Compositional and Material Properties of Rat Bone After Drug Treatment

Various X-ray imaging modalities, such as planar X-ray films, dual energy X-ray absorptiometry and computed tomography have been utilized to estimate bone strength for osteoporotic subjects. However, emerging cases of spontaneous femoral shaft fracture in osteoporotic patients after years of bisphosphonate (BP) medication and controversial gains in bone mineral density (BMD) after medication with strontium ranelate (SrR) have questioned the reliance of X-ray based imaging for accurately assessing fracture risk. Therefore, assessments of bone strength must further account for the influence of bone microarchitecture, changes in elemental composition and material properties of bone following potent drug interventions. Accordingly, in this thesis, the hypothesis was that osteoporotic bone would be influenced by alterations in bone microarchitecture, elemental composition and corresponding material properties following drug treatment, which in the aggregate, affect bone strength.

In order to investigate the elemental composition and material properties, electron probe micro analysis and nanoindentation tests were applied to bone samples following SrR and/or BP treatment. The results confirmed that elemental strontium (Sr) was incorporated into bone predominantly in regions of new bone formation, through either the bone remodelling process or by incorporation during appositional and elongating bone growth. The material properties of bone were maintained following high dose strontium treatment, however, bone hardness was degraded following BP treatment. To measure bone strength, a simplified finite element analysis was established to calculate bone strength. Those analyses indicated that the strength of bone was positively related to the structural parameters of bone volume/tissue volume, BMD and fractal dimension. To further explore the controversial increase in BMD following Sr drug therapy, a series of known solution standards for Sr and calcium (Ca) were evaluated using micro- computed tomography (Micro-CT). Our results proved that for every 1 mole% increase in Sr/(Sr+Ca), there was a corresponding 6.4% increase in BMD using X-ray based Micro-CT.

In summary, both elemental composition and material properties of rat bone were substantially altered following three months treatment with BP and/or SrR. Those alterations affected bone strength and microarchitecture, and the incorporation of Sr resulted in the bias of elevated BMD using X-ray based imaging modalities.

Year	Entry
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Year

Entry

1994

Kanis JA, Melton LJ III, Christiansen C, Johnston CC, Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res. August 1994;9(8):1137-1141.

2011

Brennan O, Kennedy OD, Lee TC, Rackard SM, O’Brien FJ, McNamara LM. The effects of estrogen deficiency and bisphosphonate treatment on tissue mineralisation and stiffness in an ovine model of osteoporosis. J Biomech. February 3, 2011;44(3):386-390.

2008

MacNeil JA, Boyd SK. Bone strength at the distal radius can be estimated from high-resolution peripheral quantitative computed tomography and the finite element method. Bone. June 2008;42(6):1203-1213.

2008

Boivin G, Bala Y, Doublier A, Farlay D, Ste-Marie LG, Meunier PJ, Delmas PD. The role of mineralization and organic matrix in the microhardness of bone tissue from controls and osteoporotic patients. Bone. September 2008;43(3):532-538.

2000

Kinney JH, Haupt DL, Balooch M, Ladd AJC, Ryaby JT, Lane NE. Three‐dimensional morphometry of the L6 vertebra in the ovariectomized rat model of osteoporosis: biomechanical implications. J Bone Miner Res. October 2000;15(10):1981-1991.