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Abstract

Ibandronate is a potent nitrogen-containing bisphosphonate that is currently available as a daily and once-monthly oral formulation for the treatment and prevention of osteoporosis. It has recently been approved for intermittent intravenous administration. The oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE), Monthly Oral iBandronate In LadiEs (MOBILE), and Dosing IntraVenous Administration (DIVA) trials demonstrated that long-term daily and intermittent administration of ibandronate was efficacious for increasing bone mineral density and reducing markers of bone turnover. BONE demonstrated that ibandronate reduced the risk of new vertebral fractures and reduced the relative risk of nonvertebral fractures in higher-risk patients. Histomorphometric evaluations in the BONE and DIVA trials have demonstrated that bone quality is maintained following treatment. Giving patients the option of choosing their dose regimen and route of administration may increase overall adherence to treatment, leading to enhanced fracture protection in patients with osteoporosis.

Keywords

bisphosphonate bone bone remodeling bone turnover ibandronate osteoporosis

Osteoporosis is a major public health concern. It is estimated that 44 million Americans are affected by osteoporosis, with 10 million people (80% women) estimated to have the disease and 34 million more estimated to have low bone mass [1]. By the year 2020, researchers estimate that over 61 million men and women aged 50 years or older will have either osteoporosis or osteopenia [1]. Inadequate patient awareness of the progression and treatment of osteoporosis is a major factor contributing to late diagnoses and ineffective therapy for the millions of patients with osteoporosis.

Most women begin to gradually lose bone mass in their mid-thirties, with the balance between bone resorption and bone formation shifting toward resorption. The loss of estrogen that occurs during menopause results in a prolongation of the lifespan of osteoclasts via a release from the proapoptotic effects of estrogen [2]. Without treatment, bones become more porous and more susceptible to fractures. It is believed that more than 1.5 million fractures annually are attributed to osteoporosis [1].

The WHO defines osteoporosis based on the number of standard deviations below average bone density (T-score) [3]. Diagnostic testing in clinical practice involves measurements of bone mineral density (BMD) by dual-energy x-ray absorptiometry at the lumbar spine and proximal femur; density scores are converted to a T-score. Each T-score unit represents one standard deviation from the standard mean for a healthy young adult population. An individual with osteopenia has a BMD T-score of between −1 and −2.5. A diagnosis of osteoporosis is made when the BMD T-score falls to equal to or below −2.5. Osteoporosis is considered severe if the individual has a BMD T-score of −2.5 or lower in the presence of one or more fragility fractures. A history of fragility fractures is indicative of a diagnosis of osteoporosis, independent of BMD scores.

Drug therapy for the prevention and treatment of osteoporosis is initiated upon consideration of the patients' risk factors and T-score. Bisphosphonates are currently the most commonly prescribed pharmacotherapy for the prevention and treatment of osteoporosis and have been demonstrated to increase BMD, suppress bone turnover markers and reduce fracture risk [4 –6].

Overview of the market

Currently available bisphosphonate therapies

Alendronate and risedronate are indicated for the prevention and treatment of postmenopausal osteoporosis. Both medications are available as once-daily and once-weekly oral formulations and can be offered for prevention (alendronate or risedronate 5 mg/day or either drug 35 mg/week). For the treatment of osteoporosis, the prescribed dosages are alendronate 10 mg or risedronate 5 mg/day, or alendronate 70 mg or risedronate 35 mg/week. Recently, new formulations and combination packages have become available: Fosamax Plus D™ (alendronate 70 mg + vitamin D 2800 IU) and Actonel with calcium® (copackaged risedronate sodium 35 mg and six calcium carbonate 500 mg tablets – risedronate tablet is taken on day 1, and one of six calcium carbonate tablets is taken on days 2–7).

Alendronate and risedronate have strict dosing requirements. To be effective, they must be taken at least 30 min before the first food, beverage or medication of the day. Patients are instructed to take these medications with a glass of plain water and remain upright for 30 min after administration. If dietary calcium and vitamin D are insufficient, patients should be told to take supplements at a different time of the day. Following the administration guidelines helps to minimize the occurrence of upper gastrointestinal (GI) disorders such as dysphagia, esophagitis and esophageal or gastric ulcer, all of which have been reported with oral bisphosphonates.

The strict posture, fasting guidelines and GI side effects of alendronate and risedronate limit patient adherence. Studies have demonstrated that adherence to daily and weekly treatment regimens is suboptimal [7,8], and strategies to improve adherence and compliance are needed [101].

Etidronate is indicated for the treatment of symptomatic Paget's disease and is approved to treat osteoporosis in postmenopausal women in many European countries. Although it has not yet been approved by the FDA specifically for this purpose in the USA, it is commonly prescribed off-label for this indication. Etidronate is available in 200 and 400 mg tablets.

Zoledronic acid and pamidronate are administered intravenously. Zoledronic acid is given as a 15-min infusion and pamidronate as a 2–4-h infusion. Both medications are currently approved in the USA for the treatment of bone metastases of breast cancer, bone lesions in myeloma, tumor-induced hypercalcemia and Paget's disease (pamidronate only). Off-label use of these medications for the treatment of osteoporosis may be expected for patients who cannot receive oral bisphosphonates; pamidronate is being developed for administration once every 3–4 months and zoledronic acid is being tested as a once-yearly dose.

Introduction

Ibandronate is a potent nitrogen-containing bisphosphonate approved for the prevention and treatment of postmenopausal osteoporosis. It is currently available in once-daily (2.5 mg) or once-monthly (150 mg) oral and once-quarterly (3 mg) intravenous formulations administered as an intravenous push infused over 15 s. It is the only oral bisphosphonate approved for once-monthly dosing.

Chemistry

The chemical name for ibandronate is 3-(N-methyl-N-pentyl) amino-1-hydroxypropane 1,1-diphosphonic acid, monosodium salt, monohydrate (Figure 1). It has the molecular formula C₉H₂₂NO₇P₂Na•H₂0 and a molecular weight of 359.24. The chemical structure of ibandronate is based upon a P–C–P backbone, similar to that of inorganic pyrophosphate. Its high affinity for bone is due to the hydroxyl group at the R1 position, which binds Ca²⁺ ions on bone mineral surfaces at sites of osteoclast activity [9 –11]. Its antiresorptive potency is determined by the introduction of a tertiary nitrogen group on the R2 side chain, a characteristic unique to ibandronate within the class of nitrogen-containing bisphosphonates [11,12]. This tertiary nitrogen moiety makes the molecule 2-, 10-, 50- and 500-fold more potent at inhibiting bone resorption in vivo than risedronate, alendronate, pamidronate and clodronate, respectively [13].

Figure 1.

Ibandronate.

Pharmacodynamics

Ibandronate inhibits osteoclast activity, thereby reducing bone turnover and increasing bone mass [14 –16]. Osteoclast activity is inhibited predominately via suppression of the mevalonate pathway, which results in inhibition of isoprenylation of small guanosine 5′-triphosphate (GTP)ases, affecting a variety of cell processes important for osteoclast function [9,16]. Patients treated with ibandronate have exhibited decreases in the bone turnover markers C-terminal telopeptide of Type I collagen (CTX) and osteocalcin [17 –19]. A Phase III study comparing oral once-monthly versus once-daily dosing regimens found that the median decrease from baseline in CTX values after 1 year of treatment was 67 and 76% for patients treated with ibandronate 2.5 mg/day and 150 mg/month, respectively [14]. Quarterly intravenous injections (3 mg) resulted in a 62.6% median decrease from baseline CTX values after 1 year [20,21].

Pharmacokinetics & metabolism

Oral ibandronate is absorbed in the upper GI tract. Plasma concentrations increase linearly with doses of less than 50 mg and nonlinearly at higher doses. Time to maximum observed plasma concentration is 0.5–2 h in fasting, healthy, postmenopausal women. The mean oral bioavailability of ibandronate is approximately 0.6%. Absorption is impaired by concomitant ingestion of food or beverages other than plain water. Oral bioavailability can be reduced by approximately 90% when patients have eaten. Therefore, ibandronate should be taken at least 60 min prior to ingestion of a meal, liquid other than plain water, or other medications.

Ibandronate is not metabolized in humans. Following absorption, ibandronate that is not removed from the circulation via bone resorption is excreted in urine (approximately 50–60% of the absorbed dose). Unabsorbed ibandronate is eliminated in feces.

Clinical efficacy

Major Phase III studies

Three major ibandronate Phase III studies have been performed in postmenopausal women. Two studies, oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe (BONE) and Monthly Oral iBandronate In LadiEs (MOBILE), compared intermittent oral dosing regimens with daily oral dosing. The third study, Dosing IntraVenous Administration (DIVA), evaluated the efficacy of intermittent intravenous administration versus the daily oral dosing regimen. BMD increases from baseline at the lumbar spine, total hip, femoral neck and hip trochanter were used as primary or secondary measures of efficacy for all three studies. All ibandronate treatment groups showed progressive increases in BMD values at all sites tested (Table 1).

Table 1.

Ibandronate efficacy in recent clinical trials.

Trial	Number of patients	Duration	Treatments	BMD increases from baseline (%)

				Lumbar spine	Total hip	Femoral neck	Hip trochanter
BONE	2946	3 years	Placebo	1.3	−0.7	−0.6	0.2
			Oral ibandronate once-daily: 2.5 mg	6.5	3.4	2.8	5.5
			Oral ibandronate intermittently: 20 mg	5.7	2.9	2.4	5.2
MOBILE	1609	2 years	Oral ibandronate once-daily: 2.5 mg	5.0	2.5	1.9	4.0
			Oral ibandronate once-monthly: 50 + 50 mg	5.3	2.8	2.1	4.6
			Oral ibandronate once-monthly: 100 mg	5.6	3.5	2.6	5.3
			Oral ibandronate once-monthly: 150 mg	6.6	4.2	3.1	6.2
DIVA	1395	2 years	Oral ibandronate once-daily: 2.5 mg	4.8	2.2	2.3	3.5
			Intravenous ibandronate every 2 months: 2 mg	6.4	3.4	2.7	5.0
			Intravenous ibandronate every 3 months: 3 mg	6.3	3.1	2.8	4.9

BMD: Bone mineral density; BONE: Oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe; DIVA: Dosing IntraVenous Administration; MOBILE: Monthly Oral iBandronate In LadiEs.

Oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe

BONE was a 3-year, randomized, double-blind, placebo-controlled, parallel-group study. The study included postmenopausal women (n = 2946) with a BMD T-score of −2.0 to −5.0 in at least one vertebra (L₁–L₄) and one to four prevalent vertebral fractures (T₄–L₄). Women received placebo or an oral ibandronate regimen of 2.5 mg/day or 20 mg every other day for 12 doses every 3 months [4]. Subjects also received calcium 500 mg and vitamin D 400 IU/day [4]. BONE is the only ibandronate trial to date that incorporated a fracture end point, with new morphometric vertebral fractures as the primary efficacy variable of the trial.

BONE demonstrated, for the first time, that an intermittently administered bisphosphonate was efficacious in reducing fractures while maintaining bone quality. The percentage of patients with new vertebral fractures was significantly reduced in the oral daily (4.7%) and intermittent (4.9%) ibandronate treatment groups compared with placebo (9.6%). Relative risk reduction reached 62% (p = 0.0001) and 50% (p = 0.0006) for daily and intermittent ibandronate treatment groups, respectively, versus placebo [4]. Although the incidence of nonvertebral fractures was similar (9.1, 8.9 and 8.2% in the daily, intermittent and placebo groups, respectively; difference between groups not significant), a post hoc analysis of a higher-risk subgroup (subjects with a femoral neck BMD T score < −3.0) demonstrated that the daily regimen reduced the risk of nonvertebral fractures (69%; p = 0.012) [4]. Histomorphometric analyses were performed on transiliac bone biopsies from 110 women at either month 22 or 34 of treatment to determine bone quality. In all the bone biopsy samples, newly formed trabecular bone retained its structure and there was no indication of woven bone, marrow fibrosis, signs of cellular toxicity or impairment in bone matrix mineralization [22]. All observations were consistent with the formation of normal-quality, newly formed bone [22].

Monthly Oral iBandronate In LadiEs study

The MOBILE study was a 2-year, randomized, double-blind, parallel-group, noninferiority study. The study enrolled postmenopausal women (n = 1609) aged 55–80 years with a mean lumbar spine (L₂–L₄) BMD T-score of −2.5 to −5.0. Women received one of four ibandronate treatment regimens: 2.5 mg/day, 50 + 50 mg/month (50 mg dose given for 2 consecutive days), 100 mg/month or 150 mg/month plus elemental calcium (500 mg/day) and vitamin D (400 IU/day) supplements. The primary efficacy end point was the change from baseline in lumbar spine BMD.

After 2 years, increases in lumbar spine, total hip, femoral neck and hip trochanter BMD in all the once-monthly treatment groups were not inferior to the daily dosing groups, whereas results for patients treated with the 150 mg dose were superior to those achieved with the 2.5 mg/day dose (p < 0.001) [23]. The 150 mg dose (twice the amount received in a month of daily dosing) represents a departure from the previous approach in which bisphosphonate regimens were based on therapeutically equivalent doses. Whether the superior increases in BMD and reductions in bone turnover markers observed with ibandronate 150 mg/month will be associated with enhanced vertebral and non-vertebral fracture efficacy remains to be determined.

Dosing IntraVenous Administration study

The DIVA study was designed to compare the efficacy and safety of bimonthly and quarterly intravenous dosing regimens with the daily oral regimen and, furthermore, to determine whether these intravenous regimens were noninferior when compared with the daily regimen. The study evaluated 1395 postmenopausal women aged 55–80 years, all of whom were at least 5 years postmenopausal. Subjects had a mean lumbar spine (L₂–L₄) BMD T-score between −2.5 and −5.0. Women received intravenous ibandronate (2 mg every 2 months or 3 mg every 3 months) or oral ibandronate (2.5 mg/day), and intravenous or oral placebo for 2 years supplemented with calcium (500 mg/day) and vitamin D (400 IU/day).

Both intravenous ibandronate regimens were well tolerated. The intravenous dosing provided superior efficacy to daily dosing at the lumbar spine and hip, as measured by BMD increases and bone turnover marker suppression, when compared with the daily oral regimen [20,21]. Intravenous dosing could provide an alternative to oral bisphosphonate treatment, especially for patients unable to utilize oral dosing.

Overall efficacy of ibandronate

Consistent increases in BMD were observed with ibandronate regardless of the dosing administration or timing (Table 1). At the lumbar spine, BMD increases of 4.8–6.6% were observed across the three trials. BMD increased by 2.2–4.2% at the total hip, 1.9–3.1% at the femoral neck and 3.5–6.2% at the hip trochanter. In BONE, slight increases in lumbar spine and hip trochanter BMD and decreases in total hip and femoral neck BMD were noted in the placebo group. BMD increases reported for patients receiving daily ibandronate were higher in BONE compared with the MOBILE or DIVA studies; this is most likely due to the 1-year difference in study duration.

Safety & tolerability

Adverse events associated with ibandronate in clinical trials are typical for bisphosphonates as a class. A summary of adverse events for the three Phase III ibandronate trials is presented in Table 2. The safety and tolerability profiles of oral once-monthly and once-daily ibandronate were similar in the MOBILE study [23]. In the DIVA study, ibandronate administered once-daily and intermittently was associated with similar safety and tolerability. Most adverse events were mild or moderate and did not lead to treatment discontinuation in any of the trials. The percentage of patients who withdrew from each of the studies due to treatment-related adverse events was similar regardless of the treatment regimen: 6.0–7.6% in patients receiving daily treatment, 5.1–6.8% in patients receiving ibandronate once-monthly, and 6.5–7.7% in patients receiving intravenous ibandronate. Withdrawal due to treatment-related adverse events was highest in patients from the placebo group: 8.1% (data from the 3-year BONE study) [4]. There has been no evidence of osteonecrosis of the jaw (ONJ) in clinical trials assessing patients with postmenopausal osteoporosis treated with ibandronate. ONJ, a rare complication, has been primarily observed in cancer patients undergoing chemotherapy who were simultaneously receiving intravenous pamidronate or zoledronic acid [24,25].

Table 2.

Overall summary of safety for the BONE, MOBILE and DIVA studies.

Trial	Treatments	Any drug-related adverse event (%)	Any serious drug-related adverse event (%)	Any drug-related adverse event leading to withdrawal (%)	GI adverse events (%)	Clinical osteoporotic fractures (%)
BONE	Placebo	17.9	0.3	8.1	9.1	10.5
	Oral ibandronateonce-daily: 2.5 mg	19.8	0.3	7.5	11.4	9.6
	Oral ibandronateintermittently: 20 mg	18.5	0.7	7.2	9.0	9.0
MOBILE	Oral ibandronateonce-daily: 2.5 mg	32.4	0.5	7.6	22.8	6.1
	Oral ibandronateonce-monthly: 50 + 50 mg	30.1	0.5	5.1	19.9	7.3
	Oral ibandronateonce-monthly: 100 mg	36.1	0.8	6.6	25.8	6.1
	Oral ibandronateonce-monthly: 150 mg	36.9	0.3	6.8	22.5	6.8
DIVA	Oral ibandronateonce-daily: 2.5 mg	36.8	0.9	6.0	19.1	6.2
	i.v. ibandronateevery 2 months: 2 mg	46.4	1.1	6.5	23.7	4.7
	i.v. ibandronateevery 3 months: 3 mg	42.0	0.4	7.7	18.6	4.9

BONE: Oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe; DIVA: Dosing IntraVenous Administration

GI: Gastrointestinal; i.v.: Intravenous; MOBILE: Monthly Oral iBandronate In LadiEs.

Regulatory affairs

Ibandronate was approved in the USA by the FDA for daily treatment (2.5 mg) in 2003, for monthly therapy (150 mg) in 2005, and for quarterly intravenous administration (3 mg) in 2006. The European Commission approval for daily ibandronate was received in 2004, for monthly administration (150 mg) in 2005, and for quarterly intravenous injections (3 mg) in 2006.

Conclusion

Ibandronate is currently the only bisphosphonate approved for once-monthly oral dosing for the treatment and prevention of osteoporosis. This treatment option offers efficacy equivalent to the daily treatment regimen while affording patients a longer between-dose interval than other currently available bisphosphonates. Preference studies have indicated that the majority of patients prefer less frequent dosing [26 –28]. In the Boniva ALendronate Trial in Osteoporosis (BALTO) I and II studies, 71.4 and 70.6% of patients, respectively, reported a statistically significant preference for once-monthly ibandronate dosing after receiving once-monthly ibandronate and once-weekly alendronate in a crossover paradigm [25,26]. In addition, 74.6 and 76.6% of women in BALTO I and II found the once-monthly dosing to be more convenient. Actual patient persistence with once-monthly ibandronate compared with available weekly regimens is currently being examined. Intravenously administered ibandronate offers another option with a longer dosing interval for patients who are GI-intolerant or unable to follow the dosing requirements of oral bisphosphonates.

Future perspective

Combination therapies with new agents

Combination therapies may offer a novel approach for the future treatment of osteoporosis. The use of anabolic agents, such as parathyroid hormone (PTH), together with bisphosphonates (antiresorptive agents), has been proposed as a therapeutic strategy that could both prevent bone resorption and increase the rate of formation of new bone. Initial studies evaluating such combination therapies have not supported a synergistic effect on changes in BMD levels when, for example, alendronate and PTH were administered concomitantly [29,30].

When dosed simultaneously, alendronate appeared to blunt the PTH-induced stimulation of bone formation [30], while administration of the two therapies sequentially was more effective in increasing vertebral bone density than treatment with alendronate alone [31]. New sequential or staggered dosing regimens may need testing, as investigators explore ways to maximize benefits from various combination therapies.

Many new agents to treat osteoporosis are currently under development, with some offering unique mechanisms of action. Possible new agents include: cathepsin K inhibitors, selective androgen receptor modulators (SARMs) and receptor activator of nuclear factor κB ligand (RANKL) antibody. Cathepsin K is a cysteine protease enzyme that is highly expressed in osteoclasts. In nonhuman primates, inhibition of cathepsin K led to inhibition of bone resorption as evidenced by a decrease in bone turnover markers [32]. SARMs selectively modulate the activity of the androgen receptor. Tissue-selective androgen-receptor agonists may be useful for treating osteoporosis [33,34]. RANKL blockade may prevent bone loss caused by osteoporosis. A single subcutaneous dose of RANKL antibody resulted in a dose-dependent and sustained decrease in urinary N-telopeptide for up to 6 months [35]. Combination therapies utilizing new agents along with bisphosphonates may prove more effective than either therapy alone. In addition, the development of a two-mechanism approach that can take advantage of the reduced dosing requirements available with once-monthly ibandronate may help minimize the impact on compliance resulting from the complexity associated with combination therapy.

The effectiveness of bisphosphonate therapy can be augmented if patients adopt simple lifestyle changes. Patients who supplement their diet with vitamin D and calcium exhibit increased bone quality and decreased risk of falling through improvements in neuromuscular coordination [36]. Exercise increases postural stability and reduces bone resorption [37]. Physical activity has also been found to help maintain BMD at total hip and intertrochanter sites [38]. Adjustments such as removing loose rugs, wearing hip padding and sturdy shoes, installing grab bars and nonskid mats in the bathroom, and using a cane or walker for those with balance problems or difficulty walking, can also reduce the risk of fractures in the elderly. Attention to preventive lifestyle measures, strength training, and the role of calcium and vitamin D in preventing osteoporotic fractures is likely to increase in the coming years.

The large numbers of patients who presently have, or will develop, osteoporosis and/or osteopenia will need effective treatment options. Future therapies should encourage patients to take a more active role in managing medications by choosing regimens that best fit their lifestyles and dosing requirements. The availability of once-monthly ibandronate and the extensive data collected in clinical trials demonstrating the superior efficacy and comparable safety of this regimen when compared with the daily ibandronate dose have vitally expanded choices for patients seeking a sustainable course of bisphosphonate therapy.

Executive summary

Mechanisms of action

Ibandronate has a high affinity for hydroxyapatite, a component of the mineral matrix of bone.

Ibandronate reduces bone turnover by inhibiting osteoclast activity and reducing bone resorption.

Pharmacokinetic properties

Oral ibandronate is absorbed in the upper gastrointestinal (GI) tract. Plasma concentration increases dose-dependently up to 50 mg and nonlinearly at higher doses.

Following oral administration, the peak concentrations are attained after 0.5–2 h in fasted individuals. Absorption is impaired by food or beverages (other than plain water).

Ibandronate rapidly binds to bone or is excreted in urine.

There is no evidence that ibandronate is metabolized in humans.

Circulating ibandronate that is not absorbed by bone is eliminated unchanged by the kidneys. Unabsorbed ibandronate is excreted unchanged in feces.

In patients with renal impairment, renal clearance of ibandronate is linearly related to creatinine clearance.

Clinical efficacy

The efficacy of oral ibandronate was demonstrated in a randomized, double-blind, placebo-controlled, multicenter study of 2946 women aged 55–80 years who had been postmenopausal for 5 years or longer, with a bone mineral density (BMD) number of standard deviations below average bone density (T-score) of −2.0 to −5.0 in at least one vertebra (L₁–L₄) and one to four prevalent vertebral fractures (T₄–L₄).

Subjects were given ibandronate 2.5 mg/day or 20 mg every other day for 12 doses every 3 months. All women received daily supplementation of vitamin D 400 IU and calcium 500 mg.

Vertebral fracture risk was 9.6% in placebo-treated women and 4.7% in women receiving daily ibandronate.

Efficacy for once-monthly ibandronate was demonstrated in a randomized, double-blind, multicenter, noninferiority trial of 1609 women aged 55–80 years and postmenopausal for 5 years or longer with a mean lumbar spine (L₂–L₄) BMD T-score between −2.0 and −5.0.

Subjects were given oral daily (2.5 mg) or once-monthly (100 or 150 mg) ibandronate. All women received daily supplementation of vitamin D 400 IU and calcium 500 mg. The 1 50 mg/month dose was shown to be noninferior and superior to the 2.5 mg/day dose in increasing BMD.

Efficacy for once-quarterly intravenous ibandronate (3 mg) was demonstrated in a randomized, double-blind, double-dummy study of 1395 postmenopausal women aged 55–80 years; all of whom were at least 5 years postmenopausal and with mean lumbar spine (L₂–L₄) BMD T-score between −2.5 and −5.0. All women received daily supplementation of vitamin D 400 IU and calcium 500 mg.

Women received intravenous ibandronate (2 mg every 2 months or 3 mg every 3 months) or oral ibandronate (2.5 mg/day), and intravenous or oral placebo. The intravenous ibandronate regimens provided superior BMD increases compared with the daily oral regimen.

Safety & tolerability

Hypocalcemia and other disturbances of bone and mineral metabolism should be effectively treated before starting ibandronate.

Ibandronate, similar to other orally administered bisphosphonates, may cause upper GI disorders such as dysphagia, esophagitis, and esophageal or gastric ulcers.

The adverse-event profile of once-daily ibandronate is similar to that of placebo. Most of the adverse events were mild or moderate and did not lead to discontinuation of treatment.

The overall safety and tolerability profiles of oral ibandronate 150 mg/monthly and 3 mg once-quarterly intravenous ibandronate were similar to the oral ibandronate 2.5 mg/day profile.

Drug interactions

Products containing calcium and other multivalent cations (including antacids, supplements and vitamins) may interfere with the absorption of ibandronate.

Dosing & administration

Available as 2.5 mg tablets for daily oral administration and 150 mg tablets for once-monthly administration.

Dose should be taken with a full glass (6–8 oz) of plain water at least 60 min before ingestion of the first food or drink of the day or any other oral medications or supplements. Patient should take medication while upright and should not lie down for 60 min after taking the medication.

The intravenous formulation of ibandronate is administered once every 3 months as an intravenous ‘push’ infused over 15 s.

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Ibandronate: Once-Monthly and Intravenous Dosing Options for Osteoporosis Treatment

Abstract

Keywords

Overview of the market

Currently available bisphosphonate therapies

Introduction

Chemistry

Pharmacodynamics

Pharmacokinetics & metabolism

Clinical efficacy

Major Phase III studies

Oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe

Monthly Oral iBandronate In LadiEs study

Dosing IntraVenous Administration study

Overall efficacy of ibandronate

Safety & tolerability

Regulatory affairs

Conclusion

Future perspective

Combination therapies with new agents

References