Abstract
Recent studies suggest that the mevalonate pathway plays an important role in skeletal metabolism. HMG CoA reductase inhibitors ("statins"), which inhibit a key enzyme in the mevalonate pathway, are widely used for the treatment of hyperlipidemia. In vitro and animal studies demonstrate that statins stimulate the production of BMP-2, a potent regulator of osteoblast differentiation and activity, suggesting that statins may have an anabolic effect on bone. Statin use in most, but not all observational studies is associated with a reduced risk of fracture, particularly hip fracture, even after adjustment for the confounding effects of age, weight and other medication use. This beneficial effect has not been observed in clinical trials designed to assess cardiovascular endpoints. The effects of statins on bone mass and bone turnover are controversial, but increased bone mass and reduced bone turnover have been observed in controlled studies. Further studies of the skeletal effects of statins are needed, particularly their effects on surrogate markers such as bone mass, bone turnover, and microarchitecture, to determine the optimal formulation, dosing and route of administration. Clinical trials with fracture endpoints are needed before statins can be recommended as therapeutic agents for osteoporosis.
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Lufkin EG, Wahner HW, O'Fallon WM, et al. Treatment of postmenopausal osteoporosis with transdermal estrogen. Ann Intern Med 1992;117:1–9.
Chesnut CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures Study. Am J Med 2000;109:267–76.
Ettinger B, Black D, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA 1999;282:637–45.
Cummings S, Black D, Thompson D, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA 1998;280:2077–82.
Harris S, Watts N, Genant H, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA 1999;282:1344–52.
McClung M, Geusens P, Miller P, et al. Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 2001;344:333–40.
Russell R, Rogers MJ. Bisphosphonates: from the laboratory to the clinic and back again. Bone. 1999;25:97–106.
Coxon F, Helfrich M, van't Hoff R, et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000;15:1467–76.
Fisher J, Rogers MJ, Halasy J, et al. Alendronate mechanism of action: geranylgeraniol, an intermediate in the mevalonate pathway, prevents inhibition of osteoclast formation, bone resorption, and kinase activation in vitro. Cell Biol 1999;96:133–8.
Luckman S, Hughes D, Coxon F, Russell R, Rogers MJ. Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 1998;13:581–9.
Riggs BL, Hodgson SF, O'Fallon WM, Chao EYS, Wahner HW, Muhs JM, Cedel SL, Melton LJ. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990;322:802–9.
Lane N, Sanchez S, Modin G, Genant H, Pierini E, Arnaud C. Parathyroid hormone treatment can reverse cortiscosteroid-induced osteoporosis. J Clin Invest 1998;102:1627–33.
Hodsman AB, Fraher LJ. Biochemical responses to sequential human parathyroid hormone (1–38) and calcitonin in osteoporotic patients. Bone Miner 1990;9:137–52.
Lindsay R, Nieves J, Formica C, et al. Randomised controlled study of effect of parathyroid hormone on vertebral bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997;350:550–5.
Neer R, Arnaud C, Zanchetta J, Prince R, Gaich G, Reginster J. Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434–41.
Barbehenn EK, Lurie P, Wolfe SM. Osteosarcoma risk in rats using PTH 1–34. Trends Endocrinol Metab 2001;12:383.
Seeman E, Delmas PD. Osteosarcoma risk in rats using PTH 1–34. Trends Endocrinol Metab. 2001;12:383.
Bellosta S, Ferri N, Bernini F, Paoletti R, Corsini A. Non-lipid related effects of statins. Ann Med 2000;32:164–76.
Rosenson R, Tangney C. Antiatherothrombotic properties of statins (implications for cardiovascular event reduction). JAMA 1998;279:1643,1615.
Rosenson R, Tangney C, Casey L. Inhibition of proinflammatory cytokine production by pravastatin. Lancet 1999;353:983–4.
Kearney D, Fitzgerald D. The anti-thrombotic effects of statins. Am J Cardiol 1999;33:1305–7.
Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science 1999;286:1946–9.
Sakou T. Bone morphogenetic proteins: from basic studies to clinical approaches. Bone 1998;22):591–603.
Sugiyama M, Kodama T, Konishi K, Abe K, Asami S, Oikawa S. Compactin and simvastatin, but not pravastatin, induce bone morphogenetic protein-2 in human osteosarcoma cells. Biochem Biophys Res Commun 2000;271:688–92.
Garrett I, Escobedo A, Esparza J, Mundy G. Cerivastatin increases BMP-2 expression in vivo and bone formation in concentration of two orders of magnitude lower than other statins. J Bone Miner Res 1999;14(Suppl 1):S180.
Gutierrez G, Garrett I, Rossini G, Ecobedo A, Horn D, Mundy G. Dermal application of lovastatin for 5 days stimulates bone formation in ovariectomized rats by 160%. J Bone Miner Res 2001;16(Suppl 1):S222.
Maeda T, Matsunuma A, Kawane T, Horiuchi N. Simvastatin promotes osteoblast differentiation and mineralization in MC3T3-E1 cells. Biochem Biophys Res Commun 2000;280:874–7.
Woo J, Kasai S, Stern P, Nagai K. Compactin suppresses bone resorption by inhibiting the fusion of prefusion osteoclasts and disrupting the actin ring in osteoclasts. J Bone Miner Res 2000;15:650–8.
Takahashi N, Yamana H, Yoshiki S, Roodman G, Mundy G, Jones S. Osteoclast-like cell formation and its regulation by osteotropic hormone in mouse bone marrow cultures. Endocrinology 1988;122:1373–82.
Perez S, Mollinedo F. Inhibition of isoprenoid biosynthesis induces cytoplasmic accumulation of inactive Ras–Raf complexes. Biochem Biophys Res Commun 1994;199:1209–15.
Stark W, Blaskovich M, Johnson B, Qian Y, Vasudevan A, Pitt B. Inhibiting geranylgeranylation blocks growth and promotes apoptosis in pulmonary vascular smooth muscle cells. Am J Physiol 1998;275:L55–63.
Bauer DC, Mundy G, Jamal S, et al. Statin use, bone mass and fracture: an analysis of two prospective studies. J Bone Miner Res 1999(Suppl):1188.
Cummings S, Bauer D. Do statins prevent both cardiovascular disease and fracture? JAMA 2000;283:3255–7.
Bauer D, Mundy G, Jamal S, et al. Use of statins and fracture: results of four prospective studies and cumulative meta-analysis of observational studies and controlled trials. Archives of Internal Medicine, 2003. In press.
Cummings SR, Nevitt MC, Browner WS, et al. Risk factors for hip fracture in white women. N Engl J Med 1995;332:767–73.
Black DM, Reiss TF, Nevitt MC, Cauley J, Karpf D, Cummings SR. Design of the Fracture Intervention Trial. Osteoporos Int 1993;3(Suppl 3):S29−39.
Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. Heart and Estrogen/progestin Replacement Study (HERS) Research Group. JAMA 1998;280:605–13.
Burger H, de Laet C, van Daele P, et al. Risk factors for increased bone loss in an elderly population: the Rotterdam study. Am J Epidemiol 1998;147:871–9.
Wang PS, Solomon DH, Mogun H, Avorn J. HMG-CoA reductase inhibitors and the risk of hip fractures in elderly patients. JAMA 2000;283:3211–6.
Chan KA, Andrade SE, Boles M, et al. Inhibitors of hydroxymethylglutaryl-coenzyme A reductase and risk of fracture among older women. Lancet 2000;355:2185–8.
LaCroix AZ, Cauley J, Jackson R, et al. Does statin use reduce risk of fracture in postmenopausal women? Results from the Womens Health Initiative Observational Study (WHI-OS). J Bone Miner Res 2000;15(Suppl):1066.
Garcia-Rodriguez L, Perez-Gutthann S. Use of the UK General Practice Research Database for pharmacoepidemiology. Br J Clin Pharmacol 1998;45:419–25.
Meier CR, Schlienger RG, Kraenzlin ME, Schlegel B, Jick H. HMG-CoA reductase inhibitors and the risk of fractures. JAMA 2000;283:3205–10.
van Staa T, Wegman S, de Vries F, Leufkens B, Cooper C. Use of statins and risk of fractures. JAMA 2001;285:1850–5.
Meier C, Schlienger R, Kraenzlin M, Schlegel B, Jick H. Statins and fracture risk. JAMA 2001;286:669.
van Staa T, Wegman S, Cooper C. Statins and fracture risk [reply]. JAMA. 2001;286:669–70.
Pasco J, Kotowicz M, Henry M, Sanders K, Nicholson G. Statin use, bone mineral density, and fracture risk: Geelong Osteoporosis Study. Arch Intern Med 2002;162:537–40.
Barengolts E, Karanouth D, Kolodny L, Kukreja S. Risk factors for hip fracture in predominantly African-American veteran male population. J Bone Miner Res 2001;16(Suppl):S170.
Adami S, Braga V, Gatti D. Association between bone mineral density and serum lipids in men. JAMA 2001;286:791–2.
Cummings SR, Browner WS, Bauer D, et al. Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group. N Engl J Med 1998;339:733–8.
Reid IR, Hague W, Emberson J, et al. Effect of pravastatin on frequency of fracture in the LIPID study: secondary analysis of a randomised controlled trial. Lancet 2001;357:509–12.
Pederson T, Berg K, Cook T, et al. Safety and tolerability of cholesterol lowering with simvastatin during 5 years in the Scandinavian Simvastatin Survival Study. Arch Intern Med 1996;156:2085–92.
NIH. Osteoporosis prevention, diagnosis, and therapy. Consensus Development Conference. NIH, March 2000;17(1):1–45.
Edwards CJ, Hart DJ, Spector TD. Oral statins and increased bone mineral density in postmenopausal women. Lancet 2000;355:2218–9.
Wada Y, Nakamura Y, Koshiyama H. Lack of positive correlation between statin use and bone mineral density in Japanese subjects with type 2 diabetes. Arch Intern Med 2000;160:2865.
Watanabe S, Fukumoto S, Takeuchi Y, Fujita H, Nakano T, Fujita T. Effects of 1-year treatment with fluvastatin or pravastatin on bone. Am J Med 2001;110:584–7.
Chung Y-S, Lee M-D, Lee S-K, Kim H-M, Fitzpatrick LA. HMG-CoA reductase inhibitors increase BMD in type 2 diabetes mellitus patients. J Clin Endocrinol Metab 2000;85:1137–42.
Sirola J, Honkanen R, Kroger H, Jurvelin JS, Maenpaa P, Saarikoski S. Relation of statin use and bone loss: a prospective population-based cohort study in early postmenopausal women. Osteoporos Int 2002;13:537–54.
Chan MH, Mak TW, Chiu RW, Chow C, Chan IH, Lam CW. Simvastin increases serum osteocalcin concentration in patients treated for hypercholesterolemia. J Clin Endocrinol Metab 2001;86:4556–9.
Stein EA, Farnier M, Waldstreicher J, Mercuri M. Effects of statins on biomarkers of bone metabolism: a randomized trial. Nutr Metab Cardiovasc Dis 2001;11:84–7.
US Food and Drug Administration. Bayer voluntarily withdraws Baycol. FDA Talk Paper. 2001. Available at: http://www.fda.gov/bbs/topics/ANSWER/2001/ANSO1095.html
Cauley J, Jackson R, Pettinger M, et al. Statin use and bone mineral density (BMD) in older women: The Womens Health Initiative Observational Study (WHI-OS) J Bone Miner Res 2000;15(Suppl 1):1068.
Mostaza J, De la Piedra C, Curiel M, Pena R, Lahoz C. Pravastatin therapy increases procollagen I N-terminal propeptide, a marker of bone formation Clin Chim Acta 2001;308:133–7.
Bjarnason NH, Riis BJ, Christiansen C. The effect of fluvastatin on parameters of bone remodeling. Osteoporos Int 2001;12:380–4.
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Bauer, D.C. HMG CoA reductase inhibitors and the skeleton: a comprehensive review. Osteoporos Int 14, 273–282 (2003). https://doi.org/10.1007/s00198-002-1323-x
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DOI: https://doi.org/10.1007/s00198-002-1323-x