spectroscopic techniques to analyze tetracycline-labeled transiliac biopsies obtained from participants at the 6-month time point. Raman spectra were acquired at forming trabecular and intra-cortical surfaces (identified by fluorescent double labels), to determine mineral, organic matrix, glycosaminoglycan, and tissue water content, as well as mineral maturity / crystallinity at three specific tissue ages (1-5, 15, and ≥25 days). Fourier transformed infrared microspectroscopy was used to determine pyridinoline / divalent collagen cross-link ratios. At 6 months, treatment with TPTD versus ZOL resulted in lower mineral and higher organic matrix content, increased tissue water content, and lower mineral / matrix, mineral maturity / crystallinity, glycosaminoglycan content, and pyridinoline / divalent enzymatic collagen cross-link ratio. Our results suggest that TPTD and ZOL have differential effects on material properties of newly formed bone at individual remodeling sites, highlighting their different mechanisms of action.Copyright © 2021. Published by Elsevier Inc.