Management of Calcium Metabolic Disorders and Osteoporosis

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N J Gittoes and others COVID-19, calcium disorders 183:2 G57–G65 Clinical Practice and osteoporosis Guidance

ENDOCRINOLOGY IN THE TIME OF COVID-19 Management of calcium metabolic disorders and osteoporosis

Neil J Gittoes1,2,3, Sherwin Criseno1,2, Natasha M Appelman-Dijkstra4, Jens Bollerslev5,6, Ernesto Canalis7, Lars Rejnmark8 and Zaki Hassan-Smith1,2,3

1Department of Endocrinology, Queen Elizabeth Hospital Birmingham, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK, 2Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners, Birmingham, UK, 3Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK, 4Centre for Bone Quality, Leiden University Medical Centre, Leiden, The Netherlands, 5Section of Specialized Endocrinology, Oslo University Hospital, Oslo, Norway, 6Faculty of Medicine, University of Oslo, Oslo, Norway, 7Departments of Orthopaedics and Medicine, UConn Health, Farmington, Connecticut, USA, and 8Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark

This manuscript is part of a commissioned series of urgent clinical guidance documents on the management of Correspondence endocrine conditions in the time of COVID-19. This clinical guidance document underwent expedited open peer should be addressed review by Bente Langdahl (Aarhus University, Denmark), Karin Amrein (Medical Univesity of Graz, Austria), and Maria to N J Gittoes Lousa Brandi (University of Florence, Italy) Email [email protected]

Abstract

Endocrinologists have had to make rapid changes to services so that resources can be focused on the COVID-19 response to help prevent spread of the virus. Herein we provide pragmatic advice on the management of commonly encountered calcium metabolic problems and osteoporosis. Non-urgent elective appointments should be postponed, and remote consultations and digital health solutions promoted. Patients should be empowered to self-manage their conditions safely. Patients, their caregivers and healthcare providers should be directed to assured national or international online resources and specific patient groups. For patients in acute hospital settings, existing emergency European Journal of Endocrinology guidance on the management of hyper- and hypo-calcaemia should be followed. An approach to osteoporosis management is outlined. IV zoledronic acid infusions can be delayed for 6–9 months during the pandemic. Patients established on denosumab, teriparatide and abaloparatide should continue planned therapy. In the event of supply issues with teriparatide or abaloparatide, pausing this treatment in the short term is likely to be relatively harmless, whereas delaying denosumab may cause an immediate increased risk of fracture. The challenge of this pandemic will act as a catalyst to innovate within our management of metabolic bone and mineral disorders to ensure best use of resources and resilience of healthcare systems in its aftermath.

European Journal of Endocrinology (2020) 183, G57–G65

Introduction

The emergence of the 2019 novel coronavirus (COVID- we respond as endocrine and metabolic bone disease 19) in Wuhan, China and subsequent global spread specialists. The first, concerns how we ensure that we has placed health systems under unprecedented strain have effective mechanisms in place to postpone non- (1). Endocrinologists, amongst others, have had to urgent elective activity whilst ensuring that we do no focus on contribution to acute care in this initial harm. As we have seen this has involved adopting new phase. There are a number of considerations as to how ways of working such as remote consultations in line

This work is licensed under a Creative Commons https://eje.bioscientifica.com © 2020 The authors Attribution 4.0 International License. https://doi.org/10.1530/EJE-20-0385 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/29/2021 04:14:04AM via free access

-20-0385 European Journal of Endocrinology https://eje.bioscientifica.com • from COVID-19? osteoporosis atincreasedrisk Are patientswithcalciumdisordersand osteoporosis. conditions focusing on hypo- and hyper-calcaemia and 19 onthemanagementofcalciummetabolicandbone ( of fluidbalanceandbiochemicaltestsmaynotbepossible large disorders needstobetailoredthesetting,suchasin this challenge. workinganddigitalhealthsolutionstomeet disciplinary specialists. Itisclearthatwewillneedtoharnessmulti- involve carefulconsiderationofwhereweaddvalueas acute phasetodevelopnovelmodelsofworking.Thiswill We willneedtotakewhatwehavelearnedduringthis likely becharacterisedbyareturntobusinessasusual. disease morbidity. Theaftermathtothepandemicwillnot planning overthemediumtermtopreventexcesschronic strategies during this time. We need to be mindful of complex healthneedsandprovideeffectivemanagement support duringthepandemic( societies, organisationsandpatientgroupstoprovide to onlineresources andhelplinesset-upbyspecialist and non-specialistcolleagues.Patientsshouldbedirected be usedtoprovideremote‘adviceandguidance’GPs specialist nursessupportedbyconsultants.ITsystemscan support arecentraltothis. communication witheffectivemessagingandeducational physical distancingtopreventdiseasespread.Clear our health care systems and tocontribute to effective These measuresarerequiredtomaintainresiliencein endocrine-diseases-ese-statement-final_23032020.pdf ( with European Society forEndocrinology (ESE) guidance 2 https://www.ese-hormones.org/media/2223/covid-and- • ). InthisreviewwefocusontheimpactofCOVID- Clinical PracticeGuidance It is,however, unknownwhetheracausal relationship due toinfectionsinpatients withhypoparathyroidism. have hypothesisedanincreased riskofhospitalization studies increased riskfromtheinfection. Observational to suggestthatpatientswith theseconditionsareat COVID-19, althoughatpresentthereis an addedcomplicationinpatientspresentingwith No. Mineralandmetabolicboneconditionsmaybe The managementapproachtocalciummetabolic We mustensurethatweidentifypatientswith Many centreshavesetuphelplinesrunbyclinical > 1000 bed‘fieldhospitals’,whereclosemonitoring Table 1 N JGittoesandothers ). no evidence ). ).

International OsteoporosisFoundation • • • • Royal OsteoporosisSociety • • • Society forEndocrinology the COVID-19pandemic. management of calcium and metabolic bone conditions during Table 1 • • Endocrine Society • ESE informationleafletonthetreatmentofchronic • European SocietyofEndocrinology(ESE)COVID-19resources • Parathyroid UK • European ReferenceNetworkonRareBoneDiseases Offers guidelinesthrougharecordedwebinarbygroupof National OsteoporosisFoundation • • • • and osteoporosis COVID-19, calciumdisorders • • • • • • • • • • • • • • • • • hypoparathyroidism inadults COVID-19 page( experts coronavirus-and-osteoporosis https://theros.org.uk/information-and-support/ managing osteoporosisthroughCOVID-19response Advice andguidanceforhealthcareprofessionalson for patientsandcarers Includes largeresourceofpracticaladviceandinformation Free osteoporosispatienthelpline+448000035 ⚬ ⚬ ⚬ ⚬ Resources relatedtometabolicboneconditionsinclude: resources-for-managing-endocrine-conditions/ https://www.endocrinology.org/clinical-practice/covid-19- COVID-19 resourcesformanagingendocrineconditions https://www.endocrine.org/ during thepandemic resources forcliniciansmanagingendocrineproblems As ofthiswriting,theEndocrineSocietyisdeveloping hypoparathyroidismpatientleaflet.pdf https://www.ese-ormones.org/media/1353/ clinical-information-and-comment-from-ese/ communities/clinicians/covid-19-and-endocrine-disease- https://www.ese-hormones.org/about-us/our- people-with-hypoparathyroidism/ https://parathyroiduk.org/news/coronavirus-advice-for- pandemic ( management ofrarebonediseasesandtheimpact Includes linkstoadvicefrominternationalbodiesonthe osteoporosis https://www.iofbonehealth.org/news/covid-19-and- Links tootherrelevantinternationalsocieties healthcare providers Questions andanswersforpatients,caregivers defensins ( cytokine profiles and induction of cathelicidins and seasonal influenza, via modulation of inflammatory infections, such as in reducing the risk of respiratory It hasbeenproposedthatvitamin Dmayplayarole infections inhypoparathyroidism. exists, andnodataareavailableonriskofCOVID-19 ⚬ ⚬ ⚬ ⚬ COVID-19 andparathyroidconditionFAQs infusion Letter templateforpostponementofzoledronicacid Denosumab patientinformationleaflet pandemic Letter templatesfordenosumabduringtheCOVID-19 Summary ofonlineresourcesavailabletosupport http://www.nof.org/covid-19-updates/ http://ernbond.eu/indications/ 3 , https://ernbond.eu/covid-19-emergency/ 4 ). Previous observational research). Previousobservational has Downloaded fromBioscientifica.com at09/29/202104:14:04AM 183 :2 ) G58 ) via freeaccess European Journal of Endocrinology • • • • • and osteoporosis? with calciummetabolicdisorders How willCOVID-19impactonpatients • • • • • • • • • Clinical PracticeGuidance and otherimagingwill shouldbepostponed, Patients awaitingdiagnostics suchasDXAscanning their chronicdiseasetostaff whenenteringtheED. departments (EDs).These patients shouldhighlight addressed conventionallyas patients attendemergency symptomatically andacutely. Suchproblems needtobe Disturbances ofmineralmetabolismcanpresent some ofthisgapinpatientcontacts. Helplines andonlineresources reduced workforce todeliveroutpatientservices. COVID-19 areasmeansthatthereissignificantly Redeployment ofoutpatient-basedstafftoinpatient decision-making. betweenbloodtests intervals will need to be made as to whether to lengthen access toregularbloodtestmonitoringanddecisions Patients shieldingorself-isolatingwillnothave driven byregularreviewandbloodtestmonitoring. in mineralmetabolism,managementisusually Once acausehasbeenelucidatedfordisturbances follow-up suchastelephoneorvideoconsultations. outpatient appointments,promotestheuseofremote outpatient setting.Theinabilitytorunface-to-face andaremanagedinan have achronicnaturalhistory The majorityofmetabolicboneandmineraldiseases appropriate. or maintenancesupplementationisadministeredas metabolic bonediseases,soitisimportantthatloading levels isacorecomponentofthemanagement Ensuring thatvitaminDstatusisoptimisedto‘sufficient’ issue specifictoCOVID-19areavailable. At thetimeofwritingnoreliabledataonthis vitamin D deficiency and with daily/weekly dosing. needed totreat( was safeandefficaciousoverall,withalownumber infectionsconcludedthattheintervention respiratory of vitaminDsupplementationtopreventacute A systematicreviewandmeta-analysisoftheuse andRCTstudiesinthisarea. previous observational heterogeneity inoutcomesandconfoundingfactors a life-threateningcomplicationofCOVID-19.Thereis for ARDSandseverityof identified vitamin Ddeficiencyasariskfactor 4 ), particularlyinthosewithsevere N JGittoesandothers toinformclinical ( can help bridge 5 ), whichcanbe

• without fullinvestigations with hypercalcaemiaorhypocalcaemia How tomanageacutelyunwellpatients • • • Acute managementofhypercalcaemia • • • and osteoporosis COVID-19, calciumdisorders • • • • • • • administer IV therapies if required, and whether in particular whetherthehealthcarefacilityisableto management of hyper- and hypo-calcaemia, in Consideration needstobemadewithregards with tocontinueuninterruptedtreatment. are likelytoexperiencesignificanthurdlescontend for osteoporosis Patients receiving definitive surgery. (PTX) suchas Patients awaitingsurgery negatively and inthemajorityofcases,this guideline onemergency managementof biochemical testing. The Society for Endocrinology to presentwithacutehypercalcaemia asdefinedbybasic Irrespective ofCOVID-19status, patientswillcontinue metabolism whoareinthelastdaysoflife. not desirable in patients with disturbances of mineral monitoring of fluid balance and routine blood tests are that doesnotprovidesymptomrelief.Intensive while supportingdiscontinuationofmedication monitoringandinvestigations unnecessary care inotherchronicdiseasesincluding advocate adhering to the principles of good palliative at the end of life, however, and in general, we would of endocrine conditions for those patients who are There isapaucityofguidanceonthemanagement followed. Wherever possible, teams tobeextremelyhelpful. medications andinvolvementofpalliativemedicine making, includingprescriptionofanticipatory pandemic wehavefoundthatproactivedecision of diseasespecialistswhereavailable.Duringthe as general physicians, with involvement and support door The above decisions should be made ‘ route maybemoreappropriate. hospital wouldbeappropriateorwhetherapalliative the eventofthesecomplications,transfertoanacute ’ withinputfromseniordecisionmakerssuch willand should bedelayed in accessing uponcare. administeredbyhealthproviders parenteral forms oftherapy parenteral forms existing guidelines Downloaded fromBioscientifica.com at09/29/202104:14:04AM https://eje.bioscientifica.com parathyroidectomy 183 will notimpact :2 at the front shouldbe avoiding G59 via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com • • • • • • • • Clinical PracticeGuidance of malignancy refractory tobisphosphonatetherapy of malignancyrefractory considered (approvedfortreatment of hypercalcaemia treatment, subcutaneous denosumab maybe levels arenotreducedinresponse tobisphosphonate effect ofthistreatment following administration,acommonside be awareof IV zoledronicacidmaybeconsidered.Teams should hypercalcemia ofmalignancy)isdeemednecessary, treatment ofnon-parathyroidhypercalcemia (e.g. to treatmentofPHPTaredetailedbelow. Iffurther (if feasible to have been elucidated). Approaches caused byexcessPTHorisofnon-parathyroidorigin on whether the hypercalcemia isconsidered to be further treatmentisneeded,theapproachdepends If adverseclinicalsigns/symptomscontinueand the hypercalcaemia. overload andnotasanintegralapproachtomanaging but furosemideshouldonlybeusedtomanagefluid of IVfurosemidemaybeconsideredinsuchscenarios COVID-19. Carefulmonitoringisrequired.Smalldoses renal impairment,whichcanbeamanifestationof the riskoffluidoverloadinolderpatientsorthosewith acute hypercalcaemia. It is important to be aware of helpful duringthefirst24or48hinmanagementof management substantially worsened byoverlyliberalfluid distress syndrome(ARDS)andthismaybe in COVID-19,thereisariskof monitored, andcliniciansshouldbemindfulthat of i.v. 0.9%saline.Responseshouldbecarefully involves rehydration with appropriate volumes Standard acute management of severe hypercalcaemia worsen rapidlyandnecessitateimmediatetreatment. malignancies or vitamin D intoxication, which may disequilibrium hypercalcemia duetoforexample, Suppressed serumPTHlevelsmayindicateastateof mmol/L. symptomatic and/or serum calcium levels are or treatment most likely. hyperparathyroidism(PHPT)is diagnosis ofprimary If serumPTHlevelsarehigh-normalorelevated,a of immediatesubsequentexaminations/treatments. of PTH levels, as this may help determine the necessity of hypercalcaemia shouldbefollowedbymeasurement far asfeasible( lab resultsareavailableandshouldbefollowedinso framework foruseinacutehospitalsettingswherebasic acute

hypercalcaemia No further immediate examinations No further 6 arerequiredunlessapatientisseverely flu-like symptomsinthedays . Treatment withcalcitoninmayalsobe ). Ifbyanymeanspossible,adiagnosis inadultpatientsprovidesa , however. Ifserumcalcium N JGittoesandothers acute respiratory acute respiratory > ~3.25 • Acute managementofhypocalcaemia • • acute crisis? and osteoporosisberemodelledinthe patients withcalciummetabolicdisorders How shouldendocrineservicesfor • • • and osteoporosis COVID-19, calciumdisorders • • • • • • emergency andrequireshospitaladmissionwith hypocalcaemia isa testing.Acutelypresenting routine biochemistry with acute hypocalcaemia that is identified by 19 status, patients will continue to present As forhypercalcaemia, irrespectiveofCOVID- hypocalcaemia. is concern about vitaminDdeficiency andrebound IU orally) if vitamin D deficiency isdetected orthere should bepragmaticallyadministered(~25,000–50,000 vitamin Ddeficiency initial hypercalcaemia, particularly inthosewith and S/Cdenosumab,eveninthosepresentingwith There is a risk of hypocalcaemia after IV bisphosphonates may behelpfulinsomecases. in the USA), as well as treatment with glucocorticoids be usedtosupportthis.This enablesindividualsto framework (Educate,Equip, Engage,Empower)can illnesses inthemidstof the pandemic.The‘4E’ strategies Promotion ofeffective self-management infection. unstable mineralmetabolismduringaCOVID-19 Hypoparathyroid patientsmayencountermore guidance foracutehypocalcaemia following the Society for Endocrinology administered inacommunitysetting,weadvocate totreatmentwithdrugtherapiesissuedand refractory In patientswithsymptomatichypocalcaemiathatis without signsofhypocalcaemiacausedbyinfections. beneficial effectsoftreatmentasymptomaticpatients are asymptomatic,andthere no datasupporting Most patientswithhypocalcaemiaduetoinfections 19 isassociatedwithdevelopmentofhypocalcaemia. but variable. No dataare available whether COVID- to hypocalcaemiadueinfectionsisoftenblunted with infectionsandsevereillness Hypocalcaemia is oftenencountered in patients appropriate monitoringandsupport. isessentialforpatients with chronic Downloaded fromBioscientifica.com at09/29/202104:14:04AM potentially life-threatening . Vitamin Dsupplementation 183 :2 . PTHresponse ( 7 emergency ). G60 via freeaccess

European Journal of Endocrinology • • • Primary hyperparathyroidism • • • • • • • • • • • • • Clinical PracticeGuidance are susceptibletodehydration, particularlyattimes Patients withPHPTshould be madeawarethatthey hypercalcaemia. they developworseningand persistentsymptomsof months. Patients should be advised to seek advice if adequate fluidintake,inparticularduringthesummer symptoms andcognitivechanges)beawareof nausea, vomiting,boneandabdominalpain,osmotic symptoms of Patients areadvisedtopayattentionpotential postponed duringthepandemic. end-organ effectsandlocalisationimagingshouldbe diagnosis ofPHPT, includinginvestigationstoassess needed andwork-upofpatientsreferredwithanew is onlyrarely before diagnosis.Acuteintervention patients havehadthediseaseforalongperiod(years) In mostinstances,PHPTevolvesslowlyandmany wasted timeforclinicalteams‘reinventingthewheel’. of resources toavoidmixed messagesforpatientsand and qualityassuredthatisavailableviaarepository have aconsistentmessagethathasbeenpeerreviewed support duringthepandemic( societies, organisationsandpatientgroupstoprovide online resources andhelplines set-upbyspecialist Patients andcaregiversshouldbedirectedtoassured readily availablebutprobablyunderutilisedcurrently. care and non-specialist colleagues are to primary IT systemsprovidingremote‘ nurses supportedbyexperiencedmedicalspecialists. Many centreshavesetup beingsuggestedmodels. services phlebotomy through’, ‘pop-up’,GPanddomiciliary away fromtheacutehospitalsites and arrangementsshouldbemadefor The needforroutinebloodtestsshouldbereviewed with theircondition. including whotocontactintheeventofanyconcerns management andfollow-upplansshouldbesent, Routine letterstoinformpatientsofchangesintheir video consultations is appropriate in these patients. converted toremotereview. Useoftelephonecallsor bone andcalciumdisorderscanhavefollow-upsafely The vast majority of patients with chronic metabolic qualityoflife. maintain asatisfactory to behavioural, andemotionalresponsesnecessary monitor theirconditionandtofacilitatethecognitive,

hypercalcaemia helplines Table 1 N JGittoesandothers advice and guidance ). Itisimportantto (e.g. anorexia, runbyspecialist blood testing with‘drive- ’ • • • • • • Hypoparathyroidism • Hypercalcaemia ofmalignancy and osteoporosis COVID-19, calciumdisorders • • • • • • • if thereissymptomatichypercalcaemia andnoaccess Cinacalcet can beappropriatelydeferreduntilsafetoproceed. take manyyearstodevelop.Intypicalcases,surgery nephrocalcinosis andreducedbonemineraldensity result inharmbecauseend-organeffectssuchas short tomediumtermthisisextremelyunlikely pandemic. Patientsshouldbereassuredthatinthe with PTXwillbepossibleduringthecourseof It is unlikely that definitive management of PHPT on changesinsymptomsandclinicalappearance. Any management decisions should be based initially Routine serumcalciumchecksshouldnotbemade. well hydratedparticularlyiftheyhavepyrexia. renal insufficiency. Patients should be advised to keep potential requirementforurgentcareadmissionand hydrated toavoidescalatinghypercalcaemia and of paramountimportancethatpatientskeepwell of intercurrent illnessandhottemperatures.Itis including thosethatmay indicatehypocalcaemia Patients areadvisedtomonitor symptomsclosely, treatments. helpful tohighlightunderlying diagnosisandplanned text reminders.Disease-specific emergencycardsare admission. Thiscanbereinforced bytelephoneor medications toavoidtheneedforemergency patients arecompliant hypocalcaemia, soitisespecially balance in hypoparathyroidism, pre-disposing to Infections canimpactonserumcalcium/phosphate for-people-with-hypoparathyroidism/ ( care clinicians endocrinologist and patients’ primary medications to havean In patientswithhypoparathyroidism,itisimportant on acutehypercalcemia ofnon-parathyroid origin. for non-palliativecaresettings,asstatedinthesection prevalence inoncology. Theseguidelinesmirrorthose established important palliativeconsiderationandtherearewell- Treatment ofsymptomatichypercalcaemia isan to definitivePTX. https://parathyroiduk.org/news/coronavirus-advice- uninterrupted supplyofprescription uninterrupted guidelines maybeconsideredasaholdingmeasure andthismayrequirecloseliaisonbetween Downloaded fromBioscientifica.com at09/29/202104:14:04AM forthisinviewofitshigh withtheirreplacement https://eje.bioscientifica.com 183 important that important :2 ). G61 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com • • • • Osteoporosis • • • • • • • • • • • • • • • • Clinical PracticeGuidance tests maybewaived,andpatients shouldbeempirically For denosumab-treatedpatients, pre-injectionblood administration shouldbeexplored. domiciliary appropriate measurestosupportself-injectionor continue their6monthlyinjections Patients establishedon conditions/ practice/covid-19-resources-for-managing-endocrine- website ( letter isavailableontheSocietyforEndocrinology according toprogressofthepandemic.Astandard their nextinfusionby~6monthsormaybelonger, or receiving IVzoledronicacid,whoweadvocatedelaying Particular attentionshouldbemadetopatients the impactofCOVID-19isoutlinedin Detailed adviceonmanagement considerations and therapy Patients on assessment. hydration willalsorequiremedicalreviewandfurther symptoms of hypercalcaemia despite appropriate management ofhypoparathyroidism.Persistent hypercalcaemia Patients shouldalsobeawareof bloodtesting. confirmatory calcitriol Empirical dose changes of hospital admission. as theyarelikelytorequiredoseadjustmentsoreven illness In theeventofaprotracted within 1–2weeks. calcitriol) are changed, blood testsshouldberepeated If dosesofmedications(particularlyalfacalcidolor advice fromanendocrinologyservice. calcium, albuminandcreatininewithsupporting pathways, andthisshouldtriggerabloodtestfor advised to seek urgent medical advice via local If symptomsdonotimprovewithabove,theyare calcium-rich foodsordrinks. additional calcium(500–1000mg) their calciumisdropping,theyareadvisedto follow adviceonself-management.Ifpatientsfeelthat (such astinglingsensationsandmusclecramps)to , theyshouldseekemergencymedicaladvice shouldcontinuetheirtreatmentasusual. shouldbeavoided ). parathyroid hormone replacement parathyroid hormone https://www.endocrinology.org/clinical- , whichcanalsooccurinthe N JGittoesandothers denosumab vomiting/

intheabsenceof alfacalcidol symptoms of Table 2 andconsume andwhere diarrhoea should . take or

• • • • • • • • needs tobeseenface-to-face? disorders andosteoporosis,whostill In patientswithcalciummetabolic and osteoporosis COVID-19, calciumdisorders • • • • • • • • more safelyberesumed. can have appropriate recall procedures when services registries toensurethatpatientsdonotgetmissedand It isessential to have in place reliable databases and effect profilesandsymptomsofCOVID-19. due toriskofconfusionwithregardspotentialside above therapiesduringtheacuteCOVID-19response Ideally, newpatientsshouldnotbecommencedonthe therapy withromosozumabshouldbedelayed. be madeoralternatetherapiesconsidered.Initiationof romosozumab Arrangements formonthlyadministrationof reduction. to bluntthelong-termbeneficialeffectonfracturerisk unlikely pauses from therapy for many weeks are very should continuewiththeirplannedtherapy. However, Patients receiving 50,000 IU)aroundthetimeofeachinjection. treated withvitaminDsupplementation(25,000– administration iftheyarenot self-administering. face-to-face interactions(addressed above)fordrug denosumab Patients withosteoporosisbeingtreated require face-to-facereview. will patientswithproblemsofcalciumhomeostasis requiring Only in exceptional clinical circumstances, or in those documentation. phone, text, e-mail and corroborated by formalletter care clinicianby by contacttopatientandprimary blood tests, and these should be acted upon promptly less than3monthly, shouldagainreceive remote less stable, measured byrequiring follow upintervals Those withcalciumhomeostasisproblemsthatare risk ofinfection. away fromacutehospitalswithminimalfootfalland accordingtoclinicalneed,thatarelocated services, remotely asmentionedabove.Usephlebotomy greater than3monthly, cangenerallybemanaged biochemically stable,requiringfollowupintervals Patients withcalciummetabolicdisorderswhoare emergency assessment or byahealth provider mightneed to

teriparatide Downloaded fromBioscientifica.com at09/29/202104:14:04AM romosozumab or 183 , addressedabove,

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European Journal of Endocrinology Equip Educate General Table 2 Clinical PracticeGuidance

considerations

Summary oftheapproachtomanagementosteoporosisduringCOVID-19pandemic. • • • • Provide patientswiththedetails ofdedicatedservicehelplineorthatthepatientsupportgroup foradviceand • • • • • • • • • • • • • • • • • • • • • • • • support. ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ following onlineresources: information andguideonexercise,healthyeatingsmoking cessation.Patientscouldbedirectedtothe Provide patientswithtoolsandresourcestosupporttheminfacilitating positivelifestylechangesincluding should notputthematincreasedriskofcontractingcoronavirus. treatment. Theyshouldalsobereassuredthatcontinuingwith Patients shouldbeinformedoftheimportancecontinuingwith theirdaily video consultation. preparation andadministrationshouldbecarriedouteitherover thephone,bywatchinganonlinevideoorvia If patients(ortheirfamily/carer)arewilling put thematincreasedriskofcontractingcoronavirus. Patients shouldbereassuredthatcontinuingwiththeir6-monthly quick ‘onandoff’effect,theadministrationscheduleofevery6monthsshouldnotbeinterruptedordelayed. Patients shouldbeinformedoftherapidonsetandoffsetaction their nextinfusionduringtheCOVID-19pandemicshouldnotputthematahigherriskofsustainingfractures. reassured thattheirlastinfusionwillcontinuetoprovideprotectionbeyond12months( Patients shouldbeinformedandreassuredaboutthelong-actingnatureof provided thatthereisnocontra-indicationforsuchtreatment. could bemistakenasCOVID-19infection.Oralbisphosphonateshouldconsideredaninterimtreatment the importanceofdelayingtreatmentduetopotentialsideeffectsmild‘flu-likesymptoms’which Patients whoareeitherduetostartorreceivetheir ⚬ the internationalosteoporosisfoundation( ( living-with-osteoporosis/exercise-and-physical-activity-for-osteoporosis resources forexercisesuchastheRoyalOsteoporosisSociety( routines thatcanbeperformedinthecomforttheirownhome.Patientsshoulddirectedtoreputableonline imposed bysocialdistancingmeasures,patientsshouldbeeducatedonsimpleweight-bearingexercise All patients supplementation (ifprescribed)ordiet. All patients should beconsidered. Alternative treatmentsuchascontinuingwithoralbisphosphonatemedication(ifnotcontraindicated) teriparatide. symptoms ordevelopingshortnessofbreath,nauseaandvomiting,fatiguepainintheextremitieswith abaloparatide No newpatientsshouldbestartedon on fractureriskreduction,however. their treatment. Periods of discontinuation for many weeks are unlikely to blunt the long-term beneficial effects Patients whoareestablishedon considered forallpatients. levels canbewaivedandempiricaltreatmentwithsingledoseofcolecalciferol25,000–50,000IU treatment withoutdelay.Theneedforpre-injectionbloodtesttocheckpatients’serumvitaminDandcalcium Patients whoareestablishedon Next zoledronicacidinfusion https://www.nof.org/patients/treatment/exercisesafe-movement/osteoporosis-exercise-for-strong-bones/ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ ⚬ http://www.nof.org https://www.iofbonehealth.org/nutrition https://theros.org.uk/information-and-support/looking-after-your-bones/bone-health-checklist https://www.nhs.uk/conditions/osteoporosis/ https://www.ncsct.co.uk/usr/pub/smoking_and_bone_health.pdf osteoporosis https://theros.org.uk/information-and-support/living-with-osteoporosis/exercise-and-physical-activity-for- iofbonehealth.org/nutrition looking-after-your-bones/bone-health-checklist conditions/osteoporosis/ ( some usefulonlineresourcessuchastheUKNationalCentreforSmokingCessationandTraining(NCST) on highlightingtheimportanceofcontinuingwithpositivelifestylemeasures.Patientscanbedirectedto sedentary lifestyle,unhealthydietandincreasingalcoholconsumption.Patienteducationshouldfocus when self-isolationishighlyimposed,manypatientswouldbetemptedtogobackoldhabitsofsmoking, maintaining ahealthybodyweight,avoidingsmokingandminimisingalcoholintake.Duringthisperiod All patients https://www.ncsct.co.uk/usr/pub/smoking_and_bone_health.pdf shouldbeeducatedontheimportanceofengaginginregularexercise.Withrestrictions shouldbeeducatedontheimportanceofcontinuingwiththeircalciumandvitaminDeitherby N JGittoesandothers duringtheCOVID-19pandemictoavoidconfusiondueriskofdevelopingmild‘flu-like’ shouldbeeducatedontheimportanceoflifestylemeasuressuchashealthy-balanceddiet, ), theRoyalOsteoporosisSociety( ), theNationalOsteoporosisFoundation( canbedelayedforatleast6–9months teriparatide, abaloparatideorromosozumab 6-monthly denosumab(Prolia®) zoledronicacidinfusion,teriparatide,romosozumabor https://www.iofbonehealth.org/exercise to self-administer and osteoporosis COVID-19, calciumdisorders ), theInternationalOsteoporosisFoundation( next zoledronicacidinfusion https://theros.org.uk/information-and-support/ theirdenosumabinjection,trainingoninjection https://theros.org.uk/information-and-support/ teriparatide orabaloparatide denosumab injectionsshouldcontinuewiththeir denosumab ), UKNHSwebsite( ), theNationalOsteoporosisFoundation http://www.nof.org zoledronic acid Downloaded fromBioscientifica.com at09/29/202104:14:04AM teriparatide andabaloparatide (Prolia®)injectionshouldnot treatment. Therefore, due to its treatment.Therefore,duetoits injectionshouldcontinuewith https://eje.bioscientifica.com shouldbeinformedof ). 8 ) and therefore delaying ) andthereforedelaying https://www.nhs.uk/ . Patients should be . Patientsshouldbe 183 ) :2 treatment https://www. (Continued) G63 ) and via freeaccess

European Journal of Endocrinology https://eje.bioscientifica.com • consequence forserviceprovision? What mightbethelonger-term See and osteoporosis? patients withcalciumdisorders Which onlineresourcesareavailablefor Table 2 Empower Engage • Clinical PracticeGuidance patients are not missed and have appropriate recall patients arenotmissedand haveappropriaterecall place reliabledatabasesand registriestoensurethat need forclinicalassessments. Itisessentialtohavein for addressinglargenumbers withpostponedcareand by areturntobusinessasusual.Therewillberequirement The aftermathofthepandemicwillnotbecharacterised Table 1

Continued. . • • • • • • • • • • • • • • • • and support. Provide patientswiththedetailsofdedicatedservicehelplineorthatpatientsupportgroupforadvice Well-informed andwell-equippedpatientsarelikelytobeempoweredfacilitateself-management. members andthepublic. with osteoporosisduringCOVID-19outbreakwillenablethemtoprovideappropriatesupporttheir the UK.Informingthemofapproachbeingadoptedlocallyorregionallyonmanagementpatients support/advocacy group.OsteoporosispatientgroupsareveryactiveinmostWesternisedcountryincluding Engaging patientsupport/advocacygroups resources-for-managing-endocrine-conditions/ osteoporosis duringtheCOVID-19pandemic( where cliniciansaresharingtheirlocalguidelineandprotocolformanagingendocrineconditionsincluding early adoptioninothercentres.AgoodexampleofthisistheinitiativefromSocietyEndocrinology(UK) practice shouldalsobefacilitatedthroughanationalplatformtoavoidreinventingthewheelandfacilitate and protocolswithpragmaticapproachtoosteoporosismanagementshouldbeshared.Sharingofinnovative clinicians specialisinginosteoporosismanagementshouldbeengagedatnationallevel.Clinicalguidelines Engaging otherosteoporosisexpertnationally programme nowoffersdedicatednursehelplinewhichwillsupportpatientonself-administration. support programmeisavailableforpatientinProliainjectionandremindspatientsoftheirnextinjection.The response totheCOVID-19pandemic,AMGENhasintensifieditsPROLONGsupportprogramme. teriparatide, denosumab),orhomecareprovisiontoassistpatientsonself-administration.Recently,in be exploredsuchasprovisiononline,telephonesupport,ofhomedeliverymedication(e.g. Engaging pharmaceuticalcompanies patients totravelthehospital. care clinicianstocontinueprescribingandadministeringpatients’denosumabinjectionwithouttheneedfor shared carearrangementshouldbediscussedandencouraged.Sharedwillenableprimary infection, wherestrictself-isolationiswarranted,primarycareengagementneverbeenmorecrucialand prescriptions arenotinterruptedordelayed.ForpatientswhoatincreasedriskofcontractingCOVID-19 by patients)itshouldbeclearlycommunicatedtotheirprimarycarecliniciansensurethatmedication delayed. For that otherosteoporosismedication(e.g.calciumand/orvitaminD)prescriptionsarenotinterruptedor acid treatmentandteriparatide Engaging primarycareclinicians. ensure safepreparationandadministrationtechniquesarefollowedonthedayofProliainjection. Following this,patients(ortheirfamily/carer)canbeguidedonself-administrationviavideoconsultationto the possibilityofself-administrationbypatient,orwithsupporttheirfamilycarer,shouldbeexplored. To enablepatientstocontinuewiththeir distancing, regularhandwashingandself-isolationwhenrequired. be involvedinthecareofpatientsandshouldencouragedtosupportobservingstringentsocial are overageof70andthereforeatthehigh-riskcategoryforcontractingCOVID-19.Familycarersshould Osteoporosis ispredominantlyadiseaseaffectingwomenovertheageof50yearsandsignificantproportion denosumab N JGittoesandothers treatment(eitherthroughprimarycare,secondarycareofself-administration shouldbeclearlycommunicatedtotheirprimarycarecliniciansensure Managementplanandarrangementforpatientstodelaytheir . Supportthatcanbeprovidedbypharmaceuticalindustryshould 6-monthly denosumab https://www.endocrinology.org/clinical-practice/covid-19- . Akeystakeholderinosteoporosismanagementisthepatient • • • • • ) and osteoporosis COVID-19, calciumdisorders • • • • • . Toensureconsistencyinthedeliveryofosteoporosiscare, should beprioritisedwhenre-implementing services. Patients withlessstabledisorders ofcalciumbalance patient scenarios. by risk assessment of disease categories and individual should be guided Reinstitution of elements of services therapeutic interventions. postponed non-urgentelectiveconsultations,testsand During theacutephaseofpandemicwehave and metabolicbonediseases. catalyst toinnovationinourmanagementofmineral asa The collectiveresponsetoCOVID-19hasserved should accesssuch. with calciummetabolicdisordersandosteoporosis When effectivevaccinesbecomeavailable,patients canberesumedmoresafely.services procedures foradministrationofdrugtherapieswhen injectionduringtheperiodofself-isolation, Downloaded fromBioscientifica.com at09/29/202104:14:04AM 183 :2 zoledronic G64 via freeaccess European Journal of Endocrinology References the public,commercialornot-for-profitsector. This research did not receive any specific grant from any funding agency in Funding be could that interest of conflict perceived asprejudicingtheimpartialityofthisguidance. no is there that declare authors The Declaration ofinterest the managementplanforaspecificpatient. care. medical of standard devising when circumstances individual consider absolute to need staff Healthcare an determine to intended not is it rapid on but meta-analysis, only; guidance as considered be should or document The consensus. expert review systematic extensive on based not is document this crisis, COVID-19 the of nature emerging the to Due Disclaimer • • • • • • 1 Clinical PracticeGuidance collective response. lie insharingknowledgeandresources toenablea challenges andvulnerabilitiesthatthesolutions The crisishashighlightedthatwesharecommon lasting legaciesofthepandemic. building strongernationalandinternationaltiesare care andsecondary between primary Patient centredmanagement, able tobuildmoreresilientsystems. appointments anddigitalhealthsolutionswewillbe their diseasemanagementandsupportingwithremote By Huang C, Wang Y, Li X,Ren L,Zhao J,Hu Y, Zhang L,Fan G,Xu J, Gu X empowering patients et al. Clinicalfeaturesofpatientsinfectedwith2019novel totakeonmorecontrolof N JGittoesandothers coordination and Accepted 11May2020 Received 17April2020

and osteoporosis COVID-19, calciumdisorders 6 5 4 3 2 8 7 Walsh J, Gittoes N,Selby P&SocietyforEndocrinology Clinical Dancer RCA, Parekh D,Lax S,Souza V, Zheng S,Bassford CR, Martineau AR, Jolliffe DA,Hooper RL,Greenberg L,Aloia JF, Grant WB, Lahore H,McDonnell SL,Baggerly CA,French CB, Chen S, Zhang Z,Yang J, Wang J, Zhai X,Bärnighausen T&Wang C. Reid IR, Horne AM,Mihov B,Stewart A,Garratt E,Wong S, Turner J, Gittoes N,Selby P&SocietyforEndocrinologyClinical com/content/70/7/617.abstract (ARDS). distress syndrome contributes directlytotheacuterespiratory Park D, Bartis DG,Mahida R,Turner AM i6583) com/content/356/bmj.i6583.abstract participant data. infections: systematicreviewandmeta-analysisofindividual Vitamin tract Dsupplementationtopreventacuterespiratory Bergman P, Dubnov-Raz G,Esposito S,Ganmaa D,Ginde AA 6643/12/4/988 Nutrients could reduceriskofinfluenzaandCOVID-19infectionsdeaths. Aliano JL &Bhattoa HP. EvidencethatvitaminDsupplementation org/10.1016/S0140-6736(20)30744-3 health emergencies. Fangcang shelterhospitals:anovelconceptforrespondingtopublic org/10.1016/S0140-6736(20)30183-5) 6736(20)30183-5/fulltext#.XpGkh30s19Q.mendeley at: coronavirus inWuhan, China. NEJMoa1808082) ofMedicine Journal with zoledronateinolderwomenosteopenia. Wiessing KR, Bolland MJ, Bastin S &Gamble GD. Fractureprevention ec/5/5/G7.xml G7–G8. (availableat: hypocalcaemia inadultpatients. EMERGENCY GUIDANCE:Emergencymanagementofacute Committee. SOCIETYFORENDOCRINOLOGYENDOCRINE ec/5/5/G9.xml G9–G11. (availableat: hypercalcaemia inadult patients. EMERGENCY GUIDANCE:Emergencymanagementofacute Committee. SOCIETYFORENDOCRINOLOGYENDOCRINE https://www.thelancet.com/journals/lancet/article/PIIS0140- Thorax 2020 ). ). 12 ). 2015 (https://doi.org/10.1530/EC-16-0056) (https://doi.org/10.1530/EC-16-0055) (https://doi.org/10.3390/nu12040988) BMJ 988.(availableat: 2018 Lancet 2017 70 https://ec.bioscientifica.com/view/journals/ https://ec.bioscientifica.com/view/journals/ 617–624.(availablefrom: 379 2020 Downloaded fromBioscientifica.com at09/29/202104:14:04AM 356 2407–2416. Lancet ) i6583.(availableat: 395 Endocrine Connections Endocrine Connections https://eje.bioscientifica.com https://www.mdpi.com/2072- ) ). 1305–1314.( 2020 (https://doi.org/10.1136/bmj. et al (https://doi.org/10.1056/ 183 395 . Vitamin Ddeficiency :2 497–506.(available https://doi. http://thorax.bmj. New England http://www.bmj. ). (https://doi. 2016 2016 5 et al. 5

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