Metabolic Bone DiseaseMetabolic Bone Diseasein Gastrointestinal Disordersin Gastrointestinal Disorders

Douglas L. Seidner, MD, FACGDouglas L. Seidner, MD, FACG

The Cleveland ClinicThe Cleveland Clinic

Digestive Disease CenterDigestive Disease Center

ObjectivesObjectives

• Review bone physiology and MBDReview bone physiology and MBD

• Discuss the most common GI Discuss the most common GI disorders that lead to MBDdisorders that lead to MBD

• Understand the rationale for Understand the rationale for preventing and treating MBD in GI preventing and treating MBD in GI disordersdisorders

Normal Trabecular Bone

www.wyethconsumerhealthcare.ie/caltrate/lc/bones.html

Bone Density During LifeBone Density During Life

00 1010 2020 3030 4040 5050 6060 7070 8080

YearsYears

Bone DensityBone DensityPercentPercent

MenMen

WomenWomen

00

2020

4040

6060

8080

100100

www.endotext.org/parathyroid/parathyroid11/parathyroid11.htm

Bone RemodelingBone Remodeling

ResorptionResorption20 Days20 Days

FormationFormation100 Days100 Days

120 Days120 Days

RANK LRANK L

RANKRANKD-PyrD-Pyr

NTxNTx CTxCTx

M-CSFM-CSFIL-1, IL-6, IL-11IL-1, IL-6, IL-11

TNF, TGF-BTNF, TGF-B

OPGOPGActivationActivationGHGHIL-1, PTH, IL-6, -E2IL-1, PTH, IL-6, -E2

OCOC OBOBCalciumCalcium

OsteocalcinOsteocalcinHydroxyprolineHydroxyproline

OsteocalcinOsteocalcinBSAPBSAP

ProteasesProteasesPICPPICP

HH++

CollagenCollagenLTBPLTBP

MatrixMatrix

TGF-BTGF-BIGF-1IGF-1IGF-2IGF-2IGF-BPIGF-BP

Osteoporosis

Osteomalacia

MBD in GI DisordersMBD in GI Disorders

• CommonCommon– Osteoporosis >>> OsteomalaciaOsteoporosis >>> Osteomalacia

• UncommonUncommon– Avascular necrosisAvascular necrosis– Hypertrophic osteoarthropathyHypertrophic osteoarthropathy– Hepatitis C-associated osteosclerosisHepatitis C-associated osteosclerosis– Hepatobiliary ricketsHepatobiliary rickets

MBD in GI DisordersMBD in GI Disorders

• Malabsorption and maldigestionMalabsorption and maldigestion– Celiac disease, post gastrectomy, short gut, Celiac disease, post gastrectomy, short gut,

pancreatic insufficiencypancreatic insufficiency

• Inflammatory Bowel Disease Inflammatory Bowel Disease – Crohn’s disease and ulcerative colitis Crohn’s disease and ulcerative colitis

• Chronic Liver DiseaseChronic Liver Disease– Cholestatic and hepatocellular diseasesCholestatic and hepatocellular diseases

• Secondary to therapy for GI diseaseSecondary to therapy for GI disease– Liver and SB transplant, medications, TPNLiver and SB transplant, medications, TPN

Osteopenia, Osteoporosis Osteopenia, Osteoporosis and Fracture Riskand Fracture Risk

• Celiac 25 %Celiac 25 % Vasquez H. Am J Gastroenterol 2000;95:183

• Post gastrectomy 55 %Post gastrectomy 55 % Zittel TT. Am J Surg 1997;174:431

• IBD 30%IBD 30% Pigot F. Dig Dis Sci. 1992;37:1396

– Fx: 1/100 pt-yr, 40% > normal Fx: 1/100 pt-yr, 40% > normal Bernstein CN. Ann Int Med 2000;133:795

• PBC 32.4%PBC 32.4% Guanabens N. J Hepatol 2005;42:573

• OLT 46.1%OLT 46.1% Sokhi RP. Liver Transpl 2004;10:648

– Fx: One year p OLT 17% Fx: One year p OLT 17% Carey EJ. Liver Transpl 2003;9:1166

Cross Sectional Studies

Fracture Risk In Celiac DiseaseFracture Risk In Celiac Disease

• Retrospective cohort study 165 CD vs. age Retrospective cohort study 165 CD vs. age and gender matched controlsand gender matched controls

• Fractures - 41 (25%) vs. 14 (8%)Fractures - 41 (25%) vs. 14 (8%)– OR 3.5 (95% CI 1.8-7.2, P=.0001)OR 3.5 (95% CI 1.8-7.2, P=.0001)

• 80% of fractures in CD were before 80% of fractures in CD were before diagnosis or poor compliance with GFDdiagnosis or poor compliance with GFD

• Advise early diagnosis and dietary Advise early diagnosis and dietary compliancecompliance

Vasquez H et al. Am J Gastro 2000;95:183

Fracture Risk In Celiac DiseaseFracture Risk In Celiac Disease

• Prospective cohort study of adults with CD born before 1950– 244 patients vs. 161 controls

• Fractures - 82 (35%) vs. 53 (33%)– OR 1.05 (95%CI 0.68-1.62)– OR 1.13 (95% CI 0.60-2.12)

• Adjusted for age, gender, BMI, tobacco

• No overall risk of fracture and do not warrant general screening for OP

Thomason K Gut 2003;52:518

Cumulative Incidence of any Fracture Among 273 Cumulative Incidence of any Fracture Among 273 Olmsted County, Minnesota Residents Diagnosed Olmsted County, Minnesota Residents Diagnosed with UC Between 1940 and 1993with UC Between 1940 and 1993

Cu

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Cu

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Time from index date (yr)Time from index date (yr)

00 55 1010 1515 2020 252500

2020

4040

6060

8080

100100ControlControlCaseCase

Loftus, EV., et al., Clinical Gastro Hepatol 2003;1:465-473

BMD after Obesity SurgeryBMD after Obesity Surgery

Bano G. Int J Obes 1999;23:361

36 subject s/p JI or PB-BP 1971-9236 subject s/p JI or PB-BP 1971-92

T scores for bone mineral density in patientsT scores for bone mineral density in patientstreated by jejunoileal bypasstreated by jejunoileal bypass

BBMDMD PremenopausalPremenopausal PostmenopausalPostmenopausal PostmenopausalPostmenopausal ReversedReversedT ScoreT Score womenwomen womenwomen women on HRTwomen on HRT MenMen postmenopausal postmenopausal

womenwomen

> -2.5 - < -1> -2.5 - < -1 2 (40%)2 (40%) 7 (53.7%)7 (53.7%) 1 (14.4%)1 (14.4%) 2 (40%)2 (40%) 1 (16.7%)1 (16.7%)

< -2.5< -2.5 0 (0%)0 (0%) 2 (15.4%)2 (15.4%) 0 (0%)0 (0%) 2 (40%)2 (40%) 0 (0%)0 (0%)

Mechanisms Leading to OsteoporosisMechanisms Leading to Osteoporosis

Key - CD=celiac disease; PGx=post gastrectomy; SBS=short bowel syndrome; RTA=renal tubular acidosis; CLD=chronic liver disease

CD, IBD, CP (etoh), CLDAbnormal gonadal axis

SBS (diarrhea), CLD (RTA)Metabolic acidosis

AllSecondary hyperparathyroidism

CD, IBD, CLDInflammation alters bone metabolism

AllSteatorrhea impairs calcium and vitamin D absorption

CD, PGx, SBSMucosal disease + decreased transit time (malabsorption)

DiseaseDiseaseFactorFactor

Unique Mechanisms Leading to OP

• Celiac disease1 – enterocytes are less responsive to 1,25 OH D2

• Gastrectomy2 – decreased gastrocalcin, which improves bone uptake of Ca Liver disease

• CLD3 - unconjugated bilirubin, copper, and bile salts impair osteoblasts function

1. Bernstein CN. Eur J Gastro Hepato 2003;15:8572. Hakanson R. Regul Pept. 1990; 28:107 3. Haaber AB. Intern J Pancr 2000; 27:21

Osteoporosis – Other FactorsOsteoporosis – Other Factors

• Menopausal statusMenopausal status

• AgeAge

• Family historyFamily history

• Low BMI and sedentary life styleLow BMI and sedentary life style

• Hypothyroidism (Celiac)Hypothyroidism (Celiac)

Drug Induced OsteoporosisDrug Induced Osteoporosis

• CorticosteroidsCorticosteroids• CholestyramineCholestyramine• TPNTPN• CyclosporineCyclosporine• TacrolimusTacrolimus

• Warfarin Warfarin • HeparinHeparin• ThyroxineThyroxine• Loop diureticsLoop diuretics• AnticonvulsantsAnticonvulsants• AlcoholAlcohol• TobaccoTobacco

Drug Induced OsteoporosisDrug Induced Osteoporosis

• CorticosteroidsCorticosteroids– Impair osteoblast functionImpair osteoblast function– Reduce GI calcium absorptionReduce GI calcium absorption– Increase renal calcium excretionIncrease renal calcium excretion– Secondary hyperparathyroidismSecondary hyperparathyroidism– HypogonadismHypogonadism– ““Low turnover” OPLow turnover” OP

Fracture Risk and Dose of CorticosteroidsFracture Risk and Dose of Corticosteroids

Van Staa TP, et al.1998

Relative risk of fracture by dosages of Relative risk of fracture by dosages of corticosteroids of prednisolonecorticosteroids of prednisolone

Hip fractureHip fractureVertebral fractureVertebral fracture

2.5 mg/d2.5 mg/d 2.5-7.5 mg/d2.5-7.5 mg/d >7.5 mg/d>7.5 mg/d

Rel

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Bone Mineral Density in Crohn’s Disease After 2 Bone Mineral Density in Crohn’s Disease After 2 Years of CorticosteroidsYears of Corticosteroids

Schoon EJ., et al., Clin Gast Hepat 2005;3:113-121

Corticosteroid-dependent (N = 90)Corticosteroid-dependent (N = 90) Corticosteroid-free (N = 181)Corticosteroid-free (N = 181)

Corticosteroid-exposed (N = 83)Corticosteroid-exposed (N = 83)

BudesonideBudesonidePrednisolonePrednisolone

T-s

co

reT

-sc

ore

Time (months)Time (months)

-0.8-0.8

-0.9-0.9

-1.0-1.0

-1.1-1.1

-1.2-1.2

-1.3-1.300 66 1212 1818 2424

T-s

co

reT

-sc

ore

Time (months)Time (months)

-0.5-0.5

-0.6-0.6

-0.7-0.7

-0.8-0.8

-0.9-0.9

-1.0-1.000 66 1212 1818 2424

P = 0.0093P = 0.0093

Corticosteroid-naive (N = 98)Corticosteroid-naive (N = 98)

T-s

co

reT

-sc

ore

Time (months)Time (months)

-0.4-0.4

-0.5-0.5

-0.6-0.6

-0.7-0.7

-0.8-0.8

-0.9-0.900 66 1212 1818 2424

P = 0.0015P = 0.0015P = 0.007P = 0.007 P = 0.008P = 0.008 P = 0.011P = 0.011

T-s

co

reT

-sc

ore

Time (months)Time (months)

-0.7-0.7

-0.8-0.8

-0.9-0.9

-1.0-1.0

-1.1-1.1

-1.2-1.200 66 1212 1818 2424

Bone Density Improves with Disease Remission in Bone Density Improves with Disease Remission in Patients with Inflammatory Bowel DiseasePatients with Inflammatory Bowel Disease

Reffitt, D., et al., European Jour of Gastro & Hepat 2003,15:1267-1273

Mea

n Z

-sco

reM

ean

Z-s

core

ActiveActive(n=41)(n=41)

-1.0-1.0

Femoral neckFemoral neck

*p<0.01; *p<0.01; ††p<0.05p<0.05

Lumbar spineLumbar spine

RemissionRemission<1 year<1 year(n=26)(n=26)

RemissionRemission1-3 years1-3 years

(n=13)(n=13)

RemissionRemission>3 years>3 years(n=57)(n=57)

-0.8-0.8

-0.6-0.6

-0.4-0.4

-0.2-0.2

0.00.0

0.20.2

0.40.4

Mea

n Z

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ean

Z-s

core

ActiveActive(n=41)(n=41)

-1.0-1.0

RemissionRemission<1 year<1 year(n=26)(n=26)

RemissionRemission1-3 years1-3 years

(n=13)(n=13)

RemissionRemission>3 years>3 years(n=57)(n=57)

-0.8-0.8

-0.6-0.6

-0.4-0.4

-0.2-0.2

0.00.0

0.20.2

0.40.4

††

** **

††

BMD in Viral Hepatitis - CirrhosisBMD in Viral Hepatitis - Cirrhosis

n=26

n=22/40

Inverse correlation between LS-BMD and sTNFR r=-0.79, p<0.001

Gonzalez-Calvin JL, et al. J Clin Endo Metab 2004;89:4325-30

00

22

44

66

88

1010

1212

ControlsControls VC withoutVC withoutosteoporosisosteoporosis

VC withVC withosteoporosisosteoporosis

rTN

FS

rTN

FS

5555(

ng

/dl)

(ng

/dl)

RANKL / OPG System in CLDRANKL / OPG System in CLD

Moschen AR, et al. J Hepatol 2005;43:973-83

CLD n=193, Age / gender matched controls n=56

00

500500

10001000

15001500

20002000

25002500

Ost

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in [

pg

/ml]

Ost

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in [

pg

/ml]

00

200200

400400

600600

800800

10001000

Rat

io (

OP

G [

pg

/ml]

/sR

AN

KL

[pg

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PG

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g/m

l]/s

RA

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L[p

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5656 56564242 7272 2323 5656 56564242 7272 2323Non-cirrh. Non-cirrh.

CLDCLDChild AChild A Child BChild B Child CChild C Control Control

patientspatientsNon-cirrh. Non-cirrh.

CLDCLDChild AChild A Child BChild B Child CChild C Control Control

patientspatients

P<0.01P<0.01P<0.001P<0.001

P<0.001P<0.001P<0.001P<0.001

P<0.001P<0.001

P<0.02P<0.02

P<0.05P<0.05P<0.001P<0.001

P<0.001P<0.001P<0.01P<0.01

P<0.001P<0.001

PN Factors Promote MBDPN Factors Promote MBD

• Increase calcium excretionIncrease calcium excretion– Amino acid (titratable acid)Amino acid (titratable acid)

– Dextrose (insulin)Dextrose (insulin)

– CalciumCalcium

– Sodium (increase GFR)Sodium (increase GFR)

– Cycled infusionCycled infusion

• Decrease calcium excretion Decrease calcium excretion – PhosphorusPhosphorus

Seidner DL. JPEN 2002;26:S37

PN Factors Promote MBDPN Factors Promote MBD

• Altered bone metabolismAltered bone metabolism– MagnesiumMagnesium

• PTH secretion and actionPTH secretion and action

– Metabolic acidosisMetabolic acidosis• Amino acids produce weak organic acidsAmino acids produce weak organic acids• Chronic diarrhea, d-lactic acidosisChronic diarrhea, d-lactic acidosis

– HeparinHeparin– Vitamin DVitamin D– AluminumAluminum

Seidner DL. JPEN 2002;26:S37

MBD in Celiac DiseaseMBD in Celiac Disease

• OP is common, even if no GI Sx.OP is common, even if no GI Sx.– 28% LS, 15% hip, risk in F=M28% LS, 15% hip, risk in F=M– A good reason to treat all with GFDA good reason to treat all with GFD

• Fracture risk is 40% by age 70, 2x NmlFracture risk is 40% by age 70, 2x Nml

• BMD increase 5% in 1y on GFDBMD increase 5% in 1y on GFD– Increase for axial > appendicularIncrease for axial > appendicular

• BMD still below normal while on dietBMD still below normal while on diet

• BMD improves in children > adultsBMD improves in children > adults

Bernstein CN, et al. Bernstein CN, et al. GastroenterologyGastroenterology. 2003;124:795-841.. 2003;124:795-841.

Serologic Screening Serologic Screening for Celiac Disease in OPfor Celiac Disease in OP

• Prevalence of CDPrevalence of CD– 1.2% (12/978) for whole cohort1.2% (12/978) for whole cohort

• 0.7% (2/304) with normal BMD0.7% (2/304) with normal BMD• 1.2% (5/431) with osteopenia1.2% (5/431) with osteopenia• 2.1% (5/243) with osteoporosis2.1% (5/243) with osteoporosis

– In patients with GI Sx (all CD had Sx)In patients with GI Sx (all CD had Sx)• 2.6% (5/191) with osteopenia2.6% (5/191) with osteopenia• 3.9% (5/127) with osteoporosis3.9% (5/127) with osteoporosis

• Advise targeted case-finding approach to Advise targeted case-finding approach to serologic testing (i.e. GI Sx) 318 vs. 978serologic testing (i.e. GI Sx) 318 vs. 978

Sanders DS. DDS 2005;50:587

MBD in IBDMBD in IBD

• Low BMD is uncommon at diagnosisLow BMD is uncommon at diagnosis• Active inflammation and Active inflammation and

corticosteroids account for most of corticosteroids account for most of the bone loss (unable to differentiate the bone loss (unable to differentiate which has the greatest effect since which has the greatest effect since both are closely linked)both are closely linked)

• OP and fractures are equal in CD vs. OP and fractures are equal in CD vs. UC and men vs. women with IBDUC and men vs. women with IBD

Bernstein CN, et al. Bernstein CN, et al. GastroenterologyGastroenterology. 2003;124:795-841. . 2003;124:795-841.

MBD Following Gastrectomy MBD Following Gastrectomy

• High risk for MBDHigh risk for MBD– Osteoporosis 32%-42%Osteoporosis 32%-42%– Osteomalacia 10%-20%Osteomalacia 10%-20%

• Risk for MBD equal for Billroth I vs. Risk for MBD equal for Billroth I vs. II, total vs. partialII, total vs. partial

• Vagotomy is not a risk factorVagotomy is not a risk factor

• Etiology multifactorial;Etiology multifactorial;– poor intake, rapid transit, steatorrheapoor intake, rapid transit, steatorrhea

Bernstein CN, et al. Bernstein CN, et al. GastroenterologyGastroenterology. 2003;124:795-841.. 2003;124:795-841.

MBD in Chronic Liver DiseaseMBD in Chronic Liver Disease

• Mild MBD is present in CLD, rates of Mild MBD is present in CLD, rates of bone loss are near normalbone loss are near normal

• OP and fractures are more common OP and fractures are more common in older age, hypogonadism, cortico-in older age, hypogonadism, cortico-steroid use and cirrhosis (PBC steroid use and cirrhosis (PBC affects older women)affects older women)

• The rate of MBD is similar for The rate of MBD is similar for cholestatic and non-cholestatic CLDcholestatic and non-cholestatic CLD

Leslie WD, et al. Gastroenterology. 2003;125:941-66.

MBD and Orthotopic Liver TxMBD and Orthotopic Liver Tx

• Pre-transplant evaluation should Pre-transplant evaluation should include investigations for MBDinclude investigations for MBD

• Bone loss after OLT is biphasic; Bone loss after OLT is biphasic; rapid loss for the first 3-6 months, rapid loss for the first 3-6 months, then level or improvement (especially then level or improvement (especially PBC)PBC)

• Most fractures occur in the first yearMost fractures occur in the first year

Leslie WD, et al. Gastroenterology. 2003;125:941-66.

Evaluation for MBDEvaluation for MBD

• HistoryHistory– GI dx, atraumatic fx, PMH, menopausal status, FH, GI dx, atraumatic fx, PMH, menopausal status, FH,

tobacco, alcohol, medications?tobacco, alcohol, medications?

• ExaminationExamination– Height, skeletal deformitiesHeight, skeletal deformities

• LaboratoryLaboratory– Blood: Ca, Phos, Mg, PTH, vitamin DBlood: Ca, Phos, Mg, PTH, vitamin D

– Urine: Ca, Mg, n-telopeptideUrine: Ca, Mg, n-telopeptide

• BMDBMD– Dual-energy absorptiometry (DEXA)Dual-energy absorptiometry (DEXA)

Dual Energy X-ray AbsorptiometryDual Energy X-ray Absorptiometry

• Quantifies bone mass of lumbar Quantifies bone mass of lumbar

spine, femoral neck, radiusspine, femoral neck, radius

• Precise, accurate (5%), quick (5 min), Precise, accurate (5%), quick (5 min),

low radiation exposure (1-3 mrem), low radiation exposure (1-3 mrem),

low costlow cost

Evaluation of OsteoporosisEvaluation of Osteoporosis

• DEXADEXA– T-score: Results compared to normal T-score: Results compared to normal

young adultsyoung adults– Z-score: Results compared to age Z-score: Results compared to age

matched controlsmatched controls– Results parallel fracture riskResults parallel fracture risk– WHO defines WHO defines

• Osteoporosis T-score Osteoporosis T-score >> -2.5, -2.5, • Osteopenia T-score -1.0 to -2.5Osteopenia T-score -1.0 to -2.5

– Can not differentiate OP versus OMCan not differentiate OP versus OM

Indications for DEXAIndications for DEXA

• IBDIBD– CS >3 months or repeated coursesCS >3 months or repeated courses– Low trauma fractureLow trauma fracture– Postmenopausal woman or man >50yPostmenopausal woman or man >50y– HypogonadismHypogonadism– Repeat in 1 year if recent initiation of Repeat in 1 year if recent initiation of

CS, 2-3 years if initial study is normal CS, 2-3 years if initial study is normal and risk factors are presentand risk factors are present

Bernstein CN, et al. Gastroenterology. 2003;124:795-841

Indications for DEXAIndications for DEXA

• Celiac DiseaseCeliac Disease– Adults after 1 year on GFDAdults after 1 year on GFD

• Postgastrectomy (same as IBD)Postgastrectomy (same as IBD)

• Chronic Liver Disease (same as IBD), Chronic Liver Disease (same as IBD), at dx of PBC and before OLTat dx of PBC and before OLT

Bernstein CN, et al. Gastroenterology. 2003;124:795-841Leslie WD, et al. Gastroenterology. 2003;125:941-66

Prevention of MBD (T > -1)Prevention of MBD (T > -1)

• Treat the underlying GI diseaseTreat the underlying GI disease• Minimize corticosteroid useMinimize corticosteroid use• Optimize nutritional statusOptimize nutritional status

– Calcium 1-1.2 g, vit D 400-800 IU, vit KCalcium 1-1.2 g, vit D 400-800 IU, vit K

• Encourage weight bearing exerciseEncourage weight bearing exercise• Minimize alcohol intake and stop smokingMinimize alcohol intake and stop smoking• Dx and Rx hypogonadism, hyper-Dx and Rx hypogonadism, hyper-

parathyroidism, thyroid diseaseparathyroidism, thyroid disease

Bernstein CN, et al. Gastroenterology. 2003;124:795-841Leslie WD, et al. Gastroenterology. 2003;125:941-66

Management of Diminished BMDManagement of Diminished BMD

• T -2.5 to -1T -2.5 to -1– Preventative measuresPreventative measures– Repeat DEXA in 2 yRepeat DEXA in 2 y– If prolonged CS consider If prolonged CS consider

bisphosphonate and DEXA in 1 ybisphosphonate and DEXA in 1 y

• T <-2.5T <-2.5– Refer to bone specialistRefer to bone specialist

Bernstein CN, et al. Gastroenterology. 2003;124:795-841Leslie WD, et al. Gastroenterology. 2003;125:941-66

Medications for OsteoporosisMedications for Osteoporosis• Inhibits osteoclastsInhibits osteoclasts

– Conjugated estrogensConjugated estrogens

– Selective estrogen receptor modulatorsSelective estrogen receptor modulators

– BisphosphonatesBisphosphonates

– CalcitoninCalcitonin

– Testosterone Testosterone

• Stimulates osteoblastsStimulates osteoblasts– Recombinant human PTH 1-34 Recombinant human PTH 1-34

– Flouride (not recommended)Flouride (not recommended)

**

Alendronate Increases Lumbar Spine Bone Mineral Alendronate Increases Lumbar Spine Bone Mineral Density in Patients with Crohn’s DiseaseDensity in Patients with Crohn’s Disease

Haderslev, K., et al., Gastroenterology 2000;119:639-648

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MonthMonth

-2-2

00

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88Lumbar spineLumbar spine Femoral neckFemoral neck

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**

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Alendronate Alendronate + 4.6% + 4.6% 1.2% 1.2%Placebo Placebo - 0.9% - 0.9% 1.0% 1.0%((PP < 0.01) < 0.01)

Alendronate Alendronate + 3.3% + 3.3% 1.5% 1.5%Placebo Placebo + 0.7% + 0.7% 1.1% 1.1%((PP = 0.08) = 0.08)

RCT of Etidronate Plus Calcium and Vitamin D for RCT of Etidronate Plus Calcium and Vitamin D for Treatment of Low Bone Mineral Density in CDTreatment of Low Bone Mineral Density in CD

Siffledeen J, et al., Clin Gastro Hepat 2005;3:122-132

Ch

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Ch

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BaselineBaseline 6 months6 months 12 months12 months 18 months18 months 24 months24 months

11

22

33

44

55Etidronate, C+D n =72Etidronate, C+D n =72C + D n =71C + D n =71

**

*P<0.05*P<0.05

00

**

**

**

**

Lumbar spineLumbar spine

PN PreparationPN Preparation

• Calcium gluconate - 15 meq (3 gm salt)Calcium gluconate - 15 meq (3 gm salt)

• Phosphate - serum conc mid-rangePhosphate - serum conc mid-range

– Ca:POCa:PO44 ratio or 5meq:10 mmol ratio or 5meq:10 mmol

– 10-14 mmol / 1000 kcal dextrose10-14 mmol / 1000 kcal dextrose

• Acetate - serum bicarb mid-rangeAcetate - serum bicarb mid-range

• Sodium – balance intake vs. outputSodium – balance intake vs. output

• Amino acids - 1.5 g/kg/d, reduce when Amino acids - 1.5 g/kg/d, reduce when visceral proteins normalize and patient is visceral proteins normalize and patient is wellwell

Medical Therapy in Long-term PNMedical Therapy in Long-term PN

• 20 HTPN pts (>1yr), DEXA T-Score <-120 HTPN pts (>1yr), DEXA T-Score <-1• D-B RCT IV clodronate vs placeboD-B RCT IV clodronate vs placebo• Results: IV BisphosphonateResults: IV Bisphosphonate

– Reduced markers of bone resorption, Reduced markers of bone resorption, p<0.05p<0.05

– Markers of bone formation unchangedMarkers of bone formation unchanged– Improved BMD at forearm (p<0.009) with a Improved BMD at forearm (p<0.009) with a

positive trend for spine and hip positive trend for spine and hip

Haderslev KV et al. AJCN 76:482,2002

RCT 45mg po vs. placebo

50 womenHCV – cirrhosis

P=0.008 @ 1yP=0.002 @ 2y

Shiomi S et al. AJG 2002;97:9789-81

Vitamin K2 (Menatetrenone) for Bone Loss in Patients with Cirrhosis of the Liver

Mean change in BMDMean change in BMD

Years of TreatmentYears of Treatment

-15-15

Ch

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Treated GroupTreated GroupControl GroupControl Group

Medications for MBD in Medications for MBD in Chronic Liver DiseaseChronic Liver Disease

• Post OLT MBD, n=63 (PBC=26, PSC Post OLT MBD, n=63 (PBC=26, PSC 37), calcitonin 100 IU/d vs. placebo x 37), calcitonin 100 IU/d vs. placebo x 6 months6 months11

• PBC with osteopenia, n=67 PBC with osteopenia, n=67 Etidronate vs. placebo X 1yearEtidronate vs. placebo X 1year22

• Bone loss and fracture risk was Bone loss and fracture risk was unchangedunchanged

1. Hay JE, et al. J Hepatol 2001;34:3372. Lindor KD, et al. J Hepatol 2000;33:878

MBD in GI: ConclusionsMBD in GI: Conclusions

• Metabolic bone disease is common in Metabolic bone disease is common in GI disordersGI disorders

• Treatment of the underlying disease Treatment of the underlying disease and nutrient supplementation may and nutrient supplementation may prevent MBDprevent MBD

• More research is needed to adequately More research is needed to adequately define the optimal use of medications define the optimal use of medications in GI patients with osteoporosis and in GI patients with osteoporosis and osteopeniaosteopenia

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