Transcript No Slide Title

Metabolic Bone Disease
in Gastrointestinal Disorders
Douglas L. Seidner, MD, FACG
The Cleveland Clinic
Digestive Disease Center
Objectives
• Review bone physiology and MBD
• Discuss the most common GI
disorders that lead to MBD
• Understand the rationale for
preventing and treating MBD in GI
disorders
Normal Trabecular Bone
Bone Density During Life
100
Men
80
Bone Density 60
Percent
Women
40
20
0
0
10
20
30
40
50
60
Years
www.wyethconsumerhealthcare.ie/caltrate/lc/bones.html
70
80
Bone Remodeling
RANK L
M-CSF
IL-1, IL-6, IL-11
D-Pyr
NTx CTx RANK
OPG
TNF, TGF-B
Calcium
Osteocalcin
Hydroxyproline
OC
H+
Proteases
Collagen
Matrix
TGF-B
LTBP
Resorption
20 Days
OB
Activation
GH
IL-1, PTH, IL-6, -E2
Osteocalcin
BSAP
PICP
IGF-1
IGF-2
IGF-BP
Formation
100 Days
120 Days
www.endotext.org/parathyroid/parathyroid11/parathyroid11.htm
Osteoporosis
Osteomalacia
MBD in GI Disorders
• Common
– Osteoporosis >>> Osteomalacia
• Uncommon
– Avascular necrosis
– Hypertrophic osteoarthropathy
– Hepatitis C-associated osteosclerosis
– Hepatobiliary rickets
MBD in GI Disorders
• Malabsorption and maldigestion
– Celiac disease, post gastrectomy, short gut,
pancreatic insufficiency
• Inflammatory Bowel Disease
– Crohn’s disease and ulcerative colitis
• Chronic Liver Disease
– Cholestatic and hepatocellular diseases
• Secondary to therapy for GI disease
– Liver and SB transplant, medications, TPN
Osteopenia, Osteoporosis
and Fracture Risk
Cross Sectional Studies
• Celiac 25 % Vasquez H. Am J Gastroenterol 2000;95:183
• Post gastrectomy 55 % Zittel TT. Am J Surg
1997;174:431
• IBD 30%
Pigot F. Dig Dis Sci. 1992;37:1396
– Fx: 1/100 pt-yr, 40% > normal Bernstein CN. Ann Int
Med 2000;133:795
• PBC 32.4% Guanabens N. J Hepatol 2005;42:573
• OLT 46.1% Sokhi RP. Liver Transpl 2004;10:648
– Fx: One year p OLT 17% Carey EJ. Liver Transpl
2003;9:1166
Fracture Risk In Celiac Disease
• Retrospective cohort study 165 CD vs. age
and gender matched controls
• Fractures - 41 (25%) vs. 14 (8%)
– OR 3.5 (95% CI 1.8-7.2, P=.0001)
• 80% of fractures in CD were before
diagnosis or poor compliance with GFD
• Advise early diagnosis and dietary
compliance
Vasquez H et al. Am J Gastro 2000;95:183
Fracture 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
Olmsted County, Minnesota Residents Diagnosed
with UC Between 1940 and 1993
Cumulative incidence (%)
100
Control
Case
80
60
40
20
0
0
5
10
15
20
25
Time from index date (yr)
Loftus, EV., et al., Clinical Gastro Hepatol 2003;1:465-473
BMD after Obesity Surgery
36 subject s/p JI or PB-BP 1971-92
T scores for bone mineral density in patients
treated by jejunoileal bypass
BMD
T Score
Premenopausal
women
Postmenopausal
women
Postmenopausal
women on HRT
Men
Reversed
postmenopausal
women
> -2.5 - < -1
2 (40%)
7 (53.7%)
1 (14.4%)
2 (40%)
1 (16.7%)
< -2.5
0 (0%)
2 (15.4%)
0
2 (40%)
0
(0%)
(0%)
Bano G. Int J Obes 1999;23:361
Mechanisms Leading to Osteoporosis
Factor
Disease
Mucosal disease + decreased
transit time (malabsorption)
CD, PGx, SBS
Steatorrhea impairs calcium and
vitamin D absorption
All
Inflammation alters bone
metabolism
CD, IBD, CLD
Secondary hyperparathyroidism
All
Metabolic acidosis
SBS (diarrhea), CLD (RTA)
Abnormal gonadal axis
CD, IBD, CP (etoh), CLD
Key - CD=celiac disease; PGx=post gastrectomy; SBS=short bowel syndrome;
RTA=renal tubular acidosis; CLD=chronic liver disease
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;15:857
2. Hakanson R. Regul Pept. 1990; 28:107
3. Haaber AB. Intern J Pancr 2000; 27:21
Osteoporosis – Other Factors
•
•
•
•
•
Menopausal status
Age
Family history
Low BMI and sedentary life style
Hypothyroidism (Celiac)
Drug Induced Osteoporosis
•
•
•
•
•
Corticosteroids
Cholestyramine
TPN
Cyclosporine
Tacrolimus
•
•
•
•
•
•
•
Warfarin
Heparin
Thyroxine
Loop diuretics
Anticonvulsants
Alcohol
Tobacco
Drug Induced Osteoporosis
• Corticosteroids
– Impair osteoblast function
– Reduce GI calcium absorption
– Increase renal calcium excretion
– Secondary hyperparathyroidism
– Hypogonadism
– “Low turnover” OP
Fracture Risk and Dose of Corticosteroids
Relative risk of fracture by dosages of
corticosteroids of prednisolone
Relative risk of fracture
compared with control
6
5
Hip fracture
Vertebral fracture
4
3
2
1
0
2.5 mg/d
2.5-7.5 mg/d
>7.5 mg/d
Van Staa TP, et al.1998
Bone Mineral Density in Crohn’s Disease After 2
Years of Corticosteroids
Corticosteroid-free (N = 181)
Corticosteroid-dependent (N = 90)
-0.8
-0.5
Budesonide
Prednisolone
-0.6
T-score
T-score
-0.9
-1.0
-1.1
-1.2
-1.3
-0.7
P = 0.0093
-0.8
-0.9
0
6
12
18
-1.0
24
0
6
Time (months)
-0.7
-0.4
-0.8
-0.5
T-score
T-score
18
24
Corticosteroid-naive (N = 98)
Corticosteroid-exposed (N = 83)
-0.9
-1.0
-1.1
-1.2
12
Time (months)
P = 0.0015
P = 0.007
P = 0.008
P = 0.011
12
18
24
-0.6
-0.7
-0.8
0
6
12
Time (months)
18
24
-0.9
0
6
Time (months)
Schoon EJ., et al., Clin Gast Hepat 2005;3:113-121
Bone Density Improves with Disease Remission in
Patients with Inflammatory Bowel Disease
Lumbar spine
0.4
0.4
0.2
0.2
0.0
*
-0.2
†
-0.4
-0.6
Mean Z-score
Mean Z-score
Femoral neck
0.0
*
-0.2
-0.4
-0.6
-0.8
-0.8
-1.0
-1.0
Active Remission Remission Remission
(n=41)
<1 year
1-3 years
>3 years
(n=26)
(n=13)
(n=57)
†
Active Remission Remission Remission
(n=41)
<1 year
1-3 years
>3 years
(n=26)
(n=13)
(n=57)
*p<0.01; †p<0.05
Reffitt, D., et al., European Jour of Gastro & Hepat 2003,15:1267-1273
BMD in Viral Hepatitis - Cirrhosis
12
rTNFS55(ng/dl)
10
n=22/40
8
6
4
2
0
n=26
Controls
VC without
VC with
osteoporosis osteoporosis
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
RANKL / OPG System in CLD
P<0.01
P<0.001
Osteoprotegerin [pg/ml]
2500
P<0.001
P<0.001
P<0.001
2000
1500
1000
500
0
56
42
Non-cirrh. Child A
CLD
72
23
56
Child B
Child C
Control
patients
Ratio (OPG [pg/ml]/sRANKL[pg/ml])
CLD n=193, Age / gender matched controls n=56
P<0.02
P<0.001
1000
P<0.05
P<0.001
P<0.001
P<0.01
800
600
400
200
0
56
42
Non-cirrh. Child A
CLD
72
23
56
Child B
Child C
Control
patients
Moschen AR, et al. J Hepatol 2005;43:973-83
PN Factors Promote MBD
• Increase calcium excretion
– Amino acid (titratable acid)
– Dextrose (insulin)
– Calcium
– Sodium (increase GFR)
– Cycled infusion
• Decrease calcium excretion
– Phosphorus
Seidner DL. JPEN 2002;26:S37
PN Factors Promote MBD
• Altered bone metabolism
– Magnesium
• PTH secretion and action
– Metabolic acidosis
• Amino acids produce weak organic acids
• Chronic diarrhea, d-lactic acidosis
– Heparin
– Vitamin D
– Aluminum
Seidner DL. JPEN 2002;26:S37
MBD in Celiac Disease
• OP is common, even if no GI Sx.
– 28% LS, 15% hip, risk in F=M
– A good reason to treat all with GFD
• Fracture risk is 40% by age 70, 2x Nml
• BMD increase 5% in 1y on GFD
– Increase for axial > appendicular
• BMD still below normal while on diet
• BMD improves in children > adults
Bernstein CN, et al. Gastroenterology. 2003;124:795-841.
Serologic Screening
for Celiac Disease in OP
• Prevalence of CD
– 1.2% (12/978) for whole cohort
• 0.7% (2/304) with normal BMD
• 1.2% (5/431) with osteopenia
• 2.1% (5/243) with osteoporosis
– In patients with GI Sx (all CD had Sx)
• 2.6% (5/191) with osteopenia
• 3.9% (5/127) with osteoporosis
• Advise targeted case-finding approach to
serologic testing (i.e. GI Sx) 318 vs. 978
Sanders DS. DDS 2005;50:587
MBD in IBD
• Low BMD is uncommon at diagnosis
• Active inflammation and
corticosteroids account for most of
the bone loss (unable to differentiate
which has the greatest effect since
both are closely linked)
• OP and fractures are equal in CD vs.
UC and men vs. women with IBD
Bernstein CN, et al. Gastroenterology. 2003;124:795-841.
MBD Following Gastrectomy
• High risk for MBD
– Osteoporosis 32%-42%
– Osteomalacia 10%-20%
• Risk for MBD equal for Billroth I vs.
II, total vs. partial
• Vagotomy is not a risk factor
• Etiology multifactorial;
– poor intake, rapid transit, steatorrhea
Bernstein CN, et al. Gastroenterology. 2003;124:795-841.
MBD in Chronic Liver Disease
• Mild MBD is present in CLD, rates of
bone loss are near normal
• OP and fractures are more common
in older age, hypogonadism, corticosteroid use and cirrhosis (PBC
affects older women)
• The rate of MBD is similar for
cholestatic and non-cholestatic CLD
Leslie WD, et al. Gastroenterology. 2003;125:941-66.
MBD and Orthotopic Liver Tx
• Pre-transplant evaluation should
include investigations for MBD
• Bone loss after OLT is biphasic;
rapid loss for the first 3-6 months,
then level or improvement (especially
PBC)
• Most fractures occur in the first year
Leslie WD, et al. Gastroenterology. 2003;125:941-66.
Evaluation for MBD
• History
– GI dx, atraumatic fx, PMH, menopausal status,
FH, tobacco, alcohol, medications?
• Examination
– Height, skeletal deformities
• Laboratory
– Blood: Ca, Phos, Mg, PTH, vitamin D
– Urine: Ca, Mg, n-telopeptide
• BMD
– Dual-energy absorptiometry (DEXA)
Dual Energy X-ray Absorptiometry
• Quantifies bone mass of lumbar
spine, femoral neck, radius
• Precise, accurate (5%), quick (5 min),
low radiation exposure (1-3 mrem),
low cost
Evaluation of Osteoporosis
• DEXA
– T-score: Results compared to normal
young adults
– Z-score: Results compared to age
matched controls
– Results parallel fracture risk
– WHO defines
• Osteoporosis T-score > -2.5,
• Osteopenia T-score -1.0 to -2.5
– Can not differentiate OP versus OM
Indications for DEXA
• IBD
– CS >3 months or repeated courses
– Low trauma fracture
– Postmenopausal woman or man >50y
– Hypogonadism
– Repeat in 1 year if recent initiation of
CS, 2-3 years if initial study is normal
and risk factors are present
Bernstein CN, et al. Gastroenterology. 2003;124:795-841
Indications for DEXA
• Celiac Disease
– Adults after 1 year on GFD
• Postgastrectomy (same as IBD)
• Chronic Liver Disease (same as IBD),
at dx of PBC and before OLT
Bernstein CN, et al. Gastroenterology. 2003;124:795-841
Leslie WD, et al. Gastroenterology. 2003;125:941-66
Prevention of MBD (T > -1)
• Treat the underlying GI disease
• Minimize corticosteroid use
• Optimize nutritional status
– Calcium 1-1.2 g, vit D 400-800 IU, vit K
• Encourage weight bearing exercise
• Minimize alcohol intake and stop smoking
• Dx and Rx hypogonadism, hyperparathyroidism, thyroid disease
Bernstein CN, et al. Gastroenterology. 2003;124:795-841
Leslie WD, et al. Gastroenterology. 2003;125:941-66
Management of Diminished BMD
• T -2.5 to -1
– Preventative measures
– Repeat DEXA in 2 y
– If prolonged CS consider
bisphosphonate and DEXA in 1 y
• T <-2.5
– Refer to bone specialist
Bernstein CN, et al. Gastroenterology. 2003;124:795-841
Leslie WD, et al. Gastroenterology. 2003;125:941-66
Medications for Osteoporosis
• Inhibits osteoclasts
– Conjugated estrogens
– Selective estrogen receptor modulators
– Bisphosphonates
– Calcitonin
– Testosterone
• Stimulates osteoblasts
– Recombinant human PTH 1-34
– Flouride (not recommended)
Alendronate Increases Lumbar Spine Bone Mineral
Density in Patients with Crohn’s Disease
Lumbar spine
Femoral neck
8
8
*
*
4
2
0
*
6
Change (%)
Change (%)
6
*
4
2
0
-2
-2
0
6
12
Month
0
6
12
Month
Alendronate + 4.6%  1.2%
Placebo
- 0.9%  1.0%
(P < 0.01)
Alendronate + 3.3%  1.5%
Placebo
+ 0.7%  1.1%
(P = 0.08)
Haderslev, K., et al., Gastroenterology 2000;119:639-648
RCT of Etidronate Plus Calcium and Vitamin D for
Treatment of Low Bone Mineral Density in CD
Lumbar spine
5
Change in BMD (%)
Etidronate, C+D n =72
C + D n =71
4
*
*P<0.05
3
*
*
2
*
*
1
0
Baseline
6 months
12 months
18 months
24 months
Siffledeen J, et al., Clin Gastro Hepat 2005;3:122-132
PN Preparation
• Calcium gluconate - 15 meq (3 gm salt)
• Phosphate - serum conc mid-range
– Ca:PO4 ratio or 5meq:10 mmol
– 10-14 mmol / 1000 kcal dextrose
• Acetate - serum bicarb mid-range
• Sodium – balance intake vs. output
• Amino acids - 1.5 g/kg/d, reduce when
visceral proteins normalize and patient is
well
Medical Therapy in Long-term PN
• 20 HTPN pts (>1yr), DEXA T-Score <-1
• D-B RCT IV clodronate vs placebo
• Results: IV Bisphosphonate
– Reduced markers of bone resorption,
p<0.05
– Markers of bone formation unchanged
– Improved BMD at forearm (p<0.009) with
a positive trend for spine and hip
Haderslev KV et al. AJCN 76:482,2002
Vitamin K2 (Menatetrenone) for Bone Loss
in Patients with Cirrhosis of the Liver
50 women
HCV – cirrhosis
P=0.008 @ 1y
P=0.002 @ 2y
+10
Changes in BMD (%)
RCT 45mg po
vs. placebo
Mean change in BMD
+5
0
-5
Treated Group
Control Group
-10
-15
0
1
2
Years of Treatment
Shiomi S et al. AJG 2002;97:9789-81
Medications for MBD in
Chronic Liver Disease
• Post OLT MBD, n=63 (PBC=26, PSC
37), calcitonin 100 IU/d vs. placebo x
6 months1
• PBC with osteopenia, n=67
Etidronate vs. placebo X 1year2
• Bone loss and fracture risk was
unchanged
1. Hay JE, et al. J Hepatol 2001;34:337
2. Lindor KD, et al. J Hepatol 2000;33:878
MBD in GI: Conclusions
• Metabolic bone disease is common
in GI disorders
• Treatment of the underlying disease
and nutrient supplementation may
prevent MBD
• More research is needed to
adequately define the optimal use of
medications in GI patients with
osteoporosis and osteopenia
Thank you