Additive protective effects of estrogen and androgen treatment on trabecular bone in ovariectomized rats.
Both ER and AR activation regulates trabecular bone mass. We show that combined estrogen and androgen treatment results in additive protection of trabecular bone in OVX rats. This may in part be attributable to the effect of AR activation to attenuate the inhibitory effect of ER activation on bone formation.


BACKGROUND
Sex steroids are important regulators of trabecular bone mass. Both estrogen receptor (ER) and androgen receptor (AR) activation results in increased trabecular bone mass. The aim of this study was to investigate if combined estrogen and androgen treatment might be beneficial in the treatment of trabecular bone loss.


METHODS
Twelve-week-old female rats were ovariectomized (OVX) and treated with vehicle (V), 17beta-estradiol (E2; ER activation), dihydrotestosterone (DHT; AR activation), or the combination (E2 + DHT) for 6 weeks. The skeletal phenotype was analyzed by pQCT, microCT, histomorphometry of growth plates, and serum levels of biochemical bone markers.


RESULTS
Both E2 (+121% over V) and DHT (+34%) preserved the trabecular volumetric BMD (tvBMD) in OVX rats. The effect of E2 and DHT on tvBMD was additive, resulting in a 182% increase over V in the rats given E2 + DHT. MicroCT analyses of the trabecular bone microstructure revealed that the effect of E2 and DHT was additive on the number of trabeculae. E2 treatment reduced serum markers of both bone resorption (collagen C-terminal telopeptide) and bone formation (osteocalcin), indicating reduced bone turnover. Addition of DHT to E2 treatment did not modulate the effects of E2 on the marker of bone resorption, whereas it attenuated the inhibitory effect of E2 on the bone formation marker, which might explain the additive protective effect of E2 and DHT on trabecular bone mass. In contrast, DHT partially counteracted the suppressive effect of E2 on longitudinal bone growth and the E2-induced alterations in growth plate morphology.


CONCLUSIONS
These findings show that combined estrogen and androgen treatment results in additive protective effects on trabecular bone in OVX rats. Our data suggest that a combined treatment with selective ER and AR modulators might be beneficial in the treatment of osteoporosis.
Wallenberg Laboratory for Cardiovascular Research, Cardiovascular Institute at the Sahlgrenska Academy, Sahlgrenska University Hospital, Göteborg, Sweden.
Asa
A
Tivesten
Sofia
S
Movérare-Skrtic
Andrei
A
Chagin
Katrien
K
Venken
Phil
P
Salmon
Dirk
D
Vanderschueren
Lars
L
Sävendahl
Agneta
A
Holmäng
Claes
C
Ohlsson
D000728:Androgens / Q000378:metabolism* / Q000627:therapeutic use; D000818:Animals; D001835:Body Weight; D015519:Bone Density; D001846:Bone Development / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000188:drug therapy*; D001842:Bone and Bones; D049109:Cell Proliferation; D013196:Dihydrotestosterone / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004958:Estradiol / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism* / Q000627:therapeutic use; D005260:Female; D005269:Femur / Q000473:pathology; D007334:Insulin-Like Growth Factor I / Q000096:biosynthesis; D009929:Organ Size; D010053:Ovary / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000473:pathology; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014599:Uterus / Q000473:pathology
D000728:Androgens; D004967:Estrogens; D013196:Dihydrotestosterone; D004958:Estradiol; D007334:Insulin-Like Growth Factor I