Changes to Bone Architecture and Mechanics within 12 Weeks of Ovariectomy
Abstract
The ovariectomised (OVX) rat is the most common preclinical research model for the study of osteoporosis. It is well suited for studying the effects of oestrogen depletion on bone microarchitecture. The recent development of in vivo micro-computed tomography (μCT) offers the possibility of monitoring microarchitectural adaptations within the same animal. Time series data provide novel insight and it has been found that, in the first 12 weeks following OVX, there is a rapid decrease in trabecular bone volume in the proximal tibia and a concurrent reduction in connectivity density and bone strength. Treatments can restore bone mass, but the topology of the structure is permanently altered – no new trabecular connections are formed. Nevertheless, μCT-based finite element simulations indicate that, despite the altered architecture, bone strength measures can be restored. The combination of the established OVX rat model and new in vivo μCT has the potential to provide important insight into microarchitecture adaptations in osteoporosis research.Acknowledgements:
This work was supported by grants from the Canadian Institute of Health Research (CIHR), Alberta Innovates – Health Solutions (AIHS), and Alberta – Innovates Technology Futures (AITF).
Citation: European Musculoskeletal Review, 2010;5(2):18–22
Rat, bone architecture, osteoporosis, in vivo, micro-computed tomography, ovariectomy
Osteoporosis is a common, multifactorial disorder of reduced bone mass and microarchitectural deterioration of bone tissue, manifesting clinically as a concurrent increase in fragility and fracture risk.1,2 Approximately 30% of post-menopausal women have osteoporosis according to the World Health Organization.3 By age 65, one in five women are estimated to have suffered osteoporotic fractures and the number doubles after this age.4 Fractures have a devastating impact on morbidity, mortality,5 social and healthcare national costs.
Traditionally, osteoporosis research has focused on bone mineral density as measured by dual-energy X-ray absorptiometry. It has increasingly become recognised, however, that factors other than density play an important role in the assessment of bone quality – a general term that describes physical changes in bone relating to increased fragility. Although a precise definition of bone quality is elusive, it is widely accepted that the four key components include bone microarchitecture, turnover, damage accumulation and mineralisation.
In the past two decades, the development of micro-computed tomography (μCT)6 has provided a non-destructive means by which to assess 3D bone microarchitecture.7 This has enabled important new insight into the role of microarchitecture on bone quality. Most recently, in vivo techniques8,9 for μCT have become available, which provide a fascinating insight into the normal development of bone microarchitecture and how that microarchitecture changes with a disease such as osteoporosis. Although there are new possibilities for measuring microarchitecture in humans,10–12 animal models of osteoporosis have advantages due to the relatively short duration of the studies, the ability to precisely control experimental conditions and the use of higher resolution in the scans.
This paper will review the recent in vivo μCT developments for the study of osteoporosis. It will focus on early changes to microarchitecture in the most common model for osteoporosis research – changes in the first 12 weeks of the rat model for the disease. It will briefly discuss the rat model for osteoporosis research and then focus on recent findings using this new technology. Considerations for osteoporosis research using the rat model in combination with in vivo μCT are also outlined.
Ovariectomised Rat Model
Although there are several animal models that have been used for osteoporosis research, ranging in size from murine to ovine models, the most widely accepted animal model for osteoporosis research is the ovariectomised (OVX) rat.13,14 The advantage of the rat model is that disease progression is relatively quick and the commonly-measured skeletal sites – proximal tibia or lumbar spine – have abundant cancellous bone.
The two most common rat strains for preclinical osteoporosis researchare the Wistar rat and the Sprague Dawley. The experimental model is based on the OVX operation, which causes an oestrogen deficiency that induces an increase in bone remodelling rate.13,15
Traditionally, histological techniques have been used to measure the effect of OVX on the rat skeleton, demonstrating rapid changes to osteoclast and osteoblast activity on the bone surface and consequently increased bone turnover. The increased turn over favouring bone resorption results in a net loss of mineralised tissue, particularly in the cancellous bone shortly after OVX (within 12 weeks).14 Over the long-term, for example 1.5 years, the change to the bone stabilises, albeit with a significantly altered microarchitecture, as measured by microradiography to estimate nodal structure analysis and anisotropy. 16
Although the OVX rat does not sustain fragility fractures, it is a useful model for understanding the progression of microarchitecture changes over time and the effect that interventions have on OVX-related bone loss. It should be noted that the age of the animal at the time of OVX may have an impact on the results. Ideally, the rats should no longer be growing; therefore the age of OVX rats should be in the order of six to eight months.
