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


BACKGROUND
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 17alpha-ethinylestradiol (EST), raloxifene (RLX), and lasofoxifene (LFX).


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.


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 muCT, 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.
Armamento-Villareal
Reina
R
Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Sheikh
Sharmin
S
Nawaz
Abroo
A
Napoli
Nicola
N
Mueller
Cheryl
C
Halstead
Linda R
LR
Brodt
Michael D
MD
Silva
Matthew J
MJ
Galbiati
Elisabetta
E
Caruso
Paola Lorenza
PL
Civelli
Maurizio
M
Civitelli
Roberto
R
D015502:Absorptiometry, Photon; D000596:Amino Acids / Q000652:urine; D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology* / Q000627:therapeutic use; D001696:Biomechanical Phenomena; D001769:Blood / Q000187:drug effects; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy*; D001842:Bone and Bones / Q000737:chemistry / Q000187:drug effects* / Q000473:pathology; D002784:Cholesterol / Q000097:blood; D019245:Compressive Strength; D020847:Estrogen Receptor Modulators / Q000494:pharmacology; D004997:Ethinyl Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D005260:Female; D005269:Femur / Q000737:chemistry / Q000187:drug effects; D005272:Femur Neck / Q000737:chemistry / Q000187:drug effects; D008159:Lumbar Vertebrae / Q000737:chemistry / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010010:Osteoclasts / Q000166:cytology; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D011759:Pyrrolidines / Q000494:pharmacology; D020849:Raloxifene Hydrochloride / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D013977:Tibia / Q000737:chemistry / Q000187:drug effects; D014057:Tomography, X-Ray Computed; D014280:Triglycerides / Q000097:blood; D014599:Uterus / Q000033:anatomy & histology / Q000187:drug effects; D016474:Weight-Bearing
C466797:3-(4-methoxy)phenyl-4-((4-(2-(1-piperidinyl)ethoxy)phenyl)methyl)-2H-1-benzopyran-7-ol; D000596:Amino Acids; D001578:Benzopyrans; D020847:Estrogen Receptor Modulators; D010880:Piperidines; D011759:Pyrrolidines; D013764:Tetrahydronaphthalenes; D014280:Triglycerides; C111332:Lasofoxifene; D004997:Ethinyl Estradiol; D020849:Raloxifene Hydrochloride; C015484:pyridinoline; C036020:deoxypyridinoline; D002784:Cholesterol