Effects of short-term treatment with the bisphosphonates zoledronate and pamidronate on rat bone: a comparative histomorphometric study on the cancellous bone formed before, during, and after treatment.
To study the anti-resorptive effects of zoledronate and pamidronate on growing long bones we have performed a histomorphometric analysis of the three regions of the proximal tibial cancellous bone of bone formed before, during, and after drug treatment. Male rats (190-220 g) were treated subcutaneously for 10 days with zoledronate (0.028-2.8 microg/kg) or pamidronate (3.7-370 microg/kg) and sacrificed 5 days later. To delineate the three regions of cancellous bone, and for dynamic bone histomorphometry, calcein and demeclocycline were injected at various times. Both bisphosphonates caused a dose-dependent suppression of cancellous bone turnover and resorption to produce an increase in cancellous bone, but zoledronate was 100 times more potent than pamidronate. The increase in the bone amount and connectivity was more pronounced in the bone formed during treatment where transient bone resorption and normal bone formation led to a positive bone balance. In the bone formed before treatment, inhibition of bone resorption associated with reduced bone formation produced a net gain in amount of bone. Although both bone regions showed a positive bone balance, more bone accumulated in the bone formed during treatment probably because its trabecular bone surface was three times greater. In the primary spongiosa formed after treatment, a moderate increase in the bone amount and connectivity was observed only at the highest dose of both bisphosphonates. The bone formed before, during, and after treatment with bisphosphonates responds differently due to differences in bone architecture, rates of modeling and remodeling, and period of drug exposure.
Pataki
A
A
Novartis Pharma Inc., Basle, Switzerland.
Müller
K
K
Green
J R
JR
Ma
Y F
YF
Li
Q N
QN
Jee
W S
WS
D000818:Animals; D000900:Anti-Bacterial Agents / Q000008:administration & dosage; D015415:Biomarkers; D001846:Bone Development / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D003707:Demeclocycline / Q000008:administration & dosage; D004164:Diphosphonates / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005269:Femur / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D005452:Fluoresceins / Q000008:administration & dosage; D006132:Growth Plate / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D006909:Hydroxyproline / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D007202:Indicators and Reagents / Q000008:administration & dosage; D007279:Injections, Subcutaneous; D008297:Male; D000077268:Pamidronate; D051381:Rats; D017207:Rats, Sprague-Dawley; D013977:Tibia / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D000077211:Zoledronic Acid
D000900:Anti-Bacterial Agents; D015415:Biomarkers; D004164:Diphosphonates; D005452:Fluoresceins; D007093:Imidazoles; D007202:Indicators and Reagents; D003707:Demeclocycline; D000077211:Zoledronic Acid; D000077268:Pamidronate; D006909:Hydroxyproline; D002118:Calcium; C007740:fluorexon