childhood osteoporosis

8/16/2019 Childhood Osteoporosis

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Childhood Osteoporosis

Khalid I. Khoshhal FRCS Ed, ABOS

Department of Orthopedics Surgery, College of MedicineTaibah University, Almadinah Almunawwarah, Kingdom of Saudi Arabia

Introduction

steoporosis is a major public healthproblem worldwide and its prevalence

is increasing. This morbidity burden hasconsiderable medical, social and financialimplications due to the fractures associatedwith the disease. Although osteoporoticfractures are an important cause of

morbidity, disability and mortality, they arepreventable. Osteoporosis is a well-estab-lished clinical worldwide problem foradults. On the other hand, osteoporosis inchildren and adolescents is rather new andincreasingly recognized with certain uniquediagnostic and clinical challenges1-2. In fact,some researchers suggested that osteo-

porosis seen later in life may originateduring childhood or adolescence years3-4.Osteoporosis is a systemic disorder definedas “decreased bone strength thatpredisposes individuals to fragilityfractures”5. Bone strength reflects theintegration of two main features: bonedensity and bone quality6. In children, asomewhat different definition exists,

requiring both a history of pathologicfractures and low bone mineral content ordensity7. These criteria are fulfilled by thediagnosis of a single significant fracture in along bone of the lower extremity, twofractures in the long bone of an upperextremity, or one vertebral compressionfracture8-9. The relationship between bone

O

AbstractOsteoporosis has long been considered a health problem unique to postmenopausal womenand elderly. It is being increasingly recognized that osteoporosis could affect children as aprimary problem and as secondary to various diseases, and medications. The present reviewdiscusses the current definition of osteoporosis in children, its causes, types and risk factorsfor low bone mineral density, in addition to prevention and treatment strategies that can helpoptimize bone health in children.

Key words: Bone mineral density, Children, Fragility fractures, Osteopenia, Osteoporosis,

Primary osteoporosis, Secondary osteoporosis.

Journal of Taibah University Medical Sciences 2011; 6(2): 61-76

Correspondence to:

Dr. Khalid I. KhoshhalDepartment of Orthopedics SurgeryAssociate Professor of Orthopedics and Consultant PediatricOrthopedics Surgeon, College of Medicine, Taibah University 30001 Almadinah AlmunawwarahKingdom of Saudi Arabia +966 4 8460008

+966 4 8232506 [email protected]

REVIEW ARTICLE


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density and fracture risk is currentlyunknown in children and therefore it is notpossible to define thresholds below whichthere is an increased fracture risk; althoughthere are now several studies that haveexamined the relationship between bone

density in healthy children andfractures10,11.Osteopenia is a term that is often confusedwith osteoporosis. Osteopenia is defined asa decrease in the amount of bone tissue,and osteoporosis is osteopenia with bonefragility. On the other hand, osteopeniashould not be confused with osteomalacia(reduction in bone mineral with theaccumulation of unmineralized bonematrix). Both osteopenia and osteomalaciaare associated with a reduction in bone

density and may result in bone pain andfracture, but their causes and managementare quite different3.

Methods

An extensive literature search of English-language electronic databases in Medline,PubMed, and Cochrane database ofevidence-based reviews was performedstarting 2000 onwards. Further articleswere obtained from the references of the

initial search. Keywords osteoporosis,children, primary osteoporosis, secondaryosteoporosis, osteopenia, bone mineraldensity and fragility fractures were used.Abstracts of the relevant articles werescrutinized, and the pertinent articles werereviewed in detail. This includednarrowing down the search forosteoporosis in children in various regionsof the world concerning its classification,presentation, pathophysiology, diagnosticmodalities and prevention and treatmentoptions, and inference was drawn.

Clinical Presentation

A common presentation of childhoodosteoporosis is recurrent long bonefractures, particularly if associated withlow impact trauma. Vertebral compressionfractures often present with symptoms ofback pain and potential spinal deformity.Occasionally, vertebral compression

fractures may be asymptomatic and mayonly be identified when a spinal X-ray isperformed in a child who is being investi-gated for a low bone density or any otherreason. Symptomatic osteoporosis may bethe first manifestation of an underlying

chronic disease such as leukemia orCrohn’s disease12. Idiopathic juvenileosteoporosis (IJO) which is a rare cause ofprimary osteoporosis will often presentwith progressive symptoms of back painand difficulty in walking.

Causes and Classification

Race and ethnicity constitute nonmodifiable risk factors for osteoporosis.Genetic predisposition to other systemic

illnesses and the treatments thusnecessitated likewise play a role in bonehealth. Childhood osteoporosis may arisefrom an intrinsic genetic bone abnormality(primary osteoporosis) or more commonlysecondary to an underlying medicalcondition and/or its treatment (secondaryosteoporosis)3,13.

Primary osteoporosisPrimary osteoporosis as defined bydecreased bone strength that predisposesindividuals to fragility fractures, is mostcommonly caused in children by one orother of the forms of osteogenesis imper-fecta (OI)14. In OI there is an underlyingabnormality in bone matrix composition,usually due to defective synthesis of type Icollagen. The original classification bySillence D, based on phenotypic features,consisted of four types which are varyingin severity. Type II OI is lethal in theperinatal period. Type III is a severe formof the disease with obvious bonydeformities and reduced bone mineral

density (BMD). Although types I and IV aremilder and less easily recognized, theyshould be considered in the differentialdiagnosis of children with multiple frac-tures4,8. Collagen can often be demon-strated with either a reduction in amount(type I) or quality (types II, III and IV). It isrecognized that some children with OI donot clearly fall into one of these four types.


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In recent years, three additional forms ofOI have been identified (types V, VI, andVII) based on a combination of phenotypicand bone histological features15.Another example of primary osteoporosis isIJO which is a rare condition with an

estimated incidence of 1 in 100,000 that ischaracteristically presents with back pain,difficulty walking and vertebral compres-sion fractures usually in early puberty(Figure 1). Its precise cause is unclearalthough on bone histology, there is anevidence of reduced bone formation.Spontaneous resolution has been reported insome IJO patients while others go on to havea severe disability with a potential loss ofwalking ability.Osteoporosis pseudoglioma syndrome is a

third very rare example in which there is acombination of osteoporosis, and congenitalblindness due to failure of peripheral retinavascularization8.

Figure 1: Vertebral compression fractures in thelumbar spine with osteopenia in a child with

idiopathic juvenile osteoporosis.

Secondary OsteoporosisChronic systemic diseases can bedetrimental to the growing skeleton inchildren. Chronic renal insufficiency leadsto abnormal bone metabolism viadisturbances in calcium and phosphatehandling, altered vitamin D and parathyroid

hormone (PTH) levels and function, andaltered renal clearance of aluminum andother metabolites. Additional factors includemalnutrition, metabolic acidosis, andanemia16. Gastrointestinal disorders such asceliac disease and inflammatory bowel

disease interfere with calcium absorptionfrom the gut and cause vitamin Dinsufficiency or deficiency. Liver dys-function can affect children and may impairbone health through calcium and vitaminmalabsorption, failure of vitamin D acti-vation, bile salt deficiency, and chronicmalnutrition12,17.Endocrine system disorders that result ininadequate or excessive levels of systemichormones can negatively impact bone healthin the growing skeleton in children. For

example, growth hormone deficiency,diabetes mellitus (DM), and hyperthyroid-dism are all risk factors for osteoporosis18,19.Bone turnover is altered in type 1 DMchildren, whereas BMD remains normalduring growth. Physical activity and optimalcalcium intakes may improve bonemetabolism and delay osteoporosis20. Pub-ertal hormones, especially estrogen, play acritical role in bone mass acquisition. Becausethe majority of BMD is accrued during theperipubertal years, recognition and timelytreatment of hypogonadism are key.Decreased muscle development and im-paired ambulation in children with cerebralpalsy (CP) and muscular dystrophycontribute to increased risk of osteoporosis(Table 1)21-22.

Causes of secondary osteoporosis

1.

Reduced mobilityBones develop to withstand the mechanicalforces applied to them in everyday life. Themagnitude of these forces and the skeleton’s

ability to sense and respond to them have amajor influence on the mineral content andarchitectural design of bone, and thereforeits strength22. In a normal ambulatory child,the major bone strains result from musclepull and growth. These factors are ofparamount importance to chronicallydiseased children, in whom reducedmobility and thus muscle load is a major


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cause of reduced bone mass and strength.This is most notable in children withneuromuscular disorders (Table 1). Themost common site of fracture in childrenwith reduced mobility is the distal femur(Figure 2). This is because their long bones

tend to be slender with thin cortices andreduced trabecular density, and the lowerlimbs are usually more subjected to traumafrom accidents or handling23-24. Vertebralcompression fractures are less frequent, butif they occur they can be complicated by thedevelopment of scoliosis.

Figure 2: Plain radiograph of the lower limbshowing osteopenia and fracture in lower third of femur in a child with cerebral palsy.

2.

Disordered puberty

Delayed or arrested pubertal developmentmay occur as a result of an underlyingchronic disease and/or its treatment, and

unless assessed prospectively may be easilyoverlooked in the care of the affected child25.Pubertal hormones, estradiol in females andtestosterone in males, influence longitudinalbone growth and bone mineral accrual, withtheir appropriate timing being important fornormal skeletal development and theattainment of peak bone mass3,26-27. It isunclear if the induction of puberty in

otherwise normal child with constitutionaldelay positively influences bone mass atfinal height. Androgen therapy does nothowever positively affect bone mass26.

3.

Malnutrition and abnormal body weight

Adequate nutrition is essential for normalgrowth and development. It is not surprise-ing; therefore, that osteoporosis is associatedwith malnutrition and low body weightdisorders (Table 1)22. The cause of theosteoporosis in such disorders ismultifactorial with interplay between lowbody weight, low calcium, vitamin D andprotein intake, gonadal deficiency, growthhormone resistance and malabsorption28.Children during both health and diseaseshould receive the recommended daily

requirement of calcium. Without adequatesun exposure, even children living in sunnyclimates can become vitamin D deficient29.Because of this, the vitamin D status ofchronically diseased children should beevaluated on an annual basis and ifnecessary, vitamin D supplementationcommenced.Conversely, the obesity epidemic amongyouth is staggering. The overweight orobese children are undernourished in thesense that their diets are generally poor andlack many important nutrients. In addition,obesity itself is a risk factor for fractures inchildren30. Although it seems counterin-tuitive, the data are convincing. Obesechildren are generally sedentary, causingpoor musculoskeletal coordination and in-adequate lean muscle mass to control theirbody mass. Because their bone developmentdoes not keep pace with their weight gain,their relatively immature skeletons mustbear a disproportionate amount of weightwhen they fall and can result in fragilityfractures30.

4.

Inflammatory cytokines and growth factors

Systemic inflammatory disorders arefrequently associated with osteopenia andosteoporosis. The cause of the bone loss ismultifactorial, but increased circulating andfocal concentrations of inflammatory cyto-kines [interleukin-1 (IL-1), IL-6, IL-7, tumornecrosis factor-α‚ and receptor activator of


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nuclear factor-κB ligand (RANKL)] andgrowth factors are likely to play an impor-tant role28. Cytokines have been shown tostimulate osteoclastogenesis, suppress

osteoblast recruitment and induce resistanceto vitamin D, thus increasing boneresorption and decreasing bone formation28.

Table 1: Classification of childhood osteoporosis. Modified from Shaw8.

5.

Systemic glucocorticoids Glucocorticoids are commonly prescribed tochildren with chronic inflammatory and

autoimmune disorders. Glucocorticoids arewell known for their potent anti-inflam-matory effects in patients with chronic

Primaryosteoporosis

Osteogenesis imperfecta

Idiopathic juvenile osteoporosis

Osteoporosis pseudoglioma syndrome

Others like Homocystinuria, Ehlers-Danlos Syndrome (type1)…

Secondaryosteoporosis

Can be discussed under the following subheadings:

Reduced mobility

Cerebral palsy

Spinal cord injury and spina bifida

Duchenne muscular dystrophy

Spinal muscle atrophyHead injury

Unknown neurodisability

Disordered puberty

Thalassemia major

Anorexia nervosa

Gonadal damage due to radiotherapy/chemotherapy

Klinefelter’s syndrome

Galactosemia

Malnutrition / abnormalbody weight

Anorexia nervosa

Chronic systemic disease

Inflammatory bowel disease

Cystic fibrosis

Inflammatory cytokines

Juvenile idiopathic arthritis

Systemic lupus erythematosis

Dermatomyositis

Inflammatory bowel disease

Systemic glucocorticoidsand other medications

Rheumatological conditionsNephrotic syndrome

Leukemia

Organ and bone marrow transplantation


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inflammatory disorders. One adverse effectof glucocorticoid use is its detrimental impacton BMD. At pharmacologic doses, glucocor-ticoids impair the function and reduce the lifeof osteoblasts31. Simultaneously, glucocorti-coids accelerate the maturation and activity

of osteoclasts while exerting antiapoptoticeffects on these cells32. In addition,glucocorticoids reduce intestinal calciumabsorption and promote renal calciumexcretion. Thus, chronic glucocorticoidtherapy results in an increase in PTHsecretion which promotes bone resorption29.Therefore, the combination of impaired boneformation and accelerated bone resorptionincreases risk of osteopenia and osteoporosis(Figure 3).

Figure 3: Left femur demonstrates severeosteoporosis with marked loss of bone density inan older child on long standing steroid therapy.

Vertebral compression fractures are themost prevalent fractures associated withglucocorticoid use in children. Gafni et al,showed that following the cessation ofglucocorticoid therapy in young rabbits,growth and modeling allowed for steroid-induced osteoporotic bone to be completelyreplaced by normal healthy bone33. This

may provide another mechanism by whichthe bone health of the children studied byLeonard et al, improved between steroiddoses34. These data also suggest that early inlife, temporary insults to the child skeletonmay not decrease peak bone mass. How-ever, insults towards the end of the growingperiod may have more long lasting effectson bone integrity33. It is unclear if there is a

safe, yet therapeutic, dose below whichglucocorticoids do not adversely influencebone in children. Until this data is available,it is essential that children be prescribed thesmallest effective dose of glucocorticoid andbe withdrawn from it and commenced on

steroid sparing medication as rapidly aspossible. Alternate day dosing may preventbone loss secondary to glucocorticoid usewhile maintaining therapeutic benefits,together with optimizing the intake ofcalcium and vitamin D3.

6.

Other medicationTable 2 outlines other agents associated withchildhood osteoporosis. The underlyingmechanism responsible for the osteoporosiscaused by these agents is unclear, and like

glucocorticoids, much prospective research isrequired.As the number of survivors of childhoodcancer increases, the toxic effects ofchemotherapy and radiation on the skeletonare becoming more apparent. Osteoporosis isone of many health issues in a long list ofpotential “late effects” caused by thesetherapies35. Therefore, pediatrician mustprovide appropriate surveillance. Patientswith disorders that require combinationtherapy and taking more than one agent at atime that may cause osteoporosis are at an

even greater risk.

Diagnosis

The most obvious clinical manifestation ofweak bones is a fracture after low-impacttrauma. Chronic back pain in predisposedchildren may indicate vertebral compressionfractures, but it is important to note thatsuch fractures may also be asymptomatic,especially in those with increased risk forlow BMD38. Conversely they may not be

reported and remain under-diagnosedradiologically with false negative rates up to45%39. When a child with one or more riskfactors for low BMD is identified, it isparticularly important to measure BMD.Most Pediatric subspecialists are aware ofthe risks to skeletal health posed by variouschronic diseases in their given fields ofpractice and routinely screen such patients


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for evidence of low BMD using dual-energyx-ray absorptiometry (DXA) scans (Table 3).DXA is the most widely used technique toassess bone mass in children. Although great

importance is often given to DXA, it shouldbe remembered that there is no evidence thatdensitometric data can predict the likelihoodof fracture in children-(Figure-4).

Table 2: Therapeutic agents associated with childhood osteoporosis. Modified from Munns

and Cowell3.

Therapeutic agent Proposed mechanism for osteoporosis

MethotrexateUncertain. Impaired osteoblastic protein synthesis, abnormalvitamin C metabolism.

CyclosporineUncertain. Possible dysregulation of the osteoprotegerin(OPG)-OPG ligand system with a resultant high turnoverstate36.

Heparin

Uncertain. a) Decreased 1-α-hydroxylase activity withreduced vitamin D and elevated PTH. b) direct effect on

cancellous bone with an increase in bone resorption anddecrease in bone formation.

RadiotherapyGrowth hormone deficiency, hypogonadism, AVN, muscleatrophy.

Depot medroxyprogesteroneacetate

Central hypogonadism.

Gonadotropin releasinghormone (GnRH) analogues

Central hypogonadism.

L-thyroxine suppressivetherapy

Increased bone resorption secondary to osteoblast mediatedT3 osteoclast activation.

Anti-convulsants

Altered liver metabolism of 25-OH vitamin D25. Low BMD is

also induced by the direct effects of anti-convulsant drugs onbone cells, resistance to PTH, inhibition of calcitonin secretion,and impaired calcium absorption37.

Table 3: Indications for considering a dual-energy x-ray absorptiometry scan for children.Modified from Henwood and Binkovitz4.

Risk factor for low bone mass density

Chronic disease

Chronic renal insufficiency

Gastrointestinal diseases

Cystic fibrosis

Endocrine system disorders

Medications or treatmentsGlucocorticoids, anti-convulsant drugs, chemotherapy andradiotherapy

Primary bone disease (i.e., osteogenesis imperfecta)

Malnutrition

Lifestyle habits Lack of physical activity

History of multiple fractures or a single fracture following low impact trauma


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Figure 4: Lateral radiograph lumbar spineshowing increased radiolucency of vertebra L1 – L4 with slightly radiodense endplates. DXA scan AP view lumbar spine showing BMD of 0.877 g/cm2 with estimated Z-Score of -2.5 indicatingestablished osteoporosis.

The Z-score is the number of standarddeviations (SD) of the patient's bone densityabove or below the values expected for thepatient's age. By comparing the patient'sBMD with the expected BMD for his or herage, the Z-score can help diagnose and

classify osteoporosis, but it is by no meansdiagnostic by itself. Other patient factorsshould be taken into account, includingheight, weight, and physiological matu-rity40,41.

Normal is a BMD that is within 1 SD ofthe young adult reference mean.

Osteopenia is a BMD between 1.0 and 2.5SD below the young adult reference mean.

Osteoporosis is a BMD more than 2.5 SDbelow the young adult reference mean42.

BMD as assessed by DXA is not a truevolumetric density, but rather, it is the massof bone mineral per projection area(grams/cm2) and is given the term ‘arealBMD’ (aBMD). Areal BMD is a size-dependent measure. Shorter childrentherefore have a reduced aBMD comparedto age-matched controls. Children withsecondary osteoporosis to chronic diseasefrequently have short stature resulting fromtheir primary disease or its treatment, andmay have a reduction in aBMD, not becausethere is anything abnormal with the

composition or structure of their bones, butsimply because the bones are small. Pubertaldisturbance is another common problemassociated with secondary osteoporosis andcan result in an erroneous reduction inaBMD when comparing results to that ofnormally developed age-matched controls.This has led some authors to suggest thatDXA results should be corrected for boneage and height when interpreting aBMD3.Methods to adjust for height and lean tissuemass have been described and can help

determine if the osteopenia/osteoporosis isin part secondary to reduction in lean tissueor a primary disorder of bone. Chronicdisease may have differential effects oncortical and trabecular bone dimensions anddensity. For example reduced mobility willhave a major effect on bone strength of thelower limbs consisting predominantly ofcortical bone, whereas chronic glucocor-


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ticoid therapy may preferentially affect thespine consisting predominantly oftrabecular bone3,43-44.Another mode of assessing osteoporosis isultrasound; by measuring the bone speedof sound at the tibial, radial, or calcaneal

bones reflecting both cortical density andthickness9. In a recent study Alwis et al45,reported the use of broadband ultrasoundattenuation in children and it seemed to bethe quantitative ultrasound parameter thatbest resembled the changes in bone mineralcontent during growth. While ultrasound isbeing used more frequently in pediatricsespecially for screening, DXA remains thegold standard as a diagnostic tool forosteoporosis. Comparison between bothmodalities in children is needed to see if

ultrasound can be used for diagnosis aswell.

Role of biochemical markers of bone turnover

Remodeling is a normal, natural process thatmaintains skeletal strength, enables repair ofmicrofractures and is essential for calciumhomeostasis. During the remodeling pro-cess, osteoblasts synthesize a number ofcytokines, peptides and growth factors thatare released into the circulation. Theirconcentration thus reflects the rate of boneformation. Bone formation markers includeserum osteocalcin, bone-specific alkalinephosphatase and procollagen-I carboxy-terminal propeptide46. Osteoclasts producebone degradation products that are alsoreleased into the circulation and areeventually cleared via the kidney. Theseinclude collagen cross-linking peptides andpyridinolines, which can be measured in theblood or urine and enable estimation ofbone resorption rate. Bone resorptionmarkers include urinary hydroxyproline,urinary pyridinoline, urinary deoxy-

pyridinoline as well as collagen Type Icross-linked N telopeptide and collagenType I cross-linked C telopeptide47-49. Mark-ers of bone formation and resorption are ofvalue in estimating bone turnover rates.These biochemical markers may be used toidentify fast bone losers50. The utility ofbone markers to identify fast bone loserswas prospectively evaluated in a large

cohort of healthy postmenopausal womenover four years50. It was not used to evaluatefast bone losers in children yet and thisneeds to be evaluated further.Higher levels of bone formation andresorption markers were significantly

associated with faster and possibly greaterBMD loss. In population studies, it appearsthat markers of bone resorption may beuseful predictors of fracture risk and boneloss. Elevated bone resorption markers maybe associated with an increased fracture riskin elderly women although the data are notuniform51. The association of markers ofbone resorption with hip fracture risk inadults is independent of BMD, but a lowBMD combined with high bone resorptionbiomarker doubled the risk associated with

either of these factors alone51

. However, thepredictive value of biomarkers in assessingan individual child has not yet beenconfirmed. Biomarkers may be of value inpredicting and monitoring response topotent antiresorptive therapy in clinicaltrials. Bone turnover markers may have afuture role in the clinical management ofosteoporosis. In population studies, thecombination of low BMD and high boneturnover markers may provide a superiorindication of fracture risk to either BMD orbone turnover markers alone51-52.

Prevention

Adult bone health is predominantlygoverned by two factors: (a) maximumattainment of peak bone mass; and (b) rate ofbone loss which occurs with ageing. Bothaspects are determined by a combination ofendogenous and exogenous factors and,although genetic influences are believed toaccount for up to three-quarters of thevariation in bone mass, there is still room for

the modifiable factors (including nutrition) toplay an important role53. The data supportthat both high physical activity —especiallyweight bearing exercise— and intake ofadequate amounts of calcium and vitamin Dare associated with a higher BMD, andattaining maximum bone mass particularly inadolescence because puberty is a critical timefor accruing bone mass (peak adult bone


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mass). Recent studies found that jumping-based activities resulted in substantialimprovements in bone mass in prepubertaland pubertal children54. The recommendeddietary allowances of calcium have beenfixed to 800 mg/d for prepubertal children

(ages 4-8 years) and for adolescents (ages 9-18years) 1300 mg/d52. On the other hand,overweight showed the opposite effect. Diethabits and exercise must be considered as themain strategies to prevent adult osteoporosisduring childhood55-56.To prevent bone loss secondary to reducedmobilization in children with chronic disease,weight-bearing activity should bemaximized, which in healthy children andadolescents has been shown to increase bonemineral accrual and bone size57. For children

with extreme bone fragility, swimming andhydrotherapy may be beneficial. In ambulantand non-ambulant children with spastic CP,weight-bearing activity has been shown tosignificantly improve femoral neck bonemineral content and volumetric BMDcompared to controls58. In non-ambulantchildren with CP, a standing frame tofacilitate an upright position has been shownto improve BMD, with the gains in BMDbeing proportional to the duration ofstanding3,59.

Treatment

The underlying principles of treatment ofsecondary osteoporosis in both children andadults is, where possible, to remove theunderlying cause. Where this is not possible,minimizing the effects of treatment withdrugs that adversely affect bone may besufficient to eliminate any deterioration inbone quality. If this is not possible, the use ofbone sparing drugs such as thebisphosphonates may be necessary whilst

ensuring that attention is paid to optimizingcalcium and vitamin D intake andencouraging mobility and exercise13.The measures outlined in the preventionsection are frequently inadequate in pre-venting the development of osteoporosis. Inthese situations, specific anti-osteoporosistherapy should be considered. While theguidelines for the treatment of osteoporosis

in adults are widely accepted, the much lessabundant data for children and adolescentswith osteoporosis makes it harder to set clearguidelines for the pediatric population.Bisphosphonates are the most widely usedmedications for the treatment of childhood

osteoporosis60. They are potent anti-resorptive agents that disrupt osteoclasticactivity33,61. Although bisphosphonates havebeen used for many years in adults, theirsystematic use in children has been limited.The majority of data pertaining to the clinicalutility and mechanism of action ofbisphosphonates in children comes fromstudies of cyclical intravenous pamidronatetherapy in moderate to severe OI. Thetreatment of osteoporosis with bisphos-phonates, specifically alendronate and

pamidronate in pediatric cancer patients isdescribed. Results showed that thesemedications were efficacious in reducingBMD loss during cancer therapy and werewell tolerated in this special population62. Inchildren and adolescents with OI, pami-dronate therapy has been associated withimprovements in muscle force, vertebralbone mass and size, bone pain, fracture rateand growth. In long bones, pamidronate hasbeen shown to increase cortical thickness andimprove bone strength15,63.Minodronate is a new nitrogen-containingbisphosphonate64. It was the first drug todemonstrate significant prevention of verte-bral fractures in patients with osteoporosis ina phase III doubleblind comparative study. Invitro studies demonstrated that minodronateis one of the most potent inhibitors of boneresorption among currently availablebisphosphonates. These data suggest thatminodronate is a promising new potentbisphosphonate for the treatment ofosteoporosis64. The use in children is not yetapproved.

The safety of bisphosphonate therapycontinues to be of concern to manyclinicians65. To allow for this issue to besystematically evaluated, it is of paramountimportance that children and adolescentsonly receive bisphosphonates as part of well-run clinical trials. Pamidronate lowers serumcalcium concentrations that is most markedfollowing the first infusion cycle15. In vitamin


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D replete individuals receiving therecommended calcium intake, the hypo-calcaemia is self-remitting15. The majority ofchildren have an acute phase reaction "flu-like” (fever, muscle pain, headache andvomiting) 12-36 hours following initial

exposure to bisphosphonates which is self-limiting66. It is unusual for this to recur withsubsequent doses, and can be limited by pre-treatment with paracetamol or ibuprofen66.Oral bisphosphonates may result in chemicalesophagitis. Transient uveitis occurs inapproximately 1% of children who receivepamidronate15. Bisphosphonates are alsoused for other diseases involving boneremodeling, such as IJO or familial hyper-phosphatemia. The question of longterm sideeffects cannot be answered with the currently

available data67

. Because bisphosphonatesaccumulate in bone, they create a reservoirleading to continued release from bone formonths or years after treatment is stopped.Studies with risedronate and alendronatesuggest that if treatment is stopped after 3-5year, there is persisting antifracture efficacy,at least for 1-2 year. It is recommended totake a drug holiday after 5-10 year ofbisphosphonate treatment. The duration oftreatment and length of the holiday arebased on fracture risk and pharmacokineticsof the bisphosphonate used. Patients at mildrisk might stop treatment after 5 year andremain off as long as BMD is stable and nofractures occur. Higher risk patients shouldbe treated for 10 year, have a holiday of nomore than a year or two, and perhaps be ona non-bisphosphonate treatment during thattime68. In general, as a substance groupbisphosphonates are well tolerated and,when applied correctly, the toxicity is low.It was noticed that vitamin D insufficiencywas remarkably common in children withprimary and secondary osteopenia or

osteoporosis. The inverse relationshipbetween vitamin D and parathyroid horm-one levels suggests a physiologic impact ofinsufficient vitamin D levels that maycontribute to low bone mass or worsen theprimary bone disease. It is suggested thatmonitoring and supplementation of vitaminD should be a priority in the management ofchildren with osteopenia or osteoporosis69.

It has been suggested that vitamin K2(which is found in meat, cheese andfermented products) may not only stimulatebone formation but also suppress boneresorption in vivo70. Clinically, vitamin K2sustains the lumbar BMD and prevents

osteoporotic fractures in patients with age-related osteoporosis and prevents vertebralfractures in patients with glucocorticoid-induced osteoporosis. Even though theeffect of vitamin K2 on the BMD is quitemodest, this vitamin may have the potentialto regulate bone metabolism and play a rolein reducing the risk of osteoporoticfractures. Prabhoo et al53, reported vitaminK2 safety in children and suggested that itcan be considered for prevention andtreatment in those conditions known to

contribute to osteoporosis.

Specific disorders resulting in osteoporosisin children1.

Cerebral palsy CP is a non-progressive encephalopathywith disordered posture and movement.Fracture incidence in children with CP isvariously reported between 5 to 30%, withthe majority of fractures occurring in thefemoral shaft and supracondylar region21-22.Reduced mobility is the major cause forbone fragility in children with CP. Reducedmobility results in bone with a low bonemass and abnormal architectural design,which is unable to withstand the occasionalmechanical challenges placed upon it, suchas forceful muscle contractures associatedwith a convulsion or unusual weightbearing or transfer22. Other factors includevitamin D deficiency from reduced sunlightexposure and possibly anti-convulsanttherapy, disorders of puberty andnutritional disorders. Lumbar spine BMD isoften normal in children with CP who

sustain a pathological fracture except inmore involved children when spine isaffected as well71.To prevent osteoporosis in children with CPa concerted effort must be made to maintainambulation and weight bearing. As outlinedabove, biomechanical stimulation of bonerequires further investigation as it holdsgreat promise. Other general measures such


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as ensuring adequate calcium and vitamin Dintake and general nutrition, minimizingiatrogenic causes of bone loss and ensuringtimely pubertal development are alsoimportant to the child with CP. Onceosteoporosis is established, the use of

bisphosphonate therapy is justified3.

2.

Leukemia The leukemias are the most common form ofchildhood malignancy. The two majorskeletal complications of leukemia areosteoporosis and AVN72. Strauss et al,reported a 5-year cumulative fracture inci-dence in children with acute lymphoblasticleukemia of 28%72. Risk factors for thedevelopment of skeletal complications inacute lymphoblastic leukemia include

glucocorticoid administration, malnutri-tion, reduced mobility, methotrexate, cranialirradiation, impaired bone mineralization,older age at diagnosis and male sex22,72. Thedevelopment of hypothyroidism, growthhormone deficiency and hypogonadism,may influence the bone health of childrenwith leukemia and requires closemonitoring22.

3.

Children with intellectual disabilities

have increased risk factors associated withosteoporosis. It has been identified that thispopulation has an increased prevalence oflow BMD, osteoporosis and osteopenia73.The main contributory factors for low BMDare age, use of anti-convulsants, reducedmobilety and diagnosis of Down'ssyndrome. In most studies individuals withintellectual disabilities presented withmore than two risk factors. It was identifiedin a survey that an increased prevalence ofrisk factors associated with osteoporosis,namely use of anti-convulsants (64%),reduced mobility (23%), history of falls

(20%) and fractures (11%). Screening for therisk factors associated with low BMD inindividuals with intellectual disabilities isimportant. If these are present furtherinvestigations should take place and thosefound to have osteopenia and osteoporosisshould have treatment at an early stage toprevent morbidity and improve theirquality of life73.

ConclusionOsteoporosis as primary disorder orsecondary to chronic disease is increasinglyrecognized major childhood health problem.With many factors influencing the bonehealth of children, the physician must take a

broad approach to the prevention andtreatment of bone disease. It is necessary toutilize nutritional, hormonal andbiomechanical therapeutic regimes, as wellas bisphosphonate therapy. With thisapproach and continued research, it may bepossible to improve, not only the bonehealth of children, but also their generalwellbeing and quality of their future life asadults and into old age. Osteoporosis inchildren is still a wide open area forresearch.

Acknowledgement

The author wishes to thank Dr. ShaistaSalman Guraya, Assistant Professor ofRadiology and Consultant Radiologist,College of Medicine, Taibah University,Almadinah Almunawwarah, Kingdom ofSaudi Arabia, who helped with the figures.

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