Osteoporos Int (2015) 26:1231–1232 DOI 10.1007/s00198-014-2912-1
LETTER
Warfarin use and fracture risk: an evidence-based mechanistic insight T. Sugiyama & F. Kugimiya & S. Kono & Y. T. Kim & H. Oda
Received: 15 August 2014 / Accepted: 19 September 2014 / Published online: 10 October 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Dear Editor, There is a long-standing debate on the association between use of warfarin, prescribed to millions of people to decrease their risk of clotting, and fracture risk [1]. In a large populationbased cohort in the UK, Misra and colleagues [2] found that warfarin use was not linked to an increase in fracture risk. Here, we would like to present an evidence-based, reasonable insight into the mechanisms by which this drug affects bone strength. Osteocalcin, the most abundant non-collagenous protein in bone, is incorporated into bone through vitamin K-dependent γ-carboxylation. Warfarin, a vitamin K antagonist, decreases osteocalcin content in bone and impairs bone material hardness in rats [3], which is consistent with data in mice that osteocalcin deficiency causes a decrease in bone tissue hardness [4]. Consistently, in older patients undergoing chronic therapy with oral vitamin K antagonists [5], undercarboxylated osteocalcin levels in blood were inversely related to cortical ultrasound velocity, an indicator of bone material quality, in agreement with a positive correlation between circulating levels of osteocalcin carboxylation and cortical ultrasound velocity in healthy children [6]. In contrast, however, skeletal strength depends on bone quality and quantity, and normally responds to mechanical environment to maintain the resulting elastic deformation of bone [7]; thus, higher bone mass but similar bone stiffness in osteocalcin-deficient mice indicates compensatory bone gain resulting from lower bone material hardness mentioned above [8]. Other examples of such a compensatory relation between bone quality and quantity include bigger skeleton in adult patients with hypophosphatemic osteomalacia characterized
by hypomineralized bone [9], in accordance with children with hypophosphatemic rickets [10]. Notably, warfarininduced impairment of cortical bone material quality can be compensated by adaptation of cortical bone structure to mechanical loading in rats [3] and urinary γ-carboxyglutamate, a parameter of osteocalcin carboxylation, was inversely related to whole body bone mass change induced by jumping exercise in healthy premenopausal women [11]. A number of studies [12–20] have investigated the association between warfarin use and fracture risk in older patients, but their findings appear to be inconsistent. There is, however, one consistent result that warfarin use was essentially not linked to hip fracture risk. This fact can be reasonably explained by the compensation between bone quality and quantity because hip is a highly weight-bearing site compared to other sites such as the spine and rib [3]. To minimize potential methodological issues considered in earlier epidemiologic studies, the recent propensity score matched cohort [2] included more than 20,000 participants with new onset atrial fibrillation, by carefully selecting older men and women without prior warfarin use or prior fracture history and long-term use of warfarin, from The Health Improvement Network followed between 2000 and 2010; as a result, no significant association between warfarin use and hip, spine or wrist fracture was detected. Thus, on the basis of the present mechanistic insight relating to skeletal adaptation to mechanical loading, further investigation about the adverse effect of vitamin K antagonists on fracture risk could not be required in patients with normal physical activity, as suggested by the authors [2].
T. Sugiyama (*) : F. Kugimiya : S. Kono : Y. T. Kim : H. Oda Department of Orthopaedic Surgery, Saitama Medical University, 38 Morohongo, Moroyama, Saitama 350-0495, Japan e-mail: [email protected]
References 1. Walsh JS, Newman C, Eastell R (2012) Heart drugs that affect bone. Trends Endocrinol Metab 23:163–168
1232 2. Misra D, Zhang Y, Peloquin C, Choi HK, Kiel DP, Neogi T (2014) Incident long-term warfarin use and risk of osteoporotic fractures: propensity-score matched cohort of elders with new onset atrial fibrillation. Osteoporos Int 25:1677–1684. doi:10.1007/s00198014-2662-0 3. Sugiyama T, Takaki T, Sakanaka K, Sadamura H, Mori K, Kato Y, Taguchi T, Saito T (2007) Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli. J Endocrinol 194:213–222 4. Kavukcuoglu NB, Patterson-Buckendahl P, Mann AB (2009) Effect of osteocalcin deficiency on the nanomechanics and chemistry of mouse bones. J Mech Behav Biomed Mater 2:348–354 5. Rey-Sanchez P, Lavado-Garcia JM, Canal-Macias ML, RodriguezDominguez MT, Bote-Mohedano JL, Pedrera-Zamorano JD (2011) Ultrasound bone mass in patients undergoing chronic therapy with oral anticoagulants. J Bone Miner Metab 29:546–551 6. Sugiyama T, Kawai S (2001) Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Metab 19:146–149 7. Sugiyama T (2013) Vitamin D and calcium supplementation to prevent fractures in adults. Ann Intern Med 159:856 8. Sugiyama T, Kawai S (2004) Quantitative ultrasound, skeletal quality, and fracture risk. Lancet 363:1076–1077 9. Shanbhogue VV, Hansen S, Folkestad L, Brixen K, Beck-Nielsen SS (2014) Bone geometry, volumetric density, microarchitecture and estimated bone strength assessed by HR-pQCT in adult patients with hypophosphatemic rickets. J Bone Miner Res. doi:10.1002/jbmr. 2310 10. Sugiyama T, Taguchi T, Kawai S (2002) Adaptation of bone to mechanical loads. Lancet 359:1160 11. Sugiyama T, Yamaguchi A, Kawai S (2002) Effects of skeletal loading on bone mass and compensation mechanism in bone: a new insight into the “mechanostat” theory. J Bone Miner Metab 20: 196–200
Osteoporos Int (2015) 26:1231–1232 12. Jamal SA, Browner WS, Bauer DC, Cummings SR (1998) Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 128:829– 832 13. Caraballo PJ, Heit JA, Atkinson EJ, Silverstein MD, O’Fallon WM, Castro MR, Melton LJ 3rd (1999) Long-term use of oral anticoagulants and the risk of fracture. Arch Intern Med 159:1750–1756 14. Mamdani M, Upshur RE, Anderson G, Bartle BR, Laupacis A (2003) Warfarin therapy and risk of hip fracture among elderly patients. Pharmacotherapy 23:1–4 15. Pilon D, Castilloux AM, Dorais M, LeLorier J (2004) Oral anticoagulants and the risk of osteoporotic fractures among elderly. Pharmacoepidemiol Drug Saf 13:289–294 16. Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF (2006) Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 166:241–246 17. Rejnmark L, Vestergaard P, Mosekilde L (2007) Fracture risk in users of oral anticoagulants: a nationwide case-control study. Int J Cardiol 118:338–344 18. Woo C, Chang LL, Ewing SK, Bauer DC, Osteoporotic Fractures in Men Study Group (2008) Single-point assessment of warfarin use and risk of osteoporosis in elderly men. J Am Geriatr Soc 56:1171– 1176 19. Sato Y, Honda Y, Jun I (2010) Long-term oral anticoagulation therapy and the risk of hip fracture in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Cerebrovasc Dis 29: 73–78 20. Fusaro M, Tripepi G, Noale M, Plebani M, Zaninotto M, Piccoli A, Naso A, Miozzo D, Giannini S, Avolio M, Foschi A, Rizzo MA, Gallieni M, The Vertebral Fractures Vascular Calcifications Study Group (2014) Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients. Curr Vasc Pharmacol. doi:10.2174/15701611113119990146
LETTER
Warfarin use and fracture risk: an evidence-based mechanistic insight T. Sugiyama & F. Kugimiya & S. Kono & Y. T. Kim & H. Oda
Received: 15 August 2014 / Accepted: 19 September 2014 / Published online: 10 October 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Dear Editor, There is a long-standing debate on the association between use of warfarin, prescribed to millions of people to decrease their risk of clotting, and fracture risk [1]. In a large populationbased cohort in the UK, Misra and colleagues [2] found that warfarin use was not linked to an increase in fracture risk. Here, we would like to present an evidence-based, reasonable insight into the mechanisms by which this drug affects bone strength. Osteocalcin, the most abundant non-collagenous protein in bone, is incorporated into bone through vitamin K-dependent γ-carboxylation. Warfarin, a vitamin K antagonist, decreases osteocalcin content in bone and impairs bone material hardness in rats [3], which is consistent with data in mice that osteocalcin deficiency causes a decrease in bone tissue hardness [4]. Consistently, in older patients undergoing chronic therapy with oral vitamin K antagonists [5], undercarboxylated osteocalcin levels in blood were inversely related to cortical ultrasound velocity, an indicator of bone material quality, in agreement with a positive correlation between circulating levels of osteocalcin carboxylation and cortical ultrasound velocity in healthy children [6]. In contrast, however, skeletal strength depends on bone quality and quantity, and normally responds to mechanical environment to maintain the resulting elastic deformation of bone [7]; thus, higher bone mass but similar bone stiffness in osteocalcin-deficient mice indicates compensatory bone gain resulting from lower bone material hardness mentioned above [8]. Other examples of such a compensatory relation between bone quality and quantity include bigger skeleton in adult patients with hypophosphatemic osteomalacia characterized
by hypomineralized bone [9], in accordance with children with hypophosphatemic rickets [10]. Notably, warfarininduced impairment of cortical bone material quality can be compensated by adaptation of cortical bone structure to mechanical loading in rats [3] and urinary γ-carboxyglutamate, a parameter of osteocalcin carboxylation, was inversely related to whole body bone mass change induced by jumping exercise in healthy premenopausal women [11]. A number of studies [12–20] have investigated the association between warfarin use and fracture risk in older patients, but their findings appear to be inconsistent. There is, however, one consistent result that warfarin use was essentially not linked to hip fracture risk. This fact can be reasonably explained by the compensation between bone quality and quantity because hip is a highly weight-bearing site compared to other sites such as the spine and rib [3]. To minimize potential methodological issues considered in earlier epidemiologic studies, the recent propensity score matched cohort [2] included more than 20,000 participants with new onset atrial fibrillation, by carefully selecting older men and women without prior warfarin use or prior fracture history and long-term use of warfarin, from The Health Improvement Network followed between 2000 and 2010; as a result, no significant association between warfarin use and hip, spine or wrist fracture was detected. Thus, on the basis of the present mechanistic insight relating to skeletal adaptation to mechanical loading, further investigation about the adverse effect of vitamin K antagonists on fracture risk could not be required in patients with normal physical activity, as suggested by the authors [2].
T. Sugiyama (*) : F. Kugimiya : S. Kono : Y. T. Kim : H. Oda Department of Orthopaedic Surgery, Saitama Medical University, 38 Morohongo, Moroyama, Saitama 350-0495, Japan e-mail: [email protected]
References 1. Walsh JS, Newman C, Eastell R (2012) Heart drugs that affect bone. Trends Endocrinol Metab 23:163–168
1232 2. Misra D, Zhang Y, Peloquin C, Choi HK, Kiel DP, Neogi T (2014) Incident long-term warfarin use and risk of osteoporotic fractures: propensity-score matched cohort of elders with new onset atrial fibrillation. Osteoporos Int 25:1677–1684. doi:10.1007/s00198014-2662-0 3. Sugiyama T, Takaki T, Sakanaka K, Sadamura H, Mori K, Kato Y, Taguchi T, Saito T (2007) Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli. J Endocrinol 194:213–222 4. Kavukcuoglu NB, Patterson-Buckendahl P, Mann AB (2009) Effect of osteocalcin deficiency on the nanomechanics and chemistry of mouse bones. J Mech Behav Biomed Mater 2:348–354 5. Rey-Sanchez P, Lavado-Garcia JM, Canal-Macias ML, RodriguezDominguez MT, Bote-Mohedano JL, Pedrera-Zamorano JD (2011) Ultrasound bone mass in patients undergoing chronic therapy with oral anticoagulants. J Bone Miner Metab 29:546–551 6. Sugiyama T, Kawai S (2001) Carboxylation of osteocalcin may be related to bone quality: a possible mechanism of bone fracture prevention by vitamin K. J Bone Miner Metab 19:146–149 7. Sugiyama T (2013) Vitamin D and calcium supplementation to prevent fractures in adults. Ann Intern Med 159:856 8. Sugiyama T, Kawai S (2004) Quantitative ultrasound, skeletal quality, and fracture risk. Lancet 363:1076–1077 9. Shanbhogue VV, Hansen S, Folkestad L, Brixen K, Beck-Nielsen SS (2014) Bone geometry, volumetric density, microarchitecture and estimated bone strength assessed by HR-pQCT in adult patients with hypophosphatemic rickets. J Bone Miner Res. doi:10.1002/jbmr. 2310 10. Sugiyama T, Taguchi T, Kawai S (2002) Adaptation of bone to mechanical loads. Lancet 359:1160 11. Sugiyama T, Yamaguchi A, Kawai S (2002) Effects of skeletal loading on bone mass and compensation mechanism in bone: a new insight into the “mechanostat” theory. J Bone Miner Metab 20: 196–200
Osteoporos Int (2015) 26:1231–1232 12. Jamal SA, Browner WS, Bauer DC, Cummings SR (1998) Warfarin use and risk for osteoporosis in elderly women. Study of Osteoporotic Fractures Research Group. Ann Intern Med 128:829– 832 13. Caraballo PJ, Heit JA, Atkinson EJ, Silverstein MD, O’Fallon WM, Castro MR, Melton LJ 3rd (1999) Long-term use of oral anticoagulants and the risk of fracture. Arch Intern Med 159:1750–1756 14. Mamdani M, Upshur RE, Anderson G, Bartle BR, Laupacis A (2003) Warfarin therapy and risk of hip fracture among elderly patients. Pharmacotherapy 23:1–4 15. Pilon D, Castilloux AM, Dorais M, LeLorier J (2004) Oral anticoagulants and the risk of osteoporotic fractures among elderly. Pharmacoepidemiol Drug Saf 13:289–294 16. Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF (2006) Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2. Arch Intern Med 166:241–246 17. Rejnmark L, Vestergaard P, Mosekilde L (2007) Fracture risk in users of oral anticoagulants: a nationwide case-control study. Int J Cardiol 118:338–344 18. Woo C, Chang LL, Ewing SK, Bauer DC, Osteoporotic Fractures in Men Study Group (2008) Single-point assessment of warfarin use and risk of osteoporosis in elderly men. J Am Geriatr Soc 56:1171– 1176 19. Sato Y, Honda Y, Jun I (2010) Long-term oral anticoagulation therapy and the risk of hip fracture in patients with previous hemispheric infarction and nonrheumatic atrial fibrillation. Cerebrovasc Dis 29: 73–78 20. Fusaro M, Tripepi G, Noale M, Plebani M, Zaninotto M, Piccoli A, Naso A, Miozzo D, Giannini S, Avolio M, Foschi A, Rizzo MA, Gallieni M, The Vertebral Fractures Vascular Calcifications Study Group (2014) Prevalence of vertebral fractures, vascular calcifications, and mortality in warfarin treated hemodialysis patients. Curr Vasc Pharmacol. doi:10.2174/15701611113119990146
