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1Department of General Medicine, Sengkang General Hospital, Singhealth, Singapore
2Duke NUS Medical School, Singapore
Copyright © 2022 Korean Endocrine Society
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
Follow-on agent | Study | Type of study | No. | Characteristics of the patient population | Duration of DMB/onset of follow-on agent |
Outcomes |
||
---|---|---|---|---|---|---|---|---|
BMD | Fracture | |||||||
Alendronate | Freemantle et al. (2012) [25] | Randomized open-label crossover study | 126 | Exploratory analysis of 126 postmenopausal women assigned to 1 year of DMB followed by 1 year of ALN. | 1 year/6 months after stopping DMB | BMD at 1 year of stopping DMB: | 1 Subject had a humerus fracture during ALN follow-on therapy. | |
• LS, 2.9% | ||||||||
• TH, 1.5% | ||||||||
• FN, 1.7% | ||||||||
Risedronate and zoledronic acid | Horne et al. (2018) [26] | Case series (subset of the phase III FRAME study) | 19 | Postmenopausal women who had received ROMO or placebo for 1 year followed by 2 years of DMB were treated with 1 year of RIS (n=5) vs. single-dose ZOL (n=11) vs. no treatment (n=3). | 2 years/median 8 months (range, 6.4–11.8) from stopping DMB | BMD at 1 year of stopping DMB: | No clinical fractures occurred. | |
• 59% and 36% loss of BMD gained (during the FRAME trial) at the LS and TH respectively with RIS. | ||||||||
• 27% and 13% loss of BMD gained (during the FRAME trial) at the LS and TH for ZOL. | ||||||||
Zoledronic acid | Lehmann et al. (2017) [27] | Case series | 22 | Postmenopausal women who had 5 doses of DMB followed by single-dose of ZOL. | 2.5 years/6 months after stopping DMB | BMD 2.5 years after stopping DMB: | No new vertebral fractures, but 1 patient had a calcaneal fracture observed during ZOL follow-on therapy. | |
• LS, –3.8% | ||||||||
• TH, –1.7% | ||||||||
• FN, –0.6% | ||||||||
Zoledronic acid | Kondo et al. (2020) [28] | Retrospective observational study | 30 | 29 Postmenopausal women and 1 male patient received an average of 3.1 doses of DMB followed by single-dose of ZOL. | Mean 1.5 years (range, 0.5–3)/mean 9 months after stopping DMB (range, 6–16.5) | BMD 1 year from ZOL therapy (n=18): | No new vertebral/nonvertebral fractures were observed during ZOL follow-on therapy. | |
• LS, 9.1% | ||||||||
• FN, 6.1% | ||||||||
Zoledronic acid | Anastasilakis et al. (2019) [29] | Open-label, multicentre, randomized, trial (AfterDmab) | 57 | Postmenopausal women treated with DMB and achieved BMD in the osteopenic range were randomized to single-dose ZOL (n=27) or continue DMB (n=30) for 1 year. No treatment was given subsequently and patients were followed until 2 years after randomization. | Mean 2.2 years/6 months from stopping DMB | BMD 2.5 years after stopping DMB with ZOL therapy: | 3 Patients in the DMB group sustained vertebral fractures at 9, 12 & 12 months after last DMB dose whereas 1 patient in the ZOL group sustained clinical vertebral fractures at 12 months of single-dose ZOL. | |
• LS, 0.1% | ||||||||
• FN, data not given | ||||||||
BMD 1 year after stopping DMB without ZOL therapy: | ||||||||
• LS, –4.8% | ||||||||
• FN, data not given | ||||||||
The change in LS BMD was significantly different between groups (P=0.021) | ||||||||
Zoledronic acid | Makras et al. (2020) [30] | Single-arm observational extension of AfterDmab | 23 | In the third-year extension of the study, 23 of the 27 postmenopausal women who had single-dose ZOL in the ZOL arm of the AfterDmab study who did not require additional treatment were followed for another year. | Mean 2.4 years/6 months from stopping DMB | BMD 3.5 years after stopping DMB: | No new vertebral fractures were observed during the extension. | |
• LS, –1.75% | ||||||||
• FN, reported as no significant change | ||||||||
Zoledronic acid | Anastasilakis et al. (2021) [31] | Single-arm observational extension of AfterDmab | 15 | To compare the 1-year effect of ZOL infusion given 6 vs. 18 months following the last DMB injection, 15 of the 30 postmenopausal women of the DMB arm received single-dose ZOL 18 months after last DMB dose (late-ZOL) and were compared to the 27 patients who had received ZOL 6 months after DMB (early-ZOL). | Mean 2.5 years/6 and 18 months from stopping DMB | BMD 1 year from ZOL therapy: | No new clinical or radiological fractures noted. | |
• Late-ZOL: LS, 1.8% | ||||||||
• Early-ZOL: LS, 1.7% (No between-group difference) | ||||||||
• Late-ZOL: FN, 3.4% | ||||||||
• Early-ZOL: FN, 0.1% (No between-group difference) | ||||||||
The mean LS BMD was significantly higher in early-ZOL at end of study than in the late-ZOL group (0.976±0.016 g/cm2 vs. 0.905±0.015 g/cm2 respectively, P=0.005). | ||||||||
Zoledronic acid | Solling et al. (2020) [19] | Randomized, open-label, interventional study | 61 | Postmenopausal women and men above 50 years of age who received DMB for at least 2 years received singledose ZOL 6 months (n=20) or 9 months (n=20) 9 months after the last DMB dose or when CTX had increased above 1.26 μg/L (OBS; n=21). | Mean 4.6 years/6 and 9 months from stopping DMB or when CTX >1.26 µg/L | BMD 1 year from ZOL therapy: | Incidental vertebral fractures were observed in 2 women in the 9 mo group. | |
• 6 mo: LS, –4.8% | ||||||||
• 9 mo: LS, –4.1% | ||||||||
• OBS: LS, –4.7% (No between-group difference) | ||||||||
• 6 mo: TH, –2.6% | ||||||||
• 9 mo: TH, –3.2% | ||||||||
• OBS: TH, –3.6% (No between-group difference) | ||||||||
• 6 mo: FN, –3.0% | ||||||||
• 9 mo: FN, –3.5% | ||||||||
• OBS: FN, –4.6% (No between-group difference). | ||||||||
Zoledronic acid | Everts-Graber et al. (2020) [32] | Retrospective observational study | 120 | Postmenopausal women reated with DMB for 2–5 years received single-dose ZOL 6 months after last DMB injection. | Mean 3 years/6 months from stopping DMB | BMD median 2.5 years (range, 1–3.5) after stopping DMB: | 3 Patients developed vertebral fractures. 4 patients developed peripheral fractures: pubis, humerus, calcaneus, and distal radius. | |
• LS, –3.3% | ||||||||
• TH, –2.2% | ||||||||
• FN, –1.5% | ||||||||
Raloxifene | Ebina et al. (2021) [33] | Retrospective study | 53 | Postmenopausal women previously treated with oral BP (n=26) or TPTD (n=27) were switched to DMB (given 2.6 doses) then either switched to RAL (n=13), weekly/monthly BP (i.e., ALN, RIS, or IBN) (wmBP; n=29) or ZOL (n=11) at a mean of 7.2 months after denosumab. | Mean 2.6 doses/7.2 months after DMB | BMD 1.5 years after stopping DMB: | Clinical vertebral fractures were present in 23.1% (RAL) vs. 3.4% (wmBP) vs. 0% (ZOL) (P=0.048 for RAL vs. ZOL). Nonvertebral clinical fractures were present in 7.7% (RAL) vs. 3.4% (wmBP) vs. 0% (ZOL) (P=0.71 between groups) | |
• RAL: LS, –2.7% | ||||||||
• wmBP: LS, 0.7% | ||||||||
• ZOL: LS, 1.9% (No betweengroup difference) | ||||||||
• RAL: FN, –3.8% | ||||||||
• wmBP: FN, –0.8% | ||||||||
• ZOL: FN, 1.8% | ||||||||
FN BMD significantly decreased in the RAL group (P=0.02 between the RAL and ZOL groups; P=0.048 between the RAL and wmBP groups) | ||||||||
Teriparatide | Leder et al. (2015) [34] | Extension study of the randomized controlled trial DATA study-The DATASwitch study | 94 | In DATA, postmenopausal women with osteoporosis were assigned to 24 months of TPTD, DMB, or both. In DATA-Switch, women assigned to TPTD received DMB (n=27), those who received DMB received TPTD (n=27) and those assigned to both received 24 months of DMB alone (n=23). | 2 years | BMD 2 years after stopping DMB: | No fracture data | |
• LS, 4.8% | ||||||||
• TH, –0.7% | ||||||||
• FN, 1.2% | ||||||||
• DR, –5.0% (In the DMB-to-TPTD group) | ||||||||
Romosozumab | Kendler et al. (2019) [35] | Phase 2, dose-finding study, randomized controlled trial | 167 | Postmenopausal women with T score ≤–2.0 and ≥–3.5 received ROMO or placebo (month 0–24) followed by placebo (n=19) or DMB (n=16) from month 24–36, followed by 1 year of ROMO (month 36–48) | 1 year | BMD 1 years after stopping DMB: | No fracture data | |
• LS, 2.3% | ||||||||
• TH, –0.0% | ||||||||
• FN, 0.8% (in the DMB-to-ROMO group) |
DMB, denosumab; ALN, alendronate; BMD, bone mineral density; LS, lumbar spine; TH, total hip; FN, femoral neck; FRAME, Fracture Study in Postmenopausal Women with Osteoporosis; ROMO, romosozumab; RIS, risedronate; ZOL, zoledronic acid; CTX, C-telopeptide; OBS, observation group; BP, bisphosphonate; TPTD, teriparatide; RAL, raloxifene; IBN, ibandronate; wmBP, weekly/monthly bisphosphonates; DATA, Denosumab and Teriparatide Administration Study.