Uso Uso Prolongado deProlongado de Esteroides y Esteroides y Metabolismo Metabolismo

de Calciode CalcioMarco Danon, M.D.Marco Danon, M.D.

Miami Children’s HospitalMiami Children’s Hospital

IV CONGRESO COLOMBIANO DE NEFROLOGÍA PEDIÁTRICA

Systemic Systemic glucocorticoidsglucocorticoids

Rheumatological conditions Inflammatory bowel diseaseNephrotic syndromeDuchenne muscular dystrophyCystic fibrosisLeukemiaOrgan & bone marrow transplantation

Disordered pubertyThalassemia majorAnorexia nervosaGonadal damage due to radiotherapy/chemotherapyKlinefelter’s syndromeTurner syndromeGalactosemia

Childhood osteoporosisChildhood osteoporosis

Primary osteoporosisPrimary osteoporosis Osteogenesis imperfectaOsteogenesis imperfecta

Idiopathic juvenile Idiopathic juvenile osteoporosisosteoporosis

Osteoporosis pseudoglioma Osteoporosis pseudoglioma syndromesyndrome

Secondary Secondary osteoporosisosteoporosis Reduced mobilityReduced mobility

Inflammatory cytokinesInflammatory cytokines

Systemic glucocorticoidsSystemic glucocorticoids

Disordered pubertyDisordered puberty

Poor nutrition/low body Poor nutrition/low body weightweight

Measurement of Bone DensityMeasurement of Bone DensityDual energy X-ray absorptiometry (DEXA)Dual energy X-ray absorptiometry (DEXA)

Direct measurement of mineral contentDirect measurement of mineral content Indirect assessment of densityIndirect assessment of density Results are affected by body size and Results are affected by body size and

skeletal maturityskeletal maturity Does not measure trabecular density Does not measure trabecular density

separatelyseparately Must be evaluated with pediatric softwareMust be evaluated with pediatric software Results must be obtained as Z-score Results must be obtained as Z-score

(subject’s results compared to age and (subject’s results compared to age and gender – matched controls)gender – matched controls)

DO NOT USE T-scoresDO NOT USE T-scores

Formation(+) and Resorption (-) activities during bone growth from A to B

Bone size effect on dual-energy x-ray absorptiometry scan results

Impact of bone size on dual X-ray absorptiometry measurements of BMD

Guidelines from Professional Guidelines from Professional SocietiesSocieties

NIH Consensus Statement 2000NIH Consensus Statement 2000 The International Society of

Clinical Densitometry (ISCD)

recommends evaluation of BMC and BMD for a child’s age 2004

BMDCS (Bone Mineral Density in BMDCS (Bone Mineral Density in Childhood Study) 2006Childhood Study) 2006

WHO 2007WHO 2007

The Bone Mineral Density in Childhood Study: Bone

Mineral Content and Density According to Age, Sex,and Race Participants: 1554 healthy children (761 male, 793 female),

ages 6–16 yr, of all ethnicities Objective: Establish reference curves for bone mineral content (BMC) and density (BMD) in children Design and Setting: The BMDC Study (measurements annually at 5 centers in US). DXA scans by bone densitometers Conclusions: Age-, race-, and sex-specific reference

curves are used to identify children with bone deficits and for monitoring bone changes in response to diseases or therapies

JCEM 92: 2087, 2007

Total hip, femoral neck, and one third radius BMD by age for non-Black (n = 603) and Black (n = 190) girls. Smoothed curves are given for the 3rd, 25th, 50th, 75th, and 97th percentiles. The plotted points represent the corresponding empirical percentile values for a given age group.

Glucorticoid induced Osteoporosis in Children: Crohn Disease & Nephrotic Syndrome

2

TABLE 2

The Anabolic Window

Canalis E et al. N Engl J Med 2007;357:905-916

Signals Determining Mesenchymal-Cell Differentiation toward Osteoblasts and Signals Acting on Mature Osteoblasts to Enhance Bone Formation

Canalis E et al. N Engl J Med 2007;357:905-916

Signaling Pathways Used by Bone Morphometric Proteins in Osteoblasts

Canalis E et al. N Engl J Med 2007;357:905-916

The Canonical Wnt–β-Catenin Signaling Pathway Used in Osteoblasts

Canalis E et al. N Engl J Med 2007;357:905-916

Therapy: General MeasuresTherapy: General Measures Reduce or eliminate skeletal risk factors Reduce or eliminate skeletal risk factors Daily Ca & vit D. Maintain 25-OH-D above 20 Daily Ca & vit D. Maintain 25-OH-D above 20

ng/ml ng/ml Address underweight or obesity. Address underweight or obesity. Avoid immobilization or excessive activity Avoid immobilization or excessive activity Correct endogenous or iatrogenic excess of Correct endogenous or iatrogenic excess of

thyroid or glucocorticoid thyroid or glucocorticoid Sex steroid replacement for 1° or 2° Sex steroid replacement for 1° or 2°

hypogonadism. hypogonadism. Reduce activity of underlying disease. May Reduce activity of underlying disease. May

require glucocorticoids, methotrexate, or require glucocorticoids, methotrexate, or other osteotoxic agents, the net benefit: other osteotoxic agents, the net benefit: reduced inflammation (cytokines act through reduced inflammation (cytokines act through the receptor activator of nuclear factor-the receptor activator of nuclear factor-[kappa]B (RANK)/RANK ligand system and [kappa]B (RANK)/RANK ligand system and ↓reduce bone formation and increase↑bone ↓reduce bone formation and increase↑bone loss similar to glucocorticoids) loss similar to glucocorticoids)

Therapy: General MeasuresTherapy: General Measures These general measures have proven These general measures have proven

effectiveeffective BMD increases with weight gain in BMD increases with weight gain in

patients with anorexia nervosa, even patients with anorexia nervosa, even without the return of spontaneous menses without the return of spontaneous menses

By contrast, sex steroids have failed to By contrast, sex steroids have failed to improve BMD in randomized controlled improve BMD in randomized controlled trials to treat anorexia nervosa in young trials to treat anorexia nervosa in young women women

For children with restricted mobility, gains For children with restricted mobility, gains in bone mass occur with even modest in bone mass occur with even modest increases in skeletal loading through increases in skeletal loading through physical therapy or standing on vibrating physical therapy or standing on vibrating platforms platforms

Pharmacological therapyPharmacological therapy When failing to general measures When failing to general measures PTH, the most effective anabolic PTH, the most effective anabolic

agent for bone in adults, has a black agent for bone in adults, has a black box warning against its use in box warning against its use in children and teens, because it has children and teens, because it has caused osteosarcoma in growing caused osteosarcoma in growing animals. animals.

Anticatabolic agents remain the Anticatabolic agents remain the only pharmacological alternative for only pharmacological alternative for younger patients at the present timeyounger patients at the present time

Growth hormone response toGrowth hormone response to prednisone dose prednisone dose

J Pediatr 125: 322, 1994

BisphosphonatesBisphosphonates Treatment for children with OI became Treatment for children with OI became

more widespread after iv pamidronate was more widespread after iv pamidronate was shown to reduce bone pain and fractures shown to reduce bone pain and fractures in an open-label trial of 30 patients in an open-label trial of 30 patients

Over the past 20 years, oral and Over the past 20 years, oral and parenteral bisphosphonates have been parenteral bisphosphonates have been used to treat OI as well as steroid-used to treat OI as well as steroid-associated osteoporosis, cerebral palsy, associated osteoporosis, cerebral palsy, muscular dystrophy, burns, idiopathic muscular dystrophy, burns, idiopathic juvenile osteoporosis, and other pediatric juvenile osteoporosis, and other pediatric disorders of bone fragility disorders of bone fragility

BisphosphonatesBisphosphonates A Cochrane review on pediatric A Cochrane review on pediatric

bisphosphonate use for secondary bisphosphonate use for secondary osteoporosis up to 2007 osteoporosis up to 2007

807 articles, only 33 were appropriate for 807 articles, only 33 were appropriate for analysis including 6 randomized controlled analysis including 6 randomized controlled trials, 2 case-controlled trials, 1 cohort trials, 2 case-controlled trials, 1 cohort study, and 24 case studies or seriesstudy, and 24 case studies or series

Because studies differed in the drugs and Because studies differed in the drugs and doses used, the disorders treated, and the doses used, the disorders treated, and the clinical endpoints assessed, findings from clinical endpoints assessed, findings from the various randomized trials could not be the various randomized trials could not be combined for analysiscombined for analysis

BisphosphonatesBisphosphonates Data from several pediatric trials: Data from several pediatric trials: BMD ↑increased in response to BMD ↑increased in response to

oral alendronate in children after oral alendronate in children after renal transplantation and other renal transplantation and other illness requiring glucocorticoids illness requiring glucocorticoids

By contrast, gains in BMD with By contrast, gains in BMD with alendronate therapy in teens with alendronate therapy in teens with anorexia nervosa were not anorexia nervosa were not significantly greater than those in significantly greater than those in patients receiving placebo after patients receiving placebo after correcting for body weight correcting for body weight

Bisphosphonate treatment protocols for pediatric disorders

J Clin Endocrinol Metab 94: 400, 2009

Nephropathy treated with glucocorticoids

Oral125 mg/dPamidronateKim 2006 (53 )

Active systemic or polyarticularjuvenile chronic arthritis

Oral1200 mg daily in three divided dosesClodronateLepore 1991 (54 )

Children with chronic illnesses treated with glucocorticoids

Oral1–2 mg/kg · wkAlendronateRudge 2005 (52 )

Anorexia nervosaOral10 mg/dAlendronateGolden 2005 (50 )

Postrenal transplantationOral5 mg/dAlendronateEl-Husseini 2004 (49 )

Rheumatological disorders treated with glucocorticoids

Oral5 mg/d 20 kg; 10 mg/d >20 kgAlendronateBianchi 2000 (56 )

OI with restricted ambulation (Sakkers) and children > age 3 (Kok)

Oral10 mg/m2 dailyOlpadronateSakkers 2004 (42 ) and Kok2007 (46 )

Various bone disorders including osteoporosis and avascular necrosis

iv0.25 mg/kg every 3 monthsZoledronateHogler 2004 (63 )

OI in prepubertal childreniv2 mg/kg every 3 monthsNeridronateGatti 2005 (43 )

OI in the neonatal periodiv2 mg/kg for 2 d every 3 monthsNeridronateAntoniazzi 2006 (47 )

OI in children > age 3Oral, ivAlendronate, 1 mg/kg · d (max 20 mg/d); pamidronate, 1 mg/kg · d for each of 3 d, every 4 months

Alendronate, pamidronate

DiMeglio 2006 (45 )

Nephrology and rheumatology patientsiv1 mg/kg (max 90 mg) every 2 monthsPamidronateAcott 2005 (55 )

Quadriplegic cerebral palsyiv1 mg/kg · d (not <15 mg or >30 mg) for each of 3 d, every 3 months

PamidronateHenderson 2002 (48 )

Children 4–16 yr of age with types III and IV OI

iv10 mg/m2 · d for each of 3 d, every 3 monthsPamidronateLetocha 2005 (44 )

OI > age 3, idiopathic juvenile osteoporosis, steroid-associated

osteoporosis, Duchenne muscular dystrophy, HIV, spina bifida

iv1 mg/kg (max 30 mg) every 3 monthsPamidronateGandrud 2003 (60 ), Steelman2003 (61), and Plotkin 2006 (62 )

OI in children age 2iv0.5–1.0 mg/kg · d for each of 3 d, every 2 to 4 months

PamidronatePlotkin 2000 (41 )

OI in children > age 3iv1 mg/kg · d for each of 3 d, every 4 monthsPamidronateGlorieux 1998 (40 )

IllnessRouteDose1DrugAuthor and year (Ref.)

Nephropathy treated with glucocorticoids

Oral125 mg/dPamidronateKim 2006 (53 )

Active systemic or polyarticularjuvenile chronic arthritis

Oral1200 mg daily in three divided dosesClodronateLepore 1991 (54 )

Children with chronic illnesses treated with glucocorticoids

Oral1–2 mg/kg · wkAlendronateRudge 2005 (52 )

Anorexia nervosaOral10 mg/dAlendronateGolden 2005 (50 )

Postrenal transplantationOral5 mg/dAlendronateEl-Husseini 2004 (49 )

Rheumatological disorders treated with glucocorticoids

Oral5 mg/d 20 kg; 10 mg/d >20 kgAlendronateBianchi 2000 (56 )

OI with restricted ambulation (Sakkers) and children > age 3 (Kok)

Oral10 mg/m2 dailyOlpadronateSakkers 2004 (42 ) and Kok2007 (46 )

Various bone disorders including osteoporosis and avascular necrosis

iv0.25 mg/kg every 3 monthsZoledronateHogler 2004 (63 )

OI in prepubertal childreniv2 mg/kg every 3 monthsNeridronateGatti 2005 (43 )

OI in the neonatal periodiv2 mg/kg for 2 d every 3 monthsNeridronateAntoniazzi 2006 (47 )

OI in children > age 3Oral, ivAlendronate, 1 mg/kg · d (max 20 mg/d); pamidronate, 1 mg/kg · d for each of 3 d, every 4 months

Alendronate, pamidronate

DiMeglio 2006 (45 )

Nephrology and rheumatology patientsiv1 mg/kg (max 90 mg) every 2 monthsPamidronateAcott 2005 (55 )

Quadriplegic cerebral palsyiv1 mg/kg · d (not <15 mg or >30 mg) for each of 3 d, every 3 months

PamidronateHenderson 2002 (48 )

Children 4–16 yr of age with types III and IV OI

iv10 mg/m2 · d for each of 3 d, every 3 monthsPamidronateLetocha 2005 (44 )

OI > age 3, idiopathic juvenile osteoporosis, steroid-associated

osteoporosis, Duchenne muscular dystrophy, HIV, spina bifida

iv1 mg/kg (max 30 mg) every 3 monthsPamidronateGandrud 2003 (60 ), Steelman2003 (61), and Plotkin 2006 (62 )

OI in children age 2iv0.5–1.0 mg/kg · d for each of 3 d, every 2 to 4 months

PamidronatePlotkin 2000 (41 )

OI in children > age 3iv1 mg/kg · d for each of 3 d, every 4 monthsPamidronateGlorieux 1998 (40 )

IllnessRouteDose1DrugAuthor and year (Ref.)

Choice of Bisphosphonates: Choice of Bisphosphonates: Agent and Dose Agent and Dose 

There is no consensus There is no consensus Comparing outcomes: ages and diagnoses Comparing outcomes: ages and diagnoses

influence the skeletal response independent influence the skeletal response independent of the drug or dose employedof the drug or dose employed

Dose of pamidronate to treat OI (1 mg/kg · d Dose of pamidronate to treat OI (1 mg/kg · d for 3 d every 4 months) was extrapolated for 3 d every 4 months) was extrapolated from treatment regimens for adults with from treatment regimens for adults with Paget’s diseasePaget’s disease

Investigators have favored a single day Investigators have favored a single day infusion of 1 mg/kg every 3 months infusion of 1 mg/kg every 3 months

The mean annualized gain in BMD treated The mean annualized gain in BMD treated with the higher-dose pamidronate regimen with the higher-dose pamidronate regimen averaged 42% as compared with 20% with averaged 42% as compared with 20% with lower doses lower doses

Adverse Effects of Adverse Effects of BisphosphonatesBisphosphonates

in Children in Children An acute-phase reaction (fever, malaise, nausea, An acute-phase reaction (fever, malaise, nausea,

diarrhea, and muscle or bone pain) in most children diarrhea, and muscle or bone pain) in most children with the initiation of iv or oral agents.with the initiation of iv or oral agents.

begin typically within 1-3 d of initial exposure, last begin typically within 1-3 d of initial exposure, last only a few days, and rarely recur with subsequent only a few days, and rarely recur with subsequent doses. doses.

Hypocalcemia, hypophosphatemia, and Hypocalcemia, hypophosphatemia, and hypomagnesemia hypomagnesemia

less common, typically asymptomatic, resolve within less common, typically asymptomatic, resolve within daysdays

To reduce the risk of these deficits, adequate vitamin To reduce the risk of these deficits, adequate vitamin D stores and calcium intake must be ensured before D stores and calcium intake must be ensured before and throughout bisphosphonate treatment; and throughout bisphosphonate treatment;

using a lower initial dose of the more potent using a lower initial dose of the more potent bisphosphonate, zoledronic acid, may also be helpful bisphosphonate, zoledronic acid, may also be helpful (73(73

The more serious side effects linked to The more serious side effects linked to bisphosphonates in adults such as uveitis, bisphosphonates in adults such as uveitis, thrombocytopenia, or esophageal or oral ulcerations thrombocytopenia, or esophageal or oral ulcerations are rare in children. are rare in children.

Avascular necrosis of the jaw has not been reported Avascular necrosis of the jaw has not been reported with bisphosphonate therapy in any child or with bisphosphonate therapy in any child or adolescent to date adolescent to date (74)(74). Regardless, a dental . Regardless, a dental evaluation is prudent before and during therapy in evaluation is prudent before and during therapy in children with poor dental health. children with poor dental health.

Other concerns may be unique to the younger Other concerns may be unique to the younger patient. Severe respiratory distress has occurred patient. Severe respiratory distress has occurred with initiation of pamidronate therapy in infants with with initiation of pamidronate therapy in infants with a prior history of reactive airway disease a prior history of reactive airway disease (75)(75). .

In teen-aged girls, there is concern for potential In teen-aged girls, there is concern for potential adverse effects on reproductive health adverse effects on reproductive health (76)(76). .

The half-life of alendronate and pamidronate is The half-life of alendronate and pamidronate is estimated in years estimated in years (77)(77), and these agents can be , and these agents can be released from bone years after termination of released from bone years after termination of therapy. therapy.

The adverse effect of greatest concern in the The adverse effect of greatest concern in the younger patient is oversuppression of bone younger patient is oversuppression of bone modeling and remodeling with bisphosphonate use. modeling and remodeling with bisphosphonate use.

Iatrogenic osteopetrosis and pathological fractures Iatrogenic osteopetrosis and pathological fractures developed in a child treated for 2.75 yr with more developed in a child treated for 2.75 yr with more than four times the high dose (9 mg/kg · yr) of than four times the high dose (9 mg/kg · yr) of pamidronate pamidronate (82)(82). .

Treatment with the standard high dose has not Treatment with the standard high dose has not been shown to delay healing of spontaneous been shown to delay healing of spontaneous fractures but may delay healing of osteotomies in fractures but may delay healing of osteotomies in children with OI children with OI (83, 84)(83, 84). .

Some investigators have hypothesized that the Some investigators have hypothesized that the oscillating saw and cautery used at surgery oscillating saw and cautery used at surgery contribute to delayed healing in this setting contribute to delayed healing in this setting (83(83

Relative potency of Relative potency of bisphosphonates to inhibit bisphosphonates to inhibit

bone resorptionbone resorption BisphosphonatesBisphosphonates

Relative Relative potencypotency

EtidronateEtidronate 11

ClodronateClodronate 1010

PamidronatePamidronate 100100

OlpadronateOlpadronate 200-500200-500

IbandronateIbandronate 500-1000500-1000

AlendronateAlendronate 1000-20001000-2000

RisedronateRisedronate 20002000

ZoledronateZoledronate 1000010000

Bisphosphonate

↓ bone pain

↑ Exercise Capacity

↓ Remodelling space leading to rapid ↑ in bone mass

↓ bone resorption

↑ Renal retention of Ca, ↑ renal losses of PO4, ↑ 1,25 (OH)2- vit D

Hypocalcemia

↑ serum PTH

Failure of normal action of PTH, 1,25 (OH)2-vit D-bone resorption by osteoclastsUnopposed anabolic actions of PTH ± 1,25 (OH)2 – vit D on bone

↑ bone strength, fewer fractures

↑Cortical bone

↓bone formation at trabecular sites

↓ release of Ca, PO4, matrix fragments and components

Bisphosphonate Research in Bisphosphonate Research in ChildrenChildren

challenges to trials (selection of subjects challenges to trials (selection of subjects and outcome measures) and outcome measures)

Risk to benefit ratio-favorable for children Risk to benefit ratio-favorable for children who have already sustained vertebral or who have already sustained vertebral or long bone fractures long bone fractures

Trials are justifiable in patients with Trials are justifiable in patients with documented longitudinal bone loss but no documented longitudinal bone loss but no fractures fractures

Define the natural history and potential Define the natural history and potential for recovery before initiating for recovery before initiating pharmacological therapy pharmacological therapy

Establishing registries for patients facing Establishing registries for patients facing skeletal risk factorsskeletal risk factors

Treatment SummaryTreatment Summary

Controversies:Controversies: Identifying child at greatest risk for Identifying child at greatest risk for fracture fracture

General measures & treatmentGeneral measures & treatment of chronic disease of chronic disease alone uncertain alone uncertain

Clinicians are pressured to use bisphosphonate by Clinicians are pressured to use bisphosphonate by anxious colleagues or parents despite a lack of evidence anxious colleagues or parents despite a lack of evidence

Evidence-basedEvidence-based optimal choice of agent, dose, and optimal choice of agent, dose, and duration of treatment will require randomized, duration of treatment will require randomized, controlled trialscontrolled trials

Until available data, Until available data, conservative useconservative use of of pharmacological agents for osteoporosis is pharmacological agents for osteoporosis is recommended. recommended.

Bisphosphonate is routine care in children with OI Bisphosphonate is routine care in children with OI For osteoporosis associated with chronic illness, For osteoporosis associated with chronic illness,

bisphosphonate is bisphosphonate is recommended onlyrecommended only in clinical trials in clinical trials or compassionate for children with ↓bone mass/density or compassionate for children with ↓bone mass/density associated with low-trauma extremity fractures and associated with low-trauma extremity fractures and symptomatic vertebral compression symptomatic vertebral compression

Albright’s dictumAlbright’s dictum

Les he hablado de esteroides y Les he hablado de esteroides y calcio mas de lo que yo mismo calcio mas de lo que yo mismo sese

Lo que les he dicho esta sujeto Lo que les he dicho esta sujeto a cambio sin previo avisoa cambio sin previo aviso

Espero que haya suscitado mas Espero que haya suscitado mas preguntas que respuestaspreguntas que respuestas

De todos modos hay que De todos modos hay que investigar mucho masinvestigar mucho mas

IV CONGRESO COLOMBIANO DE NEFROLOGÍA PEDIÁTRICA

MuchasMuchasGraciasGracias

IV CONGRESO COLOMBIANO DE NEFROLOGÍA PEDIÁTRICA

Measurement of Bone Measurement of Bone DensityDensity

Peripheral quantitative Peripheral quantitative computerized tomography computerized tomography (pQCT)(pQCT) Direct volumetric measurement of Direct volumetric measurement of

bone densitybone density Results are not affected by body sizeResults are not affected by body size Independent and direct Independent and direct

measurement of trabecular measurement of trabecular compartmentcompartment

Peripheral Quantitative Computerized Tomography