Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 5 uppsatser.

Lee, Hoi Ying. / "September 2010." / Thesis (M.Phil.)--Chinese University of Hong Kong, 2010. / Includes bibliographical references (leaves 171-189). / Abstracts in English and Chinese. / Abstract (English) --- p.i / Abstract (Chinese) --- p.iii / Acknowledgement --- p.v / Publications --- p.vi / Abbreviations --- p.vii / Table of Content --- p.x / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Human mast cells and its activation --- p.1 / Chapter 1.2 --- Role of mast cells in inflammation --- p.2 / Chapter 1.3 --- Mast cell heterogeneity --- p.5 / Chapter 1.4 --- Interaction of bone and immune system --- p.1 / Chapter 1.5 --- Introduction of bone system --- p.8 / Chapter 1.6 --- Bone remodeling --- p.9 / Chapter 1.7 --- Regulation of bone remodeling --- p.10 / Chapter 1.8 --- Introduction of Osteoporosis --- p.12 / Chapter 1.9 --- Pathophysiology of osteoporosis --- p.13 / Chapter 1.10 --- Pharmacological interventions in osteoporosis --- p.14 / Chapter 1.11 --- Involvement of mast cells in bone metabolism --- p.18 / Chapter 1.12 --- Aim of study --- p.20 / Chapter 2 --- Materials and Methods --- p.27 / Chapter 2.1 --- Materials --- p.27 / Chapter 2.2 --- Methods --- p.34 / Chapter 2.2.1 --- Human mast cells culture --- p.34 / Chapter 2.2.2 --- Human mast cells characterization --- p.35 / Chapter 2.2.3 --- Histamine release assay --- p.36 / Chapter 2.2.4 --- Immunofluorescence staining of estrogen receptors --- p.37 / Chapter 2.2.5 --- Reverse Transcriptase Polymerase Chain Reaction --- p.37 / Chapter 2.2.6 --- TNF measurement --- p.38 / Chapter 2.2.7 --- Calcium mobilization studies of mast cells --- p.38 / Chapter 2.2.8 --- Statistical analysis --- p.39 / Chapter 3 --- Effects of estrogen and selective estrogen receptor modulators (SERMs) on mediators release from human mast cells --- p.41 / Chapter 3.1 --- Introduction --- p.41 / Chapter 3.2 --- Materials and methods --- p.50 / Chapter 3.3 --- Results --- p.51 / Chapter 3.3.1 --- Characterization of human mast cells --- p.51 / Chapter 3.3.2 --- Effect of estrogen on mediator release from human mast cells --- p.52 / Chapter 3.3.2.1 --- Basal histamine release after treatment of estrogen --- p.52 / Chapter 3.3.2.2 --- Histamine release induced by immunological stimulus --- p.52 / Chapter 3.3.2.3 --- Histamine release induced by chemical secretagogues --- p.54 / Chapter 3.3.3 --- Effect of selective estrogen receptor modulators (SERMs) on mast cell activity --- p.54 / Chapter 3.3.3.1 --- Basal histamine release after SERMs treatment --- p.54 / Chapter 3.3.3.2 --- Histamine release induced by immunological stimulus --- p.55 / Chapter 3.3.3.3 --- Histamine release induced by chemical secretagogues --- p.57 / Chapter 3.3.4 --- Effect of estradiol on TNF-α release from human mast cells --- p.57 / Chapter 3.3.5 --- Effect of SERMs on TNE-α release from human mast cells --- p.58 / Chapter 3.3.6 --- Expression of estrogen receptors on human mast cells --- p.59 / Chapter 3.3.6.1 --- Expression of estrogen receptor after treatment of estradiol --- p.59 / Chapter 3.3.7 --- Expression of various bone remodeling molecules on human mast cells --- p.60 / Chapter 3.3.7.1 --- Expression of bone remodeling molecule after treatment of estradiol --- p.61 / Chapter 3.4 --- Discussion --- p.63 / Chapter 4 --- Effects of anti-osteoporosis Chinese herbal medicines on activity of human mast cells --- p.98 / Chapter 4.1 --- Introduction --- p.98 / Chapter 4.2 --- Materials and methods --- p.103 / Chapter 4.3 --- Results --- p.104 / Chapter 4.3.1 --- Effect of the anti-osteoporosis Chinese herbal formulation ELP on histamine release from human mast cells --- p.104 / Chapter 4.3.1.1 --- Histamine release induced by immunological stimulus --- p.104 / Chapter 4.3.1.2 --- Histamine release induced by chemical secretagogues --- p.105 / Chapter 4.3.2 --- Effect of Herba Epimedii (HEP) on histamine release from human mast cells --- p.105 / Chapter 4.3.2.1 --- Histamine release induced by immunological stimulus --- p.106 / Chapter 4.3.2.2 --- Histamine release induced by chemical secretagogues --- p.106 / Chapter 4.3.3 --- Effect of Fructus Ligustri Lucidi (FLL) on histamine release from human mast cells --- p.107 / Chapter 4.3.3.1 --- Histamine release induced by immunological stimulus --- p.107 / Chapter 4.3.3.2 --- Histamine release induced by chemical secretagogues --- p.107 / Chapter 4.3.4 --- Effect of Fructus Psoraleae (FP) on histamine release from human mast cells --- p.108 / Chapter 4.3.4.1 --- Histamine release induced by immunological stimulus --- p.108 / Chapter 4.3.4.2 --- Histamine release induced by chemical secretagogues --- p.109 / Chapter 4.3.5 --- Effect of various partitions from solvent extraction of HEP on histamine release from human mast cells --- p.109 / Chapter 4.3.5.1 --- Histamine release induced by immunological stimulus --- p.110 / Chapter 4.3.5.2 --- Histamine release induced by chemical secretagogue --- p.111 / Chapter 4.3.6 --- Effect of various partitions from solvent extraction of FLL on histamine release from human mast cells --- p.112 / Chapter 4.3.6.1 --- Histamine release induced by immunological stimulus --- p.113 / Chapter 4.3.6.2 --- Histamine release induced by chemical secretagogue --- p.114 / Chapter 4.3.7 --- Effect of ELP and its herbal constituents on the production of cytokine from human mast cells --- p.115 / Chapter 4.3.8 --- Modulation in calcium mobilization in activated human mast cell by ELP and its herbal constituents --- p.117 / Chapter 4.4 --- Discussion --- p.119 / Chapter 5 --- General discussion --- p.163 / Reference --- p.171

Osteoporosis is a common condition characterized by bone fragility and fractures. Hip fracture, leads to disability, morbidity, excess mortality and growing costs to health care systems. / Antiresorptive agents are used to treat osteoporosis and fractures; it is unknown if these agents are effective in preventing recurrent fractures in individuals who have sustained a hip fracture. / Using health services administrative databases, we ascertained the incidence of hip fractures and associated-mortality rates in the elderly population in Quebec, from 1996 to 2002 and, evaluated the effectiveness of antiresorptive agents for the prevention of recurrent hip fractures. / We identified 33,243 hip fractures. Age-adjusted annual rates of hip fractures decreased in women by 11% from 1996 to 2002 while they did not change in men. Overall one-year mortality rates were higher in men than in women (37% versus 24%), and remained stable over time. Patients exposed to antiresorptives had a 26% reduction in the rate of recurrent fractures (95% CI, 0.64--0.86) compared to patients who were not exposed to these agents. / Hip fractures remain a prevalent disease with serious complications. Further research is essential to confirm our results and, to clarify the association between increasing use of antiresorptive agents and the trend reversal in the incidence of hip fractures.

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Diss. (sammanfattning) Stockholm : Karolinska institutet, 2006. / Härtill 4 uppsatser.

Breast cancer, osteoporosis, and coronary heart disease (CHD) are three major threats to women’s health. Postmenopausal women with breast cancer are also at high risk for osteoporosis and CHD. Adjuvant tamoxifen therapy is not only an effective treatment for breast cancer, but has been shown to have a beneficial effect on bone and the cardiovascular system. Although tamoxifen has been convincingly demonstrated to be able to preserve bone mineral density (BMD), an unexpected increase of risk of fractures in patients treated with tamoxifen has been reported. The findings of the association of tamoxifen and CHD from previous studies were either borderline or inconsistent. To clarify the discrepancy between BMD and fractures and test the potential beneficial effect of tamoxifen on CHD, I conducted a series of retrospective studies in postmenopausal women with breast cancer who participated in the Cancer Surveillance in HMO Administrative Data (IMPACT study) or the Study of Osteoporotic Fractures (SOF). In patients who participated in the IMPACT study, I demonstrated that the association of tamoxifen and fracture incidence varied at different skeletal sites. Although the association of tamoxifen and fractures in the spine (HR=0.40, 95% CI: 0.09-1.85), wrist (HR=2.49, 95% CI: 0.88-7.06), and total body (HR=0.87, 95% CI: 0.49-1.55) was inconclusive, tamoxifen was associated with an apparent reduction of the risk of hip fracture (HR=0.41, 95% CI: 0.17-1.03, p=0.0565). Importantly, the pattern of observed association of tamoxifen with the risks of fractures among postmenopausal women with breast cancer is consistent with its widely reported preserving effect on bone mineral density. Using SOF data, I found that the association between BMD and fractures in women with breast cancer varied at different skeletal sites, and type of BMD measured. Non-specific BMD was not associated with hip fracture (HR=1.12; 95% CI: 0.78, 1.59). Site-specific BMD was more likely linked with hip fracture (HR=1.43, 95% CI: 0.99, 2.08) while change in BMD did not predict hip fracture (HR=1.05; 95% CI: 0.63, 1.72). The association of spine morphometric fracture with either non-specific or spine-specific BMD was similar (OR=1.40; 95% CI: 1.04, 1.90; OR=1.35, 95% CI: 0.99, 1.85, respectively). Overall, the association of BMD and fracture in elderly women with breast cancer is weak. Only site-specific BMD appears to have a consistently modest association with fractures in the corresponding skeletal sites. In the IMPACT study population, compared to patients without tamoxifen, the overall incidence of CHD in tamoxifen-treated patients was lower (adjusted HR=0.60, 95% CI: 0.40-0.88). For each year of tamoxifen use, there was a statistically significant decrease in the risk of CHD (HR=0.90, 95% CI: 0.82-0.98). Further analyses categorized by length of tamoxifen use showed that an apparent association with a decreased CHD risk was found in patients who received tamoxifen for two to five years (HR=0.54, 95% CI: 0.33-0.86). No association was detected after the discontinuation of tamoxifen therapy. In summary, I detected a possible benefit associated with tamoxifen on fractures in the hip, the most common fracture site. I also found that BMD did not predict osteoporotic fractures well in postmenopausal women with breast cancer. In addition, I demonstrated that tamoxifen was associated with a reduced risk of CHD in postmenopausal women with breast cancer in a dose-dependent manner. An apparent benefit was found in those patients who received tamoxifen therapy for at least two years.

Osteoporosis is a significant public health problem in the U.S. It not only affects the physical well-being of the older women but also creates a substantial financial burden for the health care system. The mainstay of osteoporosis medications is bisphosphonate treatment of which alendronate and risedronate are the most commonly prescribed in clinical practice. However, there have been no head-to-head randomized controlled trials (RCTs) evaluating the effects of these two bisphosphonates on fracture outcomes. In the absence of RCTs, observational studies are necessary to provide alternative evidence on the comparative effectiveness between alendronate and risedronate on fracture outcomes. However, existing observational studies have provided inconclusive results partially due to residual confounding from unobserved variables such as patients’ health status or behavior. IV analysis may be one method to address unmeasured confounding bias in observational studies. While it has not been applied in bisphosphonate research, it has been used in research on a variety of other prescription medications. In this dissertation, we applied the IV approach with an IV, date of generic alendronate availability, to evaluate the comparative effectiveness between alendronate and risedronate using observational data. This dissertation improved current research in several ways. First, we extended the IV approach to research on bisphosphonates. Second, compared with the current observational studies on bisphosphonates, this dissertation may more accurately estimate the relative effects between alendronate and risedronate because IV analysis is not subject to unmeasured confounding bias. Third, the study results extended the current evidence of the comparative effectiveness between the two most commonly prescribed bisphosphonates. Finally, we proposed and provided empirical evidence of a new IV that might be used for future prescription drug research. The finding of this dissertation can be summarized from three aspects. First, we found that the evidence supported the validity of the date of generic availability as an IV in the study of bisphosphonates. Second, applying IV approach to study the comparative effectiveness of alendronate and risedronate, we found that alendronate and risedronate were comparable to reduce the risk of 12-month non-vertebral fractures in older women. Since generic alendronate is availability on the market while generic risedronate is not, promoting the use of alendronate may help reduce the healthcare cost and not sacrifice the clinical effectiveness. Finally, by comparing the proposed IV with a popular IV-physician preference, we found that both the calendar time IV based on the date of generic availability and the physician preference appeared to be valid. It might be practically easier to use the calendar time IV than the physician preference IV.