A New Selective Estrogen Receptor Modulator, CHF 4227.01, Preserves Bone Mass and Microarchitecture in Ovariectomized Rats

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 17␣-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 CT, 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.

Effects of nicotine on gene expression and osseointegration in rats

“…Specimens were randomized and tested in a three‐point bend configuration in accordance with ASTM D790 (ASTM International, West Conshohocken, PA, USA) using a typical, commercially available three‐point bend fixture, which was mounted to a MTS Systems' Synergie 200 (MTS, Eden Prairie, MN, USA) electromechanical materials testing load frame. In order to introduce tension on the anterior aspect, femurs were positioned condyles up and to the right on the 15,110 mm support span (Armamento‐Villareal et al 2005). Loading was applied to the posterior aspect of the mid‐diaphysis of each femur via the loading actuator at a displacement‐control rate of 0.1 mm/s (6 mm/min).…”

Bone Loss after Temporarily Induced Muscle Paralysis by Botox Is Not Fully Recovered After 12 Weeks

“…Right and left femurs were excised and cleaned of muscle and connective tissue. Micro‐CT scans were taken of each bone sample (μCT 40, Scanco Medical AG, Basserdorf, Switzerland), using a modification of a previously described procedure 26 . Bones were stabilized in 1.5% agarose gel and 16 μm voxel resolution images of the distal femoral epiphysis and midshaft of the femoral diaphysis were scanned.…”

“…Micro-CT scans were taken of each bone sample (CT 40, Scanco Medical AG, Basserdorf, Switzerland), using a modification of a previously described procedure. 26 Bones were stabilized in 1.5% agarose gel and 16 m voxel resolution images of the distal femoral epiphysis and midshaft of the femoral diaphysis were scanned. Specifically, a 1 mm thick middiaphyseal region and a 0.5 mm thick section encompassing the distal femoral epiphysis were analyzed.…”

Potential of Selective Estrogen Receptor Modulators as Treatments and Preventives of Breast Cancer

“…CHF4227 significantly prevents the development of DMBA-induced mammary tumors in rats [184]. It preserves bone mass without affecting uterine weight and decreases serum cholesterol and fat mass in ovariectomized rats [185]. A recent phase I study showed CHF4227 is well-tolerated, as 28 days of treatment has a positive effect on the serum lipid profile and bone markers without any negative effects on the endometrium or the fibrinolytic system.…”