Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis

Chapter 74

Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis Paul D. Miller

I. Introduction and History II. Pharmacokinetics and Pharmacodynamics III. Treatment of Postmenopausal Osteoporosis: Efficacy

I.

IV. Other Forms of Osteoporosis V. Bisphosphonate Safety VI. Conclusions

INTRODUCTION AND HISTORY

Bisphosphonates are biological analogues of naturally occurring pyrophosphates. Pyrophosphates (P-O-P) are byproducts of ATP metabolism but have no biological activity because of the ubiquitous presence of pyrophosphatases. The substitution of a carbon atom in place of the oxygen atom renders the molecule a bisphosphonate (P-C-P) (Figure 74-1) [1]. Bisphosphonates are not metabolized by pyrophosphatases. Bisphosphonates have a very high affinity for the bone surface. What does not bind to bone is excreted in the urine unchanged [2–3]. Renal excretion is accomplished both by glomerular filtration as well as proximal tubular active secretion so that the clearance of bisphosphonates exceeds the clearance of inulin, an accurate measure of glomerular filtration rate (GFR). Because bisphosphonates are not metabolized, they also have no effect on the pharmacokinetics (PK) of other drugs. Thus, modification of dosing of other medications (e.g., coumadin) is not required when a bisphosphonate is added. Bisphosphonates are poorly absorbed as a class [4–6]. This poor absorption is related to the heavy negative charge of the bisphosphonate molecule, which makes transport across lipophilic cell membranes difficult. Even if a patient strictly follows the correct dosing instructions for taking oral bisphosphonates, less than 1% of the total dose is absorbed. What is absorbed usually has a powerful effect on bone turnover. Yet, there are many clinical circumstances in which absorption may be doubtful: malabsorption conditions, celiac disease, gastro-jejunostomies, small bowel resection, dumping syndromes, where rapid transit time through the intestinal tract may mitigate absorption. It certainly would make clinical management decisions easier when clinicians are uncertain if a bisphosphonate is being absorbed if we could measure bisphosphonate OSTEOPOROSIS, 3RD EDITION Marcus, Feldman, Nelson, and Rosen

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Figure 74-1

Chemical relationship among bisphosphonates.

blood levels in clinical practice. However, since we cannot measure bisphosphonate blood levels, we must rely on surrogate markers, bone mineral density (BMD), and bone turnover markers (BTM), to gain a sense of whether the bisphosphonate is being absorbed and having a positive bone biological effect. Surrogate markers are useful but imperfect indicators of bone biological effects of bisphosphonate action, though surrogates are valuable when properly employed and interpreted [7–9]. Bisphosphonates were initially developed as a spinoff from the chemistry of polyphosphates, which were being studied to inhibit soap from binding to glass. It was the scientific observations of Dr. William Neuman, Professsor Herbie Fleisch, Professor Graham Russell, and Dr. David Francis that led to the knowledge that the first bisphosphonate studied (etidronate) inhibited bone resorption or inhibited mineralization in rat bone depending on the dose [10–11]. Because etidronate in certain doses inhibits tissue mineralization, the first clinical use of a bisphosphonate (etidronate) was performed by the compassionate use application by Dr. Bassett and colleagues at the Columbia University Copyright © 2008, Elsevier, Inc. All rights reserved.

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Table 74-1 ● ●

●

Clinical Use of Bisphosphonates

Bone scanning agents Inhibition of calcification 䊊 Heterotopic bone 䊊 Dental calculus Reducing bone resorption 䊊 Osteoporosis 䊊 Myeloma and bone metastases 䊊 Hypercalcemia 䊊 Paget’s disease 䊊 Osteogenesis imperfecta 䊊 Other disorders

College of Physicians and Surgeons, New York, in a child with myositis ossificans progressive [12]. The positive clinical outcome that a bisphosphonate could benefit disease associated with metabolic bone derangements led to the subsequent clinical trial data and registration of bisphosphonate use in many diseases that have benefited humankind (Table 74-1). Abundant bisphosphonate scientific development was then achieved by the utilization of the Schenck rat model, which allowed the in vivo study of bisphosphonate mechanism(s) of action [13]. Subsequently, there has been an intense scientific and clinical refinement in understanding the mechanisms of action of the bisphosphonates, their similarities and differences [14–19].

Figure 74-2

II. PHARMACOKINETICS AND PHARMACODYNAMICS Bisphosphonates have an extremely high affinity for bone, and bone is nearly the exclusive tissue that takes up bisphosphonates. This selective tissue uptake is due to two major and distinctly different reasons: (1) Bisphosphonates bind to the denuded bone resorptive cavity that has exposed calcium-phosphorus crystal as a consequence of osteoclastic removal of bone tissue during remodeling (e.g., the physiochemical effect); and (2) only phagocytic cells (osteoclasts and macrophages) can take up bisphosphonates (cellular effect) [14–19]. Thus, bisphosphonates reduce bone turnover by two major, distinctly different mechanisms of action: a physiochemical effect and a cellular effect. From the basic P-C-P bond common to all bisphosphonates, the differences in the chemical structure among the bisphosphonates are conveyed by their side-chain moieties [18]. These side-chain differences explain, in part, differences between the aminobisphosphonates: their affinity and adherence to the hydroxyapatite surface; their diffusion into bone; their displacement from this adherence and physiochemical binding when bisphosphonates are discontinued (offset); and the differences in their ability to inhibit the mevalonic acid pathway enzyme, farnesyl pyrophosphate synthetase (FPPS) (Figures 74-2 and 74-3) [14–25].

Bisphosphonates disrupt the mevalonate pathway which is essential for osteoclast function. Scheme courtesy of Michael

Rogers.

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Chapter 74 Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis

Figure 74-3

Chemically dissimilar bisphosphonates have different binding affinities for hydroxyapatite. Adapted from [19].

The bisphosphonates, therefore, are not alike, even within the amino-bisphosphonate group, at least when it comes to their in vitro as well as in vivo effects in specific models. How these differences may become translated into differences in human beings in clinical trial outcomes or in clinical differences observed in observational studies will be explored later in this chapter. With regard to the cellular effect, there are two distinctly different fundamental molecular structures of these drugs: the nonamino bisphosphonates (etidronate and chlodronate) and the amino bisphosphonates (alendronate, risedronate, ibandronate, pamidronate, and zoledronate). The nonamino bisphosphonates have similar physiochemical but different cellular effects from the amino bisphosphonates. The nonamino bisphosphonates disrupt the ATP metabolic pathway in osteoclasts that leads to osteoclast apoptosis, while the amino bisphosphonates impair FPPS. This inhibitory effect on FPPS leads to the reduced osteoclast capacity to prenylate specific intracellular proteins necessary for normal osteoclastic cell function [25]. The end result is the reduced ability of osteoclasts to induce bone resorption and to induce programmed cell death (apoptosis) of osteoclasts. Preliminary studies are also exploring the potential effect of bisphosphonates on osteoblasts as well as osteocytes [26]. Recent data suggest that bisphosphonates increase serum osteoprotogerin (OPG) levels (an osteoblast-derived protein) and that these increases are correlated with increases in BMD [27]. It is unknown at this time if the increase in OPG is due to a direct effect of bisphosphonates on osteoblasts or an indirect effect, e.g., by altering osteoclastogenesis and thereby altering the catabolism of

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OPG. Even more recent work by Monkkonen and colleagues has identified that nitrogen containing bisphosphonates induces the intracellular accumulation of an ATP analogue APPPI (triphosphoric acid 1-adenosine5′-yl ester 3-(3-methylbut-3-enyl) ester), which inhibits a different enzyme in the mevalonic acid pathway, adenine nucleotide translocase, which also contributes to osteoclast apoptosis [28]. Hence, bisphosphonates may affect not just one but two intracellular enzymes in the mevalonic acid pathway, leading to disruption of osteoclast cellular function. In addition, attention has also been focused on potential differences in the cellular effects of FPPS activity or crystal affinity between the amino bisphosphonates that might also explain some of the differences in the onset and/or the duration of action of bisphosphonates, e.g., the ability to see earlier effects on fracture risk reduction or to apply longer dosing intervals than the initially studied daily dosing of bisphosphonates in clinical trials [29]. There are clear FPPS differences: Zolendronic acid and risedronate have a greater ability to inhibit FPPS activity than does alendronate [19–24]. Hence, the difficulty is trying to understand the differences in the pharmacodynamics that might possibly translate into any clinical differences between the most widely utilized amino bisphosphonates: alendronate, ibandronate, and zoledronate have a greater affinity for the HAP crystal, while risedronate has the greater effect on FPPS activity. It must be emphasized that there are no comparisons among the skeletal binding, skeletal half-lives, offset of activity, or FPPS activity among the bisphosphonates in similar patient populations. There are short-term studies in human beings comparing differences between urinary excretion of chlodronate, alendronate, risedronate, and zoledronate; and short-term pharmacokinetic (PK) studies in humans comparing terminal elimination half-lives between risedronate and alendronate that suggest PK differences among bisphosphonates [30–35]. How these differences translate into potential differences in the clichéd term “skeletal half-life” among bisphosphonates is unknown. In the only headto-head clinical trial between two amino bisphosphonates done in the same randomized population, the weekly alendronate and risedronate trial (FACT, fosamax-actonel comparator trial) did show differences in BMD and BTM responses between these two effective agents [36–37]. However, in FACT, there were no prospective fracture data nor any comparative PK or offset data to answer the fundamental clinical question: Are there differences between bisphosphonates with respect to fracture risk reduction or in the offset of effect after discontinuation?

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1728 The final issue to be examined in this section of this chapter is the concept of the “recycling” of bisphosphonates. This concept was initially introduced in 1999 in measuring urinary excretion of alendronate after alendronate discontinuation by high-pressure liquid chromatography (HPLC) [38]. It was observed that the alendronate molecule excreted in the urine after coming out of bone upon alendronate discontinuation is the same molecular structure as that of native alendronate. This observation and the work of Nancollas and colleagues [19] raised the probability that the re-released bisphosphonate that re-enters the systemic circulation during the bone remodeling process could still be metabolically active and reattach to newly formed bone resorptive cavities and maintain clinical activity [19, 24]. The amount and rate of the re-release of bisphosphonates from and their reattachment to a new BMU might differ among bisphosphonates according to their affinity to bone [19]. The re-release of bisphosphonates might not only come from detachment from bone surfaces, but recent data from Coxon and Rogers suggests that bisphosphonates may re-enter the circulation by coming out of the osteoclasts through a transmembrane process termed “transcytosis” [personal communication]. Bisphosphonate “recycling” could explain maintenance of BMD and BTM reduction seen in long-term bisphosphonate studies after several years of administration [39–40]. These clinical observations will be examined in greater detail later in this chapter.

III. TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS: EFFICACY The pivotal trials that have led to the registration of alendronate, risedronate, and ibandronate for the treatment of postmenopausal osteoporosis (PMO) have all fulfilled the required primary endpoint required by the United States Food and Drug Administration (FDA) for registration—evidence of significant reduction in incident vertebral fractures over a 3-year period as compared to the placebo group [41–45]. Since there are no head-to-head fracture data, it is unknown whether one bisphosphonate is superior to another for this endpoint. The FDA registration differs between the bisphosphonates for nonvertebral and hip fracture reduction, which were secondary endpoints in the pivotal alendronate, risedronate, and ibandronate vertebral fracture clinical trials. Alendronate gained an FDA registration for hip fracture but not nonvertebral fracture risk reduction, while risedronate gained registration for

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nonvertebral but not for hip fracture reduction, and ibandronate for neither nonvertebral nor hip fracture reduction. There are primary as well as secondary endpoints that must be met for FDA registration, and the lack of an FDA registration does not mean that one bisphosphonate may not have an effect on reducing the incidence of a specific type of fracture, even though that bisphosphonate did not meet FDA product labeling requirements. For example, in the FOSIT clinical trial (a nonregistration study), significant reduction in nonvertebral fracture incidence was observed with alendronate [46]. In addition, in the risedronate HIP trial, there was a significant reduction in hip fracture incidence in the largest hip fracture-bisphosphonate trial completed to date [47]. Yet, neither of these bisphosphonates has an FDA label for the specific indication (alendronate for nonvertebral and risedronate for hip fracture). In the ibandronate registration clinical trial, no effect was seen on nonvertebral or hip fracture events in prospective analysis [45]. In a post hoc analysis in the ibandronate clinical trial, there was a significant reduction in nonvertebral fracture in patients randomized with a T-score of −3.0 or below. FDA registration does not permit registration based on secondary endpoints if the primary endpoint has not been achieved; in addition, it does not permit registration on the basis of post hoc analysis. The lack of an FDA registration does not mean that a particular bisphosphonate does not have a beneficial effect on reducing fracture risk at a non-FDA product-labeling registered site. There are no data nor is there any plausible biological reason to conceive that one bisphosphonate might “prefer” one skeletal site more than another bisphosphonate. The only means to secure clinical differences between bisphosphonates are head-to-head fracture comparisons between bisphosphonates. The clinical choice of a bisphosphonate, if chosen only by FDA labeling, would restrict clinician flexibility. In the current health care economic climate, clinicians are faced with trying to manage patients who may not tolerate one bisphosphonate as opposed to another for unclear reasons. Health care provider plans may have one “preferred” bisphosphonate over another, creating unnecessary scenarios in which both the doctor and the patient have hurdles to overcome to gain access to an alternative bisphosphonate that might be preferred by medical judgment. Compliance with osteoporosis treatments is suboptimal, as it is with the treatment of many chronic asymptomatic diseases [48–49]. In addition, there is evolving evidence that patients may prefer a weekly or monthly bisphospho-

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Chapter 74 Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis

nate formulation over the fracture-proven daily dosing formulation [50–56]. Better persistence and adherence to therapy may result in better outcomes (e.g., fracture risk reduction) for some patients than for those patients who are less persistent with their medication [57–58]. In the real world of clinical practice, having choices is good. As mentioned, in the analysis of fracture outcome data and clinical practice implementation, the fact that none of the intermittent bisphosphonate dosing formulations (weekly alendronate or risedronate, monthly oral ibandronate, or quarterly intravenous ibandronate) that have been FDA and EU approved for the treatment of PMO has prospective fracture data. These alternative dosing schedules has all been approved by the use of surrogate markers using noninferiority endpoints, e.g., that the equal (noninferior) increase in BMD induced by the intermittent dosing regimen conveys the same improvement in bone strength as the fracture-proven (as compared to placebo) daily registration dosing regimen [59–61]. In the monthly oral ibandronate and the quarterly intravenous ibandronate bridging studies, the registered dose (150 mg/month and 3 mg IV Q 3 months) was not only noninferior but was also superior to the fracture proven daily (2.5 mg/day) formulation (Figure 74-4) [59–64]. Surrogate markers of fracture such as BMD increases and reduction in BTM are imperfect indicators of bone strength although they have been accepted by both the U.S. Surgeon General’s statements on surrogate marker use in osteoporosis as well as the FDA as evidence for equal increases in bone strength in clinical trial data when comparing the effects of a similar class of agents with fracture effectiveness [65]. Thus, for all physicians, patients, and health care plans that choose to select the nondaily bisphosphonate formulations,

Figure 74-4 Monthly ibandronate (150 mg) increases bone mineral density at the lumbar spine significantly more than daily ibandronate (2.5 mg) (* p<0.001). Data obtained from [61] and [62].

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they do so with the trust that the equal increases in BMD and BTM observed with the intermittent formulations compared to the daily formulations translate into equal fracture risk reduction. The recent approval of quarterly intravenous (IV) ibandronate for PMO should help to assure better persistence as well, since the IV administration will need to be overseen by a physician or hospital office that can have oversight in the adherence and persistence, and avoid the uncertainty that the bisphosphonate is getting to bone that at times exists when oral bisphosphonate absorption is in question [66–67]. Intravenous ibandronate registration was also completed on the basis of noninferiority, surrogate marker data as compared to the fracture-proven daily ibandronate formulation. There is a correlation between changes in BMD or BTM and reductions in fracture risk both in meta-analysis as well as individual clinical trials. The correlation is neither linear nor proportional [68–72]. Just recently, the pivotal IV zoledronic acid data were presented [73]. The administration of 5 mg of IV zoledronic acid every year for 3 years reduced the risk of both incident vertebral and nonvertebral as well as hip fractures as compared to placebo. The availability of an IV bisphosphonate given annually with fracture outcome data will offer another choice in bisphosphonate selection, and one with direct fracture data. It is important to point out there are data suggesting mechanisms whereby bisphosphonates may increase bone strength independent of changes in bone mineral content or bone turnover [74]. In an important study, Borah et al. showed that by preserving horizontal trabeculae in an oophorectomized minipig model, risedronate improved bone strength in part due to microarchitectural preservation [75]. Cortical porosity increases in bone with aging and contributes to impairment in bone strength and is also associated with a higher risk of hip fracture [76–77]. Preliminary data suggest that alendronate reduces cortical porosity, which may be another independent mechanism whereby bisphosphonates increase bone strength beyond BMD or turnover [78]. There also may be effects of bisphosphonates to increase bone strength by affecting bone size [79]. Suffice it to say, though the major mechanisms whereby bisphosphonates improve bone strength are by increasing bone mineral content and reducing bone turnover, other factors may also contribute to bisphosphonateinduced improvements in bone strength that future research will better clarify. Bisphosphonate registration for the treatment of PMO requires evidence of incident vertebral fracture risk reduction over a 3-year period as compared to placebo. What about effects on fracture risk reduction beyond 3 years of use? In both the alendronate as well

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1730 as the risedronate clinical trial data, there have been extension studies of the original clinical trial population in subsets of the initial randomization groups. Hence, the science is limited by the selection bias that is fundamentally inherent in non-preplanned and subset analysis, and in capturing data as adverse events where reporting may be associated with selection bias. In the alendronate dataset, there have been two extension studies: one from the initial phase III Liberman et al. study, with the 10-year data published by Bone et al. [80–81]; and second from the alendronate-FDA registration study, the fracture intervention trial (FIT), with the 10-year data given the acronym FLEX (fosamax long-term extension) [40]. The extension studies of the original Liberman study included patients who received variable doses of alendronate (5 mg–20 mg/day) and included a 3-year placebo group in the original study design. During the extension, there did not appear to be any safety issues, the fracture events during 10 years in the group that received 10 years of the treatment registered alendronate at 10 mg/day did not appear to decrease or increase, and there was a progressive rise in axial (BMD) in patients on long-term alendronate. In the patients who were off alendronate for 5 years after having been on this bisphosphonate for the first 5 years, the BMD and turnover markers remained fairly constant off alendronate. There was an increase in bone resorption markers and decline in the femoral neck BMD off treatment, though neither change in these surrogate markers approached the baseline levels, so at least a substantial persistence of effect was seen. In the FLEX trial, patients were observed for 10 years on alendronate (5 mg/day for 2 years and then 10 mg/day thereafter) versus treatment with alendronate for 5 years and then no alendronate for 5 follow-

Paul D. Miller

up years. Spine BMD increased more (+3.8%), and bone turnover reduction was maintained at a reduced level in the long-term treated groups as opposed to the placebo group. In the FLEX 5-year placebo group follow-up period, hip BMD declined a small but significant amount, although the NTX did not change, suggesting turnover suppression was maintained. There were no differences in morphometric or nonvertebral fracture events at 10 years between the two groups in FLEX. There were fewer clinical vertebral fractures in the long-term treated group (55%) that met statistical difference from the placebo group (2% vs. 5%) (Figure 74-5) [40], these data suggesting that there might be some increase in clinical vertebral fracture risk and increased bone fragility after stopping 5 years of alendronate, even though BMD and BTM did not change. In the risedronate clinical trial data set, there are 5-year data in which a subset from the original multinational group was maintained on placebo and another maintained on risedronate [82]. These data to date represent the longest placebo-controlled bisphosphonate fracture data. New incident vertebral fractures continued to be reduced during the 4th and 5th year in the treated group, which provides evidence of long-term fracture benefit through 5 years of treatment. In another risedronate data set from the North American vertebral trial treated for 3 years, there is follow-up after discontinuation for 1 year. During the 4th year in the group that had been on risedronate for 3 years and discontinued therapy, the femoral neck BMD decreased and the urinary NTX increased close to baseline, yet incident morphometric vertebral fractures continued to decline in the placebo group during the 4th year in those who had been on risedronate for the first 3 years (Figure 74-6) [83].

Figure 74-5 Cumulative incidence of vertebral fractures after long-term treatment with alendronate. Data obtained from [40].

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Chapter 74 Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis

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Figure 74-6 New vertebral fractures observed after long-term treatment with risedronate (p< 0.05 versus placebo). Data from [83].

It is unclear from these extension studies what really happens to bone strength even though BMD and BTM may either remain stable or change in directions that suggest remodeling is increasing. In clinical practice, many physicians are offering a “drug-holiday” off bisphosphonates in lower-risk patients after 3–5 years of use and monitoring BMD and BTM as a means of deciding if and when to either restart the same or different osteoporosis-specific agent. Since it is not clear what happens to bone strength after discontinuation, a drug holiday may not be advisable in high-risk patients. Since there is also not a clear scientifically based safety issue with long-term bisphosphonate use at this time, continuing to administer bisphosphonates in higher-risk patients (especially those who have had prior fragility fractures) seems plausible [84]. Why did issues of a drug holiday ever arise in discussions? When bisphosphonates were first utilized in the management of patients with PMO (1970s), most physicians did not use them in women 50–60 years of age, but in older women with high fracture risk. Decisions regarding the management of the skeletal health in the postmenopausal population shifted after July 9, 2002, with the data from the first publication of the Women’s Health Initiative (WHI) [85]. Due to concerns surrounding an increased risk of cardiovascular events in women on a specific formulation of hormonal therapy, large numbers of postmenopausal women discontinued hormonal therapy (HT) and subsequently developed concerns about their unprotected skeletal health. As a consequence, younger postmenopausal women had more BMD tests performed, were discovered to have low BMD, and many were started on bisphosphonates. At that time, physicians began to raise the question of how long to treat. The evidence of the long bone half-life of bisphosphonates and their potential for prolonged metabolic

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activity on bone remodeling even after discontinuation has raised concerns about unforeseen possible continual bisphosphonate buildup effects on bone strength [86–88] (Figure 74-7) [87]. It is clear that a single administration of an IV bisphosphonate leads to systemic skeletal accumulation that is maintained (mouse and rat) in bone for a durable period of time [89–90]. While high doses of etidronate may induce osteomalacia [91–92], lower-dose cyclical etidronate, approved for the treatment of PMO in many countries, has never been shown to induce osteomalacia [93]. Osteomalacia has never been described at any dose of amino bisphosphonate administration, in part due to the knowledge that the ratio of inhibition of mineralization to resorption with etidronate is 1:1 and >1:1,000 with the amino bisphosphonates [94]. Microdamage accumulation is also seen in animal models with amino bisphosphonate administration, but no impairment in bone strength has ever been demonstrated with any dose of amino bisphosphonates administered in animal models or human beings (Figure 74-8) [88, 95]. The normal human skeleton must undergo remodeling in order to repair microcracks that develop during normal activities. Remodeling is a prerequisite for this repair. The ideal level of remodeling and bone turnover in the human skeleton is unknown, but there are clinical examples in which no remodeling at the one end or excessive remodeling at the opposite end may lead to skeletal fragility [96, 97]. Bisphosphonates reduce remodeling but do not abolish it [98, 99], and it is unclear whether or not there is a “threshold” below which remodeling is excessive or inadequate [100, 101]. While the “normal” premenopausal range for urinary N-telopeptide (NTX) and serum C-telopeptide (CTX) has been defined in several studies [102, 103], it is not clear whether

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Figure 74-7

Paul D. Miller

Microcracks observed in dogs treated with high doses of bisphosphonates. Published with permission from [87]. (See

color plate.)

Figure 74-8 Microcrack accumulation and bone strength in dogs treated with bisphosphonates (*p < 0.01). Data adapted from [88].

there is a level below or above which remodeling is inadequate or excessive. There are clues that provide insight into this important question. In the initial IV ibandronate clinical trials that used doses of 0.5 mg, 1.0 mg versus placebo every 3 months, the increase in spinal BMD (primary endpoint) was similar to that seen in other bisphosphonate studies. Yet in the intention to treat (ITT) population, incident vertebral fractures were not significantly reduced [104]. There was a significant fracture protective effect observed in the per protocol (PP) population, but this statistical analysis was not the FDA-filed primary analysis. Clues to the lack of a statistical effect of this 1.0 mg IV every 3 month dose to reduce fractures may lie in the pattern of suppression of bone turnover with prolonged interval dosing; there may be substantial oscillation in the resorption markers such that between doses there may

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have been, at times, inadequate sustained suppression of turnover (e.g., the serum CTX may have risen above the upper limit of normal for the premenopausal range). The approved higher-dose IV ibandronate (3 mg every 3 months) for PMO has been approved on the basis of noninferiority endpoints: This dose did show increases in spine and hip BMD that were not only noninferior but superior to the fractureproven 2.5 mg/day oral dose and had little oscillation of serum CTX between doses [105]. In recent preliminary reports from the HORIZIN (zoledronic acid) clinical trials where there was clear fracture reduction with an annual dose (5 mg/year), the bone resorption marker was reduced 80–90% below the baseline value and was sustained and maintained at this lower level [73]. Hence, to date, there is no sound scientific evidence that registered bisphosphonates abolish bone

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Chapter 74 Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis

turnover, and there may be a range of bone resorption that is necessary to be maintained to observe a fracture benefit. In quantitative bone histomorphometry data comparing activation frequency (the birth rate of new bone remodeling units) of pre-menopausal women to that of elderly postmenopausal women who have a much higher bone turnover rate, a reduction of bone turnover even 70% from the higher level seen in late postmenopausal women is comparable to bone turnover of pre-menopausal women [106]. Thus, to date, there are data to suggest that a certain degree of reduction in bone turnover is necessary to have bisphosphonates reduce fracture risk and that no bisphosphonate abolishes turnover.

IV.

OTHER FORMS OF OSTEOPOROSIS

There are many secondary causes of osteoporosis [107]. Registration of bisphosphonates has been completed for both alendronate and risedronate for glucocorticoid-induced (GC) as well as male osteoporosis [108, 109]. While many clinicians effectively use bisphosphonates in the management of post-transplant osteoporosis and in mild asymptomatic primary hyperparathyroidism, their use in GC-induced bone disease and in male osteoporosis merits further discussion [110–114]. Glucocorticoids lead to fractures through multiple negative effects on bone metabolism: reduction in bone formation, increased bone resorption, increased urinary calcium excretion, and reduced gastrointestinal calcium absorption [115–117]. In addition, the relationship between BMD and fracture risk does not follow the same relationship as it does for PMO; e.g., patients fracture at higher BMD on glucocorticoids [118]. Bisphosphonates may be antiapoptotic to osteoblasts in the presence of glucocorticoids [119, 120]. In clinical trial data, bisphosphonates have been shown to prevent the loss of BMD and, in post hoc analysis, reduce the incidence of vertebral fractures [121, 122]. The loss of BMD related to glucocorticoids is dose-related, and fractures may occur early in the course in highdose glucocorticoid administration. Even low-dose (2.5 mg/day of prednisone) glucocorticoid administration results in greater fracture risk as compared to no glucocorticoid use [118, 123]. The guidelines of the American College of Rheumatology (ACR) are widely used in considerations of when to initiate bisphosphonates in patients receiving GC [124]. Patients receiving 5 mg/day of prednisone (or equivalent doses of another GC) for >3 months and whose T-scores are −1.0 or lower should receive bisphosphonates. Patients receiving higher doses (>30 mg/day) of prednisone for more than

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a few weeks should be considered for bisphosphonate administration—and, if the GC can be discontinued, so can the bisphosphonate, unless there are other justifications for bisphosphonate continuation (e.g., PMO with additional risk factors for fracture). In men, fracture risk increases at all skeletal sites after a fragility fracture in men after age 50 years [125] and, from head-to-head data, hip fractures occur at similar levels of absolute femoral neck BMD as in women [126]. The International Society for Clinical Densitometry (ISCD) has suggested that the WHO criteria for osteoporosis be applied to men after age 50 years [127]. Data from both alendronate and risedronate clinical trials have shown a benefit to protect the loss of BMD and, in small sample sizes, reduce vertebral fracture risk in men with a T-score at the spine or hip of −2.0 or below, who are at age 60 years and over [108, 109]. This effect seems to be independent of the prevailing testosterone level and strongly suggests that bisphosphonates reduce BMD loss in men aged 60+ years regardless of their gonadal function. From a clinical standpoint, men 50+ years and older with fragility fractures should be strong candidates for bisphosphonates once secondary causes for bone fragility are excluded. In addition, men 60–65+ years of age without a fracture who have T-scores of −2.0 or lower using a normal male database should be considered for bisphosphonate intervention, in addition to adequate vitamin D and calcium, once secondary causes for low BMD are excluded.

V.

BISPHOSPHONATE SAFETY

Bisphosphonate effects on bone remodeling and the implications regarding remodeling, turnover, microdamage accumulation, and repair were addressed in the previous section on efficacy. In addition to the effects of altering bone turnover and remodeling on bone strength, and microdamage repair/accumulation, there also must be some consideration of how bisphosphonates may alter the mineralization density of bone tissue. There can be divergent effects on bone strength as a function of adding mineral to bone tissue: Too much mineral can cause the bone to become brittle (e.g., osteopetrosis), while too little mineral leads to pliable and “soft” bone (e.g., osteomalacia) [96, 97, 128–130]. The ideal mineralization density of the human skeleton is unknown [131]. Nevertheless, to date, there is no evidence from animal models given very high doses of ibandronate or human data that, despite the continual secondary mineralization that occurs with persistent bisphosphonate administration, either the increase in mineralization density or the

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1734 more homogeneous tissue mineralization that one sees with bisphosphonate use impairs bone strength (Figure 74-9 and Figure 74-10) [132–137]. Thus, while there are plausible scientific reasons to be vigilant about the potential for long-term negative effects of bisphosphonates on bone strength, scientific evidence for any negative effect in human beings given registered doses for prolonged periods of time is lacking. Recent anecdotal case reports of fragility fractures occurring in patients on long-term alendronate have raised questions if there could be suppression of remodeling in certain individuals that might lead to bone fragility [138]. It is important to stress that in the cited reference report of nine cases, two of these patients were also on glucocorticoids and three were on concomitant estrogen therapy. Hence, the implications regarding alendronate alone on bone strength

Figure 74-9

Long-term risedronate treatment normalizes bone mineralization estimated by (BMR-V) in postmenopausal osteoporotic women (n = 7). Adapted from [75].

Figure 74-10

Lifelong treatment with ibandronate (15 mg/kg/d) increases bone strength in female rats (*p < 0.001) vs. control. Adapted from [132].

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are based on four patients from these data. Double tetracycline label bone biopsy showed at least single labels in these patients, so mineral was being added, as has also been seen with both long-term (5-year) risedronate and (10-year) alendronate biopsies, all indicating continual bone turnover is occurring with long-term bisphosphonate use [139–140]. Certainly, physicians must be responsible with regard to the possibility that, in an ill-defined subset of the postmenopausal population, there might be individuals who might develop increased bone fragility with long-term bisphosphonate usage. The most common safety issues revolve around the effects of bisphosphonates on upper gastrointestinal (UGI) mucosa. There is no doubt that the amino bisphosphonates may induce esophagitis and that this problem can develop anytime in the utilization of the bisphosphonate, not just at the initiation. The UGI side effect can be mitigated by carefully instructing the patient on the proper dosing of the oral bisphosphonate. If patients take the oral bisphosphonate according to the dosing instructions, the incidence of UGI side effects is small. If patients develop UGI side effects (pain, heartburn, reflux), then the bisphosphonate should be discontinued to allow the symptoms to clear. Often the patient can be rechallenged with the same or a different oral bisphosphonate and be able to tolerate the same or the new bisphosphonate. While there may be differences in the UGI tolerability between bisphosphonates, it is also probable that many UGI symptoms are related to the high background prevalence of UGI symptoms in the population at large. In the FACT trial previously mentioned, there were no differences in the UGI tolerability between weekly alendronate and weekly risedronate. Osteonecrosis of the jaw (ONJ) is an area of exposed bone in the mandible or maxilla that persists for weeks after a tooth extraction, dental implant, or, in a smaller proportion of reported cases, develops spontaneously [141–144]. There is no universally accepted definition of this condition. The vast majority of these cases are seen in the oncology population receiving high doses of monthly intravenous zoledronic acid or pamidronate and chemotherapy. There have been fewer than 100 cases reported in patients receiving oral bisphosphonates for osteoporosis or Paget’s disease, with inadequate information on the comorbidities involved in these cases. There have been no cases of ONJ in the cumulative clinical trial experience of both the oral and intravenous bisphosphonates amounting to >60,000 patient-year exposure. Clinical trial patients also have no identifiable risk factors for ONJ: cancer, chemotherapy, severe periodontal disease, or severe immunosuppression (e.g., AIDS). The median time for appearance

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Chapter 74 Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis

of ONJ in the oncology area receiving high-dose intravenous bisphosphonates is 25 months. Hence, although the estimated-calculated attributable risk of ONJ in the osteoporotic population receiving osteoporosis doses of bisphosphonates may be 0.7 per 100,000 patientyear exposure, it is unclear at this time if ONJ is a risk at all with osteoporosis doses of bisphosphonates. It is, however, necessary to be prudent and vigilant, since it is always a possibility that longer-term exposure of lower doses of bisphosphonates in an at-risk subpopulation may become a valid medical issue. At this time, the American Dental Association as well as the American Society of Bone and Mineral Research (ASBMR) Task Force on ONJ have published guidelines on suggestions for the management of patients about to receive or already on bisphosphonates [145, 146]. Most of the recommendations are based on risk/benefit ratio assessments and advice to follow proper dental hygiene and are based on opinion rather than science. Since the pathophysiology of ONJ is illdefined, decisions regarding withholding or temporarily discontinuing bisphosphonates in patients who may need dental surgery are best judged on a case-by-case basis. In patients at high risk for a fragility fracture, wide opinion is not to alter the decisions regarding bisphosphonate initiation or discontinuation, since the risk for fracture in an untreated or even in the already treated previously high-risk patient may be greater than the risk of ONJ. In lower-risk patients, general advice is to withhold bisphosphonates in treatmentnaive patients until the dental work is completed; and in already-treated patients, temporarily discontinuing bisphosphonates for 3 months before dental surgery and restarting after the oral tissue is healed. There is no evidence that any of these approaches could alter the course of ONJ, even in the oncology population. As more evidence accumulates, both the pathophysiology of ONJ and its relationship to bisphosphonate use, as well as management decisions, may become better clarified. The first phase reaction is the transient appearance of muscle pain and fever occurring in the first 1–3 days after the initiation of bisphosphonate therapy. This symptomatology is more common with intravenous than oral bisphosphonate therapy, lasts 1–3 days, is self-limiting, and has no sequelae [147]. It is associated with the lysis of circulating T-lymphocytes and the release of cytokines. There are no serious ramifications of this short-lived reaction, which occurs in <10% of patients and may be mitigated by the preadministration of acetaminophen. The FDA label advises against using bisphosphonates in patients with creatinine clearances (GFR) below 30 mL/minute. Most of this advice is based on

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high-dose rat toxicity studies where glomerular sclerosis can be seen, and a paucity of data in patients with stage 4 or 5 chronic kidney disease (GFR <30 or 15 mL/minute). Since bisphosphonates are excreted by filtration and proximal tubular secretion, their clearance probably goes down as renal function declines. In this regard, there is the potential for greater bone retention in patients with more severe CKD. In the bisphosphonate clinical trial data, inclusion or exclusion of patients was not based on a predetermined GFR measurement but on the serum creatinine concentration (usually <2.0 mg/dL). However, many elderly patients with low body mass index may have a serum creatinine <2.0 mg/dL and still have a GFR <30 mL/minute. In addition, from the NHANES III data set, nearly 25% of the population 70 years of age or older have an estimated GFR (eGFR) below 30 mL/minute, the precise population more likely to receive bisphosphonate treatment for osteoporosis [148]. Hence, there is a high probability that clinicians have already been using bisphosphonates for osteoporosis therapy in patients who fall below the caution of the FDA (30 mL/minute), since measuring GFR is not a standard of care in the management of PMO. The measurement of creatinine clearance or eGFR may become a standard of care in the future [149, 150], since the FDA labeling for intravenous zoledronic acid in oncology suggests adjusting the dose according to the creatinine clearance; and the FDA (but not European) label for intravenous ibandronate suggests measuring the serum creatinine before each quarterly injection. In the clinical trial data for zoledronic acid and ibandronate, no cases of acute renal failure were seen with the 15-minute infusion of 5 mg of zoledronate, or the 3-mg quarterly injection of ibandronate [147, 151]. Nevertheless, since clinical trial patients are not representative of the general population, it is still prudent to be cautious with IV bisphosphonates and to measure the patients’ renal function before and following administration. It is reassuring that in a post hoc analysis of the risedronate dataset (over 9000 patients), a proportion had eGFR <30 mL/minute (none <14 mL/minute) and yet had no change in serum creatinine concentration over a median of 2 years of risedronate administration in FDA-approved doses [152]. Similar observations were made in a post-hoc analysis of the alendronate data [153]. The management of patients with stage 4–5 CKD who have osteoporosis and in whom other forms of renal bone disease have been excluded is the topic of another detailed discussion. There may be reasons for considering bisphosphonates in this population who have PMO, male osteoporosis, or steroid-induced osteoporosis where bisphosphonates have been shown to be effective [110, 154, 155]. Adjustments in the dose

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of the bisphosphonate may be necessary in this population, considering the pharmacodynamics of bisphosphonates in patients with more severe CKD. Additional prospective efficacy and safety data are needed in this population. However, bisphosphonates should not be excluded for the treatment of osteoporosis in patients with stage 4–5 CKD since these agents may potentially be useful in high-risk CKD patients.

VI.

CONCLUSIONS

Bisphosphonates, administered to the appropriate population, may increase BMD, prevent bone loss of BMD, reduce bone turnover, or reduce fracture risk. They are safe in the vast majority of patients for at least 10 years of use. It remains to be defined, scientifically, if bisphosphonates have any negative effect on the human skeleton at prescribed doses. Bisphosphonates may be given in oral or intravenous formulations. While there are differences in in vitro and in vivo models among bisphosphonates with regard to their affinity for the hydroxyapatite crystal surface and their degrees of inhibition of osteoclast intracellular FPPS (farnesyl pyrophosphate synthetase), it is unknown if these differences translate into different clinical effects on fracture outcomes in human beings. The ability of various bisphosphonates to be prescribed with prolonged dose-free intervals may be related to differences in the physiochemical or cellular effects previously described, or it may be related to their potential, yet still unclear, differences in retention time in the human skeleton. It was recently discovered that bisphosphonates that have been buried in bone are re-released back into the circulation, and the molecule re-released is identical to the same native biologically active molecule. This may explain the maintenance of BMD and low bone turnover observed for years after the discontinuation of a bisphosphonate. It is presently unknown what happens to bone strength upon discontinuation of a bisphosphonate even when the BMD and low bone turnover are maintained. For this reason, decisions regarding a bisphosphonate drug holiday are based on a case-by-case basis and are based on clinical judgment alone. Bisphosphonates have no drug interactions-drug interaction, which makes them appealing to use in treating the elderly osteoporotic population, many of whom receive many medications. Preliminary post hoc data suggest that bisphosphonates seem to be safe in patients with renal impairment (GFR >15 mL/ minute) for a restricted (2-year) period of use. Bone biopsy is needed to diagnose osteoporosis and exclude other causes of bone disease in end-stage renal disease before appropriate management decisions can be made [154]

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and may also be needed in earlier chronic kidney disease (stages 3 and 4, GFR <60 mL/minute) if preliminary data are substantiated that low bone turnover may appear earlier and be more prevalent than heretofore suspected in CKD [156, 157]. Bisphosphonates are effective in osteoporosis in patients receiving glucocorticoids and in males, and are widely used to reduce bone loss in other medical conditions associated with bone loss and fractures (e.g., post-solid organ transplantation, primary hyperparathyroidism, cystic fibrosis, AIDS, etc.). There is currently little evidence to show the ability of bisphosphonates to reduce fracture risk in these conditions which are associated with bone loss and/or high bone turnover where fracture risk is high. However, bisphosphonate therapy is often utilized on the assumption that fracture risk will be reduced through one of the multiple mechanisms whereby bisphosphonates contribute to bone strength. There is a great deal of work needed to delineate the mechanisms of action of the bisphosphonates and their clinical utility alone or in combination with other agents that affect bone strength [158]. Important data also need to be obtained regarding the long-term safety and effects on bone strength with the bisphosphonates. Notwithstanding the importance of future research, at the current time, the bisphosphonates are very effective and safe bone-seeking agents that can reduce the risk of vertebral, nonvertebral, and hip fractures.

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FIGURE 74-7

Microcracks observed in dogs treated with high doses of bisphosphonates. Published with permission from [87].

FIGURE 78-14 Examples of remodeling-based formation (top) and modeling-based formation (bottom). The right panels show the fluorescent image of the double labels corresponding to the toluidine blue sections on the left panels. Note the scalloped cement line (top, arrows) and the smooth cement line in the bottom left panel (arrows). From R. Lindsay, F. Cosman, H. Zhou, M. P. Bostrom, V. W. Shen, J. D. Cruz, J. W. Nieves, and D. W. Dempster, A novel tetracycline labeling schedule for longitudinal evaluation of the short-term effects of anabolic therapy with a single iliac crest bone biopsy: Early actions of teriparatide. J Bone Miner Res 21(3),366-373 (2006).