Drug, Healthcare and Patient Safety
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`Open Access Full Text Article
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`open access to scientific and medical research
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`
`Safety and tolerability of zoledronic acid
`and other bisphosphonates in osteoporosis
`management
`
`Luca Dalle Carbonare
`Mirko Zanatta
`Adriano Gasparetto
`Maria Teresa valenti
`Clinic of internal Medicine D,
`Department of Medicine, University
`of verona, italy
`
`Correspondence: Luca Dalle Carbonare
`Department of Medicine, Medicina interna
`D, University of verona, Piazzale Scuro,
`37134 verona, italy
`Tel +39 045 812 4684
`Fax +39 045 802 7496
`email luca.dallecarbonare@univr.it
`
`Abstract: Bisphosphonates (BPs) are widely used in the treatment of postmenopausal
` osteoporosis and other metabolic bone diseases. They bind strongly to bone matrix and reduce
`bone loss through inhibition of osteoclast activity. They are classified as nitrogen- and non-
`nitrogen-containing bisphosphonates (NBPs and NNBPs, respectively). The former inhibit
`farnesyl diphosphate synthase while the latter induce the production of toxic analogs of adenosine
`triphosphate. These mechanisms of action are associated with different antifracture efficacy,
`and NBPs show the most powerful action. Moreover, recent evidence indicates that NBPs can
`also stimulate osteoblast activity and differentiation. Several randomized control trials have
`demonstrated that NBPs significantly improve bone mineral density, suppress bone turnover,
`and reduce the incidence of both vertebral and nonvertebral fragility fractures. Although they
`are generally considered safe, some side effects are reported (esophagitis, acute phase reaction,
`hypocalcemia, uveitis), and compliance with therapy is often inadequate. In particular, gastro-
`intestinal discomfort is frequent with the older daily oral administrations and is responsible for
`a high proportion of discontinuation. The most recent weekly and monthly formulations, and in
`particular the yearly infusion of zoledronate, significantly improve persistence with treatment,
`and optimize clinical, densitometric, and antifracture outcomes.
`Keywords: bisphosphonates, osteoporosis, safety, tolerability, zoledronic acid
`
`Introduction
`Bisphosphonates (BPs), synthetic analogs of the endogenous bone mineralization
`regulator pyrophosphate, are the most commonly used drugs in the treatment of post-
`menopausal osteoporosis (PO) and metabolic bone disease (MBD, such as bone loss
`induced by hormone suppressive therapy or glucocorticoids). BPs have been associated
`with significant improvement in bone mineral density (BMD), suppression of bone
`turnover, and reduction of fracture incidence. Fractures are the most important cause
`of morbidity and mortality among patients with MBD, and reduction of fracture risk
`is the main goal of treatment.1–4
`BPs have been known for more than a century, and were initially used in toothpaste
`or to soften hard water. Nowadays, they are widely used in the treatment of skeletal
`diseases and are usually classified into two classes, ie, nitrogen- and non-nitrogen-
`containing bisphosphonates (NBPs and NNBPs, respectively).
`All bisphosphonates reduce osteoclast activity, but NBPs (alendronate, risedronate,
`ibandronate, zoledronate) specifically inhibit farnesyl diphosphate synthase and block
`prenylation of guanosine triphosphate-binding protein, although other mechanisms
`of action have been recently identified.5 In contrast, NNBPs (etidronate, clodronate),
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`the older molecules, induce the production of toxic analogs
`of adenosine triphosphate. The antifracture effect is also
`dependent on the different affinity of each type of molecule
`for the bone mineral matrix and in this respect the NBPs
`show the most powerful action.
`There are various BP formulations and dosages. NBPs
`were initially administered orally once daily (alendronate
`10 mg and risedronate 5 mg), then weekly (risedronate
`35 mg and alendronate 70 mg), monthly (risedronate and
`ibandronate 150 mg), and, more recently, intravenous for-
`mulations have been developed (ibandronate 3 mg every
`3 months and zoledronate 5 mg yearly). Adherence to treat-
`ment was quite difficult with daily dosages, mainly due to
`gastrointestinal (GI) intolerance,6 which is clinical important
`because poor compliance compromises treatment efficacy,
`and increases fracture incidence and medical costs.7
`Compliance has been significantly increased with more
`recent weekly and monthly formulations,6 and particularly
`with intravenous yearly administration, which also improves
`clinical, densitometric, and antifracture outcomes.8,9
`This review summarizes the pharmacologic properties,
`efficacy, tolerability, and safety of the most common and
`effective NBPs in the treatment of PO and MBD.
`
`Pharmacokinetic
`and pharmacodynamic profiles
`BPs are analogs of inorganic pyrophosphate, and composed of
`an enzyme-resistant phosphorus-carbon-phosphorus (P-C-P)
`structure able to adhere strongly to hydroxyapatite crystals
`(Figure 1). They have a relatively simple core structure, and
`the pharmacologic properties of each BP molecule depend
`on lateral chains, named R1 and R2.8 The P-C-P nucleus and
`R1 lateral chain are responsible for anchoring the drug to the
`bone mineral matrix, while R2 has biologic and therapeutic
`actions. The presence of a hydroxyl group in R1 markedly
`increases BP affinity for the bone matrix, while the nitrogen
`atom in R2 is responsible for antiresorptive potency.5
`BPs are characterized by low GI absorption after oral
`administration, high affinity for bone matrix, urinary elimina-
`tion, and long persistence on the bone surface.10 To increase
`intestinal absorption, BPs must be taken on an empty stomach,
`with water, at least 30–45 minutes before eating. This problem
`is obviously avoided using intravenous formulations.
`Plasma half-life is very short, and BPs are cleared from
`plasma in about six hours; 50% of the absorbed drug
`adheres to the bone surface, while the remainder is excreted
`unchanged in urine.11 BPs persist in bone for a long
`time. For example, the effect of alendronate in humans is
`
` maintained for many years after discontinuation of prolonged
`treatment.1,12,13 The time that a BP resides within the skeleton,
`which is important for its biologic actions, is determined by
`three critical factors; firstly, the rate of bone remodeling in the
`host (faster remodeling means a shorter half-life), secondly,
`the side chain that, as mentioned above, greatly influences
`BP affinity for bone matrix, and, finally, the amount of drug
`reaching bone. For example, intravenous administration
`increases the speed and amount of drug reaching the bone
`and also the urinary system where the drug is eliminated; on
`the other hand, oral administrations have the problem of low
`intestinal absorption, with only a small portion of each single
`dose administered being able to reach the bone matrix.
`BPs bind to plasma proteins and are eliminated by the
`kidney.11 They are not metabolized by the liver, and no other
`metabolites have been found in serum. Drug interactions are
`very few and they relate mainly to impaired oral absorption
`if they are administered concomitantly with other drugs or
`food.14 Some cases of hypocalcemia have been observed
`during treatment with aminoglycoside antibiotics.15
`Due to their strong affinity for the skeleton, BPs are
`used in many skeletal diseases in addition to OP, including
`Paget’s disease of bone, osteogenesis imperfecta, malignant
`hypercalcemia, metastatic cancer, and fibrous dysplasia.
`Dose and frequency of BP administration depend on the
`characteristics of each compound and on the type of disease
`being treated.
`The therapeutic effect of BPs is mediated mainly by the
`inhibition of osteoclastic bone resorption, as demonstrated in
`bone biopsies, where fewer numbers of osteoclasts and lower
`bone erosion rates have been observed.12 Once embedded on
`the bone surface, BPs are slowly released into the bone matrix
`where they affect osteoclasts by reducing their differentiation,
`recruitment, and activity. In fact, it is believed that BPs are
`taken up by osteoclasts during bone resorption and, under
`their influence, osteoclasts lose their ruffled border and their
`normal cytoskeleton structure.12,17
`NBPs (eg, alendronate, risedronate, ibandronate, zole-
`dronate) interfere with protein prenylation by inhibiting
`farnesyl pyrophosphate (FPP) synthase, thereby reducing
`geranylgeranyl diphosphate metabolites involved in the
`mevalonate pathway. Inhibition of this pathway prevents
`posttranslational prenylation of small guanosine triphos-
`phate-binding proteins (eg, Ras, Rho, and Rac), which
`regulate osteoclast morphology, cytoskeletal arrangement,
`membrane ruffling and trafficking, and lead to reduced
`resorptive activity and accelerated apoptosis (programmed
`cell death).18,19 Some authors have suggested that osteoclast
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`Safety and tolerability of biphosphonates
`
`OH
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`OH
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`OH
`
`OH
`
`O
`
`P P
`
`O
`
`R2
`
`R1
`
`C
`
`OH
`OH
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`OH
`
`OH
`
`O
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`P P
`
`O
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`O
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`Pyrophosphate
`
`Bisphosphonate
`
`OH
`
`OH
`
`OH
`
`OH
`
`O
`
`PP
`
`O
`
`N
`
`OH
`
`OH
`
`OH
`
`OH
`
`OH
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`O
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`P P
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`O
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`H2N
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`OH
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`Alendronate
`
`Ibandronate
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`N
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`N
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`OH
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`O
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`P
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`P
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`O
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`OH
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`OH
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`OH
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`OH
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`OH
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`OH
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`OH
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`OH
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`O
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`P P
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`O
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`N
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`OH
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`Risedronate
`
`Zoledronate
`
`Figure 1 Molecular structure of pyrophosphate and of the most common nitrogen-containing bisphosphonates.
`
`inhibition by NBPs could also be osteoblast-mediated via the
`production of an inhibitory factor not yet characterized.20
`Moreover, increasing evidence indicates that osteoblast activ-
`ity could be directly stimulated by NBPs. Histomorphometric
`analysis in osteoporotic patients indicates that BPs may increase
`the mean wall thickness and reduce the imbalance between for-
`mation and resorption at the basic multicellular unit,16,21 leading
`to a continuing increase in BMD even after a long period of
`treatment, as demonstrated in clinical studies.1,16
`NBPs also control osteoblastic proliferation and differ-
`entiation,22 modulate osteoblast production of extracellular
`matrix proteins, regulate the secretion of several cytokines
`
`and growth factors, and enhance proliferation and maturation
`of bone marrow stromal cells into the osteoblastic lineage.23
`In addition, NBPs are able to prevent glucocorticoid-induced
`apoptosis of osteoblasts and osteocytes.24 The mechanism
`by which BPs stimulate osteoblasts is not completely
`understood. A type of anabolic effect has been associated
`with the stimulation of b-FGF.25 The involvement of bone
`morphogenetic protein 226 has been postulated, including
`a cascade of osteoblast-related genes like RUNX2, Type 1
`collagen, and bone sialoproteins. The OPG/RANKL system
`has been shown to be upregulated and significantly increased
`in bone marrow stromal cells after NBP treatment.23,27 We
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`have also recently observed (Dalle Carbonare, unpublished
`data) an upregulation of Cox-2 expression in osteoblasts after
`NBP treatment, indicating a possible role of exogenous and
`endogenous prostaglandins, known to be involved in bone
`formation and remodelling.28
`
`Mechanism of action
`of zoledronic acid
`Zoledronic acid is an NBP and, like the other molecules of
`this class, binds to hydroxyapatite in the bone mineral matrix
`and strongly inhibits bone resorption. The ability of BPs
`to persist in bone matrix and to reduce osteoclast activity
`depends on their affinity for the bone matrix and potency
`of the inhibition of FPP.18 Zoledronic acid has the highest
`affinity for bone, followed by alendronate, ibandronate,
`risedronate, etidronate, and clodronate and it also alters
`mineral-surface properties, allowing greater adsorption.
`These properties are believed to contribute to its prolonged
`action.29
`The potency of zoledronic acid appears to be related
`also to its unique chemical structure. All BPs have a P-C-P
`nucleus that acts as a bone hook, while R2 is the structure
`primarily responsible for antiresorptive potency and dura-
`tion of action. R2 in zoledronic acid is composed of a het-
`erocyclic ring containing two nitrogen atoms (Figure 1).29,30
`Biochemical assays have demonstrated the antiresorptive
`potency of this bisphosphonate. In in vitro analysis of FPP
`synthase inhibition, zoledronic acid was the most potent BP
`evaluated, followed by risedronate, ibandronate, alendronate,
`and pamidronate31 (Figure 2). The ability to inhibit FPP is
`directly correlated with effectiveness in suppressing bone
`turnover in vivo.
`As already mentioned, the bioavailability of the BPs is
`very low when they are administered orally, but this problem
`is avoided by intravenous administration, such as with the
`yearly formulation of zoledronic acid. Orally administered
`BPs have shown approximately 1% bioavailability, whereas
`intravenous formulations have shown 100% bioavailability.
`Like the other BPs, zoledronic acid is eliminated rap-
`idly in the urine, and studies of its endogenous metabolism
`have shown that it does not inhibit human cytochrome
`activity in vitro, in particular the p450 enzyme, or undergo
`biotransformation in vivo, indicating that it is not extensively
`metabolized.32–34
`
`Bone turnover markers
`Serum and urinary markers of bone metabolism are important
`biochemical tests in daily clinical practice for evaluation of
`
`PO and MBD. The most common bone resorption markers are
`serum C-terminal collagen telopeptide, urinary N-terminal
`collagen telopeptide, and deoxypyridinoline, and for bone
`formation are alkaline phosphatase (ALP) and its bone
`isoenzyme (B-ALP) and osteocalcin.35 Patients with high
`bone turnover may have a higher risk of fracture than those
`with low bone turnover, independently of BMD.36
`These bone markers are characterized by high biologic
`variability, and newer markers, such as serum RANKL, as
`well as genetic abnormalities of osteoblastic differentiation
`from mesenchymal precursors, are now under evaluation but,
`even if these are apparently more reliable, they are not still
`accessible in routine clinical practice.37,38
`Bisphosphonates are potent inhibitors of bone turnover
`and significantly decrease both resorption and formation
`markers.12,13 Bone markers could be used to assess treatment
`compliance, efficacy, and disease activity.35,39
`Inhibition of bone turnover in PO is similar for all the oral
`formulations of bisphosphonates (50%–70%), with a nadir
`after 6–12 months of treatment, and thereafter returning
`back to the premenopausal range.40–42 Inhibition of bone
`turnover is maintained for the duration of treatment and
`tends to persist even after discontinuation in terms of drug
`accumulation on the bone surface and slow release during
`osteoclastic activity.1,12,13,43 Of all the NBPs, risedronate
`seems to show the most rapid return to pretreatment levels
`(6–12 months).44
`After a single intravenous dose of zoledronate, bone
`turnover marker reduction reaches up to 80% after 1 month
`and persists over the following 12 months.9,45,46 This is
`due to the high potency and affinity of zoledronic acid for
`hydroxyapatite and the 100% bioavailability afforded by the
`intravenous infusion.29,30
`Excessive inhibition of bone turnover has been suggested
`to occur with prolonged treatment and has been considered
`potentially responsible for so-called “adynamic” bone dis-
`ease.47 Until now, there has not been any convincing evidence
`of such a problem, and the long-term efficacy and safety of
`NBPs are maintained, as demonstrated by the data collected
`for 10 years of alendronate and 7 years for risedronate.1,43,48
`
`Safety and tolerability
`Bisphosphonates are widely used in PO and MBD, and
`are usually well tolerated. Common side effects have been
`described, including GI intolerance, in particular esophagitis,
`as well as acute phase reaction and uveitis. These side effects
`are similar for all the molecules available, but some of them
`are correlated with their route of administration.
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`Safety and tolerability of biphosphonates
`
`ZOL
`
`RIS
`
`IBN
`
`ALN
`
`0
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`100
`
`200
`
`300
`
`400
`
`(
`)
`
`IC50 final (nM)
`
`Figure 2 Farnesyl pyrophosphate synthase enzyme inhibition potency (iC50) of nitrogen-containing bisphosphonates (inhibition of 50% of maximum enzyme activity). Note
`that zoledronic acid shows the higher affinity for the mineral matrix combined with the higher inhibition potency of farnesyl pyrophosphate synthase.26
`Abbreviations: ALN, alendronate; iBN, ibandronate; RiS, risendronate; ZOL, zolendronic acid.
`
`Oral administration comes with specific instructions to
`optimize the adsorption and to avoid possible esophageal
`lesions. The dose must be taken on an empty stomach, with
`abundant water intake at least 30–45 minutes before eating,
`and while sitting or standing up. It has been estimated that at
`least 50% of patients taking oral BPs discontinue the therapy
`within 1 year,26 and many patients do not take their drugs
`according to the instructions described above.49–52
`Post-marketing studies indicate that 20%–30% of patients
`treated with alendronate or risedronate discontinue the drug,
`mainly because of side effects.49,50 This is clinically relevant
`because poor compliance compromises treatment efficacy,
`and increases fracture incidence and medical costs.7,49
`
`Upper gastrointestinal intolerance
`GI intolerance, in particular in the upper GI tract (nausea,
`vomiting, epigastric pain, and dyspepsia), is often associated
`with the use of oral BPs.53 Esophagitis is the most important
`and frequent side effect, and its incidence was more or less
`similar in a head-to-head comparison between alendronate
`
`and risedronate.54 Endoscopic examination showed that
`esophagitis was caused by direct contact between the tablet
`and the mucosa. Prolonged contact of the tablet with the
`esophageal mucosa can induce local irritation; this problem
`can be prevented by strict adherence to the above-mentioned
`dosing instructions.
`Esophagitis was common with daily formulations but the
`incidence has decreased significantly after the introduction of
`weekly and monthly BP administration.55 Intravenous formu-
`lations of zoledronate and ibandronate avoid this problem.
`
`Acute phase reaction
`Acute phase reaction encompasses a variety of symptoms
`generally described as fever, myalgia, fatigue, chills, and
`arthralgia. It is common with all NBPs, whether adminis-
`tered orally or intravenously, but is certainly more frequent
`and intense with the more potent intravenous formulations.12
`Symptoms are typically transitory, resolving within 3 days
`of onset and reduced by commonly used anti-inflammatory
`and antipyretic agents.8
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`The symptoms are particularly common with zoledronic
`acid, and include pyrexia (16.1%), myalgia (9.5%), flu-like
`symptoms (7.8%), headache (7.1%), and arthralgia (6.3%).
`All these events decreased dramatically with subsequent
`infusions. Symptoms were reported in 30% of patients after
`the first infusion, in 6.6% after the second, and 2.8% after the
`third.8 The mechanism responsible for these effects is linked
`both to the direct stimulation of γ/δ lymphocytes and to the
`intracellular accumulation of isopentenyl pyrophosphate due
`to the inhibition of farnesyl diphosphate synthase.56
`Although it is usually reported as a side effect, the stimula-
`tion of a subgroup of γ/δ T-lymphocytes could be responsible
`for the indirect antineoplastic activity of zoledronic acid.57
`An interesting association between acute phase reaction
`and vitamin D deficiency has recently been demonstrated,
`indicating that adequate supplementation with vitamin D
`before the infusion contributes to reduce the incidence of
`symptoms.58
`
`Renal safety
`BPs are excreted by the urinary system and can induce
` impairment of renal function. The mechanism of the damage
`is the same as that responsible for the therapeutic effect,
`ie, blockage of the mevalonate pathway, with apoptosis of
`tubular cells.59 Because renal damage is closely correlated
`with the concentration/time ratio of drugs in the kidney,
`intravenous formulations potentially carry a higher risk of
`renal impairment.
`The renal safety of zoledronic acid has been monitored in
`the Pivotal Fracture Trial (PFT). No signs of significant renal
`dysfunction were reported following 3 years of intravenous
`treatment with zoledronic acid in patients with a baseline crea-
`tinine clearance $30 mL/min. In 31 patients treated with zole-
`dronic acid, a transient elevation of creatinine levels has been
`observed, which normalized completely within one month
`in 27 patients and in all patients by one year. Assessments
`at 12, 24, and 36 months showed no significant differences
`between groups in serum creatinine or creatinine clearance
`change from baseline.8,60 Moreover, the reduction of creatinine
`clearance in patients with mild to moderate renal dysfunction
`was not different from that in the placebo group.
`The safety of zoledronic acid has been also tested in MBD
`where the dosage and rate of infusion are much higher than for
`PO. These patients are usually at high risk of renal dysfunction
`from pre-existing renal disease, concomitant treatments,
`frequent use of non-steroidal anti-inflammatory drugs, and
`hypercalcemia, but data from a meta-analysis indicate that
`zoledronic acid infusion is generally safe.61 Nevertheless,
`
`the duration of infusion is important because a period shorter
`than 15 minutes, achieving high drug concentrations in the
`renal tubule, could damage tubular cells. This problem can be
`avoided with an infusion exceeding 15 minutes.62 Moreover,
`because clinical studies indicate that there is no evidence of
`excessive drug accumulation secondary to renal failure, no
`adjustment of the dosage is necessary in patients with PO
`and nephropathy.62
`At present, the summary of product characteristics rec-
`ommends caution when using zoledronic acid in patients
`with a creatinine clearance ,30 mL/min, not because of
`established risk of toxicity, but on the basis of the limited
`data available.63
`
`Cardiovascular safety
`Atrial fibrillation (AF) is the only relevant cardiac side effect
`reported in patients treated with BPs. AF occurred in the PFT
`in 50 patients (1.3%) treated with zoledronic acid and in
`20 patients (0.6%) treated with placebo (P , 0.001).8 Nota-
`bly, 47 of 50 cases of AF were recorded more than 30 days
`after zoledronic acid infusion, when the drug was no longer
`detectable in serum. Furthermore, an electrocardiogram
`substudy, conducted in 559 patients before study initiation
`and 9 to 11 days after the third infusion, failed to reveal any
`cardiac arrhythmias of note. Other cardiovascular adverse
`events, eg, stroke and myocardial infarction, did not show
`any significant difference between groups, nor was there a
`significant difference in the overall incidence of death from
`cardiovascular causes. A retrospective analysis of the Frac-
`ture Intervention Trial (FIT) highlighted a trend toward a
`higher incidence of AF in patients treated with alendronate,
`similar to that observed with zoledronic acid. In this study,
`47 patients (1.5%) treated with alendronate and 31 (1%) of
`those in the placebo group developed AF.64
`No studies are available to suggest a biologic mechanism
`for a relationship between BPs and development of AF.
`Alterations of serum calcium, changes in intracellular ion con-
`centrations, QT prolongation, and/or production of specific
`proinflammatory, profibrotic, and antiangiogenic cytokines
`have been suggested, but no significant treatment-related
`changes in these parameters have been observed thus far.65–67
`At present, this problem seems not to be clinically relevant,
`but more extensive and specific studies should be carried out
`to clarify the relationship between AF and BP treatment.
`
`Hypocalcemia
`BPs are potent inhibitors of osteoclast activity and could
` trigger an acute decrease of serum calcium and phosphorus
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`Safety and tolerability of biphosphonates
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`concentrations associated with a secondary parathyroid
` hormone (PTH) increase.68 PTH maintains the serum calcium
`level by increasing renal tubular reabsorption and synthesis of
`1,25-dihydroxyvitamin D, and indirectly stimulates osteoclasts
`via osteoblasts. Symptomatic hypocalcemia is uncommon
`with oral bisphosphonates,69 but the more potent intravenous
`formulations may cause symptomatic hypocalcemia within
`a few days postinfusion, overcoming the PTH effect.70 Risk
`factors for hypocalcemia include the presence of hypopara-
`thyroidism, vitamin D deficiency, and renal failure.
`In the Health Outcomes and Reduced Incidence with
`Zoledronic Acid Once Yearly (HORIZON)-PFT study, 2.3%
`of patients in the zoledronic acid group showed hypocal-
`cemia, defined as serum calcium levels ,2.075 mmol/L,
`9–11 days after the first infusion. All cases were transient
`and asymptomatic.8 In clinical practice, appropriate calcium
`and vitamin D supplementation prevents hypocalcemia, and
`correction of vitamin D deficiency is also recommended.71
`
`Ocular adverse events
`Nonspecific conjunctivitis is the most common ocular side
`effect of the BPs.72,73 This is usually transient and improves
`without specific therapy or discontinuation of BP therapy.
`Other ocular side effects, such as eye lid edema, optic or
`retrobulbar neuritis, periorbital edema, cranial nerve palsy,
`and ptosis have been reported. The most frequent cranial
`nerve side effect is optic nerve neuritis, but the release
`of cytokines after bisphosphonates administration might
`provoke also extraocular muscle inflammation and involve
`orbital motility.74
`Uveitis and scleritis are the most serious ocular com-
`plications of BP therapy, and require discontinuation of
`treatment. However, the true incidence of these side effects
`is unknown.72,73
`A large cohort study determined the six-month incidence
`of uveitis/scleritis during BP treatment. The relative risk of
`uveitis/scleritis over 6 months was 1.23 (95% confidence inter-
`val [CI] 0.85–1.79) compared with patients not treated with
`BPs. There was no significant difference in the incidence of
`uveitis/scleritis between BP users and nonusers, nor between
`oral or intravenous bisphosphonate administration.73
`An association with concomitant systemic diseases (such
`as ankylosing spondylitis, Behçet syndrome, psoriasis, Reiter
`syndrome, inflammatory bowel diseases, polychondritis,
`Wegener’s granulomatosis, rheumatoid arthritis, systemic
`lupus erythymatosus, sarcoidosis, and syphilis) or treatments
`(rifabutin, trimethoprim-sulfamethoxazole, diethylcarbamaz-
`ine, metipranolol, and cidofovir) have been reported, and it
`
`has been postulated that in these situations BPs could act as a
`precipitating factor.73 Vigilance is therefore necessary when
`BPs need to be administered in patients with these diseases
`or receiving these concomitant therapies.
`
`Atypical femoral diaphysis fractures
`In the last few years, a new association between long-term
`BP treatment and unusual, low-energy, nonvertebral fractures
`has been reported.75 Until now, this complication was reported
`only in patients taking oral BPs, in particular alendronate.76
`Bone biopsies in these patients show evidence of severely
`suppressed bone turnover, considered to be the cause of
`adynamic bone disease, which presumably accounts for
`increased bone fragility resulting in atypical fractures.75
`The radiographic pattern is distinctive, and defined as a
`simple transverse or oblique (#30°) fracture, with breaking
`of the cortex and diffuse cortical thickening of the proximal
`femoral shaft.77
`The majority of the relevant studies have concerned alen-
`dronate because this is the most widely used BP. The effect
`is probably common to all BPs, but, at the moment, there
`are no findings available for the other agents. Nevertheless,
`femoral shaft fractures are rare in BP users, indicating that
`the pathogenesis is complex and probably not directly related
`to BP treatment, and probably more related to patient charac-
`teristics. A genetic susceptibility of osteoclasts to BP-induced
`oversuppression has been postulated,78 as well as the presence
`of one or more predisposing factors, such as diabetes mellitus,
`chronic corticosteroid treatment for pulmonary diseases, rheu-
`matoid arthritis, and severe osteoarthritis,79 or the existence
`of femur cortical hypertrophy, that is often present before the
`beginning of treatment.79 The question of whether low-energy
`subtrochanteric or proximal femoral shaft fractures are more
`frequent in alendronate (or any other BP) users compared
`with nonusers cannot be answered at present.
`Patients treated with the more widely used BPs should be
`informed that persistent and increasing pain in the region of
`the upper part of the femur may be prodromal of a proximal
`diaphysis fracture, and a radiologic evaluation should be
`performed.
`
`Osteonecrosis of the jaw
`Osteonecrosis of the jaw (ONJ) developing during BP treat-
`ment is a form of chronic osteomyelitis, involving mainly the
`jaw and maxilla, and attributable to pathogens usually present
`in the mucosa of the mouth, such as Actinomyces israeli.80
`In addition to BP use, other risk factors have been identi-
`fied, including coexisting solid tumors or multiple myeloma
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`treated by chemotherapy, and other conditions associated with
` immunosuppression, such as diabetes mellitus and corticos-
`teroid treatment. A dental procedure is often the precipitating
`factor, especially if associated with bad dental hygiene and
`inadequate antibiotic propylaxis.80 The incidence is very low,
`ie, less than 1/100,000 in PO patients treated with BPs in
` Germany81 and 0.01%–0.04% in Australia.82 In the HORIZON
`study, no cases of ONJ were observed in 7000 patients, and
`a retrospective analysis showed two cases of ONJ, one in the
`treated group and one in the placebo group.83
`Many authors have suggested that the pathogenesis of
`ONJ is directly linked to osteonecrosis of bone due to exces-
`sive suppression of bone turnover.47 In contrast, histologic
`analyses showed that ONJ is a typical osteomyelitis charac-
`terized by a high cellular infiltrate, and an intense osteoclast
`and osteoblast reaction indicating that bone turnover is not
`oversuppressed by the therapy.48 Oversuppression of bone
`turnover after bisphosphonates has been discounted by
`bone biopsy analyses in osteoporotic patients treated with
`zoledronic acid.84
`The cumulative BP dose has been proposed as one of the
`most important risk factors for the development of ONJ,85
`but the wide range of doses found to have been administered
`at the onset of ONJ suggests that this is unlikely. Recently,
`it has been proposed that soft tissue toxicity from BPs might
`be involved in the pathogenesis of ONJ.86 Moreover, the
`majority of cases of ONJ reported up until now have been
`described in patients taking BPs for bone metastases, in which
`higher doses are used.
`Consequently, it can be concluded that, nowadays, the
`role of BPs in the development of ONJ is still uncertain and
`a matter of debate, given that BPs are probably only one of
`many treatment-related factors. At the moment, there are
`some guidelines and general recommendations to prevent
`ONJ, but are not widely accepted.87,88 It seems useful to
`maintain adequate oral hygiene and use antibiotic prophy-
`laxis in the event of a dental procedure, but suspension of
`BP treatment would seem unhelpful, given the long duration
`of drug persistence in bone.
`
`Efficacy
`Alendronate, risedronate, ibandronate, and zoledronate
`are approved for the t