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tant to know what happens during long-term adminis-

tration. From a clinical point of view, it is reassuring that

the inhibition of bone resorption reaches a new steady-

state level rather than becoming progressively lower,

even when the compounds are given continuously.27

The level of suppression depends on the administered

dose and has also been observed in humans.28 There

seems to be no progression of the antiresorptive effectwith time, which suggests that the bisphosphonate bur-

ied in the bone is inactive for at least as long as it remains

buried there. This also means that within the therapeu-

tic-dosage range, there is little risk of a continuous and

progressive decrease in bone turnover in the long run

that might lead to an increase in bone fragility. An

additional important pharmacologic property of bisphos-

phonates is that the total dose administered is a major

determinant of their effects. This has been well studied

for ibandronate29 and zoledronate.30 In both cases the

same inhibition of bone resorption has been docu-

mented regardless of whether the bisphosphonate wasgiven in small frequent (eg, daily) doses compared with

larger doses given less frequently. This was the basis for

the development of intermittent-dosing regimens in hu-

mans.

The pronounced selectivity of bisphosphonates for

bone rather than other tissues is the basis for their value

in clinical practice. Their preferential uptake by and

adsorption to mineral surfaces in bone bring them into

close contact with osteoclasts. During bone resorption,

bisphosphonates are probably internalized by endocyto-

sis along with other products of resorption. Many studies

have shown that bisphosphonates can affect osteoclast-mediated bone resorption in a variety of ways, including

effects on osteoclast recruitment, differentiation, and re-

sorptive activity, and may induce apoptosis.

Because mature, multinucleated osteoclasts are

formed by the fusion of mononuclear precursors of he-

matopoietic origin, bisphosphonates could also inhibit

bone resorption by preventing osteoclast formation, in

addition to affecting mature osteoclasts. In vitro,

bisphosphonates can inhibit dose-dependently the for-

mation of osteoclast-like cells in long-term cultures of

human bone marrow.31 In organ culture, also, some

bisphosphonates can inhibit the generation of mature

osteoclasts, possibly by preventing the fusion of oste-

oclast precursors.32,33

It is likely that bisphosphonates are selectively inter-

nalized by osteoclasts rather than other cell types be-

cause of their accumulation in bone and the endocytic

activity of osteoclasts. During the process of bone resorp-

tion, the subcellular space beneath the osteoclast is acid-

ified by the action of vacuolar-type proton pumps in the

ruffled border of the osteoclast membrane.34 The acidic

pH of this microenvironment causes dissolution of the

hydroxyapatite bone mineral, whereas the breakdown

of the extracellular bone matrix is brought about by the

action of proteolytic enzymes, including cathepsin K.

Because bisphosphonates adsorb to bone mineral, espe-

cially at sites of bone resorption where the mineral is

most exposed,35,36 osteoclasts are the cell type in bone

most likely to be exposed to the highest concentrations

of free, nonmineral-bound bisphosphonate as a result

of the release of the bisphosphonate from bone mineral

in the low-pH environment beneath osteoclasts. It hasbeen estimated that pharmacologic doses of alendronate

that inhibit bone resorption in vivo could give rise to

local concentrations as high as 1 mM alendronate in the

resorption space beneath an osteoclast, which is much

higher than the concentrations of bisphosphonates re-

quired to affect osteoclast morphology and cause oste-

oclast apoptosis in vitro.37

In contrast to their ability to induce apoptosis in os-

teoclasts, which contributes to the inhibition of resorp-

tive activity, some experimental studies suggest that

bisphosphonates may protect osteocytes and osteoblasts

from apoptosis induced by glucocorticoids.38

Recent ev-idence suggests that the inhibition of osteocyte apoptosis

by bisphosphonates is mediated through the opening of

connexion 43 hemichannels and activation of extracel-

lular signal-regulated kinases.39 The possibility that

bisphosphonates used clinically may get access to osteo-

cytes differentially depending on their mineral-binding

affinities and inherent structural properties needs to be

studied.

STRUCTURE-ACTIVITY RELATIONSHIPS ANDMECHANISMOF

ACTION

The features of the bisphosphonate molecule necessaryfor biological activity were well defined in the early

studies. The P-C-P moiety is responsible for the strong

affinity of the bisphosphonates for binding to hydroxy-

apatite and allows for a number of variations in structure

on the basis of substitution in the R1 and R2 positions on

the carbon atom (Fig 1). The ability of the bisphospho-

nates to bind to hydroxyapatite crystals and to prevent

both crystal growth and dissolution was enhanced when

the R1 side chain (attached to the geminal carbon atom

of the P-C-P group) was a hydroxyl group (as in eti-

dronate) rather than a halogen atom such as chlorine (as

in clodronate). The presence of a hydroxyl group at the

R1 position increases the affinity for calcium (and, thus,

bone mineral) because of the ability of bisphosphonates

to chelate calcium ions by tridentate rather than biden-

tate binding.40

The ability of bisphosphonates to inhibit bone resorp-

tion in vitro and in vivo also requires the P-C-P struc-

ture. Monophosphonates (eg, pentane monophospho-

nate) or P-C-C-P or P-N-P compounds are ineffective as

inhibitors of bone resorption. Furthermore, the antire-

sorptive effect cannot be accounted for simply by adsorp-

tion of bisphosphonates to bone mineral and prevention

of hydroxyapatite dissolution. It became clear that

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bisphosphonates must inhibit bone resorption by cellular

effects on osteoclasts rather than simply by physico-

chemical mechanisms.

After the successful clinical use of clodronate and

etidronate in the 1970s and 1980s, more potent antire-

sorptive bisphosphonates, which had different R2 side

chains but in which R1 was unaltered, were studied. In

particular, bisphosphonates containing a basic primary

amino-nitrogen atom in an alkyl chain (as in pamidr-

onate and alendronate) were found to be 10- to 100-fold

more potent than etidronate and clodronate. Then, in

the 1980s, there was a phase in which synthesis of novel

compounds took place specifically to determine their

possible effects on calcium metabolism, with the result

that compounds highly effective as inhibitors of bone

resorption were identified and studied.

These compounds, especially those that contain a ter-

tiary amino-nitrogen (such as ibandronate41 and olpad-

ronate42), were even more potent at inhibiting bone

resorption. Among this generation of compounds that

were synthesized to optimize their antiresorptive effects,

the most potent antiresorptive bisphosphonates were

those containing a nitrogen atom within a heterocyclic

ring (as in risedronate43 and zoledronate44), which are up

to 10 000-fold more potent than etidronate in some

experimental systems (Fig 2).

The analysis of structure-activity relationships al-

lowed the spatial features of the active pharmacophore

to be defined in considerable detail even before the

molecular mechanism of action was fully elucidated. For

maximal potency, the nitrogen atom in the R2 side chain

must be a critical distance away from the P-C-P group

and in a specific spatial configuration.45 This principle

was used successfully for predicting the features required

in the chemical design of new and more active com-

pounds.

Although the structure of the R2 side chain is the

major determinant of antiresorptive potency, both phos-

phonate groups are also required for the drugs to be

pharmacologically active.

FIGURE 1

The generic structure of pyrophosphate compared with bisphos-phonates and their functional domains.

FIGURE 2

Structures of the bisphosphonates used in clinical studies classi-

fied according to their biochemical mode of action.

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In summary, studies of the relationships between

bisphosphonate structure and antiresorptive potency

suggested that the ability of bisphosphonates to inhibit

bone resorption depend on 2 separate properties of the

bisphosphonate molecule. The 2 phosphonate groups,

together with a hydroxyl group at the R1 position,46

impart high affinity for bone mineral and act as a bone

hook, which allows rapid and efficient targeting ofbisphosphonates to bone mineral surfaces. Once local-

ized within bone, the structure and three-dimensional

conformation of the R2 side chain (as well as the phos-

phonate groups in the molecule) determine the biolog-

ical activity of the molecule and influence the ability of

the drugs to interact with specific molecular targets. Our

understanding of what these molecular targets might be

has become much clearer as a result of recent work.

Over the years there have been many efforts to

explain how bisphosphonates work on cells, especially

via inhibitory effects on enzymes (eg, by direct or in-

direct inhibition of the osteoclast proton-pumpingHATPase,47,48 phosphatases, or lysosomal enzymes49,50).

Because osteoclasts are highly endocytic, bisphospho-

nate present in the resorption space is likely to be inter-

nalized by endocytosis and thereby affect osteoclasts di-

rectly.25 The uptake of bisphosphonates by osteoclasts in

vivo has been confirmed by using radiolabeled51 and

fluorescently labeled alendronate, which was internal-

ized into intracellular vacuoles. After cellular uptake, a

characteristic morphologic feature of bisphosphonate-

treated osteoclasts is the lack of a ruffled border, the

region of invaginated plasma membrane facing the re-

sorption cavity. Bisphosphonates also disrupt the cy-toskeleton of the osteoclast.52 Early explanations for

these effects invoked the inhibition of protein kinases or

phosphatases that regulate cytoskeletal structure, such

as protein tyrosine phosphatases.5356 However, a more

likely mechanism by which the cytoskeleton may be

affected involves loss of function of small GTPases such

as Rho and Rac.

Since the early 1990s there has been a systematic

effort by our group and others to elucidate the molecular

mechanisms of action of bisphosphonates,5,57,58 and we

have proposed that bisphosphonates can be classified

into at least 2 major groups with different modes of

action (Fig 3). The first group comprises the nonnitro-

gen-containing bisphosphonates that perhaps most

closely resemble pyrophosphate, such as clodronate and

etidronate, and these can be metabolically incorporated

into nonhydrolyzable analogues of adenosine triphos-

phate (ATP) by reversing the reactions of aminoacyl

transfer RNA synthetases.59 The resulting metabolitescontain the P-C-P moiety in place of the ,-phosphate

groups of ATP, thus resulting in nonhydrolyzable

(AppCp) nucleotides.6063 It is likely that intracellular

accumulation of these metabolites within osteoclasts in-

hibits their function and may cause osteoclast cell death.

The AppCp-type metabolites of bisphosphonates are cy-

totoxic when internalized and cause similar changes in

morphology to those observed in clodronate-treated

cells, possibly by interference with mitochondrial ATP

translocases.64 Overall, this group of bisphosphonates,

therefore, seem to act as prodrugs, being converted to

active metabolites after intracellular uptake by oste-oclasts in vivo.

In contrast, the second group contains the more po-

tent, nitrogen-containing bisphosphonates such as alen-

dronate, risedronate, and zoledronate. Members of this

group interfere with other metabolic reactions, notably

in the mevalonate biosynthetic pathway, and affect cel-

lular activity and cell survival by interfering with protein

prenylation and, therefore, the signaling functions of

key regulatory proteins. These mechanisms have been

reviewed in detail elsewhere.1 The mevalonate pathway

is a biosynthetic route responsible for the production of

cholesterol, other sterols, and isoprenoid lipids such asisopentenyl diphosphate (also known as isopentenyl py-

rophosphate), as well as farnesyl diphosphate (FPP) and

geranylgeranyl diphosphate (GGPP). FPP and GGPP are

required for the posttranslational modification (prenyla-

tion) of small GTPases such as Ras, Rab, Rho, and Rac,

which are prenylated at a cysteine residue in character-

istic C-terminal motifs.65 Small GTPases are important

signaling proteins that regulate a variety of cell processes

important for osteoclast function, including cell mor-

phology, cytoskeletal arrangement, membrane ruffling,

trafficking of vesicles, and apoptosis.6669 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.



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required for the correct function of these proteins be-

cause the lipid prenyl group serves to anchor the pro-

teins in cell membranes and may also participate in

protein-protein interactions.70

Many observations point to the importance of the

mevalonate pathway for osteoclast function and

strengthen the proposal that the nitrogen-containing

bisphosphonates inhibit osteoclastic bone resorptionpredominantly by inhibition of this pathway. These

bisphosphonates inhibit the synthesis of mevalonate me-

tabolites including FPP and GGPP, and thereby impair

the prenylation of proteins,71 and cause alteration of

function of small GTPases. There is a strong structure-

activity relationship such that changes to the structure of

the nitrogen-containing R2 side chain or to the phospho-

nate groups, which alter antiresorptive potency, also

influence the ability to inhibit protein prenylation to a

corresponding degree.72 An important verification of the

critical importance of this pathway has come from show-

ing that the addition of intermediates of the mevalonatepathway (such as FPP and GGPP) could overcome

bisphosphonate-induced apoptosis and other events in

many cell systems. Another prediction was that if inhi-

bition of the mevalonate pathway could account for the

antiresorptive effects of bisphosphonates, then the statin

drugs should also inhibit bone resorption. Statins are

inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A

(HMG-CoA) reductase, one of the first steps in the me-

valonate pathway. They proved to be even more potent

than bisphosphonates at inhibiting osteoclast formation

and bone resorption in vitro,73,74 an effect that could also

be overcome by the addition of geranylgeraniol (whichcan be used for protein geranylgeranylation) but not

farnesol (which is used for protein farnesylation). Hence,

it seems that although nitrogen-containing bisphospho-

nates can prevent both farnesylation and geranylgera-

nylation of proteins (probably by inhibiting enzymes

required for synthesis of FPP and GGPP), loss of gera-

nylgeranylated proteins in osteoclasts is of greater con-

sequence than loss of farnesylated proteins. This is con-

sistent with the known role of geranylgeranylated

proteins such as Rho, Rac, and Rab in processes that are

fundamental to osteoclast formation and function (eg,

cytoskeletal rearrangement, membrane ruffling, and ve-

sicular trafficking75), and further work has confirmed

this, particularly the importance of Rab proteins.

The comparison between bisphosphonates and statins

is interesting. The statins are widely used as cholesterol-

lowering drugs (they are able to lower cholesterol bio-

synthesis by inhibiting 3-hydroxy-3-methylglutaryl co-

enzyme A reductase). Despite several studies, there is no

substantial evidence that statins have effects on bone

when used clinically, perhaps because they are selec-

tively taken up by the liver rather than bone, which is

the converse of the case for bisphosphonates. Therefore,

this is an excellent example of how drug specificity is

achieved by highly selective tissue targeting.

The exact enzymes of the mevalonate pathway that

are inhibited by individual bisphosphonates have been

partially elucidated. Several enzymes of the pathway use

isoprenoid diphosphates as a substrate (isopentenyl py-

rophosphate isomerase, FPP synthase, GGPP synthase,

squalene synthase) and, thus, are likely to have similarsubstrate-binding sites. Thus, if nitrogen-containing

bisphosphonates act as substrate analogues of an isopre-

noid diphosphate, it is possible that these bisphospho-

nates will inhibit more than 1 of the enzymes of the

mevalonate pathway. Early studies revealed that incad-

ronate and ibandronate, but not other bisphosphonates,

are inhibitors of squalene synthase, an enzyme in the

mevalonate pathway that is required for cholesterol bio-

synthesis.76,77 Inhibition of squalene synthase, however,

would not lead to inhibition of protein prenylation.

However, it is now clear that farnesyl pyrophosphate

synthase (FPPS) is a major site of action of the nitrogen-containing bisphosphonates (N-bisphosphonates).78

FPPS catalyzes the successive condensation of isopente-

nyl pyrophosphate with dimethylallyl pyrophosphate

and geranyl pyrophosphate. There is a strong relation-

ship among individual bisphosphonates between inhibi-

tion of bone resorption and inhibition of FPPS, with the

most potent bisphosphonates having IC50 values (con-

centration that inhibits response by 50%) in the nano-

molar range.79 Modeling studies have provided a molec-

ular rationale for bisphosphonate binding to FPPS.80 Our

recent studies using protein crystallography, enzyme ki-

netics, and isothermal titration calorimetry led to thefirst published high-resolution radiograph structures of

the human enzyme in complexes with risedronate and

zoledronate.81 These agents bind to the dimethylallyl/

geranyl pyrophosphate ligand pocket and induce a con-

formational change. The interactions of the N-bisphos-

phonate cyclic nitrogen with Thr201 and Lys200 suggest

that these inhibitors achieve potency by positioning their

nitrogen in a proposed carbocation82 binding site. This

explains how the nitrogen moiety is so important to the

potency of these bisphosphonates. Kinetic analyses re-

veal that inhibition is competitive with geranyl pyro-

phosphate and is of a slow, tight-binding character,

which indicates that isomerization of an initial enzyme-

inhibitor complex occurs after binding of the N-bisphos-

phonate.

Taken together, these observations clearly indicate

that bisphosphonates can be grouped into 2 classes:

those that can be metabolized into nonhydrolyzable an-

alogues of ATP (the least potent bisphosphonates) and

those that are not metabolized but can inhibit protein

prenylation (the potent, nitrogen-containing bisphos-

phonates). The identification of 2 such classes may help

to explain some of the other pharmacologic differences

between the 2 classes.



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CLINICAL APPLICATIONS OF BISPHOSPHONATES

After it was shown that bisphosphonates inhibited ex-

perimentally induced calcification and bone resorption,

their potential application to clinical disorders was obvi-

ous, but it took many years for them to become well

established.

The earliest clinical applications of bisphosphonates

included use of etidronate as an inhibitor of calcificationin fibrodysplasia ossificans progressiva (formerly known

as myositis ossificans) and in patients who had under-

gone total hip replacement surgery to prevent subse-

quent heterotopic ossification and improve mobility.83

One of the other early clinical uses of bisphospho-

nates was as agents for bone imaging, bone scanning,

for which they still remain outstandingly useful for de-

tecting bone metastases and other bone lesions. The

application of pyrophosphate and simple bisphospho-

nates as bone-scanning agents depends on their strong

affinity for bone mineral, particularly at sites of in-

creased bone turnover, and their ability to be linked to a-emitting technetium isotope.84,85

The most impressive clinical application of bisphos-

phonates has been as inhibitors of bone resorption, es-

pecially for diseases in which no effective treatment

existed previously. Thus, bisphosphonates became the

treatment of choice for a variety of bone diseases in

which excessive osteoclast activity is an important

pathologic feature, including Paget disease of bone, met-

astatic and osteolytic bone disease, and hypercalcemia of

malignancy, as well as osteoporosis.

The clinical pharmacology of bisphosphonates is char-

acterized by low intestinal absorption (

1%4%) buthighly selective localization and retention in bone. Sig-

nificant adverse effects of bisphosphonates are mini-

mal.8688 Although there are more similarities than dif-

ferences between individual compounds and each

bisphosphonate is potentially capable of treating any of

the disorders of bone resorption in which they are used,

in practice different compounds have come to be favored

for the treatment of different diseases. There are cur-

rently at least 10 bisphosphonates (etidronate, clodr-

onate, tiludronate, pamidronate, alendronate, risedr-

onate, zoledronate, and ibandronate and, to a limited

extent, olpadronate and neridronate) that have been

registered for various clinical applications in various

countries. To a major extent, the diseases in which they

are used reflects the history of their clinical development

and the degree of commercial interest in and sponsor-

ship of the relevant clinical trials.

Paget disease was the first clinical disorder in which a

dose-dependent inhibition of bone resorption could be

demonstrated by using bisphosphonates in humans.89,90

Bisphosphonates have become the most important drugs

used in the treatment of Paget disease.91 For many years

pamidronate given by intravenous infusion was used

extensively, 92 but the newer and more potent bisphos-

phonates can produce even more profound suppression

of disease activity than was possible with the bisphos-

phonates available in previous years.93,94 The latest ad-

vance is with zoledronate,95 which, when given as a

single 5-mg infusion, produced a greater and longer-

lasting suppression of excess bone turnover than even

oral risedronate given at 30 mg/day over 2 months,

hitherto one of the most effective treatments.In terms of commercial success, the use of bisphos-

phonates in oncology has been preeminent. Many can-

cers in humans are associated with hypercalcemia

(raised blood calcium) and/or increased bone destruc-

tion. Bisphosphonates are remarkably effective in the

treatment of bone problems associated with malignan-

cy96 and are now the drugs of choice.9799 Clinical trials

that investigate the benefit of bisphosphonate therapy

use a composite end point defined as a skeletal-related or

bone event, which typically includes pathologic fracture,

spinal cord compression, radiation or surgery to bone,

and hypercalcemia of malignancy. Bisphosphonates sig-nificantly reduce the incidence of these events in my-

eloma100 and in patients with breast cancer metasta-

ses101,102 and in metastatic prostate cancer,103 lung cancer,

renal cell carcinoma, and other solid tumors. The goals

of treatment for bone metastases are also to prevent

disease-related skeletal complications, palliate pain, and

maintain quality of life. Zoledronate,104 pamidronate,

clodronate, and ibandronate105,106 have demonstrated ef-

ficacy compared with placebo.

There is the important possibility that the survival of

patients may be prolonged107109 in some groups of pa-

tients. Recently, osteonecrosis of the jaw

110

was identi-fied as a potential complication of high-dose bisphospho-

nate therapy in malignant diseases.

The other area of outstanding commercial success

with bisphosphonates has been in the therapy of osteo-

porosis, which is a major public health problem.111,112 Up

until the 1990s, there were few treatments for osteopo-

rosis. As a drug class the bisphosphonates have emerged

in the past few years as the leading effective treatments

for postmenopausal and other forms of osteoporosis.

Etidronate was the first of these,113115 followed by alen-

dronate116118 and then risedronate.119,120 All have been

approved as therapies in many countries and can in-

crease bone mass and reduce fracture rates at the spine

by 30% to 50% and at other sites in postmenopausal

women.121 The reduction in fractures may be related not

only to the increase in bone mass arising from the inhi-

bition of bone resorption and reduced activation fre-

quency of bone-remodeling units but also to enhanced

osteon mineralization.122 These bisphosphonates also

prevent bone loss associated with glucocorticosteroid ad-

ministration. 123,124

Among the newer bisphosphonates, ibandronate125

was introduced recently as a once-monthly tablet. In

addition to formulations to be taken by mouth weekly or



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monthly, new routes of administration are being stud-

ied, especially periodic (eg, 3 monthly) injections with

ibandronate and once-yearly treatment with zoledr-

onate.126 This has the attraction of delivering a defined

dose without the variability associated with oral admin-

istration as well as avoiding potential gastrointestinal

intolerance. If these approaches are accompanied by

greater compliance and convenience, they are likely tobecome popular methods of treatment.

Other clinical issues under consideration with

bisphosphonates include the choice of therapeutic regi-

men (eg, the use of intermittent dosing rather than

continuous, intravenous versus oral therapy), the opti-

mal duration of therapy, the combination with other

drugs such as teriparatide, and their extended use in

related indications (eg, glucocorticosteroid-associated

osteoporosis, male osteoporosis, childhood osteopenic

disorders, arthritis, and other disorders). Therefore,

there is much that needs to be done to improve the way

in which existing drugs can be used and to introducenew ones.

In pediatrics, pamidronate has proved remarkably ef-

fective in increasing bone in children with the inherited

brittle-bone disorder, osteogenesis imperfecta.127,128

SOMECURRENT ISSUESWITH BISPHOSPHONATES: BONE

ARCHITECTURE, STRUCTURE, ANDSTRENGTH,ANDONBONE

HEALING ANDFRACTURE REPAIR

Many experimental and clinical studies show that

bisphosphonates conserve bone architecture and

strength.129133 However, there have been concerns about

whether the use of prolonged high doses of bisphospho-nates may impair bone turnover to such an extent that

bone strength is impaired. High doses in animals are

associated with increased microdamage134,135 and even

fractures.136 It has been suggested that bisphosphonates

might prevent naturally occurring microscopic cracks in

bone from healing. There have been isolated reports of

adynamic bone associated with bisphosphonate usage,137

but long-term use of the bisphosphonates in the therapy

of osteoporosis seems to be safe.138 Case reports of in-

duction of osteopetrosis-like lesions in children who

were treated with excessive doses of pamidronate have

been published.139

A question often asked is whether bisphosphonates

inhibit fracture repair. By reducing bone turnover one

might expect bisphosphonates to interfere with fracturehealing. However, a recent long-term study in a beagle

dog model that simulated fracture repair has demon-

strated that ibandronate treatment did not adversely

affect normal bone healing.140 Studies of repair processes

after creating drill-hole defects in dogs also showed no

impairment with ibandronate.141

Several other recent studies raised the intriguing pos-

sibility that bisphosphonates may enhance fracture re-

pair and related processes.142 In studies of the osseointe-

gration of metal implants in ovariectomized rats,

treatment with ibandronate resulted in improved os-

seointegration rather than impairment of the healingprocess.143 Potential applications of bisphosphonates in

orthopedics include protection against loosening of pros-

theses,144better integration of biomaterials and implants,

improved healing in distraction osteogenesis,145 and con-

serving bone architecture after osteonecrosis146,147 and in

Perthes disease.148

There are potentially important differences between

clinically useful bisphosphonates regarding their po-

tency and duration of action. Efficacy is closely related to

affinity for bone mineral and ability to inhibit FPP syn-

thase. Recent studies showing that there are marked

differences among bisphosphonates in binding to hy-droxyapatite149 may explain the variations in retention

and persistence of effect that have been observed in

animal and clinical studies. In the case of zoledronic acid,

in particular, the remarkable magnitude of effect and

prolonged duration of action can be explained in part by

these new observations. In explaining the long duration

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;38:617627.)



10/15

recycling of bisphosphonate off and back onto the bone

surface. This notion is supported by observations that

bisphosphonates can be found in plasma and urine

many months after dosing (Fig 4).

There are numerous examples of bisphosphonates

having effects on cells and tissues outside the skeleton.

The effects on osteoclast precursors, tumor cells, macro-

phages, and,-T cells are examples and in all cases areprobably explained by sufficient bisphosphonates enter-

ing cells to inhibit the mevalonate pathway. A well-

recognized adverse effect of the nitrogen-containing

bisphosphonates is that they cause an acute-phase re-

sponse in vivo,150,151 which can lead to induction of fever

and flu-like symptoms in patients. These effects are

transient and occur predominantly on first exposure to

the drug, especially with intravenous administration.

The mechanism has been attributed to release of proin-

flammatory cytokines, and the mechanism has been fur-

ther unraveled by showing that it involves selective re-

ceptor-mediated activation of,-T cells, leading to theirproliferation and activation.152 The bisphosphonate ef-

fect involves the mevalonate pathway in vitro and can

be overcome by using statins.153

Another interesting aspect of these nonskeletal effects

are the observations made on protozoan parasites, the

growth of which can be inhibited by bisphosphonates

acting on FPPS.154,155

In the future, other clinical indications ripe for future

study include the prevention of bone loss and erosions in

rheumatoid arthritis, possible applications in other joint

diseases, the reduction of bone loss associated with peri-

odontal disease, and loosening of joint prostheses.The recent elucidation of the likely mode of action of

bisphosphonates within cells opens up the possibility of

exploiting the subtle and potentially important differ-

ences between the classes of bisphosphonates and indi-

vidual compounds.

REFERENCES

1. Russell RGG. Bisphosphonates: from bench to bedside. Ann

N Y Acad Sci. 2006;1068:367401

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DOI: 10.1542/peds.2006-2023H2007;119;S150Pediatrics

R. Graham G. RussellBisphosphonates: Mode of Action and Pharmacology

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Graham 2014 Bifosfonato

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Transcript of Graham 2014 Bifosfonato