Once-Weekly Teriparatide Treatment Prevents Microdamage Accumulation in the Lumbar Vertebral Trabecular Bone of Ovariectomized Cynomolgus Monkeys

Abstract

The effect of teriparatide treatment on microdamage accumulation has yet to be examined in animal studies. The purpose of this study was to investigate the effect of once-weekly teriparatide treatment on bone microdamage accumulation and the relationship between microdamage parameters and bone mass, architecture, turnover, and collagen cross-linking in the lumbar vertebral trabecular bone of ovariectomized (OVX) cynomolgus monkeys. Female monkeys were divided into four groups (n = 18-20 per group): (1) SHAM group, (2) OVX group, (3) OVX with 1.2 µg/kg once-weekly teriparatide group (LOW group), (4) OVX with 6.0 µg/kg once-weekly teriparatide group (HIGH group). After 18 months, all animals were double-labeled with calcein for histomorphometry. L3 and L7 lumbar vertebrae were harvested and analyzed for differences in histomorphometry, microdamage, and collagen cross-linking. The iliac crest was also analyzed for differences in bone turnover. In the OVX group, cancellous bone mass was reduced and microdamage accumulation was increased as compared with the SHAM control. Once-weekly teriparatide at both doses prevented the decrease in bone mass and increase in microdamage accumulation, and improved the distribution of collagen cross-linkage types. Regression analyses indicated that decreased microdamage accumulation was associated with reduced non-enzymatic cross-link pentosidine rather than increased cancellous bone mass or enzymatic cross-links. These findings suggest that once-weekly teriparatide treatment decreases microdamage accumulation by recovering the balance in collagen cross-links.

A quantitative analysis of bone lamellarity and bone collagen linearity induced by distinct dosing and frequencies of teriparatide administration in ovariectomized rats and monkeys

“…There were no significant differences in parameters such as BV/TV, BS/BV, trabecular thickness, trabecular number, trabecular separation, single-labeled surface/BS, double-labeled surface/BS, mineralizing surface/BS, bone formation rate/bone and surface (bone formation rate/BV) ( Supplementary Fig. 8 , Supplementary Table 1a ), which was consistent with a previous report [ 29 ]. Based on this morphometric analysis, we selected three representative specimens from each of the Sham, OVX, TPTD-L and TPTD-H experimental groups.…”

“…After a relatively long period of TPTD treatment (18 months), none of the histomorphometric parameters in monkeys showed significant differences, indicating that the increased bone turnover induced by once-weekly TPTD treatment had already plateaued during the long treatment period in these monkey specimens, which was consistent with a previously reported observation in relation to the same monkey specimens [ 29 ]. However, a biochemical analysis of collagen cross-link properties of the same monkey specimens demonstrated that low-dose and high-dose TPTD treatments increased the content of enzymatic immature and mature cross-links and decreased advanced glycation end product cross-links, such as pentosidine, in comparison to the OVX group [ 28 ].…”

“…We also subjected these bone sections to collagen imaging by second harmonic generation (SHG) [ 20 , 23–27 ]. To statistically analyze the spatial pattern of bone formation associated with bone collagen, we re-evaluated previously reported rat and cynomolgus monkey bone specimens that were treated with TPTD [ 19 , 28 , 29 ].…”

Evaluation of cortical bone remodeling in canines treated with daily and weekly administrations of teriparatide by establishing AI-driven morphometric analyses and GIS-based spatial mapping

“…Morphometric analyses and histological measurements of trabecular bone to compare the drug administration groups in this study, however, did not show any significant differences. This was very similar to studies in ovariectomized monkey models to which TPTD was administered for a long period of 24 months, which suggested that bone remodeling did not obviously react to TPTD after long treatment ( Yoshitake et al, 2019 ). Nevertheless, histological observations of cortical bone in this study showed somewhat distinct appearances in the shape of Haversian canals, especially of specimens in the DH group, which prompted us to establish AI-driven morphometric analyses of Haversian canals to comprehensively compare remodeling features of cortical bones with distinct TPTD regimens.…”