Injectable Bisphosphonates for the Treatment of Osteoporosis

Abstract

Bisphosphonates are the current mainstay of the management of osteoporosis worldwide. Oral daily and weekly formulations have been linked to poor adherence, yielding a decrease in antifracture efficacy, in real-life settings. Development of new bisphosphonates, with increased antiosteoclastic potency and affinity for bone matrix allowed intravenous administration and intervals between dosingsto be higher than weekly. Ibandronate and zoledronic acid have been investigated in established osteoporosis. Quarterly injections of ibandronate (3 mg) have been shown to be at least as effective in increasing bone mineral density and reducing bone turnover markers as the oral ibandronate regimen, which has proven antifracture efficacy. A once-yearly infusion of zoledronic acid (5 mg) during a 3-year period significantly reduced the risk of vertebral, hip and other fractures. Intravenous administration of bisphosphonates can now be considered as an important component of the management of postmenopausal osteoporosis.

During the last two decades, several medications have been granted marketing authorization for the management of osteoporosis. Bisphosphonates are the most widely prescribed drugs in this area.

Regardless of the respective mechanism of action of the aminobisphosphonates versus non-nitrogen-containing bisphosphonates, the net result of their action is a major inhibition of osteoclastic bone resorption, resulting in decreased bone resorption activity of mature osteoclasts and inducing osteoclast apoptosis.

Oral daily bisphosphonates have been unequivocally shown to reduce the risk of spine (alendronate, risedronate, ibandronate) and nonspine (alendronate, risedronate) fractures in women with established osteoporosis [1]. However, the bisphosphonates are associated with stringent dosage and administration procedures, and some patients may experience upper gastrointestinal adverse effects following administration [2,3]. Consequently, approximately half of patients discontinue daily bisphosphonate therapy within 1 year, which negatively affects treatment outcomes, leading to a reduced antifracture effect [2,4–7]. Improving patient adherence to osteoporosis therapy is a complex process that involves effective patient–provider communication, association of treatment with expected benefits and/or positive treatment feedback (i.e., using measurements of markers of bone turnover or bone mineral density [BMD] measurements) [5]. Another primary component of improving adherence is to use simplified or user-friendly treatment programmes. It has been found across a range of therapeutic areas that adherence to medication is inversely related to frequency of administration [6]. Therefore, all currently marketed or developed bisphosphonates are now offering formulations with intermittent dosage regimens [7]. In addition to increasing the intervals between dosings, another way to optimize adherence to therapy is to have the drug administered by a health professional. Subsequently, recent developments in the field of bisphosphonate treatment for osteoporosis include intravenous injections or infusions of potent bisphosphonates. The aim of this article is to review the current evidence that intermittent intravenous bisphosphonates may be considered an important option for treatment of osteoporosis.

Historical background

Although intermittent intravenous pamidronic acid has been consistently prescribed off label for the management of osteoporosis throughout Europe and North America over the past 20 years, this compound has never been subjected to an appropriately designed study of its antifracture efficacy in osteoporosis. Various regimens have been investigated [8,9], mostly using a daily intravenous infusion of 30 mg, but with intervals between doses varying from a single monthly infusion to infusion on three consecutive days or intervals defined according to fasting calcium excretion. All of these studies concluded that intravenous pamidronic acid is effective in reducing bone turnover and/or increasing BMD at the spine and hip. However, notwithstanding a report suggesting that intravenous pamidronic acid 30 mg on three consecutive days provides rapid (7 days) and sustained (30 days) pain relief in patients with recent vertebral compression fracture [10], the lack of robust antifracture efficacy results prevents further consideration of intermittent pamidronic acid as an appropriate candidate for the long-term management of osteoporosis.

Ibandronate

Oral ibandronate 2.5 mg/day and intermittent administration of ibandronate delivering a similar cumulative exposure (20 mg every other day for 12 doses every 3 months) have been shown in a 3-year, placebo-controlled trial in 2946 osteoporotic women with prevalent spine fracture to significantly reduce spine fracture rate. The relative risk (RR) reductions compared with placebo were 62% (RR: 0.38; 95% CI: 0.25–0.59) and 50% (RR: 0.50; 95% CI: 0.34–0.74) for the daily and intermittent treatments groups, respectively. This difference in RR reductions was not statistically significant. The incidence of nonspine fractures was similar between the ibandronate and placebo groups after 3 years (9.1, 8.9 and 8.2% in the daily treatment, intermittent treatments and placebo groups, respectively). Again, the difference between arms was not significant. A post-hoc analysis has suggested a 69% reduction in nonspine fractures in the daily group (RR: 0.3; 95% CI: 0.12–0.70) when considering high-risk patients with a femoral neck T-score less than −3.0 [11].

Intermittent intravenous administration of ibandronate was investigated in postmenopausal osteoporotic women randomized to either ibandronate 2 mg every 2 months or 3 mg every 3 months, or oral ibandronate 2.5 mg/day [12]. The primary efficacy end point was a relative change from baseline in lumbar spine BMD after 1 year. The study group comprised 1395 women (aged 55–80 years) who were at least 5 years postmenopausal. All patients had osteoporosis (lumbar spine [L2–L4] BMD T-score less than −2.5). At 1 year, the mean lumbar spine BMD increases were: 5.1% among 353 patients receiving ibandronate 2 mg every 2 months, 4.8% in 365 patients receiving ibandronate 3 mg every 3 months, and 3.8% in 377 patients receiving oral ibandronate 2.5 mg/day. Both of the intravenous regimens were superior (p < 0.001) to the oral regimen. Hip BMD increases (at all regions of interest) were also greater in the groups receiving medication intravenously than in the group receiving ibandronate orally. The conclusion of the investigators is that, as assessed by changes in BMD, intravenous injections of ibandronate 2 mg every 2 months or 3 mg every 3 months are at least as effective as the oral regimen of 2.5 mg/day, which has proven antifracture efficacy and is well tolerated [2,5,13,14]. Both of the intravenous regimens did not compromise renal function.

Zoledronic acid

Zoledronic acid is one of the most potent bisphosphonates available for clinical use. It is currently approved as an intravenous treatment for Paget's disease of bone, hypercalcemia of malignancy and/or metastatic bone diseases. In Paget's disease of bone, a single infusion of zoledronic acid has been shown to produce more rapid, more complete and more sustained inhibition of bone turnover markers than daily treatment with risedronic acid [15]. In a Phase II study, performed in postmenopausal women with low BMD, increases in BMD were recorded for intravenous doses of zoledronic acid 0.25 mg, 0.5 mg or 1 mg at 3-month intervals, with values for the spine being 4.3–5.1% higher than those in the placebo group, and values for the femoral neck being 3.1–3.5% higher than those in the placebo group [16]. Biochemical markers of bone resorption were significantly suppressed throughout the study (12 months) in all of the zoledronic acid groups. The most important finding of this study was that a single baseline dose of zoledronic acid 4 mg produced equivalent suppression of bone turnover and increases in bone mass to the more frequently administered smaller doses of the same agent. These findings strongly suggest that this agent may be able to be given as infrequently as once a year for osteoporosis therapy. The results of this study therefore provided the rationale for initiating a Phase III fracture trial assessing the efficacy and safety of an annual infusion of zoledronic acid in women with postmenopausal osteoporosis [16].

In this double-blind, placebo-controlled trial, 3889 patients (mean age: 73 years) were randomly assigned to receive a single 15-min infusion of zoledronic acid (5 mg) and 3876 were assigned to receive placebo at baseline, at 12 months and at 24 months; the patients were followed until 36 months. Primary end points were new vertebral fracture (in patients not taking concomitant osteoporosis medications) and hip fracture (in all patients). Secondary end points included BMD, bone turnover markers and safety outcomes. Treatment with zoledronic acid reduced the risk of morphometric vertebral fracture by 70% during a 3-year period, as compared with placebo (3.3% in the zoledronic acid group vs 10.9% in the placebo group; RR:0.30; 95% CI: 0.24–0.38) and reduced the risk of hip fracture by 41% (1.4% in the zoledronic acid group vs 2.5% in the placebo group; hazard ratio: 0.59; 95% CI: 0.42–0.83). Nonvertebral fractures, clinical fractures, and clinical vertebral fractures were reduced by 25, 33 and 77%, respectively (p < 0.001 for all comparisons). Zoledronic acid was also associated with a significant increase in BMD and decrease in bone metabolism markers. Adverse events, including change in renal function, were similar in the two study groups. However, serious atrial fibrillation occurred more frequently in the zoledronic acid group (in 50 vs 20 patients; p < 0.001) [17]. Among the 50 patients, the events occurred more than 30 days after infusion in 47 patients. Among 559 patients who underwent electrocardiography, the prevalence of atrial fibrillation (2.1% in the zoledronic acid group and 2.8% in the placebo group) and other electrocadriographic abnormalities did not differ significantly between the study groups. No difference was observed in the occurrence of the serious adverse events of stroke (2.3% in both study groups); the incidence of death due to stroke was 0.5% in the zoledronic acid group and 0.3% in the placebo group (p = 0.15). There were no spontaneous reports of osteonecrosis of the jaw. From a search of the trial database of adverse events, which was followed by expert adjudication, two cases of potential osteonecrosis of the jaw were identified (one in the placebo group and one in the zoledronic acid group). In both patients, delayed healing followed surgical manipulation, and both cases subsequently resolved with antibiotic therapy and debridement. A similar search for, and review of, osteonecrosis of the hip or knee revealed seven cases (three in the placebo group and four in the zoledronic acid group). No adverse effect on fracture healing was observed, with three cases of nonunion (one in the placebo group and two in the zoledronic acid group). There was a significant increase (p < 0.001) in patients presenting with the five most common postdose symptoms (i.e., pyrexia, myalgia, influenza-like symptoms, headache and arthralgia, <3 days after infusion) after the first infusion. However, the number with symptoms after subsequent infusions decreased substantially. In a 5-year study involving 119 postmenopausal women, zoledronic acid 4 mg given once-yearly for 2, 3 or 5 years was well tolerated with no evidence of excessive bone turnover reduction or any safety signals. Detailed analysis of bone marker changes, however, suggests that this drug regimen causes insufficient reduction of remodeling activity in a third of patients [18]. In another study, zoledronic acid administration for 1 year to patients with hormone-sensitive prostate cancer and bone metastasis, who were receiving androgen-deprivation therapy, was safe and prevented bone loss, as demonstrated by significant increases in BMD and sustained suppression of biochemical markers of bone turnover [19].

Conclusion

In order to be considered as a first-line treatment for osteoporosis, a new chemical entity should combine an unequivocal demonstration of antifracture efficacy at the axial and appendicular skeleton, long-term skeletal and general safety, and a mode of administration that optimizes long-term adherence to treatment. Whereas oral daily and weekly bisphosphonates fulfil the first two of these requirements, they have been consistently linked to poor adherence. Demonstration that intravenous administration of bisphosphonates, quarterly (ibandronate) or yearly (zoledronic acid), are able to provide skeletal benefits at least similar to those observed with the oral formulations, without jeopardizing the long-term tolerance, are undoubtedly significant improvements in the management of osteoporosis. Their success in the real world will reflect the acceptance of injections or infusions by the patients and the medical community. Further health economic analyses are needed to clearly define the population to be treated as well as the settings (e.g., nurses, primary care physicians, hospitals and so on) where these injections or infusions should be performed.

Future perspective

The demonstration that intravenous bisphosphonates induce similar or higher benefits compared with the oral medications, without compromising long-term skeletal and general safety will, most likely, significantly impact on the prescribing habits in the management of osteoporosis. The acceptance of the intravenous route will depend upon the local health services and reimbursement schemes. Few further developments are currently considered in the therapeutic class of bisphosphonates. Combination of oral bisphosphonates with vitamin D and/or calcium are unlikely to produce sufficient incremental efficacy and compliance, compared with the original preparations, to challenge the results observed with intravenous ibandronate or zoledronic acid. The future of the management of osteoporosis will probably be directed to either specific inhibitors of bone resorption (e.g., denosumab), selective stimulators of bone formation (e.g., monoclonal antibody against sclerostin) or compounds uncoupling bone formation and bone resorption (strontium ranelate).

Executive summary

Historical background

• Changes in bone mineral density observed during quarterly intravenous administration of ibandronic acid are superior to those observed, during the same period, with the daily oral dose that was linked to a significant reduction in vertebral fractures.

• Superior increases in bone mineral density were observed, with the intravenous formulation, at the spine and at the hip.

Ibandronate

• Bisphosphonates are the most widely prescribed drugs in osteoporosis today. Daily or weekly oral administration of bisphosphonates is linked to poor adherence to treatment, which may compromise the long-term efficacy of the compounds.

• Bisphosphonates with increased antiosteoclastic potency and affinity for bone matrix have been developed with the aim of increasing intervals between doses.

Zoledronic acid

• Yearly infusion of zoledronic acid results, during a 3-year period, in a reduction in the risk of vertebral, hip and other fractures, with no evidence of increased risk of osteonecrosis of the jaw or renal toxicity.