The role of aromatase inhibitors (AIs) in breast cancer has expanded since their introduction in the mid-1990s. They are superior to tamoxifen in the treatment of postmenopausal women with oestrogen dependant tumours in the metastatic, neoadjuvant, and adjuvant settings and are currently been explored as chemopreventive agents. When compared to tamoxifen they are known to reduce bone mineral density (BMD), increase fracture rate, increase joint symptoms, and may also increase the risk of cardiovascular disease. The International Breast Cancer Intervention Study-II (IBIS-II) is the only breast cancer prevention randomised trial studying the role of anastrozole versus placebo in preventing breast cancer in postmenopausal women with a high risk of breast cancer. Methods This thesis focus on four main areas: (a) Analysis of data from the bone sub-study of the IBISII study, exploring the effects of anastrozole on bone mineral density at 12 and 36-months, and the ability of bisphosphonates treatment to reduce bone loss in women with low mineral density (BMD) at baseline. (b) Analysis of data from the prevention stratum of the IBIS-II study, exploring the effect of anastrozole on cholesterol fractions. (c) Analysis of the data from the Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial, exploring different risk factors for fractures in women with breast cancer who received either anastrozole or tamoxifen for five years (d) Analysis of data from the prevention stratum of the IBIS-II study, exploring if baseline 25(OH) vitamin D levels predicted arthralgia within one year of study. Results Women with normal BMD at baseline had a significant BMD loss at lumbar spine and total hip for both anastrozole and placebo. However, the BMD loss at lumbar spine was significantly 11 greater with anastrozole. Osteopenic women, who received anastrozole plus risedronate, after 12-months of treatment gained significant bone density at lumbar spine compared to women receiving anastrozole without risedronate, but not at total hip. At 36 months, there was no significant gain in bone density either at lumbar spine or total hip. In osteoporotic women, risedronate abrogated the detrimental effect of anastrozole, after 12 months of treatment, significantly at lumbar spine, but not at total hip. After 36 months of treatment, risedronate still abrogated the effect of anastrozole at lumbar spine, but not significantly. These 12 and 36- months data suggest that bone loss associated with anastrozole may be manageable with DXA monitoring and bisphosphonate use. Use of anastrozole did not lead to any significant changes in total cholesterol and high-density lipoprotein cholesterol levels when compared with placebo, except that anastrozole marginally decreased TC levels. These data support the lack of cardiovascular toxicity with anastrozole seen in the adjuvant trials. Using a model containing the following risk factors; age, weight/height/BMI, geographical regions, smoking, use of statins and other medication at baseline, previous chemotherapy, previous radiotherapy and trial therapy, only treatment, age and geographical regions were found to be significantly associated with fracture risk. No significant effect of baseline vitamin D levels were seen on the risk of musculoskeletal symptoms in healthy postmenopausal women at a high risk of breast cancer. The serum 25 (OH) vitamin D levels significantly increased in the anastrozole group from baseline to 12 months, when compared with placebo.

Nitrogen-containing bisphophonates (N-BPs) are a blockbuster class of drugs for the treatment of common metabolic bone diseases.  Recently, N-BPs have been shown to inhibit FPP synthase and/or isopentenyl diphosphate (IPP) isomerase (both enzymes in the mevalonate pathway), thereby preventing the synthesis of the isoprenoid lipids farnesyl diphosphate (FPP) and geranylgeranyl diphosphate (GGPP), which are vital substrates for protein prenylation.  By preventing the synthesis of FPP and GGPP, N-BPs prevent the prenylation of small GTPases and inhibit osteoclast function. This study demonstrates conclusively that the major pharmacological target of N-BPs is FPP synthase.  Furthermore, minor structural modifications to the N-BPs that govern <i>n vivo </i>potency have a marked effect on potency for inhibition of FPP synthase <i>in vitro.  </i>Non-N-BPs, such as clodronate and etidronate, did not inhibit FPP synthase, consistent with other studies suggesting that the non-N-BPs and N-BPs act by different molecular mechanisms. Clinically, N-BPs have been shown to exhibit marked differences in efficacy between patients and may lie resident in the skeleton for many years.  J774 macrophage-like cells resistant to the effects of N-BP (J774-RES) were generated to study the possible cellular mechanisms underlying clinical resistance to treatment.  The J774-RES cells accumulated N-BP to a lesser extent than parental cells and also exhibited increased expression of the MCSF receptor, although further studies are required to clarify the exact mechanism of the resistance of J774-RES cells. Finally, N-BPs have been shown to induce the proliferation of the major subset (V<span style='font-family:Symbol'>g9V<span style='font-family:Symbol'>d2) of <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-T cells in humans, attributed to an agnostic effect on the <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-T cell receptor (TCR).  The findings of this study indicate that the N-BPs act indirectly, by inhibiting FPP synthase and causing the accumulation of IPP, a known agonist of the <span style='font-family:Symbol'>g,<span style='font-family:Symbol'>d-TCR.  Furthermore, this proliferative effect of N-BPs could be abrogated by statins, possibly indicating a means of preventing the acute-phase response, the major side effect to intravenously-administrated N-BPs.