G Model
ARTICLE IN PRESS
BONSOI-4307; No. of Pages 3
Joint Bone Spine xxx (2016) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Editorial
Is it time for treat to target strategy in osteoporosis?
a r t i c l e
i n f o
Keywords: Osteoporosis Fracture Bisphosphonates Denosumab Bone mineral density
Risk-based treatment guidelines typically set a value for a biomarker that identifies individuals at high risk who require pharmacological treatment, then set a target for that biomarker that is associated with a reduced level of the risk of the clinical outcome. This treat to target (TTT) concept has become popular in the medical management of several common chronic conditions, including diabetes, hypertension, hyperlipidemia and rheumatoid arthritis. In its early formulation, TTT has been used to design diabetes trials that focused on a HbA1c target [1]. The impressive reductions in longterm diabetes-related complications and overall mortality obtained in the DCCT (type I diabetes) and UKPDS (type 2 diabetes) studies built consensus around threshold target-based therapy [2,3]. The concept was extended to the hypertension and lipid areas, where similar studies were conducted with explicit blood pressure and LDL goals, respectively. The positive long-term outcomes data from trials focused on lowering LDL, blood pressure or HbA1c lay a strong foundation for TTT. For instance, a meta-analysis of statin trials showed that reaching target LDL reduced mortality by 12% [4]. In rheumatology, the TTT strategy has been used more and more commonly in recent years to manage rheumatoid arthritis and lupus. In contrast, there is no consensus regarding goals for bone mineral density (BMD), biochemical markers of bone turnover (BTMs), or fracture risk. Some clinicians aim to keep markers of bone resorption in the lower half of the reference range for premenopausal women to maximize the effectiveness of antiresorptive therapy [5]. The lack of a BMD goal may stem from a modest effect of most current antiresorptives on BMD. Here, we will show that TTT in the field of osteoporosis could represent a more rational and effective use of osteoporosis drugs. 1. The case for treat to target 1.1. Osteoporosis treatment challenges Despite the availability of pharmacologic agents proven to reduce fracture risk, osteoporosis remains a disease that is
underdiagnosed and undertreated [6,7]. Adherence to treatment is generally poor [8]. Determining whether treatment is effective or not may be difficult for physicians who treat osteoporosis, because the occurrence of fracture in a single patient is rare in the short- and mid-term. As a result, medical decisions are sometimes inappropriate regarding changes in treatments or tests to perform. There are concerns regarding potential adverse effects of long-term therapy, particularly atypical femur fractures and osteonecrosis of the jaw, although the benefits of therapy far outweigh the risks among correctly selected patients [9]. The concept of a bisphosphonate “drug holiday” has been advocated as a way to minimize the risk of atypical femoral fractures and osteonecrosis of the jaw, taking advantage of a possible residual antifracture effect due to the persistence of the antiresorptive effect from bisphosphonate remaining in the skeleton. Of note, the prolonged antiresorptive effect after discontinuation of bisphosphonates is not encountered with other therapeutic agents. The TTT approach is thus attractive because it may help solving some of these issues. 1.2. Which targets? 1.2.1. Bone mineral density The most appealing treatment target is a measurement that is the same that is used for diagnosis. Because the definition of osteoporosis is based on a BMD T-score, the T-score could be a target, either as an absolute number or as a percent change, or as a change in WHO category. Specifically, there is a strong relationship between the T-score at the femoral neck and bone strength of the hip, with almost all hip fractures occurring at T-scores < –1.0, in both genders [10]. The same pattern exists for the relation between vertebral volumetric BMD and incident vertebral fracture [10]. To support this concept, we also need some evidence from clinical trials, to show that those patients above a certain threshold of BMD will sustain significantly fewer fractures than those below. This kind of data has been obtained in the fracture intervention trial (FIT) long term extension (FLEX) trial. In this setting, osteoporotic women who had been on alendronate for 4–5 years were re-randomized to receive either a placebo for 5 additional years, or 5 years more of alendronate. Those women whose T-score at the femoral neck was below –2.5 and who had no prevalent vertebral fracture at the time for re-randomization sustained fewer non-vertebral fractures if they took alendronate for 10 years, compared with those who stopped at 5 years of therapy [10]. In contrast, those patients whose T-score was above –2.0 after 5 years of treatment did not experience any apparent antifracture benefit. For
http://dx.doi.org/10.1016/j.jbspin.2015.12.002 1297-319X/© 2016 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Chapurlat R. Is it time for treat to target strategy in osteoporosis? Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2015.12.002
G Model BONSOI-4307; No. of Pages 3 2
ARTICLE IN PRESS Editorial / Joint Bone Spine xxx (2016) xxx–xxx
those women with prevalent vertebral fracture at the baseline for FIT, continuing alendronate provided a protective effect for clinical vertebral fracture, without difference across levels of femoral neck T-scores [11]. For those stopping alendronate, hip BMD and age were the best predictors of fracture recurrence [12]. A similar pattern has been observed in the health outcomes and reduced incidence with zoledronic acid once yearly-pivotal fracture trial (HORIZON-PFT) Extension Study. Thus, the femoral neck or total hip T-score below –2.5 after 3 annual doses of zoledronic acid was predictive of increased risk of new morphometric and non-vertebral fractures in women subsequently randomized to stop treatment [13]. Again, this suggested that this hip T-score at –2.5 target could be used to determine whether continuing therapy could be warranted. Targeting a certain level of BMD (or T-score) implies that the level of baseline BMD (or the T-score) has to be part of the initial treatment decision, which cannot rely solely on a fracture probability.
1.2.2. Bone turnover markers A decrease in BTMs with antiresorptive agents (e.g., bisphosphonates) and an increase in BTMs with an anabolic agent (e.g., teriparatide) are associated with a subsequent increase in BMD and a reduction in fracture risk [5]. With antiresorptive agents the target could be to decrease the resorption marker value down to the range below the median in premenopausal women [5]. Measurement of BTMs is also potentially useful in assessing the offset of effect after discontinuation of therapy and may provide insight on restarting treatment after a drug holiday. In parallel, the variation in BTMs has to exceed the least significance change to be meaningful at the individual level.
1.2.3. Fracture probability Fracture probability, as provided for instance by the FRAX score, is now commonly used to select patients for treatment. It is important to remember, however, that no trial for approved osteoporosis treatments has selected patients using FRAX, that were, in fact, selected based upon their T-score and fracture prevalence. In addition, there are mixed findings on post hoc analyses, with evidence for an association between a high baseline FRAX value and reduction in fracture risk with clodronate and bazedoxifene, but not for raloxifene, strontium ranelate and alendronate [14]. The FRAX algorithm was validated with data in patients who were largely untreated. Recently, FRAX has been studied in patients receiving pharmacological therapy for osteoporosis. Thus, in a large clinical cohort consisting of 11,049 women age 50 years and older in Manitoba, Canada, FRAX probabilities were linked to pharmacy claims and incident fractures [15]. Over 4 years of follow-up, the FRAX scores increased slightly, including among highly adherent women. Change in FRAX scores was not associated with incident major fracture. The slow increase in FRAX score over time was not prevented by treatment. Therefore, the FRAX was not responsive enough to be used as a target for treatment.
1.2.4. Combined targets A target that would simply use the BMD improvement or a fracture probability reduction would probably miss the issue of early treatment failure (with oral compounds) and poor adherence to treatment. Using BTM as a target during the first months of therapy as well as to detect the end of the offset period during a drug holiday could be a clinically practical option. Then, the target could be the BTMs levels in the short term and the BMD in the long term.
2. The challenges to treat to target There are potential problems with the use of T-score as a treatment target. The magnitude and the practical significance of the relationship between increase in BMD and fracture risk reduction observed with oral antiresorptive remain controversial [16,17]. There is evidence that vertebral fracture risk is reduced in women treated with teriparatide despite a decrease in femoral neck BMD, although lumbar spine BMD increased in the same patients [18]. With zoledronic acid [19] and denosumab [20], a stronger association between BMD increase and fracture risk reduction than with oral medications has been reported, so the BMD goal may be more realistic with these injectable drugs. In patients with a very low baseline T-score, it may not be possible to raise the T-score to a level that is classified as osteopenia or normal. These patients may have to stay on therapy for very long periods of time, without reaching the goal but with a long exposure to drugs that may be associated with a sizeable risk of adverse events. With this biomarker, the target may need to be different for different drugs. When a target has been achieved, a drug holiday may be advocated, but only for the drugs with residual effect when they are stopped, i.e., bisphosphonates. Other treatments (raloxifene, teriparatide, denosumab) have to be continued or replaced by another family of compounds, to maintain the BMD and antifracture benefits. 3. Conclusion The treat-to-target concept applied to the treatment of osteoporosis would change the initial selection of treatment, the way the success of therapy is considered, and decisions about stopping, continuing, or changing treatment. The treat-to-target strategy does not have to be opposed to individualized care. Compared with the approach of simply defining several agents as first line and others as second line – which is often based on economic considerations rather than clinical evidence – the treat-to-target strategy can serve to individualize the choice of treatment on the patient’s risk and/or BMD. In contrast to changing therapies based on the empirical number of years of use or failure to respond, the TTT paradigm would guide decisions to adapt therapy to maximize a patient’s likelihood to reach an acceptable level of fracture risk. There is an important need for testing and refining many of the concepts underpinning TTT in osteoporosis. We look forward to a robust research effort in response to the important potential posed by TTT. Disclosure of interest Conferences and/or advisory boards and/or clinical research for Amgen, Pfizer, Lilly, Abbvie, BMS, Merck, Chugai, Bioiberica. References [1] Garber AJ. Treat-to-target trials: uses, interpretation and review of concepts. Diabetes Obes Metab 2014;16:185–205. [2] Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53. [3] UKPDS, United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995;310:83–8. [4] Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. [5] Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 2003;18:1051–6.
Please cite this article in press as: Chapurlat R. Is it time for treat to target strategy in osteoporosis? Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2015.12.002
G Model BONSOI-4307; No. of Pages 3
ARTICLE IN PRESS Editorial / Joint Bone Spine xxx (2016) xxx–xxx
[6] Leslie WD, Giangregorio LM, Yogendran M, et al. A population-based analysis of the post-fracture care gap 1996–2008: the situation is not improving. Osteoporos Int 2012;23:1623–9. [7] Kanis JA, Svedbom A, Harvey N, et al. The osteoporosis treatment gap. J Bone Miner Res 2014;29:1926–8. [8] Confavreux CB, Canoui-Poitrine F, Schott AM, et al. Persistence at 1 year of oral antiosteoporotic drugs: a prospective study in a comprehensive health insurance database. Eur J Endocrinol 2012;166:735–41. [9] Khosla S, Bilezikian JP, Dempster DW, et al. Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab 2012;97:2272–82. [10] Kopperdahl DL, Aspelund T, Hoffmann PF, et al. Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans. J Bone Miner Res 2014;29:570–80. [11] Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res 2010;25:976–82. [12] Bauer DC, Schwartz A, Palermo L, et al. Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy. The FLEX Study. JAMA Intern Med 2014;174:1126–34. [13] Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-pivotal fracture trial (PFT). J Bone Miner Res 2012;27:243–54. [14] Lewiecki ME, Cummings SR, Cosman F. Treat for target in osteoporosis: is now the time? J Clin Endocrinol Metab 2013;98:946–53. [15] Leslie WD, Majumdar SR, Lix LM, et al. Can change in FRAX score be used to “treat to target”? A population-based cohort study. J Bone Miner Res 2014;29:1074–80. [16] Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab 2000;85:231–6. [17] Chapurlat RD, Palermo L, Ramsay P, et al. risk of fracture among women who loose bone density during treatment with alendronate. The fracture intervention trial. Osteoporos Int 2005;16:842–8.
3
[18] Watts NB, Miller PD, Kohlmeier LA, et al. Vertebral fracture risk is reduced in women who lose femoral neck BMD with teriparatide treatment. J Bone Miner Res 2009;24:1125–31. [19] Jacques RM, Boonen S, Cosman F, et al. Relationship of changes in total hip bone mineral density to vertebral and non vertebral fracture risk in women with postmenopausal osteoporosis treated with once yearly zoledronic acid 5 mg: the HORIZON-pivotal fracture trial (PFT). J Bone Miner Res 2012;27: 1627–34. [20] Austin M, Yang YC, Vittinghoff E, et al. Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and non vertebral fractures. J Bone Miner Res 2012;27:687–93.
a
Roland Chapurlat a,b,∗ Inserm UMR 1033, université de Lyon, 69437 Lyon, France b Service de rhumatologie et de pathologie osseuse, hôpital E.-Herriot, 5, place d’Arsonval, 69437 Lyon, France
∗ Correspondence
at: Service de rhumatologie et de pathologie osseuse, hôpital E.-Herriot, 5, place d’Arsonval, 69437 Lyon France. E-mail address: [email protected] Accepted 2 December 2015 Available online xxx
Please cite this article in press as: Chapurlat R. Is it time for treat to target strategy in osteoporosis? Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2015.12.002
ARTICLE IN PRESS
BONSOI-4307; No. of Pages 3
Joint Bone Spine xxx (2016) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Editorial
Is it time for treat to target strategy in osteoporosis?
a r t i c l e
i n f o
Keywords: Osteoporosis Fracture Bisphosphonates Denosumab Bone mineral density
Risk-based treatment guidelines typically set a value for a biomarker that identifies individuals at high risk who require pharmacological treatment, then set a target for that biomarker that is associated with a reduced level of the risk of the clinical outcome. This treat to target (TTT) concept has become popular in the medical management of several common chronic conditions, including diabetes, hypertension, hyperlipidemia and rheumatoid arthritis. In its early formulation, TTT has been used to design diabetes trials that focused on a HbA1c target [1]. The impressive reductions in longterm diabetes-related complications and overall mortality obtained in the DCCT (type I diabetes) and UKPDS (type 2 diabetes) studies built consensus around threshold target-based therapy [2,3]. The concept was extended to the hypertension and lipid areas, where similar studies were conducted with explicit blood pressure and LDL goals, respectively. The positive long-term outcomes data from trials focused on lowering LDL, blood pressure or HbA1c lay a strong foundation for TTT. For instance, a meta-analysis of statin trials showed that reaching target LDL reduced mortality by 12% [4]. In rheumatology, the TTT strategy has been used more and more commonly in recent years to manage rheumatoid arthritis and lupus. In contrast, there is no consensus regarding goals for bone mineral density (BMD), biochemical markers of bone turnover (BTMs), or fracture risk. Some clinicians aim to keep markers of bone resorption in the lower half of the reference range for premenopausal women to maximize the effectiveness of antiresorptive therapy [5]. The lack of a BMD goal may stem from a modest effect of most current antiresorptives on BMD. Here, we will show that TTT in the field of osteoporosis could represent a more rational and effective use of osteoporosis drugs. 1. The case for treat to target 1.1. Osteoporosis treatment challenges Despite the availability of pharmacologic agents proven to reduce fracture risk, osteoporosis remains a disease that is
underdiagnosed and undertreated [6,7]. Adherence to treatment is generally poor [8]. Determining whether treatment is effective or not may be difficult for physicians who treat osteoporosis, because the occurrence of fracture in a single patient is rare in the short- and mid-term. As a result, medical decisions are sometimes inappropriate regarding changes in treatments or tests to perform. There are concerns regarding potential adverse effects of long-term therapy, particularly atypical femur fractures and osteonecrosis of the jaw, although the benefits of therapy far outweigh the risks among correctly selected patients [9]. The concept of a bisphosphonate “drug holiday” has been advocated as a way to minimize the risk of atypical femoral fractures and osteonecrosis of the jaw, taking advantage of a possible residual antifracture effect due to the persistence of the antiresorptive effect from bisphosphonate remaining in the skeleton. Of note, the prolonged antiresorptive effect after discontinuation of bisphosphonates is not encountered with other therapeutic agents. The TTT approach is thus attractive because it may help solving some of these issues. 1.2. Which targets? 1.2.1. Bone mineral density The most appealing treatment target is a measurement that is the same that is used for diagnosis. Because the definition of osteoporosis is based on a BMD T-score, the T-score could be a target, either as an absolute number or as a percent change, or as a change in WHO category. Specifically, there is a strong relationship between the T-score at the femoral neck and bone strength of the hip, with almost all hip fractures occurring at T-scores < –1.0, in both genders [10]. The same pattern exists for the relation between vertebral volumetric BMD and incident vertebral fracture [10]. To support this concept, we also need some evidence from clinical trials, to show that those patients above a certain threshold of BMD will sustain significantly fewer fractures than those below. This kind of data has been obtained in the fracture intervention trial (FIT) long term extension (FLEX) trial. In this setting, osteoporotic women who had been on alendronate for 4–5 years were re-randomized to receive either a placebo for 5 additional years, or 5 years more of alendronate. Those women whose T-score at the femoral neck was below –2.5 and who had no prevalent vertebral fracture at the time for re-randomization sustained fewer non-vertebral fractures if they took alendronate for 10 years, compared with those who stopped at 5 years of therapy [10]. In contrast, those patients whose T-score was above –2.0 after 5 years of treatment did not experience any apparent antifracture benefit. For
http://dx.doi.org/10.1016/j.jbspin.2015.12.002 1297-319X/© 2016 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Chapurlat R. Is it time for treat to target strategy in osteoporosis? Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2015.12.002
G Model BONSOI-4307; No. of Pages 3 2
ARTICLE IN PRESS Editorial / Joint Bone Spine xxx (2016) xxx–xxx
those women with prevalent vertebral fracture at the baseline for FIT, continuing alendronate provided a protective effect for clinical vertebral fracture, without difference across levels of femoral neck T-scores [11]. For those stopping alendronate, hip BMD and age were the best predictors of fracture recurrence [12]. A similar pattern has been observed in the health outcomes and reduced incidence with zoledronic acid once yearly-pivotal fracture trial (HORIZON-PFT) Extension Study. Thus, the femoral neck or total hip T-score below –2.5 after 3 annual doses of zoledronic acid was predictive of increased risk of new morphometric and non-vertebral fractures in women subsequently randomized to stop treatment [13]. Again, this suggested that this hip T-score at –2.5 target could be used to determine whether continuing therapy could be warranted. Targeting a certain level of BMD (or T-score) implies that the level of baseline BMD (or the T-score) has to be part of the initial treatment decision, which cannot rely solely on a fracture probability.
1.2.2. Bone turnover markers A decrease in BTMs with antiresorptive agents (e.g., bisphosphonates) and an increase in BTMs with an anabolic agent (e.g., teriparatide) are associated with a subsequent increase in BMD and a reduction in fracture risk [5]. With antiresorptive agents the target could be to decrease the resorption marker value down to the range below the median in premenopausal women [5]. Measurement of BTMs is also potentially useful in assessing the offset of effect after discontinuation of therapy and may provide insight on restarting treatment after a drug holiday. In parallel, the variation in BTMs has to exceed the least significance change to be meaningful at the individual level.
1.2.3. Fracture probability Fracture probability, as provided for instance by the FRAX score, is now commonly used to select patients for treatment. It is important to remember, however, that no trial for approved osteoporosis treatments has selected patients using FRAX, that were, in fact, selected based upon their T-score and fracture prevalence. In addition, there are mixed findings on post hoc analyses, with evidence for an association between a high baseline FRAX value and reduction in fracture risk with clodronate and bazedoxifene, but not for raloxifene, strontium ranelate and alendronate [14]. The FRAX algorithm was validated with data in patients who were largely untreated. Recently, FRAX has been studied in patients receiving pharmacological therapy for osteoporosis. Thus, in a large clinical cohort consisting of 11,049 women age 50 years and older in Manitoba, Canada, FRAX probabilities were linked to pharmacy claims and incident fractures [15]. Over 4 years of follow-up, the FRAX scores increased slightly, including among highly adherent women. Change in FRAX scores was not associated with incident major fracture. The slow increase in FRAX score over time was not prevented by treatment. Therefore, the FRAX was not responsive enough to be used as a target for treatment.
1.2.4. Combined targets A target that would simply use the BMD improvement or a fracture probability reduction would probably miss the issue of early treatment failure (with oral compounds) and poor adherence to treatment. Using BTM as a target during the first months of therapy as well as to detect the end of the offset period during a drug holiday could be a clinically practical option. Then, the target could be the BTMs levels in the short term and the BMD in the long term.
2. The challenges to treat to target There are potential problems with the use of T-score as a treatment target. The magnitude and the practical significance of the relationship between increase in BMD and fracture risk reduction observed with oral antiresorptive remain controversial [16,17]. There is evidence that vertebral fracture risk is reduced in women treated with teriparatide despite a decrease in femoral neck BMD, although lumbar spine BMD increased in the same patients [18]. With zoledronic acid [19] and denosumab [20], a stronger association between BMD increase and fracture risk reduction than with oral medications has been reported, so the BMD goal may be more realistic with these injectable drugs. In patients with a very low baseline T-score, it may not be possible to raise the T-score to a level that is classified as osteopenia or normal. These patients may have to stay on therapy for very long periods of time, without reaching the goal but with a long exposure to drugs that may be associated with a sizeable risk of adverse events. With this biomarker, the target may need to be different for different drugs. When a target has been achieved, a drug holiday may be advocated, but only for the drugs with residual effect when they are stopped, i.e., bisphosphonates. Other treatments (raloxifene, teriparatide, denosumab) have to be continued or replaced by another family of compounds, to maintain the BMD and antifracture benefits. 3. Conclusion The treat-to-target concept applied to the treatment of osteoporosis would change the initial selection of treatment, the way the success of therapy is considered, and decisions about stopping, continuing, or changing treatment. The treat-to-target strategy does not have to be opposed to individualized care. Compared with the approach of simply defining several agents as first line and others as second line – which is often based on economic considerations rather than clinical evidence – the treat-to-target strategy can serve to individualize the choice of treatment on the patient’s risk and/or BMD. In contrast to changing therapies based on the empirical number of years of use or failure to respond, the TTT paradigm would guide decisions to adapt therapy to maximize a patient’s likelihood to reach an acceptable level of fracture risk. There is an important need for testing and refining many of the concepts underpinning TTT in osteoporosis. We look forward to a robust research effort in response to the important potential posed by TTT. Disclosure of interest Conferences and/or advisory boards and/or clinical research for Amgen, Pfizer, Lilly, Abbvie, BMS, Merck, Chugai, Bioiberica. References [1] Garber AJ. Treat-to-target trials: uses, interpretation and review of concepts. Diabetes Obes Metab 2014;16:185–205. [2] Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005;353:2643–53. [3] UKPDS, United Kingdom Prospective Diabetes Study (UKPDS). 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non-insulin dependent diabetes followed for three years. BMJ 1995;310:83–8. [4] Baigent C, Keech A, Kearney PM, et al. Efficacy and safety of cholesterollowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 2005;366:1267–78. [5] Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 2003;18:1051–6.
Please cite this article in press as: Chapurlat R. Is it time for treat to target strategy in osteoporosis? Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2015.12.002
G Model BONSOI-4307; No. of Pages 3
ARTICLE IN PRESS Editorial / Joint Bone Spine xxx (2016) xxx–xxx
[6] Leslie WD, Giangregorio LM, Yogendran M, et al. A population-based analysis of the post-fracture care gap 1996–2008: the situation is not improving. Osteoporos Int 2012;23:1623–9. [7] Kanis JA, Svedbom A, Harvey N, et al. The osteoporosis treatment gap. J Bone Miner Res 2014;29:1926–8. [8] Confavreux CB, Canoui-Poitrine F, Schott AM, et al. Persistence at 1 year of oral antiosteoporotic drugs: a prospective study in a comprehensive health insurance database. Eur J Endocrinol 2012;166:735–41. [9] Khosla S, Bilezikian JP, Dempster DW, et al. Benefits and risks of bisphosphonate therapy for osteoporosis. J Clin Endocrinol Metab 2012;97:2272–82. [10] Kopperdahl DL, Aspelund T, Hoffmann PF, et al. Assessment of incident spine and hip fractures in women and men using finite element analysis of CT scans. J Bone Miner Res 2014;29:570–80. [11] Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res 2010;25:976–82. [12] Bauer DC, Schwartz A, Palermo L, et al. Fracture prediction after discontinuation of 4 to 5 years of alendronate therapy. The FLEX Study. JAMA Intern Med 2014;174:1126–34. [13] Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis: a randomized extension to the HORIZON-pivotal fracture trial (PFT). J Bone Miner Res 2012;27:243–54. [14] Lewiecki ME, Cummings SR, Cosman F. Treat for target in osteoporosis: is now the time? J Clin Endocrinol Metab 2013;98:946–53. [15] Leslie WD, Majumdar SR, Lix LM, et al. Can change in FRAX score be used to “treat to target”? A population-based cohort study. J Bone Miner Res 2014;29:1074–80. [16] Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related to changes in bone density. J Clin Endocrinol Metab 2000;85:231–6. [17] Chapurlat RD, Palermo L, Ramsay P, et al. risk of fracture among women who loose bone density during treatment with alendronate. The fracture intervention trial. Osteoporos Int 2005;16:842–8.
3
[18] Watts NB, Miller PD, Kohlmeier LA, et al. Vertebral fracture risk is reduced in women who lose femoral neck BMD with teriparatide treatment. J Bone Miner Res 2009;24:1125–31. [19] Jacques RM, Boonen S, Cosman F, et al. Relationship of changes in total hip bone mineral density to vertebral and non vertebral fracture risk in women with postmenopausal osteoporosis treated with once yearly zoledronic acid 5 mg: the HORIZON-pivotal fracture trial (PFT). J Bone Miner Res 2012;27: 1627–34. [20] Austin M, Yang YC, Vittinghoff E, et al. Relationship between bone mineral density changes with denosumab treatment and risk reduction for vertebral and non vertebral fractures. J Bone Miner Res 2012;27:687–93.
a
Roland Chapurlat a,b,∗ Inserm UMR 1033, université de Lyon, 69437 Lyon, France b Service de rhumatologie et de pathologie osseuse, hôpital E.-Herriot, 5, place d’Arsonval, 69437 Lyon, France
∗ Correspondence
at: Service de rhumatologie et de pathologie osseuse, hôpital E.-Herriot, 5, place d’Arsonval, 69437 Lyon France. E-mail address: [email protected] Accepted 2 December 2015 Available online xxx
Please cite this article in press as: Chapurlat R. Is it time for treat to target strategy in osteoporosis? Joint Bone Spine (2016), http://dx.doi.org/10.1016/j.jbspin.2015.12.002
