Anti-resorptive and anabolic treatments can be used sequentially to treat osteoporosis, but their effects on bone composition are incompletely understood. Osteocytes may influence bone tissue composition with sequential therapies because bisphosphonates diffuse into the canalicular network and anabolic treatments increase osteocyte lacunar size. Cortical bone composition of osteopenic, ovariectomized (OVX) rats was compared to that of Sham-operated rats and OVX rats given monotherapy or sequential regimens of single approved anti-osteoporosis medications. Adult female Sprague–Dawley rats were OVX (N = 37) or Sham–OVXd (N = 6). After 2 months, seven groups of OVX rats were given three consecutive 3-month periods of treatment with vehicle (V), h-PTH (1–34) (P), alendronate (A), or raloxifene (R), using the following orders:​ VVV, PVV, RRR, RPR, AAA, AVA, and APA. Compositional properties around osteocyte lacunae of the left tibial cortex were assessed from Raman spectra in perilacunar and non-perilacunar bone matrix regions. Sequential treatments involving parathyroid hormone (PTH) caused lower mean collagen maturity relative to monotherapies. Mean mineral:​matrix ratio was 2.2% greater, mean collagen maturity was 1.4% greater, and mean carbonate:​phosphate ratio was 2.2% lower in the perilacunar than in the non-perilacunar bone matrix region (all P < 0.05). These data demonstrate cortical bone tissue composition differences around osteocytes caused by sequential treatment with anti-osteoporosis medications. We speculate that the region-specific differences demonstrate the ability of osteocytes to alter bone tissue composition adjacent to lacunae.