Osteoporos Int DOI 10.1007/s00198-015-3063-8
CASE REPORT
Atypical femur fracture during bisphosphonate drug holiday: a case series A. J. Lovy & S. M. Koehler & A. Keswani & D. Joseph & R. Hasija & R. Ghillani
Received: 7 December 2014 / Accepted: 2 February 2015 # International Osteoporosis Foundation and National Osteoporosis Foundation 2015
Abstract Recent studies have noted an increased risk of low energy subtrochanteric and femoral shaft fractures termed Batypical femur fractures^ (AFFs) associated with long-term bisphosphonate use. As such, many clinicians have begun recommending a Bdrug holiday^ to reduce the risks associated with long-term bisphosphonate use. We present two cases of AFFs occurring during a 4-year or greater drug holiday following long-term bisphosphonate use. These findings highlight the need to reevaluate optimal bisphosphonate therapy duration, dosage, as well as initiation and duration of a drug holiday with continued monitoring in the prevention of AFFs. Keywords Atypical femur fractures . Bisphosphonates . Drug holiday . Osteoporosis
regarding bisphosphonate use remain unanswered: the duration of treatment, the minimal efficacious dosage, and the persistence of clinical efficacy given their long half-life. These questions have become more relevant given recent studies noting an increased risk of low-energy subtrochanteric and diaphyseal femoral fractures termed Batypical femur fractures^ (AFFs) associated with long-term bisphosphonate use [6–8]. As such, many clinicians have begun recommending a Bdrug holiday^ to reduce the risks associated with long-term bisphosphonate use [9]. We present two cases of previously undescribed AFFs occurring during 4-year or greater drug holiday following long-term bisphosphonate use. These findings highlight the need to establish optimal bisphosphonate therapy duration as well as the role of a drug holiday in the prevention of AFFs.
Introduction
Case 1
As of 2008, an estimated 4 million women in the USA were prescribed bisphosphonates for the treatment of osteoporosis [1]. The benefits of bisphosphonate therapy in regard to fracture risk reduction are well documented; however, published clinical trial data regarding long-term use of 10 years is limited to alendronate [2–5]. Additionally, several questions
A 64-year-old Caucasian female presented to our trauma center with acute onset of right thigh pain after tripping without a history of a fall. Prior to tripping, the patient noted right thigh pain for 3 weeks. Review of past medical history was significant for Celiac disease, hypothyroidism, and osteoporosis with a 10-year history of alendronate (ALN) use stopped 5 years prior. Additional medications included sertraline, synthroid, gabapentin, and baclofen. Roentgenograms revealed a diaphyseal AFF according to established criteria [7]. Contralateral femur roentgenorgrams did not demonstrate signs of an impending fracture. Laboratory results at injury were notable for ionized calcium 4.87 mg/dL, Vit D 1,25 72 pg/mL, Vit D 25 47 ng/mL, PTH 82.3 pg/mL, TSH 0.29 ulU/mL, Free T4 1.14 ng/dL, and T3 79.89 ng/dL. Complete blood count and basic metabolic panel were within normal limits.
A. J. Lovy (*) : S. M. Koehler : A. Keswani : D. Joseph : R. Ghillani Department of Orthopaedic Surgery, Mount Sinai Hospital, 5 East 98th St., 9th Floor, New York, NY 10029, USA e-mail: [email protected] D. Joseph : R. Hasija : R. Ghillani Department of Orthopaedic Surgery, Elmhurst Hospital Center, 79-01 Broadway, Queens, NY 11373, USA
Osteoporos Int
Case 2 A 70-year-old Hispanic female presented to our trauma center with acute onset of right thigh pain following a mechanical fall from a standing height. The patient denied any antecedent symptoms. Review of past medical history was significant hypothyroidism, hypertension, diabetes mellitus type 2, and osteoporosis with a 14-year history of ALN use stopped 4 years prior after a left AFF. Additional medications included synthroid, omeprazole, hydrochlorothiazide, and metformin. Roentgenograms revealed a subtrochanteric AFF according to established criteria (Fig 1) [7]. The patient’s prior hip fracture was treated at an outside hospital, and this was her first presentation to us. Available laboratory results including complete blood count and basic metabolic panel were within normal limits with the exception of blood glucose of 157 mg/dL.
Discussion We report two cases of AFFs that occurred during a drug holiday in the setting of long-term bisphosphonate use. Recent literature has highlighted the risk factors and prevalence of AFFs, establishing an association between long-term bisphosphonate use and AFF. Despite increased awareness of AFFs,
Fig. 1 Anterorposterior roentgenogram of the right femur demonstrating a diaphyseal atypical femur fracture. Note the non-comminuted, transverse fracture pattern with lateral Bbeaking^
prevention strategies as well as treatment remain poorly defined [10, 11]. Bisphosphonates can be broken down into nitrogen- and non-nitrogen-containing types that reduce osteoclastic bone resorption in a dose- and compound-dependent fashion [12]. Pharmacokinetic studies show that bisphosphonates have a high affinity for bone becoming incorporated into the bone matrix where they remain inactive for many years until released with bone resorption. As a result, cited figures for the terminal half-life of ALN approach 10.5 years [13]. Using a pharmacokinetic model of 10 mg daily of ALN for 10 years with bone histomorphometry-based assumption that 15 % of the total skeleton is comprised of cancellous bone (30 % turnover yearly) and 85 % of cortical bone (3 % annual turnover), Rodan et al. [11] estimated an ALN bone load at 10 years of 37.5 ppm which would equate to a 2.5-mg oral dose of pharmacologically active ALN being released daily due to bone resorption over the next months to years. These findings demonstrate that as ALN bone load increases over time, so should the amount of active ALN released from bone turnover. At the same time, estimated bioavailability of 10 mg oral ALN ranges from 0.76 % (females) to 0.6 % (males) with 50 % of the bioavailable bisphosphonate being stored in the skeleton [14, 15]. Additionally, clinical efficacy has been demonstrated with lesser dosages of ALN (5 mg) [16] and risedronate (2.5 mg) [17]. Taken together, these findings suggest that further research is required to determine the optimal dose as well as duration of bisphosphonate therapy. Increasing levels of active bisphosphonate as treatment duration increases is not without consequence, as several studies have noted an association between long-term bisphosphonate use and risk of AFFs. Gedmintas et al. [18] found that exposure to bisphosphonates was associated with an increased risk of AFF (adjusted RR of 1.70 with 95 % CI 1.22–2.37), while Schilcher et al. [19] found that risk for AFF fracture increased progressively with duration of use. This association highlights the importance of examining the relationship between actual build-up of bisphosphonate in the skeletal system (bone load) and risk for AFF. This suggests that bisphosphonate dosing can be optimized to potentially decrease risk of AFF by (1) using a lower initial dose that achieves sufficient decrease in bone turnover markers and increases in bone mineral density, and (2) adjusting the dose and duration of treatment over time to account for increasing amounts of pharmacologically active bisphosphonate due to bone resorption. Currently, three prospective, randomized trials have evaluated fracture risk among patients continuing or stopping bisphosphonate therapy [2, 20, 21]. The Fracture Intervention Trial Long-term Extension (FLEX) study looked at the effect of discontinuing ALN after 5 years. Women who discontinued use had a moderate rise in bone mineral markers and fall in bone mineral density on a dual energy X-ray absorptiometry (DEXA) study; but, no increased risk of morphometric
Osteoporos Int
vertebral fractures or non-vertebral fractures [2]. Post hoc analysis of the FLEX study identified an increased risk of fracture among high-risk patients as defined by a T-score < −2.5 but without prevalent vertebral fracture with cessation of ALN compared to controls [22]. A similar trial comparing the effect of 3 versus 6 years of zoledronic acid noted a decreased risk of morphometric vertebral fractures among patients treated for 6 years but no difference in other fractures [20]. While these studies suggest that bisphosphonate therapy duration can be limited in the absence of high-risk criteria, optimal duration of therapy remains unknown. Several limitations to the approach mentioned are worthy of note. Though it is known that bisphosphonates inhibit osteoclast activity and encourage osteoclast apoptosis, the relationship between severe suppression of bone turnover and the incidence of AFFs is not clearly understood [23, 24]. Several studies have posited that suppression of bone turnover may allow for the accumulation of microfractures, impaired stressfracture healing, and decreased heterogeneity of bone matrix which would increase risk for AFF; but, this cannot be confirmed until more studies on bone histomorphometry are performed [25–28]. Secondly, there is little evidence describing the rate of bisphosphonate release from cortical bone due to its slower turnover rate. This makes it more difficult to accurately quantify how much pharmacologically active bisphosphonate is released at any time due to bone resorption. There is, however, literature suggesting that the kinetics of ALN release from bone are similar to those of calcium and other minerals [29, 30]. While the concept of a drug holiday may help reduce the risk of AFF as bisphosphonate levels mount over time, it is an imperfect strategy to prevent the complications of extended duration of use. In a study evaluating risk of AFF associated with bisphosphonate (BP) therapy using National Swedish Patient Registry data, Schilcher et al. [31] found that the duration of BP use was associated with risk of fracture as well as a 70 % decrease in AFF risk per year following BP cessation. However, the applicability of estimated risk reduction of AFF beyond 2 years of cessation is unclear as only 3 out of 59 cases sustained fractures ≥2 years after BP cessation. Additionally, registry data regarding long-term BP use was limited as prescription drug information was recorded for less than 3 years prior to the study. As our cases illustrate, clinicians must be aware that the risk of AFF can remain despite a drug holiday of greater than 4 years. Similarly, Giusti et al. [32] note one case of an AFF that occurred during a 5-year holiday in a patient previously treated with oral pamidronate for 12 years. Further research is required to establish standards for duration of therapy, minimal efficacious dosage, initiating drug holiday, and for duration of drug holiday. Several studies have suggested evaluating Brisk for fracture^ and using this as criteria for a drug holiday. In an effort to risk stratify fracture risk when considering a drug holiday, Diab et al. [33] has
developed four risk profiles (high, moderate, medium, low) to guide duration of therapy and initiation or termination of drug holiday based on T-score, continued monitoring for significant decrease in bone mineral density (BMD), and presence of other risk factors associated with greater fracture risk (e.g., ongoing corticosteroid therapy, history of previous fractures). In this framework, T-score and significant changes in BMD are suggested as indictors to end drug holiday and resume treatment; however, further clinical testing will be required to validate this framework [33]. Although further research is required, we believe that AFF risk is not negated by drug holiday alone and that it may be Btoo little, too late.^ Prevention of complications from bisphosphonates must occur at the outset through evidence-based standards for treatment. Lastly, physicians must be aware of continued AFF risk in patients with long-term bisphosphonate use despite lengthy Bdrug holidays^ and need for continued monitoring during holiday.
Conflicts of interest None.
References 1. Siris ES, Pasquale MK, Wang YT, Watts NB (2011) Estimating bisphosphonate use and fracture reduction among US women aged 45 years and older, 2001–2008. J Bone Miner Res 26:3–11 2. Black DM, Schwartz AV, Ensrud KE et al (2006) Effects of continuing or stopping alendronate after 5 years of treatment—the Fracture Intervention Trial long-term extension (FLEX): a randomized trial. JAMA J Am Med Assoc 296:2927–2938 3. Bone HG, Hosking D, Devogelaer J et al (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199 4. Boonen S (2007) Bisphosphonate efficacy and clinical trials for postmenopausal osteoporosis: similarities and differences. Bone 40(5): S26–S31 5. Eriksen EF, Díez-Pérez A, Boonen S (2014) Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review. Bone 58:126–135 6. Lenart BA, Lorich DG, Lane JM (2008) Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 358:1304–1306 7. Shane E, Burr D, Abrahamsen B et al (2014) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 29:1–23 8. Abrahamsen B, Eiken P, Eastell R (2010) Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis. J Clin Endocrinol Metab 95:5258–5265 9. Brown JP et al (2014) Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays. Can Fam Physician 60(4):324–333 10. Teo BJX, Koh JSB, Goh SK, Png MA, Chua DTC, Howe TS (2014) Post-operative outcomes of atypical femoral subtrochanteric fracture in patients on bisphosphonate therapy. Bone Joint J 96B:658–664
Osteoporos Int 11. Einhorn TA, Bogdan Y, Tornetta P (2014) Bisphosphonate-associated fractures of the femur: pathophysiology and treatment. J Orthop Trauma 28:433–438 12. Russell RGG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759 13. Rodan G, Reszka A, Golub E, Rizzoli R (2004) Bone safety of longterm bisphosphonate treatment. Curr Med Res Opin 20:1291–1300 14. Ananchenko G, et al (2013) Profiles of drug substances, excipients and related methodology: alendronate sodium. N.p. Elsevier, Print 15. Mitchell DY, Barr WH, Eusebio RA et al (2001) Risedronate pharmacokinetics and intra- and inter-subject variability upon single-dose intravenous and oral administration. Pharm Res 18:166–170 16. Cummings SR, Black DM, Thompson DE et al (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures—results from the fracture intervention trial. JAMA J Am Med Assoc 280:2077–2082 17. McClung MR, Geusens P, Miller PD et al (2001) Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 344:333– 340 18. Gedmintas L, Solomon DH, Kim SC (2013) Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res 28(28): 1729–1737 19. Schilcher J, Koeppen V, Aspenberg P (2014) Risk of atypical femoral fracture during and after bisphosphonate use. NEJM 371:974–976 20. Black DM, Reid IR, Boonen S et al (2012) The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27:243–254 21. Watts NB, Chines A, Olszynski WP et al (2008) Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int 19:365–372 22. Schwartz AV, Bauer DC, Cummings SR et al (2010) Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res 25:976– 982
23. Reszka AA, Rodan GA (2003) Bisphosphonate mechanism of action. Curr Rheumatol Rep 5(1):65–74 24. Russell RG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley PA, Kavanagh KL, Triffitt JT, Lundy MW, Phipps RJ, Barnett BL, Coxon FP, Rogers MJ, Watts NB, Ebetino FH (2007) Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 1117:209–257 25. Allen MR, Burr DB (2007) Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment. J Bone Miner Res 22(11):1759–1765 26. Brennan O, Kennedy OD, Lee TC, Rackard SM, O’Brien FJ (2011) Effects of estrogen deficiency and bisphosphonate therapy on osteocyte viability and microdamage accumulation in an ovine model of osteoporosis. J Orthop Res 29(3):419–424. doi:10.1002/jor.21229 27. Boskey AL, Spevak L, Weinstein RS (2009) Spectroscopic markers of bone quality in alendronate-treated postmenopausal women. Osteoporos Int 20(5):793–800 28. Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, Lorich DG, Lane JM, Boskey AL (2012) Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res 27(3):672–678 29. Marshall JH (1964) Theory of alkaline earth metabolism. The power function makes possible a simple but comprehensive model of skeletal systems. J Theor Biol 6:386–412 30. Marshall JH, Onkelinx C (1968) Radial diffusion and power function retention of alkaline earth radioisotopes in adult bone. Nature 217: 742–743 31. Schilcher J, Michaëlsson K, Aspenberg P (2011) Bisphosphonate use and atypical fractures of the femoral shaft. NEJM 364:1728–1737 32. Giusti A, Hamdy NA, Dekkers OM, Ramautar SR, Dijkstra S, Papapoulos SE (2011) Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone 48(5):966–971 33. Diab DL, Watts NB (2013) Bisphosphonate drug holiday: who, when and how long. Ther Adv Musculoskelet Dis 5:107–111
CASE REPORT
Atypical femur fracture during bisphosphonate drug holiday: a case series A. J. Lovy & S. M. Koehler & A. Keswani & D. Joseph & R. Hasija & R. Ghillani
Received: 7 December 2014 / Accepted: 2 February 2015 # International Osteoporosis Foundation and National Osteoporosis Foundation 2015
Abstract Recent studies have noted an increased risk of low energy subtrochanteric and femoral shaft fractures termed Batypical femur fractures^ (AFFs) associated with long-term bisphosphonate use. As such, many clinicians have begun recommending a Bdrug holiday^ to reduce the risks associated with long-term bisphosphonate use. We present two cases of AFFs occurring during a 4-year or greater drug holiday following long-term bisphosphonate use. These findings highlight the need to reevaluate optimal bisphosphonate therapy duration, dosage, as well as initiation and duration of a drug holiday with continued monitoring in the prevention of AFFs. Keywords Atypical femur fractures . Bisphosphonates . Drug holiday . Osteoporosis
regarding bisphosphonate use remain unanswered: the duration of treatment, the minimal efficacious dosage, and the persistence of clinical efficacy given their long half-life. These questions have become more relevant given recent studies noting an increased risk of low-energy subtrochanteric and diaphyseal femoral fractures termed Batypical femur fractures^ (AFFs) associated with long-term bisphosphonate use [6–8]. As such, many clinicians have begun recommending a Bdrug holiday^ to reduce the risks associated with long-term bisphosphonate use [9]. We present two cases of previously undescribed AFFs occurring during 4-year or greater drug holiday following long-term bisphosphonate use. These findings highlight the need to establish optimal bisphosphonate therapy duration as well as the role of a drug holiday in the prevention of AFFs.
Introduction
Case 1
As of 2008, an estimated 4 million women in the USA were prescribed bisphosphonates for the treatment of osteoporosis [1]. The benefits of bisphosphonate therapy in regard to fracture risk reduction are well documented; however, published clinical trial data regarding long-term use of 10 years is limited to alendronate [2–5]. Additionally, several questions
A 64-year-old Caucasian female presented to our trauma center with acute onset of right thigh pain after tripping without a history of a fall. Prior to tripping, the patient noted right thigh pain for 3 weeks. Review of past medical history was significant for Celiac disease, hypothyroidism, and osteoporosis with a 10-year history of alendronate (ALN) use stopped 5 years prior. Additional medications included sertraline, synthroid, gabapentin, and baclofen. Roentgenograms revealed a diaphyseal AFF according to established criteria [7]. Contralateral femur roentgenorgrams did not demonstrate signs of an impending fracture. Laboratory results at injury were notable for ionized calcium 4.87 mg/dL, Vit D 1,25 72 pg/mL, Vit D 25 47 ng/mL, PTH 82.3 pg/mL, TSH 0.29 ulU/mL, Free T4 1.14 ng/dL, and T3 79.89 ng/dL. Complete blood count and basic metabolic panel were within normal limits.
A. J. Lovy (*) : S. M. Koehler : A. Keswani : D. Joseph : R. Ghillani Department of Orthopaedic Surgery, Mount Sinai Hospital, 5 East 98th St., 9th Floor, New York, NY 10029, USA e-mail: [email protected] D. Joseph : R. Hasija : R. Ghillani Department of Orthopaedic Surgery, Elmhurst Hospital Center, 79-01 Broadway, Queens, NY 11373, USA
Osteoporos Int
Case 2 A 70-year-old Hispanic female presented to our trauma center with acute onset of right thigh pain following a mechanical fall from a standing height. The patient denied any antecedent symptoms. Review of past medical history was significant hypothyroidism, hypertension, diabetes mellitus type 2, and osteoporosis with a 14-year history of ALN use stopped 4 years prior after a left AFF. Additional medications included synthroid, omeprazole, hydrochlorothiazide, and metformin. Roentgenograms revealed a subtrochanteric AFF according to established criteria (Fig 1) [7]. The patient’s prior hip fracture was treated at an outside hospital, and this was her first presentation to us. Available laboratory results including complete blood count and basic metabolic panel were within normal limits with the exception of blood glucose of 157 mg/dL.
Discussion We report two cases of AFFs that occurred during a drug holiday in the setting of long-term bisphosphonate use. Recent literature has highlighted the risk factors and prevalence of AFFs, establishing an association between long-term bisphosphonate use and AFF. Despite increased awareness of AFFs,
Fig. 1 Anterorposterior roentgenogram of the right femur demonstrating a diaphyseal atypical femur fracture. Note the non-comminuted, transverse fracture pattern with lateral Bbeaking^
prevention strategies as well as treatment remain poorly defined [10, 11]. Bisphosphonates can be broken down into nitrogen- and non-nitrogen-containing types that reduce osteoclastic bone resorption in a dose- and compound-dependent fashion [12]. Pharmacokinetic studies show that bisphosphonates have a high affinity for bone becoming incorporated into the bone matrix where they remain inactive for many years until released with bone resorption. As a result, cited figures for the terminal half-life of ALN approach 10.5 years [13]. Using a pharmacokinetic model of 10 mg daily of ALN for 10 years with bone histomorphometry-based assumption that 15 % of the total skeleton is comprised of cancellous bone (30 % turnover yearly) and 85 % of cortical bone (3 % annual turnover), Rodan et al. [11] estimated an ALN bone load at 10 years of 37.5 ppm which would equate to a 2.5-mg oral dose of pharmacologically active ALN being released daily due to bone resorption over the next months to years. These findings demonstrate that as ALN bone load increases over time, so should the amount of active ALN released from bone turnover. At the same time, estimated bioavailability of 10 mg oral ALN ranges from 0.76 % (females) to 0.6 % (males) with 50 % of the bioavailable bisphosphonate being stored in the skeleton [14, 15]. Additionally, clinical efficacy has been demonstrated with lesser dosages of ALN (5 mg) [16] and risedronate (2.5 mg) [17]. Taken together, these findings suggest that further research is required to determine the optimal dose as well as duration of bisphosphonate therapy. Increasing levels of active bisphosphonate as treatment duration increases is not without consequence, as several studies have noted an association between long-term bisphosphonate use and risk of AFFs. Gedmintas et al. [18] found that exposure to bisphosphonates was associated with an increased risk of AFF (adjusted RR of 1.70 with 95 % CI 1.22–2.37), while Schilcher et al. [19] found that risk for AFF fracture increased progressively with duration of use. This association highlights the importance of examining the relationship between actual build-up of bisphosphonate in the skeletal system (bone load) and risk for AFF. This suggests that bisphosphonate dosing can be optimized to potentially decrease risk of AFF by (1) using a lower initial dose that achieves sufficient decrease in bone turnover markers and increases in bone mineral density, and (2) adjusting the dose and duration of treatment over time to account for increasing amounts of pharmacologically active bisphosphonate due to bone resorption. Currently, three prospective, randomized trials have evaluated fracture risk among patients continuing or stopping bisphosphonate therapy [2, 20, 21]. The Fracture Intervention Trial Long-term Extension (FLEX) study looked at the effect of discontinuing ALN after 5 years. Women who discontinued use had a moderate rise in bone mineral markers and fall in bone mineral density on a dual energy X-ray absorptiometry (DEXA) study; but, no increased risk of morphometric
Osteoporos Int
vertebral fractures or non-vertebral fractures [2]. Post hoc analysis of the FLEX study identified an increased risk of fracture among high-risk patients as defined by a T-score < −2.5 but without prevalent vertebral fracture with cessation of ALN compared to controls [22]. A similar trial comparing the effect of 3 versus 6 years of zoledronic acid noted a decreased risk of morphometric vertebral fractures among patients treated for 6 years but no difference in other fractures [20]. While these studies suggest that bisphosphonate therapy duration can be limited in the absence of high-risk criteria, optimal duration of therapy remains unknown. Several limitations to the approach mentioned are worthy of note. Though it is known that bisphosphonates inhibit osteoclast activity and encourage osteoclast apoptosis, the relationship between severe suppression of bone turnover and the incidence of AFFs is not clearly understood [23, 24]. Several studies have posited that suppression of bone turnover may allow for the accumulation of microfractures, impaired stressfracture healing, and decreased heterogeneity of bone matrix which would increase risk for AFF; but, this cannot be confirmed until more studies on bone histomorphometry are performed [25–28]. Secondly, there is little evidence describing the rate of bisphosphonate release from cortical bone due to its slower turnover rate. This makes it more difficult to accurately quantify how much pharmacologically active bisphosphonate is released at any time due to bone resorption. There is, however, literature suggesting that the kinetics of ALN release from bone are similar to those of calcium and other minerals [29, 30]. While the concept of a drug holiday may help reduce the risk of AFF as bisphosphonate levels mount over time, it is an imperfect strategy to prevent the complications of extended duration of use. In a study evaluating risk of AFF associated with bisphosphonate (BP) therapy using National Swedish Patient Registry data, Schilcher et al. [31] found that the duration of BP use was associated with risk of fracture as well as a 70 % decrease in AFF risk per year following BP cessation. However, the applicability of estimated risk reduction of AFF beyond 2 years of cessation is unclear as only 3 out of 59 cases sustained fractures ≥2 years after BP cessation. Additionally, registry data regarding long-term BP use was limited as prescription drug information was recorded for less than 3 years prior to the study. As our cases illustrate, clinicians must be aware that the risk of AFF can remain despite a drug holiday of greater than 4 years. Similarly, Giusti et al. [32] note one case of an AFF that occurred during a 5-year holiday in a patient previously treated with oral pamidronate for 12 years. Further research is required to establish standards for duration of therapy, minimal efficacious dosage, initiating drug holiday, and for duration of drug holiday. Several studies have suggested evaluating Brisk for fracture^ and using this as criteria for a drug holiday. In an effort to risk stratify fracture risk when considering a drug holiday, Diab et al. [33] has
developed four risk profiles (high, moderate, medium, low) to guide duration of therapy and initiation or termination of drug holiday based on T-score, continued monitoring for significant decrease in bone mineral density (BMD), and presence of other risk factors associated with greater fracture risk (e.g., ongoing corticosteroid therapy, history of previous fractures). In this framework, T-score and significant changes in BMD are suggested as indictors to end drug holiday and resume treatment; however, further clinical testing will be required to validate this framework [33]. Although further research is required, we believe that AFF risk is not negated by drug holiday alone and that it may be Btoo little, too late.^ Prevention of complications from bisphosphonates must occur at the outset through evidence-based standards for treatment. Lastly, physicians must be aware of continued AFF risk in patients with long-term bisphosphonate use despite lengthy Bdrug holidays^ and need for continued monitoring during holiday.
Conflicts of interest None.
References 1. Siris ES, Pasquale MK, Wang YT, Watts NB (2011) Estimating bisphosphonate use and fracture reduction among US women aged 45 years and older, 2001–2008. J Bone Miner Res 26:3–11 2. Black DM, Schwartz AV, Ensrud KE et al (2006) Effects of continuing or stopping alendronate after 5 years of treatment—the Fracture Intervention Trial long-term extension (FLEX): a randomized trial. JAMA J Am Med Assoc 296:2927–2938 3. Bone HG, Hosking D, Devogelaer J et al (2004) Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350:1189–1199 4. Boonen S (2007) Bisphosphonate efficacy and clinical trials for postmenopausal osteoporosis: similarities and differences. Bone 40(5): S26–S31 5. Eriksen EF, Díez-Pérez A, Boonen S (2014) Update on long-term treatment with bisphosphonates for postmenopausal osteoporosis: a systematic review. Bone 58:126–135 6. Lenart BA, Lorich DG, Lane JM (2008) Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 358:1304–1306 7. Shane E, Burr D, Abrahamsen B et al (2014) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 29:1–23 8. Abrahamsen B, Eiken P, Eastell R (2010) Cumulative alendronate dose and the long-term absolute risk of subtrochanteric and diaphyseal femur fractures: a register-based national cohort analysis. J Clin Endocrinol Metab 95:5258–5265 9. Brown JP et al (2014) Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays. Can Fam Physician 60(4):324–333 10. Teo BJX, Koh JSB, Goh SK, Png MA, Chua DTC, Howe TS (2014) Post-operative outcomes of atypical femoral subtrochanteric fracture in patients on bisphosphonate therapy. Bone Joint J 96B:658–664
Osteoporos Int 11. Einhorn TA, Bogdan Y, Tornetta P (2014) Bisphosphonate-associated fractures of the femur: pathophysiology and treatment. J Orthop Trauma 28:433–438 12. Russell RGG, Watts NB, Ebetino FH, Rogers MJ (2008) Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int 19:733–759 13. Rodan G, Reszka A, Golub E, Rizzoli R (2004) Bone safety of longterm bisphosphonate treatment. Curr Med Res Opin 20:1291–1300 14. Ananchenko G, et al (2013) Profiles of drug substances, excipients and related methodology: alendronate sodium. N.p. Elsevier, Print 15. Mitchell DY, Barr WH, Eusebio RA et al (2001) Risedronate pharmacokinetics and intra- and inter-subject variability upon single-dose intravenous and oral administration. Pharm Res 18:166–170 16. Cummings SR, Black DM, Thompson DE et al (1998) Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures—results from the fracture intervention trial. JAMA J Am Med Assoc 280:2077–2082 17. McClung MR, Geusens P, Miller PD et al (2001) Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 344:333– 340 18. Gedmintas L, Solomon DH, Kim SC (2013) Bisphosphonates and risk of subtrochanteric, femoral shaft, and atypical femur fracture: a systematic review and meta-analysis. J Bone Miner Res 28(28): 1729–1737 19. Schilcher J, Koeppen V, Aspenberg P (2014) Risk of atypical femoral fracture during and after bisphosphonate use. NEJM 371:974–976 20. Black DM, Reid IR, Boonen S et al (2012) The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 27:243–254 21. Watts NB, Chines A, Olszynski WP et al (2008) Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int 19:365–372 22. Schwartz AV, Bauer DC, Cummings SR et al (2010) Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res 25:976– 982
23. Reszka AA, Rodan GA (2003) Bisphosphonate mechanism of action. Curr Rheumatol Rep 5(1):65–74 24. Russell RG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley PA, Kavanagh KL, Triffitt JT, Lundy MW, Phipps RJ, Barnett BL, Coxon FP, Rogers MJ, Watts NB, Ebetino FH (2007) Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 1117:209–257 25. Allen MR, Burr DB (2007) Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment. J Bone Miner Res 22(11):1759–1765 26. Brennan O, Kennedy OD, Lee TC, Rackard SM, O’Brien FJ (2011) Effects of estrogen deficiency and bisphosphonate therapy on osteocyte viability and microdamage accumulation in an ovine model of osteoporosis. J Orthop Res 29(3):419–424. doi:10.1002/jor.21229 27. Boskey AL, Spevak L, Weinstein RS (2009) Spectroscopic markers of bone quality in alendronate-treated postmenopausal women. Osteoporos Int 20(5):793–800 28. Donnelly E, Meredith DS, Nguyen JT, Gladnick BP, Rebolledo BJ, Shaffer AD, Lorich DG, Lane JM, Boskey AL (2012) Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res 27(3):672–678 29. Marshall JH (1964) Theory of alkaline earth metabolism. The power function makes possible a simple but comprehensive model of skeletal systems. J Theor Biol 6:386–412 30. Marshall JH, Onkelinx C (1968) Radial diffusion and power function retention of alkaline earth radioisotopes in adult bone. Nature 217: 742–743 31. Schilcher J, Michaëlsson K, Aspenberg P (2011) Bisphosphonate use and atypical fractures of the femoral shaft. NEJM 364:1728–1737 32. Giusti A, Hamdy NA, Dekkers OM, Ramautar SR, Dijkstra S, Papapoulos SE (2011) Atypical fractures and bisphosphonate therapy: a cohort study of patients with femoral fracture with radiographic adjudication of fracture site and features. Bone 48(5):966–971 33. Diab DL, Watts NB (2013) Bisphosphonate drug holiday: who, when and how long. Ther Adv Musculoskelet Dis 5:107–111
