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Bisphosphonates in patients with autoimmune rheumatic diseases: Can they be used in women of childbearing age?

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Bisphosphonates in patients with autoimmune rheumatic diseases: Can they be used in women of childbearing age?
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  Review Bisphosphonates in patients with autoimmune rheumatic diseases:Can they be used in women of childbearing age? Inès Losada a , Leonardo Sartori b , Elena Di Gianantonio c , Margherita Zen d ,Maurizio Clementi c , Andrea Doria d, ⁎ a Servicio de Medicina Interna, Hospital Son Llatzer, Mallorca Spain b Clinica Medica I, Department of Medical and Surgical Sciences, University of Padova Italy c Clinical and Epidemiological Genetics, Department of Pediatrics, University of Padova Italy d Division of Rheumatology, Department of Clinical and Experimental Medicine, University of Padova Italy a b s t r a c ta r t i c l e i n f o  Article history: Received 1 March 2010Accepted 15 March 2010Available online 20 March 2010 Keywords: AutoimmunityBisphosphonatesCorticosteroidsFoetusOsteoporosisPregnancy Autoimmune rheumatic diseases (ARD) are prevalent in women during their childbearing age. For theirtreatment, high doses of corticosteroid (CS) for long-term periods are often required, increasing the risk of bone loss. According to recent guidelines, bisphosphonates (BP) should be used as  fi rst line treatment toprevent CS induced osteoporosis. However, due to their long-term release from bone and their ability tocross the placenta, it has been suggested to avoid BP in women during their fertile years.BP seem to decrease foetus bone length in pregnant animals, but not in humans, at least, when they areadministered at therapeutic dosage.BP are embryo toxic in animals when used at high dosage. In a systematic literature review, we found 58women treated with BP close before or during pregnancy, showing no related congenital malformations.However, the Unit of Clinical and Epidemiological Genetics in University of Padova collected ten cases of women treated with BP during pregnancy, reporting 20% of congenital malformations. Thus, we suggest toavoid BP during pregnancy and caution with their use in fertile women. When they have to be given beforepregnancy, speci fi c af  fi nities of the BP have to be considered to plan the washout period beforehand.© 2010 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5482. Use of BP in patients with ARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5482.1. CS induced osteoporosis (OP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5482.2. Avascular necrosis (AVN) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5482.3. Calcinosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5482.4. Other potential indications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5483. Adverse effects of BP IN patients with ARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5494. BP pharmacokinetics, pharmacodistribution, and transplacental passage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5495. Potential effects of BP on pregnancy and lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5495.1. Effects on embryogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5495.2. Effects on bone growth . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5515.3. Effects on breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5516. The timing of stopping BP before pregnancy. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5517. The experience of the unit of clinical and epidemiological genetics of the University of Padova (CEPIG) . . . . . . . . . . . . . . . . . . . 5518. Conclusion. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551.Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 551 Autoimmunity Reviews 9 (2010) 547 – 552 ⁎  Corresponding author. Division of Rheumatology, University of Padova, Via Giustiniani, 2, 35128 Padova, Italy. Tel.: +39 049 8212190, fax: +39 049 8212191. E-mail address:  adoria@unipd.it (A. Doria).1568-9972/$  –  see front matter © 2010 Elsevier B.V. All rights reserved.doi:10.1016/j.autrev.2010.03.002 Contents lists available at ScienceDirect Autoimmunity Reviews  journal homepage: www.elsevier.com/locate/autrev  1. Introduction Biphosphonates (BP) are synthetic, non-hydrolysable pyrophos-phate analogues with a high af  fi nity for bone. They bind to calciumcrystals,inhibitingtheirformationanddissolution.Atcelllevel,BPareinternalized by osteoclasts and interfere with speci fi c biochemicalprocesses impairing cell activity and inducing apoptosis [1]. BPdecrease skeletal turnover, increase bone mineral density (BMD)and improve structural and material properties of bone, therebyreducing the risk of fracture [1].BP are widely used in the treatment of osteoporosis (OP), Pagetdisease, hypercalcemia due to malignancy, osteolytic lesions of multiple myeloma, bone metastasis from solid tumours and myositisossi fi cans following total hip replacement or spinal cord injury.Moreover, BP are recommended to prevent and treat bone lossin corticosteroid (CS) induced OP [2]. CS are often administered topatients with autoimmune rheumatic diseases (ARD), even in highdoses. Notably, ARD are common in women during their childbearingage.It has been suggested that BP should not be used before or duringpregnancy, since they are released from bone over a long period of time, can cross the placenta and potentially interact with foetal boneturnover [3].When BP are given to premenopausal women, the use of anappropriate contraception and pregnancy planning are generallyrecommended [2]. However, there are some reports on women whoreceived BP during pregnancy or pre-pregnancy period without anysigni fi cant adverse effect. Thus, whether or not the use of BP is safe inwomen during their childbearing age is still a matter of debate.The aim of this review is to analyze current knowledge aboutindications, safety and risks of using BP in women with ARD duringchildbearing age. 2. Use of BP in patients with ARD  2.1. CS induced osteoporosis (OP) CS still represent the mainstay in the treatment of patients withARD including systemic lupus erytematosus (SLE), dermatomyositis,polimyositis, rheumatoid arthritis (RA), juvenile idiopathic arthritisand vasculitis. However, the long term use of these drugs has beenassociated with a huge number of side-effects such as bone loss andincreasedriskofbonefracture[4,5].Theimprovedsurvivalofpatientswith ARD [6,7] has focused our attention on the prevention andtreatment of the disease complications [8].CS are clearly involved in OP induction, mainly by affectingtrabecular bone in the vertebral spine, by reducing intestinal calciumabsorption, enhancing renal calcium excretion, impairing osteoblas-togenesis and increasing apoptosis of osteoblasts and osteocytes [4].BP are widely used in the prevention and treatment of CS inducedOP [4], since they can improve bone mass and bone quality, thusreducing the risk of bone fracture.According to the recommendations of the American College of Rheumatology(ACR)[2],BPshouldbeusedinadditiontocalciumandvitamin D in the following conditions: 1. to prevent bone loss inpatients in whom CS treatment is started at a dosage ≥ 5 mg/day andplanned for at least 3 months; 2. in patients receiving long-term CStherapy, who have OP, based on BMD or at least one osteoporoticfracture. However, according to these recommendations, when BPtherapy is considered in a premenopausal woman an appropriatecontraception is recommended.On the other hand, according to the EULAR recommendations[9], BP should be used in pre- and postmenopausal women, when CStreatment is started at a dosage ≥ 15 mg/day. In cases treated with alower dose (7.5 – 15 mg/day) for a period ≥ 3 months, BP should begiven to postmenopausal women independently of the coexistenceof other risk factors, and in premenopausal women, only if theyare at high risk, based on low BMD or low body mass index (BMI)[9].Finally, according to the Canadian Guidelines [10], BP should beused when CS treatment is administered at a dose ≥ 7.5 mg/day for atleast 3 months. When BP are considered in premenopausal women,caution is recommended; and they should be avoided when futurepregnancies are planned [10].It has been suggested that young age might be protective for CSinduced OP. However, SLE premenopausal women have signi fi cantlylower vertebral and femoral BMD [11] and a higher risk of fracturesthan healthy controls [12].The threshold of BMD for fracture risk in patients with CS inducedOP seems to be decreased. Kaji et al. [13] demonstrated a higherincidenceofvertebralfracturesinCStreatedpatientscomparedtothecontrol group, although the treated group had higher BMD and wasyounger at baseline. Notably, if low BMD is used as predictor for CSinduced OP or as indicator of BP treatment, the fracture risk will beunderestimated and CS induced OP will be undertreated.Thus, women with ARD in their childbearing age taking high CSdoses are at increased risk for OP, and BP seem to be a feasible optionfor the treatment of primary or secondary OP [2,4].Unfortunately, many issues are still unresolved: 1. the CS cut off dosage to start BP in premenopausal women ( ≥ 5 mg or ≥ 7,5 mg); 2.whether to treat with BP all premenopausal women or only those athigh risk (low BMD and low BMI); and 3. the BMD cut off level forde fi ning patients taking CS at high risk.Recently, teriparatide has shown to be at least as effective as BP inpreventing CS induced OP; however, its use in patients whose bonesare still immature (i.e. in women up to 18 – 24 years) and duringpregnancy is contraindicated [14].  2.2. Avascular necrosis (AVN) Avascular necrosis is the result of a decreased blood  fl ow in thebone with consequent bone ischemia and cell death. Many local andsystemic factors have been implicated in its pathogenesis, such as CS,hypercoagulability, antiphospholipid antibody syndrome, SLE, vascu-litis, RA, pregnancy, dyslipidemia, and genetic factors [15].The  fi nalbone collapse is a consequence of excessive bone resorption and lowregeneration rate. Thus, BP seem to be a reasonable option for thetreatment of AVN. However, their use for this indication was tested insmall trials with short-term follow up. Thus, BP cannot be recom-mended as standard treatment for AVN to date.  2.3. Calcinosis Calcinosis is an abnormal deposit of calcium salts in body tissues,commonly associated to connective tissue diseases like scleroderma,dermatomyositis,particularlyinthejuvenileform,overlapsyndromesand SLE. It can be limited or widespread causing debilitatingcomplications. Nostandardpharmacologic therapyforthe preventionor treatment of calcinosis is currently available. Since BP reduce boneturnover, they could arrest and partially reverse the process of calci fi cation even in paediatric patients. Although controlled trials arelacking, BP could be an option for treating calcinosis in patients withARD even during childbearing age.  2.4. Other potential indications BPhavebeenrecentlysuggestedforthetreatmentofRAinordertoprevent bone erosions by blocking osteoclast activity. BP have alsobeen used to treat spondyloarthritis where they seem to improvebone marrow oedema as well as clinical variables [16]. Unfortunately,as these data are very limited, BP are currently not recommended forthese indications. 548  I. Losada et al. / Autoimmunity Reviews 9 (2010) 547  – 552  3. Adverse effects of BP IN patients with ARD There arefew studies on thelong termsafety with theuse of thesedrugs. Adverse effects of BP in patients with ARD are similar to thoseobserved in patients without ARD. Some of them seem to depend onthe dosage and administration route: i.e. oral or intravenous.Acute phase reaction is manifested as self-limited transient  fl u-likesymptoms more commonly associated with intravenous administra-tion.Transienthypocalcaemiahasalsobeenreportedinpatientstreatedwith injectable BP. Risk factors are vitamin D de fi ciency, impaired PTHfunction or renal insuf  fi ciency [17]. Hypophosphataemia was alsoreported in patients treated with BP [17]. Ostenecrosis of the jaw isessentiallyanostemielitischaracterisedbypain,collapseandnecrosisof bone, which mostly affects subjects with poor dental hygiene orimmunosupressed patients, treated with very high doses of BP forcancer (10 – 15 fold higher than those used in OP). Severe esophagitiswas observed with oral aminobisphosphonates in post-marketingstudies, reducing its risk by modifying the dosing instructions. Otherrare adverse effects include blood disorders such as anaemia, throm-bocytopenia, leucopenia and elevation of liver enzymes. Uveitis,episcleritis, and orbital pain, although rare, can also be related to BP;thus, patients who develop ocular pain or vision loss during BPtreatment should stop the drug. Finally, acute renal failure has alsobeen reported after i.v. administration of BP at high doses.In children treated with BP, adverse effects are essentially thesame as in adults. The only difference is the formation of acharacteristic sclerotic line at the metaphyses of long bones andvertebrae, when the treatment is administered before the closure of the epiphyses. However, a partial or complete disappearance of thescleroticlinewasreportedafterstoppingthedrug[18].Notably,lineargrowth was normal or even increased in paediatric patients treatedwith therapeutic doses of BP [18]. 4. BP pharmacokinetics, pharmacodistribution,and transplacental passage BP are rapidly cleared from the circulation. Half of the adminis-tered dose binds to the skeleton and the rest is excreted nonmetabolized by the kidneys [1]. Their half-life in serum is short, whereas their half-life in bone may last several years. The uptake andlong-termretentionofBPinskeletondependonrenalfunction,rateof bone turnover, available binding site and, in addition, on speci fi cbinding properties and potency of the different BP [1]. As can be seenin Table 1, amino-BP are different in terms of af  fi nity, bindingproperties, and resorption rate, thus making it really dif  fi cult tocompare their action and ef  fi cacy in different clinical settings [19,20].BPbindpreferentiallytobonescharacterizedbyhighturnoverrate[21]. Lin et al. [21] demonstrated that after administration of   14 C-alendronate to rats, intra-articular epiphyses of the tibia and femur,which are mainly composed of trabecular bone and are the locationswhere 80% of bone turnover takes place, had signi fi cantly higher drugconcentration (three and two fold increased, respectively), than themiddle portions composed by cortical bone.There are some dif  fi culties in making a distinction in the pharma-cokinetics of different BP because there are few studies comparingthem. It has been reported that the binding af  fi nity to hydroxyapatitecrystals predicts the capacity of binding to bone and their subsequenteffect duration [19]. There is only one study carried out in humans inwhich retention and excretion rates of two different BP wereanalysed; in this study a signi fi cant difference in the 72 h urinaryexcretion rate of   14 C-risedronate (55%) versus  14 C-alendronate (48%)was found [20].Notably, 1 year after stopping risedronate, following a 3-yearcourse with this drug, urinary bone turnover markers were notdifferent from control patients taking calcium and vitamin D [20]. Onthe other hand, 5 years after withdrawing alendronate, following a 5-year treatment with this drug, urinary bone turnover markers werestill reduced [19].Patlas et al. [3] reported that  14 C-alendronate given to a pregnantratatadosageof0.12 mg/kg,couldbedetectedafter2and24 hinthefoetus. However,  14 C-alendronate administered at a lower dosage(0.06 mg/kg) could not be detected in the foetus. These data suggestthat BP placental cross is dose dependent.BP have been also shown to cross human placenta [22], probablydue to their low molecular weight (Table 1).Thus, the long term BP retention in bone and their potential of crossing the placenta may expose the foetus from mothers treatedwith BP to the side effects of the drug.With this caveat, when BP have to be given to a young woman inthepre-pregnancyperiod,speci fi caf  fi nitiesofthedifferentBPhavetobe considered in order to plan the washout period beforehand. 5. Potential effects of BP on pregnancy and lactation Apart from zoledronate and pamidronate, which are in class D,most of the commercialized BP are included in class C by US Food andDrug Administration. This means that animal studies showed someadverse effects for most of them, but there are no adequate and well-controlled studies in pregnant women. 5.1. Effects on embryogenesis Animal studies have not shown an increased rate of congenitalmalformations in pups from pregnant rats receiving therapeuticdosage of BP [3,23,24]; however, when administered at high dosages,BPcantriggerahighembryolethalityrateandabnormalteethgrowthin offspring [23,24].Very few reports are available in humans. We performed a sys-tematic literature review in Pubmed without any limit in publicationyears. Text words included: bisphosphonate, pregnancy, childbearingage, placental cross, adverse effects, teratogenesis, foetus and lactation.Wefound2case-controlstudies(45patients)and8casereportsorcaseseries (13 patients) of pregnant or pre-pregnancy women treatedwith BP. The results are summarized in Table 2 [25 – 34].In one of the two case control studies, Ornoy et al. [25] reported asigni fi cant lower median gestational age and neonatal birth weight,and a higher abortionrate in cases compared withcontrols, but it wasattributed to their background disease and not to BP treatment. In theother case control study, Levy et al. [26]; reported no differences interms of foetal complications between patients treated with BP andcontrols. In this paper, a case of Apert syndrome was observed [26],however,a linked genemutation wasfound, which makes a causativelink to BP exposure unlikely.Munns et al. [28] reported 1 talipes equinovarus out of 2 patientswithosteogenesis imperfecta. The incidenceof this deformity is 0.98 – 6.8 per 1000 live births in general population, but its incidence isunknown in children from mothers with osteogenesis imperfecta.Interestingly, no causal relation between talipes equinovarus and BPexposure has been reported in animals [28].  Table 1 Relative af  fi nities for human bone, binding to hydroxyapatite (HPA) crystals, inhibitionof farnesyl pyrophoshatase syntase (FPPS), and bone resorption activity of fourclinically used amino-bisphosphonates. Ki: af  fi nity constant; K L  : binding constant; IC:con fi dence interval.Bisphosphonate Boneaf  fi nityKi (µM)HPA bindingK L   (L/mol×10 6 )FPPSinhibitionIC 50  (µM)BoneresorptionIC 50  (µM)Molecularweight(g/mol)Zoledronate 80.8 3.55 0.02 0.002 272.1Risedronate 84.6 2.30 0.10 0.01 318.6Ibandronate 116 2.45 0.31 0.02 319.2Alendronate 60.9 3.00 0.50 0.05 249.1549 I. Losada et al. / Autoimmunity Reviews 9 (2010) 547  – 552   Table 2 Results of the literature review of pre-pregnancy or pregnant women treated with BP.No. of women Mean age atconception(years)Bisphosphonate Indications BisphosphonateadministrationOther drugs Newborns Meangestationalage (weeks)Mean birthweight (g)SA VA CongenitalmalformationsAdverse neonataloutcomesDunlop (1990) 1 28 Aminopropylen Malignanthyprecalcemia0 – 9 ms of preg CHT plus CS (1) 1 (100%) 36 3060 0 0 0 1 (Transienthypocalcemia)Illidge (1996) 1 42 Pamidronate Malignanthypercalcemia7th m of preg CS plusMorphine1 (100%) 29 1412 0 0 0 1 (Transienthypocalcemia anddystress syndrome)Rutgers-Verhage(2003)1 49 Alendronate OP 0 – 9 ms of preg No 1 (100%) 36 2390 0 0 0 0Biswas (2003) 2 Unknown Alendronate Unknown 2 ms before preg(1); 0 – 3ms of preg (1)No 2 (100%) NotreportedNotreported0 0 0 0Munns (2004) 2 19 Pamidronate OI Until preg No 2 (100%) 37 3230 0 0 1(Bilateral talipesequinovarus)1 (Transienthypocalcemia)Chan (2006) 4 31 Pamidronate Fibrous dysplasia(3), OI (1)3 ms before preg (1),until preg (1), 36 msbefore preg (1), 21 msbefore preg (1)No 4 (100%) 36 2385 0 0 0 0Ornoy (2006) 24 Unknown Alendronate ARD (13), OP (5),Asthma (1),Others (5)1 – 6ms before preg (8),0 – 2ms of preg (15),0 – 5ms of preg (1)CS (13) 19 (79.1%) 38 2910 5 (21%) 0 0 Not reportedCulbert (2006) 1 40 Pamidronate Malignanthypercalcemia7th m of preg CHT 1 (100%) NotreportedNotreported0 0 0 0Cabar (2007) 1 30 Pamidronate Idiopatichyperphosphatasia1 m before preg No 1 (100%) 36 3130 0 0 0 0Levy (2009) 21 32 Alendronate,Etidronate,Risendronate,PadmidronateOP (5), Metastatictumor (1), CS inducedOP (15)0 – 3 ms of preg CS (15); AZAplus SFZ (17)18 (85.7%) 38 3100 2(9.5%) 1(4.7%) 1(Apertsyndrome) 2 (1 prematurebirth and 1 jaundice)Total 58 33 50 (86.2%) 35.8 2702 7 (12%) 1(1.7%) 0m = month; ms = months; preg = pregnancy; OP = osteoporosis; OI = osteogenesis imperfecta; ARD = autoimmune rheumatic disease; CHT = Chemotherapy; CS = corticosteroids; AZA = Azathioprine; SFZ = Sulfasalazine; SA =spontaneneous abortions; VA = voluntary abortions.  5   5   0   I    .L   o  s  a  d   a  e  t   a  l    . /   A  u t   o  i    m m u n i    t    y R  e v  i    e w s  9    (  2   0  1   0    )   5  4   7   –  5   5  2    5.2. Effects on bone growth Animal studies have shownthat BP cross the placenta [3] and bindto foetal bones, which are characterised by a high turnover rate [21],decreasing bone length only when administered at high dosages.Alendronate and pamidronate when administered at an optimal dose(1  μ  M) can stimulate bone growth in foetal rat metatarsal bones,whereas at a high dose (0.1 mM) they can completely blocklongitudinal bone growth [35]. The results are in keeping with those reported by Koivukangas et al. [36], who demonstrated an increasedBMDandnormalskeletongrowthingrowingratsreceivingclodronateat a therapeutic dosage (2 mg/kg), whereas a slight decrease in tibiallength in those receiving BP at high dosage (10 mg/kg). Finally, Patlaset al. [3] reported an increase in bone trabeculae, but a decreasein diaphyseal length and foetal weight in pregnant rats receivingtherapeutic dosage of alendronate (0.1 mg/kg).Whether these observations can be translated to humans, is stillcontroversial; in fact, rats have a different bone turnover comparedtohumans. A high bone turnover rate similar to that observed in foetalbone was found in children.Antoniazzi et al. [37] carried out a study on 10 infants, less than1 year old, affected with osteogenesis imperfecta, treated withneridronate 2 mg/kg every 3 months for 18 months, showing nodetrimental effect on growth.In a prospective multicenter study on 38 prepuberal patients withconnective tissue diseases and low BMD, Bianchi et al. [38] found asigni fi cant increase in BMD in those treated with alendronatecompared to the untreated group. Treatment with BP induced theformation of a sclerotic line in the metaphyses; however, noabnormalities in skeletal growth were observed [38].In a further study on 12 young patients with OP, BP were effectiveand did not impair normal growth [39]. In 6 of them a bone biopsywas performed after the withdrawal of BP and it did not show anydefects in bone mineralization.In our literature review, 8 newborns, out of 50 referred in Table 1,wereevaluatedduringamedianperiodof0 – 4 yearsafterbirthandnoabnormalities in BMD and growth were observed.Thus, BP seem to affect foetal bone growth in animals only whentheyareusedathighdoses;however,noevidencethattheycanaffectskeletal growth of foetus or children with the use of therapeuticdosage has emerged to date. 5.3. Effects on breastfeeding  Onlyonecaseofawomantreatedwithpamidronateforsympatheticdystrophy during lactation, in which BP was measured in the milk, isavailableintheliterature.Inthiscaseexcretionofa minimalamountof BPintomaternalmilkwithoutaffectingnormalgrowthofthebabywasobserved [40]. This limitedinformation prevents any conclusion on theriskofbreastfeedingduringBPtreatment.Thesedrugsshouldthereforebe avoided until more data are available. 6. The timing of stopping BP before pregnancy  Since BP have a long-term retention rate they should be stoppedbefore pregnancy. However, how long before conception they shouldbe withdrawn is still a matter of debate.After administration of a single dose of BP, they bind to bone fromwhich they are released very slowly; in fact, their effect on boneresorption can persist for a long time. The reversal rate of the effect of each BP is different, depending on their properties, but no head-to-head studies have been performed. Moreover, most of the studies arein postmenopausal women and their results should not be extrapo-lated to premenopausal women, because of the differences in bonemetabolism. Finally, the dosage of BP taken by patients also plays akey role in the duration of action.Afteratreatmentwithalendronate,boneturnovermarkersremainsuppressedfor5 years[20].Thus,morethan5 yearsofwashoutshouldbenecessaryafteratreatmentwiththemostpotentBP,alendronateorzoledronate, in order to avoid foetal exposition to these drugs.Interestingly, after stopping etidronate and risedronate, boneturnover markers returned to baseline in less than one year [20]. As aconsequence women might get pregnant without any foetal risk 1 – 2 years after stopping risedronate. 7. The experience of the unit of clinical and epidemiologicalgenetics of the University of Padova (CEPIG) CEPIG collected data from 10 women, mean age at conception35 years,range30 – 43.TheindicationsforBPwere:CSinducedOPin7cases, OP in 1, pelvic fracture in 1, and femoralavascular necrosis in 1.Drugs taken by the patients before and during pregnancy werealendronate, pamidronate, clodronate, and neridronate. Other con-comitant treatments were: azathioprine in 2 cases, sulfasalazine in 1,CS in 2, cyclosporine in 1, and hydroxychloroquine in 1. There were 9(90%) newborns, mean gestational age was 38 weeks and mean birthweight 2890 g. One spontaneous abortion (10%), 2 congenitalmalformations(20%),1ventricularseptaldefect(exposedtoclodronicacid) and 1 kidney and cardiac malformation (exposed to alendro-nate), 1 premature birth, and 1 distress syndrome were reported. 8. Conclusion BPhavealong-termretentionrateinboneandsomeofthemwerefound to cross the placenta; thus, foetuses from mothers who took BPprior to or during pregnancy could be exposed to these drugs.Animal studies showed that BP administered during pregnancycandecreasebonelengthinfoetuses;however,inhumanstheydonotseem to affect skeletal growth in foetuses or children exposed totherapeutic dosages.Regardinghumans,poolingthedatafromtheliteraturereviewandour own experience, there are only 2 children affected withmalformation out of 68 exposed, leading to a malformation rate of 2.94%whichisnotsigni fi cantlydifferentfromthatobservedingeneralpopulation.However, the results of our small series showing malformations in2 of 10 exposed cases, raise the question of the safety of BP andsuggest caution with the use of BP in women during the fertile years.Since both children in our study had heart malformations, we suggestperforming prenatal US in exposed children.Altogether, these pieces of information suggest to avoid the use of BP prior to or during pregnancy using in their place more safertherapeutic approaches such as vitamin D and calcium supplements.In cases in which BP are strongly recommended before pregnancy,the drug with the most favourable balance between retention rate inboneandef  fi cacyshouldbepreferred,withthecaveatofwithdrawingthem at an adequate time before pregnancy.  Take-home messages •  BP have a long-term retention rate in bone and cross the placenta;consequently,foetus from mothers treated with BP before or duringpregnancy are likely to be exposed to these drugs. •  The use of BP prior to or during pregnancy as well as duringbreastfeedingshouldbeavoided,untilmoresafetydataareavailable. References [1] Papapoulos SE. Bisphosphonates: how do they work? Best Pract Res ClinEndrocrinol Metab 2008;22(5):831 – 47.[2] Recommendations for the prevention and treatment of glucocorticoid-inducedosteoporosis: 2001 update. American College of Rheumatology Adhoc Committeeon Glucocorticoid-induced Osteoporosis. Arthritis Rheum 2001;44:1496 – 503.551 I. Losada et al. / Autoimmunity Reviews 9 (2010) 547  – 552
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