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sanofi-aventis,. Bridgewater, NJ, USA. R. Eusebio. Procter & Gamble Pharmaceuticals,. Mason, OH, USA. J. Zanchetta. Instituto de Investigaciones Metabolicas,.
Osteoporos Int DOI 10.1007/s00198-007-0531-9

ORIGINAL ARTICLE

Monthly dosing of 75 mg risedronate on 2 consecutive days a month: efficacy and safety results P. D. Delmas & C. L. Benhamou & Z. Man & W. Tlustochowicz & E. Matzkin & R. Eusebio & J. Zanchetta & W. P. Olszynski & R. R. Recker & M. R. McClung

Received: 31 July 2007 / Accepted: 8 November 2007 # International Osteoporosis Foundation and National Osteoporosis Foundation 2007

Abstract Summary Postmenopausal women with osteoporosis received 75 mg risedronate on two consecutive days each month or 5 mg daily for 12 months. Changes in bone mineral density and bone turnover markers were similar between treatments. Risedronate 75 mg twice monthly was effective and safe suggesting a new, convenient dosing schedule. Introduction Patients perceive less frequent dosing as being more convenient. This 2-year trial evaluates the efficacy and safety of a new monthly oral regimen of risedronate; 1 year results are presented here. Methods Postmenopausal women with osteoporosis (n= 1229) were randomly assigned to double-blind treatment with 75 mg risedronate on two consecutive days each month (2CDM), or 5 mg daily. The primary endpoint was

the percent change from baseline in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary efficacy was evaluated by mean percent changes from baseline in BMD in LS, total hip, trochanter, and femoral neck, and bone turnover markers (BTMs). Results Risedronate 75 mg 2CDM was non-inferior to 5 mg daily (treatment difference 0.21; 95% CI -0.19 to 0.62). Mean percent change in LS-BMD was 3.4%±0.16 and 3.6%±0.15 respectively. Mean percent changes in BMD and BTMs were significant and similar for both treatment groups. New vertebral fractures occurred in 1% of subjects with either treatment. Both treatments were generally well tolerated and safe. Conclusions Risedronate 75 mg 2CDM was non-inferior in efficacy and did not show a difference in safety vs. 5 mg daily after 12 months, leading to a similar benefit.

P. D. Delmas University of Lyon and INSERM Research Unit 831, Lyon, France

J. Zanchetta Instituto de Investigaciones Metabolicas, Universidad del Salvador, Buenos Aires, Argentina

C. L. Benhamou INSERM U658, Orléans, France Z. Man Centro Tiempo, Buenos Aires, Argentina W. Tlustochowicz Department of Internal Medicine and Rheumatology, Military Institut of Medicine, Warszawa, Poland E. Matzkin sanofi-aventis, Bridgewater, NJ, USA R. Eusebio Procter & Gamble Pharmaceuticals, Mason, OH, USA

W. P. Olszynski Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada R. R. Recker Osteoporosis Research Center, Creighton University, Omaha, NE, USA M. R. McClung Oregon Osteoporosis Center, Portland, OR, USA P. D. Delmas (*) Hopital Edouard Herriot, Pavillon F, Lyon, Cedex 03 69437, France e-mail: [email protected]

Osteoporos Int

Keywords Bisphosphonates . Bone mineral density . Bone turnover markers . Fracture . Osteoporosis . Postmenopausal

Introduction The prevalence of osteoporosis is estimated at over 200 million people worldwide [1]. In the United States and Europe, about 30% of all postmenopausal women are affected by osteoporosis [1]. As the population ages worldwide, the number of people with osteoporosis is expected to rise correspondingly. Current annual rates of osteoporotic fractures are estimated at around 1.5 million in the United States, and 3.8 million in Europe [1]. In 1990, the incidence of new hip fractures worldwide was 1.7 million, but this figure was estimated to increase to 2.6 million by 2025 [1]. Direct expenditure related to osteoporotic fractures was $17 billion in the United States in 2001; in the European Union costs were 32 billion in 2000 and expected to double by 2050 [1]. Treatment to decrease the risk of osteoporotic fractures may include bisphosphonates, raloxifene, teriparatide, estrogen, calcitonin, and strontium ranelate. Due to poor longterm adherence to medication therapies for chronic diseases, maximizing compliance should be a primary focus of clinical management [2]. Dosing frequency influences compliance and currently risedronate and alendronate are available as daily and weekly dosed products, whereas ibandronate is available as a monthly therapy [3–6]. Proven treatment efficacy, however, is another important factor that affects patient preference [7–9]. A monthly therapy with vertebral, nonvertebral, and hip fracture reduction efficacy would give physicians another treatment option. This study was designed to determine if risedronate (Actonel, Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA) could be effectively and safely administered as a monthly regimen. In controlled clinical trials, risedronate 5 mg daily decreased the risk of vertebral and nonvertebral fractures during the first year of treatment, and had a sustained effect for 5 years [10–12]. In the once a week trial of risedronate the incidence of new morphometric vertebral fractures (measured as a secondary endpoint), was similar among 5 mg daily, 35 mg once weekly, or 50 mg once weekly dosing [13]. After 3 years of risedronate treatment (2.5 or 5 mg daily) the risk of hip fractures was significantly reduced in women with established osteoporosis [14, 15]. In the current study, postmenopausal women with osteoporosis are currently being treated for up to 24 months with 75 mg risedronate taken on two consecutive days each month (2CDM), in order to achieve the same 30 day dose attained by taking 5 mg daily; this dosing regimen is one of the steps taken towards a once-a-month

dosing regimen of 150 mg risedronate [16]. This study was designed to test the non-inferiority of the monthly dosing regimen compared with the daily regimen, for increasing lumbar spine bone mass in postmenopausal women with osteoporosis. Furthermore, this study investigated the efficacy of risedronate 75 mg 2CDM for increasing bone mass in the hip, as well as decreasing bone resorption. Data of the 1 year results from this ongoing, 2-year, double-blind study are presented here.

Methods Study design This international, phase III, randomized, multicenter, doubleblind, active-controlled, parallel-group study was designed to compare two oral dosing regimens of risedronate for the treatment of postmenopausal osteoporosis. The trial was conducted in accordance with the guidelines of the International Conference on Harmonization for Good Clinical Practice, and the study protocol was approved by Independent Ethics Committees at each participating study center. Subjects Healthy, ambulatory women were eligible for inclusion in this study if they were at least 50 years old and were postmenopausal for 5 years or more. Eligible subjects were required to have osteoporosis as defined by lumbar spine Tscores of 10% of subjects in either treatment group) were similar for subjects in both treatment groups and included arthralgia (10.4% in the 75 mg 2CDM group, and 9.5% with 5 mg daily), and back pain (8.8% with 75 mg 2CDM, and 10.8% in the 5 mg daily group). Other TEAEs reported by >5% of subjects treated with both risedronate treatment groups were: dyspepsia; constipation; nausea; headache; diarrhea; influenza; urinary tract infection; nasopharyngitis; upper abdominal pain; and extremity pain. Fever or influenza-like illness occurring within the first 5 days of treatment and potentially representing acute phase reactions were experienced in a higher number of subjects in the group treated with risedronate 75 mg 2CDM (4

Osteoporos Int

b

Lumbar spine 4

3

2

75-mg 2CDM 5-mg daily

1

0 Baseline

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Mean change from baseline (%)

a Mean change from baseline (%)

Fig. 2 Mean percent change in bone mineral density of the lumbar spine, total hip, femoral neck, and trochanter 2CDM=two consecutive days each month

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Total hip 3

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1 75-mg 2CDM 5-mg daily 0 Baseline

d

Femoral neck 3

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1 75-mg 2CDM 5-mg daily 0 Baseline

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12

Mean change from baseline (%)

Mean change from baseline (%)

c

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Trochanter 4

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75-mg 2CDM 5-mg daily

1

0 Baseline

Time (months)

subjects), compared to the group taking 5 mg risedronate daily (0 subjects). The incidences of vertebral and non-vertebral fracture TEAEs were similar in the two treatment groups. Vertebral fractures reported as TEAEs (clinical fractures radiographically confirmed) occurred in 0.5% (n=3) of 75 mg 2CDM subjects and 0.7% (n=4) of 5 mg daily subjects. Nonvertebral fracture TEAEs were reported by 2.6% (n=16) of

6

Time (months)

Time (months)

6

12

Time (months)

subjects treated with risedronate 75 mg 2CDM, and 3.1% (n=19) of subjects treated with 5 mg daily.

Discussion Risedronate 75 mg 2CDM is non-inferior and is as well tolerated as 5 mg daily in postmenopausal women with

Table 2 Percent change in bone mineral density from baseline* Assessment

Lumbar spine BMD 6 months 12 months Total hip BMD 6 months 12 months Femoral neck BMD 6 months 12 months Trochanter BMD 6 months 12 months

n

75 mg 2CDM (% change)

n

5 mg daily (% change)

Least squares mean difference (95% CI)

540 524

2.4 3.4

544 527

2.7 3.6

0.3 (-0.08 to 0.68) 0.2 (-0.19 to 0.62)

542 515

1.4 2.1

551 520

1.5 1.9

0.2 (-0.14 to 0.46) -0.3 (-0.60 to 0.09)

542 515

1.0 1.6

551 520

0.8 1.2

-0.2 (-0.60 to 0.13) -0.5 (-0.88 to -0.04)

542 515

2.1 3.0

551 520

2.4 3.0

0.3 (-0.15 to 0.84) 0.1 (-0.47 to 0.62)

*Differences from baseline, unadjusted for multiple comparisons, were statistically significant for both 75 mg 2CDM, and 5 mg daily groups at each follow-up assessment. 2CDM=two consecutive days each month, BMD=bone mineral density, CI=confidence interval

Osteoporos Int

b

sBAP 0 75-mg 2CDM 5-mg daily

-5 -10 -15 -20 -25 -30 -35 -40 Baseline

3

6

12

Mean change from baseline (%)

a Mean change from baseline %

Fig. 3 Mean percent change from baseline in bone turnover markers 2CDM=two consecutive days each month, sBAP=bone-specific alkaline phosphatase, uNTX=urinary type 1 collagen N-telopeptide

uNTX/creatinine 0

-20 -30 -40 -50 -60 Baseline

Time (months)

osteoporosis. Non-inferiority in increasing lumbar spine BMD was demonstrated with 75 mg 2CDM of risedronate, which represents the same cumulative monthly dose of risedronate (150 mg) as the 5 mg daily dosing regimen. Secondary efficacy analyses similarly showed no clinically relevant differences between the 75 mg 2CDM and the 5 mg daily regimens of risedronate. In the current study, new vertebral fractures occurred after 12 months in only 1% of subjects treated with either risedronate dosing regimen. Treatment efficacy in the current study was similar to earlier reports with daily or weekly risedronate for both changes in BMD [3, 11, 13] and BTMs [3, 13]. Safety and tolerability were good for both risedronate dosing regimens, with comparable overall TEAEs, TEAEs leading to withdrawal, GI tolerability, fractures, and clinical laboratory data. Only 9% of subjects in either treatment group discontinued treatment prematurely due to an AE, most commonly GI-related. Furthermore, the incidence of TEAEs potentially associated with acute phase reactions was low in both dosing groups.

75-mg 2CDM 5-mg daily

-10

3

6

12

Time (months)

The major limitation to this study is that the primary efficacy measure was BMD, rather than the measure of vertebral and non-vertebral fractures. Risedronate has proven fracture reduction efficacy at the daily dose, and per US Food and Drug Administration and European Agency for the Evaluation of Medicinal Products guidelines, alternate dose forms can be approved based upon BMD. The occurrence of new fractures, however, was used as a secondary outcome measure in this study and showed no difference between the treatment groups. In conclusion, 75 mg of risedronate dosed orally on two consecutive days each month is non-inferior to the 5 mg daily regimen with regard to increasing lumbar spine BMD after 12 months of treatment in postmenopausal women with osteoporosis. Other efficacy measures, including other BMD measures, BTMs, and incident fractures did not show a difference, and significantly improved with either dosing regimen. The 75 mg 2CDM dosing regimen is generally as safe and as well tolerated as the 5 mg daily dosing regimen. These data support this monthly dosing regimen, which

Table 3 Overview of treatment-emergent adverse events (intent-to-treat population) Number of subjects (%)

All TEAEs Serious TEAEs Possibly or probably related serious TEAEs Withdrawn due to a TEAE Withdrawn due to a GI TEAE TEAEs resulting in death Adverse events of special interest Upper GI TEAEs Moderate to severe upper GI TEAEs Vertebral body clinical fracture TEAEs Non-vertebral clinical fracture TEAEs 2CDM=two consecutive days each month, GI=gastrointestinal

75 mg 2CDM (n=616)

5 mg daily (n=613)

522 (84.7) 46 (7.5) 4 (0.6) 55 (8.9) 35 (5.7) 2 (0.3)

498 (81.2) 29 (4.7) 3 (0.5) 54 (8.8) 30 (4.9) 3 (0.5)

137 (22.2) 46 (7.5) 3 (0.5) 16 (2.6)

130 (21.2) 38 (6.2) 4 (0.7) 19 (3.1)

Osteoporos Int

provides a similar benefit as daily therapy, and will offer additional treatment options with risedronate. Acknowledgements The following investigators participated in this study: Argentina: H. Salerni, L. Plantalech, C. Mautalen, Z. Man, J. Zanchetta; Australia: G. Nicholson, T. Diamond, P.S. Brook, S. Hall, P. Nach, J. Karash; Canada: L.G. SteMarie, J. Brown, D. Hanley, A. Hodsman, W. Olszynski, R. Josse, A. Kahn, J. Wade; Czech Republic: P. Kasalichy, V. Palicka, V. Kuba, V. Vyskocil; France: P.D. Delmas, G. Werhya, P. Fardellone, M. Laroche, C.L. Benhamou, M.C. DeVernejoul; United Kingdom: I. Caldwell, T. Maxwell, D. Dutchman; Poland: W. Tlustochowicz, J. Padzur, M. Korkosz, A. FillopowivzSosnowska; Turkey: P. Yalcin, N. Parker, B. Gulekli, C. Yilmaz, N. Dursun; Lebanon: G. Maalouf; United States: M. McClung, M. Greenwald, R. Emkey, W. Ellison, S. Cohen, R. Weinstein, D. Fiske, R. Recker, R. Ackerman, H. Greisberg, J. Funk, T. Hennessey; South Africa: T.J. deVilliers, S. Lipschitz, G.C. Ellis, M. Davey, A.J. de Weerd, S. Hough.

Funding Funding for this study was provided by the Alliance for Better Bone Health (Procter & Gamble Pharmaceuticals, Cincinnati, OH, USA, and sanofi-aventis, Paris, France). The authors received editorial/writing support in the preparation of this manuscript, funded by the Alliance for Better Bone Health. The authors were fully responsible for contents and editorial decisions for this manuscript.

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Conflict of interest statement Prof. P.D. Delmas has received consultant/honorarium fees and a research grant from Procter and Gamble/sanofi-aventis. Dr Benhamou has received advisory fees and for research grants from Amgen, Lilly, Merck, Novartis, Procter and Gamble, Roche, and Servier. Prof. Dr. Man has received consulting fees or advisory fees from Novartis and lectures fees from Aventis, sanofi-aventis and Roche. Dr. Tlustochowicz has received a research grant from Procter and Gamble/sanofi-aventis. Dr Matzkin is an employee of sanofi-aventis. Dr Eusebio is an employee of Procter and Gamble. Dr. Zanchetta has received consultant fees and/or research grants from Sanofi-Aventis, GlaxoSmithKline, Merck, Lilly, Wyeth, Amgen, Pfizer, Roche and Servier. Dr. Olszynski has received a research grant from Procter and Gamble/sanofi-aventis. Dr. Recker is a consultant for Merck, Lilly, Procter and Gamble, Wyeth, Amgen, Novartis, and Roche. Dr McClung has received consulting fees and research grants from Amgen, Lilly, Merck, Novartis, Procter and Gamble, Roche and sanofi-aventis.

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