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

Abstract

An annual infusion of zoledronic acid (ZOL) reduces fracture risk in osteoporotic patients. Previously, we showed that a single ZOL injection inhibited changes in bone microstructure and strength in rat tibiae after ovariectomy. Here, we determined the effects of a single ZOL injection as preventive and restorative treatment on the bone microstructure and strength in lumbar and caudal vertebrae of ovariectomized (OVX) rats. Twenty-nine female 35-weekold Wistar rats were divided into four groups: SHAM-OVX (n = 9), OVX (n = 5), OVX and early ZOL (n = 8), and OVX and late ZOL (n = 7). ZOL was given once (20 lg/kg body weight s.c.) at OVX in the early ZOL group and 8 weeks later in the late ZOL group; rats were killed 16 weeks after OVX. Trabecular and cortical bone microarchitecture were measured in lumbar (L3) and caudal (Cd6) vertebrae using micro-computed tomography, and compressive mechanical properties were determined in L3 vertebrae. Compared to SHAM-OVX, OVX rats had significantly lower BV/TV; SMI, Tb.N, Tb.Sp, and Conn.D tended to be deteriorated in lumbar vertebrae, while both ZOL groups did not differ from the SHAM-OVX group. Both ZOL groups had significantly higher BV/TV than OVX; the early ZOL group also had significantly lower SMI and higher Tb.Th. OVX tended to decrease mechanical properties, while early and late ZOL treatment inhibited OVX-induced degeneration. Neither OVX nor ZOL induced changes in the trabecular microarchitecture of caudal vertebrae. In summary, in adult rats a single ZOL injection inhibited OVX-induced changes in lumbar vertebral bone microarchitecture and strength.Keywords Bisphosphonate Á Bone architecture/ structure Á Osteoporosis Á Animal model Bisphosphonates inhibit bone resorption and are commonly used to treat osteoporotic patients. They slow the process of bone loss and reduce the risk of fracture by maintaining bone mass and microstructure [1][2][3]. 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]. 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.

Skeletal effects of zoledronic acid in an animal model of chronic kidney disease

“…CKD animals (n=25) were given a single intraperitoneal dose of VEH or ZOL (either 20 or 100 µg/kg body weight) or administered 3 % calcium gluconate in the drinking water. Both ZOL doses have been shown to be effective in preserving bone volume in ovariectomized rats when given as a single dose [20, 21]. The calcium gluconate group was used as a positive control to simulate calcium administration as a phosphate binder, which in CKD has been shown to reduce bone remodeling [22].…”

Detecting early bone changes using in vivo micro-CT in ovariectomized, zoledronic acid-treated, and sham-operated rats

“…Zoledronic acid is a novel bisphosphonate used in antiresorptive therapies; histology and micro-CT testing has shown it to be highly effective in preventing bone loss in ovariectomized rats [9,21,[23][24][25]. The capability of in vivo micro-CT to track the efficacy of antiresorptive therapy in reversing bone mass and microarchitecture deterioration in ovariectomized rats has been demonstrated [12,16,26].…”

“…The cross-sectional design was necessary, as the quantification of the microarchitecture was done in vitro, by either histology or in vitro micro-CT [7,[13][14][15], whereas in vivo micro-CT, which allows longitudinal study designs, was accessible only at synchrotron facilities [16][17][18]. More recent developments in micro-CT technology have made compact in vivo micro-CT systems available, making it possible to then conduct longitudinal studies on animals in laboratories [11,[19][20][21][22]. A big advantage of performing longitudinal rather than cross-sectional studies is that a comparatively small number of animals is needed for making comparisons, as each animal acts as its own control.…”

Orthodontic tooth movement and root resorption in ovariectomized rats treated by systemic administration of zoledronic acid

“…15 Moreover, ZOL has been advocated by several histological and micro-CT studies showing highly effective prevention of bone loss in ovariectomized rats. [16][17][18][19][20] Rat and mouse models have been commonly used for the studies of orthodontic tooth movement and OIRR. Sirisoontorn et al 21 has…”