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
Introduction • The integrity and maintenance of bone health is dependent on multiple factors. • It is well recognized that calcium intake is essential for bone health. • Additional intake via supplementation is recommended in some patients.
Introduction • 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
Calcium Homeostasis Dietary Calcium 900mg/d Formation 240mg/d Ca ECF Absorbed 180 mg/d Resorption 240mg/d Secreted 420mg/d Feces 660mg/d URINE N-TELOPEPTIDE URINE CALCIUM / CREATININE RATIO Excreted in urine 240mg/d
Type 1 Collagen Calcified Matrix Bone +
Type 1 Collagen + Calcified Matrix Bone
Type I Collagen ******************************** C-terminal N-terminal ******************************** N-telopeptide (NTX)
Introduction • Calcium supplement bioavailability • Decreased in: • elderly • hypovitaminosis D • achlorhydria • decreased estrogen • concomitant intake of oxalate and iron elements
Introduction* • 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.
Introduction Clinical observations of increased fracture associated with PPI use • Yang and colleagues JAMA 2006 • increased risk of hip fracture with long term proton pump inhibitor (PPI) use • Targownik and colleagues CMAJ 2008 • any osteoporotic fracture increased after seven years PPI use • increased hip fractures were seen after five years PPI use
Study Objective: Is there biochemical evidence of proton pump inhibitors affecting bone metabolism? • Primary endpoint: • Is absorption of calcium citrate superior to calcium carbonate? • Calcium to creatinine ratio • Secondary endpoint: • Is there biochemical evidence of proton pump inhibitors affecting osteoclastic activity? • Urinary NTX
Methods • Randomized, open-label, crossover single-site study to evaluate the effects on calcium absorption • Institutional Review Board approval through the Catholic Health System • 31 patients were enrolled in the trial after meeting the inclusion criteria
Study Population • Post-menopausal females as defined by absence of menses greater than one year • 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
Study Criteria • Exclusion criteria • hypovitaminosis D • pre-menopausal status • males • malabsorption disorders • known diagnosis of renal insufficiency • abnormal baseline urinary N-telopeptide
Data analysis • paired t-test with a p-value of <0.05 deemed statistically significant
Results • Urinary Ca/Cr ratio • No statistically significant difference of the calcium absorption as reflected in the ratio after addition of the PPI
P = 0.1462 P = 0.7883
Results • 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
P = 0.0003 P = 0.0011
Discussion • Primary endpoint • no statistically significant difference in calcium absorption for either formulation while patients are on PPI’s • Secondary endpoint • Significant increase of almost 38% in osteoclastic activity as reflected by urinary NTX after initiation of PPI use
Discussion • Lack of difference of calcium absorption • ? Small study size • ? Not significantly affected by PPI • 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?
Conclusion • We recommend to continue with current recommendations for calcium supplementation • For those on PPI therapy, preferably calcium citrate.
Conclusion • 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
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. • 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. • 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.
References • 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. • 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.
References • Heller H, Greer L, Poindexter J, et al. Pharmacokinetic and Pharmacodynamic Comparison of Two Calcium Supplements in Postmenopausal Women. Journ Clin Pharm 2000;40:1237-1244. • Gokce C, Cokce O, Baydinc C, et al. Use of random urine samples to estimate total urinary calcium and phosphate excretion. Arch Intern Med 1991;151:1587-1588. • National Osteoporosis Foundation. www.nof.org. Last accessed May 26, 2009. • Renal Transport of Calcium, Magnesium, and Phosphorus. The Kidney. Suki W, Rouse D. 1991. 380-393.