The effect of risedronate on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover.

The primary goal of our study was to determine changes in bone mineralization in postmenopausal osteoporotic women treated for 3 years with risedronate or placebo. A secondary goal was to determine the relationship between mineralization and indices of bone turnover measured on the same biopsies. The degree of mineralization was measured by micro-computed tomography using Synchrotron radiation (Synchrotron microCT) in the trabecular bone of paired transiliac biopsies taken at baseline and after 3 years of treatment from patients receiving risedronate 5 mg daily (n=11) or placebo (n=8). In the risedronate-treated patients, the average mineralization (Avg-MIN) and peak mineralization (Peak-MIN) at 3 years were significantly increased from baseline by 4.7% (P<0.0001) and 5.4% (P=0.0003), respectively and showed significant negative correlation to turnover indices. In the placebo-treated patients, the increases in Avg-MIN (2.0%) and Peak-MIN (1.6%) were not significantly different from baseline and correlation to turnover indices was weaker. Risedronate significantly reduced the ratio of low- to high-mineralized bone fractions estimated by volume (BMR-V) and surface area (BMR-S) by 70.1% and 54.1%, respectively from baseline. These changes were consistent with the significant reduction of turnover from baseline assessed by reductions in mineralizing surface, MS/BS (-72.8%); activation frequency, Ac.F (-60.4%); and bone formation rate, BFR-BV (-63.6%) in the same biopsies in the risedronate-treated patients. Comparing the pair-wise changes from baseline, risedronate significantly reduced the low-mineralized bone fraction in comparison to placebo, as indicated by a larger reduction of BMR-V (P=0.015) and BMR-S (P=0.035). In the risedronate group, BMR-V and BMR-S showed significant positive correlation to MS/BS (R2: 0.83 and 0.92, respectively). The correlations to Ac.F and BFR-BV were also significant, with BMR-S showing a strong relation (R2: 0.77 and 0.79, respectively). The data suggest that BMR-V and BMR-S are markers of turnover of trabecular bone and may be used to assess treatment effect on turnover in bone biopsies. The results demonstrate that the reduction of turnover by risedronate increased the degree of mineralization and reduced the ratio of low- to high-mineralized bone fractions which may increase bone's resistance to fracture.

Risedronate preserves bone architecture in postmenopausal women with osteoporosis as measured by three-dimensional microcomputed tomography.

The deterioration of trabecular microarchitecture induced by elevated bone turnover is increasingly recognized as a factor in the pathogenesis of osteoporotic fractures. We investigated the effect of the reduction of turnover with risedronate on trabecular architecture in postmenopausal women with osteoporosis. Iliac crest bone biopsy specimens taken before and after 3 years of treatment from patients receiving risedronate 5 mg daily (n = 21) or placebo (n = 17) were analyzed using 3-D microcomputed tomography. We found a significant correlation between baseline bone turnover and bone loss in the placebo group, providing evidence that higher turnover induced higher bone loss leading to a greater degree of architectural degradation. When patients were classified into two groups based on baseline bone turnover (MS/BS less than or greater than the median value for the entire cohort), significant decreases in trabecular bone volume (BV/TV, P = 0.009) and trabecular thickness (Tb.Th*, P = 0.008) and an increase in marrow star volume (Ma.St.V, P = 0.008), a measure of trabecular porosity, were observed in the higher turnover (MS/BS> median) placebo-treated patients. The trabecular structure shifted from plates to rods as shown by an increase in structure model index (SMI, P = 0.028) and bone surface to bone volume ratio (BS/BV, P = 0.006). The changes from baseline in the lower turnover (MS/BS

Tyrosine phosphatase inhibition augments collateral blood flow in a rat model of peripheral vascular disease.

During embryonic development, the growth of blood vessels requires the coordinated activation of endothelial receptor tyrosine kinases (RTKs) such as vascular endothelial growth factor receptor-2 (VEGFR-2) and Tie-2. Similarly, in adulthood, activation of endothelial RTKs has been shown to enhance development of the collateral circulation and improve blood flow to ischemic tissues. Recent evidence suggests that RTK activation is negatively regulated by protein tyrosine phosphatases (PTPs). In this study, we used the nonselective PTP inhibitor bis(maltolato)oxovanadium IV (BMOV) to test the potential efficacy of PTP inhibition as a means to enhance endothelial RTK activation and improve collateral blood flow. In cultured endothelial cells, pretreatment with BMOV augmented VEGFR-2 and Tie-2 tyrosine phosphorylation and enhanced VEGF- and angiopoietin-1-mediated cell survival. In rat aortic ring explants, BMOV enhanced vessel sprouting, a process that can be influenced by both VEGFR-2 and Tie-2 activation. Moreover, 2 wk of BMOV treatment in a rat model of peripheral vascular disease enhanced collateral blood flow similarly to VEGF, and after 4 wk, BMOV was superior to VEGF. Taken together, these studies provide evidence that PTPs are important regulators of endothelial RTK activation and for the first time demonstrate the potential utility of phosphatase inhibition as a means to promote collateral development and enhance collateral blood flow to ischemic tissue.

Risedronate preserves trabecular architecture and increases bone strength in vertebra of ovariectomized minipigs as measured by three-dimensional microcomputed tomography.

Risedronate reduces the risk of new vertebral fractures up to 70% within 1 year of treatment in patients with osteoporosis. Both increases in bone mass and preservation of bone architecture are thought to contribute to antifracture effects. Our objectives were to determine the effects of risedronate on trabecular bone mass and architecture and to determine the relative contributions of mass and architecture to strength in the vertebra of ovariectomized (OVX) minipigs. The minipigs were OVX at 18 months of age and were treated daily for 18 months with either vehicle or risedronate at doses of 0.5 mg/kg per day or 2.5 mg/kg per day. The three-dimensional (3D) bone architecture of the L4 vertebral cores of Sinclair S1 minipigs was evaluated by 3D microcomputed tomography (muCT). Compared with the OVX control, the vertebral bone volume (bone volume/tissue volume [BV/TV]) was higher in both treated groups (p < 0.05). The architectural changes were more significant at the 2.5-mg/kg dose and were more prevalent at the cranial-caudal ends compared with the midsection. At the higher dose, the trabecular thickness (Tb.Th), trabecular number (Tb.N), and connectivity were higher, and marrow star volume (Ma.St.V) and trabecular separation (Tb.Sp) were lower (p < 0.05). The trabecular separation variation index (TSVI), a new measure to approximate structural variations, was smaller in the 2.5-mg/kg-treated group (p < 0.05). In this group, a significant preservation of trabeculae orthogonal to the cranial-caudal axis was confirmed by a decrease in the degree of anisotropy (DA) and an increase in the percent Cross-strut (% Cross-strut; p < 0.05). Both normalized maximum load (strength) and normalized stiffness of the same vertebral cores were higher in the 2.5-mg/kg risedronate group compared with the OVX group (p < 0.05). BV/TV alone could explain 76% of the variability of the bone strength. The combination of bone volume and architectural variables explained >90% of the strength. The study showed that risedronate preserved trabecular architecture in the vertebra of OVX minipigs, and that bone strength is tightly coupled to bone mass and architecture.