Ibandronate dose response is associated with increases in bone mineral density and reductions in clinical fractures: Results of a meta-analysis
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.
References (25)
- et al.
Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis
Bone
(2004) - et al.
Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs
Am. J. Med.
(2002) - et al.
Relationship between changes in bone mineral density and vertebral fracture risk associated with risedronate: greater increases in bone mineral density do not relate to greater decreases in fracture risk
J. Clin. Densitom.
(2004) - et al.
Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy
Bone
(2004) Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO Study Group
World Health Organ. Tech. Rep. Ser.
(1994)- et al.
Risk of hip fracture in women with vertebral fracture
J. Bone Miner. Res.
(1994) - et al.
Pharmacokinetics/pharmacodynamics of bisphosphonates: use for optimisation of intermittent therapy for osteoporosis
Clin. Pharmacokinet.
(2005) - et al.
Drug insight: existing and emerging therapies for osteoporosis
Nat. Clin. Pract. Endocrinol. Metab.
(2006) - et al.
Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2 year results from the MOBILE study
Ann. Rheum. Dis.
(2006) - et al.
Ibandronate produces significant, similar antifracture efficacy in North American and European women: new clinical findings from BONE
Curr. Med. Res. Opin.
(2005)
Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis
J. Bone Miner. Res.
Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study
J. Rheumatol.
Cited by (32)
Efficacy and safety of currently marketed antiosteoporosis medications
2014, Best Practice and Research: Clinical Endocrinology and MetabolismCitation Excerpt :It was observed that both lumbar spine and total hip BMD increased with increasing IBN dose. A statistically significant inverse linear relationship has been reported between percent change in lumbar spine BMD and the rate of clinical Fx (p = 0.005) [58]. There is no evidence, from PBO-controlled trials, for a reduction of non-vertebral Fx with IBN, but data from the MOBILE bridging study, from meta-analysis and from ACE evaluations, suggest a significant effect of the marketed oral 150 and the 3 mg i.v. IBN on the risk reduction of non-vertebral Fx.
2011 Up-date of the consensus statement of the Spanish Society of Rheumatology on osteoporosis
2011, Reumatologia ClinicaThe Efficacy of Bisphosphonates in the Prevention of Vertebral, Hip, and Nonvertebral-Nonhip Fractures in Osteoporosis: A Network Meta-Analysis
2011, Seminars in Arthritis and RheumatismCitation Excerpt :Currently ibandronate is marketed at a dose of 150 mg per month, which produces a greater mean increase in bone mineral density (20). Although it might be hypothesized this is will result in greater fracture reduction, combining the results of the 2.5-mg versus placebo trial (BONE) with the results of the 150-mg versus 2.5-mg trial (MOBILE) gives a relative risk estimate for vertebral fractures of 0.55 (0.14 -2.12) for the 150 mg versus placebo comparison, which is comparable to the estimate of ibandronate 2.5 mg versus placebo (0.51; 0.34 to 0.74) (21). Hence, the ibandronate results of the current network meta-analysis can be considered applicable to treatment with 150 mg once monthly.
Review of osteoporosis pharmacotherapy for geriatric patients
2009, American Journal Geriatric PharmacotherapyComparative adherence to weekly oral and quarterly intravenous bisphosphonates among patients with limited heath literacy who sustained distal radius fractures
2018, Journal of Bone and Mineral MetabolismMonthly oral ibandronate 100 mg is as effective as monthly intravenous ibandronate 1 mg in patients with various pathologies in the MOVEST study
2018, Journal of Bone and Mineral Metabolism