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The Designed for intravenous (IV) Ibandronate reNal safety Evaluation (DIVINE) study was a 1-year prospective, randomized, open label, multi-center study that evaluated the renal safety of quarterly (every 3 months) ibandronate IV injection given over 15-30s compared with infusion given over 15 min, and weekly oral alendronate, in women with postmenopausal osteoporosis (PMO) at increased risk for renal disease. Both injection and infusion of IV ibandronate showed comparable safety to alendronate, with only small changes in serum creatinine (sCr) for each treatment group, and AEs were generally comparable between groups. All three treatments had similar effects on renal function, measured by change in baseline of the glomerular filtration rate; the ibandronate IV injection group was noninferior to the ibandronate IV infusion and weekly oral alendronate groups at 9 months, with similar results at 1 year. The results of this study demonstrate the profile of IV ibandronate, which allows it to be dosed as an IV injection in the primary care setting without the need for an infusion, even in patients with pre-existing hypertension or diabetes mellitus., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Bisphosphonates are eliminated from the human body by the kidney. Renal clearance is both by glomerular filtration and proximal tubular secretion. Bisphosphonates given rapidly in high doses in animal models have induced a variety of adverse renal effects, from glomerular sclerosis to acute tubular necrosis. Nevertheless in the doses that are registered for the management of postmenopausal osteoporosis (PMO), oral bisphosphonates have never been shown to adversely affect the kidney, even (in post-hoc analysis of clinical trial data) down to estimated glomerular filtration rates of 15 ml/min. In addition fracture risk reduction has also been observed in these populations with stage 4 chronic kidney disease (CKD) with age-related reductions in glomerular filtration rate (GFR). Intravenous zoledronic acid is safe when the infusion rate is no faster than 15 min though there have been short-term (days 9-11 post-infusion) increases in serum creatinine concentrations in a small sub-set of patients from the postmenopausal registration trials. For these reasons intravenous zoledronic acid should be avoided in patients with GFR levels <35 ml/min; and the patients should be well hydrated and have avoided the concomitant use of any agent that may impair renal function. Intravenous ibandronate has not to date been reported to induce acute changes in serum creatinine concentrations in the PMO clinical trial data, but the lack of head-to-head comparative data between ibandronate and zoledronic acid precludes knowing if one intravenous bisphosphonate is safer than the other. In patients with GFR levels <30-35 ml/min, the correct diagnosis of osteoporosis becomes more complex since other forms of renal bone disease, which require different management strategies than osteoporosis, need to be excluded before the assumption can be made that fractures and/or low bone mass are due to osteoporosis. In addition, in patients who may have pre-existing adynamic renal bone disease, there is a lack of evidence of any beneficial effect or harm by reducing bone turnover by any pharmacological agent, including bisphosphonates on bone strength or vascular calcification. Bisphosphonates are safe and effective for the management of osteoporosis when used in the right dose and in the right patient population for the right duration., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Monthly oral ibandronate has been shown to increase bone mineral density (BMD) and reduce bone turnover in postmenopausal women with osteoporosis, but its efficacy has not been investigated in women with low bone mass. The objective of this study was to examine the efficacy and safety of monthly oral ibandronate (150 mg) treatment in postmenopausal women with low bone mass., Methods: This 1-year, double-blind, placebo-controlled, randomized study enrolled ambulatory postmenopausal women aged 45-60 years with baseline lumbar spine (LS) BMD T-score<-1.0 and >-2.5 and baseline T-score>-2.5 at the total hip, trochanter, and femoral neck (collectively defined as the proximal femur) and no prior vertebral or low-trauma osteoporotic fractures at baseline. Subjects received either 150 mg monthly oral ibandronate or placebo. All subjects received calcium and vitamin D supplements. The primary endpoint was the relative change from baseline (%) in mean LS BMD at 1 year (intent-to-treat population). Treatment groups were compared by means of a two-way ANOVA model which adjusted for independent factors including treatment group, baseline LS BMD T-score, and time since menopause. Responder analyses examined the percentage of participants with changes from baseline in LS BMD and proximal femur BMD>or=0%. Adverse events and safety laboratory parameters were monitored continuously., Results: A total of 77 women received monthly ibandronate and 83 women received placebo. Subjects treated with ibandronate achieved larger increases in LS BMD after 1 year compared with subjects receiving placebo (3.7% vs -0.4% [difference of 4.1%, p<0.0001]). After 3 months, median serum C-terminal telopeptide of type I collagen levels were reduced by >55% in the ibandronate group compared with approximately 4% in the placebo group. At 1 year, 88.2% of the participants treated with ibandronate achieved increases in LS BMD>or=0% compared with 38.6% of subjects receiving placebo. Treatment regimens were well tolerated in both the ibandronate-treated and placebo groups., Conclusion: Monthly ibandronate therapy prevents bone loss in postmenopausal women with low bone mass.

This randomized, double-blind, double-dummy, multicenter trial assessed safety and efficacy of a single dose of IV zoledronic acid (ZOL) 5 mg vs. oral alendronate (ALN) 70 mg weekly in postmenopausal women with low bone mineral density (BMD) who had previously been treated with ALN. Postmenopausal women who were receiving oral ALN for at least 1 year immediately prior to randomization and with lumbar spine or femoral neck BMD T-score values < or = -2.0 prior to initiation of ALN were randomized to one 15-min IV infusion of ZOL 5 mg plus 52 weeks of oral placebo (n=113) or one IV infusion of placebo plus 52 weeks of oral ALN 70 mg (n=112). End points included percent change in lumbar spine BMD from baseline to month 12 and relative change from baseline in urine N-telopeptide of type I collagen (NTX), serum C-telopeptide of type I collagen (CTX), amino terminal propeptides of type I collagen (PINP), and bone-specific alkaline phosphatase (bone ALP) over 12 months. Adverse events, bone histomorphometry and microscopic appearance, and patient preference for the 2 treatment regimens were also assessed. In this study, a single infusion of ZOL 5 mg maintained BMD 12 months following the switch from oral ALN in women with osteoporosis. The mean duration of prior ALN therapy at baseline was 4 years. Mean biomarker levels in the ALN 70-mg group remained at or close to baseline levels for the duration of the study. In the ZOL 5-mg group, mean biomarker levels were reduced from baseline after 3 months, returned to baseline after 6 months, and increased thereafter but remained within the premenopausal range. The overall rates of adverse events were comparable in the 2 groups (ZOL 5 mg, 86.7%; ALN 70 mg, 80.4%). Headache occurred more commonly within the first 3 days after infusion with ZOL 5 mg (12.4%) than with ALN 70 mg (6.3%). Bone biopsies indicate that both treatments decrease excessive remodeling seen in osteoporosis. The majority (78.7%) of patients expressed preference for once yearly infusion over weekly oral therapy. We conclude that patients can be switched from oral ALN to ZOL 5 mg infusion with maintenance of therapeutic effect for at least 12 months and that patients prefer a once yearly infusion to weekly oral therapy.

Abstract: The Designed for intravenous (IV) Ibandronate reNal safety Evaluation (DIVINE) study was a 1-year prospective, randomized, open label, multi-center study that evaluated the renal safety of quarterly (every 3months) ibandronate IV injection given over 15–30s compared with infusion given over 15min, and weekly oral alendronate, in women with postmenopausal osteoporosis (PMO) at increased risk for renal disease. Both injection and infusion of IV ibandronate showed comparable safety to alendronate, with only small changes in serum creatinine (sCr) for each treatment group, and AEs were generally comparable between groups. All three treatments had similar effects on renal function, measured by change in baseline of the glomerular filtration rate; the ibandronate IV injection group was noninferior to the ibandronate IV infusion and weekly oral alendronate groups at 9months, with similar results at 1year. The results of this study demonstrate the profile of IV ibandronate, which allows it to be dosed as an IV injection in the primary care setting without the need for an infusion, even in patients with pre-existing hypertension or diabetes mellitus. [Copyright &y& Elsevier]