A new selective estrogen receptor modulator, CHF 4227.01, preserves bone mass and microarchitecture in ovariectomized rats

Reina Armamento-Villareal, Sharmin Sheikh, Abroo Nawaz, Nicola Napoli, Cheryl Mueller, Linda R. Halstead, Michael D. Brodt, Matthew J. Silva, Elisabetta Galbiati, Paola Lorenza Caruso, Maurizio Civelli, Roberto Civitelli

Research output: Contribution to journalArticle

Abstract

A new SERM, CHF 4227.01, given to 6-month-old female rats immediately after ovariectomy, preserved bone mass and bone microarchitecture without affecting uterus weight. It also decreased serum cholesterol and fat mass in estrogen-deficient rats. Introduction: We tested the effect of a new benzopyran derivative, CHF 4227.01, with selective estrogen receptor modulator (SERM) activity on bone mass and biomechanics in ovariectomized (OVX) female rats in comparison with 17α-ethinylestradiol (EST), raloxifene (RLX), and lasofoxifene (LFX). Materials and Methods: Four doses of CHF 4227.01 (0.001,0.01,0.1, and 1 mg/kg body weight [bw]/day) were administered in OVX animals daily by gavage 5 days/week for 4 months. EST was administered at a dose of 0.1 mg/kg bw/day, whereas RLX and LSX were administered at doses of 1 and 0.1 mg/kg bw/day, respectively, by gavage. In one group (Sham), rats were operated but the ovaries not removed; another OVX group was treated only with placebo. Results and Conclusions: Treatment with CHF 4227.01 (1.0 and 0.1 mg/kg bw), EST (0.1 mg/kg bw), LFX (0.1 mg/kg bw), or RLX (1.0 mg/kg bw) prevented bone loss on the lumbar spine and the proximal femur assessed in vivo by DXA. Volumetric BMD obtained by pQCT ex vivo confirmed protection from bone loss in the spine and proximal femur among rats treated with CHF 4227.01. This effect was associated with strong inhibition of bone resorption both histologically and biochemically. Furthermore, CHF 4227.01 preserved trabecular microarchitecture, analyzed by μCT, and maintained biomechanical indices of bone strength in the spine and proximal femur, effects also observed for RLX, whereas LSX was less protective of microarchitecture. CHF 4227.01 treatment did not affect uterine weight, prevented the increase in body weight and fat mass seen in OVX animals, and decreased serum cholesterol to below the average of intact animals. In conclusion, CHF 4227.01 exhibits a promising therapeutic and safety profile as a new SERM on both skeletal and extraskeletal outcomes.

Original languageEnglish
Pages (from-to)2178-2188
Number of pages11
JournalJournal of Bone and Mineral Research
Volume20
Issue number12
DOIs
Publication statusPublished - Dec 2005

Keywords

  • Bone biomechanics
  • Bone mass
  • Estrogen
  • Osteoporosis
  • Selective estrogen receptor modulator

ASJC Scopus subject areas

  • Surgery

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    Armamento-Villareal, R., Sheikh, S., Nawaz, A., Napoli, N., Mueller, C., Halstead, L. R., Brodt, M. D., Silva, M. J., Galbiati, E., Caruso, P. L., Civelli, M., & Civitelli, R. (2005). A new selective estrogen receptor modulator, CHF 4227.01, preserves bone mass and microarchitecture in ovariectomized rats. Journal of Bone and Mineral Research, 20(12), 2178-2188. https://doi.org/10.1359/JBMR.050801