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Once-monthly dosing: An effective step forward
Bone 38 (2006) S18 – S22 www.elsevier.com/locate/bone
Once-monthly dosing: An effective step forward D.M. Reid ⁎ Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK Received 25 October 2005; revised 2 November 2005; accepted 26 January 2006
Abstract To improve upon the currently suboptimal level of therapeutic adherence with bisphosphonates in postmenopausal osteoporosis, there is a need to examine less-frequently dosed regimens that offer patients greater convenience than weekly dosing. Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for administration with long between-dose intervals. It has proven antifracture efficacy when administered orally, daily or intermittently (>2 months dose-free interval) and a safety profile comparable with placebo. A dose-ranging study evaluating a simplified once-monthly ibandronate dosing schedule confirmed the feasibility of the regimen. Significant decreases from baseline in the biochemical markers of bone turnover, serum and urinary C-telopeptide of the α-chain of type 1 collagen (CTX) were observed for all once-monthly doses assessed. An analysis of the area under the effect curve for these two parameters confirmed a dose–response relationship. The MOBILE study was a large (n = 1609), randomized, double-blind, non-inferiority study comparing three doses of monthly oral ibandronate (50 + 50 mg, 100 mg and 150 mg) with daily oral ibandronate (2.5 mg) in women with postmenopausal osteoporosis. Analyses have been completed at the end of 1 and 2 years of treatment. With substantial increases in lumbar spine bone mineral density (BMD; 5.3–6.6%), all of the once-monthly regimens were non-inferior, and, in addition, the 150 mg regimen was superior (P ≤ 0.002) to the daily regimen. Corresponding increases in BMD were also observed at all hip sites. The greatest gains in lumbar spine, and hip BMD were consistently seen with the 150 mg regimen. Considerable reductions in serum CTX were seen with all regimens from 3 months onwards (50.0–66.4%); these reductions were maintained throughout the 2-year period (2 years: 56.1–67.7%). The safety profile of the once-monthly regimens was comparable with the daily regimen throughout the 2 years. Once-monthly ibandronate is an effective and well-tolerated treatment for patients with postmenopausal osteoporosis. Given the recently reported strong patient preference for once-monthly regimens and the impact of patient preference on therapeutic adherence, it is anticipated that once-monthly ibandronate will offer patients an alternative convenient regimen that may improve adherence over weekly bisphosphonates and should enhance outcomes. © 2006 Elsevier Inc. All rights reserved. Keywords: Bisphosphonate; Ibandronate; Once-monthly; Osteoporosis; Postmenopausal
Introduction Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for administration with long betweendose intervals. The substantial ibandronate preclinical program demonstrated the potential for less frequent administration, demonstrating efficacy in three animal models of estrogen depletion: rat, dog and monkey [1]. With this evidence and the positive results reported with the intermittent regimen used in ⁎ Fax: +44 1224 554615. E-mail address: [email protected]. 8756-3282/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2006.01.153
the BONE (Oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) study, which demonstrated a significant vertebral fracture risk reduction of 50% [2], a phase I study was initiated to assess a patient-friendly and convenient once-monthly regimen of ibandronate. The MOPS study The MOPS (Monthly Oral Pilot Study) study was a randomized, 3-month, double-blind, placebo-controlled, doseranging trial [3]. Women, aged 55–80 years, at least 3 years postmenopause were randomized to receive three cycles of
D.M. Reid / Bone 38 (2006) S18–S22
S19
Table 1 Median change (%) from baseline in sCTX and uCTX: the MOPS study [3] Placebo (n = 36) sCTX −12.3 uCTX −5.5
50 mg (n = 18)
50/100 mg (n = 18)
100 mg (n = 36)
150 mg (n = 36)
−22.3 −13.4
−49.6 ⁎ −54.8 ⁎
−40.7 ⁎ −34.6 ⁎
−56.7 ⁎ −54.1 ⁎
⁎ P < 0.001 vs. placebo.
once-monthly ibandronate at doses of 50 mg, 100 mg or 150 mg or placebo. In the BONE study [2], a regimen with an extended (>2 months) dose-free interval using a similar cumulative dose as the daily administration resulted in comparable antifracture efficacy, which is consistent with the concept that it is the total dose that determines response [1]. However, on the basis of modeling and simulation data [4], it was considered appropriate for efficacy optimization in the MOPS study to assess oncemonthly doses beyond that provided by the cumulative daily dose (>75 mg). The aims of the MOPS study were to assess the safety, tolerability, pharmacodynamics and pharmacokinetics of the three regimens. No specific lumbar spine bone mineral density (BMD) inclusion criteria were set, and supplementary calcium and vitamin D were not provided. The 50 mg arm was split into two arms (50 mg or 100 mg) after the first dosing cycle to separate the effects of dose and first-time treatment. Participants were instructed to take their medication with 250 ml (8 oz) of plain water following an overnight fast of at least 6 h. Following dosing, participants were to remain in an upright position for 60 min, with a standardized breakfast provided 1 h after dosing. A total of 144 participants were randomized and received at least one dose of study medication [3]. The treatment groups were well-balanced in terms of baseline age, weight and height. Without a specific inclusion criterion for BMD, baseline BMD status was varied, with some participants having normal Tscores, while others were considered either osteopenic (Tscore ≤ −1 to −2.5) or osteoporotic (T-score ≤ −2.5). Overall, the three doses of once-monthly oral ibandronate were well tolerated, with a safety profile similar to placebo [3]. No differences were observed in the number of participants with adverse events considered drug-related [n = 3 (8%) for placebo; n = 3 (17%) for 50 mg dose; n = 0 for 50/50 mg dose; n = 2 (6%) for 100 mg dose; and n = 2 for and 150 mg dose regimen). Only four participants withdrew from the study due to adverse events (placebo group = 3, 150 mg group = 1), and, of these, only one patient had an adverse event considered drug-related (placebo group). The total number of upper gastrointestinal (GI) adverse events was slightly higher in the 100 mg and 150 mg groups (15 events per group vs. 12, 3 and 11 in the placebo, 50 mg and 50/ 100 mg groups, respectively). However, the number occurring within 3 days of treatment administration, which is likely to reflect a treatment-related effect, was comparable (6, 0, 4, 8 and 9 events in the placebo, 50 mg, 50/100 mg, 100 mg and 150 mg groups, respectively). There were no serious adverse events reported in this short study giving encouragement to proceed with further studies with monthly regimens. Baseline serum and urine concentrations of the C-telopeptide of the α-chain of type 1 collagen (CTX), a biochemical marker
Fig. 1. Dose-dependent reduction of bone resorption associated with oncemonthly ibandronate [3]. Copyright 2005. The Endocrine Society.
of bone resorption, were similar across the treatment groups [3]. As can be seen in Table 1, ibandronate significantly reduced the primary pharmacodynamic endpoint, bone turnover, with substantial reductions in serum CTX (sCTX) and urinary CTX (uCTX) recorded at day 91 (compared with baseline levels (P < 0.0001). Compared with placebo, the difference in median reduction was significant for all of the dose groups except the 50 mg group (P < 0.001). A dose–response relationship was demonstrated following analysis of the area under the effect curve (day 1–91) for relative change (% × days) in sCTX and uCTX for once-monthly treatment (Fig. 1). Compared to the 50 mg dose systemic exposure (AUC0–∞) with 100 mg and 150 mg ibandronate increased significantly as assessed by ANOVA. The AUC0–∞ were 130% (95% CI: 94, 180%) and 191% (95% CI: 138, 265%) for the 100 mg and 150 mg arms, respectively. The results for the 50 mg and 50/ 100 mg dose groups were consistent with those previously seen for ibandronate [5]. It was concluded that once-monthly oral ibandronate is well tolerated and provides significant reductions in bone resorption in postmenopausal women [3]. The data suggested that the Table 2 Baseline patient characteristics (safety population) [6] 2.5 mg (n = 395) Age (year) 66 Years since 18 menopause (year) Prior fracture 192 (48.9) (n, %) Lumbar spine (L2–L4) BMD (T-score) −3.3 Total hip BMD −1.8 T-score a sCTX (ng/ml) b 0.49 a b
NHANES III adjusted. Median values.
50 + 50 mg (n = 396) 66 19 183 (46.3)
−3.3 −1.8 0.52
100 mg (n = 396) 66 19 180 (45.5)
−3.3 −1.8 0.51
150 mg (n = 396) 66 18 186 (47.0)
−3.3 −1.8 0.50
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D.M. Reid / Bone 38 (2006) S18–S22
once-monthly vs. 2.5 mg daily oral ibandronate, the slightly higher total doses of the monthly regimen reflecting the possibilities of enhanced effect with a higher total dose and diminution of effect later in the month. The primary endpoint was the change (%) from baseline in lumbar spine BMD after 1 year [6]. Full details of the study methodology have previously been described and discussed [6,10]. Briefly, patients were randomized to receive either daily oral ibandronate (2.5 mg) or once-monthly oral ibandronate at doses of 50 + 50 mg (single doses on consecutive days), 100 mg or 150 mg. Daily calcium (500 mg) and vitamin D supplements (400 IU) were provided to all patients. Results
Fig. 2. Increases in lumbar spine BMD with once-monthly ibandronate at 1 and 2 years [6,11].
higher dose-containing arms (100 mg and 150 mg) had potential for clinical efficacy and therefore warranted further clinical study. The MOBILE study MOBILE (Monthly Oral iBandronate in LadiEs) is a randomized, double-blind, phase III, non-inferiority study [6]. The study was designed following the ‘bridging’ concept previously utilized with other bisphosphonates. Initial regulatory approval of a bisphosphonate, from an efficacy perspective, is based upon demonstration of fracture risk reduction, i.e. in the case of ibandronate, with the daily oral regimen (vertebral fracture risk reduction of 62% after 3 years) [2]. This regimen will represent the ‘reference regimen’. Subsequent approval of a new regimen may then be obtained based upon successful completion of an equivalence or non-inferiority study that compares the reference regimen with the new regimen [7], using a validated surrogate marker for fracture efficacy. Comparable fracture efficacy is inferred if statistical equivalence or noninferiority is demonstrated with the new regimen. BMD is an accepted surrogate marker for fracture risk reduction with bisphosphonates and is endorsed by the Food and Drug Administration (USA) and European Medicines Agency (EU). Approvals for weekly alendronate and risedronate (USA and EU) have been obtained using this methodology [8,9]. The primary objective of the MOBILE study was to demonstrate the non-inferiority of 100 mg and/or 150 mg
The MOBILE study recruited 1609 women with osteoporosis, aged 55–80 years, at least 5 years since menopause. All patients had a baseline lumbar spine (L2–L4) BMD T-score of between <−2.5 and ≥−5. Patients were randomly assigned to one of the treatment arms, and baseline characteristics were evenly distributed (Table 2) [6]. Of the 1609 patients commencing the study, 1366 completed 1 year of treatment, with 1291 completing 2 years and 292 (18.1%) participants withdrawing from the study [6,10]. The per-protocol (PP) population was used as the primary analysis population for all efficacy parameters as this was considered the most conservative approach to detecting actual differences among treatments when performing a noninferiority analysis [7]. The PP population consisted of all those participants who were randomized, received at least one dose of study medication and had at least one efficacy follow-up data point without major protocol violations at baseline or during the first year of study. Efficacy At 1 and 2 years, substantial increases in lumbar spine BMD were observed in all treatment groups (Fig. 2, Table 3) [6,11]. All of the once-monthly regimens were prospectively proven non-inferior and thus shown to be at least as effective as the daily regimen (Fig. 3). The greatest gains in lumbar spine BMD were seen consistently with the 150 mg regimen; this regimen was also, in contrast to the other monthly doses, proven to be superior to the daily regimen at both time points (P ≤ 0.002). At 1 and 2 years 150 mg was also proven statistically superior to the 100 mg dose (P = 0.024 and P = 0.011, respectively). Considerable increases in all treatment arms were also noted for proximal femur BMD (total hip, trochanter and femoral
Table 3 Mean (%) change from baseline in lumbar spine and proximal femur BMD at 2 years (PP population) (figures in parentheses relate to 95% CI of difference in means between each of the once-monthly regimens and the daily regimen) [11]
Lumbar spine Total hip Trochanter Femoral neck
2.5 mg (n = 317)
50 + 50 mg (n = 324)
100 mg (n = 313)
150 mg (n = 323)
5.0 2.5 4.0 1.9
5.3 2.8 4.6 2.1
5.6 (−0.142, 1.349) 3.5 (0.555, 1.572) 5.3 (0.615, 2.083) 2.6 (0.078, 1.414)
6.6 (0.835, 2.307) 4.2 (1.198, 2.203) 6.2 (1.459, 2.909) 3.1 (0.589, 1.909)
(−0.335, 1.133) (−0.142, 0.862) (−0.073, 1.376) (−0.468, 0.851)
D.M. Reid / Bone 38 (2006) S18–S22
Fig. 3. Once-monthly oral ibandronate is non-inferior to daily for increase in lumbar spine BMD [6,11].
neck) (Table 3) [6,11]. At the 1- and 2-year analyses, proximal femur BMD increases in the once-monthly treatment groups were numerically greater than in the daily group. As at the lumbar spine, the most substantial increases in hip BMD were observed with the 150 mg regimen. Post hoc analyses have confirmed that both the 100 mg and 150 mg regimens produced superior increases in total hip (P < 0.0001), femoral neck (P ≤ 0.029) and trochanter BMD (P < 0.0001) compared with the daily regimen (Table 3). At 1 and 2 years, independent of the ibandronate dosing regimen, most participants were classed as responders to treatment, with lumbar spine BMD, total hip BMD or both increased above baseline (Year 1: 65.6–90.8%; Year 2: 70.5– 93.5%) [6,11]. A significantly greater number of participants in the 150 mg once-monthly group responded to treatment at 1 and 2 years, with increases in lumbar spine BMD, total hip BMD or both above baseline, compared with the daily treatment group (P < 0.05). The same dose-dependent pattern of response was seen with target increases in lumbar spine (≥6%; Year 1: 24.2– 34.4%; Year 2: 35.4–54.3%) or total hip (≥3%; Year 1: 34.0– 47.8%; Year 2: 40.4–65.1%) BMD. The highest responder rates were consistently observed with the 150 mg regimen (P < 0.05 vs. daily for all responder analyses at 1 and 2 years). Substantial reductions in sCTX were noted as early as 3 months following treatment commencement with all regimens [6]. These decreases in sCTX were then maintained throughout the 2 years of the study [11]. Consistent with the changes from baseline reported for BMD, the 150 mg regimen produced the largest median reduction in sCTX when compared with the daily regimen (150 mg, 3 months: 66.4%, 2 years: 67.7%; 2.5 mg, 3 months: 53.6%, 2 years: 61.5%). Not only did the 150 mg regimen produce the largest reductions in sCTX, but also significantly more patients responded to the 150 mg regimen with reductions from baseline of ≤−30% and ≤−50% (P ≤ 0.003 vs. daily ibandronate). Tolerability After 2 years, the daily and once-monthly ibandronate regimens were similarly well tolerated [6,11]. The incidence of overall adverse events and those considered drug-related was comparable across the four groups (Table 4). The number of
S21
drug-related adverse events leading to withdrawal from treatment was low and showed little variance between groups. The number of serious adverse events determined by the investigator to be at least possibly related to treatment was <1% in all groups (Table 4). Although patients with a history of upper GI disease were not excluded from the study, upper GI tolerability was similar across the treatment arms, with between 20 and 26% of patients reporting such adverse events [11]. These event rates are very similar to those which occurred during the BONE study where the placebo, daily and intermittent arms experienced similar upper GI adverse events in 27.4%, 25.4% and 25.0% respectively [12]. These events were generally mild to moderate in severity. The number of clinical osteoporotic fractures and non-vertebral osteoporotic fractures was low and comparable across the treatment groups. Discussion Significant antifracture efficacy, a characteristic of the nitrogen-containing bisphosphonate class, has previously been demonstrated with daily and also the novel intermittent (>2 months dose-free interval) oral ibandronate regimen [2]. The MOPS study demonstrated that, based upon reductions in uCTX and sCTX, a simplified once-monthly oral ibandronate regimen was feasible [3]. The MOBILE study has subsequently proven that once-monthly ibandronate is at least as effective as daily oral ibandronate in increasing bone mass and reducing bone resorption after 1 and 2 years [6,11]. As might be expected with the higher total dose, the 150 mg once-monthly regimen consistently produced greater gains in BMD and reductions in biochemical markers of bone turnover when compared with the daily dose. By inference, the vertebral antifracture efficacy associated with daily oral ibandronate [2] can also be expected with once-monthly ibandronate. Once-monthly oral ibandronate (150 mg), which has been approved in the US and Europe for the treatment and prevention of postmenopausal osteoporosis, is therefore an effective treatment option. Following a detailed review of the safety profiles of the treatment regimens used in the MOBILE study, it can be Table 4 Adverse event incidence (n, %) for daily and once-monthly ibandronate administered over 2 years [11] 2.5 mg (n = 395) Any adverse event Any drug-related adverse event Any drug-related adverse event leading to withdrawal Any serious adverse event Any drug-related serious adverse event Any drug-related serious adverse event leading to withdrawal
50 + 50 mg (n = 396)
302 (76.5) 313 (79.0) 128 (32.4) 119 (30.1)
100 mg (n = 396)
150 mg (n = 396)
318 (80.3) 317 (80.1) 143 (36.1) 146 (36.9)
30 (7.6)
20 (5.1)
26 (6.6)
27 (6.8)
38 (9.6)
54 (13.6)
55 (13.9)
45 (11.4)
2 (0.5)
2 (0.5)
3 (0.8)
1 (0.3)
1 (0.3)
1 (0.3)
0
1 (0.3)
S22
D.M. Reid / Bone 38 (2006) S18–S22
concluded that once-monthly ibandronate has comparable safety to daily oral ibandronate [11]. This is noteworthy as daily oral ibandronate has previously demonstrated a safety profile similar to placebo [2]. The safety data from the BONE, MOPS and MOBILE studies provide a comprehensive overview of the ibandronate safety profile. Daily, intermittent and once-monthly oral ibandronate treatment regimens have consistently demonstrated good tolerability following 2–3 years of administration [2,3,11]. In the absence of comparative studies, previously conducted systematic reviews and meta-analyses have concluded that efficacy among the available nitrogen-containing bisphosphonates is comparable, despite nominal differences between their respective data sets [13–15]. Given the antifracture efficacy demonstrated with the daily and intermittent ibandronate regimens (discussed further in the article by Cooper) [2] and the substantial increases in BMD, reductions in bone turnover and number of patient responders following once-monthly ibandronate administration [6], it seems reasonable to assume that ibandronate shares comparable efficacy with the currently available bisphosphonates. Patient preference studies indicate that once-monthly compared with weekly dosing is more convenient and more likely to encourage patients to remain on therapy for longer [16,17], which is a currently unmet need in osteoporosis management. Given the impact of patient preference on therapeutic adherence, it is anticipated that taking only one tablet per month will make it easier for patients to stay on therapy. Once-monthly oral ibandronate will therefore provide an effective, well-tolerated and practical alternative to currently available daily and weekly bisphosphonates. References [1] Bauss F, Russell RGG. Ibandronate in osteoporosis: preclinical data and rationale for intermittent dosing. Osteoporos Int 2004;15:423–33. [2] Chesnut III CH, Skag A, Christiansen C, Recker RR, Stakkestad JA, Hoiseth A, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004;19:1241–9. [3] Reginster JY, Wilson KM, Dumont E, Bonvoisin B, Barrett J. Monthly oral ibandronate is well tolerated and efficacious in postmenopausal women: results from the monthly oral pilot study. J Clin Endocrinol Metab 2005;90:5018–24.
[4] Gieschke R, Reginster J-Y. Successful prediction of the effect of oncemonthly oral ibandronate on a marker of bone resorption using clinical trial simulation (CTS). Osteoporos Int 2004;15(Suppl 1):S97 [Abstract P359SU]. [5] Barrett J, Worth E, Bauss F, Epstein S. Ibandronate: a clinical pharmacological and pharmacokinetic update. J Clin Pharmacol 2004;44:951–65. [6] Miller PD, McClung MR, Macovei L, Stakkestad JA, Luckey M, Bonvoisin B, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res 2005;20:1315–22. [7] ICH harmonized tripartite guideline. Statistical principles for clinical trials. Stat Med 1999;18:1905–42. [8] Harris ST, Watts NB, Li Z, Chines AA, Hanley DA, Brown JP. Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis. Curr Med Res Opin 2004;20:757–64. [9] Rizzoli R, Greenspan SL, Bone G, Schnitzer TJ, Watts NB, Adami S, et al. Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 2002;17:1988–96. [10] Reginster J-Y, Felsenberg D, Cooper C, Stakkestad JA, Miller PD, Kendler DL, et al. A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate. Osteoporos Int 2006;17:159–66. [11] Reginster J-Y, Adami S, Lakatos P, et al. Efficacy and tolerability of oncemonthly oral ibandronate in postmenopausal osteoporosis: 2-year results from the MOBILE study. Ann Rheum Dis 2006, doi:10.1136/ard.2005.044958. [12] Rosen CJ, Delmas PD, Emkey R, Gilbride J, Schimmer RC, Leishman B. Favorable upper gastrointestinal safety profile of ibandronate in patients with a history of gastrointestinal disorders or receiving concomitant NSAIDs. Arthritis Rheum 2003;48(Suppl 9):S84–5 [Abstract 102]. [13] Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23:570–8. [14] Kanis JA, Brazier JE, Stevenson M, Calvert MW, Lioyd Jones M. Treatment of established osteoporosis: a systematic review and cost-utility analysis. Health Technol Assess 2002;6:1–146. [15] Stevenson M, Lloyd-Jones M, Brazier J, Oakley J, Peters J, Brewer N, The clinical effectiveness and cost effectiveness of prevention and treatment of osteoporosis. Report commissioned by the NHS R&D HTA Programme, on behalf of the National Institute of Clinical Excellence; 2003. [16] Simon J, Beusterien KM, Kline Leidy N, et al. Women with postmenopausal osteoporosis express a preference for once-monthly versus once-weekly bisphosphonate treatment. Female Patient 2005;30:31–6. [17] Emkey R, Binkley N, Seidman L, Rosen C. BALTO I: women treated for osteoporosis rate preference and convenience for once-monthly ibandronate versus once-weekly alendronate. J Bone Miner Res 2005;20(Suppl 1): S416 [Abstract M435].
Once-monthly dosing: An effective step forward D.M. Reid ⁎ Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, UK Received 25 October 2005; revised 2 November 2005; accepted 26 January 2006
Abstract To improve upon the currently suboptimal level of therapeutic adherence with bisphosphonates in postmenopausal osteoporosis, there is a need to examine less-frequently dosed regimens that offer patients greater convenience than weekly dosing. Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for administration with long between-dose intervals. It has proven antifracture efficacy when administered orally, daily or intermittently (>2 months dose-free interval) and a safety profile comparable with placebo. A dose-ranging study evaluating a simplified once-monthly ibandronate dosing schedule confirmed the feasibility of the regimen. Significant decreases from baseline in the biochemical markers of bone turnover, serum and urinary C-telopeptide of the α-chain of type 1 collagen (CTX) were observed for all once-monthly doses assessed. An analysis of the area under the effect curve for these two parameters confirmed a dose–response relationship. The MOBILE study was a large (n = 1609), randomized, double-blind, non-inferiority study comparing three doses of monthly oral ibandronate (50 + 50 mg, 100 mg and 150 mg) with daily oral ibandronate (2.5 mg) in women with postmenopausal osteoporosis. Analyses have been completed at the end of 1 and 2 years of treatment. With substantial increases in lumbar spine bone mineral density (BMD; 5.3–6.6%), all of the once-monthly regimens were non-inferior, and, in addition, the 150 mg regimen was superior (P ≤ 0.002) to the daily regimen. Corresponding increases in BMD were also observed at all hip sites. The greatest gains in lumbar spine, and hip BMD were consistently seen with the 150 mg regimen. Considerable reductions in serum CTX were seen with all regimens from 3 months onwards (50.0–66.4%); these reductions were maintained throughout the 2-year period (2 years: 56.1–67.7%). The safety profile of the once-monthly regimens was comparable with the daily regimen throughout the 2 years. Once-monthly ibandronate is an effective and well-tolerated treatment for patients with postmenopausal osteoporosis. Given the recently reported strong patient preference for once-monthly regimens and the impact of patient preference on therapeutic adherence, it is anticipated that once-monthly ibandronate will offer patients an alternative convenient regimen that may improve adherence over weekly bisphosphonates and should enhance outcomes. © 2006 Elsevier Inc. All rights reserved. Keywords: Bisphosphonate; Ibandronate; Once-monthly; Osteoporosis; Postmenopausal
Introduction Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for administration with long betweendose intervals. The substantial ibandronate preclinical program demonstrated the potential for less frequent administration, demonstrating efficacy in three animal models of estrogen depletion: rat, dog and monkey [1]. With this evidence and the positive results reported with the intermittent regimen used in ⁎ Fax: +44 1224 554615. E-mail address: [email protected]. 8756-3282/$ - see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2006.01.153
the BONE (Oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) study, which demonstrated a significant vertebral fracture risk reduction of 50% [2], a phase I study was initiated to assess a patient-friendly and convenient once-monthly regimen of ibandronate. The MOPS study The MOPS (Monthly Oral Pilot Study) study was a randomized, 3-month, double-blind, placebo-controlled, doseranging trial [3]. Women, aged 55–80 years, at least 3 years postmenopause were randomized to receive three cycles of
D.M. Reid / Bone 38 (2006) S18–S22
S19
Table 1 Median change (%) from baseline in sCTX and uCTX: the MOPS study [3] Placebo (n = 36) sCTX −12.3 uCTX −5.5
50 mg (n = 18)
50/100 mg (n = 18)
100 mg (n = 36)
150 mg (n = 36)
−22.3 −13.4
−49.6 ⁎ −54.8 ⁎
−40.7 ⁎ −34.6 ⁎
−56.7 ⁎ −54.1 ⁎
⁎ P < 0.001 vs. placebo.
once-monthly ibandronate at doses of 50 mg, 100 mg or 150 mg or placebo. In the BONE study [2], a regimen with an extended (>2 months) dose-free interval using a similar cumulative dose as the daily administration resulted in comparable antifracture efficacy, which is consistent with the concept that it is the total dose that determines response [1]. However, on the basis of modeling and simulation data [4], it was considered appropriate for efficacy optimization in the MOPS study to assess oncemonthly doses beyond that provided by the cumulative daily dose (>75 mg). The aims of the MOPS study were to assess the safety, tolerability, pharmacodynamics and pharmacokinetics of the three regimens. No specific lumbar spine bone mineral density (BMD) inclusion criteria were set, and supplementary calcium and vitamin D were not provided. The 50 mg arm was split into two arms (50 mg or 100 mg) after the first dosing cycle to separate the effects of dose and first-time treatment. Participants were instructed to take their medication with 250 ml (8 oz) of plain water following an overnight fast of at least 6 h. Following dosing, participants were to remain in an upright position for 60 min, with a standardized breakfast provided 1 h after dosing. A total of 144 participants were randomized and received at least one dose of study medication [3]. The treatment groups were well-balanced in terms of baseline age, weight and height. Without a specific inclusion criterion for BMD, baseline BMD status was varied, with some participants having normal Tscores, while others were considered either osteopenic (Tscore ≤ −1 to −2.5) or osteoporotic (T-score ≤ −2.5). Overall, the three doses of once-monthly oral ibandronate were well tolerated, with a safety profile similar to placebo [3]. No differences were observed in the number of participants with adverse events considered drug-related [n = 3 (8%) for placebo; n = 3 (17%) for 50 mg dose; n = 0 for 50/50 mg dose; n = 2 (6%) for 100 mg dose; and n = 2 for and 150 mg dose regimen). Only four participants withdrew from the study due to adverse events (placebo group = 3, 150 mg group = 1), and, of these, only one patient had an adverse event considered drug-related (placebo group). The total number of upper gastrointestinal (GI) adverse events was slightly higher in the 100 mg and 150 mg groups (15 events per group vs. 12, 3 and 11 in the placebo, 50 mg and 50/ 100 mg groups, respectively). However, the number occurring within 3 days of treatment administration, which is likely to reflect a treatment-related effect, was comparable (6, 0, 4, 8 and 9 events in the placebo, 50 mg, 50/100 mg, 100 mg and 150 mg groups, respectively). There were no serious adverse events reported in this short study giving encouragement to proceed with further studies with monthly regimens. Baseline serum and urine concentrations of the C-telopeptide of the α-chain of type 1 collagen (CTX), a biochemical marker
Fig. 1. Dose-dependent reduction of bone resorption associated with oncemonthly ibandronate [3]. Copyright 2005. The Endocrine Society.
of bone resorption, were similar across the treatment groups [3]. As can be seen in Table 1, ibandronate significantly reduced the primary pharmacodynamic endpoint, bone turnover, with substantial reductions in serum CTX (sCTX) and urinary CTX (uCTX) recorded at day 91 (compared with baseline levels (P < 0.0001). Compared with placebo, the difference in median reduction was significant for all of the dose groups except the 50 mg group (P < 0.001). A dose–response relationship was demonstrated following analysis of the area under the effect curve (day 1–91) for relative change (% × days) in sCTX and uCTX for once-monthly treatment (Fig. 1). Compared to the 50 mg dose systemic exposure (AUC0–∞) with 100 mg and 150 mg ibandronate increased significantly as assessed by ANOVA. The AUC0–∞ were 130% (95% CI: 94, 180%) and 191% (95% CI: 138, 265%) for the 100 mg and 150 mg arms, respectively. The results for the 50 mg and 50/ 100 mg dose groups were consistent with those previously seen for ibandronate [5]. It was concluded that once-monthly oral ibandronate is well tolerated and provides significant reductions in bone resorption in postmenopausal women [3]. The data suggested that the Table 2 Baseline patient characteristics (safety population) [6] 2.5 mg (n = 395) Age (year) 66 Years since 18 menopause (year) Prior fracture 192 (48.9) (n, %) Lumbar spine (L2–L4) BMD (T-score) −3.3 Total hip BMD −1.8 T-score a sCTX (ng/ml) b 0.49 a b
NHANES III adjusted. Median values.
50 + 50 mg (n = 396) 66 19 183 (46.3)
−3.3 −1.8 0.52
100 mg (n = 396) 66 19 180 (45.5)
−3.3 −1.8 0.51
150 mg (n = 396) 66 18 186 (47.0)
−3.3 −1.8 0.50
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D.M. Reid / Bone 38 (2006) S18–S22
once-monthly vs. 2.5 mg daily oral ibandronate, the slightly higher total doses of the monthly regimen reflecting the possibilities of enhanced effect with a higher total dose and diminution of effect later in the month. The primary endpoint was the change (%) from baseline in lumbar spine BMD after 1 year [6]. Full details of the study methodology have previously been described and discussed [6,10]. Briefly, patients were randomized to receive either daily oral ibandronate (2.5 mg) or once-monthly oral ibandronate at doses of 50 + 50 mg (single doses on consecutive days), 100 mg or 150 mg. Daily calcium (500 mg) and vitamin D supplements (400 IU) were provided to all patients. Results
Fig. 2. Increases in lumbar spine BMD with once-monthly ibandronate at 1 and 2 years [6,11].
higher dose-containing arms (100 mg and 150 mg) had potential for clinical efficacy and therefore warranted further clinical study. The MOBILE study MOBILE (Monthly Oral iBandronate in LadiEs) is a randomized, double-blind, phase III, non-inferiority study [6]. The study was designed following the ‘bridging’ concept previously utilized with other bisphosphonates. Initial regulatory approval of a bisphosphonate, from an efficacy perspective, is based upon demonstration of fracture risk reduction, i.e. in the case of ibandronate, with the daily oral regimen (vertebral fracture risk reduction of 62% after 3 years) [2]. This regimen will represent the ‘reference regimen’. Subsequent approval of a new regimen may then be obtained based upon successful completion of an equivalence or non-inferiority study that compares the reference regimen with the new regimen [7], using a validated surrogate marker for fracture efficacy. Comparable fracture efficacy is inferred if statistical equivalence or noninferiority is demonstrated with the new regimen. BMD is an accepted surrogate marker for fracture risk reduction with bisphosphonates and is endorsed by the Food and Drug Administration (USA) and European Medicines Agency (EU). Approvals for weekly alendronate and risedronate (USA and EU) have been obtained using this methodology [8,9]. The primary objective of the MOBILE study was to demonstrate the non-inferiority of 100 mg and/or 150 mg
The MOBILE study recruited 1609 women with osteoporosis, aged 55–80 years, at least 5 years since menopause. All patients had a baseline lumbar spine (L2–L4) BMD T-score of between <−2.5 and ≥−5. Patients were randomly assigned to one of the treatment arms, and baseline characteristics were evenly distributed (Table 2) [6]. Of the 1609 patients commencing the study, 1366 completed 1 year of treatment, with 1291 completing 2 years and 292 (18.1%) participants withdrawing from the study [6,10]. The per-protocol (PP) population was used as the primary analysis population for all efficacy parameters as this was considered the most conservative approach to detecting actual differences among treatments when performing a noninferiority analysis [7]. The PP population consisted of all those participants who were randomized, received at least one dose of study medication and had at least one efficacy follow-up data point without major protocol violations at baseline or during the first year of study. Efficacy At 1 and 2 years, substantial increases in lumbar spine BMD were observed in all treatment groups (Fig. 2, Table 3) [6,11]. All of the once-monthly regimens were prospectively proven non-inferior and thus shown to be at least as effective as the daily regimen (Fig. 3). The greatest gains in lumbar spine BMD were seen consistently with the 150 mg regimen; this regimen was also, in contrast to the other monthly doses, proven to be superior to the daily regimen at both time points (P ≤ 0.002). At 1 and 2 years 150 mg was also proven statistically superior to the 100 mg dose (P = 0.024 and P = 0.011, respectively). Considerable increases in all treatment arms were also noted for proximal femur BMD (total hip, trochanter and femoral
Table 3 Mean (%) change from baseline in lumbar spine and proximal femur BMD at 2 years (PP population) (figures in parentheses relate to 95% CI of difference in means between each of the once-monthly regimens and the daily regimen) [11]
Lumbar spine Total hip Trochanter Femoral neck
2.5 mg (n = 317)
50 + 50 mg (n = 324)
100 mg (n = 313)
150 mg (n = 323)
5.0 2.5 4.0 1.9
5.3 2.8 4.6 2.1
5.6 (−0.142, 1.349) 3.5 (0.555, 1.572) 5.3 (0.615, 2.083) 2.6 (0.078, 1.414)
6.6 (0.835, 2.307) 4.2 (1.198, 2.203) 6.2 (1.459, 2.909) 3.1 (0.589, 1.909)
(−0.335, 1.133) (−0.142, 0.862) (−0.073, 1.376) (−0.468, 0.851)
D.M. Reid / Bone 38 (2006) S18–S22
Fig. 3. Once-monthly oral ibandronate is non-inferior to daily for increase in lumbar spine BMD [6,11].
neck) (Table 3) [6,11]. At the 1- and 2-year analyses, proximal femur BMD increases in the once-monthly treatment groups were numerically greater than in the daily group. As at the lumbar spine, the most substantial increases in hip BMD were observed with the 150 mg regimen. Post hoc analyses have confirmed that both the 100 mg and 150 mg regimens produced superior increases in total hip (P < 0.0001), femoral neck (P ≤ 0.029) and trochanter BMD (P < 0.0001) compared with the daily regimen (Table 3). At 1 and 2 years, independent of the ibandronate dosing regimen, most participants were classed as responders to treatment, with lumbar spine BMD, total hip BMD or both increased above baseline (Year 1: 65.6–90.8%; Year 2: 70.5– 93.5%) [6,11]. A significantly greater number of participants in the 150 mg once-monthly group responded to treatment at 1 and 2 years, with increases in lumbar spine BMD, total hip BMD or both above baseline, compared with the daily treatment group (P < 0.05). The same dose-dependent pattern of response was seen with target increases in lumbar spine (≥6%; Year 1: 24.2– 34.4%; Year 2: 35.4–54.3%) or total hip (≥3%; Year 1: 34.0– 47.8%; Year 2: 40.4–65.1%) BMD. The highest responder rates were consistently observed with the 150 mg regimen (P < 0.05 vs. daily for all responder analyses at 1 and 2 years). Substantial reductions in sCTX were noted as early as 3 months following treatment commencement with all regimens [6]. These decreases in sCTX were then maintained throughout the 2 years of the study [11]. Consistent with the changes from baseline reported for BMD, the 150 mg regimen produced the largest median reduction in sCTX when compared with the daily regimen (150 mg, 3 months: 66.4%, 2 years: 67.7%; 2.5 mg, 3 months: 53.6%, 2 years: 61.5%). Not only did the 150 mg regimen produce the largest reductions in sCTX, but also significantly more patients responded to the 150 mg regimen with reductions from baseline of ≤−30% and ≤−50% (P ≤ 0.003 vs. daily ibandronate). Tolerability After 2 years, the daily and once-monthly ibandronate regimens were similarly well tolerated [6,11]. The incidence of overall adverse events and those considered drug-related was comparable across the four groups (Table 4). The number of
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drug-related adverse events leading to withdrawal from treatment was low and showed little variance between groups. The number of serious adverse events determined by the investigator to be at least possibly related to treatment was <1% in all groups (Table 4). Although patients with a history of upper GI disease were not excluded from the study, upper GI tolerability was similar across the treatment arms, with between 20 and 26% of patients reporting such adverse events [11]. These event rates are very similar to those which occurred during the BONE study where the placebo, daily and intermittent arms experienced similar upper GI adverse events in 27.4%, 25.4% and 25.0% respectively [12]. These events were generally mild to moderate in severity. The number of clinical osteoporotic fractures and non-vertebral osteoporotic fractures was low and comparable across the treatment groups. Discussion Significant antifracture efficacy, a characteristic of the nitrogen-containing bisphosphonate class, has previously been demonstrated with daily and also the novel intermittent (>2 months dose-free interval) oral ibandronate regimen [2]. The MOPS study demonstrated that, based upon reductions in uCTX and sCTX, a simplified once-monthly oral ibandronate regimen was feasible [3]. The MOBILE study has subsequently proven that once-monthly ibandronate is at least as effective as daily oral ibandronate in increasing bone mass and reducing bone resorption after 1 and 2 years [6,11]. As might be expected with the higher total dose, the 150 mg once-monthly regimen consistently produced greater gains in BMD and reductions in biochemical markers of bone turnover when compared with the daily dose. By inference, the vertebral antifracture efficacy associated with daily oral ibandronate [2] can also be expected with once-monthly ibandronate. Once-monthly oral ibandronate (150 mg), which has been approved in the US and Europe for the treatment and prevention of postmenopausal osteoporosis, is therefore an effective treatment option. Following a detailed review of the safety profiles of the treatment regimens used in the MOBILE study, it can be Table 4 Adverse event incidence (n, %) for daily and once-monthly ibandronate administered over 2 years [11] 2.5 mg (n = 395) Any adverse event Any drug-related adverse event Any drug-related adverse event leading to withdrawal Any serious adverse event Any drug-related serious adverse event Any drug-related serious adverse event leading to withdrawal
50 + 50 mg (n = 396)
302 (76.5) 313 (79.0) 128 (32.4) 119 (30.1)
100 mg (n = 396)
150 mg (n = 396)
318 (80.3) 317 (80.1) 143 (36.1) 146 (36.9)
30 (7.6)
20 (5.1)
26 (6.6)
27 (6.8)
38 (9.6)
54 (13.6)
55 (13.9)
45 (11.4)
2 (0.5)
2 (0.5)
3 (0.8)
1 (0.3)
1 (0.3)
1 (0.3)
0
1 (0.3)
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concluded that once-monthly ibandronate has comparable safety to daily oral ibandronate [11]. This is noteworthy as daily oral ibandronate has previously demonstrated a safety profile similar to placebo [2]. The safety data from the BONE, MOPS and MOBILE studies provide a comprehensive overview of the ibandronate safety profile. Daily, intermittent and once-monthly oral ibandronate treatment regimens have consistently demonstrated good tolerability following 2–3 years of administration [2,3,11]. In the absence of comparative studies, previously conducted systematic reviews and meta-analyses have concluded that efficacy among the available nitrogen-containing bisphosphonates is comparable, despite nominal differences between their respective data sets [13–15]. Given the antifracture efficacy demonstrated with the daily and intermittent ibandronate regimens (discussed further in the article by Cooper) [2] and the substantial increases in BMD, reductions in bone turnover and number of patient responders following once-monthly ibandronate administration [6], it seems reasonable to assume that ibandronate shares comparable efficacy with the currently available bisphosphonates. Patient preference studies indicate that once-monthly compared with weekly dosing is more convenient and more likely to encourage patients to remain on therapy for longer [16,17], which is a currently unmet need in osteoporosis management. Given the impact of patient preference on therapeutic adherence, it is anticipated that taking only one tablet per month will make it easier for patients to stay on therapy. Once-monthly oral ibandronate will therefore provide an effective, well-tolerated and practical alternative to currently available daily and weekly bisphosphonates. References [1] Bauss F, Russell RGG. Ibandronate in osteoporosis: preclinical data and rationale for intermittent dosing. Osteoporos Int 2004;15:423–33. [2] Chesnut III CH, Skag A, Christiansen C, Recker RR, Stakkestad JA, Hoiseth A, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 2004;19:1241–9. [3] Reginster JY, Wilson KM, Dumont E, Bonvoisin B, Barrett J. Monthly oral ibandronate is well tolerated and efficacious in postmenopausal women: results from the monthly oral pilot study. J Clin Endocrinol Metab 2005;90:5018–24.
[4] Gieschke R, Reginster J-Y. Successful prediction of the effect of oncemonthly oral ibandronate on a marker of bone resorption using clinical trial simulation (CTS). Osteoporos Int 2004;15(Suppl 1):S97 [Abstract P359SU]. [5] Barrett J, Worth E, Bauss F, Epstein S. Ibandronate: a clinical pharmacological and pharmacokinetic update. J Clin Pharmacol 2004;44:951–65. [6] Miller PD, McClung MR, Macovei L, Stakkestad JA, Luckey M, Bonvoisin B, et al. Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone Miner Res 2005;20:1315–22. [7] ICH harmonized tripartite guideline. Statistical principles for clinical trials. Stat Med 1999;18:1905–42. [8] Harris ST, Watts NB, Li Z, Chines AA, Hanley DA, Brown JP. Two-year efficacy and tolerability of risedronate once a week for the treatment of women with postmenopausal osteoporosis. Curr Med Res Opin 2004;20:757–64. [9] Rizzoli R, Greenspan SL, Bone G, Schnitzer TJ, Watts NB, Adami S, et al. Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 2002;17:1988–96. [10] Reginster J-Y, Felsenberg D, Cooper C, Stakkestad JA, Miller PD, Kendler DL, et al. A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate. Osteoporos Int 2006;17:159–66. [11] Reginster J-Y, Adami S, Lakatos P, et al. Efficacy and tolerability of oncemonthly oral ibandronate in postmenopausal osteoporosis: 2-year results from the MOBILE study. Ann Rheum Dis 2006, doi:10.1136/ard.2005.044958. [12] Rosen CJ, Delmas PD, Emkey R, Gilbride J, Schimmer RC, Leishman B. Favorable upper gastrointestinal safety profile of ibandronate in patients with a history of gastrointestinal disorders or receiving concomitant NSAIDs. Arthritis Rheum 2003;48(Suppl 9):S84–5 [Abstract 102]. [13] Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev 2002;23:570–8. [14] Kanis JA, Brazier JE, Stevenson M, Calvert MW, Lioyd Jones M. Treatment of established osteoporosis: a systematic review and cost-utility analysis. Health Technol Assess 2002;6:1–146. [15] Stevenson M, Lloyd-Jones M, Brazier J, Oakley J, Peters J, Brewer N, The clinical effectiveness and cost effectiveness of prevention and treatment of osteoporosis. Report commissioned by the NHS R&D HTA Programme, on behalf of the National Institute of Clinical Excellence; 2003. [16] Simon J, Beusterien KM, Kline Leidy N, et al. Women with postmenopausal osteoporosis express a preference for once-monthly versus once-weekly bisphosphonate treatment. Female Patient 2005;30:31–6. [17] Emkey R, Binkley N, Seidman L, Rosen C. BALTO I: women treated for osteoporosis rate preference and convenience for once-monthly ibandronate versus once-weekly alendronate. J Bone Miner Res 2005;20(Suppl 1): S416 [Abstract M435].