HMG-CoA Reductase Inhibitors and the Risk of Fractures

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

doi:10.1001/jama.283.24.3205

Cited by 412 publications

(186 citation statements)

References 22 publications

(15 reference statements)

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“…Some observational studies have also found an association between increased BMD and statin use [3,4]. In addition, other cross-sectional or retrospective case-control studies have indicated that statins may protect against fractures [5][6][7][8]. Prospective population-based cohort studies concerning effects of HMG-CoA reductase inhibitors on BMD change have not been published.…”

Section: Introductionmentioning

confidence: 99%

Relation of Statin Use and Bone Loss: A Prospective Population-Based Cohort Study in Early Postmenopausal Women

Sirola¹,

Honkanen²,

Kröger³

et al. 2002

Osteoporos Int

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Recent experimental and epidemiologic studies have suggested that the lipid-lowering drugs, statins, may have bone-protective effects. We studied the effects of statin use on the change in bone mineral density (BMD) in a prospective 4.5-year cohort study based on subjects from the Kuopio Osteoporosis Risk Factor and Prevention (OSTPRE) Study, Finland. Six hundred and twenty women aged 53-64 years were divided into four groups: 55 women reported continuous and 63 women occasional statin use during the follow-up; 142 non-users of statins reported hypercholesterolemia whereas 360 non-users did not. Spinal and femoral BMDs were measured by dual-energy X-ray densitometry in 1995-1996 and 1999-2000 and the BMD changes of the four groups were compared. Characteristics of the study population were obtained with postal inquiries. The mean annual spinal and femoral BMD changes of the study groups were 0.29% and -0.50% for the continuous statin users, 0.19% and -0.57% for the occasional statin users, 0.52% and -0.29% for the hypercholesterolemic non-users of statins, and 0.39% and -0.33% for the non-users of statins without hypercholesterolemia, ( p = 0.398 and p = 0.404) respectively. The corresponding BMD changes adjusted for age, years since menopause, body mass index, BMD at baseline, calcium intake, estrogen and cortisone therapy, duration of follow-up and statin use before the baseline were -0.20% and -0.47%, 0.19% and -0.54%, 0.54% and -0.32%, 0.47% and -0.33% ( p = 0.134 and p = 0.628), respectively. Our results suggest that statins do not protect from early postmenopausal bone loss. Randomized trials are needed to confirm these results.

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Section: Introductionmentioning

confidence: 99%

Relation of Statin Use and Bone Loss: A Prospective Population-Based Cohort Study in Early Postmenopausal Women

Sirola¹,

Honkanen²,

Kröger³

et al. 2002

Osteoporos Int

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“…Statins have recently been shown to reduce osteoclast activity and to stimulate osteoblast differentiation in vitro and bone formation in vivo (2)(3)(4). The role of statins in increasing bone mineral density in experimental animals and their role in protecting against fractures in cross-sectional or retrospective case control studies have led to testing this group of drugs for osteoporosis management (3,(5)(6)(7)(8)(9).…”

mentioning

confidence: 99%

Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation

Ghosh‐Choudhury

Mandal

Choudhury

2007

Journal of Biological Chemistry

132

109

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Lovastatin promotes osteoblast differentiation by increasing bone morphogenetic protein-2 (BMP-2) expression. We demonstrate that lovastatin stimulates tyrosine phosphorylation of the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K), leading to an increase in its kinase activity in osteoblast cells. Inhibition of PI3K ameliorated expression of the osteogenic markers alkaline phosphatase, type I collagen, osteopontin, and BMP-2. Expression of dominant-negative PI3K and PTEN, an inhibitor of PI3K signaling, significantly attenuated lovastatin-induced transcription of BMP-2. Akt kinase was also activated in a PI3K-dependent manner. However, our data suggest involvement of an additional signaling pathway. Lovastatin-induced Erk1/2 activity contributed to BMP-2 transcription. Inhibition of PI3K abrogated Erk1/2 activity in response to lovastatin, indicating the presence of a signal relay between them. We provide, as a mechanism of this cross-talk, the first evidence that lovastatin stimulates rapid activation of Ras, which associates with and activates PI3K in the plasma membrane, which in turn regulates Akt and Erk1/2 to induce BMP-2 expression for osteoblast differentiation.Statins block cholesterol biosynthesis by competitively inhibiting the rate-limiting enzyme 3-hydroxy-3-methylglutaryl-CoA reductase, which converts 3-hydroxy-3-methylglutaryl-CoA to mevalonate (1). Statins have recently been shown to reduce osteoclast activity and to stimulate osteoblast differentiation in vitro and bone formation in vivo (2-4). The role of statins in increasing bone mineral density in experimental animals and their role in protecting against fractures in cross-sectional or retrospective case control studies have led to testing this group of drugs for osteoporosis management (3, 5-9).The lipophilic statins, viz. lovastatin, fluvastatin, simvastatin, and mevastatin, specifically activate the bone morphogenetic protein-2 (BMP-2) 3 gene promoter (3). The more water-soluble pravastatin does not, however, induce BMP-2 promoter activity or BMP-2 mRNA and protein levels (10). Pravastatin does not stimulate new bone formation in neonatal murine calvaria (3). Transient exposure of bone cultures to lipophilic statins is sufficient to initiate the cascade resulting in bone formation, most probably because of the local production of BMP-2. Simvastatin-induced differentiation of MC3T3-E1 cells is accompanied by an increase in mRNA expression of BMP-2, vascular endothelial growth factor, alkaline phosphatase, type I collagen, bone sialoprotein, and osteocalcin (11). Although the expression of Cbfa-1/Runx2 was found to be unchanged by simvastatin treatment in the previous study (11), an earlier report demonstrated that lovastatin increases Cbfa-1/Runx2 expression while stimulating osteogenic differentiation of bone marrow mesenchymal cells (12). These studies clearly demonstrate a role for statins in osteoblast differentiation.Here we report that lovastatin stimulates osteoblast differentiation by activating phosphatidylinositol...

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“…Interestingly, a protective effect for fractures of the hip, vertebral body, and foot in individuals aged 50 years and older after relatively short treatment periods was reported. This protective effect was much weaker or not present when other lipid-lowering drugs were used [154]. In a first case report about the treatment of a young woman with type I osteogenesis imperfecta with 0.8 mg cerivastatin per day for 6 months, bone-forming effects were reflected in an sharp increase in specific bone-formation markers after starting the treatment.…”

Section: Effect Of Cerivastatin On Bone Formationmentioning

confidence: 99%

Cerivastatin: a cellular and molecular drug for the future?

Di¹

2003

Cellular and Molecular Life Sciences (CMLS)

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The 'statin story' began in 1987 when the first-generation, fungal HMG-CoA reductase inhibitor lovastatin received FDA approval in the USA. Ten years later, the sixth compound of this class came onto the world market--the fully synthetic statin cerivastatin. A number of clinical studies had confirmed its high pharmacological efficacy, its excellent pharmacokinetic properties with fast and nearly complete absorption after oral uptake, a linear kinetic over a broad concentration range, and its favorable safety profile. The greatest advantages, of cerivastatin, however, are its lipophilicity, its high bioavailability of about 60% after oral application and its potency at 100-fold lower doses compared to other lipophilic statins. Nevertheless, the most exciting findings are certainly its non-lipid-related, pleiotropic effects at the cellular and molecular level. Statin therapy was also found to reduce mortality in cases where cholesterol levels or atherosclerotic plaque formation remained unaltered. However, cerivastatin improves endothelial dysfunction, possesses anti-inflammatory, antioxidant, anticoagulant, antithrombotic, antiproliferative, plaque-stabilizing, immunmodulatory, and angiogenic effects, and may even prevent tumor growth, Alzheimer's disease, and osteoporosis. Most of these effects seem to be based on the inhibition of isoprenoid synthesis. Although cerivastatin is no longer on the market because of some problematic side effects, it could be one of the most potent cellular and molecular drugs for the future.

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HMG-CoA Reductase Inhibitors and the Risk of Fractures

Cited by 412 publications

References 22 publications

Relation of Statin Use and Bone Loss: A Prospective Population-Based Cohort Study in Early Postmenopausal Women

Relation of Statin Use and Bone Loss: A Prospective Population-Based Cohort Study in Early Postmenopausal Women

Statin-induced Ras Activation Integrates the Phosphatidylinositol 3-Kinase Signal to Akt and MAPK for Bone Morphogenetic Protein-2 Expression in Osteoblast Differentiation

Cerivastatin: a cellular and molecular drug for the future?

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