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The Pleiotropic Effects of HMG-CoA Reductase Inhibitors

Their Role in Osteoporosis and Dementia

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Abstract

HMG-CoA reductase is the rate-limiting enzyme for cholesterol synthesis and its inhibition exerts profound effects on cellular metabolism. Inhibitors of this enzyme are used in clinical practice to lower plasma cholesterol levels and are commonly collectively referred to as ‘statins’. A number of in vitro, in vivo animal, and clinical studies suggest that properties of statins other than cholesterol lowering may be of biological importance. These diverse properties are often referred to as ‘pleiotropic’ and suggest that statins may affect a number of diseases of ageing. In this article we review the biological plausibility and clinical evidence of a role for statins in modulating two diseases of ageing: osteoporosis and dementia (including Alzheimer’s disease). In both diseases, there is a sound cellular and laboratory basis for a plausible therapeutic effect of statins. In the case of osteoporosis, there are conflicting data regarding clinical benefit, with both negative and positive results reported. In particular, secondary analyses of randomised, controlled studies have shown no reduction of fracture risk by statins. In the case of dementia there are fewer clinical studies but there is clear anticipated benefit in macrovascular dementias attributable to statin-mediated reduction of the risk of stroke. Overall, there are a lack of prospective, placebo-controlled, randomised data testing statins and modulation of the risk of osteoporosis-related fracture or of clinical dementia, where these are primary outcomes. Until such data are available, the use of statins appears promising but cannot be recommended as a primary therapeutic modality for either condition.

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Acknowledgements

Professors J. Kril, D. LeCouteur and M. Seibel are thanked for many helpful discussions.

Dr. Kritharides is a member of the Australian Scientific Advisory Committee for rosuvastatin (Astra-Zeneca), and has given invited presentations at scientific symposia convened or supported by Bristol Myer Squibb, Astra Zeneca, and Merck Sharp and Dohme.

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  1. Department of Cardiology, Concord Hospital, University of Sydney, Hospital Rd, Concord, NSW, 2139, Australia

    Alla Waldman &  Leonard Kritharides

  2. Centre for Thrombosis and Vascular Research, University of New South Wales, NSW, Australia

    Leonard Kritharides

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Waldman, A., Kritharides, L. The Pleiotropic Effects of HMG-CoA Reductase Inhibitors. Drugs 63, 139–152 (2003). https://doi.org/10.2165/00003495-200363020-00002

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