1 / 50

Metabolic Bone Disease in Gastrointestinal Disorders

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

zinna
Download Presentation

Metabolic Bone Disease in Gastrointestinal Disorders

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Metabolic Bone Diseasein Gastrointestinal Disorders Douglas L. Seidner, MD, FACG The Cleveland Clinic Digestive Disease Center

  2. 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

  3. Normal Trabecular Bone

  4. Bone Density During Life 100 Men 80 60 Bone Density Percent Women 40 20 0 0 10 20 30 40 50 60 70 80 Years www.wyethconsumerhealthcare.ie/caltrate/lc/bones.html

  5. Bone Remodeling RANK L M-CSF IL-1, IL-6, IL-11 D-Pyr Activation GH IL-1, PTH, IL-6, -E2 OPG RANK NTx CTx TNF, TGF-B Calcium OB OC Osteocalcin Osteocalcin Hydroxyproline BSAP PICP Matrix Proteases TGF-B H+ IGF-1 IGF-2 IGF-BP LTBP Collagen Resorption 20 Days Formation 100 Days 120 Days www.endotext.org/parathyroid/parathyroid11/parathyroid11.htm

  6. Osteoporosis

  7. Osteomalacia

  8. MBD in GI Disorders • Common • Osteoporosis >>> Osteomalacia • Uncommon • Avascular necrosis • Hypertrophic osteoarthropathy • Hepatitis C-associated osteosclerosis • Hepatobiliary rickets

  9. 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

  10. 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

  11. 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

  12. 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

  13. Cumulative Incidence of any Fracture Among 273 Olmsted County, Minnesota Residents Diagnosed with UC Between 1940 and 1993 100 Control Case 80 60 Cumulative incidence (%) 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

  14. 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 B MD Premenopausal Postmenopausal Postmenopausal Reversed T Score women women women on HRT Men 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 (0%) 2 (40%) 0 (0%) Bano G. Int J Obes 1999;23:361

  15. 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

  16. 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

  17. Osteoporosis – Other Factors • Menopausal status • Age • Family history • Low BMI and sedentary life style • Hypothyroidism (Celiac)

  18. Corticosteroids Cholestyramine TPN Cyclosporine Tacrolimus Warfarin Heparin Thyroxine Loop diuretics Anticonvulsants Alcohol Tobacco Drug Induced Osteoporosis

  19. Drug Induced Osteoporosis • Corticosteroids • Impair osteoblast function • Reduce GI calcium absorption • Increase renal calcium excretion • Secondary hyperparathyroidism • Hypogonadism • “Low turnover” OP

  20. Fracture Risk and Dose of Corticosteroids Relative risk of fracture by dosages of corticosteroids of prednisolone 6 Hip fracture Vertebral fracture 5 4 Relative risk of fracture compared with control 3 2 1 0 2.5 mg/d 2.5-7.5 mg/d >7.5 mg/d Van Staa TP, et al.1998

  21. 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 -0.9 -0.6 -1.0 -0.7 P = 0.0093 T-score T-score -1.1 -0.8 -1.2 -0.9 -1.3 -1.0 0 6 12 18 24 0 6 12 18 24 Time (months) Time (months) Corticosteroid-naive (N = 98) Corticosteroid-exposed (N = 83) -0.7 -0.4 P = 0.007 P = 0.008 P = 0.011 P = 0.0015 -0.8 -0.5 -0.9 -0.6 T-score T-score -1.0 -0.7 -1.1 -0.8 -1.2 -0.9 0 6 12 18 24 0 6 12 18 24 Time (months) Time (months) Schoon EJ., et al., Clin Gast Hepat 2005;3:113-121

  22. Bone Density Improves with Disease Remission in Patients with Inflammatory Bowel Disease Femoral neck Lumbar spine 0.4 0.4 0.2 0.2 0.0 0.0 * * -0.2 -0.2 Mean Z-score Mean Z-score -0.4 -0.4 † -0.6 -0.6 † -0.8 -0.8 -1.0 -1.0 Active (n=41) Remission <1 year (n=26) Remission 1-3 years (n=13) Remission >3 years (n=57) Active (n=41) Remission <1 year (n=26) Remission 1-3 years (n=13) Remission >3 years (n=57) *p<0.01; †p<0.05 Reffitt, D., et al., European Jour of Gastro & Hepat 2003,15:1267-1273

  23. BMD in Viral Hepatitis - Cirrhosis 12 10 n=22/40 8 6 rTNFS55(ng/dl) 4 n=26 2 0 Controls VC without osteoporosis VC with 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

  24. RANKL / OPG System in CLD CLD n=193, Age / gender matched controls n=56 P<0.01 P<0.02 P<0.001 P<0.001 2500 1000 P<0.05 P<0.001 P<0.001 P<0.001 P<0.001 P<0.001 P<0.01 2000 800 1500 600 Ratio (OPG [pg/ml]/sRANKL[pg/ml]) Osteoprotegerin [pg/ml] 1000 400 500 200 0 0 56 42 72 23 56 56 42 72 23 56 Non-cirrh. CLD Child A Child B Child C Control patients Non-cirrh. CLD Child A Child B Child C Control patients Moschen AR, et al. J Hepatol 2005;43:973-83

  25. 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

  26. 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

  27. 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.

  28. 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

  29. 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.

  30. 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.

  31. 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, cortico-steroid 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.

  32. 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.

  33. 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)

  34. 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

  35. 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

  36. 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

  37. 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

  38. 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, hyper-parathyroidism, thyroid disease Bernstein CN, et al. Gastroenterology. 2003;124:795-841 Leslie WD, et al. Gastroenterology. 2003;125:941-66

  39. 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

  40. Medications for Osteoporosis • Inhibits osteoclasts • Conjugated estrogens • Selective estrogen receptor modulators • Bisphosphonates • Calcitonin • Testosterone • Stimulates osteoblasts • Recombinant human PTH 1-34 • Flouride (not recommended)

  41. Alendronate Increases Lumbar Spine Bone Mineral Density in Patients with Crohn’s Disease Lumbar spine Femoral neck 8 8 * * 6 6 * * 4 4 Change (%) Change (%) 2 2 0 0 -2 -2 0 6 12 0 6 12 Month 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

  42. RCT of Etidronate Plus Calcium and Vitamin D for Treatment of Low Bone Mineral Density in CD Lumbar spine 5 Etidronate, C+D n =72 C + D n =71 4 * *P<0.05 3 * Change in BMD (%) * 2 * * 1 0 Baseline 6 months 12 months 18 months 24 months Siffledeen J, et al., Clin Gastro Hepat 2005;3:122-132

  43. 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

  44. 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

  45. Vitamin K2 (Menatetrenone) for Bone Loss in Patients with Cirrhosis of the Liver Mean change in BMD RCT 45mg po vs. placebo 50 women HCV – cirrhosis P=0.008 @ 1y P=0.002 @ 2y +10 +5 0 Changes in BMD (%) -5 Treated Group Control Group -10 -15 0 1 2 Years of Treatment Shiomi S et al. AJG 2002;97:9789-81

  46. 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

  47. 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

  48. Thank you

More Related