Statins and bone fractures - update

Source: http://www.jr2.ox.ac.uk/bandolier/booth/cardiac/statbone.html

Clinical bottom line

In humans using statins for prevention of cardiovascular disease, there is little evidence of any significant effect on BMD or fracture rates.

Bandolier 78 reported on three observational studies [1, 2, 3] that suggested statins might reduce fractures in humans. Almost three years on, we felt it was time to revisit the subject to see if the situation is any clearer.

Additional evidence

Clinical

An observational study in 69 type 2 diabetic patients has shown increases in bone mineral density (BMD) over 14 months in those treated with statins, compared to a reduction in BMD for untreated patients [4]. Fracture rates were not reported.

Re-examination of the UK General Practice Research Database (UK GPRD) [5] found no significant effect of statins on risk of fracture at any site, any dose, or any duration of treatment, compared with non-use of statins, after adjusting for confounding variables. This contrasts with other findings [1] from the same database, but using a smaller population.

Data from the Women’s Health Initiative Observational Study [6] of postmenopausal women aged 50-79 years again found no significant reduction in risk of fracture with statin use. However, treatment for more than three years with the more potent statins (atorvastatin or simvastatin) gave modest protection to hip and lumbar vertebral BMD [7].

The BHF Heart Protection Study [8], a randomised controlled trial involving over 20,000 patients aged 40 to 80 years, treated with simvastatin for five years, prespecified hospitalisation for fracture as a tertiary outcome. It found no differences between placebo and treated groups for any fracture, or fracture at sites related to osteoporosis.

A cross-sectional study of 140 postmenopausal women treated with a statin (65% simvastatin) for at least two (median four) years, looked at markers of bone turnover, plasma levels of parathyroid hormone and BMD, compared to sex and age-matched population controls [9]. There was reduced bone turnover in statin-treated women compared to controls but there was no effect on BMD.

Experimental

Mundy et al [10, 11] have shown that statins (lovastatin, atorvastatin, mevastatin, simvastatin and cerivastatin) activate the gene promotor for bone morphogenic protein-2 (BMP-2), which triggers osteopblast differentiation, in a mouse osteoblast cell line. Pravastatin does not affect the BMP-2 promoter because it has been designed to enter only hepatocytes. Sugiyama et al [12] have reported similar results for simvastatin and mevastatin in a human osteosarcoma cell line.
What does this mean?

In humans using statins for prevention of cardiovascular disease, there is little evidence of any significant effect on BMD or fracture rates.

The biochemistry of bone regulation is complex, but what is clear is that statins can interact in these pathways given the right conditions.

Increases in bone formation have been demonstrated in mice and rats treated with simvastatin [10], with subcutaneous injection being a much more effective than oral as a route of delivery. Topical application resulted in more reliable and sustained blood concentrations of lovastatin in rats, and was 50-times more potent than when given orally [13]. Implants into the skin of mice, giving continuous release of lovastatin, have also been shown to be a highly effective delivery system.

Statins have been designed to selectively target the liver, since it is the primary site of cholesterol synthesis, and when taken orally, they undergo substantial conversion to inactive metabolites during their first passage through the liver. Much of this hepatic first-pass metabolism can be avoided by subcutaneous or transdermal delivery. Unmetabolised drug may be bound tightly to plasma proteins, further reducing systemic availability of pharmacologically active drug. It seems likely that this largely explains why experimental effects in animals are not reliably transformed in to clinical effects in humans.
Comment

In the future topical delivery of a statin with, perhaps, reduced affinity for the liver, may give us a means for treating osteoporosis, perhaps with the added benefit of protection against cardiovascular disease. Watch this space.

In the meantime, statins should not be used to treat osteoporosis, and do not assume that patients taking statins who are at risk of osteoporosis are protected in any way.

Reference

1. CR Meier et al. HGM-CoA reductase inhibitors and the risk of fractures. JAMA 2000 283: 3205-3210.
2. PS Wang et al. HGM-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA 2000 283: 3211-3216.
3. KA Chan et al. Inhibitors of hydroxymethylglutaryl-CoA reductase and risk of fracture among older women. Lancet 2000 355: 2185-2188.
4. YS Chung et al. HGM-CoA reductase inhibitors increase BMD in Type 2 diabetes mellitus patients. J Clin Endocrinol Metab 2000 85: 1137-1142.
5. van Staa T-P et al. Use of statins and risk of fractures. JAMA 2001 285: 1850-1855.
6. LaCroix AZ et al. Does statin use reduce the risk of fracture in postmenopausal women? Results from the Women's Health Initiative Observational Study (WHI-OS). J Bone Miner Res 2000 15: S155 (abstract).
7. JA Cauley et al. Statin use and bone mineral density (BMD) in older women: the Women's Health Initiative Observational Study (WHI-OS). J Bone Miner Res. 2000 15: S155 (abstract).
8. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002 360: 7-22.
9. L Rejnmark et al. Statins decrease bone turnover in postmenopausal women: a cross-sectional study. Eur J Clin Invest 2002 32: 581-589.
10. G Mundy et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999 286: 1946-1949.
11. IR Garrett et al. Statins and bone formation. Curr Pharm Design 2001 7: 715-736.
12. M Sugiyama et al. Compactin and simvastatin, but not pravastatin, induce bone morphogenic protein-2 in human osteosarcoma cells. Biochem Biophys Res Commun 2000 271: 688-692.
13. G Gutierrez et al. Dermal application of lovastatin to rats causes greater increases in bone formation and plasma concentration than when administered by oral gavage. J Bone Miner Res 2000 15: S427 (abstract).