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CRITICAL REVIEWS IN ORAL BIOLOGY & MEDICINE |
Mechanism of Action, Pharmacokinetic and Pharmacodynamic Profile, and Clinical Applications of Nitrogen-containing Bisphosphonates
D.B. Kimmel
Department of Molecular Endocrinology and Bone Biology, WP26A-1000, Merck Research Laboratories, West Point, PA 19486, USA; donald_kimmel{at}merck.com
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ABSTRACT
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Nitrogen-containing bisphosphonates (nBPs) are bone-specific agents that inhibit farnesyl diphosphate synthase. nBPs’ strong affinity for bone, and not for other tissues, makes them potent inhibitors of bone resorption and bone remodeling activity, with limited potential for side-effects in non-skeletal tissues. Five nBPs are currently approved in the United States. The primary indications are for treatment of osteoporosis (alendronate, ibandronate, and risedronate) and treatment/prevention of skeletal-related events (SREs) in multiple myeloma and breast and prostate cancer patients (ibandronate, pamidronate, and zoledronic acid). nBPs are the most efficacious drugs available for these diseases, reducing osteoporotic fracture risk by 50–60% in persons with low bone mass or prior osteoporotic fracture, and SREs by one-third in cancer patients. The absorbed nBP dose for cancer patients is from seven to ten times that in osteoporosis patients. nBPs are unique in that they first exert profound pharmacodynamic effects long after their blood levels reach zero. Current pharmacokinetic studies indicate that approximately half of any nBP dose reaches the skeleton, with an early half-life of ten days, and a terminal half-life of about ten years. Practical study design limitations and theoretical considerations suggest that both the half-life and the amount of nBP retained in the skeletons of patients on long-term nBP therapy are substantially overestimated by extrapolation directly from current pharmacokinetic data. In fact, the amount of nBP being released from skeletal tissues of long-term-treated patients, particularly in osteoporosis patients, becomes insufficient to maintain full pharmacodynamic efficacy relatively soon after dosing is interrupted.
Key Words: farnesyl pyrophosphase synthase • osteoclast • osteoporosis • bone metastasis • half-life • bone remodeling
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INTRODUCTION
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The nitrogen-containing bisphosphonates (nBPs) are pharmaceutical agents possessing a pyrophosphate-like chemical substructure that confers a strong affinity for calcium. This tridentate structure causes them to chelate circulating calcium and to bind to the mineral at bone surfaces (Fig. 1 ) (Jung et al., 1973; Rodan and Fleisch, 1996; Rogers et al., 1997; Cremers et al., 2005; Papapoulos, 2006; Russell, 2006, 2007). The pyrophosphate-like structure substituted by a P-C-P bond is poorly metabolized by the biologic enzymes that customarily degrade foreign chemicals, causing nBPs to circulate in and exit living organisms as the parent molecule. The hydroxyl group on the carbon atom is responsible for the high affinity of nBPs for bone surfaces. This strong specificity for bone and minimal metabolism combine to make nBPs remarkably efficacious bone drugs, with notably few adverse effects in non-skeletal tissues.
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Figure 1. Bisphosphonates used most frequently in the clinic today have a characteristic structure. All have a hydroxyl group on the carbon atom that confers high affinity for calcium and the skeleton. They vary only at the R-group, which always contains a nitrogen atom that is in either an alkyl or a heterocyclic structure.
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MECHANISM OF ACTION OF NITROGEN-CONTAINING BISPHOSPHONATES
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Early bisphosphonates often had neither the nitrogen-containing side-chain nor the opposed hydroxyl group (Fig. 1 ), causing them to lack sufficient potency and bone specificity to be efficacious, safe bone agents. These included etidronate, clodronate, and tiludronate (Russell, 2006). These bisphosphonates were first recognized for their ability to inhibit mineral dissolution in non-biologic situations. At one time, this property was considered responsible for the anti-resorptive activity of all bisphosphonates. Recent research (Cremers et al., 2005; Papapoulos, 2006; Russell, 2006) has disclosed the molecular mechanisms by which bisphosphonates, particularly nBPs, not only inhibit resorption, but also may exert biologic activities in the non-skeletal tissues in which they achieve sufficient concentrations. The purpose of this section is to clarify the mechanism of action of nBPs.
It is now clear that, while nBPs are attracted to bone because of their structural similarity to pyrophosphate, their ability to inhibit resorption rests with their interference with enzyme activity, rather than their propensity to affect mineral dissolution in vitro (Papapoulos, 2006; Russell, 2006). This has been best proven by in vitro experiments showing that nBPs with hydroxyl groups that vary only at the R-group (Fig. 1) have similar affinities for bone mineral, but widely divergent abilities to inhibit osteoclast or macrophage functional activity (van Beek et al., 1999b; Leu et al., 2006). Conversely, data obtained from Dictyostelium discoideum, a non-bone-containing in vitro model for testing nBP activity, showed that nBPs that vary at the hydroxyl group, but contain the same R-group, have the same surrogate anti-resorptive activity (van Beek et al., 1998, 1999b).
nBPs inhibit farnesyl diphosphate synthase (FPP synthase), an enzyme in the mevalonate pathway (Fig. 2) (van Beek et al., 1999a). This property was discovered during a medicinal chemistry program that aimed to understand structural activity relationships among squalene synthase (farnesyl-diphosphate:farnesyl-diphosphate farnesyl-transferase) inhibitors as potential cholesterol-lowering agents. Lipophilic 1,1-bisphosphonates, tested because of their structural similarity to active-site catalysts of squalene synthase, were shown to be potent squalene synthase inhibitors (Amin et al., 1992; Ciosek et al., 1993). Subsequent investigations established that other bisphosphonate compounds inhibited squalene synthase and lowered serum cholesterol in vivo by also accelerating the degradation of HMG-CoA reductase (Berkhout et al., 1996). These findings led to the recognition of their action on FPP synthase (Magnin et al., 1995), and to the subsequent studies with pre-existing nBPs that had been approved as bone drugs in the preceding half-decade. FPP synthase stimulates isoprenylation, a process that activates small GTPases, such as Rab, Rac, Ras, and Rho (Luckman et al., 1998). FPP synthase inhibition appears to be responsible for the pharmacologic effects of the nBPs at the tissue level (Fisher et al., 1999). Variation in the R-group (Fig. 1)—the only position at which the five US-approved nBPs discussed below differ, including both alkyl and heterocyclic structures—causes at least a 500-fold variation in the potency with which individual nBPs inhibit FPP synthase (van Beek et al., 1998, 1999b; Dunford et al., 2001; Szabo et al., 2002; Sanders et al., 2003, 2005).
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Figure 2. Nitrogen-containing bisphosphonates inhibit farnesyl diphosphate (FPP) synthase, an enzyme in the mevalonate pathway. FPP synthase is responsible for isoprenylation of small GTPases that promote an array of activities in the osteoclasts that control bone resorption. Without this activity, bone resorption is slowed.
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Small GTPases are signaling proteins that, when activated, positively regulate several structural properties and processes important for osteoclast function, including morphology, cytoskeletal arrangement, vesicular trafficking (Alakangas et al., 2002; Pavlos et al., 2005), and membrane ruffling. Vesicular trafficking in osteoclasts is responsible for concentrating and transporting enzymes involved in bone resorption. Bone resorption, which requires sequential demineralization of collagen and collagenous matrix dissolution, occurs in the ruffled or brush border region of osteoclasts (Mulari et al., 2003). The ruffled border, a membrane-rich area of the cell surrounded by a sealing zone within the osteoclast, creates an acidified compartment between the cell and the bone surface. Mineral is removed from the bone, leaving bare collagen that is degraded by collagenolytic enzymes. When vesicular trafficking and membrane ruffling are inhibited, the activities that specifically facilitate bone resorption are also reduced. In addition, there is indication that geranylgeranylation of Rho and Rac is involved in the early differentiation of mononuclear phagocytes into TRAP-positive (tartrate-resistant acid phosphatase) pre-osteoclasts (Zhang et al., 1995; Coxon et al., 2005; Woo et al., 2005). Rho and Rac also regulate apoptosis, albeit at 100-µM concentrations (Stark et al., 1998; Suri et al., 2001; Fujita et al., 2005).
Thus, the fundamental biology indicates a high likelihood that FPP synthase inhibition in osteoclasts is involved in reducing bone resorption in three ways that appear to be dose-dependent. At relatively low concentrations, the functional activities that involve the cytoskeleton, vesicular trafficking, and membrane ruffling, which are related to bone mineral dissolution and collagen degradation, are inhibited. At somewhat higher concentrations, osteoclast differentiation is inhibited. Finally, at concentrations approaching 100 µM, osteoclast apoptosis is induced. These actions point to the fact that nBPs are excellent inhibitors of bone resorption at the tissue level.
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PHARMACOKINETICS OF NITROGEN-CONTAINING BISPHOSPHONATES
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It is often implied that nBPs given to living individuals enter and then are sequestered in bone tissue for long periods of time (e.g., decades) in ever-increasing quantities, as treatment continues (Dunn and Goa, 2001; Sambrook, 2002; Stepensky et al., 2003; Papapoulos, 2006; Russell, 2006). The purpose of this section is to examine the data and skeletal biology considerations that support this contention, in light of the fact that few/no pharmacokinetic studies of nBP have been reported in individuals who have taken significant amounts of past nBP treatment.
More than two dozen nBP pharmacokinetic studies, most lasting less than one month, have been completed (Cremers et al., 2005). Any nBP absorbed into the body of a bisphosphonate-naïve adult human is partitioned, within hours, approximately equally between the skeleton and kidneys. All approved nBPs contain the hydroxyl group that confers a high affinity for elemental calcium, including both that found at the bone surface and that in the circulation. Intravenously administered nBPs can cause significant hypocalcemia (Mishra et al., 2001; Peter et al., 2004) soon after administration. Whether given intravenously or orally, bisphosphonates are eliminated quickly from the circulation, independent of agent (Lin, 1996; Cremers et al., 2005). The portion reaching the kidneys is eliminated through the urine unmetabolized within a few hours. The remainder, also unmetabolized, is deposited in the skeleton (Lin, 1996). However, it is crucial to recognize that local concentrations and retention times are determined by the cellular status of individual bone surfaces.
The main determinant of the kidney/bone partition is the bone turnover rate, with individuals with higher bone turnover rates retaining more nBP in their skeleton than those exhibitin low turnover (Fogelman et al., 1978; Khan et al., 1997; Cremers et al., 2003). This important concept has multiple implications, particularly when one considers that most of the nBP taken by an individual on chronic treatment is consumed long after the initially high turnover rate encountered in post-menopausal osteoporosis (Recker et al., 2004) has been reduced by 70% or more.
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INTRASKELETAL FATE OF NITROGEN-CONTAINING BISPHOSPHONATES
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nBP that reaches the skeleton is partitioned across bone surfaces, mainly those with adjacent marrow, the endocortical and trabecular surfaces (Masarachia et al., 1996). A minor amount reaches more lightly vascularized cortical bone surfaces (Lin et al., 1992). The affinity for specific surface regions is determined by the local bone cell activity (Fig. 3). The bone surface cell status is determined by the ongoing stage of bone remodeling activity. In the adult skeleton, the possibilities at trabecular surfaces are resting (with bone-lining cells), resorbing (with osteoclasts), and forming (with osteoblasts). In the adult skeleton, these types of surfaces are arranged to accomplish bone remodeling, representing different phases of bone multicellular units (BMUs) that proceed sequentially in situ from resorption to formation to completion (Frost, 1969; Parfitt, 1976), leaving behind new bone structural units (BSUs). It is important to recognize that when fewer BMUs initiate resorption, at some subsequent time, there will eventually be fewer units doing formation, a phenomenon called ’coupling’.
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Figure 3. Artists’ depiction of trabecular bone and location of nBP as affected by time and bone remodeling activity. This Fig. attempts to put theory into pictures. (a) A bone multicellular unit (BMU) with an osteoclast and osteoblasts is at the lower right. At six hours after administration of a bolus dose of an nBP, the drug is found at all surfaces. The concentration is lowest at resting surfaces, highest at resorption surfaces, and in between at formation surfaces. (b) At three days after nBP administration of a bolus dose, the nBP concentration at resting surfaces has declined significantly. nBP under osteoblasts has become buried by ongoing bone formation activity, and diffuse deposits in newly formed bone from recirculated nBP are appearing. The concentration remains high under osteoclasts and in their brush border. (c) At ten days after nBP administration, the nBP concentration at resting surfaces has declined further from the three-day level, and now is markedly lower than at six hours. nBP under osteoblasts has become more deeply buried by ongoing bone formation activity, with diffuse deposits accumulating in newly forming bone, from recirculated nBP. The concentration remains high under osteoclasts, but the brush border has started to become disorganized, and the osteoclast is aging. (d) At 30 days after nBP administration, the nBP concentration at resting surfaces has declined further, with little remaining. The BMU has completed its work, leaving a bone structural unit (BSU). Note that the completed BSU has buried nBP where osteoblasts have finished, with a line from the initial deposit and diffuse nBP closer to the surface that came from recirculation. While the nBP at resting surfaces is still available for exchange to fluids, the buried nBP will not be removed and become biologically active, until resorption associated with a new BMU begins work in the area. The buried nBP is biologically inert. A new BMU has begun resorption in the upper left. (e) A new bolus dose of nBP is given. At 60 days after nBP administration, the nBP concentration at resting surfaces is minimal. The BMU at the upper left has completed its work, leaving another BSU with a concentrated line and diffuse deposit. The nBP in the BSU at the lower right is stable. (f) At 60 days after nBP, the picture of nBP location after weekly dosing is somewhat different, with no concentrated line visible, but more diffuse deposits to BSUs that were forming bone along the way. The nBP in the BSU at the lower right, even during weekly dosing, is stable. With less frequent, but equal, cumulative dosing, new BMUs will encounter fewer deposits of old nBP, but the ones they encounter are likely to be more concentrated, as compared with more frequent dosing.
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One should first consider the trabecular bone of the vertebral body, a site of relatively high turnover, at ~ 25%/year (Podenphant et al., 1986; Recker et al., 1988). Resting surfaces—comprising ~ 85% of all surfaces in a trabecular bone region like the thoracolumbar vertebral body of an average post-menopausal adult female, and occupied by bone-lining cells—have the lowest affinity for nBP. The nBP deposited at resting surfaces is bound loosely. The surface-to-fluid concentration gradient equilibrium favors net movement of nBP from the resting surface into the bone fluids and then into blood, into which the nBP is eventually recycled. This exchange occurs within hours to days, removing the vast majority of nBP from resting surfaces within days (Masarachia et al., 1996). For resting surfaces, despite the relatively low unit concentration, the comparatively vast amount of available surface means that a significant amount of nBP is processed through resting surfaces. Little nBP is retained at resting surfaces, due to the low affinity and the absence of cellular activity that buries nBP.
Resorbing surfaces, comprising only ~ 2% of trabecular surfaces in the vertebral body, have about eight times the affinity of resting surfaces for nBP (Masarachia et al., 1996). This high affinity may be due to the low pH at resorbing surfaces, or to the relatively high concentration of free calcium being liberated from the bone tissue by osteoclast action, and thus available for chelation by nBPs. nBP attracted to actively resorbing surfaces under osteoclasts is liberated to the blood as the bone is resorbed by osteoclasts. The nBP concentrations that develop in these regions appear sufficient to cause inhibition of FPP synthase (Sato et al., 1991). The removal of nBP occurs within days to weeks, with essentially full removal of nBP from resorbing surfaces and liberation to the blood, from where the nBP is recycled anew across the kidney and skeleton. For resorbing surfaces, their relatively high unit concentration of nBP, despite the extremely small amount of surface available, means that they too process a significant amount of nBP. For both resting and resorbing surfaces, the fate of nBP that initially reaches them is the same, to be returned within days to weeks to the bone fluids and, eventually, to the blood for recycling.
Forming surfaces, comprising 10–12% of trabecular surfaces in the vertebral body and less at most other endocortical and trabecular surfaces, have about four times the affinity of resting surfaces for nBP. This high affinity is most likely due to the high concentration of calcium being affixed to osteoid by osteoblast action at these surfaces during the bone mineralization process. This calcium is available for chelation by the nBP before it becomes secured to the osteoid. Unlike at resting and resorbing surfaces, from which nBP is removed, nBP at forming surfaces under osteoblasts chelates calcium that is being affixed to the osteoid. As the osteoid mineralizes, the nBP is bound in the newly mineralized bone tissue. This, too, occurs within hours to days, with essentially full retention and burial of all nBP at these surfaces. Buried nBP remains in bone tissue until it is liberated by osteoclasts during the resorption phase of a new bone-remodeling cycle. nBP buried in bone tissue beneath the bone surface is considered biologically inert, because it cannot influence bone surface cells. There are a few data indicating that nBPs may decrease osteocyte apoptosis (Plotkin et al., 1999; Follet et al., 2007). There is no evidence that buried nBP has deleterious effects on nearby osteocytes.
To summarize, after a single administration of nBPs to a bisphosphonate-naïve individual, a large portion of the dose that reaches the skeleton, and which was initially deposited at the resting and resorbing surfaces, is released and recycled within days to the blood for excretion through the kidney and redistribution across bone surfaces. nBP is secured in bone tissue only at sites of bone formation, from which it is released only when osteoclasts resorb that region of bone. Bone-buried nBP does not exert anti-resorptive activity only when it is released from bone, suggesting that, despite the persistence of skeletally retained nBP, newly dosed nBP is responsible for most of the persistent low bone turnover phenotype that is associated with long-term nBP treatment. The importance of the buried nBP may be greater when high absorbed doses of nBPs are used, which bury larger amounts of nBP at the few forming surfaces in the skeleton of a person on chronic nBP therapy. When these concentrated deposits are encountered and released by osteoclasts, they may be of sufficient quantity to exert anti-resorptive activity, than when lower doses are used.
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RELEVANCE OF CURRENT DATA ON nBP SKELETAL HALF-LIFE IN TREATED PATIENTS
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All reported pharmacokinetic studies tabulate results after nBP administration to bisphosphonate-naïve individuals. Information from both post-menopausal osteoporotic and cancer patients is available. These individuals generally have high bone turnover rates, and always experience a significant reduction in turnover rate after several doses of nBP. It would be important to realize that, in a patient who takes an nBP for three years, given that most turnover reduction occurs within a month or two of commencing dosing, 97% of the nBP consumed has entered a skeleton with a much lower bone turnover rate than has been studied during any currently recorded pharmacokinetic studies. No pharmacokinetic studies of persons who have been on nBP therapy for six months or more have been completed.
It has been reported that alendronate has a skeletal half-life of 10.9 years (Khan et al., 1997) in bisphosphonate-naïve post-menopausal osteoporotic patients, when data reflecting 8–18 months’ follow-up are considered. No other nBP pharmacokinetic studies report such long follow-up. Moreover, when only the first month’s data are considered, the full length of most reported nBP pharmacokinetic studies (Cremers et al., 2005), alendronate half-life was 11 days (Lasseter et al., 2005). In a 30-day study, risedronate half-life was nine days (Mitchell et al., 2001). In a similar 29-day study, zoledronic acid half-life was seven days (Berenson et al., 2002). A pamidronate study that did not specifically report half-life showed concentration/time data indicative of an early-phase half-life that differed little from that of alendronate, risedronate, and zoledronic acid (Cremers et al., 2002). These studies generally indicated skeletal/renal partitions similar to those discussed above. Though retention of only one nBP has been studied for longer than 60 days, the parallels in the first-month data suggest that long-term retention of all are likely to be similar, varying perhaps only by the extent of difference, if any, of long-term suppression of bone remodeling by individual nBPs.
For example, with alendronate or ibandronate, half the absorbed dose is excreted through the kidneys within five days (Khan et al., 1997; Barrett et al., 2004). For alendronate, one-sixth of the initial dose is then removed in exponential fashion during the next 90 days, but only another 5% is removed during the next 450 days. The early part of the 90 days represents rapid exchange occurring at resting surfaces. The latter part of the 90 days represents the slower release of concentrated initial deposits at resorption surfaces by osteoclasts. As the nBP from the resting and resorption surface deposits is released to the blood, it is recycled to the kidney and skeleton, and deposited once more across bone surfaces, at appropriately lower concentrations than following the initial dose. The remainder of the skeletally absorbed nBP dose reaches forming surfaces, where it is buried in bone tissue and can be released only by osteoclastic resorption at some future time. Recall that nBP buried in bone is biologically inert, becoming active only when an osteoclast encounters and releases it during a future remodeling cycle.
Following discontinuation of oral nBP treatment, bone resorption marker values begin to rise within a few months (Black et al., 2006). This implies that the amount of nBP being released from bone is insufficient to maintain the full level of anti-resorptive efficacy that is achieved by active dosing over a long period of time. One can conclude that it is the new doses of nBP that are responsible for maintaining full inhibition of resorption. Though it is many months before bone resorption markers begin to rise after administration of intravenous zoledronic acid or ibandronate (Black et al., 2007), the fact is that when new nBP is not introduced, the markers reflecting turnover rate eventually rise. This provides pharmacodynamic evidence that, for osteoporosis patients in the short run and even cancer patients in the long run, recirculated nBP coming from the skeleton may itself be insufficient to maintain the low remodeling rates seen on active nPB therapy and associated with anti-fracture and anti-SRE efficacy, respectively.
It should now be clear that the relevance of the published pharmacokinetic studies to actual nBP pharmacokinetics in persons taking ongoing nBP treatment is limited, because the turnover rate of the nBP-treated skeleton is about three-fold higher than that of the nBP-naïve skeleton (Black et al., 2007), due to the known pharmacologic action of nBPs. The nBP-treated skeleton has fewer sites of bone formation that bury nBP than does the nBP-naïve skeleton. The bone:kidney nBP ratio of distribution should thus be appreciably lower in the nBP-treated skeleton than in the nBP-naïve skeleton. The nBP-treated skeleton thus should "reject" nBP at a higher rate than is expected from current pharmacokinetic data. In fact, this concept is consistent with current clinical data describing bone resorption rates in patients taking oral nBPs for up to ten years. If nBP continued to be distributed and accumulate at the rate implied by current pharmacokinetic data, the bone resorption rate could continue to decline indefinitely. In fact, the bone resorption rate declines by 70% in the first three months, then never goes any lower.
In particular, designing studies to evaluate long-term pharmacokinetics and the skeletal half-life of efficacious doses of oral nBPs in patients taking long-term treatment, while desirable, presents difficulties for three reasons:
First, the nBPs are a type of metabolic auto-inducer—that is, their own pharmacodynamic effects influence both their skeletal distribution and retention. In drug metabolism, this phenomenon is not infrequently encountered when a drug influences an enzyme in the metabolic pathway responsible for its breakdown. nBPs represent a unique case, in that it is their pharmacologic effects on the skeleton that influence their half-life, by changing initial deposition patterns in, and release rates from, the skeleton. Essentially, nBPs directly inhibit resorption and, indirectly, through coupling, formation, leaving more resting sites for relatively rapid chemical exchange and fewer sites for burial, reducing initial skeletal uptake, and reducing the bone remodeling rate, reducing the escape rate of buried nBP, thus causing a longer measured half-life.
Second, if only a single dose of an oral nBP at its efficacious dose is administered, there is insufficient nBP mass to be assayed in fluids for more than several weeks, because the amount found in any single interim fluid sample is below the limits of detection of the assays. Administering enough nBP mass to yield sufficient nBP for assay in fluid specimens at long times requires a supra-efficacious single initial dose of an oral nBP. Such a dose delivers significantly more anti-resorptive activity than the treatment dose, giving an artificially long half-life, because bone turnover is suppressed more than in clinical use. For example, in a study by Khan et al.(1997), 60 weeks’ worth of alendronate was administered during four consecutive days, suppressing remodeling much more, in both an acute and chronic sense, than is done in clinical practice with alendronate. Half-life during treatment of osteoporotic patients is certain to be appreciably less than ten years, and perhaps logistically impossible to evaluate. Essentially, this amount of alendronate confers the same anti-resorptive activity at the tissue level as one dose of yearly zoledronic acid (5 mg intravenously) (Liberman et al., 1995; Black et al., 2007).
Third, the notion that the skeleton of a person on active nBP treatment collects and retains the same fraction of newly dosed nBP as does an nBP-naïve patient is inaccurate. Within six weeks of the initiation of nBP treatment for osteoporosis, and within days of the first dose of nBP for cancer treatment, bone remodeling and bone resorption rates are suppressed by 70–80% (Khan et al., 1997; Cremers et al., 2002). This suppression is most profound at the trabecular and endocortical surfaces, where nBP is most prominently distributed (Bone et al., 1997). In nBP-treated patients, most trabecular surface is resting. Resorption surface and formation surface are much less than in nBP-naïve patients. Most importantly, the number of surfaces where nBP is affixed to mineral and buried is dramatically lower in nBP-treated patients than in nBP-naïve patients. The skeletal/renal partition must shift to favor higher renal elimination. The skeleton of a person on active nBP treatment, with the lower turnover rate, collects and retains less nBP than that of an nBP-naïve patient (Fogelman et al., 1978).
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OTHER EFFECTS OF nBPs
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Angiogenesis
Current evidence describing the relationship of nBPs to angiogenesis provides an incomplete picture. Several studies have indicated that nBPs can inhibit angiogenesis (Fournier et al., 2002; Ribatti et al., 2002, 2007; Wood et al., 2002; Hamma-Kourbali et al., 2003; Clezardin et al., 2005). This inhibition may not only be mechanism-based, but may also involve endothelial cell adhesion, migration, and survival (Hasmim et al., 2007). The early experiments generally used pre-clinical models of angiogenesis, such as the chick embryo chorioallantoic membrane or human umbilical cord endothelial cells (HUVECs). In these models, high concentrations of nBP can be reached in the region of proliferating blood vessels without consideration for bone and renal tissue adverse effects. The effective concentrations, generally 10 µM or greater, are difficult to achieve in vivo in non-skeletal tissue. Analysis of these data seems to suggest that if/when sufficient concentrations of nBP are achieved in regions of active angiogenesis, nBPs can have an inhibitory effect on the process that is likely based on inhibition of FPP synthase.
There is little evidence to indicate that nBPs directly and significantly inhibit angiogenesis in vivo. Reduced circulating levels of VEFG (vascular endothelial growth factor) have been reported in cancer patients with bone metastases treated with zoledronic acid (Santini et al., 2007). These reduced circulating levels of VEGF may be linked to a decreased incidence of SREs (Vincenzi et al., 2005). It is possible that the combination of the nBP doses used in cancer patients and the bone specificity of nBPs for bone tissue allows them to reach efficacious anti-angiogenic concentrations near blood vessels in the skeleton of these patients. An nBP phenotype relating specifically to reduced angiogenesis in the primary spongiosa of growing long bones, a region where rapidly sprouting blood vessels are close to bone surfaces, has not been noticed, even though inhibition of bone resorption in that location is very apparent (Schenk et al., 1986).
Microcracks
Several pre-clinical studies indicated that nBP treatment at and somewhat above osteoporosis doses reduces bone remodeling rate and is associated with accumulation of microcracks in dogs (Mashiba et al., 2000, 2001; Komatsubara et al., 2004). It has been theorized that these microcracks represent damage to bones that reduces bone strength. In one study, decreased toughness was reported (Mashiba et al., 2000), but, in general, the bones with increased microcrack density had higher strength than bones from untreated dogs with fewer microcracks (Mashiba et al., 2001; Komatsubara et al., 2004). Increased microcrack density has not been associated with any other pathology, including death of osteocytes and the surrounding bone tissue. In fact, several publications suggest that nBP treatment prevents the death of osteocytes seen after treatment with glucocorticoids (Plotkin et al., 1999) and during the application of mechanical loads (Follet et al., 2007), at 10- to 100 nM, concentrations that are achievable in bone tissue in vivo. Though nBPs reduce bone turnover by inhibiting the FPP synthase that blocks osteoclast differentiation, reducing both their numbers and the rate of bone turnover, the reduced turnover and longer persistence of individual regions of bone tissue have not been associated with any change in bone strength in pre-clinical studies of canines. Moreover, in osteoporotic humans, reduction in bone turnover rate has been associated with reduction in hip and vertebral fracture risk (Liberman et al., 1995; Black et al., 1996, 2007; Cummings et al., 1998). Existing studies of microcracks in humans do not suggest a relationship of microcracks to osteoporotic fracture, turnover rate, or nBP treatment in either cadaveric material (Mori et al., 1997) or transilial biopsy samples from osteoporotic humans (Chapurlat et al., 2007). Analysis of some data suggests an increase with age and an inverse relationship with bone volume (Schaffler et al., 1995; Wenzel et al., 1996; Mori et al., 1997). The human and animal data concerning microcracks are in disagreement, causing concern for the relevance of the animal data on microcracks to the human condition.
Acute Phase Reaction
nBPs can cause a transient acute phase response, in vivo, associated clinically with flu-like symptoms and fever (Adami et al., 1987). This occurs predominantly on first exposure with a higher incidence after IV formulations, affecting about one-third of patients. The acute phase reaction appears to be mechanism-based and has been attributed to release of pro-inflammatory cytokines (Thiebaud et al., 1997) associated with proliferation and selective receptor-mediated activation of gamma-delta T-cells (Sanders et al., 2004) through the mevalonate pathway (Thompson and Rogers, 2005). The majority of patients who experience acute phase reaction during first exposure report a marked reduction, or complete lack, upon re-challenge.
Oral Bioavailabililty, Food Interaction, and Esophagitis
The oral bioavailability of alendronate, risedronate, and ibandronate ranges from 0.6 to 1% (Mitchell et al., 2001). All three exhibit a food interaction that reduces oral bioavailability approximately ten-fold. Thus, oral dosing of nBPs requires consumption on an empty stomach, with no subsequent food intake for ~ 60 minutes.
All nBPs may be administered orally. In a significant number of patients, all induce esophagitis that may be based upon inhibition of FPP synthase (Graham, 2002). During the early development of nBPs, this esophagitis appeared frequently enough and with sufficient severity for pamidronate and zoledronic acid that they are now administered to patients only intravenously (Lufkin et al., 1994). Ibandronate is approved for administration by both routes (Bauss and Russell, 2004). When initially approved, both alendronate and risedronate were given once daily by mouth. By 2001, both had been adapted to weekly dosing that delivered the same cumulative dose and produced the same efficacy on bone mass as once-weekly dosing, with an improved patient preference profile for dosing (Simon et al., 2002; Gold et al., 2006; Lo et al., 2006).
Renal Effects
When given intravenously to humans, zoledronic acid and pamidronate induce a transient rise in serum creatinine, due to renal toxicity. The histopathologic changes that may accompany these clinical changes in humans have been documented in rats. After four days of daily dosing at 3 mg/kg IV of ibandronate or 10 mg/kg IV of zoledronate, dose-dependent degeneration occurs at the proximal convoluted tubule (Pfister et al., 2005). The degeneration is characterized by cytoplasmic swelling, fragmentation and/or loss of the brush border membrane, and condensation in the subcapsular region in the P1 and P2 segments of the proximal convoluted tubules. Cytoplasmic swelling and basophilia also occur in the outer medulla. Both non-calcified granular deposits and cellular detritus and homogenous proteinaceous (PAS-positive) material are also seen in the lumen.
Interestingly, the mevalonate pathway is involved in renal diseases that include acute tubular injury (Scoppola and Galiano, 1998; Zager et al., 2002), suggesting that FPP synthase inhibition by nBPs could be involved in renal toxicity (Pfister et al., 2005). Since it is known that nBPs promote apoptosis in macrophage-like cells (Benford et al., 1999; Dunford et al., 2001), cancer cells (Shipman et al., 1998), and CaCo-2 cells (Suri et al., 2001), it is possible that apoptosis in the lining cells of the proximal convoluted tubules may also be mediated through inhibition of FPP synthase.
This renal toxicity seems to be due to the high serum levels achieved during bolus dosing. It is managed successfully by extending the duration of the infusion (Chen et al., 2002; Chang et al., 2004). The currently recommended infusion duration for intravenous nBPs is a compromise among renal toxicity, patient convenience, and infusion center availability. All nBPs are contraindicated in persons with chronic renal failure.
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CURRENT nBPs AND THEIR THERAPEUTIC INDICATIONS
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Because of their specificity for bone, their potency, and their ability to inhibit bone resorption and reduce bone remodeling activity, nBPs are ideal treatments for diseases characterized by tissue-level problems that include negative bone balance, excessive bone resorption, and high rates of bone remodeling activity. The most prominent nBPs approved for use in humans in the United States are: Zometa (zoledronic acid) and Aredia (pamidronate), used to treat and prevent malignant hypercalcemia and bone metastases in cancer (including multiple myeloma) patients; and Fosamax (alendronate) and Actonel (risedronate), used to treat post-menopausal, glucocorticoid-induced, and male osteoporosis. A fifth, Boniva (ibandronate), is used in both cancer and osteoporosis patients. Pamidronate was approved in October, 1991, for the treatment of malignant hypercalcemia. Alendronate was approved in October, 1995, for the treatment of post-menopausal osteoporosis; risedronate was approved in April, 2000. Zoledronic acid was approved in August, 2001, for the treatment of malignant hypercalcemia and the prevention of skeletal-related events (SREs). Ibandronate was approved in March, 2005, for the treatment of post-menopausal osteoporosis. Zoledronic acid once yearly by intravenous injection was approved in August, 2007, for the treatment of post-menopausal osteoporosis. Other diseases for which these agents are indicated include glucocorticoid-induced osteoporosis (Ringe and Farahmand, 2007), Paget’s disease (Langston and Ralston, 2004; Whyte, 2006; Hosking et al., 2007), and osteogenesis imperfecta (Rauch et al., 2003; Arikoski et al., 2004).
The approved doses used for the treatment of malignant hypercalcemia and the prevention of SREs in cancer patients are five- to ten-fold greater per unit time than those used for the treatment of osteoporosis. Moreover, analysis of prescription data indicates that, in 2006, approximately 50 times as many patient-years of nBP therapy were given for the prevention of osteoporotic fracture as for the prevention of sequelae of metastatic bone disease (see below).
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OSTEOPOROSIS
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The most frequent clinical indication for nBPs is treatment of post-menopausal osteoporosis. Approximately 98% of prescribed nBPs are given to osteoporosis patients (see below). Post-menopausal osteoporosis is characterized by low bone mass and a syndrome of low trauma fractures of the thoracic/lumbar spine and hip (Poole and Compston, 2006). The lifelong risk for osteoporotic fracture in a 50-year-old woman of average bone mass is ~ 40% (Cummings et al., 1989; Hui et al., 1989). For the 15% of the adult female population with bone mass one standard deviation or more below ’young adult normal’, the lifelong risk of osteoporotic fracture is approximately 100%. In women in their eighth decade and older, the clinical outcomes of a hip fracture and a stroke are identical. Twenty percent die within one year, and half the survivors retain significant permanent physical disability with reduced mobility (Robbins et al., 2006; Giversen, 2007). About 30% of all hip fractures occur in men in their eighth decade and older; mortality and permanent disability are even more prevalent in men with hip fractures than in women (Orwoll and Klein, 1995). It is estimated that there are currently 250,000 hip fractures annually in the United States, and that the costs of care exceed those for acute myocardial infarction (Piscitelli et al., 2007). Osteoporotic fracture, particularly that of the hip, is a life-altering event whose risk is reduced ~ 50% by the use of nBPs (Liberman et al., 1995; Epstein, 2006; Black et al., 2007).
Though as much of 60–70% of adulthood low bone mass is determined by inheritance (Giguere and Rousseau, 2000; Recker and Deng, 2002), individuals with osteoporosis always display measurable ongoing decline in bone mineral density (BMD), indicating a negative bone balance at the tissue level (Parfitt et al., 1983). This BMD decline is associated with a bone remodeling rate in osteoporotic individuals that is approximately three-fold higher than in pre-menopausal women (Garnero et al., 2000). The menopausal transition itself is associated with a doubling in bone turnover rate and a five-to seven-year period of accelerated bone loss, in which the average woman loses ~ 15% in spine and hip BMD (Lindsay et al., 1977; Heaney et al., 1978; Recker et al., 1978). Thus, the tissue-level lesions underlying osteoporosis lend themselves to anti-resorptive therapy.
Estrogen replacement (ERT), during menopause and thereafter, reduces the risk of osteoporotic fracture (Weiss et al., 1980; Paganini-Hill et al., 1981; Kiel et al., 1987; Cauley et al., 1995). Eventually, it was established that ERT acts at the tissue level to reduce bone resorption rate and bone turnover, since it slowed bone loss (Lindsay et al., 1977; Heaney et al., 1978; Recker et al., 1978; Steiniche et al., 1989). The recognized efficacy of ERT as an anti-resorptive approach to reducing the risk of osteoporotic fracture paved the way for pharmaceutical companies to test and gain approval for nBPs as non-hormonal anti-resorptive and turnover-reducing agents that are as efficacious as ERT in preventing spine and hip fracture. Oral alendronate, risedronate, and ibandronate, given once daily, significantly reduce risk of spine fracture (Reginster et al., 2000; McClung et al., 2001; Reginster, 2005). Zoledronic acid (5 mg intravenously once yearly) (Black et al., 2007) and oral alendronate (10 mg/day) significantly reduce the risk of hip fracture by 40–51% (Liberman et al., 1995; Black et al., 1996; Cummings et al., 1998). Risedronate and ibandronate tend to reduce hip fracture. Intermittent dosing of nBPs (once-weekly oral risedronate and alendronate, and once-monthly ibandronate) affects bone mineral density to the same degree as daily administration of the same amount of the agent (Rizzoli et al., 2002; Rosen et al., 2005). More than 29 million prescriptions for oral bisphosphonates, including Actonel (9.2 mil), Boniva (3.2 mil), and Fosamax (16.7 mil), were written in the United States during 2006 (Drug Topics, 2007). This equates to approximately 2.4 million patient-years of therapy. The recent approval of once-yearly IV zoledronic acid for the treatment of osteoporosis (mid-2007), and the introduction of generic alendronate (second quarter, 2008), may influence these numbers in the near future. Though a few other pharmaceutical agents are approved for the treatment of osteoporosis in the United States, including raloxifene (Evista, Lilly Corp.) and calcitonin (Miacalcin, Novartis AG), none reduces the risk of hip fracture.
Administration of oral nBPs to osteoporotic individuals is associated with ~ 6% gain in lumbar spine BMD after two years, ~ 9% gain after three years (Liberman et al., 1995), and up to 14% lumbar spine BMD increase after ten years (Black et al., 2006). nBPs cause ~ 6% gain in femoral neck BMD and ~ 8% gain in trochanteric BMD after three years (Liberman et al., 1995). Additional studies document increases of ~ 9% in lumbar spine BMD, ~4% in femoral neck BMD, and ~ 6% in trochanteric BMD after four years (Black et al., 2006). Bone resorption rate, measured by urinary markers of collagen breakdown, is durably suppressed by ~ 60–70% during daily or weekly therapy (Black et al., 2006). Since osteoporotic individuals enter treatment with a turnover rate three-fold above that in pre-menopausal women (Recker et al., 2005), nBPs re-establish the normal pre-menopausal rate of bone turnover (de Papp et al., 2007). nBPs are the most efficacious non-hormonal treatment available for reducing the risk of osteoprotic fracture, particularly that of the hip.
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OPTIMAL DURATION OF OSTEOPOROSIS THERAPY WITH nBPs
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The four nBPs approved for osteoporosis treatment were accepted based on three-year studies of sufficient numbers of patient-years of follow-up to demonstrate significant anti-fracture efficacy, usually ~ 2500 patient-years for vertebral deformity and ~ 10,000 to 15,000 for non-vertebral and hip fracture. In cases where enough patient-years of follow-up allowed for the accumulation of enough hip fracture events, anti-hip-fracture efficacy was demonstrated. It is important to note that no report contains enough patients on study for up to ten years’ continuous treatment for the proper evaluation of their continued anti-fracture efficacy over ten years (Mellström et al., 2005; Briot et al., 2007). Existing studies are thus heavily prone to Type II error.
The main study that addressed the interruption of nBP therapy compared patients who stopped 10 mg/day alendronate after four years with those who continued for another five years (Black et al., 2006). Though the main endpoint was BMD, clinical vertebral fractures were also studied. There were insufficient numbers included for the study of morphometric vertebral fracture and hip fracture. Analysis of the data indicates that patients who stopped alendronate lost a significant amount of bone at the hip, compared with those who continued. In addition, patients who stopped stabilized lumbar spine BMD, while those who continued gained additional BMD. Furthermore, patients who continued had significantly fewer clinical vertebral fractures, but experienced no reduction in morphometric vertebral fractures or hip fracture, compared with those who continued. While it can be inferred that the patients who stopped were "better off" after nine total years than their counterparts who never accepted treatment, analysis of the data indicates that they were "worse off" than their colleagues who took alendronate for nine years. A second study reported data from persons who took risedronate 5 mg/day continuously for seven years (Mellström et al., 2005). Analysis of the data indicates that the rate of incident vertebral fracture was the same in newly treated patients after two years, compared with that in patients who had been taking risedronate for seven years. Because there are no definitive prospective fracture data in either study (Mellström et al., 2005; Black et al., 2006), it should be clear that no recommendation based on fracture risk reduction data regarding continuing nBP therapy can be made at this time. However, the arrest of gain in spine BMD and the loss of BMD at the hip after the interruption of alendronate (Black et al., 2006) may suggest that anti-fracture efficacy will wane after treatment interruption.
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METASTATIC BONE DISEASE
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The second most frequent clinical indication for nBPs is reducing the risk of skeletal-related events (SREs) in persons with metastatic breast, lung, and prostate cancer, and multiple myeloma (Fleisch, 1991; Berenson et al., 1998; Ali et al., 2001; Saad et al., 2002, 2004; Body et al., 2003; Brown et al., 2004; Santini et al., 2006a; Saad, 2007). SREs include malignant severe hypercalcemic episodes, new bone metastases, diffuse bone pain, and pathologic fractures due to bone metastases. Severe hypercalcemia, not infrequent in cancer patients, is life-threatening, with significant morbidity (Kristensen et al., 1998). Bone metastases, particularly those that occur in the vertebral bodies, lead to pain and can cause vertebral compression fracture that is paralyzing and permanently disabling. Intravenously administered nBPs, specifically zoledronic acid, pamidronate, and ibandronate, are used because of the high doses that seem necessary, at this time approximately seven- to ten-fold greater than for osteoporosis, and the desire of the oncologist to ensure compliance. The monthly dose for zoledronic acid appears to be based upon the minimum to achieve durable 28-day suppression of bone resorption markers by 70%, while avoiding renal toxicity (Chen et al., 2002). Though intravenous nBPs do not extend the lifespans of cancer patients (Diel et al., 2004), they reduce the risk of SREs by 30–40% and significantly extend time to first new event, thereby measurably improving the patients’ quality of life and reducing bone pain (Brown et al., 2004), reducing the patients’ need for narcotics to control bone pain. IV zoledronic acid reduces the severity of skeletal lesions in the great majority of multiple myeloma patients. Approximately 650,000 prescriptions were written for zoledronic acid in the United States in 2006 (Drug Topics, 2007), equating to approximately 55,000 patient-years of therapy. The number of prescriptions for generic Aredia in 2006 is not known. Intravenously administered nBPs are by far the most efficacious treatment available for reducing the risk of SREs in breast, lung, and prostate cancer patients and in multiple myeloma patients.
Received for publication July 31, 2007.
Revision received September 23, 2007.
Accepted for publication September 24, 2007.
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Journal of Dental Research, Vol. 86, No. 11,
1022-1033 (2007)
DOI: 10.1177/154405910708601102
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ABSTRACT
INTRODUCTION