1. A Randomized, Cross-over Study to Evaluate the Effect of Proton Pump Inhibitors on the Absorption of Two Different Calcium Formulations in Post Menopausal Women Linda M. Burns, DO Joseph M. Grisanti, MD

2. Introduction The integrity and maintenance of bone health is dependent on multiple factors. The integrity and maintenance of bone health is dependent on multiple factors. It is well recognized that calcium intake is essential for bone health. It is well recognized that calcium intake is essential for bone health. Additional intake via supplementation is recommended in some patients. Additional intake via supplementation is recommended in some patients.

3. Introduction 1994 National Institute of Health Consensus Statement 1994 National Institute of Health Consensus Statement –Dietary calcium is preferred source –Additional supplementation available in form of calcium carbonate or calcium citrate recommended with consideration to other factors –1200mg to 1500mg / day recommended

4. Calcium Homeostasis Ca ECF Dietary Calcium 900mg/d Feces 660mg/d Absorbed 180 mg/d Secreted 420mg/d Formation 240mg/d Resorption 240mg/d Excreted in urine 240mg/d URINE CALCIUM / CREATININE RATIO URINE N-TELOPEPTIDE

5. Reinforced Concrete: Steel Lattice + Cement Matrix

6. Bone Type 1 Collagen Calcified Matrix +

7. Bone Type 1 Collagen + Calcified Matrix

8. Osteoclast Phagocytizes Bone

9. Type I Collagen C-terminalN-terminal N-telopeptide (NTX)

10. Introduction Calcium supplement bioavailability Calcium supplement bioavailability –Decreased in: elderly elderly hypovitaminosis D hypovitaminosis D achlorhydria achlorhydria decreased estrogen decreased estrogen concomitant intake of oxalate and iron elements concomitant intake of oxalate and iron elements

11. Introduction* Effect of gastric acidity on calcium absorption Effect of gastric acidity on calcium absorption –Calcium carbonate has been demonstrated to be better absorbed in an acidic environment –Calcium citrate absorption is not dependent on acidity Recker RR. Calcium Absorption and Achlorhydria. NEJM. 313:70-73. 1985.

12. Introduction Clinical observations of increased fracture associated with PPI use Yang and colleagues JAMA 2006 Yang and colleagues JAMA 2006 –increased risk of hip fracture with long term proton pump inhibitor (PPI) use Targownik and colleagues CMAJ 2008 Targownik and colleagues CMAJ 2008 –any osteoporotic fracture increased after seven years PPI use –increased hip fractures were seen after five years PPI use

13. Study Objective: Is there biochemical evidence of proton pump inhibitors affecting bone metabolism? Primary endpoint: Primary endpoint: –Is absorption of calcium citrate superior to calcium carbonate? Calcium to creatinine ratio Calcium to creatinine ratio Secondary endpoint: Secondary endpoint: –Is there biochemical evidence of proton pump inhibitors affecting osteoclastic activity? Urinary NTX Urinary NTX

14. Methods Randomized, open-label, crossover single-site study to evaluate the effects on calcium absorption Randomized, open-label, crossover single-site study to evaluate the effects on calcium absorption Institutional Review Board approval through the Catholic Health System Institutional Review Board approval through the Catholic Health System 31 patients were enrolled in the trial after meeting the inclusion criteria 31 patients were enrolled in the trial after meeting the inclusion criteria

15. Study Population Post-menopausal females as defined by absence of menses greater than one year Post-menopausal females as defined by absence of menses greater than one year Inclusion criteria: Inclusion criteria: –Normal vitamin D level (>30mg/dL) –No use of proton pump inhibitors, H2 Blockers, or prednisone within 8 weeks prior to the study Wash out period Wash out period

16. Study Criteria Exclusion criteria Exclusion criteria –hypovitaminosis D –pre-menopausal status –males –malabsorption disorders –known diagnosis of renal insufficiency –abnormal baseline urinary N-telopeptide

17. 31 patients 16 Calcium citrate 4 weeks Citrate + PPI 4 weeks Carbonate + PPI 4 weeks 15 Calcium carbonate 4 weeks Carbonate + PPI 4 weeks Citrate + PPI 4 weeks Pt excluded

18. Data analysis paired t-test with a p-value of <0.05 deemed statistically significant paired t-test with a p-value of <0.05 deemed statistically significant

19. Results

20. Results Urinary Ca/Cr ratio Urinary Ca/Cr ratio –No statistically significant difference of the calcium absorption as reflected in the ratio after addition of the PPI

21. P = 0.1462 P = 0.7883

22. Results Urinary NTX- marker of bone resorption Urinary NTX- marker of bone resorption –Dramatic increase of 37.9% in both groups following the addition of PPI after 4 weeks, and remained elevated after 8 weeks

23. P = 0.0003 P = 0.0011

24. Discussion Primary endpoint Primary endpoint –no statistically significant difference in calcium absorption for either formulation while patients are on PPI’s Secondary endpoint Secondary endpoint –Significant increase of almost 38% in osteoclastic activity as reflected by urinary NTX after initiation of PPI use

25. Discussion Lack of difference of calcium absorption Lack of difference of calcium absorption –? Small study size –? Not significantly affected by PPI Increase urinary NTX Increase urinary NTX –Evidence that PPI’s do affect bone metabolism –Despite no difference in calcium absorption… is there an independent process of PPI affect on bone?

26. Conclusion We recommend to continue with current recommendations for calcium supplementation We recommend to continue with current recommendations for calcium supplementation –For those on PPI therapy, preferably calcium citrate.

27. Conclusion Based on our data, we also recommend considering PPI use as an independent risk factor for osteoporosis: Based on our data, we also recommend considering PPI use as an independent risk factor for osteoporosis: –DEXA scan –25 Hydroxy-Vitamin D level –Weight bearing exercise –Tobacco cessation –Calcium supplementation

28. References Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis- related fractures. CMAJ 2008;179:319-326. Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis- related fractures. CMAJ 2008;179:319-326. George M, Stein B, Muller O, et al. Metabolic activation stimulates acid secretion and expression of matrix degrading proteases in human osteoblasts. Ann Rheum Dis 2004;63;67-70. George M, Stein B, Muller O, et al. Metabolic activation stimulates acid secretion and expression of matrix degrading proteases in human osteoblasts. Ann Rheum Dis 2004;63;67-70. Straub D. Calcium Supplementation in Clinical Practice: A Review of Forms, Doses, and Indications Nutr Clin Pract 2007; 22:286-296. Straub D. Calcium Supplementation in Clinical Practice: A Review of Forms, Doses, and Indications Nutr Clin Pract 2007; 22:286-296. Yang, Y.-X., Lewis, J. D., Epstein, S., Metz, D. C. Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture. JAMA 2006;296:2947-2953. Yang, Y.-X., Lewis, J. D., Epstein, S., Metz, D. C. Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture. JAMA 2006;296:2947-2953.

29. References Ilich J, Kerstetter J. Nutrition in Bone Health Revisited: A Story Beyond Calcium. Am J Clin Nutr 2000;19:715-737. Ilich J, Kerstetter J. Nutrition in Bone Health Revisited: A Story Beyond Calcium. Am J Clin Nutr 2000;19:715-737. Heaney R, Dowell S, Bierman J, et al. Absorbability and Cost Effectiveness in Calcium Supplementation. Am J Clin Nutr 2001;20:239-246. Heaney R, Dowell S, Bierman J, et al. Absorbability and Cost Effectiveness in Calcium Supplementation. Am J Clin Nutr 2001;20:239-246. NIH Consensus Developmental Panel on Optimal Calcium Intake. JAMA 1994;272:1942-1948. NIH Consensus Developmental Panel on Optimal Calcium Intake. JAMA 1994;272:1942-1948. Recker RR. Calcium absorption and achlorhydria. N Engl J Med. 1985;313:70-73. Recker RR. Calcium absorption and achlorhydria. N Engl J Med. 1985;313:70-73.

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31. QUESTIONS