Steroids and Bones

1. Steroids and Bones Sarah Ehtisham Consultant Endocrinologist Royal Manchester Children’s Hospital

2. Outline of Presentation • Secondary bone disease • Adverse effects of corticosteroids on bone • Impact of inflammation • Consequences • Management • Cases

3. Secondary Osteoporosis • Secondary 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 medications • Leukaemia • Neuromuscular Disorders associated with Immobilisation • Cerebral Palsy, Duchenne Muscular Dystrophy • Primary & Secondary Hypogonadism • Anorexia Nervosa, Thalassaemia, Galactosaemia

4. Secondary Osteoporosis • Secondary 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 medications • Leukaemia • Neuromuscular Disorders associated with Immobilisation • Cerebral Palsy, Duchenne Muscular Dystrophy • Primary & Secondary Hypogonadism • Anorexia Nervosa, Thalassaemia, Galactosaemia

5. ‘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

6. Growth Plate Vascular development  Proliferation & hypertrophy of chondrocytes  Paracrine IGF1 in growth plate Primary disease GH Somatostatin Bone loss and growth retardation IGF1 Bone Altered bone remodelling in favour of resorption Matrix synthesis  Skeletal load  Glucocorticoids LH/FSH Oestrogens Testosterone - Osteoblast activity Osteoclast activity Nutrition & Vit D + Renal & GI calcium loss PTH Inflammatory Cytokines Muscle bulk

7. Mechanisms of GC induced bone loss • Reduced bone formation • Increased osteoclast activity • Stimulate 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 activity • Inhibition of osteoblastogenesis • Shift in mesenchymal cell differentiation towards adipocytes rather than osteoblasts • Inhibition of terminal osteoblast differentiation Mushtaq. Arch Dis Child 2002;87:93–96

8. Mechanisms of GC induced bone loss • Decreased intestinal Ca and PO4 absorption • Increased renal Ca excretion • secondary hyperparathyroidism • Myopathy and muscle weakness • Reduce bone strain and mechanical stimuli • Reduction in synthesis of other bone constituents • Type 1 collagen • Delayed puberty • Delay in acquisition of peak bone mass • Effects of disease itself

9. Type of glucocorticoid • Dexamethasone • Prednisolone • Hydrocortisone Dexamethasone: up to 10x more potent at suppressing bone turnover than Prednisolone POTENCY

10. The role of inflammation 11betaHSD1 + Cortisol (active) Cortisone (inactive) Inflammatory cytokines TNFα, IL-1β - Osteoblast 11betaHSD2 Cooper. J Endocrinology 1999;163:159-164

11. Consequences • Reduced linear growth • Delayed bone maturation • Delayed bone mass accrual • Secondary osteoporosis • Can be generalised but predominantly affects trabecular bone in the vertebrae > cortical bone • Wedging of vertebrae & Kyphosis • Back pain • Increased fracture risk • Avascular necrosis

12. Changes in Bone Mass with Age Puberty

14. 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 days • Compared 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

15. 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

16. Vertebral Fracture & BMD 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.

17. Management • Aim to reduce GC doses if possible • Improve mobility / muscle strength and action • Assess Ca and Vit D status & Rx if low • Bone densitometry • Vertebral QCT and VFA most useful • Consider spine X ray if back pain / kyphosis / reduction in height / low QCT on DXA • MRI more sensitive than X rays • Consider bisphosphonate Rx • Low trauma fractures or vertebral wedging

18. Assessing dietary Calcium intake 1 ml ~ 1mg 1 oz ~ 200 mg 1 pot ~ 150 mg ~ 35 mg/slice 1 Bowl ~ 80 mg

19. Case 1 • Duchenne Muscular Dystrophy • Rx Prednisolone 15mgs daily • Short stature – Rx Growth Hormone • Decline in LS BMAD March 08 and May 10 z - 0.7 z - 1.1 z - 1.3

20. Case 1 • Cushingoid • Deterioration in mobility • c/o Back pain • Tender on percussion • over spinous processes • Spinal radiographs • Rx IV Pamidronate Review July 2010 z - 0.7 z - 1.1 z - 1.3 z + 0.1

21. Duchenne Muscular Dystrophy • X-linked disorder  progressive muscle weakness in affected ♂ • Treatment with oral corticosteroids improves muscle function & reduces the risk of developing scoliosis • Corticosteroid Rx increases the risk of a vertebral compression fracture, which may be asymptomatic Vertebral fracture(s) occurred 40 months after starting Rx with oral corticosteroids. Bothwell JE, et. al. Clin Pediatr 2003:42(4):353-356.

22. Case 2 • Duchenne Muscular Dystrophy • Rx Prednisolone 10mgs daily • Decline in Height Velocity – 9th to < 2nd Centile over 3 years • LS BMAD measurements: z - 1.5 z - 1.7 z - 1.7

23. Case 2 • Mildly Cushingoid • Deterioration in mobility • c/o Back pain • No tenderness on • percussion over • spinous processes • Spinal radiographs • Rx IV Pamidronate Review May 2011

24. Case 3 • 16 ♀ diagnosed with ALL 2 years previously • Multifocal avascular necrosis – shoulders and hips • Pain • Limited hip abduction • Secondary amenorrhoea • Dietary Calcium intake estd. 800mg; Vit D replete • MRI hips – showed extent of the AVN • Bone densitometry – reduced spine trabecular bone density • Dental assessment in preparation for Pamidronate

25. Case 3 - 2010

26. 2010 2008

27. External fixators for 4 months Bisphosphonate Rx OCP Physiotherapy & Hydrotherapy

29. Case 4 • 14y ♀ - asthma from age 4 • Prolonged 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 osteopenia • Kyphotic, cushingoid (plethora, striae, buffalo hump) • DXA – low trabecular BMD, Z score -3.8 • Xray thoracic spine

30. Case 4 Kyphosis Osteopenia Vertebral wedging Candidate for Pamidronate Rx