Effect of treatment for 6 months with human parathyroid hormone (1-34) peptide in ovariectomized cynomolgus monkeys (Macaca fascicularis).
A potential negative side effect of intermittent parathyroid hormone (PTH) therapy to treat osteoporosis is the loss of cortical bone concomitant with increased cancellous bone mass. We addressed this issue by studying the effects of PTH on whole-body, axial, and appendicular bone mass in an animal model with haversian cortical bone remodeling. Ovariectomized, young adult female cynomolgus monkeys were assigned to placebo (n = 9) or PTH groups (n = 10). The PTH group received 10 microg/kg synthetic human PTH(1-34) peptide by subcutaneous injection, 3 days/week for 6 months, and the placebo group received vehicle. Multiple endpoints of bone mass, strength, and turnover in the axial and appendicular skeleton were assessed, including dual-energy X-ray absorptiometry (DEXA), quantitative computed tomography (qCT), analysis of serum (calcium, phosphorus, alkaline phosphatase, osteocalcin, and tartrate-resistant acid phosphatase) and urinary (calcium and creatinine) biomarkers, histomorphometry, and biomechanical testing. Compared with placebo-treated animals, PTH-treated monkeys had no change in whole-body bone mass, but a 6.7% increase in spinal areal bone mineral density (aBMD) was observed. Cortical bone mass measured by qCT at appendicular sites was not affected by PTH treatment, but there were significant increases in cancellous bone mass in the proximal tibia, and a similar trend in the distal radius. Small, transient increases in serum and urinary calcium were observed, but there were no treatment-related effects on other biochemical endpoints. Increased bone formation rate (BFR/BV) in the midradius and midfemur was accompanied by a nonsignificant increase in midfemur porosity. Increased vertebral cancellous bone volume (BV/TV) was associated with greater trabecular and interstitial thickness with no effect on wall thickness. Increases in bone strength were observed in both axial (vertebral maximum stress and load at fracture) and appendicular (femoral neck fracture load) skeleton. Together, these results indicate that PTH therapy in the cynomolgus monkey results in a net gain of spinal and appendicular cancellous bone mass with no adverse effect on cortical bone.
Jerome
C P
CP
SkeleTech, Inc., Bothell, WA 98021, USA. cjerome@skeletech.com
Johnson
C S
CS
Vafai
H T
HT
Kaplan
K C
KC
Bailey
J
J
Capwell
B
B
Fraser
F
F
Hansen
L
L
Ramsay
H
H
Shadoan
M
M
Lees
C J
CJ
Thomsen
J S
JS
Mosekilde
L
L
D015502:Absorptiometry, Photon; D000135:Acid Phosphatase / Q000097:blood; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D015519:Bone Density / Q000187:drug effects*; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D002118:Calcium / Q000097:blood / Q000652:urine; D003404:Creatinine / Q000652:urine; D005260:Female; D007279:Injections, Subcutaneous; D007527:Isoenzymes / Q000097:blood; D008252:Macaca fascicularis; D015675:Osteocalcin / Q000097:blood; D010024:Osteoporosis / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use*; D010758:Phosphorus / Q000097:blood; D000071681:Tartrate-Resistant Acid Phosphatase; D015899:Tomography, Emission-Computed, Single-Photon; D016474:Weight-Bearing / Q000502:physiology
D007527:Isoenzymes; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D015675:Osteocalcin; D010758:Phosphorus; D003404:Creatinine; D000469:Alkaline Phosphatase; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D002118:Calcium