Dose-response effects of intermittent PTH on cancellous bone in hindlimb unloaded rats.
HLU suppressed bone formation and resulted in bone loss in the tibial metaphysis of 6-month-old male rats. A human therapeutic dose of intermittent PTH (1 microg/kg/day) prevented the skeletal changes associated with HLU.


BACKGROUND
Skeletal unloading of skeletally mature rats results in trabecular thinning in the proximal tibial metaphysis, which is in part caused by a decrease in bone formation. We examined the efficacy of PTH in preventing the detrimental skeletal effects that occur with hindlimb unloading (HLU).


METHODS
Six-month-old male Fisher 344 rats were HLU and treated with vehicle or recombinant human PTH(1-34) at 1, 5, 20, or 80 microg/kg/day for 2 weeks. The bone response was measured by microCT analysis of bone structure, histomorphometric analysis of static and dynamic bone parameters, and Northern blot analysis of mRNA levels for bone matrix proteins. The PTH-treated HLU animals were compared with vehicle-treated HLU and pair-fed normal weight-bearing controls.


RESULTS
Unloading resulted in a decrease in cancellous bone volume that was caused in part by a dramatic 83% decrease in bone formation. All dose rates (1-80 microg/kg/day) of human PTH(1-34) significantly increased bone formation rates compared with vehicle-treated HLU controls. There was a dose response, and the highest dose rate of the hormone increased bone formation compared with normal weight-bearing rats by 708% (p < 0.0001). The increases in bone formation were accompanied by increases in mRNA levels for type 1 collagen, osteocalcin, and osteonectin. Also, treatment with PTH resulted in increases in mineral apposition rate and double-labeled perimeter, but the latter was disproportionally increased at high dose rates. A therapeutic dose of PTH (1 microg/kg/day) prevented disuse-induced trabecular thinning, whereas high-dose PTH (80 microg/kg/day) increased trabecular thickness compared with normal weight-bearing rats.


CONCLUSIONS
These findings reveal that administration of a therapeutic dose of PTH to HLU rats prevents the decrease in bone formation and trabecular thinning, whereas high dose rates of the hormone increase bone formation and trabecular thickness to values that exceed normal values.
Turner
Russell T
RT
Department of Nutrition and Exercise, Oregon State University, Corvallis, OR 97330, USA. russell.turner@oregonstate.edu
Evans
Glenda L
GL
Lotinun
Sutada
S
Lapke
Paul D
PD
Iwaniec
Urszula T
UT
Morey-Holton
Emily
E
D000818:Animals; D001835:Body Weight / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005269:Femur / Q000187:drug effects / Q000502:physiology*; D006614:Hindlimb; D006801:Humans; D008297:Male; D010281:Parathyroid Hormone / Q000097:blood / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology*; D051381:Rats; D012669:Seminal Vesicles / Q000187:drug effects / Q000502:physiology; D016474:Weight-Bearing
D010281:Parathyroid Hormone; D010446:Peptide Fragments