Steroids and BonesSarah Ehtisham

Consultant EndocrinologistRoyal Manchester Children’s Hospital

Outline of PresentationSecondary bone diseaseAdverse effects of corticosteroids on boneImpact of inflammationConsequencesManagementCases

Secondary OsteoporosisSecondary bone disorders Long-term Rx with oral Corticosteroids Chronic Inflammatory Disorders

Juvenile Arthritis, IBD Other Chronic Childhood illnesses

Cystic fibrosis Childhood Cancers and Rx with Chemotherapy, Corticosteroids & Anti-rejection

medicationsLeukaemia

Neuromuscular Disorders associated with Immobilisation Cerebral Palsy, Duchenne Muscular Dystrophy

Primary & Secondary Hypogonadism Anorexia Nervosa, Thalassaemia, Galactosaemia

Secondary OsteoporosisSecondary bone disorders Long-term Rx with oral Corticosteroids Chronic Inflammatory Disorders

Juvenile Arthritis, IBD Other Chronic Childhood illnesses

Cystic fibrosis Childhood Cancers and Rx with Chemotherapy, Corticosteroids & Anti-rejection

medicationsLeukaemia

Neuromuscular Disorders associated with Immobilisation Cerebral Palsy, Duchenne Muscular Dystrophy

Primary & Secondary Hypogonadism Anorexia Nervosa, Thalassaemia, Galactosaemia

‘The greatly compressed bodies of the vertebrae ... were so soft they could easily be cut with a knife’

Description of bones in Cushing’s syndrome

1932

Glucocorticoids

Renal & GI calcium loss

PTH

Muscle bulk

Paracrine IGF1 in growth plate

LH/FSH Oestrogens Testosterone

Osteoblast activity

Osteoclast activity

Growth PlateVascular development

Proliferation & hypertrophy of chondrocytes

Primary disease

Bone loss and growth retardation

Nutrition & Vit D

Inflammatory Cytokines

SomatostatinGH

IGF1BoneAltered bone remodelling in favour of resorption

Matrix synthesis

Skeletal load

-

+

Mechanisms of GC induced bone lossReduced bone formation

Increased osteoclast activityStimulate osteoclastogenesis

Increased osteoclast survival (early)Osteocyte and osteoblast apoptosis (late)

Net effect is higher rate of bone loss initially which slows down after the first few months

Reduced osteoblast activityInhibition of osteoblastogenesisShift in mesenchymal cell differentiation

towards adipocytes rather than osteoblastsInhibition of terminal osteoblast differentiation

Mushtaq. Arch Dis Child 2002;87:93–96

Mechanisms of GC induced bone lossDecreased intestinal Ca and PO4 absorption

Increased renal Ca excretion secondary hyperparathyroidism

Myopathy and muscle weaknessReduce bone strain and mechanical stimuli

Reduction in synthesis of other bone constituents Type 1 collagen

Delayed pubertyDelay in acquisition of peak bone mass

Effects of disease itself

Type of glucocorticoid

Dexamethasone

Prednisolone

Hydrocortisone

PO

TEN

CY

Dexamethasone: up to 10x more

potent at suppressing bone

turnover than Prednisolone

The role of inflammation

Osteoblast

Cortisol

(active)

Cortisone

(inactive)

11betaHSD1

11betaHSD2

Inflammatory cytokines

TNFα, IL-1β

+

-

Cooper. J Endocrinology 1999;163:159-164

ConsequencesReduced linear growthDelayed bone maturationDelayed bone mass accrualSecondary osteoporosis

Can be generalised but predominantly affects trabecular bone in the vertebrae > cortical bone

Wedging of vertebrae & KyphosisBack painIncreased fracture riskAvascular necrosis

Changes in Bone Mass with Age

Puberty

Oral GC Rx & fractures in children

Case control study>37000 children Rx with 4 or more courses of oral GC for a mean duration of 6.4 daysCompared to controls, GC Rx children had adjusted OR for fracture of 1.32 (1.03-1.69)Reversible – children who stopped Rx were comparable to control group

van Staa JBMR 2003;18:913-918

Vertebral Fractures in Chronically ill Children

Vertebral fractures without high-energy injury are indicative of bone fragility Not uncommon in chronically ill children & may be asymptomatic 7% of 134 children (median age 10 yrs) with rheumatic conditions had

vertebral fractures before or within 30 days of starting Rx corticosteroids - Almost 70% # clustered in the mid-thoracic region - Mean L-spine aBMD Z score: Those without vert # - 0.51 ± 1.2

& Those with vert # -1.2 ± 1.0 (NS)

Huber AM, et al. Arthritis Care Res 2010;62:516-26

Twenty-nine patients (16%) of 186 newly diagnosed children (median age 5.3 yrs) with ALL had vertebral compression fractures (71% thoracic region)

Halton J et al J Bone Miner Res 2009; 24:1326–1334

Huber AM, et al. (STOPP) Consortium Prevalent vertebral fractures among children initiating glucocorticoid therapy for the treatment of rheumatic disorders. Arthritis Care Res 2010;62(4):516-26.

Vertebral Fracture & BMD

ManagementAim to reduce GC doses if possibleImprove mobility / muscle strength and actionAssess Ca and Vit D status & Rx if lowBone densitometry

Vertebral QCT and VFA most usefulConsider spine X ray if back pain / kyphosis / reduction in

height / low QCT on DXAMRI more sensitive than X raysConsider bisphosphonate Rx

Low trauma fractures or vertebral wedging

Assessing dietary Calcium intake

RNI in the UK mg/day

Infants up to 1 yr 525

Children 1- 3 yrs 350

Children 2-6 yrs 450

Children 7-10 yrs 550Adolescent boys 11-18 yrs 1000Adolescent girls 11-18 yrs 800

1 ml ~ 1mg

1 oz ~ 200 mg

1 pot ~ 150 mg

~ 35 mg/slice

1 Bowl ~ 80 mg

Case 1Duchenne Muscular DystrophyRx Prednisolone 15mgs dailyShort stature – Rx Growth HormoneDecline in LS BMAD March 08 and May 10

z - 0.7z - 0.7

z - 1.1z - 1.1

z - 1.3z - 1.3

Case 1

Cushingoid

Deterioration in mobility

c/o Back pain

Tender on percussion over spinous processes

Spinal radiographs

Rx IV Pamidronate

Review July 2010Review July 2010

z - 0.7z - 0.7

z - 1.1z - 1.1

z - 1.3z - 1.3

z + 0.1z + 0.1

Duchenne Muscular DystrophyX-linked disorder progressive muscle weakness in affected ♂Treatment with oral corticosteroids improves muscle function &

reduces the risk of developing scoliosisCorticosteroid Rx increases the risk of a vertebral compression

fracture, which may be asymptomatic

Bothwell JE, et. al. Clin Pediatr 2003:42(4):353-356.

Vertebral fracture(s) occurred 40 months after starting Rx with oral corticosteroids.

z - 1.5z - 1.5

z - 1.7z - 1.7

z - 1.7z - 1.7

Case 2Duchenne Muscular DystrophyRx Prednisolone 10mgs dailyDecline in Height Velocity – 9th to < 2nd Centile over 3

years LS BMAD measurements:

Mildly Cushingoid

Deterioration in mobility

c/o Back pain

No tenderness on percussion over spinous processes

Spinal radiographs

Rx IV Pamidronate

Review May 2011

Case 2

Case 316 diagnosed with ALL 2 years previously♀Multifocal avascular necrosis – shoulders and hips

PainLimited hip abduction

Secondary amenorrhoea

Dietary Calcium intake estd. 800mg; Vit D repleteMRI hips – showed extent of the AVNBone densitometry – reduced spine trabecular bone densityDental assessment in preparation for Pamidronate

Case 3 - 2010

2010 2008

External fixators for 4 months

Bisphosphonate Rx

OCP

Physiotherapy & Hydrotherapy

Case 414y ♀ - asthma from age 4Prolonged oral corticosteroid Rx for 9 years & high dose

inhaled (seretide 250 x 4 puffs/d)Prednisolone 10mg daily maintenance, monthly

courses of 40mg x5d for exacerbations# toe – traumatic – xrays showed osteopeniaKyphotic, cushingoid (plethora, striae, buffalo hump)DXA – low trabecular BMD, Z score -3.8Xray thoracic spine

Kyphosis

Osteopenia

Vertebral wedging

Candidate for Pamidronate Rx

Case 4