| 1 |
Cummings et al, 200928
|
Randomised controlled trial (FREEDOM; ClinicalTrials.gov: NCT00089791) |
A total of 7808 postmenopausal women aged 60–90 years with a T score < −2.5 at the lumbar spine or total hip. |
Subjects received subcutaneous injections of either 60 mg denosumab or placebo every 6 months for 36 months.
All women received daily supplements containing calcium (≥1 g) and vitamin D (≥400 IU). |
↓ risk of new vertebral fracture by 68% after 36 months [relative risk (RR)= 0.32; 95% confidence interval (CI) 0.26–0.41; p < 0.001]. Similar trends of new vertebral fracture reduction were identified for 0–12 [RR= 0.39], 12–24 [RR= 0.22] and 24–36 months intervals [RR= 0.35] (all p < 0.001). ↓ risk of secondary non-vertebral fracture by 19% [hazard ratio (HR)= 0.80; 95% CI 0.67–0.95; p < 0.05], risk of hip fracture by 41% [HR= 0.60; 95% CI 0.37–0.97; p < 0.05], risk of new clinical vertebral fracture by 69% [HR= 0.31; 95% CI 0.20–0.47; p < 0.001] and risk of multiple new vertebral fractures by 63% after 36 months [HR= 0.39; 95% CI 0.24–0.63; p < 0.001]. ↓ incidence of falls that were not associated with a fracture to 4.5% as compared with 5.7% in the placebo group after 36 months (p<0.05). No significant difference between subjects who received denosumab and placebo in the total incidence of adverse events, serious adverse events, or discontinuation of study treatment because of adverse events (p>0.05). |
| 2 |
Papapoulos et al, 201230
|
FREEDOM and FREEDOM extension study (ClinicalTrials.gov: NCT00523341) |
A total of 7808 subjects from FREEDOM trial and 4550 subjects from both placebo (N=2207) and denosumab groups (N=2343) who completed the 3-year FREEDOM trial and did not discontinue investigational product or miss >1 dose in the first 2 years of FREEDOM extension study. |
Similar intervention as Cummings et al 2009.
During the FREEDOM extension, all subjects (denosumab and placebo) were administrated 60 mg denosumab subcutaneously every 6 months for the first 2 years with daily calcium and vitamin D supplementation.
Cross-over group: all subjects from placebo of FREEDOM study who received the denosumab in the extension.
Long-term group: Subjects who continued denosumab for 2 years in addition to the 3 years initial treatment (total 5 years of treatment). |
↓ risk of new vertebral and non-vertebral fractures for each year of denosumab in FREEDOM trial compared with placebo. New vertebral fracture incidence remained low at 1.4% for “long-term group” during the FREEDOM extension and ↓ sharply to 0.9% for “cross-over group”. ↓ non-vertebral fracture incidence reaching 1.4% and 1.1% for “long-term group” at 4th and 5th year of treatment. ↓ non-vertebral fracture incidence, reaching 2.4% and 1.7% during 1st and 2nd year of FREEDOM extension, respectively, with trends similar to conventional denosumab group in original FREEDOM trial. Adverse events did not increase with 5 years of denosumab administration. |
| 3 |
Ferrari et al, 201529
|
FREEDOM and FREEDOM extension study (ClinicalTrials.gov:
NCT00523341) |
A total of 4074 subjects (N=2343 denosumab; N=1731 placebo) who completed the 3-year FREEDOM trial and did not discontinue investigational product or miss >1 dose for the first 4 years in the FREEDOM extension. |
Similar intervention as
Papapoulos et al 2012 but up to 3 years.
Cross-over group: all subjects from placebo of FREEDOM study who received the denosumab in the extension.
Long-term group: Subjects who continued denosumab for 4 years in addition to the 3 years initial treatment (total 7 years of treatment). |
Low non-vertebral fracture incidences in the first 4 years of denosumab extension for both long-term group (1.5%, 1.2%, 1.8% and 1.6%, respectively) and cross-over group (2.3%, 2.1%, 2.7% and 1.2%, respectively). Non-vertebral fracture rate per 100 participant-years among all subjects in FREEDOM extension was 2.15% in the first 3 years of extension and then ↓ by 36% in the 4th year of extension [RR=0.64; 95% CI 0.48–0.85; p< 0.01]. Non-vertebral fracture rate among cross-over group was 2.37% in the first 3 years of extension and then ↓ by 49% in the 4th year of extension [RR= 0.51; 95% CI 0.32–0.82; p<0.01). Non-vertebral fracture rate was similar between the first 3 years of denosumab (FREEDOM) and 1st year of extension in the long-term group (p=0.127). The fracture rate ↓ by 21% in the long-term group [RR=0.79; 95% CI 0.62–1.00, p<0.05]. Non-vertebral fracture rate reductions in 4th year of extension were most prominent for subjects with hip BMD between −1.0 and −2.5 [RR=0.47; 95% CI 0.30–0.73; p-value NA] and femoral neck BMD T-score of ≤-2.5 [RR=0.37; 95% CI 0.18–0.77; p< 0.01]. The reduction was not significant between the first 3 years and 4th year of extension (p>0.05). |
| 4 |
Papapoulos et al, 201531
|
FREEDOM and FREEDOM extension study (ClinicalTrials.gov:
NCT00523341) |
A total of 7808 subjects from FREEDOM trial and 3004 subjects from both placebo (N=1462) and denosumab groups (N=1542) who completed the 3-year FREEDOM trial and did not discontinue investigational product or miss >1 dose in the first 5 years of FREEDOM extension. |
Similar intervention as Cummings et al 2009.
and Papapoulos et al 2012 (up to 5 years).
Cross-over group: all subjects from placebo of FREEDOM study who received the denosumab in the extension.
Long-term group: Subjects who continued denosumab for 5 years in addition to the 3 years initial treatment (total 8 years of treatment). |
Low incidence of new vertebral fractures in the “long-term group” at 1.5%, 1.3% and 1.3% for 4/5th, 6th and 7/8th year of treatment. ↓ incidence of new vertebral fractures in the “cross-over group” compared to placebo period in FREEDOM, at 0.9% (1/2nd year), 1.6% (3rd year of extension) and 1.8% (4/5th year of extension). ↓ incidence of non-vertebral fractures in “long-term group” at 1.5% (4th year), 1.2% (5th year), 1.8% (6th year), 1.6% (7th year) and 0.7% (8th year of treatment). ↓ incidence of non-vertebral fractures in “cross-over group” compared to placebo in FREEDOM, at 0.9% (1/2nd years), 1.6% (3rd years of extension) and 1.8% (4/5th years of extension). The cumulative incidence of hip fractures for 1st to 5th year of the extension was 0.7% and the annualized incidence of hip fractures with up to 8 years of denosumab treatment was 0.2% for “long-term group”. The cumulative incidence of hip fractures for 1st to 5th year of the extension was 1.1% for “cross-over group”. The incidence of adverse and serious adverse events did not increase over time regardless of the length of denosumab treatment. |
| 5 |
Bone et al, 201727
|
FREEDOM and FREEDOM extension study (ClinicalTrials.gov:
NCT00523341) |
A total of 7808 subjects from FREEDOM trial and 2626 subjects from both placebo (N=1283) and denosumab groups (N=1343) who completed the 3-year FREEDOM trial and did not discontinue investigational product or miss >1 dose for 7 years in the FREEDOM extension. |
Similar intervention as Cummings et al 2009.
and Papapoulos et al 2012 (up to 7 years).
Cross-over group: all subjects from placebo of FREEDOM study who received the denosumab in the extension.
Long-term group: Subjects who continued denosumab for 7 years in addition to the 3 years initial treatment (total 10 years of treatment). |
The new vertebral fracture incidences in the long-term group were maintained at 0.86%, 0.70% and 1.08% during FREEDOM trial and then 1.47%, 1.16%, 1.36% and 1.28% in the 4/5th, 6th, 7/8th and 9/10th year of denosumab treatment. The non-vertebral fracture incidences in long-term group were maintained at 2.59%, 2.09% and 2.15% during FREEDOM trial and then ↓ to 1.49%, 1.23%, 1.77%, 1.55%, 0.84%, 1.05% and 1.91% for 4–10 years of denosumab. The hip fracture incidences in the long-term group were consistently maintained at 0.29%, 0.08% and 0.32% in FREEDOM trial and then 0.22%, 0.05%, 0.15%, 0.05%, 0.18%, 0.00% and 0.42% during 4–10 years of denosumab. The new vertebral fracture incidences in cross-over group remained low at 0.90%, 1.47%, 1.86% and 1.58% during the 1/2nd, 3rd, 4/5th and 6/7th year of denosumab extension treatment. The non-vertebral fracture incidences in cross-over group were maintained at 2.55%, 2.00%, 2.55%, 1.18%, 1.77%, 1.53% and 1.72% for the 1–7 years of denosumab extension, respectively. The hip fracture incidences in cross-over group were maintained at 0.61% in the first year of denosumab treatment and ↓ to 0.14%, 0.16%, 0.06%, 0.13%, 0.14% and 0.07% during 2–7 years of denosumab, respectively. The cumulative new vertebral fracture incidence in the long-term group was ↓ by 68% to 2.3% (placebo 7.2%) in FREEDOM trial, but ↑ back to baseline at 7.0% in the FREEDOM 7-year extension with a much higher estimated virtual twin-placebo (11.5%). The cumulative non-vertebral fracture incidence in the long-term group ↓ by 19% to 6.5% (placebo 8.0%) in FREEDOM trial and then ↑ 9.3% during the FREEDOM 7-year extension with a relatively higher estimated virtual twin-placebo (14.5%). The estimated relative risk for new vertebral fracture in the long-term group was 0.62 (95% CI 0.47–0.80), while the non-vertebral fracture was 0.54 (95% CI 0.43–0.68) with the unknown p-value. All and serious adverse events including infections, malignancy, eczema, hypocalcaemia, pancreatitis, cellulitis and fatality remained stable over the time for both placebo (FREEDOM) and denosumab-treated group (long-term and cross-over group). |
| 6 |
Kendler et al, 201933
|
Post-hoc analysis of FREEDOM and FREEDOM extension study (ClinicalTrials.gov:
NCT00523341) |
A total of 710 FREEDOM subjects and 794 subjects from FREEDOM and FREEDOM extension respectively who had an osteoporotic fracture (new vertebral or non-vertebral fracture) and then continued post-fracture treatment at least ≥ 2 doses of placebo or denosumab. |
Similar intervention as Cummings et al 2009.
and Papapoulos et al 2012 (up to 7 years).
Cross-over group: all subjects from placebo of FREEDOM study who received the denosumab in the extension.
Long-term group: Subjects who continued denosumab for 7 years in addition to the 3 years initial treatment (total 10 years of treatment).
Combined denosumab group: Denosumab users in long-term group and/or cross-over group. |
↓ multiple new vertebral fracture by 62.5% as compared with placebo (1.6%) [RR= 0.39, 95% CI 0.24–0.63]. ↓ exposure-adjusted subsequent osteoporotic fracture rate, per 100 subject-years (vertebral or non-vertebral fracture) in combined denosumab group (but not FREEDOM denosumab group) by 43% to 5.8% compared with placebo (10.1%) from FREEDOM [HR= 0.59; 95% CI 0.43–0.81; p <0.01] ↓ exposure-adjusted subsequent osteoporotic fracture rate by 40% to 10.4 for denosumab FREEDOM [HR= 0.54; 95% CI: 0.29–0.99; p <0.05] and by 55% to 7.8 in combined denosumab group compared with placebo (17.4%) [HR= 0.41; 95% CI: 0.26–0.65; p< 0.0001]. |
| 7 |
Bilezikian et al, 201932
|
Post hoc analysis of FREEDOM and FREEDOM extension study (ClinicalTrials.gov:
NCT00523341) |
A total of 2207 subjects from FREEDOM extension study who had an osteoporotic fracture (new vertebral or non-vertebral fracture) and then continued post-fracture treatment at least ≥ 2 doses of placebo or denosumab.
A total of 441 subjects were identified in a BMD sub-study with 209 placebo and 232 denosumab. |
Similar intervention as Cummings et al 2009.
and Papapoulos et al 2012 (up to 7 years).
Cross-over group: all subjects from placebo of FREEDOM study who received the denosumab in the extension.
Long-term group: Subjects who continued denosumab for 7 years in addition to the 3 years initial treatment (total 10 years of treatment).
Extension group: Cross-over and long-term groups. |
A 7-year denosumab significantly decreased the overall rate of entire upper limb fractures in extension group during 4th-7th year [48% reduction; RR= 0.52; 95% CI 0.37–0.72; p< 0.0001], including the wrist [43% reduction; RR= 0.57; 95% CI 0.38–0.86; p= 0.0077], forearm [43% reduction; RR= 0.57; 95% CI 0.39–0.84; p= 0.0042] and humerus [59% reduction; RR= 0.42; 95% CI 0.21–0.83; p= 0.0129] as compared with FREEDOM placebo. The entire upper limb fracture rates including wrist and forearm were similar between FREEDOM placebo and extension group in the 1st-3rd year, except for humerus [54.5% reduction; RR= 0.45; 95% CI: 0.23–0.89; p<0.05]. |
| 8 |
Boonen et al, 201135
|
Post hoc analysis of FREEDOM data |
A total of 7808 postmenopausal women from FREEDOM trial, who were grouped as high- and low-risk subgroups based on fracture prevalent, femoral neck BMD and/or age. |
Similar intervention as Cummings et al 2009. |
↓ new vertebral fracture incidence at 12, 24 and 36 months by 61% [95% CI 42–74%], 71% [95% CI 61–79%] and 68% [95% CI 59–74%], respectively (all p<0.001). ↓ incidence of new vertebral fractures in high-risk subgroup based on prevalent vertebral fracture status [55% reduction; absolute risk reduction (ARR)= 9.2%]; baseline femoral neck BMD T-score ≤−2.5 [69% reduction; ARR= 6.8%]; and high-risk combined subgroup (those with both risk factors) [60% reduction; ARR=12.3%] (all p≤ 0.001) after 36 months. ↓ incidence of new vertebral fractures in the low-risk subgroup based on absence of prevalent vertebral fracture [71% reduction; ARR= 4.4%]; baseline femoral neck BMD T-score > −2.5 [66% reduction; ARR= 3.7%]; and low-risk combined subgroup (those without one or both of these risk factors) [68% reduction; ARR= 4.5%] (all p< 0.001) after 36 months. ↓ incidence of new vertebral fractures for the high-risk subgroup (based on prevalent vertebral fracture status) by 64% and high-risk combined subgroup by 71% at 24 months (all p<0.001) but not for 12 months (p>0.05). ↓ incidence of new vertebral fractures for low-risk subgroup and low-risk combined subgroup by 66% and 62% at 12 months and further reduced to 73% and 71% at 24 months, respectively (all p< 0.001). ↓ risk of hip fractures in high-risk subgroups: aged ≥75 years [62% reduction; ARR= 1.4%]; baseline femoral neck BMD T-score ≤ −2.5 [47% reduction; ARR=1.4%] and high-risk combined subgroup (those with both risk factors) [60% reduction; ARR=2.4%] (all p< 0.05). No significant difference was found in the risk of hip fracture between denosumab and placebo treatment for all low-risk subgroups (all p >0.05) The anti-fracture efficacy of denosumab against new vertebral fracture and hip fracture was consistent among each low- and high-risk subgroups (with interaction p>0.05). The frequencies of adverse events were found similar between denosumab and placebo regardless of age (all p>0.05). Denosumab treatment significantly reduced the fatality rate in high-risk subgroups with prevalent vertebral fracture status, with or without a low femoral neck BMD T-score (all p <0.05) |
| 9 |
Jamal et al, 201136
|
Post-hoc analysis of FREEDOM data |
A total of 7808 postmenopausal women from FREEDOM trial, who were grouped based
on the modified National Kidney Foundation classification of
CKD. |
Similar intervention as Cummings et al 2009. |
↓ incidence of new vertebral fracture [odds ratio (OR)= 0.30; 95% CI 0.23–0.39; p < 0.001] and non-vertebral fractures [OR= 0.78; 95% CI 0.66–0.93] after 36 months. ↓ incidence of new vertebral fractures [OR= 0.30; 95% CI 0.23–0.39] in stages 1, 2 and 3 of CKD and ↓ non-vertebral fractures incidence [OR= 0.78; 95% CI 0.66–0.93] in stages 1 and 2 CKD (p values are not provided by authors). The anti-fracture effects of denosumab were not statistically significant among subjects with different kidney function (p>0.05). Denosumab is safe and effective among subjects with stage 1 to stage 4 CKD with similar adverse events. |
| 10 |
McClung, et al 201238
|
Post-hoc analysis of FREEDOM data |
A total of 7808 postmenopausal women from FREEDOM trial, who were grouped into subgroups (age, body mass index, estimated creatinine clearance, region, femoral neck BMD, prevalent vertebral fracture, prior non-vertebral fracture, race and prior use of osteoporosis medications) with their new vertebral fracture, non-vertebral fracture and femoral neck BMD outcomes. |
Similar intervention as Cummings et al 2009. |
↓ incidence of new vertebral fractures by 68% to 2.3% [HR= 0.32; 95% CI 0.26–0.41; p<0.001] and non-vertebral fractures by 19% to 6.5% [HR= 0.80; 95% CI 0.67–0.95; p=0.01] for the entire study population after 36 months. ↓ new vertebral fracture risk regardless of age, BMI, estimated creatinine clearance, region, femoral neck BMD, prevalent vertebral fracture, prior non-vertebral fracture, race and prior use of osteoporosis medications (all p>0.05). ↓ non-vertebral fracture risk regardless of age groups and those with or without prior history of non-vertebral fracture (all p>0.05). ↓ non-vertebral fracture risk in those subgroups with BMI <25 kg/m2 [38% reduction; ARR=3.4%; 95% CI 1.5–5.3%], with femoral neck BMD T-score ≤-2.5 [35% reduction; ARR=4.1%; 95% CI 1.8–6.5%] and in those subgroups without a prevalent vertebral fracture [29% reduction; ARR=2.1%; 95% CI 0.7–3.4%] (all p<0.05). |
| 11 |
Austin et al, 201234
|
Post-hoc analysis of FREEDOM data |
A total of 7808 postmenopausal osteoporotic women from FREEDOM study with their total hip BMD and fracture outcomes. |
Similar intervention as Cummings et al 2009. |
↓ new or worsening vertebral fracture risk after 12 months [RR= 0.39, 95% CI 0.26–0.58], 24 months [RR= 0.29; 95% CI 0.21–0.39] and 36 months of treatment [RR= 0.32; 95% CI 0.26–0.41] ↓ non-vertebral fracture risk at 24 months [HR=0.79; 95% CI 0.64–0.96] and 36 months [HR=0.80; 95% CI 0.67–0.95] but not 12 months. ↓ new or worsening vertebral fracture (but not nonvertebral fracture) with ↑ total hip BMD in both denosumab and placebo group. The slope of the curves for denosumab was significantly higher than placebo (p=0.0003). |
| 12 |
McCloskey et al, 201237
|
Post-hoc analysis of FREEDOM data |
Calculation of FRAX based on clinical risk factors and BMD data from the 7808 postmenopausal osteoporotic women in FREEDOM study. |
Similar intervention as Cummings et al 2009. |
↓ clinical osteoporotic (vertebral and non-vertebral) fractures [RRR=32%; 95% CI 20–42%; p<0.001], but not hip fractures [RRR=36%; 95% CI −2–60%; p>0.05] compared with placebo after adjusted for age and FRAX major osteoporotic fracture probability. Better efficacy of fracture risk reduction in those with moderate to high fracture risk (p≤0.001). Denosumab was equally effective regardless of age, BMD value, prior fracture, parental history of hip fracture, secondary causes of osteoporosis, smoking or alcohol intake (all p>0.05). A low body mass index (BMI) was associated with greater efficacy of denosumab (p<0.05). |
| 13 |
Simon et al, 201339
|
Post-hoc analysis of FREEDOM data |
A total of 7808 postmenopausal women from FREEDOM trial with wrist fracture incidence, radius BMD, bone mineral content and strength data. |
Similar intervention as Cummings et al 2009. |
Denosumab significantly reduced wrist fracture incidence for participants with a femoral neck T-score ≤ −2.5 in comparing with placebo [RRR= 40%; ARR= 1.6%; p < 0.05]. Denosumab did not alter the wrist fracture incidence for the entire FREEDOM group [HR= 0.84; RRR= 16%; p = 0.21] or participants with a femoral neck T-score > −2.5 [RRR= −4%; p = 0.82]. |
| 14 |
Palacios et al, 201548
|
Post-hoc analysis of FREEDOM data |
A total of 7808 postmenopausal women from FREEDOM trial with the onset of secondary fragility fracture. |
Similar intervention as Cummings et al 2009. |
↓ incidence of primary or secondary fragility fracture (new vertebral and low-trauma non-vertebral fracture) in total FREEDOM subjects [RRR=40%; ARR= 5.3%] after 36 months. Similar anti-fracture effects of denosumab were reported on FREEDOM subpopulations with prior fragility fracture [RRR=39%; ARR= 6.8%] or without prior fragility fracture [RRR=40%; ARR= 4.1%], aged ≥75 years [RRR=35%; ARR= 5.3%] or <75 years [RRR=42%; ARR= 5.2%]; with prevalent vertebral fracture [RRR= 35%] or prior non-vertebral fracture [RRR= 34%]; past osteoporotic treatment [RRR=48%] or without previous osteoporotic medication [RRR=35%] (all p<0.0001). No significant differences observed among the subjects receiveing denosumab regardless of fragility fracture incidence, age subgroups, fracture site and past osteoporotic treatment history (all p > 0.05). Denosumab treatment did not increase the adverse events, including serious, fatal cases or any discontinuation due to adverse effects compared to placebo. |
| 15 |
Cosman et al 201642
|
An international, randomized, double-blind, placebo-controlled, phase 3 fracture study on Japanese postmenopausal women with osteoporosis [FRActure study in postmenopausal
woMen with ostEoporosis (FRAME) study]; (ClinicalTrials.gov:
NCT01575834) |
A total of 7180 postmenopausal women, age 55–90 years with osteoporosis (BMD T-score −3.5 to −2.5 at total hip or femoral neck). |
Subjects were randomized 1:1 to receive subcutaneous romosozumab 210 mg (N=3589) or placebo (N=3591) once monthly for 12 months. All subjects were transitioned to open-label denosumab 60 mg subcutaneously every 6 months for the first 12 months.
All subjects received a minimum daily calcium (500–1000 mg) and vitamin D (600–800 IU) supplementation throughout the study. |
↓ cumulative new vertebral fracture risk in the romosozumab-to-denosumab group compared to the placebo-to-denosumab group in the 2 years of study [RR=0.25; 95% CI 0.16–0.40; p<0.001]. No significant difference in non-vertebral and clinical fracture risk between 24 months of romosozumab-to-denosumab and placebo-to-denosumab group [all p>0.05]. The incidence of adverse events through 24 months was similar between the romosozumab-to-denosumab and placebo-to-denosumab groups. |
| 16 |
Miyauchi et al, 201943
|
Sub-group analysis of
FRAME data |
A total of 492 Japanese postmenopausal women, age 55–90 years with osteoporosis (BMD T-score −3.5 to −2.5 at total hip or femoral neck) were used in this FRAME sub-analysis with a total of 7180 subjects. |
Subjects were randomized 1:1 to receive subcutaneous romosozumab 210 mg (N=190) or placebo (N=209) once monthly for 12 months. All subjects were transitioned to open-label denosumab 60 mg subcutaneously every 6 months for another 24 months.
All subjects were prescribed a minimum daily calcium (500–1000 mg) and vitamin D (600–800 IU) supplementation throughout the study. |
New vertebral fracture risk between romosozumab-to-denosumab and placebo-to-denosumab group was similar throughout these 3 years of study [all p>0.05]. Clinical, non-vertebral, major non-vertebral, major osteoporotic, clinical new or worsening vertebral and hip fracture risks were similar between 36 months of romosozumab-to-denosumab and placebo-to-denosumab group [all p>0.05]. The incidences of adverse events through 36 months were similar between the romosozumab-to-denosumab and placebo-to-denosumab groups (87.8% vs 89.8%, respectively). |
| 17 |
Nakamura et al, 201441
|
A randomized, double-blind, placebo-controlled trial on Japanese postmenopausal women and men with osteoporosis [Denosumab fracture Intervention RandomizEd placebo Controlled Trial (DIRECT)]; (ClinicalTrials.gov:
NCT00680953) |
A total of 1034 Japanese postmenopausal women and men aged 50 years or older with osteoporosis (BMD T-score <-1.7 (lumbar spine) or <-1.6 (total hip) with one to four prevalent vertebral fractures completed the study. |
Subjects were randomly assigned in a 2:2:1 ratio to either receive placebo (N=416), denosumab 60 mg subcutaneous every 6 months (N=414), or open-label oral alendronate 35 mg weekly (N=204) for 24 months.
At least 600 mg calcium and 400 IU vitamin D were supplemented daily throughout the study period. |
↓ risk of new or worsening vertebral fracture by 65.7% [HR= 0.343; 95% CI 0.194–0.606; p=0.0001] and new vertebral fracture by 74.0% [HR= 0.273; 95% CI 0.136–0.553; p=0.0001] in all respondents as compared to placebo after 24 months. ↓ risk of new or worsening vertebral fracture by 63.2% in postmenopausal women [HR= 0.368; 95% CI 0.207–0.653 p=0.004). The 24-month denosumab did not significantly alter the risk of non-vertebral fracture and major non-vertebral fracture (all p>0.05) but significantly ↓ the risk of non-major non-vertebral fracture (2.5%) as compared to placebo (0.4%) (p<0.05). The 24-month denosumab therapy was well tolerated with no obvious difference in adverse events, serious adverse events or fatality between denosumab and placebo. ↑ incidence of adverse events including hypocalcaemia (+0.4%), bacterial cellulitis (+0.7%), infection (+4.3%) and cardiovascular disorder (+1.2%). |
| 18 |
Gnant et al, 201540
|
A prospective, double-blind,
placebo-controlled, multicentre phase 3 study on postmenopausal women with hormone receptor-positive breast cancer and aromatase inhibitor as treatment [Austrian Breast Cancer Study Group (ABCSG-18); (ClinicalTrials.gov: NCT00556374) |
A total of 3420 postmenopausal women with early-stage hormone receptor-positive breast cancer and underwent aromatase inhibitor treatment completed the study. |
Subjects received either 60 mg subcutaneous denosumab (N=1274) or placebo (N=1188) every 6 months up to 7 years with a median time of study of 38 months.
Daily administration of 500 mg calcium and at least 400 IU vitamin D were supplemented throughout the study period. |
Delayed the first clinical fracture [HR= 0.5; 95% CI 0.39–0.65; p < 0.0001] which was independent to BMD T-score with the estimated first clinical fracture of 5% (placebo 9.6%) and 11.1% (placebo 26.2%) at 36 and 84 months, respectively. ↓ new vertebral fracture [OR= 0.53; 95% CI 0.33–0.85; p = 0.009] and new or worsening vertebral fracture incidence [OR= 0.54; 95% CI 0.34–0.84; p = 0.007] after 36 months. The incidences of adverse events and serious adverse events were similar between the denosumab (80% and 30%, respectively) and placebo group (79% and 30%, respectively). No neutralizing anti-denosumab antibodies were identified in plasma samples at any time point. |
| 19 |
Saag et al, 201844
|
A phase 3, international, randomized, double-blind, double-dummy, active-controlled, non-inferiority study on glucocorticoid-initiating and glucocorticoid-continuing patients (ClinicalTrials.gov: NCT01575873) |
A total of 691 glucocorticoid-treated participants with osteoporosis (BMD T-score ≤ −2.0 or ≤ −1.0 with fracture history) or past osteoporosis-related fracture history. |
Subjects with glucocorticoid therapy for < 3 months before screening was grouped as “glucocorticoid-initiating group” (N=253) while those with > 3 months therapy were grouped as “glucocorticoid-continuing group” (N=438).
Subjects were then randomized 1:1 within each group to receive either subcutaneous denosumab 60 mg every 6 months and oral placebo daily for 12 months, or oral risedronate 5 mg daily with subcutaneous placebo every 6 months for 12 months.
All patients were assigned to receive daily supplementation with at least 1000 mg calcium and 800 IU vitamin D. |
The fracture incidences were found similar between 12 months risedronate and denosumab treatment including osteoporosis-related fractures (denosumab 7% vs risedronate 6%), new and worsening vertebral fractures (denosumab 1% vs risedronate 3% in men only; denosumab 4% vs risedronate 5% in women only; denosumab 0% vs risedronate 3% in premenopausal women only; both 5% in postmenopausal women only) and low-trauma non-vertebral fractures (denosumab 4% vs risedronate 3%). The 12-month denosumab was comparable with risedronate in reducing glucocorticoid-induced osteoporosis. Similar anti-osteoporosis effect by denosumab can be observed as early as 6 months treatment for both “glucocorticoid-continuing group” and “glucocorticoid-initiating group”. Adverse events, serious adverse events, fractures and discontinuation of the study were similar between denosumab and risedronate. |
| 20 |
Saag et al, 201945
|
A phase 3, international, randomized, double-blind, double-dummy, active-controlled, parallel-group study on glucocorticoid-initiating and glucocorticoid-continuing patients (ClinicalTrials.gov: NCT01575873) |
A total of 590 glucocorticoid-treated participants with osteoporosis (BMD T-score ≤ −2.0 or ≤ −1.0 with fracture history) or past osteoporosis-related fracture history. |
Same as Saag et al 2018 but with 226 subjects in “glucocorticoid-initiating group” and 364 subjects in “glucocorticoid-continuing group” up to 24 months of treatment. |
The fracture incidences for any osteoporosis-related fractures (denosumab 8.8% vs risedronate 9.1%), new and worsening vertebral fractures (denosumab 4.4% vs risedronate 6.9% for all subjects; denosumab 1.0% vs risedronate 5.0% in men only; denosumab 5.9% vs risedronate 7.8% in women only; denosumab 6.1% vs risedronate 6.9% in premenopausal women only; denosumab 5.9% vs risedronate 7.6% in postmenopausal women only) and low-trauma non-vertebral fractures (denosumab 5.3% vs risedronate 3.8%) were statistically similar for both denosumab and risedronate groups upon 24 months of treatment. Anti-osteoporotic effect of denosumab was reported at earlier time points (6 and 12 months) on both “glucocorticoid-continuing group” and “glucocorticoid-initiating group”. The incidences of adverse events, fatality, infection and discontinuation of the study were similar between denosumab and risedronate. |
| 21 |
Behanova et al (2019)25
|
A retrospective cohort study on Austria national data with propensity score matching for antiresorptive-treated and untreated patients |
Previous data from a total of 47,139 patients aged ≥ 50 years old who experienced a hip fracture between January 2012 and December 2016 and follow-up with or without treatment (bisphosphonates or denosumab). |
Hip fracture patients either received oral or intravenous bisphosphonates (N= 3789), denosumab (N=555) or no treatment (N=42,795), up to 60 months. However, the treatment dosage and interval are unknown. |
There was higher risk of a subsequent hip fracture for denosumab-treated patients as compared to untreated patients [subdistribution hazard ratio, SHR= 1.67; 95% CI 1.04–2.66; p<0.05], especially on women [SHR= 1.77; 95% CI 1.08–2.91; p<0.05] but not on men subgroup [SHR= 0.93; 95% CI 0.22–4.05; p>0.05]. No significant difference in subsequent hip fracture risk was detected between denosumab and bisphosphonate groups (oral and intravenous; all p>0.05). Significantly lower risk of mortality by 26% on denosumab-treated patients was detected as compared with untreated patients [HR= 0.74; 95% CI 0.58–0.94; p<0.05] but similar as with those bisphosphonate groups. Similar lower risk of mortality result was reported on denosumab-treated men [HR=0.465; 95% CI 0.24–0.85; p<0.05] but not women [HR= 0.81; 95% CI 0.62–1.06; p>0.05]. |
| 22 |
Pedersen, Heide-Jorgensen, Sorensen, Prieto-Alhambra, and Ehrenstein, 201926
|
A retrospective cohort study using a nationwide, population-based, historical cohort study from Danish health registries/database with complete follow-up |
Previous data from a total of 92,355 subjects aged ≥ 50 years who received the first dispensing of denosumab or alendronate
from May 2010 to December 2017 without any antiosteoporosis
medication within 1 year. |
Patients either received denosumab (N=4624) or alendronate
(N=87,731) and then followed-up up to 7.5 years (median= 3.3 years). However, the treatment dosage and interval are unknown. |
Within the first 3 years of follow-up, initiation of denosumab was associated with a similar risk on the hip or any fracture as alendronate [adjusted hazard ratio (aHR)=1.08; 95% CI 0.92–1.28]. The risk of hip fracture was similar between denosumab and alendronate in each subpopulation including male [aHR=1.24, 95% CI 0.79–1.95], female [aHR=1.03; 95% CI 0.87–1.22], <80 years [aHR=1.00; 95% CI 0.78–1.28], ≥80 years [aHR=1.21; 95% CI 0.97–1.51], those with history of any fracture [aHR=1.07; 95% CI 0.85–1.34], those without any fracture [aHR=1.05; 95% CI 0.83–1.32], those with previous hip fracture [aHR=1.25; 95% CI 0.89–1.76] and those without previous hip fracture [aHR=1.04; 95% CI 0.86–1.26]. The risk of any fracture was similar between denosumab and alendronate for men [aHR=0.96, 95% CI 0.68–1.36], ≥80 years [aHR=1.06; 95% CI 0.89–1.26] and those with previous hip fracture [aHR=1.11; 95% CI 0.85–1.44]. The risk of any fracture was slightly lower in denosumab group as compared with alendronate especially for women [aHR=0.89; 95% CI 0.88–0.99], <80 years [aHR=0.85; 95% CI 0.75–0.97], those with history of any fracture [aHR=0.84; 95% CI 0.71–0.98], those without any fracture [aHR=0.77; 95% CI 0.64–0.93], and those without previous hip fracture [aHR=0.89; 95% CI 0.79–0.99]. |
