Abstract
The use of Parathyroid Hormone (PTH) as bone anabolic is limited due to cost-benefit assessments. Preclinical studies evaluating the effects of PTH on bone have reported variable and often contradictory results. Here, we have applied a new approach using a combination of in-vivo longitudinal µCT, image processing techniques and finite element models to monitor early local changes in the whole tibia (divided in 40 compartments) and mechanical properties of female C57BL/6J mice treated with PTH 1-34, compared to controls. Compared with standard 3D bone morphometric analysis, our new approach allowed detection of much smaller and localised changes in bone mineral content (BMC) at very early time points (1 week vs 3 weeks with standard methods) and showed that changes do not occur uniformly over time and across the anatomical space. Indeed, in the PTH treated mice, significant changes in BMC were observed in the medial and posterior sectors of the proximal tibia, a week after treatment, and in the medial sector of the tibia midshaft region a week later (p < 0.05). By the third week, two thirds of the regions showed significantly higher values of BMC (p < 0.05). The effect of PTH on bone regional volume is similar to that on BMC, but there is almost no effect of PTH on bone tissue mineral density. The differences in estimated mechanical properties became significant after three weeks of treatment (p < 0.05). These results provide the first evidence of an early and localised PTH effect on murine bone, and show that our novel partitioning approach, compared to the standard evaluation protocol, allows a more precise quantification of bone changes following treatment, which would facilitate preclinical testing of novel mono- and/or combination therapies throughout the bone.
Highlights
Osteoporotic fractures are a major clinical problem that increases the mortality and morbidity of our ageing society [1, 2]
The total bone mineral content (BMC) measured at week 22 culling the animals on the non-irradiated tibia was lower than that measured on the irradiated tibia
Considering that similar differences were found for both intervention and vehicle groups we believe that our approach is reliable for evaluating the changes induced by parathyroid hormone (PTH)
Summary
Osteoporotic fractures are a major clinical problem that increases the mortality and morbidity of our ageing society [1, 2]. The combination of in vivo micro computed tomography (μCT) and image registration improve the measurement of bone properties by reducing measurements uncertainties [17] This approach has been used to study in mice models the effect of interventions and/or mechanical loading on bone remodelling in the trabecular centrum of the caudal vertebrae [18,19,20], in the proximal tibia [21,22,23] or in the tibia midshaft [24, 25]. To the authorsÕ knowledge no studies have used the in vivo μCTbased FE models to reveal longitudinal changes in the whole tibia mechanical properties and their relations with the spatiotemporal changes of bone morphological and densitometric properties This would be fundamental to understand if the pre-clinically tested intervention would be effective in improving the bone competence of resisting fractures, which is the final clinical goal of anti-osteoporosis treatments
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