Osteoporosis in Osteoporosis in ChildrenChildren

Nasir A.M. Al-JurayyanNasir A.M. Al-JurayyanProfessor of Paediatrics andProfessor of Paediatrics andConsultant Paediatric EndocrinologistConsultant Paediatric EndocrinologistCollege of Medicine and King Khalid University College of Medicine and King Khalid University HospitalHospitalKing Saud University, RiyadhKing Saud University, Riyadh

Bone consists of a collagen matrix into Bone consists of a collagen matrix into which calcium, in the form of hydroxy which calcium, in the form of hydroxy apatite, is deposited. The accumulation apatite, is deposited. The accumulation and maintenance of the substance of and maintenance of the substance of bone is the result of a continuous bone is the result of a continuous process of process of formationformation, predominantly , predominantly mediated by mediated by osteoblasosteoblast, and t, and resorptionresorption, , facilitated by osteoclast. During facilitated by osteoclast. During childhood and adolescence, formation childhood and adolescence, formation predominates, leading to a net increase predominates, leading to a net increase in bone mass and size, with infancy and in bone mass and size, with infancy and adolescence being periods of adolescence being periods of particularly rapid formation.particularly rapid formation.

OsteoporosisOsteoporosis is defined as a is defined as a systematic disease characterized by systematic disease characterized by

low bone mass and low bone mass and microarchictectural deterioration of microarchictectural deterioration of

bone tissue with a consequent bone tissue with a consequent increase in bone fragility and increase in bone fragility and

susceptibility to fractures, while susceptibility to fractures, while Rickets and osteomalaciaRickets and osteomalacia are due to are due to

failure of bone mineralization.failure of bone mineralization.

Osteoporosis remains the most Osteoporosis remains the most common metabolic bone disorder common metabolic bone disorder

in adults. However, there is now in adults. However, there is now increasing evidence that the increasing evidence that the rootsroots

of osteoporosis lie in childhood.of osteoporosis lie in childhood.

Peak bone mass is achieved Peak bone mass is achieved shortly after completion of shortly after completion of puberty and normally remains puberty and normally remains stable until the 3stable until the 3rdrd decade of life decade of life when age-related (involutional) when age-related (involutional) bone loss begins with a steady bone loss begins with a steady decline (about 1% per year).decline (about 1% per year).

Failure to achieve optimal peak Failure to achieve optimal peak bone mass represents a bone mass represents a significant and preventable risk significant and preventable risk factor for osteoporosis in later factor for osteoporosis in later years.years.

Osteoporosis that is symptomatic Osteoporosis that is symptomatic during childhood is currently during childhood is currently emerging as a emerging as a newlynewly recognized recognized problem among specific at risk problem among specific at risk populations.populations.

Bone Mineral Density DeterminantsBone Mineral Density Determinants

– Intrinsic (unmodifiable) factors (70-Intrinsic (unmodifiable) factors (70-80%)80%)

GenderGender

EthnicityEthnicity

Family BackgroundFamily Background

Males achieve a higher peak bone Males achieve a higher peak bone mass, and because of both larger bone mass, and because of both larger bone size and slower decline in sex steroid size and slower decline in sex steroid levels, aging men have a lower levels, aging men have a lower incidence of osteoporotic fractures than incidence of osteoporotic fractures than women.women.

Boot et al JCEM 1997Boot et al JCEM 1997

Kelly et al J Bone Mineral Res 1990Kelly et al J Bone Mineral Res 1990

Bone Mineral Density DeterminantsBone Mineral Density Determinants

– Intrinsic (unmodifiable) factors (70-Intrinsic (unmodifiable) factors (70-80%)80%)

GenderGender

EthnicityEthnicity

Family BackgroundFamily Background

Osteoporosis and fracture risk is Osteoporosis and fracture risk is lower among African-Americans, lower among African-Americans, both males and females, due to both males and females, due to higher bone mass relative to their higher bone mass relative to their peers in other ethnic groups.peers in other ethnic groups.

Bachrach et al JCEM Bachrach et al JCEM 19991999

Bone mineral density (BMD) in Bone mineral density (BMD) in Saudi children, adolescents and Saudi children, adolescents and adults is low compared to adults is low compared to Caucasian Americans.Caucasian Americans.

**El Desouki MEl Desouki M Saudi Med J 1999Saudi Med J 1999

** El Desouki M El Desouki M Saudi Med J 1995Saudi Med J 1995

Bone Mineral Density Bone Mineral Density DeterminantsDeterminants

– Intrinsic (unmodifiable) factors (70-Intrinsic (unmodifiable) factors (70-80%)80%)

GenderGender

EthnicityEthnicity

Family BackgroundFamily Background

There is a strong familial component to There is a strong familial component to bone mineral density in adults, for bone mineral density in adults, for example; maternal bone mass is a strong example; maternal bone mass is a strong predictor of BMD in both prepubertal boys predictor of BMD in both prepubertal boys and girls, and twins are strongly and girls, and twins are strongly concordant for BMD.concordant for BMD.

A specific genetic marker?A specific genetic marker?

* * Jones G and Nguyen TU J Bone Miner Res Jones G and Nguyen TU J Bone Miner Res 20002000

* Seeman et al Am J Physiol 1996* Seeman et al Am J Physiol 1996

Bone Mineral Density DeterminantsBone Mineral Density Determinants– Extrinsic (modifiable) factorsExtrinsic (modifiable) factors

DietDiet Lifestyle habitsLifestyle habits Hormonal milieuHormonal milieu IllnessIllness MedicationsMedications

Nutritional Rickets and Nutritional Rickets and Osteomalacia in Saudi school Osteomalacia in Saudi school children and adolescentschildren and adolescents

Al-Jurayyan et al Saudi Med J 2002

Are Saudis at risk of developing Are Saudis at risk of developing

Vitamin D deficiency? Vitamin D deficiency?

Sedrani SH. Saudi Med J 1986

Long-term-adult Long-term-adult presentationpresentation

v.s.v.s.

Acute-Pediatric-Acute-Pediatric-PresentationPresentation

Acute Pediatric PresentationAcute Pediatric Presentation

– Primary Risk FactorsPrimary Risk Factors Chronic illnessChronic illness

ImmobilityImmobility

MedicationMedication

Conditions with Impaired Bone Mineral DensityConditions with Impaired Bone Mineral Density

IllnessIllness TreatmentTreatmentOsteogenesis ImperfectionOsteogenesis Imperfection

Malignancy Malignancy

GIT DeficiencyGIT Deficiency

Cortisol ExcessCortisol Excess

HypogonadismHypogonadism

Anorexia NervosaAnorexia Nervosa

HyperthyroidismHyperthyroidism

HyperparathyroidismHyperparathyroidism

GastrointestinalGastrointestinal

CNS/NeuromuscularCNS/Neuromuscular

GlucocorticoidsGlucocorticoids

Immuno suppressantsImmuno suppressants

IrradiationIrradiation

Anti convulsantAnti convulsant

Evaluation and Evaluation and Treatment of Treatment of Osteoporosis in ChildrenOsteoporosis in Children InformationInformation

– History of risk FactorsHistory of risk Factors– Physical ExaminationPhysical Examination– Critical Interpretation of DEXA dataCritical Interpretation of DEXA data– Other Laboratory StudiesOther Laboratory Studies

DecisionDecision– Risk v.s. BenefitRisk v.s. Benefit– Observation or TreatmentObservation or Treatment

Evaluation of the Evaluation of the Osteoporotic PatientOsteoporotic Patient HistoryHistory

– Fracture history-early fracture suggest Fracture history-early fracture suggest genetic abnormality – OIgenetic abnormality – OI

– History of underlying chronic illness – History of underlying chronic illness – patient at risk?patient at risk?

– Dietary history – Calvit D intakeDietary history – Calvit D intake– Medication history Medication history

glucocorticoid, anti convulsantglucocorticoid, anti convulsant

– Activity historyActivity history Immobility / wt bearingImmobility / wt bearing

Evaluation of the Evaluation of the Osteoporotic PatientOsteoporotic Patient

Physical ExaminationPhysical Examination

– Growth patternGrowth pattern Disease or treatment affecting growthDisease or treatment affecting growth

Evidence for collagen diseaseEvidence for collagen disease

Cushingoid featuresCushingoid features

ScoliosisScoliosis

Evaluation of the Evaluation of the Osteoporotic PatientOsteoporotic Patient Laboratory evaluationLaboratory evaluation Ca / P / Alk phosCa / P / Alk phos

– Disorders of calcium metabolismDisorders of calcium metabolism Intact PTH, Vit D metabolitesIntact PTH, Vit D metabolites

– HypoparathyroidismHypoparathyroidism– Vitamin D deficiencyVitamin D deficiency

Free TFree T44, TSH – hyperthyroidism, TSH – hyperthyroidism Urine Calcr - hypercalciuriaUrine Calcr - hypercalciuria Urine amino acidUrine amino acid

– Lysine metabolitesLysine metabolites Skull x-ray for wormian bonesSkull x-ray for wormian bones

– O IO I Spine films – vertebral #Spine films – vertebral # Skin biopsy or DNA – OISkin biopsy or DNA – OI Bone metabolism markers?Bone metabolism markers?

Bone metabolism markers (such as Bone metabolism markers (such as AP, osteocalcin, hydroxyproline) in AP, osteocalcin, hydroxyproline) in serum or urine are inferior to serum or urine are inferior to radiologic BMD measurementsradiologic BMD measurements– Diurnal variationDiurnal variation– Influenced by pubertyInfluenced by puberty– Limited pediatric referenceLimited pediatric reference

RangeRange

De Ridder et al. Curr Opin Pediatr 1998

Evaluation of the Evaluation of the Osteoporotic patientOsteoporotic patient

Determination of BMDDetermination of BMD– Screening at risk patientsScreening at risk patients– Patients with fractures with Patients with fractures with

minimal traumaminimal trauma– Osteopenia on plain film in an Osteopenia on plain film in an

individual with one or more risk individual with one or more risk factorfactor

Whole body – insensitiveWhole body – insensitive Lumbar spine – glucocorticoidsLumbar spine – glucocorticoids Hip – non – wt - bearingHip – non – wt - bearing

The DEXA AlphabetThe DEXA Alphabet BMC – bone mineral content – gBMC – bone mineral content – g BMD – bone mineral density – g/cmBMD – bone mineral density – g/cm22

BMAD – bone mineral areal density = BMDBMAD – bone mineral areal density = BMD BMDBMDvolvol – bone mineral volumetric density – g/cm – bone mineral volumetric density – g/cm33

BMD X [4/(BMD X [4/( x L2-L4 width)] x L2-L4 width)]

T-score – SDS score compared to T-score – SDS score compared to adultadult gender-matched peak gender-matched peak bone mass (25, 35, 45 yo)bone mass (25, 35, 45 yo)*T = -2 means density is 2 SDS below the mean for peak BMD*T = -2 means density is 2 SDS below the mean for peak BMD

Z-score – SDS score compared to age- and gender-matched bone Z-score – SDS score compared to age- and gender-matched bone massmassZ = -2 means density is 2 SDS below the mean for age Z = -2 means density is 2 SDS below the mean for age matched BMDmatched BMD

Calculating and Calculating and Correcting Z-ScoresCorrecting Z-Scores

DEXA values must be analyzed in relation DEXA values must be analyzed in relation to age and gender normal values for the to age and gender normal values for the machine and modelmachine and model– Machine determined Z-score (makers data Machine determined Z-score (makers data

base)base)– Calculation of Z-score based on published dataCalculation of Z-score based on published data– Then correction of Z-score for:Then correction of Z-score for:

ShortnessShortness– Height age normsHeight age norms– Volumetric correctionVolumetric correction

Pubertal delayPubertal delay– Bone age normsBone age norms

Choice of the “right” Choice of the “right” Z-scoreZ-score

??

Diagnosing Pediatric Diagnosing Pediatric OsteoporosisOsteoporosis

Barriers:Barriers:– Lack of diagnostic criteria Lack of diagnostic criteria

What BMD is associated with increased fracture What BMD is associated with increased fracture risk?risk?

– Lack of adequate normative data by age, Lack of adequate normative data by age, gender, racegender, race

– Lack of interchangeability between data Lack of interchangeability between data from different DEXA machinesfrom different DEXA machines

– Antifact may be introduced by variation in Antifact may be introduced by variation in height and puberty.height and puberty.

Treatment of the Osteoporotic Treatment of the Osteoporotic PatientsPatients

BarriersBarriers– No standard definitionNo standard definition– No consensus on the degree of BMD No consensus on the degree of BMD

impairment that places a child at riskimpairment that places a child at risk– No large, well controlled studies No large, well controlled studies

assessing safety and efficacyassessing safety and efficacy

Treatment of the Treatment of the Osteoporotic ChildOsteoporotic Child

A modest proposalA modest proposal– Z-score > -1.5 and no fracturesZ-score > -1.5 and no fractures

Optimize Ca and Vit D Optimize Ca and Vit D

(? 800 iu/d)(? 800 iu/d) Increase activity – wt bearingIncrease activity – wt bearing Repeat DEXA in 6 m.Repeat DEXA in 6 m. ConsiderConsider

– Pubertal v.s. prepubertal on goingRx v.s. Pubertal v.s. prepubertal on goingRx v.s. D/C. D/C.

A modest proposalA modest proposal– Z-score < -1.5 and/or active Z-score < -1.5 and/or active

fracturingfracturing Optimize Ca / Vit DOptimize Ca / Vit D Pharmacological optionsPharmacological options

– Correct known abn.Correct known abn.

– GH↓ - GH -= RGH↓ - GH -= Rxx

– Hyperthyroidism – Antithyroid medicationHyperthyroidism – Antithyroid medication– BiphosphonatesBiphosphonates

Treatment of the Treatment of the Osteoporotic ChildOsteoporotic Child

Treatment of the Treatment of the Osteoporotic ChildOsteoporotic Child Bisphosphonate optionsBisphosphonate options

– Alendronate (Fosamax)Alendronate (Fosamax) Daily oral medication with GI IrritationDaily oral medication with GI Irritation No data in pediatric patientsNo data in pediatric patients

– Pamidronate (Arredia)Pamidronate (Arredia) Most highly studied of the bisphophonates in childrenMost highly studied of the bisphophonates in children Treatment of OI based on Paget disease in adults – 3 Treatment of OI based on Paget disease in adults – 3

day infusion every 2-3 months (0.25 – 1 mg/kg/day)day infusion every 2-3 months (0.25 – 1 mg/kg/day) TCH – 3hr IV infusion every 3 months (30 – 45 mg/day)TCH – 3hr IV infusion every 3 months (30 – 45 mg/day) Well-tolerated with minimal side effects (fever)Well-tolerated with minimal side effects (fever)

– Risedronate (Actonel)Risedronate (Actonel) New oral agent - ? Better toleratedNew oral agent - ? Better tolerated No data in pediatric patientsNo data in pediatric patients

Prevention of Prevention of OsteoporosisOsteoporosis

““Optimizing Peak Bone Mass”Optimizing Peak Bone Mass” Most important – Pick the right Most important – Pick the right

parentsparents Regular weight-bearing activityRegular weight-bearing activity Well-balanced dietWell-balanced diet

– Adequate calciumAdequate calcium– Adequate Vitamin DAdequate Vitamin D

Health life habitsHealth life habits– E.g. avoiding smokingE.g. avoiding smoking

SummarySummary

The prevalence, morbidity and mortality The prevalence, morbidity and mortality of adult osteoporosis continues to growof adult osteoporosis continues to grow

The roots of osteoporosis begin in The roots of osteoporosis begin in childhoodchildhood

Optimization of bone density accretion Optimization of bone density accretion during childhood can be assumed to during childhood can be assumed to have long-term benefitshave long-term benefits

Osteoporosis is also a symptomatic Osteoporosis is also a symptomatic disease of childhood in the setting of disease of childhood in the setting of chronic illness and its treatmentchronic illness and its treatment

Symptomatic Pediatric Symptomatic Pediatric OsteoporosisOsteoporosis

A previously under-recognized problem, with A previously under-recognized problem, with increasing prevalenceincreasing prevalence

Well-defined high-risk populationsWell-defined high-risk populations Significant short-term morbidity promotes a Significant short-term morbidity promotes a

cycle of disabilitycycle of disability Long-term consequences likely, but not studiedLong-term consequences likely, but not studied Effective, well-tolerated treatment options are Effective, well-tolerated treatment options are

now availablenow available Clinicians should actively identify at-risk Clinicians should actively identify at-risk

patients, evaluate bone density, and consider patients, evaluate bone density, and consider treatment.treatment.