Raloxifene Improves Bone Mechanical Properties in Mice Previously Treated with Zoledronate

Abstract

Bisphosphonates represent the gold-standard pharmaceutical agent for reducing fracture risk. Long-term treatment with bisphosphonates can result in tissue brittleness which in rare clinical cases manifests as atypical femoral fracture. Although this has led to an increasing call for bisphosphonate cessation, few studies have investigated therapeutic options for follow-up treatment. The goal of this study was to test the hypothesis that treatment with raloxifene, a drug that has cell-independent effects on bone mechanical material properties, could reverse the compromised mechanical properties that occur following zoledronate treatment. Skeletally mature male C57Bl/6J mice were treated with vehicle (VEH), zoledronate (ZOL), or ZOL followed by raloxifene (RAL; 2 different doses). At the conclusion of 8 weeks of treatment femora were collected and assessed with microCT and mechanical testing. Trabecular BV/TV was significantly higher in all treated animals compared to VEH with both RAL groups having significantly higher BV/TV compared to ZOL (+21%). All three drug-treated groups had significantly more cortical bone area, higher cortical thickness, and greater moment of inertia at the femoral mid-diaphysis compared to VEH with no difference among the three treated groups. All three drug-treated groups had significantly higher ultimate load compared to VEH-treated animals (+14 to 18%). Both doses of RAL resulted in significantly higher displacement values compared to ZOL-treated animals (+25 to +50%). In conclusion, the current work shows beneficial effects of raloxifene in animals previously treated with zoledronate. The higher mechanical properties of raloxifene-treated animals, combined with similar cortical bone geometry compared to animals treated with zoledronate, suggest the raloxifene treatment is enhancing mechanical material properties of the tissue.

Synthesis and biological evaluation of novel benzothiophene derivatives

“…Solvents, reagents, and chemicals used for reactions were purchased from commercial suppliers. Synthesized molecules were analyzed by 1 H and 13 C NMR. 1 H and 13 C NMR spectra were recorded on an Agilent NMR (400 MHz) spectrometer.…”

“…Synthesized molecules were analyzed by 1 H and 13 C NMR. 1 H and 13 C NMR spectra were recorded on an Agilent NMR (400 MHz) spectrometer. Chemical shifts were reported in parts per million (ppm) downfield from an internal TMS (trimethylsilane) reference.…”

“…In addition, spin multiplicities were presented by the following symbols: s (singlet), brs (broad singlet), d (doublet), t (triplet), q (quartet), and m (multiplet). DEPT 13 C NMR information was given in parentheses as C, CH, CH 2 and CH 3 . Flash chromatography was done using thick-walled glass columns and 'flash grade' silica 60 (Merck 230-400 mesh).…”

“…1 H NMR (400 MHz, CDCl 3 ) 7.43 (dd, J = 7, 7, 1.5 Hz; 1H), 7.27 (td, J = 7.5, 1.5 Hz; 1H), 7.11 (d, J = 7.4 Hz; 1H), 7.05 (td, J = 7.5, 1.2 Hz; 1H), 2.46 (s, 3H), 0.32 (s, 9H). 13 . The spectral data were in agreement with those reported previously for this compound.…”

“…In addition, they are known as strong inhibitors of lipid peroxidation, 9 potassium channel openers, 10 topoisomerase inhibitors, 11 and L1210 cell selectors. 12 Benzothiophenes and thiophenes are well-known candidates of heteroaromatic compounds and used as pharmaceuticals like Raloxifene 1, 13 Zileuton 2, 14 and Sertaconazole 3 (Scheme 1). 15 Raloxifene, whose commercial brand name is Evista, is used for the treatment of breast cancer.…”