Does simvastatin stimulate bone formation in vivo?
BACKGROUND
Statins, potent compounds that inhibit cholesterol synthesis in the liver have been reported to induce bone formation, both in tissue culture and in rats and mice. To re-examine potential anabolic effects of statins on bone formation, we compared the activity of simvastatin (SVS) to the known anabolic effects of PTH in an established model of ovariectomized (OVX) Swiss-Webster mice.


METHODS
Mice were ovariectomized at 12 weeks of age (T0), remained untreated for 5 weeks to allow development of osteopenia (T5), followed by treatment for 8 weeks (T13). Whole, trabecular and cortical femoral bone was analyzed by micro-computed tomography (micro CT). Liquid chromatography/mass spectrometry (LC/MS) was used to detect the presence of SVS and its active metabolite, simvastatin beta-hydroxy acid (SVS-OH) in the mouse serum.


RESULTS
Trabecular BV/TV at T13 was 4.2 fold higher in animals treated with PTH (80 micro-g/kg/day) compared to the OVX-vehicle treated group (p < 0.001). However, the same comparison for the SVS-treated group (10 mg/kg/day administered by gavage) showed no significant difference (p = NS). LC/MS detected SVS and SVS-OH in mouse serum 20 minutes after gavage of 100 mg SVS. A serum osteocalcin assay (OC) demonstrated that neither bone formation nor osteoblast activity is significantly enhanced by SVS treatment in this in vivo study.


CONCLUSIONS
While PTH demonstrated the expected anabolic effect on bone, SVS failed to stimulate bone formation, despite our verification by LC/MS of the active SVS-OH metabolite in mouse serum. While statins have clear effects on bone formation in vitro, the formulation of existing 'liver-targeted' statins requires further refinement for efficacy in vivo.
von Stechow
Dietrich
D
Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA. dvonstec@caregroup.harvard.edu
Fish
Susan
S
Yahalom
Dror
D
Bab
Itai
I
Chorev
Michael
M
Müller
Ralph
R
Alexander
Joseph M
JM
D000818:Animals; D001862:Bone Resorption / Q000188:drug therapy / Q000209:etiology; D004333:Drug Administration Routes; D005260:Female; D005269:Femur / Q000187:drug effects; D007279:Injections, Subcutaneous; D007441:Intubation, Gastrointestinal / Q000379:methods; D051379:Mice; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000187:drug effects*; D010052:Ovariectomy / Q000009:adverse effects; D010053:Ovary / Q000502:physiology / Q000601:surgery; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology; D019821:Simvastatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*
D010281:Parathyroid Hormone; D015675:Osteocalcin; C063287:simvastatin acid; D019821:Simvastatin