HMG-CoA Reductase Inhibitors and the Risk of Fractures

Meier, CR; Schlienger, Raymond G.; Kraenzlin, Marius E.; Schlegel, Brigitta; Jick, Hershel

doi:10.1097/00006254-200011000-00020

Cited by 81 publications

(111 citation statements)

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“…We found no clear evidence of a protective effect against infections. The lack of any effect on fractures in our study disagrees with earlier reports of a protective effect [26]. However, later work has suggested that the protective effect observed may have been due to confounding [27,28].…”

Section: Comparison Of Results With Previous Studiescontrasting

confidence: 99%

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Smeeth

Douglas

Hall

et al. 2008

Brit J Clinical Pharma

215

201

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• The effect of statins on cardiovascular outcomes is well established.• Effects on numerous other health outcomes have been claimed, but results have been inconsistent.• Previous observational studies may have been affected by selection bias and confounding. WHAT THIS STUDY ADDS• This study was larger and more statistically powerful than the combined total of data from all randomized trials of statins undertaken to date.• The validity of the study is supported by findings for vascular outcomes being comparable to those observed in large randomized controlled trials.• There was little evidence to support effects of statins beyond their established effects on cardiovascular disease. AIMSTo assess the effect of statins on a range of health outcomes. METHODSWe undertook a population-based cohort study to assess the effect of statins on a range of health outcomes using a propensity score-based method to control for differences between people prescribed and not prescribed statins. We validated our design by comparing our results for vascular outcomes with the effects established in large randomized trials. The study was based on the United Kingdom Health Improvement Network database that includes the computerized medical records of over four and a half million patients. RESULTSPeople who initiated treatment with a statin (n = 129 288) were compared with a matched sample of 600 241 people who did not initiate treatment, with a median follow-up period of 4.4 years. Statin use was not associated with an effect on a wide range of outcomes, including infections, fractures, venous thromboembolism, gastrointestinal haemorrhage, or on specific eye, neurological or autoimmune diseases. A protective effect against dementia was observed (hazard ratio 0.80, 99% confidence interval 0.68, 0.95). There was no effect on the risk of cancer even after Ն8 years of follow-up. The effect sizes for statins on vascular end-points and mortality were comparable to those observed in large randomized trials, suggesting bias and confounding had been well controlled for. CONCLUSIONSWe found little evidence to support wide-ranging effects of statins on health outcomes beyond their established beneficial effect on vascular disease.

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Section: Comparison Of Results With Previous Studiescontrasting

confidence: 99%

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Smeeth

Douglas

Hall

et al. 2008

Brit J Clinical Pharma

215

201

View full text Add to dashboard Cite

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“…This has been well-documented for polymers and copolymers of lactic and glycolic acid (Bergsma et al, 1993;Agrawal, et al, 1995;Suganuma and Alexander, 1993;Daniels et al, 1992;Daniels et al, 1994;Edwards et al, 2000;Meir et al, 2000). When biodegradable materials are implanted, however, the concentration of toxic byproducts is reduced via dilution in extracellular fluids and blood and by clearance via the circulatory and lymphatic systems.…”

Section: Discussionmentioning

confidence: 95%

Bioerodible devices for intermittent release of simvastatin acid

Jeon

Thomas

Puleo

2007

International Journal of Pharmaceutics

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The association polymer system of cellulose acetate phthalate (CAP) and Pluronic F-127 (PF-127) was used to create intermittent release devices for mimicking the daily injection of simvastatin that has been reported to stimulate bone formation. To enhance solubility in water, prodrug simvastatin was modified by lactone ring opening, which converts the molecule to its hydroxyacid form. CAP/ PF-127 microspheres incorporating simvastatin acid were prepared by a water-acetone-oil-water (W/ A/O/W) triple emulsion process. Devices were then fabricated by pressure-sintering UV-treated blank and drug-loaded microspheres. Using a multilayered fabrication approach, pulsatile release profiles were obtained. Delivery was varied by changing loading, number of layers, blend ratio, and incubation conditions. To determine the cellular effects of intermittent exposure to simvastatin acid, MC3T3-E1 cells were cultured with either alternating or sustained concentrations of simvastatin acid in the medium, and DNA content, alkaline phosphatase activity, and osteocalcin secretion were measured. For all three cell responses, cultures exposed to simvastatin acid showed higher activity than did control cultures. Furthermore, cell activity was greater for cells cultured with intermittent concentrations of simvastatin acid compared to cells that were constantly treated. These results imply that devices intermittently releasing simvastatin acid warrant further study for locally promoting osteogenesis.

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“…(14,15) Though not confirmed in prospective, randomized trials, observational studies suggest that lipid-lowering agents reduce fracture risk. (16,17) In animal models, diet-induced hyperlipidemia is associated with a reduction in BMD and BMC in both mice and canines. (9,18,19) High-density lipoprotein (HDL) functions as an anti-inflammatory and antiatherosclerotic agent through reverse cholesterol transport of oxidized lipids from lipid-laden cells.…”

Section: Introductionmentioning

confidence: 99%

Hyperlipidemia induces resistance to PTH bone anabolism in mice via oxidized lipids

Sage

Atti

et al. 2010

Journal of Bone and Mineral Research

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In hyperlipidemia, oxidized lipids accumulate in vascular tissues and trigger atherosclerosis. Such lipids also deposit in bone tissues, where they may promote osteoporosis. We found previously that oxidized lipids attenuate osteogenesis and that parathyroid hormone (PTH) bone anabolism is blunted in hyperlipidemic mice, suggesting that osteoporotic patients with hyperlipidemia may develop resistance to PTH therapy. To determine if oxidized lipids account for this PTH resistance, we blocked lipid oxidation products in hyperlipidemic mice with an ApoA-I mimetic peptide, D-4F, and the bone anabolic response to PTH treatment was assessed. Skeletally immature Ldlr À/À mice were placed on a high-fat diet and treated with D-4F peptide and/or with intermittent PTH(1-34) injections. As expected, D-4F attenuated serum lipid oxidation products and tissue lipid deposition induced by the diet. Importantly, D-4F treatment attenuated the adverse effects of dietary hyperlipidemia on PTH anabolism by restoring micro-computed tomographic parameters of bone quality-cortical mineral content, area, and thickness. D-4F significantly reduced serum markers of bone resorption but not bone formation. PTH and D-4F, together but not separately, also promoted bone anabolism in an alternative model of hyperlipidemia, Apoe À/À mice. In normolipemic mice, D-4F cotreatment did not further enhance the anabolic effects of PTH, indicating that the mechanism is through its effects on lipids. These findings suggest that oxidized lipids mediate hyperlipidemia-induced PTH resistance in bone through modulation of bone resorption. ß

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HMG-CoA Reductase Inhibitors and the Risk of Fractures

Cited by 81 publications

References 0 publications

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Effect of statins on a wide range of health outcomes: a cohort study validated by comparison with randomized trials

Bioerodible devices for intermittent release of simvastatin acid

Hyperlipidemia induces resistance to PTH bone anabolism in mice via oxidized lipids

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