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`The
`-
`ncolog1st
`
`®
`
`This malarial is protected by U.S. Copyright law.
`
`Unauthorized reproduction is prohibited. For reprints contact: Reprintswlphauadi'resscom
`
`Safety of Intravenous and Oral Bisphosphonates
`and Compliance With Dosing Regimens
`
`PIERFRANCO CONTE, VALENTINA GUARNERI
`
`Department of Oncology and Hematology, University Hospital, Modena, Italy
`
`Key Words. Advanced cancer - Bone metasmses - Bisphoxphonales - Zoledronic acid
`
`
`
`LEARNING OBJECTIVES
`
`After completing this course. the reader will be able to:
`
`1. Describe the differences between oral and i.v. bisphosphonate therapy in terms of safety and side effects.
`
`2. Explain the renal effects of long-term i.v. bisphosphonate treatment.
`
`3. Discuss the importance of patient compliance in long-term disease management.
`
`-) Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit atW
`a:-' Elli]:
`
`
`ABSTRACT
`
`Patients with advanced cancers—particularly breat
`and prostate cancers —are at high risk for bone metasta-
`sis, leading to accelerated bone resorption and clinically
`significant skeletal morbidity. Bisphosphonates are
`effective inhibitors of bone resorption and reduce the
`risk of skeletal complications in patients with bone
`metastases. The standard routes of administration for
`
`bisphosphonates used in clinical practice are either oral
`or i.v. infusion. Oral administration of bisphosphonates
`is complicated by poor binavailability (generally 6%)
`and poor gastrointestinal tolerability. First-generation
`bisphosphonates, such as clodronate (Bonefos‘; Anthra
`Pharmaceuticals; Princeton, NJ), must be administered
`at high oral doses (l,600-3,200 mg/day) to achieve thera-
`peutic effects, which leads to poor tolerability and com-
`pliauce with oral dosing regimens.
`Infusion of
`bisphosphonates is associated with dose- and infusion-
`rate-dependent effects on renal function. In particular,
`high bisphosphonate doses (e.g., 1,500 mg clodronate)
`
`can cause severe renal toxicity unless infused slowly
`over many hours. In contrast, the newer, more potent
`bisphosphonates effectively inhibit bone resorption at
`micromolar concentrations, and the small doses
`required can be administered via relatively short i.v.
`infusions without adversely affecting renal function.
`Zoledronic acid (Zometa"‘; Novartis Pharmaceuticals
`Corp.; East Hanover, NJ) is a new generation bisphos-
`phonate, and the recommended dose of 4 mg can be
`safely infused over 15 minutes. The 90-mg dose of
`pamidronate (Aredia‘; Novartis Pharmaceuticals
`Corp.) and the 6-mg dose of ibandronate (Bondronata;
`Hoffmann-La Roche Inc.; Nutley, NJ) require 1- to 4-
`hour infusions. Intravenous bisphosphonates require
`less frequent dosing (once a month) and are generally
`well tolerated with long-term use in patients with bone
`metastases. Zoledronic acid has demonstrated the
`
`broadest clinical activity in patients with bone metas-
`tases. The Oncologist 2004;9(suppl 4).'28-37
`
`Correspondence: PierFranca Come, M.D., Department of Oncology and Hematology, University Hospital, via (12]
`Pozzo 71. 41100 Modena, Italy. Telephone: 39-059‘4224538t4224019 (secretary); Fax: 39-059-4224429; e-mail:
`conte .pierfranco@unimore .it
`Received July 19. 2004; accepted for publication August 3, 2004. ©AlphoMed Press
`1083-7159i2004/$12 .00/0
`
`
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`

`

`Conte, Guameri
`
`INTRODUCTION
`
`inhibitors of osteoclast-
`Bisphosphonates are potent
`mediated bone resorption and are effective in the treatment of
`malignant bone disease [1]. Intravenous bisphosphonates are
`the current standard of care for the treatment of hypercal-
`cemia of malignancy (HCM) and for the prevention of skele-
`tal complications associated with bone metastases. Currently,
`zoledronic acid (Zometa‘z; Novartis Pharmaceuticals Corp.;
`East Hanover, NJ) (4 mg via a 15-minute infusion) and
`pamidronate (Arediai'; Novartis Pharmaceuticals Corp.)
`(90 mg via a 2-hour infusion) are the only agents recom-
`mended by the American Society of Clinical Oncology
`(ASCO) for the treatment of bone lesions from breast cancer
`and multiple myeloma [2]. Furthermore, zoledronic acid is
`approved by both the US. Food and Drug Administration
`and the European Agency for the Evaluation of Medicinal
`Products for the prevention of skeletal complications in
`patients with multiple myeloma or bone metastases sec-
`ondary to a variety of solid tumors, including breast, prostate,
`and lung cancer [3].
`Bisphosphonates have undergone considerable evolu-
`tion since the early 19705, and the potency of these com—
`pounds has been steadily improved with each successive
`generation [4]. The first-generation bisphosphonates,
`etidronate (Didronelf‘; Procter and Gamble Pharmaceuticals,
`Inc.; Cincinnati, OH) and clodronate (Bonefos“; Anthra
`Pharmaceuticals; Princeton, ND—which lack a nitrogen
`
`atom—require relatively high molar concentrations to
`achieve clinical activity. Etidronate and clodronate also have
`low therapeutic ratios. Therefore, at the high doses required to
`effectively inhibit bone resorption, etidronate has the potential
`to adversely affect bone mineralization and may cause osteo-
`malacia [5]. The i.v. infusion of etidronate and clodronate has
`also been associated with acute renal failure [6]. Therapeutic
`doses of etidronate and clodronate must be infused slowly
`
`over many hours with careful monitoring of serum creatinine
`to ensure renal safety. The first nitrogen-containing bisphos-
`phonates, pamidronate and alendronate (Fosamax‘l; Merck
`and Company, Inc.; West Point, PA), were developed in the
`early 1980s and were found to be 10- to IOU-fold more potent
`inhibitors of bone resorption than etidronate and clodronate
`[7, 8]. Ibandronate (Bondronat'fi; Hoffmann-La Roche Inc.;
`Nutley, NJ) was subsequently developed and shown to be
`approximately 10-fold more potent
`than pamidronate.
`Zoledronic acid and risedronate (Actonel‘a‘; Proctor and
`Gamble Phannaceuticals, Inc.) are members of the newest
`
`generation of bisphosphonates that contain heterocyclic side
`chains. Zoledronic acid is unique in that it contains two nitro-
`gen atoms, and it has been shown to be 40- to 850-fold more
`potent than pamidronate in various preclinical models of
`osteoclast-mediated bone resorption [7].
`
`29
`
`The development of highly potent nitrogen-containing
`bisphosphonates improved the convenience of i.v. adminis-
`tration because it allowed infusion times to be dramatically
`
`shortened. Infusion of all bisphosphonates is associated with
`dose- and infusion-rate-dependent effects on renal function
`as evidenced by increases in serum creatinine [9, 10].
`Therefore, the more potent agents, which achieve therapeutic
`activity at micromolar concentrations, require lower doses
`and shorter infusion times. Zoledronic acid has the shortest
`
`approved infusion time of any bisphosphonate (15 minutes),
`compared with the 1-4 hours required for pamidronate and
`ibandronate. In addition, zoledronic acid (4 mg) is unique
`among other bisphosphonates because it effectively reduces
`the incidence and delays the onset of skeletal complications
`in patients with osteolytic, mixed, and osteoblastic bone
`lesions from a wide range of primary malignancies, includ-
`ing multiple myeloma, breast, prostate, and lung cancer, as
`well as a variety of other solid tumors {1 1-15].
`Bisphosphonates used to treat malignant bone disease are
`administered either orally or via an i.v. infusion. Each route
`has it advantages and disadvantages, and this review focuses
`on those issues. Although daily oral bisphosphonate therapy
`can be administered at home and may seem more convenient
`than i.v. administration for the patient, oral bisphosphonate
`therapy appears to be less effective and may not be any more
`convenient than monthly infusions [16-18]. Oral bisphospho-
`nates are less effective for the treatment of HCM (i.e., less
`
`rapid and sustained normalization of serum calcium) and
`appear to have limited activity in patients with bone metas-
`tases compared with i.v.
`therapy [16, 17]
`(reviewed by
`Coleman [19]). Furthermore, the oral administration of bis-
`
`phosphonates is limited by poor bioavailability (<5%) and
`gastrointestinal (GI) toxicities (primarily esophagitis and diar-
`rhea) [16, 18, 20]. Because of poor GI tolerability, compliance
`with oral bisphosphonate therapy is also an issue, and many
`patients require dose adjustments or discontinue therapy as a
`result, which can adversely affect efficacy. Therefore, in line
`with the updated ASCO guidelines on bisphosphonate ther-
`apy in breast cancer and multiple myeloma [2], as well as con-
`sensus guidelines and recommendations for bisphosphonate
`therapy in prostate cancer [21-23] and lung cancer [24], most
`physicians prefer i.v. bisphosphonates for the treatment of
`malignant bone disease, wherein strict compliance with the
`regimen is critical to achieve maximum therapeutic benefit.
`
`SAFETY PROFILE OF BISPHOSPHONATE THERAPY
`
`Both the i.v. and oral administration of bisphosphonates
`are associated with adverse events, but the safety profile
`varies somewhat depending on the route of administration.
`Intravenous administration is associated with mild-to—mod-
`
`crate flu-Iike symptoms following the initial
`
`infusions,
`
`
`
`“oz‘5z.raqwa/toNuorsanfi,(q[flm'ssaadpauraqd[a‘rsrfioloouoaqwduqtum;papeolumoq
`
`
`
`
`
`

`

`30
`
`whereas oral administration is associated with a significant
`incidence of GI adverse events. Oral administration is gen-
`erally not associated with adverse effects on renal function,
`whereas renal function can be affected by i.v. administra-
`tion. However, when bisphosphonates are administered at
`the recommended doses and infusion rates, the incidence of
`
`elevated serum creatinine is generally low (<10%), and
`severe renal adverse events are rare.
`
`Intravenous Bisphosphonates
`
`In general, the i.v. administration of bisphosphonates is
`well
`tolerated with a predictable and manageable side-
`effect profile that may include acute-phase responses, fluc-
`tuations in serum ion levels (calcium, magnesium, and
`phosphorus), and occasional elevations in serum creatinine
`[9, 10]. However, i.v. bisphosphonates are associated with
`a low incidence of serious adverse events. In addition, there
`
`are no known interactions between bisphosphonates and
`anticancer agents. Self-limiting, transient, acute-phase reac-
`tions resulting in mild to moderate flu-like symptoms have
`been reported in approximately one-third of patients—pri-
`marily after the first infusion [9]. These reactions occur
`with similar frequencies among patients treated with all i.v.
`bisphosphonates and are characterized by transient low-
`grade fever, fatigue, arthralgia or myalgia, nausea, and
`increased bone pain. In the comparative phase III trial of
`4 mg zoledronic acid versus 90 mg pamidronate in patients
`with breast cancer or multiple myeloma, the most common
`adverse events in both treatment groups were mild to mod-
`erate bone pain, nausea, fatigue, and fever, and these events
`
`Safety of Bisphosphonates and Patient Compliance
`
`and asthenia [25]. Intravenous bisphosphonates are also
`associated with a slightly higher incidence of mild anemia
`[13] and with serum electrolyte imbalances. The latter can
`be minimized with administration of vitamin D and calcium
`
`(500 mg/day) supplements [11, 13]. Ibandronate has also
`been associated with lymphocytosis [9].
`Recently, retrospective case studies have reported an
`association between long-term bisphosphonate therapy and
`osteonecrosis of the jaws [26-28]. The incidence of
`osteonecrosis was very rare, occurring in <1
`in
`10,000 patients receiving i.v. bisphosphonate therapy since
`2001. Historically, the risk of developing osteonecrosis (at
`any site) is four times higher in cancer patients than in the
`normal population and has multiple risk factors, including
`previous/concomitant chemotherapy, steroid therapy, or
`radiation therapy, as well as trauma, infection, and a history
`of dental procedures [29]. Therefore, it is recommended
`that physicians assess the dental status of patients before
`administration of bisphosphonate therapy, avoid invasive
`dental procedures in patients receiving bisphosphonate
`therapy, and monitor patients for good oral hygiene and the
`occurrence of jaw osteonecrosis. Importantly, a causal rela-
`tionship between bisphosphonate use and osteonecrosis has
`not been established, and it is unclear as to why this condi-
`tion develops preferentially in the jawbones. Furthermore,
`cases of osteonecrosis in patients receiving bisphospho-
`nates have only been observed since 2001, indicating that
`new concomitant anticancer therapies could be contributing
`to the development of the disease.
`
`occurred with similar frequencies in both treatment groups
`(Table l) [11, 12]. In a recent study of i.v. ibandronate (2 or
`6 mg) in patients with breast cancer, serious adverse events
`
`Renal Effects of i.v. Bisphosphonates
`All i.v. bisphosphonates are associated with dose- and
`infusion-rate-dependent effects on renal function [6, 9,
`
`related to the study drug included bone pain, lung edema,
`
`
`
`
`
`L[oz‘6Z.Iaquia/toNuolsanfi,(qfiro‘ssardpauqule'istfloloouoaqwzduqmoi;papnolumoq
`
`Table 1. Most frequently reported adverse events regardless of
`relationship to study drug
`
`30]. Therefore, bisphosphonates should always be infused
`at the recommended doses and schedules, and renal func-
`
`tion should be monitored. Doses of pamidronate higher
`than the recommended 90 mg have been associated with a
`higher risk of nephrotoxicity [31]. In addition, the infusion
`time for zoledronic acid was lengthened from 5 to 15 min-
`utes and the 8-mg dose was discontinued because of renal
`
`safety concerns [11, 13, 14]. Patients receiving long-term
`biSphosphonate therapy may experience a rise in serum cre-
`atinine. In general, however, clinically significant serum
`creatinine increases are rare among patients treated with i.v.
`bisphosphonates.
`The long-term safety of zoledronic acid was investi-
`gated in three large clinical
`trials involving more than
`3,000 cancer patients with multiple myeloma, breast can-
`cer, prostate cancer, and lung cancer or other solid tumors
`[12, 13, 32]. These trials used prospectively applied con-
`servative criteria to evaluate notable serum creatinine
`
`n of patients ('79)
`
`Zoledronic acid
`(4 mg) (n = 563)
`325 (58)
`
`Pamidronate
`(90 mg) (n = 556)
`316 (57)
`
`270 (48)
`241 (43)
`213 (38)
`187 (33)
`
`181 (32)
`153 (27)
`
`266 (48)
`240 (43)
`I72 (31)
`183 (33)
`
`175 (32)
`143 (26)
`
`Adverse event
`Bone pain
`
`Nausea
`Fatigue
`Fever
`Vomiting
`
`Anemia
`Myalgia
`
`Adapted with permission from Roren et a]. [12].
`
`

`

`Conte, Guameri
`
`31
`
`Ea
`
`E'5
`3i5
`5iII.
`
`Time (days':
`
`— Zolodronrc send 4 mg
`Pamidronam 90 mg
`
`272
`
`1 057
`
`pvalua
`0 839
`
`360
`
`Figure 1. Kaplan-Meier estimates oftime tofirst notable serum cre-
`atinine increase in patients with multiple myeloma or breast cancer
`with bone metastases receiving 4 mg zoledronic acid or 90 mg
`pamidronate and Andersen-Gill multiple event analysis of the risk
`ofelevated serum creatinine between treatment groups. *Afier start
`ofstudy drug.
`
`increases after bisphosphonate infusion (defined as an
`increase 20.5 mgr’dl for patients with normal baseline serum
`creatinine levels [<1.4 mgtdl], an increase 21.0 mgldl for
`patients with abnormal baseline serum creatinine levels, or
`22 times the baseline value). Importantly, changes in serum
`creatinine were defined according to baseline measure-
`ments. After 2 years of monthly infusions, overall renal
`safety was similar for patients with breast cancer and mul-
`tiple myeloma who were treated with either zoledronic acid
`or pamidronate [12]. More importantly, the renal safety
`profile of zoledronic acid was not significantly different
`than that of placebo in patients with prostate cancer or lung
`cancer and other solid tumors [13, 32].
`
`in patients with multiple
`In the comparative trial
`myeloma or breast cancer, Kaplan-Meier estimates of time
`to first notable serum creatinine increase (Fig. 1) demon-
`strated comparable risks for decreased renal function (risk
`ratio = 1.057; p = 0.839) for patients treated with zoledronic
`acid (4 mg via a 15vminute infusion) or pamidronate (90 mg
`via a 2-hour infusion) [12]. Furthermore, among patients with
`breast cancer receiving 4 mg zoledronic acid via a 15-minute
`infusion (n = 181), there were no National Cancer Institute
`
`Common Toxicity Criteria (CTC) grade 3 or 4 serum creati-
`nine increases, and the percentage of patients receiving zole-
`dronic acid who experienced a notable serum creatinine
`increase was similar to that of pamidronate (9.4% versus
`6.5% for pamidronate) (Table 2) [33]. The long-tenn safety of
`zoledronic acid and pamidronate has also been demonstrated
`beyond 2 years of therapy. A subset analysis in 22 patients
`with multiple myeloma or breast cancer who received i.v.
`zoledronic acid or pamidronate therapy for a median of
`3.6 years (range 2.2-6 years) showed no clinically relevant
`changes in complete blood cell count, platelet count, calcium
`analysis, electrolyte analysis, or kidney function tests, thus
`demonstrating that prolonged bisphosphonate therapy is well
`tolerated [34]. The renal safety of long-term zoledronic acid
`was confirmed by a recent analysis performed at our institu-
`tion; 53 patients with breast cancer (44), multiple myeloma
`(7), or other tumor types (2) were treated with i.v. bisphos-
`phonates for a median of 30 months (range 24+ to
`124+ months), with CTC grade 1 renal toxicity observed in
`7.5% of patients.
`Recently, the renal safety profile of i.v. ibandronate
`(6 mg via a 1- to 2-hour infusion every 3-4 weeks) in
`patients with breast cancer was reported, and it was similar
`to that of zoledronic acid in the breast cancer subset [25,
`
`35]. In a post-hoc analysis using the same criteria defined
`in the zoledronic acid trials, 6% of patients receiving either
`ibandronate or placebo experienced a notable increase in
`serum creatinine after 2 years of therapy (Table 2) [35]. The
`incidences of clinically significant renal adverse events
`
`
`
`“oz‘62.raquraAONuorsanfiliqfiso‘ssasdpauqule'rsifloloouoaqw2d11qmos;paprzolumog
`
`Table 2. Percentage of breast cancer patients with notable serum
`creatinine increases' after 2 years of i.v. bisphosphonate therapy
`n of
`Patients with
`patients
`an increase (%)
`
`Treatment
`Zoledronic acid [33]
`{4 mg over 15 minutes}
`Pamidronate
`
`181
`
`9.4
`
`levels >1.4 mg1d1,or any increase 22 times the baseline value.
`
`6.5
`
`184
`
`(90 mg over 2 hours)
`Ibandronate [35]
`6
`152
`(6 mg over 1 hour)
`
`
`158Placebo 6
`'Notable serum creatinine increase defined as an increase of 20.5
`mg/dl for patients with baseline serum creatinine levels 51 .4 mgldl,
`an increase of 21 .0 mydl for patients with baseline serum creatinine
`
`were also similar between the ibandronate and placebo
`
`groups (4.5% for ibandronate versus 4.0% for placebo), and
`none of these were considered serious adverse events [36].
`
`the percentage of patients experiencing a
`However,
`decrease in creatinine clearance was twofold higher in the
`ibandronate group (2.6% versus 1.3% for placebo).
`Zoledronic acid (4 mg via a 15-minute infusion) has
`also demonstrated a favorable renal safety profile when
`compared with placebo in two long-term, randomized trials
`[13, 32, 37]. In a study of 643 men with advanced prostate
`cancer, Kaplan-Meier estimates of time to first notable
`serum creatinine increase (Fig. 2) demonstrated comparable
`risks of elevated serum creatinine for patients treated with
`zoledronic acid and those given placebo for 24 months (risk
`ratio = 1.137; p = 0.752) [37]. Similarly, in a study in patients
`with lung cancer or other solid tumors, the incidences of
`serum creatinine increases in patients with non-small cell
`lung cancer were similar in the zoledronic acid and placebo
`groups after 21 months of treatment (1) = 0.920) [38]. Only
`
`

`

`Safety of Bisphosphonates and Patient Compliance
`
`oral dose is typically absorbed) and can cause esophagitis
`and other GI adverse events [41]. Because of their low
`
`bioavailability, high oral doses may be required. This is
`particularly problematic for clodronate, which is one of the
`
`least potent bisphosphonates available. Consequently,
`patients must swallow several large tablets or capsules. In
`addition, oral bisphosphonates must be administered on an
`empty stomach to improve bioavailability. The typical daily
`dosing regimen specifies that the tablets be taken on an
`empty stomach with 6-8 ounces of water, and patients must
`fast and remain upright for at least 30 minutes to avoid epi-
`gastric pain. If not taken properly, oral bisphosphonates can
`cause a high incidence of GI adverse events, including
`esophagitis, mucositis, nausea, vomiting, and diarrhea, and
`may exacerbate the side effects of anticancer therapy.
`Evidence of GI toxicity associated with oral bisphos-
`phonate therapy is available from studies of clodronate and
`ibandronate in cancer patients and in postmenopausal
`women with osteoporosis. In a long-term trial of oral clo-
`dronate (1,600 mg/day for 2 years) in patients with breast
`cancer, GI adverse events were significantly more common
`for patients receiving oral clodronate than for those receiv-
`ing placebo (Table 3) [42, 43]. Although the overall inci-
`dences of adverse events were similar in the two treatment
`
`groups, the incidence of GI adverse events was signifi-
`cantly higher among patients treated with clodronate (57%
`versus 45% for placebo; p < 0.05). The incidence of upper
`GI adverse events was only slightly higher in the clodronate
`group (22% for clodronate versus 19% for placebo) [43], but
`diarrhea was significantly more common in the clodronate
`group, particularly during the treatment period (15% versus
`7%; p < 0.05). In a pooled analysis of two recent trials of oral
`ibandronate in breast cancer patients with bone metastases,
`
`
`
`“oz‘62.laqwaAONuo1san3Kq[310'ssaJdpauqu|n'rsifioloouoaqmfluqmoi;popnolumoq
`
`Table 3. Most common gastrointestinal adverse events associated
`with oral clodronate therapy
`
`Placebo
`(n = 541)
`245 (45.3)
`104 (19.3)
`
`37 (6.8)
`126 (23.3)
`49 (9.1)
`
`53 (9.8)
`27 (5.0)
`
`Modified with permission from Atulu et al. [42].
`
`in of patients (%)
`
`Adverse
`event
`GI system disorders'
`Upper GI [43]
`
`Clodronate
`(1,600 mglday) (n = 538)
`307 (57.1)
`120 {22.3)
`
`Diarrhea*
`Nausea
`Dyspepsia
`
`Vomiting
`Abdominal pain
`
`81 (15.1)
`120 (22.3)
`56 (10.4)
`
`60 (11.2)
`39 (7.2)
`
`'Statistically significant difference between groups (p < 0.05).
`
`32
`
`E3fl
`
`2§ 3E2gE
`
`
`
`— Zolodmnlc acid 4 mg
`-
`Placebo
`
`R-sk ratio
`
`Figure 2. KapIan-Meier estimates oftime lofirst notable serum cre-
`atinine increase in patients with prostate cancer and bone metas-
`tases receiving 4 mg zoledronic acid or placebo and Andersen-Gill
`multiple event analysis of the risk of elevated serum creatinine
`between treatment groups. *After start ofstudy drug.
`
`one patient in each treatment group had a grade 3 serum
`creatinine increase, and no patient experienced a grade 4
`increase.
`
`Because of the potential for decreased renal function,
`guidelines for the long-term use of iv. bisphosphonates in
`patients with malignant bone disease recommend that serum
`creatinine levels be monitored before each infusion [2]. In
`
`addition, the prescribing information for pamidronate, zole-
`dronic acid, and ibandronate recommends monitoring serum
`creatinine or creatinine clearance [10, 39, 40]. If a patient
`receiving zoledronic acid or pamidronate has a notable serum
`creatinine increase, as defined in the zoledronic acid trials,
`infusion of the next dose should be withheld until semm cre-
`
`atinine returns to within 10% of baseline. Moreover, zole-
`
`dronic acid and pamidronate are not recommended for
`patients with baseline serum creatinine levels >3.0 mg/dl
`unless the clinical benefit outweighs the risk [10, 39]. Infusion
`of ibandronate at a lower dose (2 mg) is recommended for
`patients with creatinine clearance <30 ml/minute; however,
`there is no evidence that this dose has clinical activity [25,
`40]. In general, the use of i.v. bisphosphonates in patients
`with significantly impaired renal function is not recom-
`mended. Othenvise, i.v. bisphosphonates may be used in
`patients at risk for decreased renal function as long as serum
`creatinine is closely monitored. In particular, patients with
`multiple myeloma are at increased risk of renal failure
`because of the name of their disease and use of nephrotoxic
`chemotherapy. Increasing the infusion time and addition
`of hydration therapy may be appropriate in some clinical
`situations to reduce the risk.
`
`Oral Bisphosphonates
`
`Oral bisphosphonates, including clodronate and iban-
`dronate, are used for the treatment of bone metastases in
`
`patients with advanced breast cancer. However, bisphos-
`phonates are poorly absorbed in the GI tract (<5% of the
`
`

`

`Conte, Guameri
`
`patients receiving ibandronate (50 mg/day) were twice as
`likely to experience treatment-related GI adverse events,
`including abdominal pain, dyspepsia, nausea, and esophagitis,
`than those receiving placebo (Table 4) [44]. A randomized
`trial of oral ibandronate in 240 postmenopausal women with
`osteoporosis also demonsuated that diarrhea was more com-
`mon in patients receiving ibandronate than in those receiving
`placebo (10% and 11% for two different schedules of iban-
`dronate versus 1% for placebo) [45,46]. In addition, a higher
`percentage of patients in the daily ibandronate group experi-
`enced constipation than in the placebo group (6% versus 0%).
`
`COMPLIANCE WITH ORAL BISPHOSPHONATE
`THERAPY
`
`A major issue with the use of oral bisphosphonate therapy
`is patient compliance with the dosing regimen. Compliance
`with oral medication is influenced by a variety of factors,
`including age, disease type and duration, lifestyle, treatment
`regimen, and tolerability [47, 48]. In addition, compliance
`rates reported from well—controlled clinical trials might be
`higher than those observed in “real-world” situations. Oral
`medications that elicit GI or other side effects that signifi-
`
`cantly affect quality of life are less likely to be taken than
`treatment regimens without major side effects. In addition,
`when the adverse events associated with an oral therapy can
`
`be directly attributed to the drug—for example, if adverse
`events occur in close temporal proximity to dosing—patients
`are less likely to comply. Oral bisphosphonate therapy has
`been associated with a fairly high rate of noncompliance and
`early study withdrawal because of its complicated treatment
`regimen and high rate of GI adverse events [40, 49-52].
`The global rate of noncompliance with long-term oral
`bisphosphonate therapy for osteoporosis has been reported
`as >50% [53]. However, there are limited data on the rate of
`noncompliance with oral bisphosphonate therapy among
`patients with bone metastases from advanced cancer, which
`also involves chronic dosing. The only available data
`
`regarding compliance with oral bisphosphonate therapy in
`patients with bone metastases are from clinical trials of oral
`
`33
`
`Table 4. Most common treatment-related gastrointestinal adverse
`events associated with oral ibandronate therapy
`
`Adverse
`event
`
`61 system disorder
`Abdominal pain
`
`Dyspepsia
`Nausea
`
`n of patients (%)
`
`Ibandronate
`(50 mg/day) (n = 287)
`
`42 (14.6)
`6 (2.1)
`
`20 (7.0}
`10 (35)
`
`Placebo
`(n = 277)
`
`2| (7.6)
`2 (0.7)
`
`13 (4.7)
`4 (1.4)
`
`
`
`6 (2.11Esophagitis 2 (0.7)
`
`
`
`
`
`Data from Body er a]. [44].
`
`clodronate conducted in Europe. Because clodronate has a
`low potency and thus requires high doses to achieve thera-
`peutic concentrations,
`treatment with oral clodronate
`(1,600 mglday) is further complicated by the large tablets
`that are difficult for many patients to swallow. Although
`there are no studies that were specifically designed to eval-
`uate compliance, several studies have reported data on com-
`pliance. In a clinical trial of oral clodronate in breast cancer
`patients with bone metastases (n = 173), compliance was
`evaluated in 78% of patients in the clodronate group who
`survived longer than 6 months. Of these, 74% were partially
`or frilly compliant (i .e., self-administered the study medica-
`tion during part or all of the study, respectively) and 26%
`were completely noncompliant with the oral regimen [49].
`In addition, 16% of patients receiving clodronate and 18%
`of patients receiving placebo reported difficulty swallowing
`the capsules. In another study of oral clodronate in patients
`with metastatic bone pain (n = 55), overall compliance was
`reported as >90%, but a number of patients withdrew pre-
`maturely because of difficulty swallowing the capsules [50].
`Another way to assess noncompliance is to examine the
`reasons for study termination and the extent to which his-
`phosphonate-related adverse events contribute to early with-
`drawal (Table 5). In the study cited above in 173 patients
`with breast cancer, 34% of patients in the clodronate group
`
`
`
`
`
`L[oz‘62.iaquiaAoNuolsanfiAqfire'ssaadpaumqdle'zsgfioloouoamy:duuLLIOJ}papeolumoa
`
`Table 5. Summary of oral bisphosphonate studies and most common reasons for early study withdrawal
`
`Abbreviation: NR = not reported.
`
`Study
`Paterson et al. [49]
`Robertson er a]. [50]
`
`:1
`173
`55
`
`Study drug (n)
`Clodronate (85}
`Clodronate (27)
`
`Kristensen er al. [51]
`
`100
`
`Patients discontinuing
`study drug (%)
`34
`37
`35
`
`Most common reasons for
`discontinuing study drug
`Early noncompliance (22%)
`Difficulty swaliowing capsules (11%)
`GI adverse events (14%)
`
`Clodronate (49)
`GI adverse events (1 1%)
`NR
`Clodronate (538}
`1,079
`Atula et al. [42]
`
`NR G1 adverse events (8%)
`Ibandronate (77}
`110
`Coleman er al. [52]
`
`

`

`34
`
`discontinued the study drug, including 22% of patients who
`withdrew because of early noncompliance (i.e., <6 weeks)
`[49]. A recent randomized trial of oral clodronate in the
`
`adjuvant setting for the prevention of bone metastasis in
`patients with breast cancer demonstrated higher incidences
`of GI adverse events and early study discontinuation due to
`adverse events in the clodronate group than in the placebo
`group [42]. In that large, multicenter trial, 1,079 patients
`were randomized to receive either oral clodronate (1,600
`mg/day) or placebo for 2 years. GI adverse events resulted
`in early study withdrawal for 6.3% of patients in the clo-
`dronate group and for 3.9% of patients in the placebo group.
`Two additional studies have also reported high rates of study
`discontinuation among breast cancer patients receiving oral
`clodronate for the treatment of bone metastases [50, 51]. In
`
`one study involving 100 patients, 35% of patients discontin-
`ued the study drug, and 14% of patients treated with clo-
`dronate discontinued treatment because of GI adverse events
`
`(primarily nausea and diarrhea) [51]. In a study involving
`55 patients, 37% of patients receiving oral clodronate with-
`drew from the study, and difficulty swallowing the capsules
`was reported to contribute to study withdrawal in 11% of
`patients [50]. These studies suggest that as many as one-
`third of patients may not receive the full benefit of oral clo-
`dronate
`either
`because
`of
`early withdrawal
`or
`noncompliance.
`A high rate of early study withdrawal due to GI adverse
`events was also reported in a study of oral ibandronate in
`patients with metastatic bone disease [52]. That study
`involved 110 patients with bone metastases secondary to a
`variety of cancers, who received either oral ibandronate at
`doses ranging from 5-50 mg/day or placebo; 8% of patients
`discontinued within 1 month because of GI intolerability.
`During the first month of treatment, a dose-dependent inci-
`dence of GI adverse events was reported; 50% of patients
`treated with the 50-mg ibandronate dose experienced GI
`toxicity compared with 30% of patients in the placebo
`group. Notably, one patient treated with the 20-mg iban-
`dronate dose developed radiographically confirmed
`esophageal ulceration. Similarly, in a pooled analysis of
`two recent trials of oral ibandronate (50 mg/day for up to
`96 weeks) in breast cancer patients with bone metastases
`(n = 564), 10% of patients receiving ibandronate withdrew
`from the study because of adverse events [44].
`Noncompliance can also adversely affect treatment out-
`come. If the dosing regimen for oral bisphosphonates is not
`