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Oral anticoagulants and fracture risk: Clinical perspectives
International Journal of Cardiology 127 (2008) 425 – 426 www.elsevier.com/locate/ijcard
Letter to the Editor
Oral anticoagulants and fracture risk: Clinical perspectives Atila Iyisoy a , Turgay Celik a,⁎, Hurkan Kursaklioglu a , Abdi Bozkurt b , Sait Demirkol c a
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey b Cukurova University, School of Medicine, Department of Cardiology, Balcali-Adana, Turkey c Malatya Army District Hospital, Department of Cardiology, Malatya, Turkey Received 9 January 2007; accepted 1 April 2007 Available online 4 June 2007
In their recently published large population-based case control study, Rejnmark and coworkers have demonstrated that current use of small, accumulated amounts of vitamin K antagonists (VKA) was associated with increased fracture risk. However, they found that risk of fracture was not increased in patients who had used a large accumulated dose. They proposed that risk of fracture was increased due to circumstances related to initiation therapy rather than due to a direct pharmacological effect of VKA [1]. As far as every clinician knows, warfarin decreases the tendency of blood to clot by inhibiting the vitamin Kdependent gamma-carboxylation of clotting factors, namely II, VII, IX and X [2]. Interestingly, warfarin inhibits the gamma-carboyxlation of osteocalcin; non-carboxylated osteocalcin cannot bind calcium effectively [3]. Moreover, vitamin K might directly reduce bone resorption by the mechanisms of decreased prostaglandin E2 synthesis and osteoclast-like cell formation [4,5]. Those data have led the clinicians to suspect that warfarin may adversely affect bone metabolism. Some important clinical findings have supported this hypothesis. First, mean serum vitamin K concentrations in patients with fractures have been found to be lower than in normals [6,7]. Second, it was shown that the percentage of non-carboyxlated osteocalcin in elderly women was higher than in young women [8]. Third, another study clearly demonstrated that the risk of hip fracture in women with high serum levels of non-carboyxlated osteocalcin were higher than in women with low levels [9]. Lastly, vitamin K therapy has been shown to reduce urinary excretions of hydroxyproline which is a marker of bone ⁎ Corresponding author. Department of Cardiology, Gulhane School of Medicine, 06018 Etlik-Ankara, Turkey. Tel.: +90 312 3044268; fax: +90 312 3044250. E-mail address: [email protected] (T. Celik). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.04.025
resorption in postmenopausal women [10]. On contrast, no effects of VKA on risk of fracture were found in a prospective cohort study during a relatively long time period [11]. We think that a clinician has to be very cautious when using those data into clinical practice. Because the studies showing adverse effects of VKA on bone metabolism including the present one by Rejnmark et al. are mainly retrospective, case-control studies which have inherently major drawbacks. The advantages of case-control studies lead to their disadvantages. Of all study methods, they have the largest number of possible biases and they depend completely on high-quality existing records [12]. One of the greatest problems in a case-control study is selection of an appropriate control group. But, results from a well-designed prospective-cohort study carry more weight in understanding a disease than do results from a case-control study. In conclusion, the clinical importance of those observations is uncertain and prospective randomized studies are needed to elucidate the clinical implications of adverse effects of warfarin use on bone metabolism. As for now, we believe that it is too early to recommend any specific treatment directed toward bone metabolism in patients with warfarin. References [1] Rejnmark L, Vestergaard P, Mosekilde L. Fracture risk in users of oral anticoagulants: A nationwide case-control study. Int J Cardiol June 12 2007;118(3):338–44. [2] Hirsh J. N Engl J Med 1991;324:1865–75. [3] Lian JB, Gundberg CM. Osteocalcin. Biochemical considerations and clinical applications. Clin Orthop Relat Res 1988;226:267–91. [4] Hara K, Akiyama Y, Tajima T, Shiraki M. Menatetrenone inhibits bone resorption partly through inhibition of PGE2 synthesis in vitro. J Bone Miner Res 1993;8:535–42. [5] Takeuchi Y, Suzawa M, Fukumoto S, Fujita T. Vitamin K(2) inhibits adipogenesis, osteoclastogenesis, and ODF/RANK ligand expression in murine bone marrow cell cultures. Bone 2000;27:769–76.
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A. Iyisoy et al. / International Journal of Cardiology 127 (2008) 425–426
[6] Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD. Circulating levels of vitamins K1 and K2 decreased in elderly women with hip fracture. J Bone Miner Res 1993;8:1241–5. [7] Bitensky L, Hart JP, Catterall A, Hodges SJ, Pilkington MJ, Chayen J. Circulating vitamin K levels in patients with fractures. J Bone Joint Surg Br 1988;70:663–4. [8] Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD. Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J Bone Miner Res 1991;6:1211–6. [9] Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 1993;91:1769–74.
[10] Knapen MH, Hamulyak K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med 1989;111:1001–5. [11] Jamal SA, Browner WS, Bauer DC, Cummings SR. Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1998;128:829–32. [12] Dawson B, Trapp RG. Study Designs in Medical Research. In: Dawson B, Trapp RG, editors. Basic & Clinical Biostatistics. 4th ed. New York: McGraw-Hill Companies, Inc; 2004. p. 8–18.
Letter to the Editor
Oral anticoagulants and fracture risk: Clinical perspectives Atila Iyisoy a , Turgay Celik a,⁎, Hurkan Kursaklioglu a , Abdi Bozkurt b , Sait Demirkol c a
Gulhane Military Medical Academy, School of Medicine, Department of Cardiology, Etlik-Ankara, Turkey b Cukurova University, School of Medicine, Department of Cardiology, Balcali-Adana, Turkey c Malatya Army District Hospital, Department of Cardiology, Malatya, Turkey Received 9 January 2007; accepted 1 April 2007 Available online 4 June 2007
In their recently published large population-based case control study, Rejnmark and coworkers have demonstrated that current use of small, accumulated amounts of vitamin K antagonists (VKA) was associated with increased fracture risk. However, they found that risk of fracture was not increased in patients who had used a large accumulated dose. They proposed that risk of fracture was increased due to circumstances related to initiation therapy rather than due to a direct pharmacological effect of VKA [1]. As far as every clinician knows, warfarin decreases the tendency of blood to clot by inhibiting the vitamin Kdependent gamma-carboxylation of clotting factors, namely II, VII, IX and X [2]. Interestingly, warfarin inhibits the gamma-carboyxlation of osteocalcin; non-carboxylated osteocalcin cannot bind calcium effectively [3]. Moreover, vitamin K might directly reduce bone resorption by the mechanisms of decreased prostaglandin E2 synthesis and osteoclast-like cell formation [4,5]. Those data have led the clinicians to suspect that warfarin may adversely affect bone metabolism. Some important clinical findings have supported this hypothesis. First, mean serum vitamin K concentrations in patients with fractures have been found to be lower than in normals [6,7]. Second, it was shown that the percentage of non-carboyxlated osteocalcin in elderly women was higher than in young women [8]. Third, another study clearly demonstrated that the risk of hip fracture in women with high serum levels of non-carboyxlated osteocalcin were higher than in women with low levels [9]. Lastly, vitamin K therapy has been shown to reduce urinary excretions of hydroxyproline which is a marker of bone ⁎ Corresponding author. Department of Cardiology, Gulhane School of Medicine, 06018 Etlik-Ankara, Turkey. Tel.: +90 312 3044268; fax: +90 312 3044250. E-mail address: [email protected] (T. Celik). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.04.025
resorption in postmenopausal women [10]. On contrast, no effects of VKA on risk of fracture were found in a prospective cohort study during a relatively long time period [11]. We think that a clinician has to be very cautious when using those data into clinical practice. Because the studies showing adverse effects of VKA on bone metabolism including the present one by Rejnmark et al. are mainly retrospective, case-control studies which have inherently major drawbacks. The advantages of case-control studies lead to their disadvantages. Of all study methods, they have the largest number of possible biases and they depend completely on high-quality existing records [12]. One of the greatest problems in a case-control study is selection of an appropriate control group. But, results from a well-designed prospective-cohort study carry more weight in understanding a disease than do results from a case-control study. In conclusion, the clinical importance of those observations is uncertain and prospective randomized studies are needed to elucidate the clinical implications of adverse effects of warfarin use on bone metabolism. As for now, we believe that it is too early to recommend any specific treatment directed toward bone metabolism in patients with warfarin. References [1] Rejnmark L, Vestergaard P, Mosekilde L. Fracture risk in users of oral anticoagulants: A nationwide case-control study. Int J Cardiol June 12 2007;118(3):338–44. [2] Hirsh J. N Engl J Med 1991;324:1865–75. [3] Lian JB, Gundberg CM. Osteocalcin. Biochemical considerations and clinical applications. Clin Orthop Relat Res 1988;226:267–91. [4] Hara K, Akiyama Y, Tajima T, Shiraki M. Menatetrenone inhibits bone resorption partly through inhibition of PGE2 synthesis in vitro. J Bone Miner Res 1993;8:535–42. [5] Takeuchi Y, Suzawa M, Fukumoto S, Fujita T. Vitamin K(2) inhibits adipogenesis, osteoclastogenesis, and ODF/RANK ligand expression in murine bone marrow cell cultures. Bone 2000;27:769–76.
426
A. Iyisoy et al. / International Journal of Cardiology 127 (2008) 425–426
[6] Hodges SJ, Akesson K, Vergnaud P, Obrant K, Delmas PD. Circulating levels of vitamins K1 and K2 decreased in elderly women with hip fracture. J Bone Miner Res 1993;8:1241–5. [7] Bitensky L, Hart JP, Catterall A, Hodges SJ, Pilkington MJ, Chayen J. Circulating vitamin K levels in patients with fractures. J Bone Joint Surg Br 1988;70:663–4. [8] Plantalech L, Guillaumont M, Vergnaud P, Leclercq M, Delmas PD. Impairment of gamma carboxylation of circulating osteocalcin (bone gla protein) in elderly women. J Bone Miner Res 1991;6:1211–6. [9] Szulc P, Chapuy MC, Meunier PJ, Delmas PD. Serum undercarboxylated osteocalcin is a marker of the risk of hip fracture in elderly women. J Clin Invest 1993;91:1769–74.
[10] Knapen MH, Hamulyak K, Vermeer C. The effect of vitamin K supplementation on circulating osteocalcin (bone Gla protein) and urinary calcium excretion. Ann Intern Med 1989;111:1001–5. [11] Jamal SA, Browner WS, Bauer DC, Cummings SR. Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 1998;128:829–32. [12] Dawson B, Trapp RG. Study Designs in Medical Research. In: Dawson B, Trapp RG, editors. Basic & Clinical Biostatistics. 4th ed. New York: McGraw-Hill Companies, Inc; 2004. p. 8–18.