IBD and Bone Healthin Adults and Children

Francisco A. Sylvester, MDAssociate Professor of Pediatrics

GoalsT i b i b bi l• To review basic bone biology

• To understand the principles of DXA and its pitfalls

• To examine how IBD subverts normal bone function

• To review therapeutic options to increase BMD in patients with IBD

Bone And IBD

• Decreased bone mineral density– Males = Females– CD = UC (?)

• Fracture risk?– Vertebral fractures

Bernstein CN et al. Ann Intern Med 2000;133:795Bernstein CN et al. Gastroenterology 2003;124:795Heijckmann AC et al. Eur J Gastroenterol Hepatol 2008;20:740Semeao EJ et al. Gastroenterology 1997;112:1710Siffledeen JS et al. Clin Gastroenterol Hepatol 2007;5:721

Vertebral Fractures - IBD

Klaus J et al. Gut. 2002 Nov;51(5):654-8

Goal

To review basic bone biology

Compact Bone

Haversian System

Lamellae

Osteocytes

Periosteum

80% Bone Mass

Trabecular Bone

Trabeculae

80% Bone Metabolic Activity

http://www.geo.ucalgary.ca/~macrae/t_origins/carbbones/dinobone.html

Osteoclasts

OC

OC

OC

OC

Sylvester FA, E Canalis 2006

Osteoblasts

E Canalis

Osteocytes

Bone Remodeling

• Osteoclasts followed by osteoblasts• Act on the same bone surface

http://www.umich.edu/news/Releases/2005/Feb05/img/bone.jpg

Abnormal Bone Remodeling: Osteoporosis

• Reduced bone mass• Architectural deterioration of the skeleton• Increased risk of fracture

Bone Mass and Age

ModelingRemodeling Remodeling

Seeman E JCEM 2001;86:4576-84

Modeling Changes Bone Shape

Leonard,MB Pediatrics 2007;119:S166-74

Determinants of Bone Mass

Inactivity

EndocrineDisorders Inflammation

GeneticsMedications

Poor Nutrition

ChronicIllness

Goal

To understand the principles of DXA and its pitfalls

DXA Technology

Patient

Detector (detects 2 tissue types - bone and soft tissue)

Photons

Patient

X-ray Source (produces 2 photon energies with different attenuation profiles)

DXA: Size Matters!Areal

Projection

Emerging photons

ProjectionOf Bone

Bone

Different SizeScanning path

Incident photons

Different Size But….

Same Material Density (in g/cm3)

DXA: Size Matters!Areal

Projection Different “Areal” Density

Emerging photons

ProjectionOf Bone

“More Dense” “Less Dense”

y(in g/cm2)

Bone

Scanning path

Incident photons

Reporting DXAT- scores vs. Z-scores

= BMD (Observed – Normal for Age/Sex)SD

= BMD (Observed – Normal for Young Adult)SD

Definition of Osteoporosis

WHO d fi iti (2000) b d T• WHO definitions (2000) based on T-score– > -1 = Normal– < -1 but > -2.5 = Osteopenia– < -2.5 = Osteoporosis

• Only applicable to post-menopausal women

• Not intended as thresholds for treatment

• Not validated in patients with IBD

Fracture Risk Gradient – T-Score

Relative 20

25

30

35

Risk

for Fracture

5

10

15

20

Bone Density (T-score)

0-5.0 -4.0 -3.0 -2.0 -1.0 0.0 1.0

Age

8050

Bone Density & Age vs. Fracture Risk

10-Year Fracture

Probability

8070

60

5020

30

40

50

y(%)

0

10

20

1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5 -4.0

Adapted from Kanis JA et al. Osteoporosis Int. 2001;12:989-995.

Probability of first fracture of hip, distal forearm, proximal humerus, and symptomatic vertebral fracture in women of Malmö, Sweden.

Femoral Neck T-score

Who Should Have DXA?

• Pre-existing fragility fracture• > 65 years of age• Patients with risk factors for low

BMD/f tBMD/fracture• Exposure to glucocorticoids ≥ 3 months• Consider repeating in 6 – 12 months

Lichtenstein GR et al. Inflamm Bowel Dis 2006;12:797-813

Vertebral Fractures – Crohn Disease

C ti l l f t b l• Cross-sectional prevalence of vertebral fractures

• 224 patients – 70 (36%) normal BMD70 (36%) normal BMD– 123 (51%) osteopenia– 31 (13%) osteoporosis

• Mean age 38.7± 11.8 y• 45 patients – 88 fractures

– 16 with normal BMD

Siffledeen J et al. Clin Gastroenterol Hepatol 2007;5:721-8

Goal

To examine how IBD subverts normal bone function

IBD - Bone

• Malnutrition• Malabsorption• Decreased physical

activityactivity• Delayed puberty• Medications• Inflammation

Hypothesis

IBD:A Gut BoneA Gut – Bone

Axis?

Gut – Bone Axis Candidates

• Immunological factors– Soluble factors– Cells (circulating/local)

• Nutritional deficiencies– Direct effects– Indirect effects

• Body compositionBody composition• Hormonal axes

Infliximab – Bone BiomarkersLuminal Crohn

Fistulizing Crohn

Franchimont N et al. Aliment Pharmacol Ther 2004;20:607

Pediatric Bone ≠ Adult Bone!

www.keithryan.com/Images/strongbaby.jpg

Effect of InfliximabREACH Study

100

140

1000

1400

1800BSAP (U/L) CTX (μg/μmol Cr)

20

60

Baseline Week 10

200

600

1000

Baseline Week 10

Thayu M et al. Bone 2007;40: 6(Supplement 1): S81

Baseline Week 10 Baseline Week 10

% Change 109 ± 97P<0.001

% Change 43 ± 78P<0.001

IBD - Infliximab – Bone

• Increased markers of bone formation• No effect on resorptive markers in adults• Increased bone turnover in children• Improved BMD

Franchimont N et al. Aliment Pharmacol Ther 2004;20:607.Ryan BM, et al. Aliment Pharmacol Ther 2004;20:851.Bernstein M, et al. Am J Gastroenterol 2005;100:2031.Abreu MT, et al. J Clin Gastroenterol 2006;40:55.Pazianas M, et al. Ann N Y Acad Sci 2006;1068:543Thayu M et al. Bone 2007;40: 6(Supplement 1): S81

Osteoclasts

OC

OC

OC

OC

Sylvester FA, E Canalis 2006

Osteoclast Development

Krane SM N Engl J Med 2002; 347:210-212

IBD – RANKL – OPG

M d t i i OPG/ RANKL• Modest increases in serum OPG/sRANKL

• OPG and BMD inversely correlated

In mice OPG increases BMD/treats colitis• In mice OPG increases BMD/treats colitis

• OPG is a regulator of intestinal immune responses

•Franchimont N et al. Clin Exp Immunol 2004;138:491-8•Vidal K et al. Am J Physiol Gastrointest Liver Physiol 2004;287:G836-44•Bernstein CN et al. Inflamm Bowel Dis 2005;11:325-30•Moschen AR et al. Gut 2005;54:479-87

OPG/RANKL in Children with IBD

Serum

234567

11.5

22.5

3* *

OPG (pmol/L) sRANKL (pmol/L)

012

00.5

Control

Sylvester FA et al. J Pediatr. 2006;148:461-466

Crohn

The Colon: A Source of OPG

Moschen, A R et al. Gut 2005;54:479-487

Macrophages/dendritic cells

Gut – Bone Axis:Indirect Effects?

Effect of Lean Body Mass

• Muscle strain drives bone formation

• LBM deficits present at diagnosis in IBD

• Persist despite weight gain/symptom improvement

Burnham JM et al. Am J Clin Nutr. 2005 Aug;82(2):413-20Sylvester FA et al. DDW 2007

Gut – Bone Axis – Indirect Effects

G th t ti• Growth stunting

• Nutrient intake/absorption/utilizationCalcium– Calcium

– Vitamin D– Vitamin K– Zinc

Immune FactorsT cells (INF- γ, RANKL) Cytokines (TNF-α, IL-6)

OPG

NutritionCalcium, vitamin D

Caloric/Protein intakeVitamin K/Others

HypogonadismIGF-I

InactivityLean tissue mass

Medications

Bone and IBD - Unknowns

• Disease duration?• Activity of disease?• Site of IBD involvement?• Small bowel surgery?• Diagnosis in childhood?• Skeletal site susceptibility?• Effect of remission?

P OCO

OHOH

P

R1

==Goal

OHOH R2To review therapeutic options to increase BMD in patients with IBD

Risk Factors – FractureModifiable

• Lifestyle factors• Low BMI• Risk of falling• Lifelong low Ca intake• Vitamin D deficiency/insufficiency• Use of glucocorticoids• Concurrent medical conditions

Calcium

• Women– Pregnant and nursing 1200 mg– 25-50 y 1000 mg

> 65 y 1500 mg– > 65 y 1500 mg

• Men– 25-65 y 1000 mg25 65 y 1000 mg– > 65 y 1500 mg

Vitamin D2 vs. Vitamin D3

D DD2 D3

Ergocalciferol Cholecalciferol

Derived from fungal/plant Produced in the sking psources

Drisdol, Chewable vitamins

Poly-Vi-Sol, Delta-D

B th ll ff ti t i it i D l lBoth equally effective to increase vitamin D levels(Some studies show D3 > D2)

Dietary Sources of Vitamin DS S i Si Vit i D (IU)Source Serving Size Vitamin D (IU)Milk 1 cup 98Baked herring 3 oz. 1,775Baked salmon 3 oz. 238Baked salmon 3 oz. 238Canned tuna 3 oz. 136Sardines 1 oz. 77Raisin bran cereal ¾ cup 42Pork sausage 1 oz. 31Egg yolk 1 25

USDA 2002

Bisphosphonates

The Future

Take Home Points

• Bone mass deficits occur in patients with IBD

Ri k f f t ildl i d• Risk of fractures mildly increased– Vertebral fracture prevalence?

M ltif t i l th i• Multifactorial pathogenesis

Take Home Points

• Bone mass can be measured by DXA– Be aware of pitfalls

Id tif d dd difi bl i k f t• Identify and address modifiable risk factors

• Control of inflammation, calcium/vitamin D, activity may increase bone massactivity may increase bone mass

Acknowledgements

NIH t R01 DK 066303• NIH grant R01-DK-066303 • Donaghue Foundation• CCMC • Dr Ernesto Canalis (Saint Francis• Dr. Ernesto Canalis (Saint Francis

Hospital & Medical Center)