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LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.
The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.
How common are atypical femoral fractures?
"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.
"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."
"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.
However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.
Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).
There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.
Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.
What are atypical hip fractures?
Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.
"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.
There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.
The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).
The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."
Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.
What should clinicians do if AFF is suspected?
"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.
In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.
In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.
Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.
In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."
Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."
Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.
Atypical femoral fracture register planned
"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.
"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.
Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.
LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.
The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.
How common are atypical femoral fractures?
"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.
"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."
"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.
However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.
Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).
There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.
Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.
What are atypical hip fractures?
Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.
"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.
There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.
The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).
The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."
Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.
What should clinicians do if AFF is suspected?
"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.
In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.
In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.
Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.
In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."
Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."
Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.
Atypical femoral fracture register planned
"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.
"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.
Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.
LIVERPOOL, ENGLAND – The risk of atypical femoral fractures with long-term bisphosphonate treatment may be relatively low overall, but clinicians need to be aware, experts said at the recent British Society for Rheumatology annual conference.
The topic was debated during an Osteoporosis Special Interest Group Session, with the motion put forth that the risk of atypical femoral fractures (AFFs) with bisphosphonates was a "ticking time bomb about to explode." While that was a rather extreme view to support, there is still cause for concern, according to Dr. Michael Stone, who examined the case in favor of the motion.
How common are atypical femoral fractures?
"The estimated prevalence is probably 2%-3% in patients taking bisphosphonates for 5 years or more," suggested Dr. Stone, who is director of the Bone Research Unit at Cardiff University and a consultant at the University Hospital Llandough in Cardiff, Wales. Importantly, the risk might be highest in patients who are taking glucocorticoids, so in that population of patients the use of bisphosphonates may need to be more cautious.
"We always suspected atypical fractures might happen [with long-term bisphosphonate use] and now we know that they do," he said, noting that there was a plausible mechanism of action with antiresorptive agents."
"It’s a type of fracture we’ve not really seen before, except in the context of hypophosphatasia, and particularly in the context of steroids, and the risk may well outweigh the benefits," Dr. Stone observed.
However, Dr. Emma Clark, consultant senior lecturer at the University of Bristol and a consultant at Southmead Hospital in Bristol, England, countered that the absolute prevalence of these unusual hip fractures was low. In one Swedish population study, for example, the absolute rate was 5 per 10,000 patient-years (N. Engl. J. Med. 2011;364:1728-37). While there are lots of data, none of them are particularly convincing that AFF are an explosion waiting to happen, she argued.
Recently, the American Society for Bone and Mineral Research (ASBMR) reported that the absolute risk of AFFs in patients treated with bisphosphonates may range from 3.2 to 50 cases per 100,000 person-years (J. Bone Miner. Res. 2014;29:1-23). However, long-term use may be associated with higher risk (around 100 per 100,000 person-years).
There is some evidence that the risk of AFF rises with treatment duration, perhaps as high as 100 cases per 100,000 patient years, and the ASBMR and the Medicines and Healthcare Products Regulatory Agency (MHRA) in England have both issued guidance on the long-term use of bisphosphonates in this context.
Atypical fractures are less common than osteoporotic fractures, Dr. Stone noted, and while confidence limits are wide, in the worst-case scenario, the risk might outweigh the benefits after about 7 years’ continuous use, according to the same Swedish population study cited above.
What are atypical hip fractures?
Part of the problem of determining the extent of the problem lies in defining exactly what constitutes an atypical fracture. These fractures are "strikingly different" from the compression fractures that are commonly seen in patients with osteoporosis, Dr. Stone said, with the notable feature that they tend to affect the lateral rather than medial cortex.
"They are quite often bilateral, and they often occur at the same level; it is quite extraordinary," he said.
There is no distinct diagnostic code for these, Dr. Clark pointed out, so data routinely collected on fractures in national registries in the United Kingdom cannot be used and X-rays are needed to really look at the association between bisphosphonate use and their development. She observed that patients who are taking bisphosphonates should have a higher risk of all fractures and not just AFF, compared with the general population, because that is why these patients are being given the drugs in the first place.
The ASBMR developed a working definition of AFF in 2010, which stated that to be defined as atypical these fractures must meet certain criteria. These included their location in the subtrochanteric region and femoral shaft, associated with minimal or no trauma, a fracture line that originates in the lateral cortex and is transverse or short oblique in orientation, affects only the lateral cortex, with no comminution, and a medial spike when the fracture is complete (J. Bone Miner. Res. 2010;25:2267-94).
The society has recently updated their definition (J. Bone Miner. Res. 2014;29:1-23) based on evidence available since 2010 that suggests that AFFs are "stress or insufficiency fractures." The authors of the ASBMR report note "the original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution."
Dr. Clark observed that the ASBMR task force conclusion was that a causal relationship between bisphosphonates and atypical femoral fractures has not been established, but data continue to accumulate.
What should clinicians do if AFF is suspected?
"A significant number of atypical fractures are asymptomatic prior to completion," Dr. Stone warned. He noted that he had a relatively low threshold for scanning someone if he suspected AFF, but advised using "a reasonable amount of common sense" in that one might consider it in someone who is experiencing any new groin, thigh, or hip pain, or if there is worsening pain. In such cases, he might initially perform radiography, and then, if the level of clinical suspicion remains high, proceed to magnetic resonance imaging (MRI) or an isotope bone scan.
In terms of managing a patient with osteoporosis who develops AFF while taking bisphosphonates and is at high risk for other fractures, it is very difficult to know what to do. Stopping bisphosphonates might need to be considered because these drugs can impair healing of the fracture. Use of an alternative, such as strontium or teriparatide might be considered if the risk of fracture remains high.
In fact, according to MHRA guidance, stopping bisphosphonate therapy should be considered in patients suspected of AFF while they are evaluated, and should be based on an assessment of the benefits and risks of continuing treatment. The regulatory body also suggests that the need to continue therapy should be periodically evaluated, particularly after 5 or more years of use.
Drug manufacturer information provides guidance on the use of bisphosphonates and should be consulted regarding stopping treatment, Dr. Clark advised.
In an interview, Dr. Stone noted that patients on glucocorticoids should probably stop bisphosphonate treatment much sooner than the recommended 5 years, perhaps after 2-3 years of use. Conceding that that was controversial, because that’s not what the MHRA guidelines say, he noted that "for patients on glucocorticoids, where in the longer term you are going to be suppressing bone turnover and where the evidence of bisphosphonates reducing the risk of nonvertebral fracture is pretty much nonexistent, the concern should be higher in my opinion, and one needs to be cautious committing everybody without careful consideration to bisphosphonates beyond 2 or 3 years."
Dr. Clark observed in an interview: "I would also say I think we use bisphosphonates slightly differently now. We don’t consider them a treatment for people at low risk; we don’t give them to osteopenic, perimenopausal women who have not had a fracture; and we do not say it is a treatment for life anymore. We say it is a treatment for a fixed period of time at which point we should reassess."
Dr. Clark added: "I think it is something that we should all be aware of and we shouldn’t just use these medications without considering the risks." With regard to informing patients, she noted that she tells them that these sorts of fractures are rare, and the fracture-reducing benefits of bisphosphonates in high-risk patients with osteoporosis far outweigh their potential to cause these unusual fractures.
Atypical femoral fracture register planned
"We shouldn’t throw the baby out with the bath water," commented Dr. Eugene McCloskey, professor of adult bone disease at the University of Sheffield and a consultant at the Northern General Hospital in Sheffield, England.
"Osteoporotic fractures will remain a big problem, but we can’t ignore the fact that we are seeing patients with these atypical fractures, and I think they are really a heterogeneous group of patients that we need to categorize better," Dr. McCloskey added, noting that there were plans to set up a national AFF register in the United Kingdom.
Dr. Stone, Dr. Clark, and Dr. McCloskey have received research support, honoraria, or acted as consultants for several pharmaceutical companies involved in bone research, including Eli Lilly and Co., who provided an unrestricted educational grant to fund the Osteoporosis Special Interest Group Session.
EXPERT ANALYSIS FROM RHEUMATOLOGY 2014
