Osteoporosis, a prevalent metabolic bone disorder, predisposes individuals to increased susceptibility to fractures. It is also, somewhat controversially, thought to delay or impair the regenerative response. Using high-resolution Fourier-transform infrared spectroscopy and small/wide-angle X-ray scattering we sought to answer the following questions: Does the molecular composition and the nano-structure in the newly regenerated bone differ between healthy and osteoporotic environments? And how do pharmacological treatments, such as bone morphogenetic protein 7 (BMP-7) alone or synergistically combined with zoledronate (ZA), alter callus composition and nano-structure in such environments? Cumulatively, on the basis of compositional and nano-structural characterizations of newly formed bone in an open-osteotomy rat model, the healing response in untreated healthy and ovariectomy-induced osteoporotic environments was fundamentally the same. However, the BMP-7 induced osteogenic response resulted in greater heterogeneity in the nano-structural crystal dimensions and this effect was more pronounced with osteoporosis. ZA mitigated the effects of the upregulated catabolism induced by both BMP-7 and an osteoporotic bone environment. The findings contribute to our understanding of how the repair processes in healthy and osteoporotic bone differ in both untreated and treated contexts and the data presented represents the most comprehensive study of fracture healing at the nanoscale undertaken to date.