Pharmacokinetics of Alendronate
Arturo G. Porras, Sherry D. Holland and Barry J. Gertz
Merck Research Laboratories, Clinical Pharmacology and Drug Metabolism, Rahway, New Jersey and West Point, Pennsylvania, USA
Contents
Abstract Alendronate (alendronic acid; 4-amino-1-hydroxybutylidene bisphosphonate) has demonstrated effectiveness orally in the treatment and prevention of post- menopausal osteoporosis, corticosteroid-induced osteoporosis and Paget’s dis- ease of the bone. Its primary mechanism of action involves the inhibition of osteoclastic bone resorption. The pharmacokinetics and pharmacodynamics of alendronate must be interpreted in the context of its unique properties, which include targeting to the skeleton and incorporation into the skeletal matrix.
Preclinically, alendronate is not metabolised in animals and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although soon after administration the drug distributes widely in the body, this transient state is rapidly followed by a nonsaturable redistribution to skeletal tissues. Oral bioavailability is about 0.9 to 1.8%, and food markedly inhibits oral absorption. Removal of the drug from bone reflects the underlying rate of turnover of the skeleton. Renal clearance appears to involve both glomerular filtration and a specialised secretory pathway.
Clinically, the pharmacokinetics of alendronate have been characterised al- most exclusively based on urinary excretion data because of the extremely low concentrations achieved after oral administration. After intravenous administra- tion of radiolabelled alendronate to women, no metabolites of the drug were detectable and urinary excretion was the sole means of elimination. About 40 to
60% of the dose is retained for a long time in the body, presumably in the skeleton, with no evidence of saturation or influence of one intravenous dose on the phar- macokinetics of subsequent doses.
The oral bioavailability of alendronate in the fasted state is about 0.7%, with no significant difference between men and women. Absorption and disposition appear independent of dose. Food substantially reduces the bioavailability of oral alendronate; otherwise, no substantive drug interactions have been identified.
The pharmacokinetic properties of alendronate are evident pharmacodynam- ically. Alendronate treatment results in an early and dose-dependent inhibition of skeletal resorption, which can be followed clinically with biochemical markers, and which ultimately reaches a plateau and is slowly reversible upon discontin- uation of the drug. These findings reflect the uptake of the drug into bone, where it exerts its pharmacological activity, and a time course that results from the long residence time in the skeleton. The net result is that alendronate corrects the underlying imbalance in skeletal turnover characteristic of several disease states. In women with postmenopausal osteoporosis, for example, alendronate treatment results in increases in bone mass and a reduction in fracture incidence, includ- ing at the hip.
Alendronate (alendronic acid) is one of a growing class of bisphosphonate compounds in clinical use or under investigation.[1,2] Bisphosphonates are non- hydrolysable analogues of inorganic pyrophosphate in which the bridging oxygen has been replaced by a carbon, with, most commonly, an aliphatic side chain. They were developed after the discovery that pyrophosphate inhibits both the formation and dissolution of calcium phosphate crystals.[3] These properties suggested a potential utility as an inhib- itor of bone resorption or ectopic calcification. How- ever, the nearly ubiquitous presence of inorganic pyrophosphatase prevents the direct use of the in- organic compound as a modifier of bone metabo- lism. In contrast, the bisphosphonates have demon- strated biochemical stability and pharmacological activity as inhibitors of bone resorption and, thus, have an expanding role in the clinical management of patients with bone disease.
Intravenous alendronate has been used investi-
gationally for the management of hypercalcaemia of malignancy.[4-6] Alendronate is approved as an oral medication for both the treatment and prevention of postmenopausal osteoporosis,[7-13] corticosteroid- induced osteoporosis[14] and the treatment of Paget’s disease.[15-18] Alendronate is approved for use orally in over 80 countries worldwide.
Alendronate is monosodium 4-amino-1-hydroxy- butylidene bisphosphonate (fig. 1). The amino group in the side chain appears to yield much higher potency and far greater selectivity for inhib- iting bone resorption, over reducing mineralisation, than is observed with etidronate, one of the first bisphosphonates used clinically and one which does not contain nitrogen.[19]
This review provides some background on the biochemical mechanism of action of bisphosphon- ates, focusing on studies with alendronate, as it is relevant to a complete understanding of the pharma- cokinetics and pharmacodynamics of alendronate and their relationship to each other. Furthermore, because some of the properties of alendronate are characteristic of the bisphosphonate class, notably its limited oral bioavailability and prolonged resi- dence in the target organ of interest (i.e. the skele- ton), a brief summary of the preclinical pharmaco- kinetics of alendronate is provided as several important pharmacokinetic questions with alendron- ate can only be addressed within animals. Finally, the pharmacokinetic-pharmacodynamic relation- ship will be reviewed as it relates most importantly to the beneficial effects of alendronate for the treat- ment of postmenopausal osteoporosis.
HO
NaO
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OH
yielding a quiescent cell.[2,19] Not only is osteoclast activity reduced, but the number of osteoclasts is also significantly reduced after long term adminis- tration of alendronate. Whether this is secondary to the reduction in bone resorption and the dynam- ics of bone turnover, or a separate effect to reduce osteoclast recruitment and/or differentiation, or in-
Fig. 1. Structure of alendronate (alendronic acid; monosodium
⦁ amino-1-hydroxybutylidene bisphosphonate).
⦁ Mechanism of Action
Although all the details of the pharmacological action of bisphosphonates have not been clearly defined, the data permit a general description of the mechanism of action of alendronate.
Alendronate is rapidly cleared from plasma, either eliminated in the urine or taken up by the skele- ton.[20] However, this uptake is not uniform throughout bone; rather, it is focused in areas of high physiological activity, where bone turnover is greatest.[21] Specifically, alendronate concentrates in a relatively selective manner at sites of bone resorption.[21,22]
Following binding to the hydroxyapatite of bone exposed at sites of bone resorption, alendron- ate can be mobilised by osteoclasts as these cells generate acidic conditions and dissolve the inor- ganic phase, thereby solubilising the bound alend- ronate.[23] Alendronate is then taken up by the osteoclasts and, through biochemical effects, rend- ers the osteoclast inactive for bone resorption.[21] This is observable on electron microscopy as a loss of the ‘ruffled border’ of the osteoclast, a sign that they are no longer active.
Two recently described biochemical effects in- clude an inhibition of protein tyrosine phospha- tase[24-26] and inhibition of protein prenylation.[27,28] This latter mechanism appears to result from the inhibition in osteoclasts of enzyme(s) involved in cholesterol biosynthesis by nitrogen-containing bisphosphonates.[27,28] Although numerous other biochemical effects have been described which may lead to the inhibition of osteoclast resorptive capabilities and its structural changes, inhibition of prenylation is most likely the one responsible for
duce osteoclast apoptosis,[29] or all of the above, is not certain. Furthermore, some investigators have proposed that bisphosphonates, such as alendron- ate, must interact with the bone forming cells, the osteoblasts, in order to exert their inhibitory influ- ence on the osteoclasts.[30]
The alendronate deposited at sites of bone turn- over, if not taken up by the osteoclasts, is ultimately incorporated within the matrix as newly formed bone encases it.[19,21] This is similar to the tetracy- clines, which are deposited in bone along the mineralisation front, a characteristic exploited by investigators who study its fluorescence in bone as a marker of bone formation. The alendronate incor- porated in the mineralised bone matrix is no longer pharmacologically active until the time when bone resorption removes the overlaying layers of bone, bringing the alendronate back to the surface and allowing it to interact with osteoclasts again.
Most importantly, these data indicate that the primary effect of alendronate on the skeleton is to inhibit bone resorption. Other manifestations of its skeletal influence after long term administration, such as reduced bone formation and turnover, de- rive from this primary pharmacological activity.
⦁ Preclinical Pharmacokinetics
⦁ Metabolism
As with most other bisphosphonates, alendron- ate appears not to be metabolised in mammals.[31] Following administration of a dose of radiolabelled alendronate, Lin et al.[20] demonstrated, by high performance liquid chromatography (HPLC), that unmodified alendronate accounts for all the radio- activity recovered in urine of rats, dogs and mon- keys, as well as that deposited in the skeletons of
rats and dogs, indicating that metabolism of alen- dronate in vivo is absent or at most negligible.
It has recently been reported that other bisphos- phonates, for example clodronate, may be metabo- lised by mammalian cells in vitro to yield an ana- logue of adenosine triphosphate; this could play a role in the mechanism of action of that drug.[32] In contrast, such metabolism was not demonstrable with alendronate.[32]
Because of its high potency, the relatively low oral dosages used clinically produce plasma con- centrations of alendronate which fall below the limit of reliable quantification of the assay. The absence of discernible metabolism thus proved es- sential to examination of the pharmacokinetics of this compound, given that plasma pharmacokinet- ics after oral administration could not be quanti- fied. Drug uptake was, therefore, characterised by following deposition in bone of radiolabelled drug. For example, bioavailability was examined by de- termining the ratio of 14C and 3H in bone following administration of a 14C-labelled oral dose and a 3H-labelled intravenous dose.[20]
⦁ Absorption
As with other bisphosphonates, the oral absorp- tion of alendronate in animals is limited under fast- ing conditions and negligible in the presence of food. The fasting oral bioavailability of alendron- ate was estimated as 0.9% in rat, 1.8% in dog and 1.7% in monkey.[20] Oral administration to rats in the presence of food decreases bioavailability about 6- to 7-fold.[20] Since alendronate is highly polar and charged at physiological pH, absorption across the gastrointestinal tract has been proposed to occur primarily by the paracellular, rather than transcellular, route.[33] Alendronate is better ab- sorbed from segments of the gastrointestinal tract with larger surface areas, that is the jejunum > duo- denum > ileum.[33]
⦁ Distribution
Over the concentration range of 0.1 to 0.5 mg/ml, alendronate is approximately 80, 73 and 70% protein bound in rats, dogs and monkeys, re- spectively. Albumin is the predominant protein that binds alendronate, with pH and calcium concentra-
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Fig. 2. Distribution of alendronate to soft tissues and bone in rats (n = 3 to 4) following administration of a single intravenous dose of 1 mg/kg.[20]
tion modulating the extent of alendronate bind- ing.[31,34]
An intravenous dose of alendronate 1 mg/kg in rats is quickly and widely distributed throughout the body followed by redistribution to its ultimate site of sequestration (bone) or elimination. About 63% of the dose is present in noncalcified tissues at 5 minutes post-dose. This is reduced to about 5% by 1 hour and about 1% at 6 to 24 hours post-dose. Areciprocal pattern is evident in bone, where about 30% of the dose can be found 5 minutes after ad- ministration, reaching some 60 to 70% of dose by 1 hour, and remaining constant for the next 71 hours (fig. 2).[20]
Distribution of alendronate within bone is de- termined by blood flow and favours deposition at sites of the skeleton undergoing active resorption. Thus a larger proportion of the dose is taken up by trabecular as compared with cortical bone, and in the latter at the metaphysis compared with the dia- physis.[20] The uptake of alendronate in the skele- ton was linear (proportional to dose) in rats which received radiolabelled alendronate (0.2, 1 or 5 mg/kg intravenously or 1, 5 or 25 mg/kg orally).[20] When multiple intravenous doses (totalling 35 mg/kg) were given to rats every 3 days for 21 days, the bone deposition of the first (3H-labelled) and last (14C-labelled) doses was similar. Thus, the up- take of drug in bone was not saturated with re- peated doses, nor did prior administration of al- endronate affect the distribution of subsequent doses, at least up to the extent of drug delivered in this experiment.[35]
⦁ Elimination
Alendronate is cleared from plasma by deposi- tion in bone and urinary excretion. Only a negli- gible amount of the drug (<0.2%) is detected in faeces after intravenous administration, suggesting little, if any, is excreted in bile. About 30 to 40% of a 1 mg/kg dose in rats is eliminated in the urine by 24 hours post-dose.[20] About 60 to 70% of an alendronate dose is sequestered in bone over the short term. The drug is then slowly released from the skeletal deposits, accounting for the prolonged
multiple-phase elimination of this drug.[20] The ter- minal half-life (t12) of alendronate is related to the rate of bone turnover in each of the species studied; thus a half-life of approximately 300 days in rats and at least 1000 days in dogs has been esti- mated.[20]
The observation that the renal clearance of alen- dronate in the rat exceeded that expected from the glomerular filtration rate and unbound concentra- tion of the drug suggested that a secretory mecha- nism was involved in renal elimination. Renal ex- cretion of alendronate appears to utilise an active secretory system with a maximum rate of about 25 mg/min/kg in the rat.[36] High concentrations of classical inhibitors of the secretion of acidic (pro- benecid, p-aminohippuric acid) and basic (quinine and cimetidine) compounds do not influence uri- nary excretion of alendronate in the rat.[36] How- ever, etidronate, a structurally related member of the bisphosphonate class, did reduce the renal clearance of alendronate in a dose-dependent man- ner, as did high concentrations of inorganic phos- phate.[36] Dose-dependent decreases in renal func- tion induced in rats by administration of increasing doses of uranyl nitrate produced graded reductions in renal clearance of alendronate with increases in bone deposition.[36]
In summary, the preclinical pharmacokinetics of alendronate are similar to those of other bisphos- phonates and permit construction of the model de- picted in figure 3. Many of the experiments sup- porting the model cannot be performed in humans. However, as the data will show, the available in- formation strongly indicate that this model also applies to the pharmacokinetics of alendronate in humans.
⦁ Clinical Pharmacokinetics
The pharmacokinetics of bisphosphonates in humans have been characterised to a limited extent. These compounds are difficult to measure in bio- logical fluids and their disposition characteristics make it difficult to examine their pharmacokinetic behaviour in plasma. Concentrations in plasma following therapeutic doses generally fall below
Fig. 3. Pharmacokinetic model for alendronate based on pre- clinical data and assumed to apply to humans. Access to the systemic circulation is followed by rapidly reversible distribution to noncalcified tissues and the primary competing processes of sequestration into the skeleton, from which a slow release can occur, and elimination of drug by the kidney. The skeleton is depicted as 2 pools of drug, the first of which may be mobilised during the process of bone turnover and the second repre- senting drug incorporated in the matrix of bone which is rela- tively quiescent and not actively turning over.
the limits of sensitivity of the assay. Consequently, most of the clinical pharmacokinetic information on bisphosphonates has been derived from urinary excretion data. Alendronate is no exception. A sen- sitive method has been developed for the quantifi- cation of alendronate through fluorescence detec- tion (limit of quantification 1 g/L in urine, 5 g/L in plasma).[37] However, concentrations in plasma following oral administration do not rise suffi- ciently even after 3 years of daily administration to allow examination of plasma kinetics with thera- peutically relevant doses (10mg daily).[38] There- fore, the pharmacokinetic characteristics of alen- dronate in humans have been derived mostly from urinary excretion data.
⦁ Disposition of Intravenous Alendronate
The disposition of radiolabelled alendronate was studied in 12 patients with bone disease sec- ondary to metastatic breast cancer who were given single intravenous doses of 10mg of [14C]alendron- ate (approximately 26 Ci).[39] Extensive examina- tion of plasma, faeces and urine samples collected from these patients failed to reveal evidence of metabolism, leading to the conclusion that the met- abolism of alendronate is negligible or nonexistent.
Furthermore, alendronate was found to be elimi- nated exclusively through urinary excretion. These findings allowed for the use of urinary excretion alone to monitor the disposition of doses of alen- dronate delivered systemically.
The pharmacokinetics of intravenous alendron- ate have been examined for doses ranging from 20g to 10mg.[39,40] Independent of dose, a sub- stantial fraction of the administered drug was found to be promptly excreted in urine (approxi- mately 45% of an intravenous dose in the first 8 hours), with subsequent excretion proceeding much more slowly (approximately 5% of the dose be- tween 8 and 72 hours) as can be seen in figure 4. By 72 hours post-dose, 40 to 60% of administered drug has been recovered in urine, leaving the re- mainder still resident in the body. By this time, however, urinary excretion has fallen to exceedingly low concentrations, indicating that the remaining alendronate has been tightly sequestered in a com- partment from which it is released very slowly.
By analogy with the results in animals, alendron- ate is probably bound to the mineral phase of the skeleton, from which it is released at a rate that is proportional to the rate of bone turnover. This hypo- thesis was examined in 11 patients who were ad- ministered 7.5mg intravenous doses of alendronate once daily over 4 days (totalling 30mg) and closely followed for 18 months to provide an estimate of
the t12.[40] Approximately 48% of the total intrave- nous dose was initially retained. Elimination was then multi-phasic, with approximately one-third of the alendronate initially retained excreted over the first 6 months. Subsequent slow excretion yielded
an estimate of t12 with a mean value of 10.5 years (95% confidence interval = 7.9, 13.2 years). It is not possible from these data to rule out even slower phases of elimination. Even so, an estimate of this magnitude is consistent with the very long t12 ob- served preclinically (approximately 300 days in rats and >1000 days in dogs) and, therefore, in agreement with the hypothesis derived from pre-
clinical work that alendronate is sequestered in the skeleton.
A 10mg intravenous dose is large enough to al- low for the analytical detection of alendronate in plasma for about 15 hours from the initiation of infusion (fig. 5).[39] Given the very long elimina- tion t12 of alendronate, it is clear that figure 5 does not depict the complete profile of alendronate in plasma, rather a substantial fraction of this profile
falls below the assay’s limit of reliable quantifica- tion. Under these circumstances, exact estimates of pharmacokinetic parameters are only possible for renal clearance, which was found to average
4.26 L/h. Additionally, systemic clearance was es- timated to be no more than 11.94 L/h and the steady-state volume of distribution (Vss) was esti- mated at more than 28L.[39] Given that renal clear- ance appears to be the sole means of elimination [therefore giving that plasma clearance (CLp) = renal clearance (CLR)], it appears that some two- thirds of the area under the concentration-time curve (AUC) is not detectable because of limits on assay sensitivity. Additionally, the calculated or apparent Vss would appear to be quite large given that alendronate binds to bone with no hint of sat- uration.
⦁ Reproducibility of Intravenous Pharmacokinetics
As a substantial fraction of a dose is retained long after administration, the effect of previous ex- posure to alendronate on the short term (less than 72 hours) elimination of intravenous doses was ex- amined in 10 healthy postmenopausal women.[39] This group were administered a total of 7 intra- venous doses of alendronate 125g over the course of 18 days. Urinary excretion following the last dose was found to be comparable with that from the first dose, demonstrating that previously ad- ministered alendronate has no significant impact on the disposition of subsequent doses.
⦁ Oral Dose Proportionality and Bioavailability
Bioavailability of alendronate was evaluated in 3 studies in postmenopausal women and in 1 study in men.[41] Oral doses ranged from 5 to 80mg and intravenous reference doses were 125 or 250g. Comparison of the dose-adjusted urinary excretion profiles of alendronate following various oral doses showed no effect of dose on the extent of
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Fig. 4. Urinary excretion of alendronate following administration of a 10mg dose, infused intravenously over 2 hours, to postmenopausal women (n = 6) with metastatic breast cancer (adapted from Coquyt et al.[39] ).
urinary excretion at the individual collection inter- vals. Recovery of alendronate in urine was linear with dose, indicating that both absorption and dis- position are linear with dose over the range studied (5 to 80mg). Overall, the bioavailability of alen- dronate in postmenopausal women was about 0.76% of the oral dose. Bioavailability in men was similar to that in women (averaging about 0.6%).
⦁ Influence of Food, Beverages and Calcium on Absorption
Since alendronate, like other bisphosphonates, has very low bioavailability and forms insoluble complexes with multivalent cations, the effect of the timing of meals, dietary calcium supplements and beverages other than water on the bioavailabil- ity of the drug were studied. Two studies were car- ried out in postmenopausal women to investigate the effect of the timing of the meals and of calcium supplementation of the meal on the oral absorption of alendronate.[41] In one study, 15 women were given doses of 20mg at 1 or 2 hours before break- fast with or without 1g elemental calcium supple- ment, or 20mg 30 minutes before breakfast without calcium. In the other study, 49 women received doses of 10mg at 30 minutes, 1 or 2 hours before, immediately after, or 2 hours after, breakfast. Rel- ative to administration of alendronate 2 hours be-
fore breakfast with no calcium supplement, food decreased absorption of the drug to varying de- grees depending on the timing. On average, eating the meal either 30 minutes or 1 hour after adminis- tration diminished bioavailability by the same pro- portion, about 40%.[41] Taking alendronate either immediately after or 2 hours after breakfast low- ered bioavailability by about 85 to 90%. Including the calcium supplement with the meal given 1 or 2 hours post-dose had no additional effect beyond that of the meal itself.
The effect of beverages taken with the dose on the bioavailability of alendronate was examined in 42 healthy postmenopausal women who were given a 10mg dose with coffee, orange juice or water.[41] Ingestion of either coffee or orange juice was found to decrease the bioavailability of alendronate by about 60% compared with water.[41] Efficacy was demonstrated in clinical trials with alendronate ad- ministered from 30 minutes to 2 hours before breakfast and after an overnight fast. Thus, a prac- tical and effective recommendation is for alendron- ate to be taken with water after an overnight fast and at least 30 minutes before any other food, bev- erage or medication.[42] It is also recommended that patients remain upright for at least 30 minutes after drug administration and until eating to mini- mise the risk of oesophageal irritation.[42,43]
⦁ Influence of Gastric pH on Absorption
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The effect of increased gastric pH on the absorp- tion of alendronate was evaluated in a crossover study in 10 postmenopausal women given simulta- neous intravenous (20g with 0.5 Ci of [14C]alen- dronate tracer) and oral (40mg) doses of alendron- ate when their stomach pH was less than 2 (native) or elevated to more than 6 by administration of intravenous ranitidine.[41] Urinary excretion of al- endronate and radioactivity were monitored for 30 hours post-dose. Elevation of stomach pH by rani- tidine, in simulation of hypo- or achlorhydria, had
Fig. 5. Plasma concentration profile of alendronate following
administration of a 10mg intravenous dose to postmenopausal women with metastatic breast cancer (adapted from Coquyt et al.[39]).
no measurable effect on the systemic disposition of alendronate but increased absorption by about 2- fold compared with native stomach pH.
As doses of alendronate greater than the 10mg dose used for the treatment of osteoporosis in post- menopausal women produce little or no additional increases in bone mass or reduction in bone turn- over,[8,9] it is unlikely that increased gastric pH has an important effect on the efficacy or safety of al- endronate. Dosage adjustments are, therefore, not necessary in such circumstances.
⦁ Potential for Drug Interactions
Although no drug interaction studies have been carried out between alendronate and other thera- peutic agents likely to be used in the target popu- lations, a thorough review of concomitant medica- tions in the clinical trials data failed to suggest any such interactions of significance.[42] The substan- tial effects of food and beverages on oral absorp- tion[41] argue against administration concurrently with other substances. The drug should be admin- istered after an overnight fast and no medication or nutritional supplement should be administered sooner than 30 minutes after alendronate. The very low plasma concentrations of alendronate produced by therapeutic oral doses make it highly unlikely that plasma protein displacement interactions will occur.
Alendronate is neither metabolised nor elimi- nated in bile but is excreted intact exclusively by the kidney.[39] The active renal secretory pathway that appears to be involved, based on the preclini- cal data, is specialised, involving neither the acidic nor basic tubular transport processes;[36] therefore it is unlikely to contribute to drug-drug interac- tions.
In summary, alendronate is believed unlikely to interact with other drugs through changes in protein binding, metabolism, or biliary or renal excretion. Oral administration of other drugs along with al- endronate could potentially interfere with the oral absorption of alendronate and should be avoided.
As alendronate is neither metabolised nor ex- creted in bile, studies in hepatic insufficiency were not performed. Dosage adjustments are not neces- sary for altered hepatic function.[42] Given the low circulating concentrations of drug, and the fact that
50 to 60% of the systemically available drug is presumably taken up by the skeleton, even a sub- stantial reduction in the renal elimination of alen- dronate would lead to only a relatively minor frac- tional increase in the amount of drug taken up by bone, which over a large dose range appears to be nonsaturable.[39] Dosage adjustment is therefore not necessary in patients with mild-to-moderate re- nal insufficiency. There is insufficient clinical ex- perience in patients with more severe renal com- promise [creatinine clearance <2.1 L/h (<35 ml/min)].
⦁ Pharmacokinetic- Pharmacodynamic Relationships with Alendronate
The evaluation of the pharmacokinetic-pharma- codynamic relationship for alendronate is compli- cated by its unique pharmacokinetics, in that its plasma concentration profile is neither fully defin- able at therapeutic doses nor especially relevant. It is the alendronate taken up by bone and the con- centration of alendronate present in the resorption space between active osteoclasts and bone which should determine its inhibition of bone resorption. While this concentration may be estimated in care- fully controlled in vitro studies, it cannot be deter- mined in either people or animals. Moreover, the unique nature of skeletal biology – particularly the long time scale over which normal bone remodell- ing takes place – demands a prolonged period of observation to fully define the pharmacodynamic response to the drug. Thus a complete picture of the relationship between dose, plasma concentration and response, as in a more typical pharmaco- kinetic-pharmacodynamic assessment, is not pos- sible. Nonetheless, many aspects of the dose- response relationship can be explored and provide clinically important insights into the mechanisms of the beneficial effects of alendronate in patients with skeletal disorders such as Paget’s disease and osteoporosis.
To appreciate what can be learned from an as- sessment of the pharmacodynamics of alendronate, one must address some fundamental aspects of
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Fig. 6. Mean ( standard error) change from baseline in (top) urinary hydroxyproline/creatinine and (bottom) serum alkaline phos- phatase in 2 parallel groups of patients with Paget’s disease receiving either increasing dosages of oral alendronate (n = 12) or placebo (n = 10). Alendronate treatment included low (25mg once daily on days 1 to 5), intermediate (50mg once daily on days 8 to 12) and high (100mg once daily on days 15 to 19) dosages. Patients were then observed for a subsequent 180 days.
bone biology. The adult skeleton may be considered as 2 primary compartments; trabecular and cortical bone, comprising roughly 20 and 80% of the skel- eton, respectively. Both compartments undergo a process of continuous remodelling or turnover (al- beit at very different rates), in which bone resorp- tion precedes bone formation with replacement of resorbed bone at each locus of remodelling.[44]
Approximately 25% of trabecular bone and 3% of cortical bone undergoes turnover each year by virtue of this process.[44] Furthermore, bone resorp- tion and formation are usually tightly coupled,
through ‘crosstalk’ between the bone-resorbing os- teoclasts and bone-forming osteoblasts, such that any influence on one component of turnover (e.g. inhi- bition of bone resorption) is ultimately followed by a response in its complementary process (e.g. an inhibition of bone formation).[44] In addition, input from mechanoreceptors in bone which respond to skeletal loading influence both the rate of turnover and the balance between resorption and formation. An imbalance of these processes under pathologi- cal conditions, such that resorption is greater than formation, will ultimately result in a deficit of bone
mass as observed in postmenopausal bone loss.[45] As discussed earlier in section 1, alendronate acts primarily on osteoclasts to inhibit bone resorption. This can be readily monitored clinically by the use of biochemical markers of collagen degradation such as the traditional index, urinary hydroxyprol- ine, and newer, more specific, markers such as uri- nary deoxypyridinoline and N-telopeptide cross- links of collagen.[46-48]
⦁ inhibition of bone resorption is demonstrable earliest, consistent with the primary mechanism of action of alendronate
⦁ a secondary reduction of bone formation fol-
lows
⦁ both resorption and formation processes are al- tered in a dose-dependent fashion.[9]
Paget’s disease offers a useful clinical model to readily demonstrate the dynamic activity of bisphos- phonates such as alendronate, as it is characterised by focal areas of markedly accelerated bone turn- over which accentuate the biochemical influence of the drug.[49] This disease provides an opportu- nity to obtain dose-response information over a rel- atively brief time period (days to weeks as opposed to months to years for osteoporosis). As illustrated in figure 6, sequentially increasing doses of al- endronate progressively reduced urinary hydroxy- proline excretion in patients with Paget’s disease within days of dose escalation, reflecting the pri- mary inhibition of bone resorption by the drug.[15] This suppression of resorption is followed by the more slowly evolving secondary inhibition of bone formation, as evidenced by the subsequent fall in serum alkaline phosphatase, a marker of osteoblast activity (fig. 6).[15]
This biochemical sequence of events – inhibi- tion of bone resorption with subsequent reduction in bone formation – is also manifested in postmeno- pausal women with osteoporosis treated with alen- dronate, although the time frame is extended, re- flecting the moderate but generalised increase in
the rate of bone turnover in osteoporosis as op-
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posed to very large, but focal, increases found in the affected bones of patients with Paget’s dis- ease.[8,9,11,12,16,17] Figure 7 illustrates the dose-re- sponse relationship, and temporal profile, for the biochemical markers of bone resorption and for- mation, respectively, following administration of alendronate 5 to 40mg once daily to women with osteoporosis.
Several important pharmacodynamic points are evident in these women with osteoporosis (fig. 7):
0 3 6 9 12 15 18 21 24
Time (months)
Fig. 7. Mean ( standard error) change from baseline in (top) urinary deoxypyridinoline/creatinineand (bottom) serum alkaline phosphatase for postmenopausal women treated orally with various dosages of alendronate, and/or placebo, once daily. The placebo and alendronate 5 and 10 mg/day groups received the same dosage for 24 months. The 40/2.5mg group received al- endronate 40 mg/day for 3 months followed by 2.5 mg/day for 21 months. The 20mg/placebo and 40mg/placebo groups re- ceived alendronate 20 or 40 mg/day, respectively, for 12 months followed by placebo for 12 months (after Chestnut et al.,[9] with permission).
Because of the imbalance favouring resorption and increased turnover rates in osteoporosis, the net influence of alendronate is to reduce the turn- over and allow formation to become more closely aligned with, or even to exceed, resorption. These effects on skeletal dynamics result in a gradual ac- cumulation of bone mass.[8-12] The precise time it will take to reach a steady state for changes in bone mineral density is difficult to predict, as it depends both on the rate of underlying bone turnover and the rate and magnitude of the impact of alendronate on that turnover. Nonetheless, a slowing in the rate of change of bone mineral density is generally ap- preciable by the third year of therapy.
Closer examination of both panels in figure 7 also reveals that despite continued administration of alendronate there is a plateau effect on the bio- chemical markers of bone turnover. This is thought to reflect the previously described fate of alendron- ate – its incorporation into the bone matrix at the site of bone remodelling. In this location it is no longer pharmacologically active until it is unveiled by a newly initiated focus of resorption. Thus it is primarily the recently administered drug, targeted to actively resorbing surfaces, which produces by far the greatest proportion of the biochemical re- sponse.
Cumulative accretion of the drug in the skeleton does not result in progressive suppression of bone turnover beyond that evident as plateauing of the biochemical markers. Indeed, this is achieved with very small amounts of drug accumulating in the skeleton (estimated to be approximately 100mg after 10 years of treatment with alendronate 10mg daily).
A study of the biochemical markers as well as bone mineral density following the discontinuation of alendronate reveals that turnover is re-initiated once administration stops, albeit requiring a pro- longed period to re-attain baseline concentrations (fig. 7). Changes in bone mineral density lag fur- ther behind, but nonetheless do occur, even though drug is clearly retained for much longer periods in the skeleton as revealed by the animal studies dis-
cussed in section 2 and the human pharmacokinetic data.
Although plasma concentrations of alendronate cannot be followed, there is a predictable relation- ship between dose (as a surrogate for drug in the skeleton) and the biochemical and bone mass re- sponse. The temporal characteristics of these re- sponses are a function both of the underlying skeletal disorder, with its own pathophysiological dynamics, and the fundamental mechanism-based interplay between alendronate and the processes of bone turnover. The net effect of alendronate is expressed clinically as increased bone mineral den- sity, enhanced bone strength and reduced risk of fracture.[7-13]
⦁ Conclusion
Alendronate possesses unusual pharmacokinetic and pharmacodynamic properties because of its singular target organ of activity. Its notably low bioavailability is offset by its concentration in bone and its potent ability to hinder osteoclast-mediated bone resorption; these properties have been associ- ated clinically with increased bone mass and re- duced fracture risk in women with osteoporosis.
Acknowledgements
The authors would like to thank Ms Carmen Inoa for her conscientious attention to the preparation of the manuscript and to Drs Arthur Santora and A. John Yates for their review and suggestions.
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Correspondence and reprints: Dr Barry J. Gertz, Merck Re- search Laboratories, P.O. Box 2000, RY33-600, Rahway, NJ 07065-0914, USA.
E-mail: [email protected]