Ibandronate: The Evolution of a Once-a-Month Oral Therapy for Postmenopausal Osteoporosis

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1 Journal of Clinical Densitometry, vol. 9, no. 1, 58 65, 2006 Ó Copyright 2006 by The International Society for Clinical Densitometry /06/9:58 65/$32.00 DOI: /j.jocd Original Article Ibandronate: The Evolution of a Once-a-Month Oral Therapy for Postmenopausal Osteoporosis David W. Dempster,*,1 and Michael A. Bolognese 2 1 Department of Pathology, Columbia University, New York, NY and Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY; and 2 Bethesda Health Research, Bethesda, MD Abstract Bisphosphonates have been shown to be highly effective in preventing and treating postmenopausal osteoporosis (PMO) and the associated risk of fracture. However, poor adherence with bisphosphonate therapies for PMO results in a high incidence of otherwise preventable fractures. The chronicity of this condition requires long-term treatment, but fewer than one in two women remains on daily bisphosphonate therapy for 1 yr. A good way to reduce the risk of osteoporotic fractures is through development of equally efficacious formulations with more convenient dosing regimens. Weekly formulations of bisphosphonates have been introduced that demonstrate comparable efficacy to daily formulations with slightly improved adherence. Recently, a new formulation utilizing a third-generation nitrogencontaining bisphosphonatedibandronatedhas been approved with a monthly dosing regimen. The pharmacokinetics and high potency of ibandronate, similar with other bisphosphonates, facilitate lower mg doses and longer-interval dosing frequencies with similar efficacy and enhanced tolerability. Preclinical studies and clinical trials have consistently demonstrated that it is the total cumulative dose of ibandronate that determines efficacy. The convenience of once-monthly dosing may ultimately improve adherence and clinical outcomes among the growing population of postmenopausal women at risk of osteoporosis. Key Words: Adherence; bisphosphonates; ibandronate; osteoporosis; postmenopause. Introduction Medicine only works if patients take it. Despite the availability of numerous effective therapies, many women fail to perceive the importance of preventing and treating postmenopausal osteoporosis (PMO)duntil a fracture occurs. Consequently, women do not persist with taking their recommended therapies as directed, leading to a high incidence of otherwise preventable fractures (1). Aiming to mitigate a national health crisis, the US Surgeon General recently emphasized the urgent need to improve adherence to treatments for this asymptomatic condition to address the Received 07/26/05; Revised 09/13/05; 09/23/05; Accepted 09/23/05. *Address correspondence to David W. Dempster, PhD, Director, Regional Bone Center, Helen Hayes Hospital, Route 9W, West Haverstraw, NY dempster@helenhayeshosp.org; ddempster9@aol.com currently suboptimal therapeutic outcomes (2). To respond to this mandate, new formulations that are convenient and effective have recently been introduced. Osteoporotic fractures are three times as common in women as in men (3). Approximately 8 million women in the United States are currently diagnosed with osteoporosis (4) and 54% of postmenopausal Caucasian women in the United States are believed to have osteopenia (5). A 50-yrold woman has a 40% overall lifetime risk of fracture (3), including an 18% risk of hip and 16% risk of spinal fracture (6). The chronic pain, deformity, and disability of osteoporotic fractures significantly reduce quality of life (7). A hip fracture reduces survival by 10% to 20% (6,8). Hip fractures appear to increase the risk of dying from other diseases (7). Similarly, women with vertebral fractures have a two- to threefold increase in mortality rate from pulmonary disease, as well as an age-adjusted 35% to 40% increased risk of cancer death 58

2 Ibandronate Once-Monthly Therapy 59 (9). Reducing the number of osteoporotic fractures via effective treatment of osteoporosis could have a dramatic impact on the health and well-being of the increasing number of women now facing life after menopause (10). Effective and well-tolerated therapy for PMO is now available in the form of oral bisphosphonates. When taken correctly, bisphosphonates reduce the incidence of postmenopausal fractures by 33% to O60% (11214). Their safety profile addresses safety concerns associated with hormone replacement therapy identified in the Heart and Estrogen/progestin Replacement Study and Women s Health Initiative trials (15217). Although effective treatment with bisphosphonates requires at least 1 yr of therapy (12,14), an estimated 54% of patients discontinue daily bisphosphonate therapy within a year of receiving their first prescription (18). A retrospective analysis of more than 58,100 postmenopausal women with osteoporosis found that fewer than 25% could be categorized as compliant (defined as achieving 1 yr of uninterrupted therapy with no lapse O14 d) with their osteoporosis medication (19). A Canadian study demonstrated that high refill compliance with any treatment for PMO (defined as medication available 80% of the time) reduced the fracture rate by 16% when compared with poor refill compliance (20). Another retrospective analysis of claims data from nearly 37,700 postmenopausal women demonstrated that high refill compliance (80%) with daily or weekly bisphosphonates reduced the fracture rate by 20% within 24 months, and persistence on treatment for 24 months (defined as no gap in refills O30 d) reduced the risk of fracture by 24% (21). Additional analysis on a subset of that cohort involving 6825 women with an explicit diagnosis of PMO showed that (1) compliance with bisphosphonate therapy led to a 26% relative reduction in fracture risk, and (2) persistence with the therapy led to a 21% reduction in overall fracture risk (1). These data suggest that efforts to improve adherence to bisphosphonate therapy are likely to be rewarded with reductions in rates of osteoporotic fractures. Many studies on a variety of drugs indicate that less-frequent (nondaily) oral dosing regimens enhance adherence, which ultimately improves clinical outcomes (such as reduced fracture rates) in osteoporosis. For example, weekly dosing of fluconazole was shown to be highly effective in the treatment of pediatric tinea capitis and was associated with high compliance (22). Less-frequent dosing regimens also have demonstrated value in the management of psychiatric disorders: fluoxetine once-weekly is safe and effective for maintenance therapy of depression (23) and biweekly injections of a long-acting formulation of risperidone demonstrate high safety and efficacy in patients requiring long-term antipsychotic treatment (24). Compliance with oral daily hormonal contraceptives is notoriously poor, resulting in development of numerous contraceptive options utilizing less-frequent dosing regimens, such as trimonthly hormonal injections, a weekly transdermal hormonal patch, a monthly vaginal ring, monthly hormonal injections, and long-acting intrauterine systems. Contraceptive efficacy is greater as a result of enhanced compliance associated with the weekly patch (25). In a recent study of 211,319 women receiving bisphosphonate therapy for osteoporosis, approximately 48% of women maintained on weekly vs 35% of women on daily regimens had adequate adherence (medication in the patient s possession 80% of days) ( p! 0.001). However, adherence remained suboptimal (!50%) in each group (18). In an effort to facilitate greater adherence, bisphosphonate dosing has evolved from daily oral regimens to weekly and monthly options, and intravenous (IV) dosing is an additional option that may make bisphosphonate therapy more practical in selected patients. The most recent bisphosphonate regimen to become available is once-monthly oral ibandronate (150 mg). Studies with ibandronate, a third-generation nitrogen-containing bisphosphonate, have shown reduced fracture rates with dosing regimens that are less frequent than once daily. Two of the currently available bisphosphonatesdalendronate and risedronatedare approved for both daily and weekly oral dosing, but no alendronate or risedronate studies with weekly regimens have provided direct fracture data; rather, antifracture efficacy was assumed based on bioequivalence of weekly regimens with daily regimens. A large-scale study has demonstrated that the effect on bone mineral density (BMD) of monthly ibandronate is comparable to that of more-frequent dosing regimens, with similar tolerability, which may facilitate the enhanced adherence needed to reduce the risk of fracture (26). Progress in Bisphosphonate Development Orally administered nitrogen-containing bisphosphonates, such as alendronate and risedronate, are the most commonly used drugs for PMO in the United States. Nitrogen-containing bisphosphonates inhibit osteoclast activity and are the most potent antiresorptive agents currently available (27). They reduce the concentration of biochemical markers of bone turnover and maintain or improve BMD, which has been shown to correlate with reduced risk of osteoporotic fracture (28). Currently approved bisphosphonates have similar efficacy and safety profiles. Both alendronate and risedronate reduce the risk of vertebral fractures by 40% to 50% and the risk of nonvertebral fractures by about a third (11 14). Ibandronate has comparable efficacy to alendronate and risedronate in the prevention of vertebral fractures associated with PMO. Bisphosphonates are safe and well-tolerated agents when taken as advised. The most common adverse events are esophagitis and gastrointestinal (GI) distress, which are minimized if the agent is taken along with 628 oz of water. To facilitate absorption and enhance tolerability, patients are advised to follow these guidelines: (1) patients must ingest the drug before the first food or beverage of the day and continue to fast for at least 30 min afterward; (2) patients must ingest the drug with at least 628 oz of water; and (3) patients must remain upright for at least 30 min after ingestion (29). The inconvenience of these dosing guidelines may impair adherence with daily regimens of alendronate and risedronate. These findings led to the investigation and subsequent introduction of less-frequent dosing regimens for bisphosphonate therapy.

3 60 Dempster and Bolognese Research suggests that adherence with weekly bisphosphonate therapy is slightly greater than that with daily dosing (30,31). It is believed that the convenience of ibandronate s monthly dosing regimen may facilitate greater adherence. alendronate (37). Non nitrogen-containing bisphosphonates, such as clodronate, are metabolized intracellularly to nonhydrolyzable analogs of adenosine triphosphate (ATP), leading to osteoclast apoptosis (36). Bisphosphonates: Structure, Mechanism of Action, and Potency Bisphosphonates are bone-tissue2specific agents with minimal side effects and no known cancer risks (32). All bisphosphonates are comprised of a core phosphate-carbonphosphate (P2C2P) structure that acts as a bone hook, permanently binding the agent to mineralized bone surfaces and inhibiting osteoclast-mediated bone resorption (33). Bisphosphonates are deposited preferentially beneath osteoclasts; administration of small amounts can facilitate high local concentrations that can have a prolonged effect (34). Modifications to the two side chainsdr 1 and R 2 ddetermine the antiresorptive potency and therapeutic characteristics of each agent (Fig. 1). The currently available nitrogen-containing bisphosphonate agents used in the management of osteoporosis have more similarities than differences with regard to their mechanisms of action and efficacy (33,35). All current agents have a hydroxyl (OH) group in the R 1 side chain, which has been shown to enhance the strength of binding to mineral surfaces in bone where they inhibit the action of osteoclasts, the cells responsible for bone resorption (28,33). The mode of action and level of antiresorptive potency is determined by the presence or absence of nitrogen in the R 2 side chain (Table 1). The addition of nitrogen substantially increases potency (34). Nitrogen-containing bisphosphonates, including alendronate, risedronate, and ibandronate, prevent protein prenylation in osteoclasts through inhibition of farnesyl diphosphate synthase in the mevalonate pathway (35 37). The antiresorptive potency of the specific agent determines the potency for inhibiting prenylation, with risedronate and ibandronate more potent than Fig. 1. The basic structure of bisphosphonates. Reprinted with permission from Barrett et al. (44). The Newest Bisphosphonate: Ibandronate Overview Ibandronate, or 1-hydroxy-3- (methyl pentyl amino) propylidene bisphosphonate, is a third-generation nitrogen-containing bisphosphonate indicated for the prevention and treatment of PMO. As with alendronate and risedronate, ibandronate has a hydroxyl group on the R 1 side chain to facilitate binding to bone. In addition, it has a tertiary nitrogen group in the R 2 side chain, significantly increasing its potency (28). Ibandronate is currently the most active bisphosphonate agent for inhibition of bone resorption (38). It has a twofold and 10-fold greater potency than risedronate and alendronate, respectively, (39) which enables dosing in lower mg quantities than previously available bisphosphonates (28). Furthermore, the greater potency allows for extended between-dose intervals (e.g., oncea-month dosing) (40). Oral ibandronate has been approved by the Food and Drug Administration (FDA) for the prevention and treatment (2.5 mg/d and 150 mg/mo) of PMO. The greater potency of ibandronate facilitated research into its use in less-frequent dosing regimens, including intermittent oral, intermittent IV, and monthly dosing regimens. Results from a large, 3-yr, placebo-controlled, multinational phase III fracture-prevention study (oral ibandronate Osteoporosis vertebral fracture trial in North America and Europe [BONE]) involving 2946 postmenopausal women with osteoporosis demonstrated a 52% and 50% reduction in relative risk of new vertebral fractures with daily oral ibandronate and intermittent ibandronate, respectively (41). A subanalysis of the North American cohort showed a 62% reduction in relative risk of new vertebral fractures with daily oral ibandronate ( p ), and a 50% reduction with an intermittent regimen (20 mg every other day for 12 doses every 3 months; p ) (42). Both dosing regimens significantly increased BMD at the lumbar spine (6.5% and 5.7%, respectively; p! ) and total hip (3.4% and 2.9%, respectively; p! ) after 3 yrs (43). The BONE study was specifically designed to assess vertebral fracture efficacy of ibandronate. In addition, the population was possibly at relatively low risk for hip or other nonvertebral fractures and was underpowered to demonstrate a possible effect on these fractures. However, a post-hoc analysis of a subgroup of women at elevated risk for nonvertebral fracture (femoral neck baseline BMD T-score of! 23.0) found significant risk reduction of nonvertebral fractures with oral daily and intermittent ibandronate [69% ( p ) and 37% ( p ), respectively] (43). As of yet, no prospective nonvertebral fracture data are available for ibandronate. Nevertheless, ibandronate is the only bisphosphonate proven to offer sustained antifracture efficacy in regimens with dosing intervals of 2 months or greater.

4 Ibandronate Once-Monthly Therapy 61 Table 1 Relative Potency of Bisphosphonates for Inhibiting Bone Resorption Drug Ibandronate has proven to be safe and well tolerated, with no adverse effects on hepatic and renal function (44). A 3-yr trial involving over 3900 women with PMO found no difference in type and incidence of adverse effects between oral administration of ibandronate and placebo (45). Adverse events of the digestive system were the most common reason for withdrawal for both ibandronate and placebo. A 1-yr multicenter trial found no differences in safety and tolerability of daily and monthly ibandronate dosing regimens with regard to incidence and type (45). Pharmacodynamics: Preclinical Data The similar consequences of estrogen deficiency on bone after menopause observed between humans and mammals suggested that preclinical investigations on the pharmacodynamics of ibandronate are likely to have clinical relevance (46). Initial studies on ovariectomized rats found that treatment with ibandronate was safe and effective, in a dose-related manner, resulting in improvements in BMD at both trabecular and cortical bone sites (47249). The studies on rats, in addition to similar studies on larger mammals, concluded that it is the total administered dose of ibandronate, and not the dosing regimen, that determines effects on bone mass (46,50252). Long-term administration (1 mcg/kg/d) improved bone quality in both ovariohysterectomized beagle dogs or ovariectomized cynomolgus monkeys (52,53). The preclinical trials consistently demonstrated that treatment with ibandronate prevented estrogen-mediated bone loss and maintained or increased bone mass, architecture, and strength in a dose-dependent fashion, with efficacy determined by the total cumulative dose. Pharmacokinetic Profile in Humans Relative potency Etidronate 1 Clodronate 10 Tiludronate 10 Pamidronate 100 Neridronate 100 Alendronate 100!1000 Climadronate 100!1000 EB !1000 Olpadronate 100!1000 Ibandronate 1000!10,000 Risedronate 1000!10,000 YH 529 O10,000 Zoledronate O10,000 Reprinted with permission from Bell and Johnson (34). The pharmacokinetics of ibandronate is similar to that of other nitrogen-containing bisphosphonates. Ibandronate has a fast and specific bone uptake (40250%) regardless of dose, dosing regimen, or underlying disease (44). The agent is rapidly absorbed in the upper areas of the GI tract and has a low bioavailability (0.63%), which is further reduced in the presence of food or calcium (28,44). Within hours of ingestion, ibandronate binds to bone or is excreted unmetabolized in the urine (44). The in vitro binding and release of ibandronate is similar to that of other nitrogen-containing bisphosphonates, with minimal accumulation in soft tissues and a slow release from bone occurring over months to years (44). It is recommended that women receiving bisphosphonates, including ibandronate, receive concomitant adequate intake of calcium and vitamin D. As was demonstrated in the preclinical trials, efficacy is determined by the total cumulative dose rather than the frequency of the dosing schedule (54). Evolution of Ibandronate Clinical Trials for PMO Increasingly Longer Dosing Intervals Ibandronate was originally studied and approved for daily oral dosing (2.5 mg/d). However, the enhanced potency of ibandronate suggested that longer intervals between dose administrations might provide comparable efficacy and possibly enhance safety and adherence. Investigations have substantiated the comparable efficacy of daily dosing with a variety of longer-dosing regimens, including IV injections scheduled once every 3 months, a weekly oral program, intermittent oral administration, and a new monthly oral regimen. Intermittent IV Regimen The pharmacodynamics and high in vivo potency of ibandronate are compatible with IV administration as a bolus injection (2 mg given over s), which may be preferred for patients who have difficulty swallowing or who are taking other medications (55). Owing to its high potency and subsequently lower mg dose, intermittent IV injection of ibandronate, as compared with rapid IV infusion of other bisphosphonates, allows for enhanced bioavailability and may minimize potential GI side effects and/or risk of renal adverse events (39,56). Thiebaud et al. (57) investigated the safety and efficacy of bolus IV administration of ibandronate (0.25, 0.5, 1, or 2 mg) given once every 3 mo to postmenopausal women with osteoporosis (lumbar spine BMD! 22.5 SD T-score). Compared with placebo, treatment with all four doses of ibandronate led to increases in lumbar spine BMD. Three of the four treatment arms demonstrated a significant dose-dependent increase in lumbar spine BMD at 12 months, ranging from 3.5% (0.5 mg; p ) to 5.2% (2 mg; p ), with a similar trend for hip BMD. A clear dose-dependent effect on biochemical markers was apparent 1 month after the first injection. The adverse effect profile of all four treatment arms was comparable to that of placebo, with no dose-dependent changes. The Ibandronate Intravenous Study Group enrolled 629 postmenopausal women into a multicenter, double-blind,

5 62 Dempster and Bolognese placebo-controlled trial of IV ibandronate injections (58). Two women received no study drug; the remaining women were randomized to receive either placebo (n 5 156) or ibandronate 0.5 mg (n 5 157), 1.0 mg (n 5 156), or 2.0 mg (n 5 158) by IV bolus injection every 3 months for 1 yr (four injections). As was observed in the Thiebaud study, mean lumbar spine ( p ) and total hip ( p! 0.05) BMD increased in a dose-dependent manner vs placebo at 12 months. Although all three doses suppressed biochemical markers of bone resorption (serum C-telopeptide and urinary C-telopeptide/creatinine), the greatest effect was observed with the two highest doses after 12 months. The 2-mg dose was shown to have the greatest effect in preventing bone loss and normalizing bone turnover, with the greatest benefits among osteopenic women who were 3 yr postmenopausal. The observed mean gains in lumbar spine BMD (2.5%) and total hip (1.7%) associated with the 2-mg IV dose once every 3 mo are similar to the gains observed with daily administration of other oral bisphosphonates (58). A recent trial highlighted the suboptimal clinical effects associated with the ibandronate IV dosing regimens utilizing! 2 mg. Recker et al. (59) investigated the dose-dependent benefits of IV injections of ibandronate to BMD and suppression of bone turnover in a recent phase III study involving 2862 women with PMO (59). Women received injections every 3 mo of either placebo (n 5 950) or ibandronate 1 mg (n 5 961) or 0.5 mg (n 5 951) for 3 yr. In a dose-dependent manner, ibandronate injections increased BMD and suppressed biochemical markers of bone turnover, albeit to a lesser extent than observed with the 2-mg IV dose or with oral ibandronate. Although incidence of morphometric vertebral fractures, the primary trial end point, was reduced in treatment groups compared to placebo, the reduction did not reach statistical significance (59). Results from the Intermittent Regimen Intravenous Ibandronate Study substantiated that the optimal dose for IV injections of ibandronate is 2 mg administered once every 3 mo (56). The 2-mg dose was found to be well tolerated (56). These studies support earlier preclinical studies suggesting that it is the total cumulative dose, and not the specific dosing regimen, that determines efficacy. (Fig. 2). In addition, daily and intermittent treatment regimens resulted in comparable and significant increases in bone density of the spine (6.5% and 5.7%, respectively) and total hip (3.4% and 2.9%, respectively) vs placebo (p! ) (43). As would be expected, both treatment regimens also led to significant and comparable decreases in urinary excretion of the C- and N-telopeptides of the a-chain of type 1 collagen compared to placebo ( p! ). The median decreases in these biochemical markers were evident by the third month after treatment initiation. The study found no significant differences in frequency of upper GI adverse events among any of the study arms (43). The BONE study (North America and Europe) was the first to prospectively examine the antifracture efficacy of a nitrogencontaining bisphosphonate when administered less frequently than daily. In the North American subgroup, both oral daily and intermittent ibandronate reduced the risk of new vertebral fractures by 60% and 54%, respectively, compared with placebo ( p and p , respectively) (41). Both the daily and intermittent dosing regimens were equally well tolerated. The four-times-per-year regimen proved to be equally efficacious to the daily regimen. A similar trial involving 240 women with PMO found equivalent mean lumbar spine and total hip gains after 2 yr of either daily (2.5 mg) or intermittent (20 mg every other day for 12 doses every 3 mo) treatment with ibandronate. Changes in biochemical markers were similar between the two active treatment arms and were clinically significant compared to placebo at 12 mo (60). Weekly Oral Ibandronate A noninferiority study by Cooper et al. (61) demonstrated comparable efficacy between weekly oral administration of Oral Ibandronate: Efficacy Determined by Total Dose, Not Dosing Frequency Intermittent Oral Ibandronate The BONE study examined the efficacy and tolerability of a unique intermittent dosing regimen that allowed a dose-free interval of O 2 mo(43). Approximately 3000 women with PMO and at least one vertebral fracture were randomized to receive placebo, oral daily ibandronate (2.5 mg), or oral intermittent ibandronate (20 mg every other day for 12 doses every 3 mo). This 3-yr fracture prevention trial demonstrated overall significant relative risk reductions of new radiographically diagnosed or confirmed vertebral fracture of 62% with daily dosing and 50% with intermittent dosing vs placebo Fig. 2. Cumulative effect of oral daily and intermittent ibandronate on new radiographic vertebral fractures during each year of a 3-yr study. Reprinted with permission from Chesnut et al. (43).

6 Ibandronate Once-Monthly Therapy 63 ibandronate 20 mg and oral daily administration of 2.5 mg over 48 wk. Both daily and weekly regimens produced substantial and nearly identical increases in lumbar spine BMD (3.47% and 3.53%, respectively), hip BMD (2.15% and 1.74%, respectively), and femoral neck (1.62% and 1.67%, respectively), as well as similar and substantial decreases in biochemical markers of bone turnover (61). Weekly administration led to an enhanced safety profile over daily administration, with 25% fewer GI adverse events reported. The authors concluded that weekly ibandronate is as safe and effective as daily dosing. Tanko et al. (54) recruited 200 healthy postmenopausal women to participate in a study investigating the comparative efficacy of seven different ibandronate regimens, including daily (2.5 mg) or weekly (20 mg/wk) dosing for 84 days, as well as five intermittent dosing regimens that attempted to mimic noncompliance. The study demonstrated that frequency of dosing is less important than achieving optimal dosing levels within a period of time with regard to markers of bone turnover, with the weekly dosing regimen (cumulative dose 240 mg) demonstrating slightly greater inhibition of bone turnover than the daily regimen (cumulative dose 210 mg) (54). A multicenter, placebo-controlled phase II/III study by the Oral Ibandronate Group determined that once-weekly therapy with oral ibandronate (20 mg) for 24 mo is a safe and effective treatment for women with PMO (62). The therapeutic outcomes with the 20-mg/wk dosing regimen were comparable to those observed with daily ibandronate (2.5 mg) regimens. Monthly Oral Dosing The efficacy and safety of weekly and intermittent ibandronate dosing regimens led researchers to investigate a monthly oral dosing regimen. A 2-yr, multinational, phase III, noninferiority study (Monthly Oral Ibandronate in Ladies) compared daily oral ibandronate (2.5 mg) with 3 monthly regimens [50/50 mg (single doses of 50-mg each on 2 consecutive days), 100 mg (single day), and 150 mg (single day)] in 1609 postmenopausal women with osteoporosis (26). The primary efficacy endpoint in this study was percent change from baseline in mean lumbar spine BMD. Results after 1 yr demonstrated therapeutic noninferiority of all monthly regimens to daily ibandronate, and the 150-mg/mo regimen was found to be superior to the daily regimen ( p ) (26). Comparable lumbar spine BMD increases were observed in all treatment groups: 3.9% (2.5 mg/d), 4.3% (50 mg/50 mg), 4.1% (100 mg), and 4.9% (150 mg) (Fig. 3), with similar increases observed in hip BMD (total hip, trochanter, and femoral neck). Significant, dose-dependent decreases in biochemical markers of bone turnover were observed with all monthly regimens (median reductions in serum C-telopeptide %, 66.7%, 75.8%, respectively). The 150-mg/mo regimen provided the greatest suppression at all time points. No differences in type or frequency of adverse events were apparent between groups, and upper GI adverse events irrespective of relationship to study drug were the most commonly Fig. 3. Mean (standard deviation) percent change from baseline in lumbar spine bone mineral density with daily and monthly oral ibandronate after 1 yr (per protocol population). Reprinted with permission from Miller et al. (26). reported events. The incidence of upper GI adverse events irrespective of relationship to study drug was low and comparable across all treatment groups (15.9%, 21.7%, and 16.9% with the 50/50-mg, 100-mg, and 150-mg monthly oral regimens compared with 18.0% in the daily oral group). In contrast, the 150-mg group had a slightly higher incidence of reports of flu-like symptoms within 3 d of administration than the daily regimen (8.3% vs 2.8%, respectively). Most events were mild to moderate in severity and resolved without treatment. In summary, monthly administration of ibandronate was shown to be comparable in safety and efficacy to daily ibandronate (2.5 mg) for the management of PMO. Additionally, 150 mg/mo of ibandronate was demonstrated to be superior to daily administration. The convenience of a monthly oral regimen that affords at least comparable efficacy and safety to daily administration may facilitate greater patient adherence, thereby leading to improved therapeutic outcomes. In conclusion, currently available bisphosphonate agents have similar efficacy, safety, and tolerability. Nevertheless, poor adherence with daily and even weekly dosing regimens results in an excess of preventable fractures among postmenopausal women. Ibandronate is the most recent addition to the PMO armamentarium. The very high potency of this nitrogen-containing bisphosphonate allows for lower dosing levels and less-frequent utilizationdwith similar efficacy and tolerability. Ibandronate can be administered as a daily, weekly, or monthly oral dose, as well as through an IV bolus injection every 3 mo. When administered daily, oral ibandronate (2.5 mg) was associated with a 62% reduction in relative risk of new vertebral fractures over 3 yr. Numerous preclinical and clinical trials have demonstrated that it is the total cumulative dose of ibandronate, and not the dosing frequency, that determines efficacy. These trials have demonstrated comparable efficacy between daily, weekly (20 mg), and monthly dosing

7 64 Dempster and Bolognese (150 mg) in terms of increased BMD in the lumbar spine and total hip, as well as biochemical markers of bone turnover. Prevention and management of PMO requires long-term adherence to an effective therapeutic regimen. While all current bisphosphonate agents afford protection against osteoporosis-related fracture, adherence with daily and weekly bisphosphonate therapies is notably poor, resulting in a high incidence of otherwise preventable fractures. The convenience of a monthly regimen may be preferable to a more frequent dosing regimen, with the potential of improving clinical outcomes and reducing the risk of fracture in the growing population of postmenopausal women. Acknowledgments We would like to thank Lynne Kolton Schneider, PhD, for help in preparation of the manuscript. References 1. 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