Daily treatment of aged ovariectomized rats with human parathyroid hormone (1-84) for 12 months reverses bone loss and enhances trabecular and cortical bone strength.
Most studies that have investigated the anabolic effects of parathyroid hormone (1-84) (PTH) or PTH fragments on the skeleton of ovariectomized (OVX) rats have evaluated the short-term effects of high-dose PTH(1-34) in young animals. This study used densitometry, histomorphometry, and biomechanical testing to evaluate the effects of 12-month daily treatment with low-dose PTH (15 or 30 microg/kg) in rats that were 10 months old at baseline, 4 months after OVX. Bone mineral density (BMD) and bone strength were reduced substantially in control OVX rats. The 15 microg/kg dose of PTH restored BMD to levels similar to those in sham animals within 6 months at the lumbar spine, distal and central femur, and whole body and maintained the BMD gain from 6 to 12 months. The 30 microg/kg dose produced greater effects. Both PTH doses normalized the trabecular bone volume-to-total volume ratio (BV/TV) at lumbar vertebra 3 but not at the proximal tibia (where baseline BV/TV was very low), solely by increasing trabecular thickness. PTH dose-dependently increased bone formation by increasing the mineralizing surface, but only the 30 microg/kg dose increased resorption. PTH increased cortical BMD, area, and thickness, primarily by increasing endocortical bone formation, and restored all measures of bone strength to levels similar to those in sham animals at all skeletal sites. PTH increased bone mass safely; there was no osteoid accumulation, mineralization defect, or marrow fibrosis and there were no abnormal cells. Thus, long-term PTH therapy normalized bone strength in the aged OVX rat, a model of postmenopausal osteoporosis, through increased bone turnover and enhanced formation of both trabecular and cortical bone.
Fox
J
J
NPS Pharmaceuticals, 383 Colorow Drive, Salt Lake City, UT 84108, USA. jfox@npsp.com
Miller
M A
MA
Newman
M K
MK
Metcalfe
A F
AF
Turner
C H
CH
Recker
R R
RR
Smith
S Y
SY
D015502:Absorptiometry, Photon; D000367:Age Factors; D000596:Amino Acids / Q000187:drug effects / Q000652:urine; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008159:Lumbar Vertebrae / Q000033:anatomy & histology / Q000187:drug effects; D015675:Osteocalcin / Q000097:blood / Q000187:drug effects; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy*; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000033:anatomy & histology / Q000187:drug effects
D000596:Amino Acids; D010281:Parathyroid Hormone; D015675:Osteocalcin; C036020:deoxypyridinoline