CLIMACTERIC 2015;18:1–3
Invited Editorial
For how long should osteoporosis treatment continue? E. Boschitsch KLIMAX Menopause and Osteoporosis Clinic, Vienna, Austria
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
Key words: ZOLEDRONIC ACID, DENOSUMAB, MENOPAUSAL HORMONE THERAPY, EFFICACY, SAFETY, PERSISTENCE
ABSTRACT Studies on the most effective of the commonly used bone-specific drugs, the antiresorptives zoledronic acid and denosumab, as well as up-to-date menopausal hormone therapy for early prevention refer to sound longterm safety data. However, depending on both the patient’s characteristics and the properties of the respective regimens, the rates of side-effects, tolerability and persistence differ substantially. They are crucial limiting factors for actual efficacy in the clinical setting and thus determine the length and continuation of treatment.
The question of how long osteoporosis treatment should continue was raised after a recent publication on zoledronic acid by Black and colleagues. They examined the effect of 6 versus 9 years of zoledronic acid treatment in a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT)1. The first extension study with zoledronic acid 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), a decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers compared with discontinuation after 3 years, but left the optimal duration of treatment uncertain. To investigate the longer-term efficacy and safety of zoledronic acid, a second extension study was conducted for up to 9 years, in which 190 women, out of 451 women on zoledronic acid for 6 years in the first extension study, were randomized to either zoledronic acid (Z9) (n ⫽ 95) or placebo (Z6P3) (n ⫽ 95) for 3 additional years. The primary endpoint was the change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Secondary endpoints included fractures, bone turnover markers, and safety. From year 6 to year 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval -0.37–1.93%; p ⫽ 0.183). Bone turnover markers showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias
(combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits. Thus Black and colleagues showed for the first time reliable study outcomes on the efficacy and safety of zoledronic acid1. But what about the other effective osteoporosis regimens, which are listed, for example by Kanis and colleagues, in the periodically published European guidance for the management of osteoporosis: menopausal hormone therapy, orally administered bisphosphonates, and the subcutaneously applicable denosumab, to mention the most frequently used2? Menopausal hormone therapy (MHT) has been shown in observational studies and randomized, placebo-controlled trials to decrease the incidence of all osteoporosis-related fractures, including vertebral and hip fractures, by about 30%2. In general, MHT can be considered as one of the first-line therapies for the prevention and treatment of osteoporosis-related fractures in at-risk postmenopausal women younger than 60 years, or within 10 years of menopause3. In particular, newer long-term data support the non-increased risk for breast cancer (up to 8 years), thromboembolic events, and cardiovascular disease, when transdermal estradiol is combined with oral natural progesterone instead of synthetic progestins4–6. However, in many countries MHT usage is still very low after the misinterpreted initial results of the Women’s Health Initia-
Correspondence: Dr E. Boschitsch, KLIMAX Menopause and Osteoporosis Clinic, Vienna, Austria; E-mail: [email protected]
INVITED EDITORIAL © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1065061
Received 06-06-2015 Accepted 07-06-2015
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
For how long should osteoporosis treatment continue? tive of 20027, which had an immediate impact on MHT prescription patterns. Data from a large cohort (n ⫽ 81 000) of a Californian health management organization revealed that women who discontinued MHT were at 55% greater risk of hip fractures compared with those who continued MHT, in spite of an increased prescription rate for bisphosphonates from 8% to 23%8. Oral bone-specific regimens for the treatment of osteoporosis, mostly oral bisphosphonates, show only low efficacy due to their relatively high rates of side-effects and adverse events, with very low persistence rates9 of about 30% and 9% after 1 and 5 years, respectively10. The introduction of intravenous bisphosphonates definitely improved persistence. Nevertheless, according to a former study with zoledronic acid, approximately one-third of patients suffer from postinfusion symptoms such as pyrexia, influenza-like symptoms, myalgia, headache and arthralgia after the first infusion, and the number of patients with arrhythmia or serious atrial fibrillation is significantly higher in the zoledronic acid group than in the placebo group11. Such side-effects and adverse events might be one reason for the small participation rate (only 190 patients started the second extension study out of the 451 patients who had completed the first extension study) and the additional high discontinuation rate of 27% in the HORIZON-PFT1. Persistence with zoledronic acid in the realworld setting of an outpatient clinic has also been shown to be suboptimal: only 94 out of 259 patients (36.3%) agreed to a second infusion and 83% declared the post-infusion syndrome responsible for declining the second administration12. When the authors of the HORIZON-PFT state that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits, this has to be put into the perspective of a considerable number of non-persistent patients. Persistence with another potent antiresorptive regimen, denosumab 60 mg s.c. every 6 months, is clearly higher according to both the first results of an ongoing, prospective, observational study in routine clinical practice conducted in Germany, Austria, Greece and Belgium, with 91.5% of patients being persistent at year 113, and to the results of our prospective observational study with persistence of 92% at month 6, 88% at month 12, 83% at month 24, and 81% at month 4814. These high rates of persistence with denosumab compared to reported rates of other bone-specific regimens may be attributed to a low frequency of side-effects and adverse events, with a concurrent high efficacy and the very comfortable method of subcutaneous administration every 6 months. In regard to the efficacy measurements of BMD and bone turnover markers in the randomized, clinical trials, there is only a small additional benefit with zoledronic acid over placebo in years 7–9 (second extension study) of the HORIZON-PFT1 in contrast to the benefit with denosumab, which revealed continued increases in BMD and a persistent reduction of bone turnover markers compared to placebo in years 4–8 of the FREEDOM Extension Study15. While the HORIZONPFT was underpowered to detect differences in fracture rates, incidences of new fractures (vertebral, non-vertebral and hip)
2
Boschitsch in the FREEDOM Extension Study remained constantly low. These data suggest that treatment with denosumab can be prolonged for 8 years or more – the recent presentation of the 9-year data at the WCO-IOF-ESCEO Congress supports the benefits of an extended duration of use16 – without increasing disruptive side-effects and adverse events. The most potent antiresorptive drugs, zoledronic acid and denosumab, display different mechanisms of action. One key pharmacological distinction is their distribution within bone. Bisphosphonates bind to bone mineral surfaces, where they are engulfed by migrating mature osteoclasts. Once intracellular, bisphosphonates interfere with the cell metabolism of osteoclasts and inhibit their resorptive activities. These inactive, bisphosphonate-loaded osteoclasts accumulate at the sites of bone resorption and are buried there under de novo synthesized bone much longer than the biochemically determined half-lives of the respective bisphosphonates. Their final elimination depends on the on-site remodeling process, which per se is, as is therapeutically intended, decreased, and on their renal excretion and re-uptake, thus explaining the overall prolonged actions of bisphosphonates in the skeleton17. Denosumab, a fully human antibody to the receptor activator of nuclear factor κB ligand (RANKL), exhibits entirely different mechanisms of action. It mimics the properties of the body’s own osteoprotegerin. In postmenopausal life, without MHT, osteoprotegerin levels are decreased to a minimum since the level of estradiol, as the main stimulating factor for its synthesis, has decreased. Both osteoprotegerin and denosumab act as decoy receptors for RANKL, capturing it before its binding to RANK, the transmembrane receptor of osteoclast precursor cells and mature osteoclasts, thereby inhibiting the differentiation of precursors and the formation into mature osteoclasts as well as the activities and the survival of mature osteoclasts themselves. Denosumab is evenly distributed throughout the trabecular and cortical compartments of bone, thus protecting cortical bone from porosity and promoting cortical thickness and strength, while bisphosphonates mainly bind to the mineral surfaces of predominantly trabecular resorption sites. As a protein, the degradation and elimination of denosumab does not depend on the kidney’s clearance capacities and therefore can also be used in patients with severely reduced glomerular filtration or renal insufficiency18. In contrast, bisphosphonates are contraindicated or have to be used with utmost caution in patients with these conditions, who constitute a relatively large group in the elderly. Thus the question of how long osteoporosis treatment should continue cannot be answered without considerations of the specific characteristics of the individual patients with their diverse ages, lifestyles and co-morbidities, as well as the characteristics of the respective regimens with their distinct parameters of efficacy, safety and persistence. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
Climacteric
For how long should osteoporosis treatment continue?
Boschitsch
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
References 1. Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2015;30:934–44 2. Kanis JA, McCloskey E, Johansson VH, et al. Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). Osteoporos Int 2013;24:23–57 3. de Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013;16:316–37 4. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–11 5. Cordina-Duverger E, Truong T, Anger A, et al. Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France. PLoS One 2013;8:e78016 6. Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause 2014;21:769–83 7. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33 8. Karim R, Dell RM, Greene DF, et al. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization. Menopause 2011;18:1172–7 9. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health 2008;11:44–7
Climacteric
10. Li L, Roddam A, Gitlin M, et al. Persistence with osteoporosis medications among postmenopausal women in the UK General Practice Research Database. Menopause 2012;19: 33–40 11. Black DM, Delmas PD, Eastell R, et al. HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356: 1809–22 12. Lee YK, Nho JH, Ha YC, Koo KH. Persistence with intravenous zoledronate in elderly patients with osteoporosis. Osteoporos Int 2012;23:2329–33 13. Hadji P, Papaioannou NA, Gielen E, et al. 12-Month persistence with denosumab in women with postmenopausal osteoporosis: interim results of a 24-month prospective observational study in Germany, Austria, Greece and Belgium. Presented at WCO-IOF-ESCEO, Seville, Spain; April 2–5, 2014, Poster Nr. P150 14. Boschitsch E, Trinker N. Persistence with denosumab in a menopause and osteoporosis clinic. Presented at ECTS-IBMS 2015 Congress, Rotterdam, The Netherlands; April 25–28, 2015, Poster Nr. P357 15. Papapoulos S, Lippuner K, Roux C, et al. Eight years of denosumab treatment in postmenopausal women with osteoporosis: results from the first five years of the FREEDOM Extension. Presented at ASBMR, Baltimore, USA; October 4–7, 2013, presentation number: LB-MO26 16. Papapoulos S, Roux C, Bone HG, et al. Denosumab treatment in postmenopausal women with osteoporosis for up to 9 years: results through year 6 of the FREEEDOM extension. Presented at WCO-IOF-ESCEO, Milan, Italy; March 27, 2015, OC4 17. Pazianas M, Cooper C, Ebetino FH, et al. Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis. Ther Clin Risk Manag 2010;6:325–43 18. Baron R, Ferrari S, Russell RG. Denosumab and BPs: different mechanisms of action and effects. Bone 2011;48:677–92
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Invited Editorial
For how long should osteoporosis treatment continue? E. Boschitsch KLIMAX Menopause and Osteoporosis Clinic, Vienna, Austria
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
Key words: ZOLEDRONIC ACID, DENOSUMAB, MENOPAUSAL HORMONE THERAPY, EFFICACY, SAFETY, PERSISTENCE
ABSTRACT Studies on the most effective of the commonly used bone-specific drugs, the antiresorptives zoledronic acid and denosumab, as well as up-to-date menopausal hormone therapy for early prevention refer to sound longterm safety data. However, depending on both the patient’s characteristics and the properties of the respective regimens, the rates of side-effects, tolerability and persistence differ substantially. They are crucial limiting factors for actual efficacy in the clinical setting and thus determine the length and continuation of treatment.
The question of how long osteoporosis treatment should continue was raised after a recent publication on zoledronic acid by Black and colleagues. They examined the effect of 6 versus 9 years of zoledronic acid treatment in a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT)1. The first extension study with zoledronic acid 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), a decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers compared with discontinuation after 3 years, but left the optimal duration of treatment uncertain. To investigate the longer-term efficacy and safety of zoledronic acid, a second extension study was conducted for up to 9 years, in which 190 women, out of 451 women on zoledronic acid for 6 years in the first extension study, were randomized to either zoledronic acid (Z9) (n ⫽ 95) or placebo (Z6P3) (n ⫽ 95) for 3 additional years. The primary endpoint was the change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Secondary endpoints included fractures, bone turnover markers, and safety. From year 6 to year 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval -0.37–1.93%; p ⫽ 0.183). Bone turnover markers showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias
(combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits. Thus Black and colleagues showed for the first time reliable study outcomes on the efficacy and safety of zoledronic acid1. But what about the other effective osteoporosis regimens, which are listed, for example by Kanis and colleagues, in the periodically published European guidance for the management of osteoporosis: menopausal hormone therapy, orally administered bisphosphonates, and the subcutaneously applicable denosumab, to mention the most frequently used2? Menopausal hormone therapy (MHT) has been shown in observational studies and randomized, placebo-controlled trials to decrease the incidence of all osteoporosis-related fractures, including vertebral and hip fractures, by about 30%2. In general, MHT can be considered as one of the first-line therapies for the prevention and treatment of osteoporosis-related fractures in at-risk postmenopausal women younger than 60 years, or within 10 years of menopause3. In particular, newer long-term data support the non-increased risk for breast cancer (up to 8 years), thromboembolic events, and cardiovascular disease, when transdermal estradiol is combined with oral natural progesterone instead of synthetic progestins4–6. However, in many countries MHT usage is still very low after the misinterpreted initial results of the Women’s Health Initia-
Correspondence: Dr E. Boschitsch, KLIMAX Menopause and Osteoporosis Clinic, Vienna, Austria; E-mail: [email protected]
INVITED EDITORIAL © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1065061
Received 06-06-2015 Accepted 07-06-2015
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
For how long should osteoporosis treatment continue? tive of 20027, which had an immediate impact on MHT prescription patterns. Data from a large cohort (n ⫽ 81 000) of a Californian health management organization revealed that women who discontinued MHT were at 55% greater risk of hip fractures compared with those who continued MHT, in spite of an increased prescription rate for bisphosphonates from 8% to 23%8. Oral bone-specific regimens for the treatment of osteoporosis, mostly oral bisphosphonates, show only low efficacy due to their relatively high rates of side-effects and adverse events, with very low persistence rates9 of about 30% and 9% after 1 and 5 years, respectively10. The introduction of intravenous bisphosphonates definitely improved persistence. Nevertheless, according to a former study with zoledronic acid, approximately one-third of patients suffer from postinfusion symptoms such as pyrexia, influenza-like symptoms, myalgia, headache and arthralgia after the first infusion, and the number of patients with arrhythmia or serious atrial fibrillation is significantly higher in the zoledronic acid group than in the placebo group11. Such side-effects and adverse events might be one reason for the small participation rate (only 190 patients started the second extension study out of the 451 patients who had completed the first extension study) and the additional high discontinuation rate of 27% in the HORIZON-PFT1. Persistence with zoledronic acid in the realworld setting of an outpatient clinic has also been shown to be suboptimal: only 94 out of 259 patients (36.3%) agreed to a second infusion and 83% declared the post-infusion syndrome responsible for declining the second administration12. When the authors of the HORIZON-PFT state that almost all patients who have received six annual infusions of zoledronic acid can stop medication for up to 3 years with apparent maintenance of benefits, this has to be put into the perspective of a considerable number of non-persistent patients. Persistence with another potent antiresorptive regimen, denosumab 60 mg s.c. every 6 months, is clearly higher according to both the first results of an ongoing, prospective, observational study in routine clinical practice conducted in Germany, Austria, Greece and Belgium, with 91.5% of patients being persistent at year 113, and to the results of our prospective observational study with persistence of 92% at month 6, 88% at month 12, 83% at month 24, and 81% at month 4814. These high rates of persistence with denosumab compared to reported rates of other bone-specific regimens may be attributed to a low frequency of side-effects and adverse events, with a concurrent high efficacy and the very comfortable method of subcutaneous administration every 6 months. In regard to the efficacy measurements of BMD and bone turnover markers in the randomized, clinical trials, there is only a small additional benefit with zoledronic acid over placebo in years 7–9 (second extension study) of the HORIZON-PFT1 in contrast to the benefit with denosumab, which revealed continued increases in BMD and a persistent reduction of bone turnover markers compared to placebo in years 4–8 of the FREEDOM Extension Study15. While the HORIZONPFT was underpowered to detect differences in fracture rates, incidences of new fractures (vertebral, non-vertebral and hip)
2
Boschitsch in the FREEDOM Extension Study remained constantly low. These data suggest that treatment with denosumab can be prolonged for 8 years or more – the recent presentation of the 9-year data at the WCO-IOF-ESCEO Congress supports the benefits of an extended duration of use16 – without increasing disruptive side-effects and adverse events. The most potent antiresorptive drugs, zoledronic acid and denosumab, display different mechanisms of action. One key pharmacological distinction is their distribution within bone. Bisphosphonates bind to bone mineral surfaces, where they are engulfed by migrating mature osteoclasts. Once intracellular, bisphosphonates interfere with the cell metabolism of osteoclasts and inhibit their resorptive activities. These inactive, bisphosphonate-loaded osteoclasts accumulate at the sites of bone resorption and are buried there under de novo synthesized bone much longer than the biochemically determined half-lives of the respective bisphosphonates. Their final elimination depends on the on-site remodeling process, which per se is, as is therapeutically intended, decreased, and on their renal excretion and re-uptake, thus explaining the overall prolonged actions of bisphosphonates in the skeleton17. Denosumab, a fully human antibody to the receptor activator of nuclear factor κB ligand (RANKL), exhibits entirely different mechanisms of action. It mimics the properties of the body’s own osteoprotegerin. In postmenopausal life, without MHT, osteoprotegerin levels are decreased to a minimum since the level of estradiol, as the main stimulating factor for its synthesis, has decreased. Both osteoprotegerin and denosumab act as decoy receptors for RANKL, capturing it before its binding to RANK, the transmembrane receptor of osteoclast precursor cells and mature osteoclasts, thereby inhibiting the differentiation of precursors and the formation into mature osteoclasts as well as the activities and the survival of mature osteoclasts themselves. Denosumab is evenly distributed throughout the trabecular and cortical compartments of bone, thus protecting cortical bone from porosity and promoting cortical thickness and strength, while bisphosphonates mainly bind to the mineral surfaces of predominantly trabecular resorption sites. As a protein, the degradation and elimination of denosumab does not depend on the kidney’s clearance capacities and therefore can also be used in patients with severely reduced glomerular filtration or renal insufficiency18. In contrast, bisphosphonates are contraindicated or have to be used with utmost caution in patients with these conditions, who constitute a relatively large group in the elderly. Thus the question of how long osteoporosis treatment should continue cannot be answered without considerations of the specific characteristics of the individual patients with their diverse ages, lifestyles and co-morbidities, as well as the characteristics of the respective regimens with their distinct parameters of efficacy, safety and persistence. Conflict of interest The author reports no confl ict of interest. The author alone is responsible for the content and writing of this paper. Source of funding
Nil.
Climacteric
For how long should osteoporosis treatment continue?
Boschitsch
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
References 1. Black DM, Reid IR, Cauley JA, et al. The effect of 6 versus 9 years of zoledronic acid treatment in osteoporosis: a randomized second extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res 2015;30:934–44 2. Kanis JA, McCloskey E, Johansson VH, et al. Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF). Osteoporos Int 2013;24:23–57 3. de Villiers TJ, Pines A, Panay N, et al. Updated 2013 International Menopause Society recommendations on menopausal hormone therapy and preventive strategies for midlife health. Climacteric 2013;16:316–37 4. Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–11 5. Cordina-Duverger E, Truong T, Anger A, et al. Risk of breast cancer by type of menopausal hormone therapy: a case-control study among post-menopausal women in France. PLoS One 2013;8:e78016 6. Simon JA. What if the Women’s Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause 2014;21:769–83 7. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:321–33 8. Karim R, Dell RM, Greene DF, et al. Hip fracture in postmenopausal women after cessation of hormone therapy: results from a prospective study in a large health management organization. Menopause 2011;18:1172–7 9. Cramer JA, Roy A, Burrell A, et al. Medication compliance and persistence: terminology and definitions. Value Health 2008;11:44–7
Climacteric
10. Li L, Roddam A, Gitlin M, et al. Persistence with osteoporosis medications among postmenopausal women in the UK General Practice Research Database. Menopause 2012;19: 33–40 11. Black DM, Delmas PD, Eastell R, et al. HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356: 1809–22 12. Lee YK, Nho JH, Ha YC, Koo KH. Persistence with intravenous zoledronate in elderly patients with osteoporosis. Osteoporos Int 2012;23:2329–33 13. Hadji P, Papaioannou NA, Gielen E, et al. 12-Month persistence with denosumab in women with postmenopausal osteoporosis: interim results of a 24-month prospective observational study in Germany, Austria, Greece and Belgium. Presented at WCO-IOF-ESCEO, Seville, Spain; April 2–5, 2014, Poster Nr. P150 14. Boschitsch E, Trinker N. Persistence with denosumab in a menopause and osteoporosis clinic. Presented at ECTS-IBMS 2015 Congress, Rotterdam, The Netherlands; April 25–28, 2015, Poster Nr. P357 15. Papapoulos S, Lippuner K, Roux C, et al. Eight years of denosumab treatment in postmenopausal women with osteoporosis: results from the first five years of the FREEDOM Extension. Presented at ASBMR, Baltimore, USA; October 4–7, 2013, presentation number: LB-MO26 16. Papapoulos S, Roux C, Bone HG, et al. Denosumab treatment in postmenopausal women with osteoporosis for up to 9 years: results through year 6 of the FREEEDOM extension. Presented at WCO-IOF-ESCEO, Milan, Italy; March 27, 2015, OC4 17. Pazianas M, Cooper C, Ebetino FH, et al. Long-term treatment with bisphosphonates and their safety in postmenopausal osteoporosis. Ther Clin Risk Manag 2010;6:325–43 18. Baron R, Ferrari S, Russell RG. Denosumab and BPs: different mechanisms of action and effects. Bone 2011;48:677–92
3
