Comment
The absolute risk reduction of an intervention is greatest for patients with more severe underlying disease (ie, at high risk of the adverse event).11 Previous fracture is a powerful predictor of a future fracture;12 however, a substantial care gap has been created in treatment of individuals with fracture in part due to an overemphasis on BMD values. Previous fracture, particularly hip or vertebral fracture, should undoubtedly be sufficient criteria for the diagnosis of osteoporosis in the absence of BMD, particularly in frail elderly individuals. *Alexandra Papaioannou, Courtney Kennedy Division of Geriatric Medicine, McMaster University, St Peter’s Hospital, GERAS Centre, Hamilton, ON L8M 1W9, Canada (AP, CK) [email protected]
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AP reports grants and personal fees from Amgen, grants and personal fees from Eli Lilly, grants from Merck Canada, and grants from Werner Chilcott, outside the submitted work. CK declares no competing interests. 1
2 3
Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int 1994; 4: 368–81. Kanis JA. An update on the diagnosis of osteoporosis. Curr Rheumatol Rep 2000; 2: 62–66. Papaioannou A, Morin S, Cheung AM, et al, for the Scientific Advisory Council of Osteoporosis Canada. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 2010; 182: 1864–73.
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National Institute for Health and Care Excellence. Osteoporosis: assessing the risk of fragility fracture 2012. NICE guidelines CG146. http://www.nice. org.uk/guidance/cg146. (accessed Jan 20, 2015). Felsenberg D, Boonen S. The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 2005; 27: 1–11. Schuit S, Van der Klift M, Weel A, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 2004; 34: 195–202. Sornay-Rendu E, Munoz F, Duboeuf F, Delmas PD. Rate of forearm bone loss is associated with an increased risk of fracture independently of bone mass in postmenopausal women: the OFELY study. J Bone Miner Res 2005; 20: 1929–35. Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM, for the Fracture Intervention Trial Research Group. Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc 2005; 80: 343–49. Kanis JA, McCloskey E, Johansson H, Oden A, Leslie WD. FRAX(®) with and without bone mineral density. Calcif Tissue Int 2012; 90: 1–13. Greenspan SL, Perera S, Nace D, et al. FRAX or fiction: determining optimal screening strategies for treatment of osteoporosis in residents in long-term care facilities. J Am Geriatr Soc 2012; 60: 684–90. Barratt A, Wyer PC, Hatala R, et al, for the Evidence-Based Medicine Teaching Tips Working Group. Tips for learners of evidence-based medicine: 1. Relative risk reduction, absolute risk reduction and number needed to treat. CMAJ 2004; 171: 353–58. Gehlbach S1, Saag KG, Adachi JD, et al. Previous fractures at multiple sites increase the risk for subsequent fractures: the Global Longitudinal Study of Osteoporosis in Women. J Bone Miner Res 2012; 27: 645–53.
DNA Illustrations/Science Photo Library
Diagnostic criteria for osteoporosis should not be expanded
See Online for interviews with Alexandra Papaioannou and John Schousboe
236
In 1994, WHO1 defined osteoporosis as a disorder of skeletal fragility with the hallmark of low bone mass (defined as femoral neck bone mineral density [BMD] 2·5 or more standard deviations less than the average of healthy 30-year-old women [T-score –2·5 or less]), or a prevalent radiographic vertebral fracture (indicative of bone structural weakness and fragility). This definition is also the clinical criteria for the diagnosis of osteoporosis in most countries, although clinicians in the USA often use a T-score of –2·5 or less at the lumbar spine, total hip, or femoral neck.2 However, most individuals who have low-trauma age-related fractures do not have osteoporosis by BMD criteria,3 prompting efforts to use fracture risk algorithms to identify, as candidates for drug therapy, people who are at higher absolute risk of fracture. Several US organisations have recommended 10 year fracture risk (by the FRAX algorithm) intervention thresholds of 3% for hip fracture and 20% for major osteoporotic fracture (clinical vertebral,
forearm, hip, or proximal humerus fracture) as cutpoints for starting drug treatment in adults aged 50 years and older. A recent position statement from the National Bone Health Alliance Working Group4 (a consortium of musculoskeletal societies and industry partners) proposed expansion of the definition of osteoporosis to include adults aged 50 years and older with BMD T-score of –2·5 or less at spine or hip, recent hip or clinical vertebral fracture, or FRAX 10 year fracture probability higher than either of the intervention thresholds defined above. Because of its inclusion of FRAX intervention thresholds, this expanded definition would greatly increase the proportion of US adults aged 65 years and older who are labelled as having a diagnosis of osteoporosis from an estimated 40% to 72% of women5 and from 7% to 34% of men.6 Broadening of the definition of a disease can have adverse consequences, including labelling a substantial www.thelancet.com/diabetes-endocrinology Vol 3 April 2015
Comment
proportion of the population with a problem that might not benefit from treatment and placing higher demands on the health-care system to identify and treat the greater number of patients meeting expanded criteria. If treatments are not effective, health-care resources are wasted and there is a diversion of those resources away from other disorders for which treatment benefits are better established. Thus, before expansion of the definition of osteoporosis, the benefits of broadening of the diagnostic criteria must be shown to clearly outweigh the associated harms. Particularly for the position statement, higher estimated fracture probabilities are not yet known to identify a subgroup of patients who benefit from treatment. Pivotal trials of alendronate, risedronate, and denosumab showed efficacy of drug treatment in reductions in clinical fractures in postmenopausal women with a BMD T-score of –2·5 or less or those who had existing vertebral fractures, but not in the subset of women enrolled with a BMD T-score of more than –2·5 and no prevalent vertebral fracture.7,8 Clodronate reduced clinical fractures in one trial of older women not selected on the basis of BMD, but fracture reduction benefit has not been shown for women with neither a traditional diagnosis of osteoporosis based on T score nor the presence of radiographic vertebral fracture.9 The hypothesis that the efficacy of available osteoporosis drugs in reduction of fracture events is substantially lower among the large subgroup of patients with BMD T-scores of more than –2·5 and without existing vertebral fracture is reasonable and biologically plausible. Fracture risk in these patients could be driven mainly by other skeletal factors such as altered bone type 1 collagen, hydroxyapatite crystal structure, and bone microarchitecture, as well as non-skeletal factors such as fall propensity. Although available anti-remodelling drugs can preserve bone microarchitecture, they do not improve other aspects of impaired bone quality (eg, altered bone mineral crystallinity, microdamage, increased formation of non-enzymatic bone collagen crosslinks, and homogenisation of the distribution of hydroxyapatite mineral throughout the bone cortex).10 Thus, before expansion of the criteria for the diagnosis of osteoporosis, randomised trials are warranted to establish the efficacy of treatment in adults without osteoporosis diagnosed by traditional criteria but who www.thelancet.com/diabetes-endocrinology Vol 3 April 2015
exceed the proposed intervention threshold based on estimated absolute fracture risk. These specific FRAX intervention thresholds (included in the proposed expanded criteria) were endorsed by US professional societies as criteria for treatment initiation (not diagnosis) based on findings from one cost-effectiveness study.11 However, specific cutpoints driven by cost-effectiveness vary according to diagnosis and treatment expense, and from country to country. Moreover, estimates of major osteoporotic fracture risk are imprecise at the individual level. Over a 10 year follow-up period, the performance of the FRAX algorithm in discriminating those who will have a major osteoporotic fracture among people aged 50 years and older, and a hip fractures among those aged 70 years and older, is only poor to fair (areas under receiving operator characteristics curves
The absolute risk reduction of an intervention is greatest for patients with more severe underlying disease (ie, at high risk of the adverse event).11 Previous fracture is a powerful predictor of a future fracture;12 however, a substantial care gap has been created in treatment of individuals with fracture in part due to an overemphasis on BMD values. Previous fracture, particularly hip or vertebral fracture, should undoubtedly be sufficient criteria for the diagnosis of osteoporosis in the absence of BMD, particularly in frail elderly individuals. *Alexandra Papaioannou, Courtney Kennedy Division of Geriatric Medicine, McMaster University, St Peter’s Hospital, GERAS Centre, Hamilton, ON L8M 1W9, Canada (AP, CK) [email protected]
4
5
6
7
8
9 10
11
AP reports grants and personal fees from Amgen, grants and personal fees from Eli Lilly, grants from Merck Canada, and grants from Werner Chilcott, outside the submitted work. CK declares no competing interests. 1
2 3
Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int 1994; 4: 368–81. Kanis JA. An update on the diagnosis of osteoporosis. Curr Rheumatol Rep 2000; 2: 62–66. Papaioannou A, Morin S, Cheung AM, et al, for the Scientific Advisory Council of Osteoporosis Canada. 2010 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada: summary. CMAJ 2010; 182: 1864–73.
12
National Institute for Health and Care Excellence. Osteoporosis: assessing the risk of fragility fracture 2012. NICE guidelines CG146. http://www.nice. org.uk/guidance/cg146. (accessed Jan 20, 2015). Felsenberg D, Boonen S. The bone quality framework: determinants of bone strength and their interrelationships, and implications for osteoporosis management. Clin Ther 2005; 27: 1–11. Schuit S, Van der Klift M, Weel A, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 2004; 34: 195–202. Sornay-Rendu E, Munoz F, Duboeuf F, Delmas PD. Rate of forearm bone loss is associated with an increased risk of fracture independently of bone mass in postmenopausal women: the OFELY study. J Bone Miner Res 2005; 20: 1929–35. Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM, for the Fracture Intervention Trial Research Group. Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of-1.6 to -2.5 at the femoral neck: the Fracture Intervention Trial. Mayo Clin Proc 2005; 80: 343–49. Kanis JA, McCloskey E, Johansson H, Oden A, Leslie WD. FRAX(®) with and without bone mineral density. Calcif Tissue Int 2012; 90: 1–13. Greenspan SL, Perera S, Nace D, et al. FRAX or fiction: determining optimal screening strategies for treatment of osteoporosis in residents in long-term care facilities. J Am Geriatr Soc 2012; 60: 684–90. Barratt A, Wyer PC, Hatala R, et al, for the Evidence-Based Medicine Teaching Tips Working Group. Tips for learners of evidence-based medicine: 1. Relative risk reduction, absolute risk reduction and number needed to treat. CMAJ 2004; 171: 353–58. Gehlbach S1, Saag KG, Adachi JD, et al. Previous fractures at multiple sites increase the risk for subsequent fractures: the Global Longitudinal Study of Osteoporosis in Women. J Bone Miner Res 2012; 27: 645–53.
DNA Illustrations/Science Photo Library
Diagnostic criteria for osteoporosis should not be expanded
See Online for interviews with Alexandra Papaioannou and John Schousboe
236
In 1994, WHO1 defined osteoporosis as a disorder of skeletal fragility with the hallmark of low bone mass (defined as femoral neck bone mineral density [BMD] 2·5 or more standard deviations less than the average of healthy 30-year-old women [T-score –2·5 or less]), or a prevalent radiographic vertebral fracture (indicative of bone structural weakness and fragility). This definition is also the clinical criteria for the diagnosis of osteoporosis in most countries, although clinicians in the USA often use a T-score of –2·5 or less at the lumbar spine, total hip, or femoral neck.2 However, most individuals who have low-trauma age-related fractures do not have osteoporosis by BMD criteria,3 prompting efforts to use fracture risk algorithms to identify, as candidates for drug therapy, people who are at higher absolute risk of fracture. Several US organisations have recommended 10 year fracture risk (by the FRAX algorithm) intervention thresholds of 3% for hip fracture and 20% for major osteoporotic fracture (clinical vertebral,
forearm, hip, or proximal humerus fracture) as cutpoints for starting drug treatment in adults aged 50 years and older. A recent position statement from the National Bone Health Alliance Working Group4 (a consortium of musculoskeletal societies and industry partners) proposed expansion of the definition of osteoporosis to include adults aged 50 years and older with BMD T-score of –2·5 or less at spine or hip, recent hip or clinical vertebral fracture, or FRAX 10 year fracture probability higher than either of the intervention thresholds defined above. Because of its inclusion of FRAX intervention thresholds, this expanded definition would greatly increase the proportion of US adults aged 65 years and older who are labelled as having a diagnosis of osteoporosis from an estimated 40% to 72% of women5 and from 7% to 34% of men.6 Broadening of the definition of a disease can have adverse consequences, including labelling a substantial www.thelancet.com/diabetes-endocrinology Vol 3 April 2015
Comment
proportion of the population with a problem that might not benefit from treatment and placing higher demands on the health-care system to identify and treat the greater number of patients meeting expanded criteria. If treatments are not effective, health-care resources are wasted and there is a diversion of those resources away from other disorders for which treatment benefits are better established. Thus, before expansion of the definition of osteoporosis, the benefits of broadening of the diagnostic criteria must be shown to clearly outweigh the associated harms. Particularly for the position statement, higher estimated fracture probabilities are not yet known to identify a subgroup of patients who benefit from treatment. Pivotal trials of alendronate, risedronate, and denosumab showed efficacy of drug treatment in reductions in clinical fractures in postmenopausal women with a BMD T-score of –2·5 or less or those who had existing vertebral fractures, but not in the subset of women enrolled with a BMD T-score of more than –2·5 and no prevalent vertebral fracture.7,8 Clodronate reduced clinical fractures in one trial of older women not selected on the basis of BMD, but fracture reduction benefit has not been shown for women with neither a traditional diagnosis of osteoporosis based on T score nor the presence of radiographic vertebral fracture.9 The hypothesis that the efficacy of available osteoporosis drugs in reduction of fracture events is substantially lower among the large subgroup of patients with BMD T-scores of more than –2·5 and without existing vertebral fracture is reasonable and biologically plausible. Fracture risk in these patients could be driven mainly by other skeletal factors such as altered bone type 1 collagen, hydroxyapatite crystal structure, and bone microarchitecture, as well as non-skeletal factors such as fall propensity. Although available anti-remodelling drugs can preserve bone microarchitecture, they do not improve other aspects of impaired bone quality (eg, altered bone mineral crystallinity, microdamage, increased formation of non-enzymatic bone collagen crosslinks, and homogenisation of the distribution of hydroxyapatite mineral throughout the bone cortex).10 Thus, before expansion of the criteria for the diagnosis of osteoporosis, randomised trials are warranted to establish the efficacy of treatment in adults without osteoporosis diagnosed by traditional criteria but who www.thelancet.com/diabetes-endocrinology Vol 3 April 2015
exceed the proposed intervention threshold based on estimated absolute fracture risk. These specific FRAX intervention thresholds (included in the proposed expanded criteria) were endorsed by US professional societies as criteria for treatment initiation (not diagnosis) based on findings from one cost-effectiveness study.11 However, specific cutpoints driven by cost-effectiveness vary according to diagnosis and treatment expense, and from country to country. Moreover, estimates of major osteoporotic fracture risk are imprecise at the individual level. Over a 10 year follow-up period, the performance of the FRAX algorithm in discriminating those who will have a major osteoporotic fracture among people aged 50 years and older, and a hip fractures among those aged 70 years and older, is only poor to fair (areas under receiving operator characteristics curves
