Osteoporosis medications and renal failure

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  • Joint Bone Spine 78 (2011) 228229

    Editorial

    Osteop

    Keywords:OsteoporosisRenal failureOsteoporosis t

    All currecated in patcontraindicand safety oIn phase IIIterion. Thisage of patierenal functiwith bone daddressed hety of boneadynamic o

    The typewhen discuis largest forenal failurpamidronatmyeloma [used medicrenal failurphonates (aprecautionstinine clearis consideredronate andbelow thespatients, mstudy [2] omethod [3]risedronatefailure (CrCl < 30mL/min). In this subgroup with severe renal fail-ure, the adverse event rate was not signicantly different betweenthe risedronate-treated and the placebo-treated patients. Renalfunction remained unchanged throughout the study period in bothtreatment groups. Finally, the fracture rate decline seen with rise-dronate wamild, modeobtained foa Cockcrofteral density

    enalfrac

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    oft-Gto 60urpriteriouncteporrepoistedk facnt uamm

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    mula604pinedonitois in

    hat aong onalys7316aloxr BMCl d

    diminishing the fracture risk [7].Denosumab is a human monoclonal antibody to the RANK lig-

    and thatwas licensed for use in osteoporosis in Europe inMay2010.However, denosumab is not yet available in France. Given itsmech-anism of action, this new drug can be used in patients with renal

    1297-319X/$ doi:10.1016/j.s not signicantly different across the groups withrate, and severe renal failure [2]. Similar ndings werer alendronate in a study that dened renal failure as-Gault CrCl inferior to 45mL/min [4]. The bone min-(BMD) increase at the hip was greater in the patients

    failure of any severity [8].Among anabolic agents, teriparatide was assessed in patients

    with osteoporosis and renal dysfunction, based on Fracture Preven-tion Trial data [9]. Renal dysfunction was dened as a glomerularltration rate superior or equal to 80mL/min, probably because

    see front matter 2010 Socit francaise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.jbspin.2010.11.014orosis medications and renal failure

    reatment

    ntly available osteoporosis medications are contraindi-ients with severe renal failure. The main reason for thisation is that very few data are available on the efcacyf osteoporosis medications in this patient population.clinical trials, severe renal failure was an exclusion cri-issue is very relevant clinically, given the increasingnts receiving osteoporosis treatment and the gradualon decline with advancing age. End-stage renal failureemineralization is a different problem that will not beere. End-stage renal failure is associated with a vari-diseases related to very different mechanisms, such assteopathy and autonomous hyperparathyroidism.ofosteoporosismedicationsmustbe taken intoaccountssing the impact of renal failure. The amount of datar bisphosphonates, for several reasons. Cases of acutee have been reported in patients given high-dosee or zoledronic acid for metastatic bone disease or1]. In addition, bisphosphonates are the most widelyations for osteoporosis. In the prescribing information,e is listed as a contraindication for some bisphos-lendronate and risedronate) and as requiring specialfor others (ibandronate and zoledronic acid). The crea-

    ance (CrCl) cutoff below which bisphosphonate therapyd inadvisable is 30mL/min for risedronate and iban-35mL/min for alendronate and zoledronic acid. Valuese cutoffs are commonly found among osteoporosisost notably those who are elderly. In a retrospectivef CrCl values computed using the Cockcroft and Gaultin patients included in the phase III efcacy trials ofin osteoporosis, about 7% of patients had severe renal

    with rfor the[5], sercommOveralthree-the twsignicporoticnor theCockcrequalseem ssion crrenal fwere rThesetions lhad riscomitaantiinvasculprior ocases othe cuis 777,determninemcautiondrugs t

    Amof an ain thegiven rgreateline Crfailure, although no signicant difference was foundture risk [4]. In the HORIZON trial of zoledronic acidcreatinine elevation by more than 0.5mg/dL was more

    the active drug group than in the placebo group.wever, changes in the Cockcroft-Gault CrCl over thestudy period were not signicantly different betweenups, andneitherwas the incidenceof severe renal failurey different at the end of each study year. Among osteo-men given zoledronic acid, neither the BMD changesture risk differed signicantly between the groups withault CrCl values inferior to 60mL/min or superior ormL/min [6]. The choice of this high CrCl cutoff may

    ising; however, CrCl inferior to 30mL/minwas an exclu-n for the HORIZON trial [6]. Recently, several cases of

    ion deterioration after treatment with zoledronic acidted spontaneously (18 cases per 100,000patient-years).rts prompted changes in the warnings and precau-in the prescribing information. Most of the patientstors for renal dysfunction, such as advanced age, con-se of diuretics or nephrotoxic drugs (e.g., nonsteroidalatorydrugs), and/orpreexisting comorbidities (cardio-ease, metabolic disease, prior renal dysfunction, and/orncomitant dehydration). In addition, the number ofnal function deterioration should be weighed againsttive number of zoledronic acid-treated patients, whichatients/treatment/year worldwide. The CrCl should bebefore each zoledronic acid infusion, and serum creati-ring should be considered in high-risk patients. Finally,order when using zoledronic acid in combination withre known to induce renal dysfunction.ther antiresorptive drugs, raloxifene has been the focusis similar to that done on risedronate and alendronate,patients included in the MORE trial [7]. In the group

    ifene, lower baseline CrCl values were associated withD gains at the femoral neck but not at other sites. Base-id not signicantly affect the efcacy of raloxifene in

  • Editorial / Joint Bone Spine 78 (2011) 228229 229

    of the small sample size compared to other studies. The ndingswere in line with those obtained in comparable studies. Nei-ther the efcacy nor the safety of teriparatide was signicantlyaffected by baseline renal function. Very few data are availableabout renal dysfunction and strontium ranelate. Drug dispositionis through the kidneys for half of the dose. No dosage adjustmentis required in patients with mild-to-moderate renal dysfunction(CrCl, 30 to70mL/min).Nostudies inpatientswith severe renal fail-ure (CrCl < 30mL/min) are available, and strontium ranelate shouldnot be used in this situation [10].

    Thus, although all the currently available osteoporosis medica-tions are contraindicated in patients with severe renal failure, thepublisheddata in this population are reassuring. Caution is in order,however, given the limited value of the Cockcroft-Gaultmethod forrenal function evaluation, most notably in elderly patients. At theslightest doubt, and routinely before the initiation of zoledronicacid therapy, CrCl should be measured using the standard tech-nique. In the very near future, the introduction of denosumab canbe expected to facilitate the treatment of osteoporosis in patientswith renal failure.

    Conict of interest statement

    Bernard Cortet has made timely intervention for laboratories(or companies) following: Amgen, Lilly, Medtronic, MSD, Novartis,Servier.

    References

    [1] Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int2008;74:138593.

    [2] Miller PD, Roux C, Boonen S, et al. Safety and efcacy of oral risedronatein patients with reduced renal function as assessed by the Cockcroft-Gault method: a pooled analysis from 9 clinical trials. J Bone Miner Res2005;20:210515.

    [3] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum crea-tinine. Nephron 1976;16:3141.

    [4] Jamal SA, BauerDC, EnsrudKE, et al. Alendronate treatment inwomenwithnor-mal to severely impaired renal function: an analysis of the fracture interventiontrial. J Bone Miner Res 2007;22:5038.

    [5] Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acidfor treatment of postmenopausal osteoporosis. N Engl J Med 2007;358:180922.

    [6] Boonen S, Black, Sellmeyer D, et al. The skeletal response to zoledronicacid is not affected by mild to moderate renal impairment. Calcif Tissue Int2008;82:S214.

    [7] Ishani A, Blackwell T, Jamal SA, et al. The effect of raloxifene treat-ment in postmenopausal women with CKD. J Am Soc Nephrol 2008;19:14308.

    [8] Cummings SR, San Martin J, McClung MR, et al. Denosumab for preven-tion of fractures in postmenopausal women with osteoporosis. N Engl J Med2009;361:75665.

    [9] Miller PD, Schwartz EN, Chen P, et al. Teriparatide in postmenopausal womenwith osteoporosis and mild or moderate renal impairment. Osteoporos Int2007;18:5968.

    [10] Deeks ED, Dhillon S. Strontium ranelate: a review of its use inthe treatment of postmenopausal osteoporosis. Drugs 2010;70:73359.

    Bernard Corteta,,b,ca Universit Lille Nord de France, rue du Pr

    Emile-Laine, 59000 Lille, Franceb UDSL, EA 4490, 59000 Lille, France

    c Service de rhumatologie, CHU de Lille, 59000 Lille,France

    Corresponding author.E-mail address: bernard.cortet@chru-lille.fr

    5 November 2010

    Available online 8 January 2011