Murray, Alastair William

2018-03-29T12:19:08Z

2018-03-29T12:19:08Z

2007

Despite recent improvements in the ability to prevent osteoporotic fracture a vast number of mainly elderly patients continue to sustain fractures resulting in significant morbidity and a huge demand on health care services. Current knowledge of the process of fracture healing in osteoporotic bone is limited but there is a suggestion that it may differ from that of normal bone. An improved knowledge of the mechanical and biological properties of healing fractures in osteoporosis could ultimately lead to an enhancement of our ability to treat this problem by both medical and surgical means.

The aim of this study was firstly to use an animal model to investigate the histological and mechanical properties of fracture healing in osteopenic bone. Secondly, the same model and outcome parameters were used to study the effect on fracture healing of the systemic administration of simvastatin, which recent studies have suggested, promotes both bone formation and inhibits bone resorption.

In part one of the study 20, 3-month-old female, Wistar rats underwent ovariectomy (Ovx) while a further 20 had a sham procedure to act as controls. Seven weeks later a transverse fracture was created in the proximal tibia of each animal by three-point bending with the resulting fractures supported by an intramedullary wire. Half of the animals in each group were euthanased at two weeks and the remainder at four weeks post fracture with the tibiae removed post mortem. All tibiae were then xrayed. The mechanical properties of half of the healing fractures were ascertained by four-point bending to failure while the remaining specimens were prepared for histological analysis and immunohistochemistry. There were no mechanical differences in the fracture calluses from the ovx animals compared with control at two weeks but by four weeks post fracture the ultimate load at failure of the fractures from the ovx animals was reduced to 71% of that from controls. Stiffness (54%) and stress at yield (74%) were also reduced while the strain at yield was increased by 40% in fractures from the ovx group. Histological differences were also seen with an increased porosity of the calluses from the ovx group at four weeks. No radiological differences were note and there was no difference in the expression of the key growth factors BMP 2, BMP 6 or Smadl. No difference in the replication of key cell populations was seen.

In the second part of the study the same animal model was used with the groups once again divided into ovx and sham controls. Half of each group received placebo while the other half received simvastatin 20mg/kg daily for 14 days post fracture. The same time points and outcome measures were used as in the first part of the study. In the sham groups simvastatin had no detectable effect on the radiological or mechanical features of the fractures or on the expression of the growth factors studied. The only difference was a higher proportion of immature bone in the four-week-old calluses from the simvastatin group (40%) versus placebo (34%). In the ovx animals simvastatin had a more noticeable effect with, once again, a higher proportion of immature bone in the four week old calluses in the drug group (43%) versus 28% in the placebo group. In addition the four-week-old healing fractures in the statin group had smaller calluses (16mm2 compared with 28mm2) and were able to withstand only 76% of the ultimate load before failure than the fractures from the placebo fed ovx controls. An increased level of Smadl expression was also seen in the chondrocytes of the statin fed ovx group.

The findings from the first part of this study provide evidence that an osteopenic environment has a deleterious effect on the mechanical properties of healing fractures in the rat model with an associated impairment of callus maturation. Contrary to previous work the dose and method of delivery of simvastatin in the second part of this study had no apparent effect on the fracture healing in normal bone. However simvastatin appeared to have a deleterious effect on fracture healing in the osteopenic model causing a reduction in callus size and maturity and reducing the healing fractures' ability to withstand load. This study does not support a role for simvastatin in the enhancement of fracture healing in osteopenia.

http://hdl.handle.net/1842/29286

The University of Edinburgh

Annexe Thesis Digitisation Project 2018 Block 17

Already catalogued

Fracture healing in osteopenic bone and the influence of simvastatin

Thesis or Dissertation

Doctoral

MD Doctor of Medicine