Osteoporos Int DOI 10.1007/s00198-015-3406-5
LETTER
A BMD threshold for treatment efficacy in osteoporosis? A need to consider the whole evidence base E. McCloskey 1
Received: 26 October 2015 / Accepted: 4 November 2015 # International Osteoporosis Foundation and National Osteoporosis Foundation 2015
Dear Editor, In assuming that osteoporosis therapies have no effect in individuals with a T-score of >−2.5 SD, Dr. Uzoigwe [1] falls into the trap, as have many others, of over-interpretation of subgroup analyses. He is correct to infer that any approach that adheres to the slavish devotion to a BMD T-score of −2.5 or less being a prerequisite for efficacy of bisphosphonates, or indeed any Bosteoporosis^ medication, will have limited impact on the total number of fractures (though potentially a substantial effect on hip fractures) [2]. He reiterates and expands on the question raised by Jarvinen and colleagues [3], namely BIn those who breach the treatment threshold, on the basis of FRAX 10-year fragility fracture risk, but who are not osteoporotic, do bisphosphonates reduce the risk of fragility fracture?^ The conclusion that these drugs only act in BMD proven osteoporosis is a flawed one, driven by the aforementioned subgroup analyses, most of which are post hoc. If one asks the question in a more statistically appropriate manner, i.e. is there a statistically significant interaction between the effect of treatment and baseline BMD, is the same conclusion reached? All studies that have examined this for the outcome of vertebral fractures have not shown any significant impact of baseline BMD on risk reduction during osteoporosis therapy [4–10]. Published studies describing the interaction between efficacy for a variety of non-vertebral fracture outcomes and BMD, handled correctly as a continuous variable, are few in number (Table 1). Of the three studies that we could identify [10–12], only the alendronate study reported a significant
* E. McCloskey [email protected] 1
Academic Unit of Bone Metabolism, Department of Oncology and Metabolism Metabolic Bone Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK
interaction, yet this single study features prominently in the case argued for the lack of efficacy above the ‘mystical’ T-score threshold. This ignores the totality of the evidence. Having recorded a significant interaction with BMD, the authors undertook a subgroup analysis in T-score categories and revealed a significant reduction in clinical fractures in those with T-score osteoporosis (relative hazard 0.64, 96 % CI 0.50–0.84) [10]. The upper confidence limit is well below unity suggesting that, if a threshold existed, then it was somewhere above a T-score of −2.5. Indeed, even within the same paper, the authors reported that BWe observed a 22 % lower risk of clinical fracture in those whose T-scores were more than 2.0 SDs below the normal mean (RH 0.78; 95 % CI 0.65–0.94)….^ A BMD efficacy threshold is even less clear when we try to enhance the evidence base by examining studies that have examined the interaction with BMD considered as a categorical variable (e.g. osteoporosis vs. non-osteoporotic, efficacy within tertiles of BMD etc.), although such studies inherently recapitulate the errors of subgroup analysis [4, 8, 9, 13]. With this caveat in mind, it is worthy to note that the majority of these analyses demonstrate, similarly to the continuous BMD analyses, that there is little evidence of a significant interaction between BMD and clinical or non-vertebral fracture efficacy (Table 1). This is not to say that treatments might indeed be more effective at lower BMDs, it is just that the concept of a BMD threshold for efficacy at a T-score of −2.5 is a gross misinterpretation. To take denosumab as a further example, in an analysis of its efficacy against baseline BMD, there was no statistically significant interaction (p=0.28) when BMD was considered as a continuous variable [12]. In contrast in the same trial, using a pre-specified subgroup analysis but a subgroup analysis nonetheless, a significant interaction was shown for femoral neck BMD (p=0.023) with efficacy Bonly^ being seen in the osteoporotic subgroup [9]. Two points can be made.
Osteoporos Int Table 1 Summary of studies assessing interactions between treatment efficacy on clinical (predominantly non-vertebral) fractures and baseline BMD at entry to phase 3 studies of various osteoporosis therapies Agent
Selected by BMD at entry
Fracture outcome
Significant interaction (p value, if available)
Reference
BMD as continuous variable Alendronate
Y
Clinical
Y (p=0.01)
Cummings et al. [10]
Clodronate
N
Clinical
N
McCloskey et al. [11]
Denosumaba
Y
Clinical
N (p=0.28)
McCloskey et al. [12]
Clinical
N (p>0.49)
Ensrud et al. [4]
BMD as a categorical variable
a
Alendronate
Y
a
Zoledronate
Y
Hip
N (p=0.45)
Eastell et al. [8]
Zoledronatea
Y
Non-vertebral
N (p=0.46)
Eastell et al. [8]
Denosumaba
Y
Non-vertebral
Y (p=0.023)
McClung et al. [9]
Oestrogen/progestin
N
Clinical
N (p=0.15)
Cauley et al. [13]
Data from within a single clinical trial of that agent
Firstly, the same subgroup study showed a greater, and more statistically significant, relationship of anti-fracture efficacy with BMI and the BMD analysis did not adjust for BMI (an established covariant of BMD). Secondly, it is important to note that the upper confidence interval for fracture reduction in the osteoporosis subgroup was only 0.83, suggesting that if there is a Bthreshold^ for efficacy of denosumab then it lies somewhat north of the T-score of −2.5. The absurdities of such post hoc analyses are beautifully illustrated in the paper examining the impact of various Brisk factors^ on the efficacy of zoledronate (zoledronic acid) on vertebral, non-vertebral and hip fracture risk [8]. From this study, one could mount an argument, albeit an irrational one, that zoledronate should not be used for the prevention of hip fractures in the Americas or Asia or in women who walk more than 22 h per week or in women with the lowest total hip BMD [8]. Indeed, the effect of zoledronate was only significant in those within the highest tertile of total hip BMD, but as this does not fit with the Bdrugs only work in the presence of osteoporosis^ assumption, it is conveniently ignored. What is clear is that bizarre conclusions can be drawn from multiple subgroup analyses despite the fact that few of these show any significant interaction with treatment efficacy. What about studies that have not restricted their inclusion criteria to subjects with BMD-defined osteoporosis? Of all the studies listed in Table 1, only the clodronate [11] and oestrogen/progestin [13] trials selected subjects regardless of BMD; in both studies, the results showed a reduction in clinical osteoporotic fractures that was not statistically dependent on baseline BMD where this was examined as a continuous or categorical variable. Very recently, results from a study of denosumab to prevent fractures in postmenopausal patients with early hormone receptor positive breast cancer being treated with aromatase inhibitors have been presented at the American Society of Clinical Oncology [14]. In this double-blind, placebo-controlled trial involving almost 3500
postmenopausal women, denosumab significantly delayed the time to first clinical fracture compared to placebo (HR= 0.5, 95 % CI 0.39–0.65, p−1) and in those who entered the trial with osteopenia; the BMD at entry was well above the putative efficacy threshold but the treatment still worked. The lack of evidence for an efficacy threshold of BMD does not mean that treatment should be targeted to all. The greatest benefit of treatment, and the best risk-benefit ratio, will be achieved in those at highest risk of fracture. It is important to note that the FRAX tool has been constructed with clinical risk factors that are largely, but not totally, independent of BMD so that they can complement BMD assessments [15, 16]. Nonetheless, it has been demonstrated that, as intended, the presence of a high FRAX probability assessed without BMD is associated with an underlying low BMD [17–19], with several analyses demonstrating a trend for greater efficacy at these higher fracture probabilities [12, 20, 21]. Dr Uzoigwe also raised the potential for lack of efficacy of treatments in the very old. A similar critique to that for BMD above can be applied to analyses of the interaction between age and efficacy—whereas some have suggested a lack of effect at older ages, only one that I am aware of has shown a significant age interaction [22], though this did not examine age as a continuous variable and was observed for hip fractures only but not the other fracture outcomes examined. In conclusion, the totality of the evidence suggests that the concept of a BMD threshold for the efficacy of osteoporosis therapies is a misinterpretation driven by post hoc subgroup analyses. There is certainly a complete lack of evidence to suggest that if a threshold exists, it happily and fortuitously coincides with the WHO definition of osteoporosis. The use of osteoporosis therapies in patients at high risk of fracture should not be withheld due to flawed reasoning.
Osteoporos Int
References 1. 2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Uzoigwe CE (2015) The real enemy is fragility fracture, not osteoporosis. Osteoporos Int. doi:10.1007/s00198-015-3405-6 Oden A, McCloskey EV, Johansson H, Kanis JA (2013) Assessing the impact of osteoporosis on the burden of hip fractures. Calcif Tissue Int 92(1):42–9 Jarvinen TL, Michaelsson K, Jokihaara J et al (2015) Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 350: h2088 Ensrud KE, Black DM, Palermo L et al (1997) Treatment with alendronate prevents fractures in women at highest risk: results from the Fracture Intervention Trial. Arch Intern Med 157(22): 2617–24 Roux C, Reginster JY, Fechtenbaum J et al (2006) Vertebral fracture risk reduction with strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res 21(4):536–42 Kanis JA, Barton IP, Johnell O (2005) Risedronate decreases fracture risk in patients selected solely on the basis of prior vertebral fracture. Osteoporos Int 16(5):475–82 McCloskey E, Selby P, Davies M et al (2004) Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res 19(5):728–36 Eastell R, Black DM, Boonen S et al (2009) Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. J Clin Endocrinol Metab 94(9): 3215–25 McClung M, Boonen S, Torring O et al (2011) Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. J Bone Miner Res 27:211–218 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 280(24):2077–82 McCloskey EV, Beneton M, Charlesworth D et al (2007) Clodronate reduces the incidence of fractures in communitydwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 22(1):135–41
12.
McCloskey EV, Johansson H, Oden A et al (2012) Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX. J Bone Miner Res 27(7):1480–6 13. Cauley JA, Robbins J, Chen Z et al (2003) Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 290(13):1729–38 14. Gnant M, Pfeifer G, Dubsky PC, et al (2015) Adjuvant denosumab in breast cancer: Results from 3,425 postmenopausal patients of the ABCSG-18 trial.Adjuvant denosumab in breast cancer: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. American Society of Clinical Oncology, J Clin Oncol 33, 2015 (suppl; abstr 504) 15. Johansson H, Kanis JA, Oden A, Johnell O, McCloskey E (2009) BMD, clinical risk factors and their combination for hip fracture prevention. Osteoporos Int 20(10):1675–82 16. Kanis JA, on behalf of the WHO Scientific Group (2008) Assessment of osteoporosis at the primary health-care level. Technical Report. Sheffield: WHO Collaborating Centre, University of Sheffield, UK 17. Johansson H, Oden A, Johnell O et al (2004) Optimization of BMD measurements to identify high risk groups for treatment—a test analysis. J Bone Miner Res 19(6):906–13 18. Leslie WD, Morin S, Lix LM et al (2012) Fracture risk assessment without bone density measurement in routine clinical practice. Osteoporos Int 23(1):75–85 19. Leslie WD, Majumdar SR, Lix LM et al (2012) High fracture probability with FRAX usually indicates densitometric osteoporosis: implications for clinical practice. Osteoporos Int 23(1):391–7 20. McCloskey EV, Johansson H, Oden A et al (2009) Ten-year fracture probability identifies women who will benefit from clodronate therapy—additional results from a double-blind, placebo-controlled randomised study. Osteoporos Int 20(5):811–7 21. Kanis JA, Johansson H, Oden A, McCloskey EV (2009) Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone 44(6):1049–54 22. Boonen S, Black DM, Colon-Emeric CS et al (2010) Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older. J Am Geriatr Soc 58(2):292–9
LETTER
A BMD threshold for treatment efficacy in osteoporosis? A need to consider the whole evidence base E. McCloskey 1
Received: 26 October 2015 / Accepted: 4 November 2015 # International Osteoporosis Foundation and National Osteoporosis Foundation 2015
Dear Editor, In assuming that osteoporosis therapies have no effect in individuals with a T-score of >−2.5 SD, Dr. Uzoigwe [1] falls into the trap, as have many others, of over-interpretation of subgroup analyses. He is correct to infer that any approach that adheres to the slavish devotion to a BMD T-score of −2.5 or less being a prerequisite for efficacy of bisphosphonates, or indeed any Bosteoporosis^ medication, will have limited impact on the total number of fractures (though potentially a substantial effect on hip fractures) [2]. He reiterates and expands on the question raised by Jarvinen and colleagues [3], namely BIn those who breach the treatment threshold, on the basis of FRAX 10-year fragility fracture risk, but who are not osteoporotic, do bisphosphonates reduce the risk of fragility fracture?^ The conclusion that these drugs only act in BMD proven osteoporosis is a flawed one, driven by the aforementioned subgroup analyses, most of which are post hoc. If one asks the question in a more statistically appropriate manner, i.e. is there a statistically significant interaction between the effect of treatment and baseline BMD, is the same conclusion reached? All studies that have examined this for the outcome of vertebral fractures have not shown any significant impact of baseline BMD on risk reduction during osteoporosis therapy [4–10]. Published studies describing the interaction between efficacy for a variety of non-vertebral fracture outcomes and BMD, handled correctly as a continuous variable, are few in number (Table 1). Of the three studies that we could identify [10–12], only the alendronate study reported a significant
* E. McCloskey [email protected] 1
Academic Unit of Bone Metabolism, Department of Oncology and Metabolism Metabolic Bone Centre, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK
interaction, yet this single study features prominently in the case argued for the lack of efficacy above the ‘mystical’ T-score threshold. This ignores the totality of the evidence. Having recorded a significant interaction with BMD, the authors undertook a subgroup analysis in T-score categories and revealed a significant reduction in clinical fractures in those with T-score osteoporosis (relative hazard 0.64, 96 % CI 0.50–0.84) [10]. The upper confidence limit is well below unity suggesting that, if a threshold existed, then it was somewhere above a T-score of −2.5. Indeed, even within the same paper, the authors reported that BWe observed a 22 % lower risk of clinical fracture in those whose T-scores were more than 2.0 SDs below the normal mean (RH 0.78; 95 % CI 0.65–0.94)….^ A BMD efficacy threshold is even less clear when we try to enhance the evidence base by examining studies that have examined the interaction with BMD considered as a categorical variable (e.g. osteoporosis vs. non-osteoporotic, efficacy within tertiles of BMD etc.), although such studies inherently recapitulate the errors of subgroup analysis [4, 8, 9, 13]. With this caveat in mind, it is worthy to note that the majority of these analyses demonstrate, similarly to the continuous BMD analyses, that there is little evidence of a significant interaction between BMD and clinical or non-vertebral fracture efficacy (Table 1). This is not to say that treatments might indeed be more effective at lower BMDs, it is just that the concept of a BMD threshold for efficacy at a T-score of −2.5 is a gross misinterpretation. To take denosumab as a further example, in an analysis of its efficacy against baseline BMD, there was no statistically significant interaction (p=0.28) when BMD was considered as a continuous variable [12]. In contrast in the same trial, using a pre-specified subgroup analysis but a subgroup analysis nonetheless, a significant interaction was shown for femoral neck BMD (p=0.023) with efficacy Bonly^ being seen in the osteoporotic subgroup [9]. Two points can be made.
Osteoporos Int Table 1 Summary of studies assessing interactions between treatment efficacy on clinical (predominantly non-vertebral) fractures and baseline BMD at entry to phase 3 studies of various osteoporosis therapies Agent
Selected by BMD at entry
Fracture outcome
Significant interaction (p value, if available)
Reference
BMD as continuous variable Alendronate
Y
Clinical
Y (p=0.01)
Cummings et al. [10]
Clodronate
N
Clinical
N
McCloskey et al. [11]
Denosumaba
Y
Clinical
N (p=0.28)
McCloskey et al. [12]
Clinical
N (p>0.49)
Ensrud et al. [4]
BMD as a categorical variable
a
Alendronate
Y
a
Zoledronate
Y
Hip
N (p=0.45)
Eastell et al. [8]
Zoledronatea
Y
Non-vertebral
N (p=0.46)
Eastell et al. [8]
Denosumaba
Y
Non-vertebral
Y (p=0.023)
McClung et al. [9]
Oestrogen/progestin
N
Clinical
N (p=0.15)
Cauley et al. [13]
Data from within a single clinical trial of that agent
Firstly, the same subgroup study showed a greater, and more statistically significant, relationship of anti-fracture efficacy with BMI and the BMD analysis did not adjust for BMI (an established covariant of BMD). Secondly, it is important to note that the upper confidence interval for fracture reduction in the osteoporosis subgroup was only 0.83, suggesting that if there is a Bthreshold^ for efficacy of denosumab then it lies somewhat north of the T-score of −2.5. The absurdities of such post hoc analyses are beautifully illustrated in the paper examining the impact of various Brisk factors^ on the efficacy of zoledronate (zoledronic acid) on vertebral, non-vertebral and hip fracture risk [8]. From this study, one could mount an argument, albeit an irrational one, that zoledronate should not be used for the prevention of hip fractures in the Americas or Asia or in women who walk more than 22 h per week or in women with the lowest total hip BMD [8]. Indeed, the effect of zoledronate was only significant in those within the highest tertile of total hip BMD, but as this does not fit with the Bdrugs only work in the presence of osteoporosis^ assumption, it is conveniently ignored. What is clear is that bizarre conclusions can be drawn from multiple subgroup analyses despite the fact that few of these show any significant interaction with treatment efficacy. What about studies that have not restricted their inclusion criteria to subjects with BMD-defined osteoporosis? Of all the studies listed in Table 1, only the clodronate [11] and oestrogen/progestin [13] trials selected subjects regardless of BMD; in both studies, the results showed a reduction in clinical osteoporotic fractures that was not statistically dependent on baseline BMD where this was examined as a continuous or categorical variable. Very recently, results from a study of denosumab to prevent fractures in postmenopausal patients with early hormone receptor positive breast cancer being treated with aromatase inhibitors have been presented at the American Society of Clinical Oncology [14]. In this double-blind, placebo-controlled trial involving almost 3500
postmenopausal women, denosumab significantly delayed the time to first clinical fracture compared to placebo (HR= 0.5, 95 % CI 0.39–0.65, p−1) and in those who entered the trial with osteopenia; the BMD at entry was well above the putative efficacy threshold but the treatment still worked. The lack of evidence for an efficacy threshold of BMD does not mean that treatment should be targeted to all. The greatest benefit of treatment, and the best risk-benefit ratio, will be achieved in those at highest risk of fracture. It is important to note that the FRAX tool has been constructed with clinical risk factors that are largely, but not totally, independent of BMD so that they can complement BMD assessments [15, 16]. Nonetheless, it has been demonstrated that, as intended, the presence of a high FRAX probability assessed without BMD is associated with an underlying low BMD [17–19], with several analyses demonstrating a trend for greater efficacy at these higher fracture probabilities [12, 20, 21]. Dr Uzoigwe also raised the potential for lack of efficacy of treatments in the very old. A similar critique to that for BMD above can be applied to analyses of the interaction between age and efficacy—whereas some have suggested a lack of effect at older ages, only one that I am aware of has shown a significant age interaction [22], though this did not examine age as a continuous variable and was observed for hip fractures only but not the other fracture outcomes examined. In conclusion, the totality of the evidence suggests that the concept of a BMD threshold for the efficacy of osteoporosis therapies is a misinterpretation driven by post hoc subgroup analyses. There is certainly a complete lack of evidence to suggest that if a threshold exists, it happily and fortuitously coincides with the WHO definition of osteoporosis. The use of osteoporosis therapies in patients at high risk of fracture should not be withheld due to flawed reasoning.
Osteoporos Int
References 1. 2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Uzoigwe CE (2015) The real enemy is fragility fracture, not osteoporosis. Osteoporos Int. doi:10.1007/s00198-015-3405-6 Oden A, McCloskey EV, Johansson H, Kanis JA (2013) Assessing the impact of osteoporosis on the burden of hip fractures. Calcif Tissue Int 92(1):42–9 Jarvinen TL, Michaelsson K, Jokihaara J et al (2015) Overdiagnosis of bone fragility in the quest to prevent hip fracture. BMJ 350: h2088 Ensrud KE, Black DM, Palermo L et al (1997) Treatment with alendronate prevents fractures in women at highest risk: results from the Fracture Intervention Trial. Arch Intern Med 157(22): 2617–24 Roux C, Reginster JY, Fechtenbaum J et al (2006) Vertebral fracture risk reduction with strontium ranelate in women with postmenopausal osteoporosis is independent of baseline risk factors. J Bone Miner Res 21(4):536–42 Kanis JA, Barton IP, Johnell O (2005) Risedronate decreases fracture risk in patients selected solely on the basis of prior vertebral fracture. Osteoporos Int 16(5):475–82 McCloskey E, Selby P, Davies M et al (2004) Clodronate reduces vertebral fracture risk in women with postmenopausal or secondary osteoporosis: results of a double-blind, placebo-controlled 3-year study. J Bone Miner Res 19(5):728–36 Eastell R, Black DM, Boonen S et al (2009) Effect of once-yearly zoledronic acid five milligrams on fracture risk and change in femoral neck bone mineral density. J Clin Endocrinol Metab 94(9): 3215–25 McClung M, Boonen S, Torring O et al (2011) Effect of denosumab treatment on the risk of fractures in subgroups of women with postmenopausal osteoporosis. J Bone Miner Res 27:211–218 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 280(24):2077–82 McCloskey EV, Beneton M, Charlesworth D et al (2007) Clodronate reduces the incidence of fractures in communitydwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study. J Bone Miner Res 22(1):135–41
12.
McCloskey EV, Johansson H, Oden A et al (2012) Denosumab reduces the risk of osteoporotic fractures in postmenopausal women, particularly in those with moderate to high fracture risk as assessed with FRAX. J Bone Miner Res 27(7):1480–6 13. Cauley JA, Robbins J, Chen Z et al (2003) Effects of estrogen plus progestin on risk of fracture and bone mineral density: the Women's Health Initiative randomized trial. JAMA 290(13):1729–38 14. Gnant M, Pfeifer G, Dubsky PC, et al (2015) Adjuvant denosumab in breast cancer: Results from 3,425 postmenopausal patients of the ABCSG-18 trial.Adjuvant denosumab in breast cancer: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. American Society of Clinical Oncology, J Clin Oncol 33, 2015 (suppl; abstr 504) 15. Johansson H, Kanis JA, Oden A, Johnell O, McCloskey E (2009) BMD, clinical risk factors and their combination for hip fracture prevention. Osteoporos Int 20(10):1675–82 16. Kanis JA, on behalf of the WHO Scientific Group (2008) Assessment of osteoporosis at the primary health-care level. Technical Report. Sheffield: WHO Collaborating Centre, University of Sheffield, UK 17. Johansson H, Oden A, Johnell O et al (2004) Optimization of BMD measurements to identify high risk groups for treatment—a test analysis. J Bone Miner Res 19(6):906–13 18. Leslie WD, Morin S, Lix LM et al (2012) Fracture risk assessment without bone density measurement in routine clinical practice. Osteoporos Int 23(1):75–85 19. Leslie WD, Majumdar SR, Lix LM et al (2012) High fracture probability with FRAX usually indicates densitometric osteoporosis: implications for clinical practice. Osteoporos Int 23(1):391–7 20. McCloskey EV, Johansson H, Oden A et al (2009) Ten-year fracture probability identifies women who will benefit from clodronate therapy—additional results from a double-blind, placebo-controlled randomised study. Osteoporos Int 20(5):811–7 21. Kanis JA, Johansson H, Oden A, McCloskey EV (2009) Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX. Bone 44(6):1049–54 22. Boonen S, Black DM, Colon-Emeric CS et al (2010) Efficacy and safety of a once-yearly intravenous zoledronic acid 5 mg for fracture prevention in elderly postmenopausal women with osteoporosis aged 75 and older. J Am Geriatr Soc 58(2):292–9
