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Abstract: FR-PO306

4-[(Methylthio)-Phenylthio]-Methan Bisphosphonate Improves Bone Elastic Mechanical Properties in Uremic Rats

Session Information

Category: Bone and Mineral Metabolism

  • 501 Bone and Mineral Metabolism: Basic

Authors

  • Kazama, Junichiro James, Fukushima Kenritsu Ika Daigaku, Fukushima, Fukushima, Japan
  • Iwasaki, Yoshiko, Nihon Bunri University, Oita, Oita, Japan
  • Horita, Shoichiro, Fukushima Kenritsu Ika Daigaku, Fukushima, Fukushima, Japan
  • Watanabe, Guy, Fukushima Kenritsu Ika Daigaku, Fukushima, Fukushima, Japan
  • Suzuki, Keiko, Showa Daigaku Daigakuin Shigaku Kenkyuka, Ota-ku, Tokyo, Japan
Background

Recent clinical studies no longer reveal a strong relationship between parathyroid function and fracture risk in patients on maintenance hemodialysis therapy. However, fracture risks in this patient population remains high. We have previously reported that oxidative stress-derived deterioration in bone elastic material properties could induce bone fragility in uremic conditions. The compound 4-[(methylthio)-phenylthio]-methan bisphosphonate(MPMBP)is a non-nitrogen-containing bisphosphonate, exhibiting little anti-osteoclastic activity, with an antioxidant methylthio phenylthiol group on its side chain.

Methods

An adenine-containing chew was fed to 9-week-old Sprague-Dawley male rats for 7weeks, and the treatment groups were administered 0.6 or 1.2 mg/kgBW of MPMBP subcutaneously once per week.

Results

The serum creatine levels were elevated by 2-3 folds in the adenine-fed rat groups more than those in the non-adenine-fed groups. Subsequently, the bone turnover rate was significantly elevated in the adenine-fed rat groups, while the mineral densities of femoral bone decreased regardless of MPMBP administration. Furthermore, the amount of malondialdehyde content in the tibia increased to 3-fold more in the adenine-fed groups than that in the non-adenine-fed groups. Additionally, MPMBP decreased the malondialdehyde content in a dose-dependent manner. In the adenine-fed rats, the pentosidine/amino ratio, monitored by Raman spectroscopy, significantly increased; however, MPMBP administration decreased it in a dose-dependent manner. Finally, the femoral bone storage module that was reduced to approximately half its value in the non-adenine-fed rats was almost completely recovered by MPMBP administration.

Conclusion

According to the nature of bisphosphonates, most of the MPMBP molecules administered were immediately delivered to the calcified tissue. The accumulated MPMBP molecules could scavenge reactive oxygen species, forming an antioxidant barrier around the bone. The barrier aided in oxidative stress-derived non-physiological collagen crosslink formation and reduced osteocyte apoptosis-dependent apatite disorientation, thus improving the bone elastic material properties. MPMBP exhibits the potential to serve as a new therapeutic device for uremic bone owing to a novel pharmacological mechanism.