Elsevier

Bone

Volume 44, Issue 3, March 2009, Pages 423-427
Bone

Ibandronate dose response is associated with increases in bone mineral density and reductions in clinical fractures: Results of a meta-analysis

https://doi.org/10.1016/j.bone.2008.10.052Get rights and content

Abstract

This meta-analysis pooled data from the four phase III clinical trials of ibandronate to assess the relationship between ibandronate dose, changes in bone mineral density, and rates of both clinical and non-vertebral fractures. Individual patient data from the intent-to-treat population of the BONE, IV fracture prevention, MOBILE, and DIVA studies were included for analysis. The relationship between ibandronate dose and bone mineral density at both the lumbar spine and at the total hip was assessed qualitatively. The relationship between lumbar spine bone mineral density and clinical fracture rate, and the relationship between total hip bone mineral density and non-vertebral fracture rate, were assessed both qualitatively and using mathematical models.

A total of 8710 patients were included in this analysis. Both lumbar spine and total hip bone mineral density were observed to increase with increasing ibandronate dose. The incidence of all clinical fractures was observed to decrease as lumbar spine bone mineral density increased. A statistically significant inverse linear relationship was observed between percent change in lumbar spine bone mineral density and the rate of clinical fractures (P = 0.005). A non-significant curvilinear relationship was observed between percent change in total hip bone mineral density and non-vertebral fracture rate. Increased ibandronate exposure is associated with increasing gains in the lumbar spine bone mineral density and decreasing clinical fracture rates. A non-linear relationship may exist between increases in the total hip bone mineral density and non-vertebral fracture rate.

Introduction

Osteoporosis, a bone disease characterized by low bone mass and deterioration of microarchitecture leading to an increased risk of fractures, has emerged as a serious public health concern [1]. Vertebral fractures are among the most common type of osteoporotic fractures, whereas non-vertebral fractures such as hip tend to be more debilitating [2].

Bisphosphonates (BPs), which function by suppressing osteoclast-mediated bone resorption, are the most widely used group of drugs for the treatment of osteoporosis [3], [4]. Ibandronate is a highly potent, nitrogen-containing BP with proven clinical efficacy in the prevention and treatment of osteoporosis. Ibandronate has been shown to increase bone mineral density (BMD) [5]. The oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE) demonstrated that daily ibandronate therapy (2.5 mg oral) reduced vertebral fracture risk in postmenopausal women [6]. Additionally, a post-hoc analysis found that ibandronate decreased the risk of non-vertebral fracture in a high-risk subgroup of patients with femoral neck T-score <  3.0 [7].

Further trials revealed that 150 mg monthly oral ibandronate and 3 mg quarterly intravenous (IV) ibandronate resulted in greater increases in BMD compared with the daily oral regimen [5], [8]. These monthly and IV regimens, which are the currently FDA-approved doses in the USA, deliver approximately twice the annual cumulative exposure (ACE) of ibandronate compared with the daily regimen. In the 2-year study Monthly Oral iBandronate In LadiEs (MOBILE), women receiving 150 mg monthly oral ibandronate exhibited significantly larger increases in lumbar spine (LS) BMD compared with women receiving 2.5 mg daily oral ibandronate (6.6% versus 5.0%, P < 0.001) [5]. Significantly larger increases in LS BMD have also been reported in women receiving 3 mg quarterly IV ibandronate for 2 years compared with women receiving the 2.5 mg daily oral regimen (6.3% versus 4.8%, P < 0.001) [8].

The relatively wide range of doses that were investigated in the clinical development program of ibandronate provides a unique opportunity to explore the relationships between dose, BMD change and fracture rate.

In this meta-analysis, data from the four phase III clinical trials of ibandronate were pooled to determine the relationship between ibandronate dose and BMD change at the LS and total hip (TH) and the relationship between BMD change and the rates of all clinical fractures or non-vertebral fractures, in women receiving treatment for post-menopausal osteoporosis.

Section snippets

Study design

Individual patient data from four phase III clinical trials of ibandronate (IV fracture prevention study [9], BONE [6], MOBILE [5], [10], and Dosing IntraVenous Administration study [DIVA] [8], [11]) were pooled and analyzed. BONE and the IV fracture prevention study were 3 year placebo-controlled fracture endpoint trials which collected clinical fractures as secondary endpoints. MOBILE and DIVA were active-controlled 2 year BMD studies that were of identical design, ran simultaneously, and had

Patient characteristics

This meta-analysis included 8710 patients from the ITT populations of the four phase III clinical trials. Patient characteristics are summarized by study in Table 1. Patients in the BONE trial were slightly older (mean age 68.7 years, compared with 65.9, 66.0, and 67.0 years in the DIVA, MOBILE and IV fracture prevention trials, respectively). Baseline mean LS T-scores were lower for patients in the MOBILE and DIVA trials (− 3.28 and − 3.26, respectively) compared with the BONE and IV fracture

Discussion

This pooled analysis from the four phase III clinical trials of ibandronate assessed the relationships between ibandronate dose, BMD change, and fracture rates for both clinical and non-vertebral fractures. Increasing ibandronate drug exposure was found to be associated with increases in BMD at both the LS and TH, suggesting that with respect to BMD, higher doses of ibandronate are efficacious at both vertebral and non-vertebral sites. Higher drug exposure was also associated with a lower

Conclusions

The results of this meta-analysis demonstrate that increasing exposure to ibandronate is associated with increasing gains in LS BMD and decreasing rates of clinical fractures, with a significant correlation between increasing BMD and decreasing fracture rate. A non-significant, non-linear inverse relationship was also observed between increases in TH BMD and non-vertebral fracture rate, suggesting little or no effect on non-vertebral fracture with smaller increases in BMD. The marketed monthly

Acknowledgments

The authors acknowledge the editorial assistance of Andrew Cooper, BSc of Envision Pharma Inc, in the preparation of the manuscript. Drs. Sebba, Emkey and Sambrook provided input to, critical review of, and approval of the manuscript. Dr. Joseph Kohles developed the study concept and analysis plan.

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