Review

Continuing Medical EducationNature Clinical Practice Endocrinology & Metabolism (2006) 2, 211-219
doi:10.1038/ncpendmet0121  
Received 31 August 2005 | Accepted 3 January 2006

Drug Insight: bisphosphonates for postmenopausal osteoporosis

Roland D Chapurlat and Pierre D Delmas*  About the authors

Correspondence *Department of Rheumatology and Bone Diseases and INSERM Unit 403, Hôpital E Herriot, Lyon 69437, France

Email delmas@lyon.inserm.fr

Summary

Bisphosphonates are potent antiresorptive agents, which have largely been used for the treatment of postmenopausal osteoporosis during the past 10 years. When embedded in bone matrix, bisphosphonates are taken up by osteoclasts engaged in bone resorption, leading—mainly by inhibition of farnesyl diphosphate synthase, a key enzyme of the mevalonate pathway—to osteoclast apoptosis. Bone resorption decreases, with consequent improvement in the mechanical properties of bone and a reduced risk of fracture. Alendronate and risedronate are oral nitrogen-containing bisphosphonates. Several randomized, placebo-controlled trials have shown the ability of these bisphosphonates to halve the risk of vertebral fracture when taken daily for 3 years. Nonvertebral fracture risk, including that at the hip, was also significantly decreased. Weekly regimens have simplified the administration of bisphosphonates and, probably, improved adherence to treatment. A significant reduction in the risk of vertebral fracture has also been demonstrated with an intermittent regimen of ibandronate, which is a new, potent, nitrogen-containing bisphosphonate. Ibandronate was recently marketed for use in an oral, once-monthly dose of 150 mg, with the goal of improving compliance. Bisphosphonates are usually well tolerated in the long term. Intravenous administration of bisphosphonates in women with osteoporosis, which is currently under investigation, might be an interesting future option for women who cannot tolerate oral regimens, and for enhancing compliance.

Review criteria

In this review, we have focused on articles and abstracts between 1998 and 2005, which were published in the internal-medicine and endocrinology literature and reported on the pharmacology and clinical evaluation of bisphosphonates. The principal sources were PubMed and journals covering endocrinology and internal medicine.

Keywords:

alendronate, bisphosphonates, ibandronate, osteoporosis, risedronate

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Introduction

The goal of treatment in patients with postmenopausal osteoporosis is to reduce the risk of fractures. The clinical efficacy of new drugs to treat osteoporosis must be judged in clinical trials that use the reduction of fracture risk as the main end point, rather than trials that use surrogate end points, such as changes in BMD. Bisphosphonates are the first class of drugs that unequivocally demonstrated their ability to reduce fracture risk in good-quality clinical trials. Today, they are often the first-line therapy for postmenopausal osteoporosis.

These compounds have been developed, in various forms and dosages, to decrease osteoclastic bone resorption. The first such compound to be marketed for osteoporosis was etidronate, but its antifracture efficacy remains controversial, especially at nonvertebral sites. Etidronate is no longer used in most countries and, therefore, we will not describe data for this compound. We will focus this review on more potent bisphosphonates—their pharmacology and their clinical efficacy—and the potential use of newer molecules.

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Pharmacology

Bisphosphonates are characterized by a phosphorus–carbon–phosphorus (P–C–P) structure so they are chemical analogs of inorganic pyrophosphate, which is characterized by a phosphorus–oxygen–phosphorus (P–O–P) structure (Figure 1). The P–C–P structure is resistant to enzymatic degradation. Bisphosphonates have a strong affinity for solid-phase calcium phosphate. The pharmacologic properties of each bisphosphonate depend on the structure of the two side chains.1 The P–C–P moiety and first side chain, R1 (Figure 1), are involved in binding the bisphosphonate to the mineralized matrix ('bone hook'), whereas the second chain, R2, is responsible for the biological properties. The affinity for mineral calcium is increased by the presence of a hydroxyl group in the R1 chain.2 The potency of the compound is enhanced by the presence of a nitrogen atom in the R2 chain.1

Figure 1 Structure of pyrophosphate and bisphosphonates
Figure 1 : Structure of pyrophosphate and bisphosphonates Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

P–C–P, phosphorus–carbon–phosphorus moiety.

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Pharmacokinetics

Bisphosphonates have common properties, including poor intestinal absorption, high affinity for bone mineral, inhibitory effects on osteoclastic bone resorption, prolonged bone retention, and elimination in the urine.1 Absorption is impaired by food—especially foods containing calcium—so bisphosphonates should be given when fasting, with water, and without dairy products, orange juice, or drinks containing caffeine. The patient should not eat for at least 30 min after taking bisphosphonates.3 The plasma half-life of bisphosphonates is short, and essentially all bisphosphonates are cleared from plasma within 6 h of administration. Approximately 50% of the absorbed dose is concentrated in the skeleton, depending on the rate of bone turnover and the type of bisphosphonate, and the remaining amount is excreted, unaltered, in the urine.

Bisphosphonates stay embedded in bone for a very long time; for example, the terminal half-life of alendronate in humans has been estimated to be about 10 years. No serum metabolite of bisphosphonates has been described so far. Bisphosphonates seem to bind to plasma proteins, and some of them are eliminated by a renal tubular secretory mechanism.4, 5 The suppressive effect of bisphosphonates on bone resorption is delayed by at least 1–2 days, in contrast to the more rapid effect of calcitonin. Both the concentration of bisphosphonate present in bone mineral at any time and the total dose administered over a long period of time seem to be important for the magnitude of the reduction in bone turnover.3, 4, 5, 6, 7 Drug interactions are limited to aminoglycoside antibiotics, with which severe hypocalcemia can occur.8 Calcium and magnesium salts impair intestinal absorption of oral bisphosphonates.

Pharmacodynamics

Bisphosphonates are internalized by ostoclasts, through endocytosis, and inhibit bone resorption by cellular effects that impair osteoclast recruitment, differentiation, and action on the bone surface.9 Bisphosphonates are released from bone mineral as a result of the dissolution of hydroxyapatite crystals by the acidic pH beneath osteoclasts, which are the most exposed to bisphosphonate of all bone cells. Exposed osteoclasts lose their ruffled border, and their cytoskeleton is also affected. So, bisphosphonates inhibit osteoclastic bone resorption by a direct effect on osteoclasts.

It has been suggested that bisphosphonates can be divided into two classes according to their modes of action. Thus, it has been shown, first in amoebae10 and then in J774 macrophage-like cells,11 that compounds closely related to pyrophosphate (e.g. etidronate, clodronate, and tiludronate), can be transformed into an analog of ATP. The resulting metabolites, containing the P–C–P moiety, are potentially cytotoxic. It seems that these three bisphosphonates, but not bisphosphonates with a larger R2 side chain or containing a nitrogen group, can be accommodated in the active site of type II aminoacyl-transfer-RNA synthetases and thus replace pyrophosphate.2 Accumulation of this analog of ATP in the cell cytoplasm probably results in inhibition of numerous enzymes and, therefore, increasing the rate of apoptosis in osteoclasts.

By contrast, more potent, nitrogen-containing bisphosphonates (N-bisphosphonates, such as alendronate and ibandronate) are not metabolized by osteoclasts and have different mechanisms of action from that of etidronate, clodronate, and tiludronate. These N-bisphosphonates inhibit the MEVALONATE PATHWAY, which is critical for production of cholesterol and isoprenoid lipids.12 Some of these lipids (e.g. farnesyl pyrophosphate [FPP] and geranylgeranyl pyrophosphate) are necessary for the prenylation of some GTPases (e.g. Ras, Rho, and Rac). These GTPases regulate osteoclast morphology, cytoskeletal arrangement, membrane ruffling, trafficking, and cell survival (i.e. they regulate apoptosis).13 These N-bisphosphonates could, therefore, indirectly inhibit prenylation of proteins, with loss of function of small GTPases. The potency of N-bisphosphonates seems to be proportional to their ability to inhibit protein prenylation. N-bisphosphonates are potent inhibitors of FPP synthase, thereby preventing the synthesis of FPP and geranylgeranyl pyrophosphate, which are required for protein prenylation, with an increase in the osteoclast apoptosis rate as a consequence.14

Osteoblasts could also mediate the activity of bisphosphonates, by inducing the production of an osteoclast-inhibitory factor, although this has never been characterized.15 The structure and clinical relevance of this factor remain to be determined. Bisphosphonates prevent osteocyte and osteoblast apoptosis, probably by interfering with the phosphorylated fraction of extracellular-signal-regulated kinases.16 The formation of osteoblast precursors is also stimulated by bisphosphonates in murine and human bone-marrow cultures in vitro, as well as osteoblastogenesis in mice in vivo;17 nevertheless, in 231 women with postmenopausal osteoporosis who were treated with alendronate, there was no evidence of an increase in bone formation. By contrast, there was a marked reduction in the activation frequency of new REMODELING UNITS and active BONE-FORMING SURFACES.18 The increase in BMD induced by bisphosphonates seems to be related to an initial filling of the remodeling space, followed by an increased degree of mineralization that results from the globally slowed rate of bone turnover.19

Although bisphosphonates act mostly through inhibition of protein prenylation, their ability to adsorb to bone mineral also contributes to their antiresorptive potency and duration of action. The binding affinities of various bisphosphonates were shown to vary according to differences in the R2 side chain, with a rank order (from highest to lowest) of zoledronate > alendronate > ibandronate = risedronate > etidronate.20 The clinical differences between these different compounds, such as potency, pharmacokinetics, and persistence of effect, probably result, at least in part, from this variable binding affinity.

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Clinical efficacy

Two bisphosphonates—alendronate and risedronate—have been used in the treatment of postmenopausal osteoporosis for several years, with a daily dosage regimen. Recently, they have been marketed with weekly dosage regimens. Ibandronate is now available for use in a monthly dosage regimen. The antifracture efficacy of these three compounds is summarized in Figure 2.

Figure 2 Antifracture efficacy of bisphosphonates
Figure 2 : Antifracture efficacy of bisphosphonates Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, or to obtain a text description, please contact npg@nature.com

In the first Fracture Intervention Trial,24 patients with prevalent vertebral fractures were given alendronate (5 mg daily) for 2 years and then either alendronate (10 mg daily) or placebo for a further year. In the second Fracture Intervention Trial,25 patients without prevalent vertebral fractures (aged 55–80 years, with a T score below -1.6 according to the National Health and Nutrition Examination Survey reference database) were given alendronate (5 mg daily) for 2 years and then either alendronate (10 mg daily) or placebo for 2 more years. In the North American vertebral fractures trial32 and the multinational vertebral fractures trial,33 women with prevalent vertebral fractures received risedronate (5 mg daily) or placebo for 3 years. In the Hip Intervention Program study,34 women with prevalent vertebral fractures and women without prevalent fractures were enrolled to receive risedronate (either 2.5 mg or 5.0 mg daily) or placebo for 3 years. In the ibandronate trial,41 women with prevalent vertebral fractures received ibandronate (2.5 mg daily or intermittent) or placebo for 36 months. A subgroup analysis showed a relative-risk reduction for nonvertebral fractures with oral daily (69%; P = 0.013) and oral intermittent (37%; P = 0.22) ibandronate in patients with a baseline bone mineral density T score less than -3.0 at the femoral neck.HIP, Hip Intervention Program; FIT, Fracture Intervention Trial; VERT-MN, multinational vertebral fractures trial; VERT-NA, North American vertebral fractures trial.

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Alendronate

Alendronate is an N-bisphosphonate that prevents bone loss in women without osteoporosis when taken at an oral dose of 5 mg daily,21 and increases BMD at the hip and spine in women with osteoporosis at an oral dose of either 5 mg or 10 mg daily.22, 23 Alendronate also reduces the incidence of vertebral22, 23 and nonvertebral fractures23 in women with osteoporosis and prevalent fractures, as well as in women with osteoporosis but without prevalent fractures.24 Antifracture efficacy seems to be maintained in those women who are at the highest risk of fracture because of their advanced age or severe osteoporosis.25 The quality of life of women treated with alendronate seemed to be improved, because the number of days in bed and days of limited activity were also reduced, in the Fracture Intervention Trial (FIT).26 In these studies, the women also received calcium supplements and vitamin D when necessary.

The development of this compound has been continued in recent years, with the introduction of an intermittent weekly regimen (a 70 mg tablet once weekly, instead of the usual daily 10 mg tablet). Only studies of pharmacologic equivalence between daily and weekly alendronate regimens have been conducted, so there are no fracture data available for the intermittent weekly regimen. In a randomized double-blind trial of 1,258 postmenopausal women with osteoporosis who were assigned to receive alendronate at a dose of 70 mg once weekly, 35 mg twice weekly, or 10 mg once daily, the increases in BMD at the spine and hip and the decreases in bone turnover markers were not statistically different between the three dosage regimens.27 The incidence of clinical fractures—considered to be a secondary outcome—were similar in the three treatment groups. So, these data support the concept that once-weekly alendronate is therapeutically equivalent to daily dosing, provided that the patients are receiving an adequate cumulative dose.

The antifracture efficacy of alendronate was established in trials of 3–4 years duration, but long-term fracture data are lacking. Some patients in the initial phase-III trial were subsequently followed up, and their data showed that 10 years of treatment with alendronate was associated with a continued increase in BMD (13.7% at the lumbar spine and 6.7% at the total hip).28 In patients who stopped the medication but were followed up, BMD tended to diminish. Markers of bone turnover had a tendency to rise, but remained substantially lower than their baseline levels. No serious adverse event was described. In the FIT Long-term Extension (FLEX), patients from the FIT study who had all received alendronate for 4–5 years were randomly allocated to receive either placebo or alendronate (5 mg or 10 mg daily) and followed up for an additional 5 years.29 In those patients, BMD decreased in those who received placebo after 5 years of alendronate therapy, whereas in those still receiving alendronate, BMD tended to plateau.

Of note, biochemical markers of bone resorption remained suppressed in patients in the placebo group to the same extent as in patients receiving alendronate, suggesting that inhibition of bone resorption persisted for at least 5 years in women who had received 5 years of alendronate treatment previously. But bone resorption tended to increase mildly after 1 year in one-quarter of the patients, and this change correlated with a subsequent decrease in BMD.30 This might indicate that those women could be good candidates for restarting treatment with alendronate, but this should be proven in long-term studies, with an assessment of fracture outcome if possible. Importantly, the incidence of morphometric vertebral and nonvertebral fractures in the FLEX trial was not different between the two groups. In the few bone biopsies that were available for analysis, bone remodeling was markedly suppressed, with no obvious mineralization defect in women who had received alendronate for 10 years.31 In conclusion, the optimal duration of treatment with alendronate remains uncertain, because no significant toxicity was found after 10 years of treatment with alendronate but, on the other hand, the benefit of taking the drug for more than 5 years has also not been established.

Risedronate

The antifracture efficacy of this N-bisphosphonate has also been established in randomized, placebo-controlled trials. The incidence of new vertebral fractures in osteoporotic women treated with risedronate (5 mg daily) was reduced in two studies.32, 33 In a trial that had hip fracture as the main end point, a 40% reduction in relative risk was observed in women aged 70–79 years who had osteoporosis and were receiving risedronate (2.5 mg or 5.0 mg daily) compared with those taking placebo; by contrast, in women aged 80 years and over who were selected because of their propensity to fall but not their BMD (which was known for only 31% of women at baseline), there was no significant decrease in the risk of hip fracture in women receiving risedronate compared with those in the placebo group.34 In these studies, risedronate was well tolerated. Women enrolled in these trials also received calcium and vitamin D supplements.

Pharmacokinetic data suggest that intermittent administration of risedronate might have a similar influence on BMD compared with a daily dosage regimen, as long as the total cumulative dose is adequate.35 In a double-blind trial that randomly allocated 1,456 women to receive risedronate at doses of either 5 mg once daily, 35 mg once weekly, or 50 mg once weekly, no significant difference in the increase in BMD at the lumbar spine and hip was observed between the three treatment groups after 1 year of treatment.36 Similarly, there was no significant difference between the three treatment options in the reduction in the levels of markers of bone turnover. This was a noninferiority trial, however, so there are no fracture data for the weekly treatment regimens. On the basis of these data, a once-weekly dose of risedronate (35 mg) was marketed as an alternative to the daily dosage regimen, with the advantage of a simplified mode of administration, which might improve adherence to treatment.

In an extension to a 3-year vertebral fracture study,37 it was shown that BMD at the spine and hip continued to increase in women who had received risedronate for 7 years, whereas their biochemical markers of bone resorption remained steadily suppressed. When risedronate was stopped after 3 years of treatment, however, the level of bone resorption tended to increase for 1 year after the drug had been stopped.38 There are currently no published data on the attenuation of the therapeutic effect after a longer period of treatment with risedronate when the treatment is stopped. The differences in attenuation of the treatment effect between risedronate and alendronate could also, at least in part, stem from the difference in the degree of suppression of bone resorption. Histomorphometry performed in women who had received risedronate for 5 years showed a significant reduction in OSTEOID SURFACES and MINERALIZING SURFACES, as well as a reduction in the activation frequency of new remodeling units compared with baseline, and persistent bone remodeling could be identified.39

Ibandronate

This N-bisphosphonate was developed more recently than alendronate. Ibandronate has been shown to prevent bone loss40 and reduce the risk of vertebral fracture.41 In a double-blind, randomized, placebo-controlled trial,41 2,946 women aged 55–80 years who had a lumbar spine T SCORE below -2 and between one and four prevalent vertebral fractures were randomly allocated to receive either placebo (n = 982) or oral ibandronate. Women who received ibandronate were given either a continuous regimen (2.5 mg daily; n = 982) or an intermittent regimen (20 mg every other day for the first 24 days, followed by 9 weeks without treatment; n = 982). Both treatment groups received the same cumulative dose of ibandronate. All patients received calcium (500 mg daily) and vitamin D (400 international units). The primary end point was the incidence of new vertebral fractures after 3 years of treatment.

The incidence of new vertebral fractures (as defined by vertebral morphometry) was significantly reduced by a daily dose of oral ibandronate (62%) and by the intermittent dose of oral ibandronate (50%) compared with placebo. A significant reduction in the incidence of clinical vertebral fracture was demonstrated. Biochemical markers of bone remodeling were significantly decreased. A post hoc subgroup analysis also suggested that nonvertebral fracture risk might be reduced by ibandronate in patients with the lowest baseline BMD at the femoral neck (T score below -3). Oral ibandronate was well tolerated, with no significant difference between treatment and placebo.

The antifracture efficacy of ibandronate was initially proven with a daily regimen and an intermittent regimen that were not applicable to clinical practice. The most attractive current bisphosphonate treatment regimens are intermittent; a monthly oral dose of ibandronate (150 mg) has been evaluated. This monthly dosage was shown to be at least equivalent to the oral daily regimen that has proven antifracture efficacy.42 Surrogate markers, such as biochemical measures of bone resorption and change in BMD at the hip and spine after 1 year of treatment, were used to show that the monthly oral regimen of ibandronate (150 mg) was not inferior to the proven daily regimen. Increases in BMD at the spine were greater in patients who received a monthly dose of ibandronate than in patients who received a daily dose. There are no fracture data available for the monthly dosage regimen of ibandronate, which is also the case for the weekly treatment regimens of alendronate and risedronate.

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Potential future treatment options for bisphosphonates

Intermittent administration of intravenous bisphosphonates could be useful for treating postmenopausal osteoporosis when adherence to treatment or gastrointestinal tolerance of oral bisphosphonates is an issue, or because of patient preference. Several compounds with 3-monthly or annual schedules are currently under development.

Ibandronate

Intravenous ibandronate was also tested in a trial with fracture as the main endpoint. In this trial,43 2,862 postmenopausal women with a BMD T score at the spine of -2 or lower and at least one vertebral fracture were randomly allocated (in a blinded fashion) to receive either placebo or intravenous injections of ibandronate (0.5 mg or 1.0 mg) every 3 months for 3 years. All patients received calcium (500 mg daily) and vitamin D (400 international units daily). After 3 years, BMD at the spine increased by about 5.0% from baseline, and the BMD at the femoral trochanter increased by about 3.5%. The incidence of vertebral fracture was low in women in both the placebo and 1 mg ibandronate groups (10% compared with 8%, respectively), corresponding to a (nonsignificant) reduction of 24% in risk of vertebral fracture in the intention-to-treat analysis.

Choosing an adequate cumulative dose and treatment interval for intermittent treatment regimens of bisphosphonates is critical, as shown with the various trials that have tested the antifracture efficacy of ibandronate. A recent trial showed that intravenous infusion of 2 mg ibandronate every 3 months was associated with larger increases in BMD than 1 mg ibandronate at the same interval between intravenous infusions.44 Ongoing studies are testing the hypothesis that intravenous infusions of 3 mg ibandronate every 3 months are no less efficacious than the standard daily regimen of on changes of surrogate markers, such as BMD and bone turnover.

Zoledronate

Zoledronate is a potent N-bisphosphonate, which is used in the treatment of several conditions: hypercalcemia; multiple myeloma; bone loss caused by androgen deficiency in men treated for prostate cancer; bone metastases in men with prostate cancer; and osteolytic bone metastases. Its value in the treatment of postmenopausal osteoporosis is also under investigation.

In a phase-II, randomized, double-blind, placebo-controlled trial, 351 postmenopausal women with low BMD (T score below -2) received either placebo or zoledronate at a dose of 0.25 mg, 0.50 mg, or 1 mg intravenously every 3 months for 1 year, 2 mg every 6 months for 1 year, or a single annual dose of 4 mg.45 All women received a calcium supplement (1 g daily).

All of the zoledronate treatment regimens produced similar increases in BMD at the lumbar spine (4.3–5.1%) and femoral neck (3.1–3.5%) compared with a stable BMD in the placebo group. Biochemical markers of bone resorption (urinary N-terminal telopeptide of type I collagen and serum C-telopeptide of type I collagen) were rapidly and consistently suppressed during the trial, while markers of bone formation were also diminished, although this was not evident until later after beginning treatment. Myalgia and transient fever were the most common adverse events. The effects on surrogate markers were as great as those observed with the bisphosphonates that have proven efficacy to reduce osteoporotic fracture risk. This trial paved the way for a large ongoing phase III trial (the Horizon trial), which was designed to demonstrate the ability of zoledronate (at an intravenous dose of 5 mg once yearly) to reduce osteoporotic fracture risk. The trial results, however, will not be published for some time.

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Safety issues

Bisphosphonates are generally well tolerated, but side effects, including myalgia, esophagitis, and uveitis, have been described. In a randomized, head-to-head comparison of alendronate and risedronate, the overall incidence of clinical adverse events was similar for both compounds.46 With intravenous bisphosphonates, venous irritation or thrombophlebitis might be encountered.

Slowed bone remodeling and an increased degree of mineralization are assumed to result in improved bone quality, with greater bone strength as a consequence. The prolonged use of bisphosphonates at high doses might be associated, however, with the accumulation of microcracks. Indeed, in Beagle dogs receiving risedronate (5 mg/kg body weight daily) or alendronate (10 mg/kg body weight daily) for 1 year, microdamage accumulation has been described in ribs47 and vertebrae.48 Simultaneously, trabecular bone volume and vertebral strength increased significantly, while toughness tended to be reduced. Another group also showed microdamage accumulation in the vertebrae of Beagle dogs receiving a high dose of another bisphosphonate (incadronate), while vertebral strength improved and vertebral toughness was reduced.49 The clinical significance of these findings, however, remains unclear, because the doses of bisphosphonates used in these animal studies were between sixfold and sevenfold greater than those used in the treatment of humans, and some parameters of bone quality were improved, while others tended to deteriorate slightly.

A recent study examined the occurrence of microcracks in the bones of Beagle dogs receiving risedronate or alendronate at doses comparable to those used in humans for the treatment of osteoporosis. The analysis showed that both compounds increased microdamage accumulation, but without significant negative effects on the mechanical properties of bone.50 As no obvious mineralization defect was observed in bone biopsies collected from women who had received alendronate for 10 years in the FLEX trial,31 despite their markedly suppressed bone turnover, there is currently no evidence of substantial bone toxicity of bisphosphonates administered in the long term.

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Conclusion

Oral bisphosphonates have become the mainstay of the treatment of postmenopausal osteoporosis, because of their proven, substantial antifracture efficacy. Adherence to treatment with daily regimens, is poor, however, at least in part because of the necessity of fasting before and after intake. It is likely that compliance and long-term adherence to treatment have improved since the development of weekly regimens. Newer regimens, such as the ibandronate monthly dosage regimen, could also be of interest in fostering adherence to treatment, so as to enhance long-term antifracture effectiveness. Intravenous bisphosphonate regimens currently under development might also represent a useful therapeutic option in patients who have contraindications to oral bisphosphonates or who prefer an intravenous route.

Key points

  • Bisphosphonates are the most widely used drugs in the treatment of osteoporosis

  • In postmenopausal women, bisphosphonates halve the osteoporotic fracture rate

  • Bisphosphonates are well tolerated, but long-term adherence to treatment is poor

  • Intermittent regimens could improve compliance

  • New intermittent regimens with intravenously administered bisphosphonates are under investigation

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References

  1. Fleisch HA (ed.; 1997) Bisphosphonates in Bone Disease. In From the Laboratory to the Patient, edn 3. New York: Parthenon Publishing
  2. Russell RGG et al. (1999) Bisphosphonates: pharmacology, mechanisms of action and clinical uses. Osteoporos Int 10 (Suppl 2): S66–S80 | Article |
  3. Papapoulos SE (2001) Bisphosphonates in the management of postmenopausal osteoporosis. In Osteoporosis, edn 2, 631–650 (Eds Marcus R et al.) San Diego: Academic Press
  4. Lin JH et al. (1992) Renal handling of alendronate in rats. An uncharacterized renal transport system. Drug Metab Dispos 20: 608–613 | PubMed | ISI | ChemPort |
  5. Lin JH et al. (1993) The role of calcium in plasma protein binding and renal handling of alendronate in hyper- and hypocalcemic rats. J Pharmacol Exp Ther 267: 670–675 | PubMed | ISI | ChemPort |
  6. Riis BJ et al. (2001) Ibandronate: a comparison of oral daily dosing versus intermittent dosing in postmenopausal osteoporosis. J Bone Miner Res 16: 1871–1878 | PubMed | ISI | ChemPort |
  7. Tanko LB et al. (2003) Oral ibandronate: changes in markers of bone turnover during adequately dosed continuous and weekly therapy and during different suboptimally dosed treatment regimens. Bone 32: 687–693 | PubMed | ISI | ChemPort |
  8. Pedersen-Bjergaard U and Myhre J (1991) Severe hypocalcaemia after treatment with diphosphonate and aminoglycoside. BMJ 302: 295 | PubMed | ChemPort |
  9. Salo J et al. (1997) Removal of osteoclast bone resorption products by transcytosis. Science 276: 270–273 | Article | PubMed | ISI | ChemPort |
  10. Rogers MJ et al. (1994) Inhibitory effects of bisphosphonates on growth of amoebae of the cellular slime mould Dictyostelium discoideum. J Bone Miner Res 9: 1029–1039 | PubMed | ISI | ChemPort |
  11. Frith JC et al. (1996) Clodronate and liposome-encapsulated clodronate are metabolized to a toxic ATP analog, adenosine 5'-beta,gamma-dichlormethylene triphosphate, by mammalian cells in vitro. J Bone Miner Res 12: 1358–1367 | ISI |
  12. Luckman SP et al. (1998) Nitrogen-containing bisphosphonates inhibit the mevalonate pathway and prevent post-translational prenylation of GTP-binding proteins, including Ras. J Bone Miner Res 13: 581–589 | PubMed | ISI | ChemPort |
  13. Ridley AJ and Hall A (1992) The small GTP-binding-protein Rho regulates the assembly of focal adhesions and actin stress fibers in response to growth factors. Cell 70: 389–399 | Article | PubMed | ISI | ChemPort |
  14. Dunford JE et al. (2001) Structure-activity relationships for inhibition of farnesyl diphosphate synthase in vitro and inhibition of bone resorption in vivo by nitrogen-containing bisphosphonates. J Pharmacol Exp Ther 296: 235–242 | PubMed | ISI | ChemPort |
  15. Vitte C et al. (1996) Bisphosphonates induce osteoblasts to secrete an inhibitor of osteoclast-mediated resorption. Endocrinology 137: 2324–2333 | Article | PubMed | ISI | ChemPort |
  16. Plotkin LI et al. (1999) Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin. J Clin Invest 104: 1363–1374 | Article | PubMed | ISI | ChemPort |
  17. Giuliani N et al. (1998) Bisphosphonates stimulate formation of osteoblast precursors and mineralized nodules in murine and human bone marrow cultures in vitro and promote early osteoblastogenesis in young and aged mice in vivo. Bone 22: 455–461 | Article | PubMed | ISI | ChemPort |
  18. Chavassieux PM et al. (1997) Histomorphometric assessment of the long-term effects of alendronate on bone quality and remodeling in patients with osteoporosis. J Clin Invest 100: 1475–1480 | PubMed | ISI | ChemPort |
  19. Boivin GY et al. (2000) Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone 27: 687–694 | Article | PubMed | ISI | ChemPort |
  20. Nancollas GH et al. (2005) Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone [doi: doi: 10.1016/j.bone.2005.05.003] | Article | PubMed | ISI | ChemPort |
  21. McClung M et al. (1998) Alendronate prevents postmenopausal bone loss in women without osteoporosis. Ann Int Med 128: 253–261 | PubMed | ISI | ChemPort |
  22. Liberman UA et al. (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 333: 1437–1443 | Article | PubMed | ISI | ChemPort |
  23. Black DM et al. (1996) Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348: 1535–1541 | Article | PubMed | ISI | ChemPort |
  24. Cummings SR et al. (1998) Effect of alendronate on risk of fracture in women with low bone mineral density but without vertebral fractures. JAMA 280: 2077–2082 | Article | PubMed | ISI | ChemPort |
  25. Ensrud KE et al. (1997) Treatment with alendronate prevents fractures in women at highest risk. Arch Int Med 157: 2617–2624 | ISI | ChemPort |
  26. Nevitt MC et al. (2000) Effect of alendronate on limited-activity days and bed-disability days caused by back pain in postmenopausal women with existing vertebral fractures. Arch Int Med 160: 77–85 | ISI | ChemPort |
  27. Rizzoli R et al. (2002) Two-year results of once-weekly administration of alendronate 70 mg for the treatment of postmenopausal osteoporosis. J Bone Miner Res 17: 1988–1996 | PubMed | ISI | ChemPort |
  28. Bone HG et al. (2004) Ten years' experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med 350: 1189–1199 | Article | PubMed | ISI | ChemPort |
  29. Black DM et al. (2004) A 5 year randomized trial of the long-term efficacy and safety of alendronate: the FIT Long-term Extension (FLEX). J Bone Miner Res 19 (Suppl 1): S45
  30. Bauer DC et al. (2005) Increased bone turnover after discontinuing alendronate predicts bone loss over 5 years: the FLEX Study. J Bone Miner Res 20 (Suppl 1): S95
  31. Recker RR et al. (2004) Normal bone histomorphometry and 3D microarchitecture after 10 years of alendronate treatment of postmenopausal women. J Bone Miner Res 19 (Suppl 1): S45
  32. Harris ST et al. (1999) Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis. JAMA 282: 1344–1352 | Article | PubMed | ISI | ChemPort |
  33. Reginster J-Y et al. (2000) Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Osteoporos Int 11: 83–91 | Article | PubMed | ISI | ChemPort |
  34. McClung MR et al. (2001) Effect of risedronate on the risk of hip fracture in elderly women. N Engl J Med 344: 333–340 | Article | PubMed | ISI | ChemPort |
  35. Mitchell DY et al. (2000) Dose-proportional pharmacokinetics of risedronate on single-dose oral administration to healthy volunteers. J Clin Pharmacol 40: 258–265 | Article | PubMed | ISI | ChemPort |
  36. Brown JP et al. (2002) The efficacy and tolerability of risedronate once a week for the treatment of postmenopausal women. Calcif Tissue Int 71: 103–111 | Article | PubMed | ISI | ChemPort |
  37. Mellström DD et al. (2004) Seven years of treatment with risedronate in women with postmenopausal osteoporosis. Calcif Tissue Int 75: 462–468 | Article | PubMed | ChemPort |
  38. Watts NB et al. (2004) Effect of risedronate treatment discontinuation on bone turnover and BMD. Calcif Tissue Int 74 (Suppl 1): S79
  39. Ste-Marie LG et al. (2004) Five years of treatment with risedronate and its effects on bone safety in women with postmenopausal osteoporosis. Calcif Tissue Int 75: 469–476 | Article | PubMed | ISI | ChemPort |
  40. Tanko LB et al. (2003) Oral weekly ibandronate prevents bone loss in postmenopausal women. J Int Med 254: 159–167 | ISI | ChemPort |
  41. Chestnut CH III et al. (2004) Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res 19: 1241–1249 | PubMed |
  42. Miller PD et al. (2005) Monthly oral ibandronate therapy in postmenopausal osteoporosis: 1-year results from the MOBILE Study. J Bone Miner Res 20: 1315–1322 | Article | PubMed | ISI | ChemPort |
  43. Recker RR et al. (2004) Insufficiently dosed intravenous ibandronate injections are associated with suboptimal antifracture efficacy in postmenopausal osteoporosis. Bone 34: 890–899 | Article | PubMed | ISI | ChemPort |
  44. Adami S et al. (2004) Efficacy and safety of ibandronate given by intravenous injection once every 3 months. Bone 34: 881–889 | Article | PubMed | ISI | ChemPort |
  45. Reid IR et al. (2002) Intravenous zoledronic acid in postmenopausal women with low bone mineral density. N Engl J Med 346: 653–661 | Article | PubMed | ISI | ChemPort |
  46. Rosen CF et al. (2005) Treatment with once-weekly alendronate 70 mg compared with once-weekly risedronate 35 mg in women with postmenopausal osteoporosis: a randomized double-blind study. J Bone Miner Res 20: 141–151 | Article | PubMed | ISI | ChemPort |
  47. Mashiba T et al. (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15: 613–620 | Article | PubMed | ISI | ChemPort |
  48. Mashiba T et al. (2001) Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in Beagles. Bone 28: 524–531 | Article | PubMed | ISI | ChemPort |
  49. Komatsubara S et al. (2003) Long-term treatment of incadronate disodium accumulates microdamage but improves the trabecular bone microarchitecture in dog vertebra. J Bone Miner Res 18: 512–520 | Article | PubMed | ISI | ChemPort |
  50. Allen MR et al. (2005) Risedronate and alendronate similarly suppress bone remodeling and increase microdamage in Beagles after 1 year of treatment at clinical doses. J Bone Miner Res 20 (Suppl 1): S22
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Competing interests

RD Chapurlat has received consulting or lecture fees from Eli Lilly and Novartis. PD Delmas has received consulting or lecture fees from Procter and Gamble, Sanofi-Aventis, Roche, Novartis, Eli Lilly, Nicomed, Wyeth, Pfizer.

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Subject areas under which this article appears: Bone and mineral metabolism