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This dissertation, Novel Strontium Fortified Calcium Salt for Enhancing Bone Formation: an in Vitro and in Vivo Large Animal Model Study by Zhaoyang, Li, 李朝陽, was obtained from The University of Hong Kong (Pokfulam, Hong Kong) and is being sold pursuant to Creative Commons: Attribution 3.0 Hong Kong License. The content of this dissertation has not been altered in any way. We have altered the formatting in order to facilitate the ease of printing and reading of the dissertation. All rights not granted by the above license are retained by the author. Abstract: Abstract of thesis entitled Novel strontium fortified calcium salt for enhancing bone formation: An in vitro and in vivo large animal model study Submitted by Zhaoyang LI for the degree of Doctor of Philosophy at The University of Hong Kong in July, 2007 Strontium is a mineral that closely resembles calcium and traces of strontium can be found in various foods and in drinking water. Most importantly, the use of strontium in the treatment of osteoporosis has been one of the most exciting prospects observed during the last 20 years. This element in the form of a ranelate compound has become increasingly popular in prevention and treatment of osteoporosis by concomitantly inhibiting bone resorption and enhancing bone formation. Since in this drug, strontium acts as the sole active component, strontium compound is postulated to have a favorable effect for osteoporosis treatment. The new bone formed under the influence of strontium therapy might not have been of high quality, so the dosage of strontium that provides the balance of safety and efficacy need further optimization. Previously, we had developed a novel strontium fortified calcium phosphate compound. The incorporation of strontium into calcium phosphate increased the solubility of this calcium supplementing compound and therefore increased the absorbability of calcium. Calcium, being an essential bone healthy nutrient, has a central role in the efficacy of all osteoporosis treatment. We hypothesized that, with the supplementation of this novel compound, calcium will supply nutrition for bone while strontium will display synergistic effects for enhancing bone formation activity. This is the first study to evaluate low dosage strontium combined with calcium for enhancing bone formation in a large animal model of osteoporosis. Oral administration of strontium fortified calcium compound significantly increased expression of IGF-I and Runx2 in bone matrix. Both IGF-I and Runx2 levels were positively associated with the bone mineral apposition rate (MAR). The anabolic effect of low dosage of strontium was further confirmed by the increase in bone mineral density (BMD) and bone volume of the lumbar spine. Despite the fact that the overall mechanical properties were not improved except for a slight increase in fracture toughness of single trabecula, the improvement in the above two parameters of MAR and BMD clearly demonstrated the activity of low dosage strontium for enhancing bone formation. Another important finding was the effect of combination treatment on bone quality. After oral administration of strontium fortified calcium compound, strontium concentration was much higher in cancellous bone than that in cortical bone, and strontium mainly deposited in newly formed bone. The chemical composition of bone mineral crystals of new bone did not change with the incorporation of strontium, which corresponded well with the in vitro results. These results together with histomorphometric analysis substantially confirmed the safety of low dosage of strontium combined with calcium treatment. In conclusion, low dosage strontium combined with calcium treatment considerably increased bone matrix osteogenic factors expression, stimulated new bone formation and increased bone mass without changing the composition and structure of bone mineral. Although significant improvement in bone mechanical property was not

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