Thiazolidinedione Use and the Longitudinal Risk of Fractures in Patients with Type 2 Diabetes Mellitus

Habib, Zeina; Havstad, Suzanne; Wells, Karen; Divine, George; Pladevall, Manel; Williams, L. Keoki

doi:10.1210/jc.2009-1385

Cited by 144 publications

(90 citation statements)

References 44 publications

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“…(22)(23)(24) However, consistent with in vitro study results, clinical studies have shown that diabetic patients taking TZD have significantly higher risk of major osteoporotic fractures compared with those on other antidiabetic agents. (25)(26)(27) Since type 2 diabetes itself imposes a higher risk for fractures, (28)(29)(30)(31)(32) the additional compounding effects of TZD on bone loss would increase the risk of fracture substantially. Similar to human studies, loss of bone mass by activation of PPARg also has been demonstrated in animal models.…”

Section: J Jbmrmentioning

confidence: 99%

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Cho

Yang

Her

et al. 2011

Journal of Bone and Mineral Research

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PPARg has critical role in the differentiation of mesenchymal stem cells into adipocytes while suppressing osteoblastic differentiation. We generated transgenic mice that overexpress PPARg specifically in osteoblasts under the control of a 2.3-kb procollagen type 1 promoter (Col.1-PPARg). Bone mineral density (BMD) of 6-to 14-week-old Col.1 À PPARg male mice was 8% to 10% lower than that of their wildtype littermates, whereas no difference was noticed in Col.1-PPARg female mice. Col.1-PPARg male mice exhibited decreased bone volume (45%), trabecular thickness (23%), and trabecular number (27%), with a reciprocal increase in trabecular spacing (51%). Dynamic histomorphometric analysis also revealed that bone-formation rate (42%) and mineral apposition rate (32%) were suppressed significantly in Col.1-PPARg male mice compared with their wild-type littermates. Interestingly, osteoclast number and surface also were decreased by 40% and 58%, respectively, in Col.1-PPARg male mice. In vitro whole-marrow culture for osteoclastogenesis also showed a significant decrease in osteoclast formation (approximately 35%) with the cells from Col.1-PPARg male mice, and OPG/RANKL ratio was reduced in stromal cells from Col.1-PPARg male mice. Although there was no significant difference in BMD in Col.1-PPARg female mice up to 30 weeks, bone loss was accelerated after ovariectomy compared with wild-type female mice (À3.9% versus À6.8% at 12 weeks after ovariectomy, p < .01), indicating that the effects of PPARg overexpression becomes more evident in an estrogen-deprived state in female mice. In conclusion, in vivo osteoblast-specific overexpression of PPARg negatively regulates bone mass in male mice and accelerates estrogen-deficiency-related bone loss in female mice. ß

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Section: J Jbmrmentioning

confidence: 99%

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Cho

Yang

Her

et al. 2011

Journal of Bone and Mineral Research

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“…Due to side effects [25,26] cost and concern about adverse effects on fetal skeletal development, alternative treatments to reduce hyperinsulinemia in PCOS are needed. Metformin, which has little effect on ambient insulin concentrations, produces modest decreases in fasting plasma glucose, and triglyceride concentrations, and restores ovulation in some women with PCOS [41][42][43].…”

Section: Discussionmentioning

confidence: 99%

“…While metformin is frequently used to treat PCOS, it is not a true insulin sensitizer, and thiazolidinediones, while effective in reducing insulin resistance and ambient insulin concentrations [21], cause weight gain, may increase risk of cardiovascular events [24], potentiate osteoporosis [25], fluid retention [26], and are not approved for use in pregnancy. Dietary weight loss, the first line intervention, is safe and can reduce ambient insulin concentrations by 30% [23], but is infrequently sustained [27], and thus long-term benefits are rarely realized.…”

Section: Introductionmentioning

confidence: 99%

Substituting Poly and Mono-unsaturated Fat for Dietary CarbohydrateReduces Hyperinsulinemia in Women with Polycystic Ovary Syndrome

Dalia¹,

Nicole²,

Cindy³

et al. 2015

J Nutr Food Sci

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Objective: Hyperinsulinemia is a prevalent feature of Polycystic Ovary Syndrome (PCOS), contributing to metabolic and reproductive manifestations of the syndrome. Weight loss reduces hyperinsulinemia but weight regain is the norm, thus preventing long-term benefits. In the absence of weight loss, replacement of dietary carbohydrate (CHO) with mono/polyunsaturated fat reduces ambient insulin concentrations in non-PCOS subjects. The current study evaluated whether this dietary intervention could ameliorate hyperinsulinemia in women with PCOS.Design/Setting/Patients: Obese women with PCOS (BMI 39 ± 7 kg/m2) and insulin resistance completed a crossover study (Stanford University Clinical Research Center) comparing two isocaloric diets, prepared by research dietitians, containing 60% CHO/25% fat versus 40% CHO/45% fat (both 15% protein and ≤ 7% saturated fat). After 3 weeks on each diet, day-long glucose, insulin, and fasting lipid/lipoproteins were measured.Results: Day-long glucose did not differ according to diet. Day-long insulin concentrations were substantially (30%) and significantly lower on the low-CHO/higher fat diet. Beneficial changes in lipid profile were also observed. Conclusions:Replacement of dietary CHO with mono/polyunsaturated fat yields clinically important reductions in day-long insulin concentrations, without adversely affecting lipid profile in obese, insulin-resistant women with PCOS. This simple and safe dietary intervention may constitute an important treatment for PCOS.

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“…More recently, Habib et al [70] showed an increased risk in women >65 years, but not in men and Dormuth et al [71], showed a higher risk with pioglitazone, affecting men and women.…”

Section: Bone Fracturesmentioning

confidence: 98%

Diabetes-Old Therapies Revisited

Guimarães¹

2016

EMIJ

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Today, there are many therapeutic options for the treatment of type 2 Diabetes, which means that therapeutic decision making has become increasingly challenging and complex. With the recent introduction in clinical practice of new classes, with different mechanisms of action, what is the role of the older drugs? This article reviews these drugs, with recently published data update. Today, recommendations are not based on a simple algoritm, but in a patient centered approach. Besides the phenotypic heterogeneity of patients with type 2 diabetes, there is also a great diversity in response to treatment. This concept of personalized medicine has changed in recent years. The new era of personalized medicine evolves in order to identify molecular and clinical signs that can predict therapeutic response, reducing uncertainty in decision making. The "old" drugs may resurface, with more precise indications, in selected groups of patients.

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Thiazolidinedione Use and the Longitudinal Risk of Fractures in Patients with Type 2 Diabetes Mellitus

Abstract: TZD use was associated with an increased risk for fractures in women, particularly at ages above 65 yr. Clinicians should be aware of this association when considering TZD therapy so as to appropriately manage and counsel their patients.

Cited by 144 publications

References 44 publications

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Osteoblast-targeted overexpression of PPARγ inhibited bone mass gain in male mice and accelerated ovariectomy-induced bone loss in female mice

Substituting Poly and Mono-unsaturated Fat for Dietary CarbohydrateReduces Hyperinsulinemia in Women with Polycystic Ovary Syndrome

Diabetes-Old Therapies Revisited

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