Bone 61 (2014) 44–47
Contents lists available at ScienceDirect
Bone journal homepage: www.elsevier.com/locate/bone
Case Report
Bilateral atypical femoral fractures in a patient prescribed denosumab — A case report Robin N. Thompson ⁎, Ciara L. Armstrong, Gary Heyburn Fracture Unit, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6BA, UK
a r t i c l e
i n f o
Article history: Received 14 October 2013 Revised 19 December 2013 Accepted 23 December 2013 Available online 31 December 2013 Edited by: Michael Amling Keywords: Atypical femoral fracture Denosumab Rheumatoid arthritis Prophylactic nailing
a b s t r a c t Atypical fractures of the diaphyseal femoral shaft have been reported in the literature at an increasing rate over the past few years. They have been observed mostly in patients who have been on prolonged courses of bisphosphonates, with no reported cases of atypical femoral fractures in those treated with other antiresorptive medications. A 59 year old woman sustained an atypical fracture of her right femur in March 2013. She had a past medical history of rheumatoid arthritis and osteoporosis. She had been on alendronate but it was discontinued after five years in 1999. She received denosumab by subcutaneous injection in December 2012. At follow up, she complained of pain in her left femur and a radiograph revealed atypical appearances. She was admitted in June 2013 for prophylactic nailing of the left femur. To our knowledge, this is the first reported case of bilateral atypical femoral changes in a patient prescribed denosumab. Given that denosumab has been on the market for a short time period, we expect that the number of these cases will increase with time. We emphasise previous guidance that patients who present with new onset hip or thigh pain should be screened for atypical femoral fractures. © 2013 Elsevier Inc. All rights reserved.
Introduction Atypical fractures of the diaphyseal femoral shaft have been reported in the literature at an increasing rate over the past few years. The fracture configuration is invariably a non-comminuted transverse fracture through an area of thickened cortex, associated with minimal or no trauma. While no process or agent has been identified as the cause of these atypical fractures to date, they have been observed mostly in patients who have been on prolonged courses of bisphosphonates, with no reported cases of atypical femoral fractures in those treated with other anti-resorptive medications. Cases of atypical femoral fracture have been reported where no anti-resorptive medication has been prescribed [1]. Denosumab is a novel RANKL inhibitor that has demonstrated efficacy and safety in the treatment of postmenopausal osteoporosis. It is used as an alternative to bisphosphonates in patients who cannot tolerate them [2]. We report a case of atypical femoral fracture in a female patient who had treatment with denosumab. Case report A 59 year old woman presented to our unit's outpatient clinic for follow up of a right femoral fracture. She had fallen whilst on holiday ⁎ Corresponding author. E-mail address: [email protected] (R.N. Thompson). 8756-3282/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bone.2013.12.027
in March 2013 and suffered a fracture of the right femoral shaft. She had described pain in her thigh before the fall. She underwent cephalomedullary nailing of the right femur and had an uneventful post-operative recovery. She has a past medical history of sero-negative rheumatoid arthritis, osteoporosis, thyroidectomy and compression fracture of a vertebra. Her rheumatoid arthritis had been treated with infliximab, enbrel, humira, tocilizumab, leflunomide and methylprednisolone. She was diagnosed with osteoporosis in 1994 and had been on alendronate. This was discontinued after five years in 1999. She was reviewed by a rheumatology consultant in December 2012 who thought that she would benefit from a long acting anti-resorptive agent. She received denosumab by subcutaneous injection in December 2012. Review of her post operative radiographs in our unit (United Kingdom) suggested an atypical fracture, i.e. a transverse fracture pattern in an area of thickened lateral cortex (Figs. 1a and b). Further questioning revealed that she had been having pain in her left thigh as well. Radiographs of her left femur showed appearances of endosteal reaction in the lateral aspect of the femoral shaft (Fig. 2). Table 1 lists the major and minor criteria for atypical fractures as defined by the American Society for Bone and Mineral Research. She was therefore admitted to our unit in June 2013 for prophylactic nailing of the left femur. There were no post-operative complications. An intramedullary biopsy of bone was taken in theatre. This was analysed by the histopathology laboratory using standard techniques. Using light microscopy with haematoxylin and eosin staining, overall the findings were non-specific. There were fragments of cancellous bone with some
R.N. Thompson et al. / Bone 61 (2014) 44–47
45
Table 2 Investigations performed as part of a full pathological work up. Investigation
Result
Unit
Laboratory reference range
Parathyroid hormone Adjusted calcium Phosphate Vitamin D Alkaline phosphatase Haematology indices Urea and electrolytes Liver function tests
54 2.35 1.22 81 101 Normal Normal Normal
pG/mL mmol/L mmol/L nmol/L U/L
15–65 2.20–2.60 0.8–1.37 N75 30–130
1.0 9 b1 Not detected 6.30 1.19 0.99 72 No paraprotein detected No pathological abnormality detected
ng/mL u/mL u/mL
0.0–4.0 0–35 0–37
g/L g/L g/L g/L
6.0–16.0 0.80–4.00 0.50–2.00 60–80
Pathological work up Tumour markers CEA CA125 CA19.9 Bence Jones protein Immunogloblins IgG IgA IgM Total protein Serum protein electrophoresis CT of chest, abdomen and pelvis
Fig. 1. a and 1b. Atypical fracture configuration.
investigations are listed in Table 2. Fig. 3 shows her bone scan which identifies focal areas of uptake in the location of the atypical changes on her femoral radiographs. Discussion
Fig. 2. Area of endosteal reaction and hypertrophy.
trabeculae appearing necrotic and some which appeared recently remodeled. No specific markers of bone turnover were available at the laboratory. During her admission, a full pathological work up was performed which did not identify anything abnormal. Details of the
To our knowledge, this is the first reported case in the peer-reviewed literature of an atypical femoral fracture with bilateral changes in a patient prescribed denosumab. Denosumab is a human monoclonal antibody that works as an inhibitor of RANKL (receptor activator of glycoprotein nuclear factor-KB ligand). RANK is expressed on osteoclasts and when RANKL is bound with RANK, osteoclast formation is promoted, hence increasing bone resorption [3–5]. It is thought that RANKL levels are increased in the perimenopausal period [3]. Denosumab is an IgG2 immunogloblin that binds with RANKL, preventing it from binding to RANK therefore decreasing osteoclast activity, and helping to modulate bone remodeling [4,5]. The mechanism behind the development of atypical femoral fractures is unclear. A proposed model is that of suppression of bone turnover and impaired bone strength [6]. Whilst atypical fractures occur in those who have not been exposed to bisphosphonates, it is thought that bisphosphonates may contribute to the development of atypical femoral fractures by suppressing remodeling [7]. Ettinger et al. [8] hypothesise several pathophysiological steps that lead to atypical femoral fractures. Suppression of bone turnover leads to full mineralisation of
Table 1 The major and minor criteria for atypical fractures as defined by the American Society for Bone and Mineral Research (Revised 2013) [1]. Major criteria
Present in this case
Minor criteria
Present in this case
Located anywhere along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare Associated with no trauma or minimal trauma, as in a fall from a standing height or less
Yes
Generalized increase in cortical thickness of the diaphysis Prodromal symptoms such as dull or aching pain in the groin or thigh Bilateral fractures and symptoms
No
Delayed healing
?
The fracture line originates at the lateral cortex and is substantially transverse in its orientation, although it may become oblique as it progresses medially across the femur Noncomminuted or minimally comminuted Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex. Localized periosteal reaction of the lateral cortex
Yes Yes Yes Yes Yes
Yes Yes
46
R.N. Thompson et al. / Bone 61 (2014) 44–47
new onset hip or thigh pain, and consideration for discontinuation of denosumab in such cases [13]. Including this case, there have been three cases of atypical femoral fracture reported to the MHRA adverse drug reaction reporting system [14] within the UK. Between 2010 and 2012, four cases of atypical femoral fracture have been reported to the Food and Drug Administration (FDA) in the US [15]. Denosumab is used in higher dose and frequency for the prevention of bone related events in adults with bone metastases from solid tumours. Whilst an advisory regarding severe hypocalcaemia has been published [16], a thorough search of the literature could not identify any reporting of occurrence of atypical femoral fractures using this dosing regime. The patient in this case had been prescribed bisphosphonates in the past. This had been discontinued for at least 12 years prior to fracture. However, bisphosphonates have approximately a 5–10 year half life in bone [17]. Therefore, it could be argued that the development of her atypical fracture was related, in part, to treatment with previous bisphosphonates. This patient's fracture occurred within three months of her being administered denosumab. It has been shown that it takes approximately one month for denosumab to have its maximal effect on bone turnover markers. Furthermore, she did not describe thigh pain prior to her denosumab injection. It is possible to suggest that the development of her fracture was related to the use of denosumab. Equally, this patient had rheumatoid arthritis and was prescribed glucocorticoids. These are other factors that have been noted in cases of atypical femoral fracture and it therefore could be the combination of glucocorticoids, bisphosphonates and denosumab that leads to the development of her atypical femoral fractures. Fig. 3. Bone scan showing uptake in areas of atypical changes.
cortical bone osteons which causes bone microstructure to become more homogeneous. Furthermore, as a form of premature bone aging, bone turnover suppression allows accumulation of collagen “advanced glycation end-products” leading to increased brittleness. Combining these two factors with the suppression of the targeted bone repair process allows a single microcrack to progress unimpeded, eventually resulting in a completed fracture. Therefore, if the underlying mechanism in the development of atypical femoral fractures is related to the modulation of osteoclast activity, it would seem reasonable for all medications that act on this to be associated with the development of atypical femoral fractures. However, this has not been reflected in the published literature. The incidence of atypical femoral fractures varies widely in the literature. An American review of large cohort of femoral shaft fractures revealed an incidence of 113 per 100,000 patients per year in those treated with bisphosphonates for 8–9 years [9]. 90% of their study's subjects had been prescribed bisphosphonates. A European study places the incidence at 61 per 100,000 patients per year [10]. In our own unit, we have published a cohort study of 29 fractures in a 2 year period, 81% of those were on bisphosphonates at time of fracture [11]. Few adverse events have been reported with the use of denosumab in the treatment of osteoporosis. A large international, randomized, placebo-controlled trial (FREEDOM) reported no fractures of the femoral shaft within the denosumab group as a specific adverse outcome at the time of original publication of results [12]. However, there has been a recent advisory from the Medicines and Healthcare Product Regulatory Agency (MHRA, United Kingdom) that 2 cases of atypical femoral fractures have been reported from the long term follow up of the original FREEDOM trial participants. The guidance advises screening for atypical fractures in those who present with
Conclusion The definitive factor in this patient's case will not be known for certain. It is however, worth highlighting that caution should be noted before prescribing denosumab in a patient who has been on previous long term bisphosphonates. This has emphasised that screening radiographs of femurs should be considered in such cases where the patient has received treatment with multiple anti-resorptives. Given that denosumab has been on the market for a short time period, we expect that the number of these cases will increase with time. We emphasise previous guidance which states that patients who present with new onset hip or thigh pain should be screened for atypical femoral fractures.
References [1] Shane E, Burr D, et al. 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 2014. http://dx.doi.org/10.1002/jbmr.1998. [2] Sutton E, Riche DM. Denosumab, a RANK ligand inhibitor, for postmenopausal women with osteoporosis. Ann Pharmacother 2012;46:1000–9. [3] Watts B, Bilezikian JP, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2010(Suppl. 3):1–37. [4] Burkiewicz JS, Scarpace SL, Bruce SP. Denosumab in osteoporosis and oncology. Ann Pharmacother 2009;43:1445–55. [5] McClung M. Role of RANKL inhibition in osteoporosis. Arthritis Res Ther 2007;9(Suppl. 1):S3. [6] Seraphim A, Al-Hadithy N, Mordecai SC, Al-Nammari S. Do bisphosphonates cause femoral insufficiency fractures? J Orthop Traumatol 2012;13:171–7. [7] Compston J. Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw. Osteoporos Int 2011;22:2951–61. [8] Ettinger B, Burr DB, Ritchie RO. Proposed pathogenesis for atypical femoral fractures: lessons from materials research. Bone 2013;55:495–500. [9] Dell RM, Adams AL, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012;27:2544–50. [10] Tamminen IS, Yli-Kyyny T, et al. Incidence and bone biopsy findings of atypical femoral fractures. J Bone Miner Metab 2013;31:585–94.
R.N. Thompson et al. / Bone 61 (2014) 44–47 [11] Thompson RN, Phillips JR, McCauley SH, Elliott JR, Moran CG. Atypical femoral fractures and bisphosphonate treatment: experience in two large United Kingdom teaching hospitals. J Bone Joint Surg (Br) 2012;94:385–90. [12] Cummings SR, San Martin J, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65. [13] MHRA Drug Safety Update 2013 Volume 6, Issue 7. Denosumab 60 mg: rare cases of atypical femoral fracture with long-term use. http://www.mhra.gov.uk/ Safetyinformation/DrugSafetyUpdate/CON239411 . [accessed 28/8/2013]. [14] MHRA drug analysis print. http://www.mhra.gov.uk/home/groups/public/documents/ sentineldocuments/dap_1374834463819.pdf. [accessed 28/8/2013].
47
[15] FDA Adverse Event Reporting System (FAERS): latest quarterly data files. http:// www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ AdverseDrugEffects/ucm082193.htm. [accessed 1/11/2013]. [16] MHRA Drug Safety Update 2012 Volume 6, Issue 3. Denosumab: fatal cases of severe symptomatic hypocalcaemia, and risk of hypocalcaemia at any time during treatment – monitoring recommended. http://www.mhra.gov.uk/ Safetyinformation/DrugSafetyUpdate/CON199560. [accessed 28/8/2013]. [17] Khan SA, Kanis JA, et al. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 1997;12: 1700–7.
Contents lists available at ScienceDirect
Bone journal homepage: www.elsevier.com/locate/bone
Case Report
Bilateral atypical femoral fractures in a patient prescribed denosumab — A case report Robin N. Thompson ⁎, Ciara L. Armstrong, Gary Heyburn Fracture Unit, Royal Victoria Hospital, Grosvenor Road, Belfast, BT12 6BA, UK
a r t i c l e
i n f o
Article history: Received 14 October 2013 Revised 19 December 2013 Accepted 23 December 2013 Available online 31 December 2013 Edited by: Michael Amling Keywords: Atypical femoral fracture Denosumab Rheumatoid arthritis Prophylactic nailing
a b s t r a c t Atypical fractures of the diaphyseal femoral shaft have been reported in the literature at an increasing rate over the past few years. They have been observed mostly in patients who have been on prolonged courses of bisphosphonates, with no reported cases of atypical femoral fractures in those treated with other antiresorptive medications. A 59 year old woman sustained an atypical fracture of her right femur in March 2013. She had a past medical history of rheumatoid arthritis and osteoporosis. She had been on alendronate but it was discontinued after five years in 1999. She received denosumab by subcutaneous injection in December 2012. At follow up, she complained of pain in her left femur and a radiograph revealed atypical appearances. She was admitted in June 2013 for prophylactic nailing of the left femur. To our knowledge, this is the first reported case of bilateral atypical femoral changes in a patient prescribed denosumab. Given that denosumab has been on the market for a short time period, we expect that the number of these cases will increase with time. We emphasise previous guidance that patients who present with new onset hip or thigh pain should be screened for atypical femoral fractures. © 2013 Elsevier Inc. All rights reserved.
Introduction Atypical fractures of the diaphyseal femoral shaft have been reported in the literature at an increasing rate over the past few years. The fracture configuration is invariably a non-comminuted transverse fracture through an area of thickened cortex, associated with minimal or no trauma. While no process or agent has been identified as the cause of these atypical fractures to date, they have been observed mostly in patients who have been on prolonged courses of bisphosphonates, with no reported cases of atypical femoral fractures in those treated with other anti-resorptive medications. Cases of atypical femoral fracture have been reported where no anti-resorptive medication has been prescribed [1]. Denosumab is a novel RANKL inhibitor that has demonstrated efficacy and safety in the treatment of postmenopausal osteoporosis. It is used as an alternative to bisphosphonates in patients who cannot tolerate them [2]. We report a case of atypical femoral fracture in a female patient who had treatment with denosumab. Case report A 59 year old woman presented to our unit's outpatient clinic for follow up of a right femoral fracture. She had fallen whilst on holiday ⁎ Corresponding author. E-mail address: [email protected] (R.N. Thompson). 8756-3282/$ – see front matter © 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bone.2013.12.027
in March 2013 and suffered a fracture of the right femoral shaft. She had described pain in her thigh before the fall. She underwent cephalomedullary nailing of the right femur and had an uneventful post-operative recovery. She has a past medical history of sero-negative rheumatoid arthritis, osteoporosis, thyroidectomy and compression fracture of a vertebra. Her rheumatoid arthritis had been treated with infliximab, enbrel, humira, tocilizumab, leflunomide and methylprednisolone. She was diagnosed with osteoporosis in 1994 and had been on alendronate. This was discontinued after five years in 1999. She was reviewed by a rheumatology consultant in December 2012 who thought that she would benefit from a long acting anti-resorptive agent. She received denosumab by subcutaneous injection in December 2012. Review of her post operative radiographs in our unit (United Kingdom) suggested an atypical fracture, i.e. a transverse fracture pattern in an area of thickened lateral cortex (Figs. 1a and b). Further questioning revealed that she had been having pain in her left thigh as well. Radiographs of her left femur showed appearances of endosteal reaction in the lateral aspect of the femoral shaft (Fig. 2). Table 1 lists the major and minor criteria for atypical fractures as defined by the American Society for Bone and Mineral Research. She was therefore admitted to our unit in June 2013 for prophylactic nailing of the left femur. There were no post-operative complications. An intramedullary biopsy of bone was taken in theatre. This was analysed by the histopathology laboratory using standard techniques. Using light microscopy with haematoxylin and eosin staining, overall the findings were non-specific. There were fragments of cancellous bone with some
R.N. Thompson et al. / Bone 61 (2014) 44–47
45
Table 2 Investigations performed as part of a full pathological work up. Investigation
Result
Unit
Laboratory reference range
Parathyroid hormone Adjusted calcium Phosphate Vitamin D Alkaline phosphatase Haematology indices Urea and electrolytes Liver function tests
54 2.35 1.22 81 101 Normal Normal Normal
pG/mL mmol/L mmol/L nmol/L U/L
15–65 2.20–2.60 0.8–1.37 N75 30–130
1.0 9 b1 Not detected 6.30 1.19 0.99 72 No paraprotein detected No pathological abnormality detected
ng/mL u/mL u/mL
0.0–4.0 0–35 0–37
g/L g/L g/L g/L
6.0–16.0 0.80–4.00 0.50–2.00 60–80
Pathological work up Tumour markers CEA CA125 CA19.9 Bence Jones protein Immunogloblins IgG IgA IgM Total protein Serum protein electrophoresis CT of chest, abdomen and pelvis
Fig. 1. a and 1b. Atypical fracture configuration.
investigations are listed in Table 2. Fig. 3 shows her bone scan which identifies focal areas of uptake in the location of the atypical changes on her femoral radiographs. Discussion
Fig. 2. Area of endosteal reaction and hypertrophy.
trabeculae appearing necrotic and some which appeared recently remodeled. No specific markers of bone turnover were available at the laboratory. During her admission, a full pathological work up was performed which did not identify anything abnormal. Details of the
To our knowledge, this is the first reported case in the peer-reviewed literature of an atypical femoral fracture with bilateral changes in a patient prescribed denosumab. Denosumab is a human monoclonal antibody that works as an inhibitor of RANKL (receptor activator of glycoprotein nuclear factor-KB ligand). RANK is expressed on osteoclasts and when RANKL is bound with RANK, osteoclast formation is promoted, hence increasing bone resorption [3–5]. It is thought that RANKL levels are increased in the perimenopausal period [3]. Denosumab is an IgG2 immunogloblin that binds with RANKL, preventing it from binding to RANK therefore decreasing osteoclast activity, and helping to modulate bone remodeling [4,5]. The mechanism behind the development of atypical femoral fractures is unclear. A proposed model is that of suppression of bone turnover and impaired bone strength [6]. Whilst atypical fractures occur in those who have not been exposed to bisphosphonates, it is thought that bisphosphonates may contribute to the development of atypical femoral fractures by suppressing remodeling [7]. Ettinger et al. [8] hypothesise several pathophysiological steps that lead to atypical femoral fractures. Suppression of bone turnover leads to full mineralisation of
Table 1 The major and minor criteria for atypical fractures as defined by the American Society for Bone and Mineral Research (Revised 2013) [1]. Major criteria
Present in this case
Minor criteria
Present in this case
Located anywhere along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare Associated with no trauma or minimal trauma, as in a fall from a standing height or less
Yes
Generalized increase in cortical thickness of the diaphysis Prodromal symptoms such as dull or aching pain in the groin or thigh Bilateral fractures and symptoms
No
Delayed healing
?
The fracture line originates at the lateral cortex and is substantially transverse in its orientation, although it may become oblique as it progresses medially across the femur Noncomminuted or minimally comminuted Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex. Localized periosteal reaction of the lateral cortex
Yes Yes Yes Yes Yes
Yes Yes
46
R.N. Thompson et al. / Bone 61 (2014) 44–47
new onset hip or thigh pain, and consideration for discontinuation of denosumab in such cases [13]. Including this case, there have been three cases of atypical femoral fracture reported to the MHRA adverse drug reaction reporting system [14] within the UK. Between 2010 and 2012, four cases of atypical femoral fracture have been reported to the Food and Drug Administration (FDA) in the US [15]. Denosumab is used in higher dose and frequency for the prevention of bone related events in adults with bone metastases from solid tumours. Whilst an advisory regarding severe hypocalcaemia has been published [16], a thorough search of the literature could not identify any reporting of occurrence of atypical femoral fractures using this dosing regime. The patient in this case had been prescribed bisphosphonates in the past. This had been discontinued for at least 12 years prior to fracture. However, bisphosphonates have approximately a 5–10 year half life in bone [17]. Therefore, it could be argued that the development of her atypical fracture was related, in part, to treatment with previous bisphosphonates. This patient's fracture occurred within three months of her being administered denosumab. It has been shown that it takes approximately one month for denosumab to have its maximal effect on bone turnover markers. Furthermore, she did not describe thigh pain prior to her denosumab injection. It is possible to suggest that the development of her fracture was related to the use of denosumab. Equally, this patient had rheumatoid arthritis and was prescribed glucocorticoids. These are other factors that have been noted in cases of atypical femoral fracture and it therefore could be the combination of glucocorticoids, bisphosphonates and denosumab that leads to the development of her atypical femoral fractures. Fig. 3. Bone scan showing uptake in areas of atypical changes.
cortical bone osteons which causes bone microstructure to become more homogeneous. Furthermore, as a form of premature bone aging, bone turnover suppression allows accumulation of collagen “advanced glycation end-products” leading to increased brittleness. Combining these two factors with the suppression of the targeted bone repair process allows a single microcrack to progress unimpeded, eventually resulting in a completed fracture. Therefore, if the underlying mechanism in the development of atypical femoral fractures is related to the modulation of osteoclast activity, it would seem reasonable for all medications that act on this to be associated with the development of atypical femoral fractures. However, this has not been reflected in the published literature. The incidence of atypical femoral fractures varies widely in the literature. An American review of large cohort of femoral shaft fractures revealed an incidence of 113 per 100,000 patients per year in those treated with bisphosphonates for 8–9 years [9]. 90% of their study's subjects had been prescribed bisphosphonates. A European study places the incidence at 61 per 100,000 patients per year [10]. In our own unit, we have published a cohort study of 29 fractures in a 2 year period, 81% of those were on bisphosphonates at time of fracture [11]. Few adverse events have been reported with the use of denosumab in the treatment of osteoporosis. A large international, randomized, placebo-controlled trial (FREEDOM) reported no fractures of the femoral shaft within the denosumab group as a specific adverse outcome at the time of original publication of results [12]. However, there has been a recent advisory from the Medicines and Healthcare Product Regulatory Agency (MHRA, United Kingdom) that 2 cases of atypical femoral fractures have been reported from the long term follow up of the original FREEDOM trial participants. The guidance advises screening for atypical fractures in those who present with
Conclusion The definitive factor in this patient's case will not be known for certain. It is however, worth highlighting that caution should be noted before prescribing denosumab in a patient who has been on previous long term bisphosphonates. This has emphasised that screening radiographs of femurs should be considered in such cases where the patient has received treatment with multiple anti-resorptives. Given that denosumab has been on the market for a short time period, we expect that the number of these cases will increase with time. We emphasise previous guidance which states that patients who present with new onset hip or thigh pain should be screened for atypical femoral fractures.
References [1] Shane E, Burr D, et al. 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 2014. http://dx.doi.org/10.1002/jbmr.1998. [2] Sutton E, Riche DM. Denosumab, a RANK ligand inhibitor, for postmenopausal women with osteoporosis. Ann Pharmacother 2012;46:1000–9. [3] Watts B, Bilezikian JP, et al. American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract 2010(Suppl. 3):1–37. [4] Burkiewicz JS, Scarpace SL, Bruce SP. Denosumab in osteoporosis and oncology. Ann Pharmacother 2009;43:1445–55. [5] McClung M. Role of RANKL inhibition in osteoporosis. Arthritis Res Ther 2007;9(Suppl. 1):S3. [6] Seraphim A, Al-Hadithy N, Mordecai SC, Al-Nammari S. Do bisphosphonates cause femoral insufficiency fractures? J Orthop Traumatol 2012;13:171–7. [7] Compston J. Pathophysiology of atypical femoral fractures and osteonecrosis of the jaw. Osteoporos Int 2011;22:2951–61. [8] Ettinger B, Burr DB, Ritchie RO. Proposed pathogenesis for atypical femoral fractures: lessons from materials research. Bone 2013;55:495–500. [9] Dell RM, Adams AL, et al. Incidence of atypical nontraumatic diaphyseal fractures of the femur. J Bone Miner Res 2012;27:2544–50. [10] Tamminen IS, Yli-Kyyny T, et al. Incidence and bone biopsy findings of atypical femoral fractures. J Bone Miner Metab 2013;31:585–94.
R.N. Thompson et al. / Bone 61 (2014) 44–47 [11] Thompson RN, Phillips JR, McCauley SH, Elliott JR, Moran CG. Atypical femoral fractures and bisphosphonate treatment: experience in two large United Kingdom teaching hospitals. J Bone Joint Surg (Br) 2012;94:385–90. [12] Cummings SR, San Martin J, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65. [13] MHRA Drug Safety Update 2013 Volume 6, Issue 7. Denosumab 60 mg: rare cases of atypical femoral fracture with long-term use. http://www.mhra.gov.uk/ Safetyinformation/DrugSafetyUpdate/CON239411 . [accessed 28/8/2013]. [14] MHRA drug analysis print. http://www.mhra.gov.uk/home/groups/public/documents/ sentineldocuments/dap_1374834463819.pdf. [accessed 28/8/2013].
47
[15] FDA Adverse Event Reporting System (FAERS): latest quarterly data files. http:// www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/ AdverseDrugEffects/ucm082193.htm. [accessed 1/11/2013]. [16] MHRA Drug Safety Update 2012 Volume 6, Issue 3. Denosumab: fatal cases of severe symptomatic hypocalcaemia, and risk of hypocalcaemia at any time during treatment – monitoring recommended. http://www.mhra.gov.uk/ Safetyinformation/DrugSafetyUpdate/CON199560. [accessed 28/8/2013]. [17] Khan SA, Kanis JA, et al. Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis. J Bone Miner Res 1997;12: 1700–7.
