Long-Term Zoledronic Acid Treatment Increases Bone Structure and Mechanical Strength of Long Bones of Ovariectomized Adult Rats

Abstract

Zoledronic acid (ZOL) is a highly potent heterocyclic bisphosphonate which has been shown to inhibit bone resorption in short-term experiments in young growing animals. In this investigation we have evaluated the effects of a 1-year administration to mature, ovariectomized (OVX) rats as a model for postmenopausal osteoporosis in order to elucidate (1) the temporal changes in urinary biochemical markers of bone turnover and femoral bone mineral density (BMD), (2) to measure changes of static and dynamic histomorphometric parameters and mechanical strength, and (3) to assess the preventive effects of chronic treatment with ZOL on these parameters. In urine, deoxypyridinoline increased after OVX and was significantly reduced by ZOL administration, indicative of a reduced bone collagen turnover. These changes were accompanied by alterations of tibial cancellous bone: trabecular bone volume and parameters of bone architecture were significantly augmented by ZOL and bone formation rates fell as a consequence of suppressed bone turnover, but were still measurable. No signs of "frozen bone" or osteomalacia could be detected. BMD of the whole femurs rose in sham-operated control animals (SHAM) during the entire experimental period, whereas in OVX animals, BMD plateaued after 32 weeks at a lower level. ZOL at a low dose (0.3 mg/kg/week s.c.) did not alter whole femur BMD, but at higher doses (1.5 and 7.5 mg/kg/week s.c.) BMD increased to the level of the SHAM group. A distinct pattern was noted for the distal quarter of the femur, a region rich in cancellous bone: BMD initially increased in all treatment groups except the OVX group, and at a later stage fell again at a comparable rate irrespective of treatment. Mechanical stability, as assessed by a 3-point bending test, was significantly increased by all doses of ZOL and exceeded OVX and sham-operated controls. The effects on mechanical properties were observed at a low dose which did not measurably increase femoral BMD after 1-year treatment. Multiregression analysis revealed a significant positive correlation between maximum load and BMD, and a significant negative correlation of maximum load with labeled perimeter, a marker of bone formation and turnover. No significant correlation was found with urinary deoxypyridinoline, a marker of bone resorption. The data show that mechanical testing detects improvements of functional bone quality following low dose bisphosphonate treatment which are not identified by standard DXA measurements of BMD.

Influence of Early and Late Zoledronic Acid Administration on Vertebral Structure and Strength in Ovariectomized Rats

“…Previously, it was shown that 1 year of weekly injections of ZOL inhibited OVX-induced changes in bone microstructure and bone strength of femora and lumbar vertebrae of rats [7][8][9]. Also, in the same rats as used in this study, a single injection of ZOL prevented deterioration of bone microstructure and strength in tibiae of OVX rats for 16 weeks and a single injection at 8 weeks after OVX prevented further deterioration of structure and strength [10].…”

“…Thus, although the study did not have the power to detect a small difference of 10%, it was adequately powered to answer the primary question and to answer secondary questions if the differences were large enough to be clinically relevant (i.e., on the order of 20%). It should also be noted that in previous studies on the effects of weekly ZOL injections on mechanical properties, group sample sizes were 16-20, offering a higher power to detect differences [7,9]. Therefore, further studies with a larger sample size are needed to distinguish between the effects of early and late ZOL treatments on vertebral trabecular microarchitecture and strength.…”

“…Furthermore, a single injection of ZOL 8 weeks after OVX inhibited further deterioration of the bone microstructure and strength in rat tibiae compared to untreated OVX rats. Other studies have shown that weekly injections of ZOL inhibit changes in bone microstructure and strength in rat vertebrae after OVX [8,9]. However, it is not known to what extent a single dose of ZOL is able to inhibit and restore OVX-induced loss of bone mass, structure, and strength in rat vertebrae.…”

“…Zoledronic acid (ZOL) is a potent bisphosphonate that has recently been shown to significantly reduce fracture risk in osteoporotic patients who received once-yearly doses [4,5]. As the number and depth of in vivo analyses in patients are limited, animal research is ongoing to further elucidate the effects of ZOL on skeletal fragility [6][7][8][9]. Previously, we showed in a longitudinal study of adult rats that a single injection of ZOL at the time of ovariectomy (OVX) inhibited OVX-induced deterioration of bone microstructure and strength in the proximal tibiae for up to 16 weeks [10].…”

Efeito do ácido zoledrônico em tíbias de ratas ooforectomizadas: estudo prospectivo e randomizado

“…Após o climatério, em função da alteração não apenas da distribuição de tecido adiposo, causado pela deficiência de estrógenos, mas também pelo acú-mulo periférico de gordura, ocorre alteração do perfil lipídico e aumento da massa corporal (31) . Não verificamos, neste estudo, a influência do ácido zoledrônico no aumento da massa corporal dos animais, fato também comprovado por Reid et al (16) , Hornby et al (32) , Otrock et al (33) e Gilfillan et al (34) . Conclui-se, portanto, que o aumento da massa corpórea foi causado pela retirada dos ovários (ooforectomia) e não pelas substâncias administradas.…”