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Home , Bisphosphonate

SUPPLEMENT ARTICLE

Bisphosphonates: Mode of Action and

R. Graham G. Russell, MD, PhD

Botnar Research Centre and Oxford University Institute of Musculoskeletal Sciences, Oxford, United Kingdom

The author has indicated he has no financial relationships relevant to this article to disclose.

ABSTRACT The profound effects of the bisphosphonates on were discov- ered over 30 years ago, and they are now well established as the major used for the treatment of diseases associated with excessive resorption. Their www.pediatrics.org/cgi/doi/10.1542/ peds.2006-2023H principal uses are for Paget disease of bone, myeloma, bone metastases, and doi:10.1542/peds.2006-2023H in adults, but there has been increasing and successful application in Key Words pediatric bone diseases, notably . Bisphosphonates are , , structural analogues of inorganic pyrophosphate but are resistant to enzymatic and bisphosphonates, osteoporosis chemical breakdown. Bisphosphonates inhibit bone resorption by selective ad- Abbreviations PPi—inorganic pyrophosphate sorption to surfaces and subsequent internalization by bone-resorbing ATP— osteoclasts where they interfere with various biochemical processes. The simpler, FPP—farnesyl diphosphate non–-containing bisphosphonates (eg, clodronate and etidronate) can be GGPP—geranylgeranyl diphosphate FPPS—farnesyl pyrophosphate synthase metabolically incorporated into nonhydrolysable analogues of adenosine triphos- Accepted for publication Oct 5, 2006 phate (ATP) that may inhibit ATP-dependent intracellular enzymes. In contrast, Address correspondence to R. Graham G. the more potent, nitrogen-containing bisphosphonates (eg, pamidronate, alendro- Russell, MD, PhD, Botnar Research Centre, Nuffield Department of Orthopaedic Surgery, nate, risedronate, ibandronate, and zoledronate) inhibit a key enzyme, farnesyl University of Oxford, Headington, Oxford OX3 pyrophosphate synthase, in the , thereby preventing the 7LD, United Kingdom. E-mail: graham.russell@ biosynthesis of isoprenoid compounds that are essential for the posttranslational ndos.ox.ac.uk PEDIATRICS (ISSN Numbers: Print, 0031-4005; modification of small guanosine triphosphate (GTP)-binding proteins (which are Online, 1098-4275); published in the public also GTPases) such as Rab, Rho, and Rac. The inhibition of protein and domain by the American Academy of Pediatrics the disruption of the function of these key regulatory proteins explains the loss of activity. The recently elucidated crystal structure of farnesyl diphosphate reveals how bisphosphonates bind to and inhibit at the active site via their critical nitrogen atoms. Although bisphosphonates are now established as an important class of drugs for the treatment of many bone diseases, there is new knowledge about how they work and the subtle but potentially important differences that exist between individual bisphosphonates. Understanding these may help to ex- plain differences in potency, onset and duration of action, and clinical effectiveness.

S150 RUSSELL Downloaded from www.aappublications.org/news by guest on September 29, 2021 HE DISCOVERY AND development of the bisphospho- tion by physicochemical mechanisms that produce direct Tnates as a major class of drugs for the treatment of impairment of the calcification process by acting as crys- bone diseases was recently reviewed1 and represents a tal poisons after adsorption to mineral surfaces rather fascinating story that has its origins in studies of biolog- than by effects on the deposition of matrix. ical calcification processes. There are many books and Perhaps the most important step toward the future review articles available that describe the chemistry, use of bisphosphonates occurred when we found that pharmacology, and clinical applications of bisphospho- bisphosphonates, as we had already shown for PPi,17 also nates.2–5 had the novel property of being able to inhibit the dis- It had been known since the 1930s that trace solution of hydroxyapatite crystals.18 This finding led to amounts of polyphosphates were capable of acting as studies to determine if they might also inhibit bone water softeners by inhibiting the crystallization of cal- resorption, which they did in many different experimen- cium salts, such as calcium carbonate,6 and in the 1960s tal models.19,20 In growing intact rats, the bisphospho- Fleisch et al7,8 showed that inorganic pyrophosphate, a nates block the removal of both bone and cartilage, thus naturally occurring polyphosphate and a known byprod- retarding the modeling of the metaphysis, which be- uct of many biosynthetic reactions in the body, was comes club-shaped and radiologically denser than nor- present in serum and urine and could prevent calcifica- mal. This effect is the basis of the Schenk model21 and is tion by binding to newly forming crystals of hydroxyap- a phenomenon of interest in pediatrics because it is also atite. It was proposed that inorganic pyrophosphate (PPi) observed in children who are treated with high doses of might be the body’s own natural “water softener” that bisphosphonates. normally prevents calcification of soft tissues and regu- The bisphosphonates are also effective in preventing lates bone mineralization. It subsequently became clear bone destruction in a number of animal models of hu- that calcification disorders might be linked to distur- man disease, such as immobilization osteoporosis,22 and bances in PPi metabolism. The first example was an the prevention of bone loss associated with ovariectomy. inherited disorder, hypophosphatasia, in which lack of If not given in excess, bisphosphonates do not impair alkaline phosphatase is associated with mineralization bone growth and can maintain or improve the biome- defects of the skeleton and elevated PPi levels,9 indicat- chanical properties of bone in both normal animals and ing that alkaline phosphatase is probably the key extra- experimental models of osteoporosis.23 cellular enzyme responsible for hydrolyzing pyrophos- In general, there is a good correlation between po- phate. tency and structure-activity relationships in vitro and in Attempts to exploit these concepts by using pyro- vivo.24 In the presence of bisphosphonates, isolated os- phosphate and polyphosphates to inhibit ectopic calcifi- teoclasts form fewer and smaller erosion cavities on var- cation in vessels, skin, and kidneys in laboratory ious mineralized matrices in vitro.25 animals were successful only when the compounds were injected.10 Orally administered pyrophosphate and PHARMACOLOGY AND CELLULAR ACTIONS polyphosphates were inactive because of their hydrolysis Etidronate was the first bisphosphonate to be used in in the . During the search for more humans for fibrodysplasia ossificans progressiva and stable analogues of pyrophosphate that might also have Paget disease.26 Once the potential clinical value of the antimineralization properties of pyrophosphate but bisphosphonates had been appreciated, research efforts would be resistant to hydrolysis, several different chem- were devoted to the development of compounds with a ical classes were studied. The bisphosphonates (at that more powerful antiresorptive activity but without a cor- time called diphosphonates), characterized by P-C-P mo- responding ability to inhibit mineralization. With com- tifs, were among these classes.11–13 pounds such as etidronate there was only a 10- to 100- Like pyrophosphate, bisphosphonates had high affin- fold difference between doses that inhibit mineralization ity for bone mineral14 and were found to prevent calci- compared with doses that reduce bone resorption. En- fication both in vitro and in vivo but, unlike pyrophos- hancing this window was readily achieved, and many phate, were also able to prevent experimentally induced hundreds of bisphosphonates have been synthesized; pathologic calcification when given orally to rats in more than a dozen have been used in humans. With the vivo.15 This property of being active by mouth was key to development of bisphosphonates that were more potent their future use in humans. inhibitors of bone resorption, these dose differences wid- In these early studies bisphosphonates were shown ened to several orders of magnitude, which meant that not only to prevent the experimentally induced calcifi- inhibition of skeletal mineralization observed with etidr- cation of many soft tissues, including skin, kidneys, and onate ceased to be a major clinical concern. The grada- blood vessels in vivo but, with some of the compounds tion of potency evaluated in the animal models corre- (eg, etidronate), to also inhibit mineralization of ectopic sponded quite well with that found in humans, although bone as well of normal calcified tissues such as bone and the differences in potency are much smaller in humans. cartilage.16 Bisphosphonates seem to prevent calcifica- Bisphosphonates accumulate in bone, so it is impor-

PEDIATRICS Volume 119, Supplement 2, March 2007 S151 Downloaded from www.aappublications.org/news by guest on September 29, 2021 tant to know what happens during long-term adminis- action of proteolytic enzymes, including . tration. From a clinical point of view, it is reassuring that Because bisphosphonates adsorb to bone mineral, espe- the inhibition of bone resorption reaches a new steady- cially at sites of bone resorption where the mineral is state level rather than becoming progressively lower, most exposed,35,36 osteoclasts are the type in bone even when the compounds are given continuously.27 most likely to be exposed to the highest concentrations The level of suppression depends on the administered of free, non–mineral-bound bisphosphonate as a result dose and has also been observed in humans.28 There of the release of the bisphosphonate from bone mineral seems to be no progression of the antiresorptive effect in the low-pH environment beneath osteoclasts. It has with time, which suggests that the bisphosphonate bur- been estimated that pharmacologic doses of alendronate ied in the bone is inactive for at least as long as it remains that inhibit bone resorption in vivo could give rise to buried there. This also means that within the therapeu- local concentrations as high as 1 mM alendronate in the tic-dosage range, there is little risk of a continuous and resorption space beneath an osteoclast, which is much progressive decrease in bone turnover in the long run higher than the concentrations of bisphosphonates re- that might lead to an increase in bone fragility. An quired to affect osteoclast morphology and cause oste- additional important pharmacologic property of bisphos- oclast in vitro.37 phonates is that the total dose administered is a major In contrast to their ability to induce apoptosis in os- determinant of their effects. This has been well studied teoclasts, which contributes to the inhibition of resorp- for ibandronate29 and zoledronate.30 In both cases the tive activity, some experimental studies suggest that same inhibition of bone resorption has been docu- bisphosphonates may protect osteocytes and mented regardless of whether the bisphosphonate was from apoptosis induced by .38 Recent ev- given in small frequent (eg, daily) doses compared with idence suggests that the inhibition of osteocyte apoptosis larger doses given less frequently. This was the basis for by bisphosphonates is mediated through the opening of the development of intermittent-dosing regimens in hu- connexion 43 hemichannels and activation of extracel- mans. lular signal-regulated kinases.39 The possibility that The pronounced selectivity of bisphosphonates for bisphosphonates used clinically may get access to osteo- bone rather than other tissues is the basis for their value cytes differentially depending on their mineral-binding in clinical practice. Their preferential uptake by and affinities and inherent structural properties needs to be adsorption to mineral surfaces in bone bring them into studied. close contact with osteoclasts. During bone resorption, bisphosphonates are probably internalized by endocyto- STRUCTURE-ACTIVITY RELATIONSHIPS AND MECHANISM OF sis along with other products of resorption. Many studies ACTION have shown that bisphosphonates can affect osteoclast- The features of the bisphosphonate molecule necessary mediated bone resorption in a variety of ways, including for biological activity were well defined in the early effects on osteoclast recruitment, differentiation, and re- studies. The P-C-P moiety is responsible for the strong sorptive activity, and may induce apoptosis. affinity of the bisphosphonates for binding to hydroxy- Because mature, multinucleated osteoclasts are apatite and allows for a number of variations in structure formed by the fusion of mononuclear precursors of he- on the basis of substitution in the R1 and R2 positions on matopoietic origin, bisphosphonates could also inhibit the atom (Fig 1). The ability of the bisphospho- bone resorption by preventing osteoclast formation, in nates to bind to hydroxyapatite crystals and to prevent addition to affecting mature osteoclasts. In vitro, both crystal growth and dissolution was enhanced when bisphosphonates can inhibit dose-dependently the for- the R1 side chain (attached to the geminal carbon atom mation of osteoclast-like cells in long-term cultures of of the P-C-P group) was a hydroxyl group (as in eti- human bone marrow.31 In organ culture, also, some dronate) rather than a halogen atom such as chlorine (as bisphosphonates can inhibit the generation of mature in clodronate). The presence of a hydroxyl group at the osteoclasts, possibly by preventing the fusion of oste- R1 position increases the affinity for calcium (and, thus, oclast precursors.32,33 bone mineral) because of the ability of bisphosphonates It is likely that bisphosphonates are selectively inter- to chelate calcium ions by tridentate rather than biden- nalized by osteoclasts rather than other cell types be- tate binding.40 cause of their accumulation in bone and the endocytic The ability of bisphosphonates to inhibit bone resorp- activity of osteoclasts. During the process of bone resorp- tion in vitro and in vivo also requires the P-C-P struc- tion, the subcellular space beneath the osteoclast is acid- ture. Monophosphonates (eg, pentane monophospho- ified by the action of vacuolar-type proton pumps in the nate) or P-C-C-P or P-N-P compounds are ineffective as ruffled border of the osteoclast membrane.34 The acidic inhibitors of bone resorption. Furthermore, the antire- pH of this microenvironment causes dissolution of the sorptive effect cannot be accounted for simply by adsorp- hydroxyapatite bone mineral, whereas the breakdown tion of bisphosphonates to bone mineral and prevention of the extracellular bone matrix is brought about by the of hydroxyapatite dissolution. It became clear that

S152 RUSSELL Downloaded from www.aappublications.org/news by guest on September 29, 2021 FIGURE 1 The generic structure of pyrophosphate compared with bisphos- phonates and their functional domains.

bisphosphonates must inhibit bone resorption by cellular were synthesized to optimize their antiresorptive effects, effects on osteoclasts rather than simply by physico- the most potent antiresorptive bisphosphonates were chemical mechanisms. those containing a nitrogen atom within a heterocyclic After the successful clinical use of clodronate and ring (as in risedronate43 and zoledronate44), which are up etidronate in the 1970s and 1980s, more potent antire- to 10 000-fold more potent than etidronate in some sorptive bisphosphonates, which had different R2 side experimental systems (Fig 2). chains but in which R1 was unaltered, were studied. In The analysis of structure-activity relationships al- particular, bisphosphonates containing a basic primary lowed the spatial features of the active pharmacophore amino-nitrogen atom in an alkyl chain (as in pamidr- to be defined in considerable detail even before the onate and alendronate) were found to be 10- to 100-fold molecular mechanism of action was fully elucidated. For more potent than etidronate and clodronate. Then, in maximal potency, the nitrogen atom in the R2 side chain the 1980s, there was a phase in which synthesis of novel must be a critical distance away from the P-C-P group compounds took place specifically to determine their and in a specific spatial configuration.45 This principle possible effects on calcium metabolism, with the result was used successfully for predicting the features required that compounds highly effective as inhibitors of bone in the chemical design of new and more active com- resorption were identified and studied. pounds. These compounds, especially those that contain a ter- Although the structure of the R2 side chain is the tiary amino-nitrogen (such as ibandronate41 and olpad- major determinant of antiresorptive potency, both phos- ronate42), were even more potent at inhibiting bone phonate groups are also required for the drugs to be resorption. Among this generation of compounds that pharmacologically active.

FIGURE 2 Structures of the bisphosphonates used in clinical studies classi- fied according to their biochemical mode of action.

PEDIATRICS Volume 119, Supplement 2, March 2007 S153 Downloaded from www.aappublications.org/news by guest on September 29, 2021 In summary, studies of the relationships between into at least 2 major groups with different modes of bisphosphonate structure and antiresorptive potency action (Fig 3). The first group comprises the non–nitro- suggested that the ability of bisphosphonates to inhibit gen-containing bisphosphonates that perhaps most bone resorption depend on 2 separate properties of the closely resemble pyrophosphate, such as clodronate and bisphosphonate molecule. The 2 groups, etidronate, and these can be metabolically incorporated together with a hydroxyl group at the R1 position,46 into nonhydrolyzable analogues of adenosine triphos- impart high affinity for bone mineral and act as a “bone phate (ATP) by reversing the reactions of aminoacyl– hook,” which allows rapid and efficient targeting of transfer RNA synthetases.59 The resulting metabolites bisphosphonates to bone mineral surfaces. Once local- contain the P-C-P moiety in place of the ␤,␥-phosphate ized within bone, the structure and three-dimensional groups of ATP, thus resulting in nonhydrolyzable conformation of the R2 side chain (as well as the phos- (AppCp) nucleotides.60–63 It is likely that intracellular phonate groups in the molecule) determine the biolog- accumulation of these metabolites within osteoclasts in- ical activity of the molecule and influence the ability of hibits their function and may cause osteoclast cell death. the drugs to interact with specific molecular targets. Our The AppCp-type metabolites of bisphosphonates are cy- understanding of what these molecular targets might be totoxic when internalized and cause similar changes in has become much clearer as a result of recent work. morphology to those observed in clodronate-treated Over the years there have been many efforts to cells, possibly by interference with mitochondrial ATP explain how bisphosphonates work on cells, especially translocases.64 Overall, this group of bisphosphonates, via inhibitory effects on enzymes (eg, by direct or in- therefore, seem to act as prodrugs, being converted to direct inhibition of the osteoclast proton-pumping active metabolites after intracellular uptake by oste- HϩATPase,47,48 phosphatases, or lysosomal enzymes49,50). oclasts in vivo. Because osteoclasts are highly endocytic, bisphospho- In contrast, the second group contains the more po- nate present in the resorption space is likely to be inter- tent, nitrogen-containing bisphosphonates such as alen- nalized by endocytosis and thereby affect osteoclasts di- dronate, risedronate, and zoledronate. Members of this rectly.25 The uptake of bisphosphonates by osteoclasts in group interfere with other metabolic reactions, notably vivo has been confirmed by using radiolabeled51 and in the mevalonate biosynthetic pathway, and affect cel- fluorescently labeled alendronate, which was internal- lular activity and cell survival by interfering with protein ized into intracellular vacuoles. After cellular uptake, a prenylation and, therefore, the signaling functions of characteristic morphologic feature of bisphosphonate- key regulatory proteins. These mechanisms have been treated osteoclasts is the lack of a ruffled border, the reviewed in detail elsewhere.1 The mevalonate pathway region of invaginated plasma membrane facing the re- is a biosynthetic route responsible for the production of sorption cavity. Bisphosphonates also disrupt the cy- , other sterols, and isoprenoid lipids such as toskeleton of the osteoclast.52 Early explanations for isopentenyl diphosphate (also known as isopentenyl py- these effects invoked the inhibition of protein kinases or rophosphate), as well as farnesyl diphosphate (FPP) and phosphatases that regulate cytoskeletal structure, such geranylgeranyl diphosphate (GGPP). FPP and GGPP are as protein tyrosine phosphatases.53–56 However, a more required for the posttranslational modification (prenyla- likely mechanism by which the cytoskeleton may be tion) of small GTPases such as Ras, Rab, Rho, and Rac, affected involves loss of function of small GTPases such which are prenylated at a cysteine residue in character- as Rho and Rac. istic C-terminal motifs.65 Small GTPases are important Since the early 1990s there has been a systematic signaling proteins that regulate a variety of cell processes effort by our group and others to elucidate the molecular important for osteoclast function, including cell mor- mechanisms of action of bisphosphonates,5,57,58 and we phology, cytoskeletal arrangement, membrane ruffling, have proposed that bisphosphonates can be classified trafficking of vesicles, and apoptosis.66–69 Prenylation is

FIGURE 3 Two distinct molecular mechanisms of action of bisphospho- nates (BPs) that both inhibit osteoclasts (see text for details). GTP indicates guanosine triphosphate.

S154 RUSSELL Downloaded from www.aappublications.org/news by guest on September 29, 2021 required for the correct function of these proteins be- this is an excellent example of how specificity is cause the lipid prenyl group serves to anchor the pro- achieved by highly selective tissue targeting. teins in cell membranes and may also participate in The exact enzymes of the mevalonate pathway that protein-protein interactions.70 are inhibited by individual bisphosphonates have been Many observations point to the importance of the partially elucidated. Several enzymes of the pathway use mevalonate pathway for osteoclast function and isoprenoid diphosphates as a substrate (isopentenyl py- strengthen the proposal that the nitrogen-containing rophosphate isomerase, FPP synthase, GGPP synthase, bisphosphonates inhibit osteoclastic bone resorption squalene synthase) and, thus, are likely to have similar predominantly by inhibition of this pathway. These substrate-binding sites. Thus, if nitrogen-containing bisphosphonates inhibit the synthesis of mevalonate me- bisphosphonates act as substrate analogues of an isopre- tabolites including FPP and GGPP, and thereby impair noid diphosphate, it is possible that these bisphospho- the prenylation of proteins,71 and cause alteration of nates will inhibit more than 1 of the enzymes of the function of small GTPases. There is a strong structure- mevalonate pathway. Early studies revealed that incad- activity relationship such that changes to the structure of ronate and ibandronate, but not other bisphosphonates, the nitrogen-containing R2 side chain or to the phospho- are inhibitors of squalene synthase, an enzyme in the nate groups, which alter antiresorptive potency, also mevalonate pathway that is required for cholesterol bio- 76,77 influence the ability to inhibit protein prenylation to a synthesis. Inhibition of squalene synthase, however, corresponding degree.72 An important verification of the would not lead to inhibition of protein prenylation. critical importance of this pathway has come from show- However, it is now clear that farnesyl pyrophosphate ing that the addition of intermediates of the mevalonate synthase (FPPS) is a major site of action of the nitrogen- 78 pathway (such as FPP and GGPP) could overcome containing bisphosphonates (N-bisphosphonates). FPPS catalyzes the successive condensation of isopente- bisphosphonate-induced apoptosis and other events in nyl pyrophosphate with dimethylallyl pyrophosphate many cell systems. Another prediction was that if inhi- and geranyl pyrophosphate. There is a strong relation- bition of the mevalonate pathway could account for the ship among individual bisphosphonates between inhibi- antiresorptive effects of bisphosphonates, then the tion of bone resorption and inhibition of FPPS, with the drugs should also inhibit bone resorption. are most potent bisphosphonates having IC values (con- inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A 50 centration that inhibits response by 50%) in the nano- (HMG-CoA) reductase, one of the first steps in the me- molar range.79 Modeling studies have provided a molec- valonate pathway. They proved to be even more potent ular rationale for bisphosphonate binding to FPPS.80 Our than bisphosphonates at inhibiting osteoclast formation recent studies using protein crystallography, enzyme ki- and bone resorption in vitro,73,74 an effect that could also netics, and isothermal titration calorimetry led to the be overcome by the addition of geranylgeraniol (which first published high-resolution radiograph structures of can be used for protein geranylgeranylation) but not the human enzyme in complexes with risedronate and farnesol (which is used for protein farnesylation). Hence, zoledronate.81 These agents bind to the dimethylallyl/ it seems that although nitrogen-containing bisphospho- geranyl pyrophosphate ligand pocket and induce a con- nates can prevent both farnesylation and geranylgera- formational change. The interactions of the N-bisphos- nylation of proteins (probably by inhibiting enzymes phonate cyclic nitrogen with Thr201 and Lys200 suggest required for synthesis of FPP and GGPP), loss of gera- that these inhibitors achieve potency by positioning their nylgeranylated proteins in osteoclasts is of greater con- nitrogen in a proposed carbocation82 binding site. This sequence than loss of farnesylated proteins. This is con- explains how the nitrogen moiety is so important to the sistent with the known role of geranylgeranylated potency of these bisphosphonates. Kinetic analyses re- proteins such as Rho, Rac, and Rab in processes that are veal that inhibition is competitive with geranyl pyro- fundamental to osteoclast formation and function (eg, phosphate and is of a slow, tight-binding character, cytoskeletal rearrangement, membrane ruffling, and ve- which indicates that isomerization of an initial enzyme- sicular trafficking75), and further work has confirmed inhibitor complex occurs after binding of the N-bisphos- this, particularly the importance of Rab proteins. phonate. The comparison between bisphosphonates and statins Taken together, these observations clearly indicate is interesting. The statins are widely used as cholesterol- that bisphosphonates can be grouped into 2 classes: lowering drugs (they are able to lower cholesterol bio- those that can be metabolized into nonhydrolyzable an- synthesis by inhibiting 3-hydroxy-3-methylglutaryl co- alogues of ATP (the least potent bisphosphonates) and enzyme A reductase). Despite several studies, there is no those that are not metabolized but can inhibit protein substantial evidence that statins have effects on bone prenylation (the potent, nitrogen-containing bisphos- when used clinically, perhaps because they are selec- phonates). The identification of 2 such classes may help tively taken up by the liver rather than bone, which is to explain some of the other pharmacologic differences the converse of the case for bisphosphonates. Therefore, between the 2 classes.

PEDIATRICS Volume 119, Supplement 2, March 2007 S155 Downloaded from www.aappublications.org/news by guest on September 29, 2021 CLINICAL APPLICATIONS OF BISPHOSPHONATES phonates can produce even more profound suppression After it was shown that bisphosphonates inhibited ex- of disease activity than was possible with the bisphos- perimentally induced calcification and bone resorption, phonates available in previous years.93,94 The latest ad- their potential application to clinical disorders was obvi- vance is with zoledronate,95 which, when given as a ous, but it took many years for them to become well single 5-mg infusion, produced a greater and longer- established. lasting suppression of excess bone turnover than even The earliest clinical applications of bisphosphonates oral risedronate given at 30 mg/day over 2 months, included use of etidronate as an inhibitor of calcification hitherto one of the most effective treatments. in fibrodysplasia ossificans progressiva (formerly known In terms of commercial success, the use of bisphos- as myositis ossificans) and in patients who had under- phonates in oncology has been preeminent. Many can- gone total hip replacement surgery to prevent subse- cers in humans are associated with hypercalcemia quent heterotopic ossification and improve mobility.83 (raised blood calcium) and/or increased bone destruc- One of the other early clinical uses of bisphospho- tion. Bisphosphonates are remarkably effective in the nates was as agents for bone imaging, “bone scanning,” treatment of bone problems associated with malignan- for which they still remain outstandingly useful for de- cy96 and are now the drugs of choice.97–99 Clinical trials tecting bone metastases and other bone lesions. The that investigate the benefit of bisphosphonate therapy application of pyrophosphate and simple bisphospho- use a composite end point defined as a skeletal-related or nates as bone-scanning agents depends on their strong bone event, which typically includes pathologic fracture, affinity for bone mineral, particularly at sites of in- spinal cord compression, radiation or surgery to bone, creased bone turnover, and their ability to be linked to a and hypercalcemia of . Bisphosphonates sig- ␥-emitting technetium isotope.84,85 nificantly reduce the incidence of these events in my- The most impressive clinical application of bisphos- eloma100 and in patients with metasta- phonates has been as inhibitors of bone resorption, es- ses101,102 and in metastatic ,103 lung cancer, pecially for diseases in which no effective treatment renal cell carcinoma, and other solid tumors. The goals existed previously. Thus, bisphosphonates became the of treatment for bone metastases are also to prevent treatment of choice for a variety of bone diseases in disease-related skeletal complications, palliate pain, and which excessive osteoclast activity is an important maintain quality of life. Zoledronate,104 pamidronate, pathologic feature, including Paget disease of bone, met- clodronate, and ibandronate105,106 have demonstrated ef- astatic and osteolytic , and hypercalcemia of ficacy compared with placebo. malignancy, as well as osteoporosis. There is the important possibility that the survival of The clinical pharmacology of bisphosphonates is char- patients may be prolonged107–109 in some groups of pa- acterized by low intestinal absorption (ϳ1%–4%) but tients. Recently, osteonecrosis of the jaw110 was identi- highly selective localization and retention in bone. Sig- fied as a potential complication of high-dose bisphospho- nificant adverse effects of bisphosphonates are mini- nate therapy in malignant diseases. mal.86–88 Although there are more similarities than dif- The other area of outstanding commercial success ferences between individual compounds and each with bisphosphonates has been in the therapy of osteo- bisphosphonate is potentially capable of treating any of porosis, which is a major public health problem.111,112 Up the disorders of bone resorption in which they are used, until the 1990s, there were few treatments for osteopo- in practice different compounds have come to be favored rosis. As a drug class the bisphosphonates have emerged for the treatment of different diseases. There are cur- in the past few years as the leading effective treatments rently at least 10 bisphosphonates (etidronate, clodr- for postmenopausal and other forms of osteoporosis. onate, tiludronate, pamidronate, alendronate, risedr- Etidronate was the first of these,113–115 followed by alen- onate, zoledronate, and ibandronate and, to a limited dronate116–118 and then risedronate.119,120 All have been extent, olpadronate and neridronate) that have been approved as therapies in many countries and can in- registered for various clinical applications in various crease bone mass and reduce fracture rates at the spine countries. To a major extent, the diseases in which they by 30% to 50% and at other sites in postmenopausal are used reflects the history of their clinical development women.121 The reduction in fractures may be related not and the degree of commercial interest in and sponsor- only to the increase in bone mass arising from the inhi- ship of the relevant clinical trials. bition of bone resorption and reduced activation fre- Paget disease was the first clinical disorder in which a quency of bone-remodeling units but also to enhanced dose-dependent inhibition of bone resorption could be osteon mineralization.122 These bisphosphonates also demonstrated by using bisphosphonates in humans.89,90 prevent bone loss associated with glucocorticosteroid ad- Bisphosphonates have become the most important drugs ministration.123,124 used in the treatment of Paget disease.91 For many years Among the newer bisphosphonates, ibandronate125 pamidronate given by intravenous infusion was used was introduced recently as a once-monthly tablet. In extensively,92 but the newer and more potent bisphos- addition to formulations to be taken by mouth weekly or

S156 RUSSELL Downloaded from www.aappublications.org/news by guest on September 29, 2021 monthly, new routes of administration are being stud- but long-term use of the bisphosphonates in the therapy ied, especially periodic (eg, 3 monthly) injections with of osteoporosis seems to be safe.138 Case reports of in- ibandronate and once-yearly treatment with zoledr- duction of osteopetrosis-like lesions in children who onate.126 This has the attraction of delivering a defined were treated with excessive doses of pamidronate have dose without the variability associated with oral admin- been published.139 istration as well as avoiding potential gastrointestinal A question often asked is whether bisphosphonates intolerance. If these approaches are accompanied by inhibit fracture repair. By reducing bone turnover one greater compliance and convenience, they are likely to might expect bisphosphonates to interfere with fracture become popular methods of treatment. healing. However, a recent long-term study in a beagle Other clinical issues under consideration with dog model that simulated fracture repair has demon- bisphosphonates include the choice of therapeutic regi- strated that ibandronate treatment did not adversely men (eg, the use of intermittent dosing rather than affect normal bone healing.140 Studies of repair processes continuous, intravenous versus oral therapy), the opti- after creating drill-hole defects in dogs also showed no mal duration of therapy, the combination with other impairment with ibandronate.141 drugs such as , and their extended use in Several other recent studies raised the intriguing pos- related indications (eg, glucocorticosteroid-associated sibility that bisphosphonates may enhance fracture re- osteoporosis, male osteoporosis, childhood osteopenic pair and related processes.142 In studies of the osseointe- disorders, arthritis, and other disorders). Therefore, gration of metal implants in ovariectomized rats, there is much that needs to be done to improve the way treatment with ibandronate resulted in improved os- in which existing drugs can be used and to introduce seointegration rather than impairment of the healing new ones. process.143 Potential applications of bisphosphonates in In pediatrics, pamidronate has proved remarkably ef- orthopedics include protection against loosening of pros- fective in increasing bone in children with the inherited theses,144 better integration of biomaterials and implants, “brittle-bone” disorder, osteogenesis imperfecta.127,128 improved healing in distraction osteogenesis,145 and con- serving bone architecture after osteonecrosis146,147 and in SOME CURRENT ISSUES WITH BISPHOSPHONATES: BONE Perthes disease.148 ARCHITECTURE, STRUCTURE, AND STRENGTH, AND ON BONE There are potentially important differences between HEALING AND FRACTURE REPAIR clinically useful bisphosphonates regarding their po- Many experimental and clinical studies show that tency and duration of action. Efficacy is closely related to bisphosphonates conserve bone architecture and affinity for bone mineral and ability to inhibit FPP syn- strength.129–133 However, there have been concerns about thase. Recent studies showing that there are marked whether the use of prolonged high doses of bisphospho- differences among bisphosphonates in binding to hy- nates may impair bone turnover to such an extent that droxyapatite149 may explain the variations in retention bone strength is impaired. High doses in animals are and persistence of effect that have been observed in associated with increased microdamage134,135 and even animal and clinical studies. In the case of , fractures.136 It has been suggested that bisphosphonates in particular, the remarkable magnitude of effect and might prevent naturally occurring microscopic cracks in prolonged duration of action can be explained in part by bone from healing. There have been isolated reports of these new observations. In explaining the long duration adynamic bone associated with bisphosphonate usage,137 of action, it has been proposed that there is continual

FIGURE 4 Bisphosphonate (BP) uptake and detachment from bone surfac- es: effect of binding affinity on recirculation of bisphosphonate on and off bone surfaces. The differences in mineral-binding af- finity may affect distribution into different bone compartments and persistence of drug action at bone surfaces. (Adapted from Nancollas GH, Tang R, Phipps RJ, et al. Bone. 2006;38:617–627.)

PEDIATRICS Volume 119, Supplement 2, March 2007 S157 Downloaded from www.aappublications.org/news by guest on September 29, 2021 recycling of bisphosphonate off and back onto the bone 9. Russell RG. Excretion of inorganic pyrophosphate in hy- surface. This notion is supported by observations that pophosphatasia. Lancet. 1965;10:461–464 bisphosphonates can be found in plasma and urine 10. Schibler D, Russell RGG, Fleisch H. Inhibition by pyrophos- phate of aortic calcification induced by D3 in rats. Clin many months after dosing (Fig 4). Sci. 1968;35:363–372 There are numerous examples of bisphosphonates 11. Fleisch H, Russell RGG, Bisaz S, Casey PA, Muehlbauer RC. having effects on cells and tissues outside the skeleton. The influence of pyrophosphate analogues (diphosphonates) The effects on osteoclast precursors, tumor cells, macro- on the precipitation and dissolution. Calcif Tissue Res. 1968; (suppl):10–10A phages, and ␥,␦-T cells are examples and in all cases are 12. Francis MD, Russell RGG, Fleisch H. Diphosphonates inhibit probably explained by sufficient bisphosphonates enter- formation of calcium phosphate crystals in vitro and patho- ing cells to inhibit the mevalonate pathway. A well- logical calcification in vivo. Science. 1969;165:1264–1266 recognized adverse effect of the nitrogen-containing 13. Fleisch H, Russell RGG, Francis MD. Diphosphonates inhibit bisphosphonates is that they cause an acute-phase re- hydroxyapatite dissolution in vitro and bone resorption in tissue culture in vivo. Science. 1969;165:1262–1264 sponse in vivo,150,151 which can lead to induction of fever 14. Jung A, Bisaz S, Fleisch H. The binding of pyrophosphate and and “flu-like” symptoms in patients. These effects are two diphosphonates by hydroxyapatite crystals. Calcif Tissue transient and occur predominantly on first exposure to Res. 1973;11:269–280 the drug, especially with intravenous administration. 15. Fleisch H, Russell RGG, Bisaz S, Muehlbauer RC, Williams The mechanism has been attributed to release of proin- DA. The inhibitory effect of on the formation of calcium phosphate crystals in vitro and on aortic and kidney flammatory cytokines, and the mechanism has been fur- recalcification in vivo. Eur J Clin Invest. 1970;1:12–18 ther unraveled by showing that it involves selective re- 16. Schenk R, Merz WA, Muhlbauer R, Russell RGG, Fleisch H. ceptor-mediated activation of ␥,␦-T cells, leading to their Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and proliferation and activation.152 The bisphosphonate ef- dichloromethylene diphosphonate (Cl 2 MDP) on the calcifi- fect involves the mevalonate pathway in vitro and can cation and resorption of cartilage and bone in the tibial epiph- ysis and metaphysis of rats. Calcif Tissue Res. 1973;11:196–214 153 be overcome by using statins. 17. Fleisch H, Maerki J, Russell RGG. Effect of pyrophosphate on Another interesting aspect of these nonskeletal effects dissolution of hydroxyapatite and its possible importance in are the observations made on protozoan parasites, the calcium . Proc Soc Exp Biol Med. 1966;122:317–320 growth of which can be inhibited by bisphosphonates 18. Russell RGG, Muhlbauer RC, Bisaz S, Williams DA, Fleisch H. acting on FPPS.154,155 The influence of pyrophosphate, condensed phosphates, phosphonates and other phosphate compounds on the disso- In the future, other clinical indications ripe for future lution of hydroxyapatite in vitro and on bone resorption study include the prevention of bone loss and erosions in induced by parathyroid hormone in tissue culture and in rheumatoid arthritis, possible applications in other thyroparathyroidectomised rats. Calcif Tissue Res. 1970;6: diseases, the reduction of bone loss associated with peri- 183–196 odontal disease, and loosening of joint prostheses. 19. Trechsel U, Stutzer A, Fleisch H. 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