Effects of intermittent hPTH(1-34) alone and in combination with 1,25(OH)(2)D(3) or risedronate on endosteal bone remodeling in canine cancellous and cortical bone.
Therapies utilizing intermittent human parathyroid hormone(1-34) (hPTH[1-34]) in combination with other agents have recently been proposed as possible anabolic regimens for the treatment of osteoporosis. We conducted a 24 week study in aged beagle dogs to determine the effects of intermittent hPTH(1-34) administered alone or in combination with 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) on the endosteal remodeling in cancellous and cortical bone. Additionally, we tested the interaction between hPTH(1-34) and a new potent bisphosphonate, risedronate. The three treatment groups were compared with a vehicle control group. Kinetic reconstruction of the remodeling unit revealed substantial differences between the groups in resorption and formation at the basic multicellular unit level. Although the estimates of final erosion depth were unaffected by treatment, tunneling resorption was noted in six of the eight dogs administered hPTH(1-34) alone. These qualitative morphological changes in the resorption lacunae were attenuated or absent in dogs administered hPTH(1-34) in combination with either 1,25(OH)(2)D(3) or risedronate. Functional periods for resorption were significantly increased, and the resorption rates were significantly decreased in the hPTH(1-34) + risedronate group. Analyses of the formative site demonstrated that the wall thickness was significantly increased and the bone balance significantly more positive in all three hPTH(1-34) treatment groups. The most positive bone balance was achieved in the combined hPTH(1-34) + risedronate group (+ 15.6 + or - 14.2 mm, p <0.05). Increases in the mineral apposition rate in the early phases of the formative period suggest that an increase in osteoblastic activity (number or function) may contribute to the increase in wall thickness. Treatment with hPTH(1-34) alone or in combination with 1,25(OH)(2)D(3) caused an approximately 2-fold increase in the activation frequency in cancellous bone, which was essentially normalized to control values by the coadministration of risedronate. The impact of these changes on the cancellous bone microstructure was significant only in the combined hPTH(1-34) + risedronate group where normalized bone turnover in the face of a positive bone balance effected a significant increase in the trabecular thickness. Analyses of sequential fluorochrome labels, administered to reconstruct the temporal changes in intracortical activation, demonstrated the presence of an apparent cyclic pattern of activation in the cortex of placebo-treated dogs. Generally, activation was increased throughout the study in dogs administered hPTH(1-34) alone or in combination. However, in the hPTH(1-34) + risedronate group, activation was significantly blunted toward the end of the study, and the cyclic pattern of activation was modulated. These data suggest that intermittent hPTH(1-34) in combination with risedronate may be superior to hPTH(1-34) in combination with 1,25(OH)(2)D(3) as a therapeutic regimen for osteoporosis due to the protective effect of this bisphosphonate on the cortical and endocortical envelope.
Boyce
R W
RW
Procter and Gamble Pharmaceuticals, Norwich, New York, USA.
Paddock
C L
CL
Franks
A F
AF
Jankowsky
M L
ML
Eriksen
E F
EF
D000818:Animals; D016723:Bone Remodeling / Q000187:drug effects*; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D002117:Calcitriol / Q000008:administration & dosage*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000008:administration & dosage*; D004285:Dogs; D004359:Drug Therapy, Combination; D012968:Etidronic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D000068296:Risedronic Acid; D019379:Teriparatide / Q000008:administration & dosage*
D002121:Calcium Channel Blockers; D019379:Teriparatide; D002117:Calcitriol; D000068296:Risedronic Acid; D012968:Etidronic Acid; D002118:Calcium