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Bisphosphonates and Cancer

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Bisphosphonates and Cancer
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   Review  J Vet Intern Med   2004;18:597–604 Bisphosphonates and Cancer Rowan J. Milner, James Farese, Carolyn J. Henry, Kim Selting, Timothy M. Fan, andLouis-Philippe de Lorimier Bisphosphonates form a family of drugs characterized pharmacologically by their ability to inhibit bone resorption and pharma-cokinetically by similar intestinal absorption, skeletal distribution, and renal elimination. Two groups of bisphosphonates existchemically, non–amino-bisphosphates and amino-bisphosphonates. The amino-bisphosphonates have greater antiresorptive capa-bilities and represent a newer generation of bisphosphonates. The primary mechanism of action of bisphosphonates is inhibitionof osteoclastic activity. Non–amino-bisphosphonates are incorporated into the energy pathways of the osteoclast, resulting indisrupted cellular energy metabolism leading to apoptosis. Amino-bisphosphonates exert their effect on osteoclasts via their inhi-bition of the mevalonate pathways, resulting in disruption of intracellular signaling and induction of apoptosis. Bisphosphonatesalso inhibit cancer cell proliferation, induce apoptosis in in vitro cultures, inhibit angiogenesis, inhibit matrix metalloproteinase,have effects on cytokine and growth factors, and are immunomodulatory. Clinical applications in oncology could include therapyfor hypercalcemia of malignancy, inhibition of bone metastasis, and therapy for bone pain. Although bisphosphonates are regardedas metabolically inert in the body, adverse effects do occur and include esophagitis, gastritis, suppression of bone repair, andallergic reactions. Little is published on the effects of bisphosphonates in dogs with cancer. Further research into the role of bisphosphonates in veterinary oncology is needed to identify clinical efficacy and safety of these potentially beneficial drugs. Key words:  Adverse effects; Alendronate; Etidronate; Hypercalcemia of malignancy; Multiple myeloma; Osteosarcoma; Pam-idronate; Zoledronate. B isphosphonates form a family of drugs characterizedpharmacologically by their ability to inhibit bone re-sorption, and pharmacokinetically by similar absorption,distribution and elimination. 1 The ability to inhibit bone re-sorption makes them useful drugs in the control of bonemetabolism. The development of bisphosphonates wasprompted by studies that showed that inorganic pyrophos-phate binds strongly with calcium phosphate, thereby in-hibiting crystal formation and dissolution in vitro. 2,3 How-ever, no in vivo effect occurred because of the hydrolysisof pyrophosphate before it reached the bone. 2,3 Bisphos-phonates were developed in an effort to circumvent thishydrolysis and are characterized by the presence of a gem-inal carbon (Fig 1). Bisphosphonates have been used forsome time in human medicine as therapeutic agents for os-teoporosis, bone pain associated with metastatic disease,Paget’s disease of bone, and hypercalcemia of malignancyand in diagnostic nuclear medicine and targeted radiother-apy. 1,4–6 Numerous reports exist on the experimental use of bisphosphates in dogs, primarily as a model of human bonedisease. 7–27 The reported use of bisphosphonates in veteri-nary oncology is limited to a single peer-reviewed publi-cation, 28 although a number of conference proceedings and From the Department of Small Animal Clinical Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL (Milner,Farese); the Department of Veterinary Medicine and Surgery, Collegeof Veterinary Medicine, University of Missouri–Columbia, Columbia, MO (Henry, Selting); and the Department of Veterinary Clinical Med-icine, Veterinary Teaching Hospital, University of Illinois at Urbana-Champaign, IL (Fan, de Lorimier). Reprint requests: Rowan J. Milner, BVSc (Hons), MMed Vet (Med), Dip. ECVIM, Department of Small Animal Clinical Sciences, Collegeof Veterinary Medicine, University of Florida, P.O. Box 100126,Gainesville, FL 32610-0126; e-mail: milnerr@mail.vetmed.ufl.edu.Submitted August 20, 2003; Revised January 9, February 17, 2004; Accepted March 9, 2004.Copyright     2004 by the American College of Veterinary Internal Medicine0891-6640/04/1805-0001/$3.00/0 continuing education articles also report their use. 29–31 These early reports indicate that bisphosphonate use in vet-erinary oncology may include treatment of primary andmetastatic bone cancers, therapy for hypercalcemia of ma-lignancy, and possible antimetastatic and antitumor ef-fects. 28–31 Based on these reports, the use of bisphospho-nates in veterinary medicine likely will increase. In light of this, we review the human and veterinary literature for re-ports of experimental and clinical use of bisphosphonatesin dogs, with emphasis on pharmacodynamics, pharmaco-kinetics, dosing schemes, adverse effects, efficacy, and an-ticancer effect. Bisphosphonate Chemistry Bisphosphonates have a structure similar to that of in-organic pyrophosphate, but with a carbon atom (geminal)substitution for the central oxygen atom (Fig 1). 32 Two ad-ditional covalent bonds (side chains) to the geminal carboncan be formed and are referred to as R 1  and R 2 . 33 The abilityof these side chains to bind carbon, oxygen, halogen, sulfur,or nitrogen atoms gives rise to numerous possibilities forthe development of unique molecules. 33 As with inorganicpyrophosphate, bisphosphonates form a 3-dimensionalstructure that is capable of binding divalent metal ions suchas Ca 2  , Mg 2  , and Fe 2  in a bi- or tridentate manner. Bind-ing occurs by coordination of oxygen from the phosphonategroup with the divalent cation. Affinity for Ca 2  can beincreased by manipulating the R 1  side chain, such as by theaddition of a hydroxyl group, which is common to mostbisphosphonates. The addition of a hydroxyl or primaryamine group on the R 2  side chain allows for the formationof a tridentate conformation with more effective binding tohydroxyapatite. 33 The aliphatic carbon chain (R 2 ) length appears to be animportant factor affecting the antiresorptive capability of bisphosphonates. 1 For example, alendronate has 100–1,000times greater antiresorptive capacity than does etidronate.Table 1 compares the relative in vivo potency of the most  598 Milner et al Fig 1.  The development of bisphosphonates from pyrophosphate bythe substitution of the central oxygen by a carbon (geminal) atom isshown. The 2 main classes of bisphosphonates are represented by alen-dronate (amino-bisphosphonates) and etidronate (non–amino-bisphos-phonates). The presence of a primary amine group on the R 2  side chainoffers significant improvement in therapeutic activity. Zoledronate isan example of a 3rd-generation amino-bisphosphonate with a tertiaryamine in a ring structure on the R 2  side chain. The addition of an OHgroup on the R 1  side chain enhances binding to hydroxyapatite. Table 1.  Antiresorptive potency of bisphosphonates. In vivo PotencyNon–amino-bisphosphonatesEtidronateClodronate1  10  Amino-bisphosphonatesPamidronateAlendronateRisedronateIbandronateZoledronate100  100–  1,000  1,000–  10,000  1,000–  10,000  10,000 common bisphosphonates. 34 Further manipulation of thisprimary R 2  chain amine to form a tertiary amine increasesits potency. 35 The most potent bisphosphonates to date ap-pear to be those that contain a tertiary amine in a ringstructure, for example, zoledronate, which has   10,000times the potency of etidronate. 35 Pharmacokinetics of Bisphosphonates Bisphosphonates are administered PO or IV. 1 Routes of administration in experimental animals include intraperito-neal and SC injection. 36 Absorption is complete from thesesites but tissue damage and pain at SC injection sites makethis route of administration undesirable.A number of important therapeutic bisphosphonates thatcan be given PO, such as alendronate, are poorly absorbedfrom the gastrointestinal tract for many reasons includingthe size of bisphosphonates (  0.150 kd), low lipophilicity,and ionization state (negatively charged). 1 These factorsprevent transcellular transport and significantly reduce in-tercellular transport from the gastrointestinal tract. Absorp-tion can be reduced further when bisphosphonates formcomplexes with calcium or other divalent cations. 1 Similar-ly, the presence of food in the stomach profoundly reducesabsorption for etidronate from an already low rate of 3–7%to 0%. 37 Oral absorption of bisphosphonates can be im-proved marginally (5–10%) by increasing the dose becauseabsorption is dose-dependent. 1,36 The increased absorptionis thought to be due to binding of the bisphosphonates withcations at the epithelial tight junctions in a dose-dependentmanner, this results in a widening of the tight junctionsallowing more drug to pass through. 1 After absorption into the blood stream, bisphosphonatescan bind to plasma proteins because of complete ionizationat physiologic pH (7.4). Factors that affect binding includedrug concentration, species variation, pH, and calcium con-centration. The concentration of protein-bound bisphospho-nate is lower in dogs and humans than in rats. A change inpH from 6.6 to 8.6 results in a corresponding increase inbinding from 50% to 98% for alendronate. Hypocalcemialeads to lower bisphosphonate binding to albumin, althoughparadoxically, hypercalcemia does not to lead to an increasein binding in experimental studies. It is also unclear wheth-er bisphosphonates bind directly to albumin or to calcium,which in turn binds to albumin. 1 After IV administration, bisphosphonates are rapidlycleared from the plasma with a half-life of 1–2 hours. Boneshows an increase in uptake over time (1 hour) consistentwith movement of bisphosphonates from noncalcified tissueto bone. 1 Any areas in the bone that are metabolically activesuch as trabecular bone, growing bone, areas of osteolysis,or bone repair will receive more blood and have a largeramount of exposed hydroxyapatite crystals, and will there-fore accumulate more bisphosphonate. 5 Importantly, withincreasing dose, the uptake of bisphosphonates in bone issaturable because of competitive binding of exposed hy-droxyapatite crystals. 1,38 However, if the dose is fractionatedand given over time, this effect seems to be attenuated. 1 Elimination from bone is prolonged with release occurringonly when the bone undergoes resorption. Accordingly, thehalf-life of bisphosphonates in bone depends upon the in-dividual’s rate of bone turnover. For example, the half-lifefor alendronate is estimated to be 300 days in dogs (adults)and 10 years in humans (adults). 23,39 Renal elimination of bisphosphonates is thought to occur through a concentra-tion-dependent saturable active transport mechanism. 1 Theprocess of excretion is not via the typical anion or cationrenal transport systems, because inhibitors (eg, probenecid)of these systems do not inhibit renal bisphosphonate excre-tion in rats. In addition, bisphosphonates competitively in-hibit renal excretion of each other.Dosing rates have been reported for dogs in experimentaland clinical oncology (Table 2). Many dosages are higherthan is clinically relevant but these data represent a startingpoint for canine clinical trials. Dosing frequencies are var-  599Bisphosphonates and Cancer Table 2.  Bisphosphonate dosages reported for dogs. Trade Name Route Dosage Range FrequencyNon–amino-bisphosphonatesEtidronate 7,8 Clodronate 11 DidronelBonefosSCPO0.5 mg/kg20–40 mg/kgDailyDailyAmino-bisphosphonatesPamidronate 12,13,31 Aredia IV 1.3 mg/kg in 150 ml of 0.9%saline, given over 2 hoursCan be repeated in 7daysAlendronate 17,22,28 Risedronate 25,26 ZoledronateFosamaxActonelZometaPOPOIV0.5–1 mg/kg0.5–1 mg/kgUndeterminedDailyUndeterminedUndetermined Fig 2.  Mevalonate pathway inhibition by amino-bisphosphonates viathe key regulatory enzyme farnesyl pyrophosphate synthase. Inhibitionof this pathway prevents the biosynthesis of isoprenoid compoundsthat are essential for the posttranslational farnesylation and geranyl-geranylation of small guanosine triphosphatases. Guanosine triphos-phatases are important signaling proteins that regulate cell processessuch as cell morphology, integrin signaling, membrane ruffling, traf-ficking of endosomes, and apoptosis. 33 iable depending on the bisphosphonate. Commonly, POpreparations are given daily, whereas IV formulations aregiven every 3 weeks. Recently, daily versus intermittent POdosing regimes have been debated in the human literature.Intermittent regimes may reduce the incidence of drug com-plications such as esophagitis and inhibition of microda-mage bone repair. 40–42 Cost versus benefit of dosing regimesalso is being debated in the human literature because of thechronic nature of the diseases being treated with bisphos-phonates and cost-benefit factors are likely to be significantin the use of bisphosphonates in veterinary oncology. 43 Pharmacodynamics of Bisphosphonates(Mechanism of Action) The primary effect of bisphosphonates is to inhibit boneresorption. 1 The osteoclast, the cell responsible for boneresorption, is the main target of bisphosphonates; it arisesfrom hematopoietic stem cells of monocytic-macrophagelineage. 44 Therefore, it is not surprising that cytokines thatstimulate hematopoietic tissue, such as interleukin (IL)-1,IL-3, IL-6, and IL-11, tumor necrosis factor, granulocyte-macrophage colony-simulating factor, macrophage colony-simulating factor, and c-kit ligand, also stimulate osteoclas-tic differentiation. Inhibiting cytokines include IL-4, IL-10,IL-18, and   -interferon (  -INF). Parathyroid hormone andvitamin D 3  are potent initiators of osteoclastogenesis. Cal-citonin inhibits osteoclast development and promotes oste-oclast apoptosis. Other hormones affecting bone include sexhormones, glucocorticoids, and thyroid hormone. 44–46 Glu-cocorticoids negatively affect bone mass via osteoblast in-hibition and osteoclast stimulation. Interestingly, glucocor-ticoids have been shown to inhibit bisphosphonate-inducedosteoclastic apoptosis. 46 Bisphosphonates are released fromhydroxyapatite during the osteoclastic-mediated resorptionprocess and are taken up by the osteoclast cell. This resultsin disruption of intracellular metabolism, which may leadto apoptosis. 33 Two distinct mechanisms of action are proposed depend-ing on the bisphosphonate group, whether amino-bisphos-phonates or non–amino-bisphosphonates. 33 Because somenon–amino-bisphosphonates (etidronate and clodronate) re-semble inorganic pyrophosphate, they are incorporated intononhydrolyzable analogues of adenosine triphosphate,thereby denying the osteoclast energy. It is likely that ac-cumulations of these analogues would inhibit osteoclastfunction and cause apoptosis. The more potent amino-bis-phosphonates (alendronate, pamidronate, risedronate, andzoledronate) are not metabolized but act as transition-stateanalogues of isoprenoid diphosphates, thereby inhibitingfarnesyldiphosphate synthase and perhaps additional en-zymes of the mevalonate pathway (Fig 2). 33 The process of apoptosis in osteoclasts can be recognizedby early morphological changes such as detachment frombone with the loss of ruffled borders, degradation of Golgiapparatus, fusion of nuclear envelope, appearance of ladderstructures, nuclear pyknosis associated with condensationand margination of chromatin, and formation of apoptoticbodies. 47 Interestingly, osteoclastic apoptosis is required forinhibition of bone resorption in non–amino-bisphospho-nates such as etidronate, but not in amino-bisphospho-nates. 48 Bisphosphonates also are postulated to exert an ef-fect because of the inhibition of IL-6 release from osteo-blasts. 1,33,49,50 Adverse Effects of Bisphosphonates Reports suggest that most bisphosphonates are relativelynontoxic because they are inert substances that do not un-  600 Milner et al dergo significant metabolism. 1,51 However, adverse effectshave been reported and include esophageal and gastroin-testinal tract irritation, bone and renal toxicity, electrolyteabnormalities, and acute-phase reactions. Oral bisphospho-nates can be irritating to the esophagus if the drug is al-lowed prolonged contact with the tissue either due to acidreflux or to retention of the tablet in the esophagus. 19,52,53 The resulting esophagitis is attributed to inhibition of ke-ratinocytes secondary to continuous bisphosphonate expo-sure and subsequent inhibition of tissue repair. 19,52 Addi-tional evidence for mucosal toxicity comes from experi-mentation with Caco-2 cells, which mimic mucosal surfaceswhen differentiated. 54 Bisphosphonates demonstrated in vi-tro cytotoxicity in these cell lines.As expected, bone, the target organ of bisphosphonates,can be adversely affected by high doses of these drugs. 51 One potential adverse effect is referred to as ‘‘frozenbone.’’ In this syndrome, bone remodeling and repair areinhibited to such an extent that the bone is weakened andfractures occur. 17,51 The syndrome has been reported in thedog and occurs more frequently when moderately high dos-es of non–amino-bisphosphonates such as etidronate areused. 7 Non–amino-bisphosphonates are implicated becauseof their narrow therapeutic index, which is the differencein dose between inhibition of bone resorption and inhibitionof normal bone repair and mineralization. 22 Newer amino-bisphosphonates are safer because they inhibit osteoclasticactivity at lower doses and have a wider antiresorption toantimineralization ratio. 22 Renal toxicity occurs with bisphosphonate use. 51,55–57 Factors that appear to affect renal toxicity include infusionrate and type of bisphosphonate. One report 51 indicated thata too rapid infusion of a bisphosphonate leads to acute renalfailure and this could be prevented by slowing the infusionrate to   200 mg/h. However, other clinical studies havenot demonstrated renal toxicity in humans receiving IV in-fusion of pamidronate. 57,58 No reports of renal toxicity havebeen found for dogs in the experimental or clinical litera-ture. 22 In experimental dogs poisoned with vitamin D 3  andtreated with pamidronate IV infusions for hypercalcemia,no renal toxicity was observed. 12,13 In a rat model, zoled-ronate was shown to be less nephrotoxic than pamidron-ate. 55 Although not reported as occurring in experimentaldogs, adverse effects (human) should be mentioned. Theseinclude inflammatory or acute-phase response, 51 variousophthalmic syndromes such as scleritis, 57 transient bonepain, 57 and hypocalcemia. 51 Bisphosphonates and Cancer In addition to their inhibitory effect on osteoclasts, whichwould be beneficial in controlling osteolysis and hypercal-cemia in the cancer patient, bisphosphonates also exert di-rect effects on cancer cells. These effects are thought to bedue to induction of apoptosis, 59,60 inhibition of angiogene-sis, 61–63 reduction of tumor cell adhesion to bone matrix, 63  - and   -T-cell stimulation, 63 and inhibition of matrix me-talloproteinases. 64,65 These effects have resulted in the clin-ical use and investigation of bisphosphonates in humans tocontrol hypercalcemia of malignancy, reduce pathologicfractures in metastatic bone disease, control bone pain, andpossibly prevent metastatic events. 66  Inhibition of Tumor Cell Proliferation and Induction of Apoptosis In Vitro Initial in vitro studies with human cancer cell lines(breast, myeloma, prostate, bone, and pancreas) have shownthat bisphosphonates exert cytostatic and pro-apoptotic ef-fects in a time- and dose-dependent manner. Concentrationsused are high but are similar to those found in bone afterIV administration. 66 Zoledronate, a new-generation amino-bisphosphonate, induces apoptosis in human breast cancercells. It is associated with mitochondrial cytochrome  c  re-lease into the cytosol and resultant activation of the caspase(caspase-3) cascade leading to apoptosis. This effect can beblocked by the forced expression of   BCL2. 60  BCL2  (tumorsuppressor genes) and other homologues are potent inhib-itors of apoptosis caused by cytotoxic insults. 60,67 These re-searchers also demonstrated a role for prenylation via themevalonate pathway leading to impaired  RAS   membranelocalization in apoptosis (Fig 2).  RAS,  a proto-oncogene,and its proteins play pivotal roles in the control of normaland transformed cell growth. 60 Numerous malignancies ex-press mutations of the  RAS   oncogene. 68 Some researchershave examined the effects of bisphosphonates on osteosar-coma cell lines. 28,49,69–74 Some indication exists that the ami-no-bisphosphonate pamidronate may be more effective thanclodronate in inhibiting cell growth in these cell lines. 69 Research also has shown that marked synergy exists whenbisphosphonates are combined with chemotherapy drugssuch as taxanes, doxorubicin, dexamethasone, and cyclo-oxygenase 2 inhibitors. 35,66  Inhibition of Angiogenesis Wood et al 62 reported that zoledronate had significant an-tiangiogenic properties in several different in vitro and invivo models. Angiogenesis stimulated by human basic fi-broblast growth factor was inhibited at lower dosages thanangiogenesis induced by human vascular endothelialgrowth factor (VEGF), on the order of a 33-fold differencein dosage. The mechanism by which this occurs is notknown. 62 In the clinical setting, Santini et al 63 treated 25patients having various solid tumors with a single dose of pamidronate and measured blood concentrations of VEGF,  -INF, IL-6, and IL-8 on days 1, 2, and 7. Pamidronatedepressed VEGF concentrations for the full 7 days. VEGFhas been shown to be an independent prognostic factor inseveral malignancies and is useful in predicting the re-sponse to treatment. IL-6 and   -INF concentrations wereincreased on day 1 but rapidly decreased 2 days after in-fusion. IL-6 is an acute-phase cytokine and could be re-sponsible for the some of the adverse effects of bisphos-phonate. 51 Pamidronate has been linked with a transient IL-6-mediated acute-phase reaction that is thought to be duethe production of IL-6 from macrophage monocytic cells.  -INF is a cytokine endowed with potent immunostimula-tory effects and is secreted by activated CD4 and CD8 T-cells. 63 In addition,   -INF inhibits osteoclast differentia-tion. 44  601Bisphosphonates and Cancer Fig 3.  Graphic summary of hypothesized bisphosphonate (BPS) ef-fect on osteosarcoma cells in bone showing the  (1)  direct effect onthe cancer cell via caspase-3 activation;  (2)  inhibition of osteoclastdifferentiating factor ligand (receptor activator of nuclear factor-   Bligand [RANKL],) mRNA allowing osteoprotegerin (OPG osteoclastinhibitory factor) to block RANK leading to decreased osteoclast pro-genitor cell differentiation to osteoclasts; and  (3)  direct osteoclast in-hibition via mevalonate pathway leading to apoptosis. 70,77  Inhibition of Matrix Metalloproteinase Bisphosphonates are now recognized as having anti–ma-trix metalloproteinase (MMP) effects. 64,65 Teronen et al 65 observed in vitro inhibition and down-regulation of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-12,and MMP-13 by various bisphosphonates. Also, severalbisphosphonates were shown to decrease the invasivenessof malignant melanoma and fibrosarcoma cell lines throughan artificial basement membrane. 65 More recently, Heikkilaet al 64 found that bisphosphonates can achieve therapeuticconcentrations in vivo to inhibit MMPs and they concludedthat bisphosphonates are broad-spectrum MMP inhibitorsand that this inhibition involves cation chelation. Impor-tantly, they also found that bisphosphonates have antime-tastatic, anti-invasive, and cell adhesion–promoting prop-erties, which may be helpful in preventing metastases notonly into hard tissues but also into soft tissues. 64 Converse-ly, in a large open-labeled clodronate trial, no effect wasseen on the rate of bone metastases; however, a deleteriousinfluence on nonbony metastases was found. 75 A possibleexplanation could be that clodronate is not an amino-bis-phosphonate and therefore it would lack the expected in-hibition of mevalonate pathway. Derenne et al 76 reportedthat although amino-bisphosphonates and more specificallyzoledronate are effective MMP inhibitors, the up-regulationof MMP-2 from bone marrow stromal cells by amino-bis-phosphonates is cause for concern. MMP-2 is involved inbone resorption and the metastatic process. 76 Possible com-bination of bisphosphonates with an MMP-2 inhibitor mayprevent up-regulation of the MMP. 35  Effects on Cytokines and Growth Factors Local growth of osteosarcoma involves destruction of bone by proteolytic mechanisms, host osteoclast activation,or both. 35,70 Osteoclast formation and activity are regulatedby osteoblast-derived factors such as the osteoclast differ-entiating factor, receptor activator of nuclear factor-   B li-gand (RANKL), and the inhibitor osteoprotegerin (OPG)(Fig 3). Mackie et al 70 reported that expression of mRNAfor osteopontin and RANKL was down-regulated by bothclodronate and pamidronate, whereas the expression of mRNA for alkaline phosphatase, pro-alpha1(l) collagen,and OPG was unchanged. Clinical Trials: Hypercalcemia of Malignancy Bisphosphonates are now currently the standard therapyfor cancer hypercalcemia in humans. The recommended IVdose is 90 mg pamidronate or 1,500 mg clodronate; theformer compound is more potent and has a longer-lastingeffect. 78 Pamidronate should be considered a viable optionin veterinary medicine because it has been used for treatinghypercalcemia due experimental cholecalciferol toxicity inthe dog. Although not hypercalcemia of malignancy, thedoses used would be a good starting point for clinical trials.Rumbeiha et al 12,13 showed that dosages of 1.3–2 mg/kg areneeded to control hypercalcemia in these cases. However,a lower dosage of 0.65 mg/kg was not effective in con-trolling the hypercalcemia. A recent peer-reviewed continu-ing education article on the diagnosis and treatment of hu-moral hypercalcemia discusses pamidronate as a therapeuticoption. 31 The authors reference Rumbeiha et al 12,13 as thesource of the recommended dosage of 1.3 mg/kg (see Table2 for more detail). Clinical Trials: Inhibition of Bone Metastasis and  Bone Pain Numerous articles exist indicating the benefits of thesedrugs in metastatic bone pain in humans. 79–83 Repeatedpamidronate infusions exert clinically relevant analgesic ef-fects in more than one half of patients. Regular pamidronateinfusions also can achieve a partial objective response ac-cording to conventional Union Internationale Contre leCancer criteria, and they can almost double the objectiveresponse rate to chemotherapy. Lifelong administration of PO clodronate to patients with breast cancer metastatic tobone reduces the frequency of morbid skeletal events bymore than one-fourth. Two double-blind randomized pla-cebo-controlled trials comparing monthly 90-mg pamidron-ate infusions to placebo infusions for 1–2 years in additionto hormone or chemotherapy in patients with at least 1 lyticbone metastasis have shown that the mean skeletal morbid-ity rate could be reduced by 30–40%. The results obtainedwith IV bisphosphonates are generally viewed as better thanthose obtained with PO clodronate. However, preferencecan be given to the PO route when bisphosphonates arestarted early in the process of metastatic bone disease in a
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