A Randomized, Cross-over Study A Randomized, Cross-over Study to Evaluate the Effect of Proton to Evaluate the Effect of Proton

Pump Inhibitors on the Absorption Pump Inhibitors on the Absorption of Two Different Calcium of Two Different Calcium

Formulations in Formulations in Post Menopausal WomenPost Menopausal Women

Linda M. Burns, DOLinda M. Burns, DO

Joseph M. Grisanti, MDJoseph M. Grisanti, MD

IntroductionIntroduction

The integrity and maintenance of bone The integrity and maintenance of bone health is dependent on multiple factors.health is dependent on multiple factors.

It is well recognized that calcium intake It is well recognized that calcium intake is essential for bone health. is essential for bone health.

Additional intake via supplementation is Additional intake via supplementation is recommended in some patients.recommended in some patients.

IntroductionIntroduction

1994 National Institute of Health 1994 National Institute of Health Consensus StatementConsensus Statement– Dietary calcium is preferred sourceDietary calcium is preferred source– Additional supplementation available in Additional supplementation available in

form of calcium carbonate or calcium form of calcium carbonate or calcium citrate recommended with consideration citrate recommended with consideration to other factorsto other factors

– 1200mg to 1500mg / day recommended1200mg to 1500mg / day recommended

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

Reinforced Concrete: Reinforced Concrete: Steel Lattice + Cement Steel Lattice + Cement MatrixMatrix

BoneBone

Type 1 CollagenType 1 Collagen Calcified MatrixCalcified Matrix

+

BoneBone

Type 1 Collagen Type 1 Collagen

++Calcified MatrixCalcified Matrix

Osteoclast Phagocytizes Osteoclast Phagocytizes BoneBoneOsteoclast Phagocytizes Osteoclast Phagocytizes BoneBone

Type I CollagenType I Collagen

C-terminal N-terminal

N-telopeptide (NTX)

IntroductionIntroduction

Calcium supplement bioavailabilityCalcium supplement bioavailability– Decreased in:Decreased in:

elderlyelderly hypovitaminosis Dhypovitaminosis D achlorhydriaachlorhydria decreased estrogendecreased estrogen concomitant intake of oxalate and concomitant intake of oxalate and

iron elements iron elements

Introduction*Introduction*

Effect of gastric acidity on calcium Effect of gastric acidity on calcium absorptionabsorption– Calcium carbonate has been Calcium carbonate has been

demonstrated to be better absorbed demonstrated to be better absorbed in an acidic environment in an acidic environment

– Calcium citrate absorption is not Calcium citrate absorption is not dependent on aciditydependent on acidity

Recker RR. Calcium Absorption and Achlorhydria. NEJM. 313:70-73. 1985.

IntroductionIntroduction

Clinical observations of increased fracture Clinical observations of increased fracture associated with PPI useassociated with PPI use

Yang and colleagues Yang and colleagues JAMAJAMA 2006 2006– increased risk of hip fracture with long increased risk of hip fracture with long

term proton pump inhibitor (PPI) use term proton pump inhibitor (PPI) use

Targownik and colleagues Targownik and colleagues CMAJCMAJ 2008 2008– any osteoporotic fracture increased after any osteoporotic fracture increased after

sevenseven years PPI use years PPI use– increased hip fractures were seen after increased hip fractures were seen after

fivefive years PPI use years PPI use

Study Objective: Study Objective: Is there biochemical evidence of Is there biochemical evidence of proton pump inhibitors affecting proton pump inhibitors affecting

bone metabolism?bone metabolism? Primary endpoint:Primary endpoint:

– Is absorption of calcium citrate Is absorption of calcium citrate superior to calcium carbonate?superior to calcium carbonate? Calcium to creatinine ratioCalcium to creatinine ratio

Secondary endpoint:Secondary endpoint:– Is there biochemical evidence of Is there biochemical evidence of

proton pump inhibitors affecting proton pump inhibitors affecting osteoclastic activity?osteoclastic activity? Urinary NTXUrinary NTX

MethodsMethods

Randomized, open-label, crossover Randomized, open-label, crossover single-site study to evaluate the single-site study to evaluate the effects on calcium absorption effects on calcium absorption

Institutional Review Board approval Institutional Review Board approval through the Catholic Health System through the Catholic Health System

31 patients were enrolled in the trial 31 patients were enrolled in the trial after meeting the inclusion criteria after meeting the inclusion criteria

Study PopulationStudy Population

Post-menopausal females as defined Post-menopausal females as defined by absence of menses greater than by absence of menses greater than one yearone year

Inclusion criteria:Inclusion criteria:– Normal vitamin D level (>30mg/dL)Normal vitamin D level (>30mg/dL)– No use of proton pump inhibitors, H2 No use of proton pump inhibitors, H2

Blockers, or prednisone within 8 weeks Blockers, or prednisone within 8 weeks prior to the studyprior to the study Wash out periodWash out period

Study CriteriaStudy Criteria

Exclusion criteriaExclusion criteria– hypovitaminosis Dhypovitaminosis D– pre-menopausal statuspre-menopausal status– malesmales– malabsorption disordersmalabsorption disorders– known diagnosis of renal insufficiencyknown diagnosis of renal insufficiency– abnormal baseline urinary N-abnormal baseline urinary N-

telopeptidetelopeptide

31 patients

16 Calcium citrate 15 Calcium carbonate

4 weeks 4 weeks

Citrate + PPI Carbonate + PPI

4 weeks 4 weeks

Carbonate + PPI Citrate + PPI

4 weeks 4 weeks

Pt excluded

Data analysisData analysis

paired t-test with a p-value of paired t-test with a p-value of <0.05 deemed statistically <0.05 deemed statistically significant significant

ResultsResults

ResultsResults

Urinary Ca/Cr ratioUrinary Ca/Cr ratio– No statistically significant difference No statistically significant difference

of the calcium absorption as of the calcium absorption as reflected in the ratio after addition reflected in the ratio after addition of the PPIof the PPI

2.075

1.642

2.223

0

0.5

1

1.5

2

2.5

Calciumalone

Ca citrate +PPI

Ca carbonate+ PPI

Urinary Calcium / Creatinine Ratio Following Addition of PPI

Mean Ca/Cr ratio

P =

0.1462

P =

0.7883

ResultsResults

Urinary NTX- marker of bone Urinary NTX- marker of bone resorptionresorption– Dramatic increase of Dramatic increase of 37.9%37.9% in both in both

groups following the addition of PPI groups following the addition of PPI after 4 weeks, and remained elevated after 4 weeks, and remained elevated after 8 weeksafter 8 weeks

29

40 40

0

5

10

15

20

25

30

35

40

45

50

Calcium alone Ca citrate +PPI

Ca carbonate+ PPI

Urinary NTX Following Addition of PPI

Mean Urinary NTXnmol/mmol Cr

P =

0.0003

P =

0.0011

DiscussionDiscussion

Primary endpointPrimary endpoint– no statistically significant difference no statistically significant difference

in calcium absorption for either in calcium absorption for either formulation while patients are on formulation while patients are on PPI’sPPI’s

Secondary endpointSecondary endpoint– Significant increase of almost 38% in Significant increase of almost 38% in

osteoclastic activity as reflected by osteoclastic activity as reflected by urinary NTX after initiation of PPI useurinary NTX after initiation of PPI use

DiscussionDiscussion

Lack of difference of calcium Lack of difference of calcium absorptionabsorption– ? Small study size? Small study size– ? Not significantly affected by PPI? Not significantly affected by PPI

Increase urinary NTXIncrease urinary NTX– Evidence that PPI’s do affect bone Evidence that PPI’s do affect bone

metabolismmetabolism– Despite no difference in calcium Despite no difference in calcium

absorption… absorption… is there an independent is there an independent process of PPI affect on bone?process of PPI affect on bone?

ConclusionConclusion

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

calcium citrate.calcium citrate.

ConclusionConclusion

Based on our data, we also Based on our data, we also recommend considering PPI use recommend considering PPI use as an as an independent risk factorindependent risk factor for osteoporosis:for osteoporosis:– DEXA scanDEXA scan– 25 Hydroxy-Vitamin D level25 Hydroxy-Vitamin D level– Weight bearing exerciseWeight bearing exercise– Tobacco cessationTobacco cessation– Calcium supplementationCalcium supplementation

ReferencesReferences

Targownik LE, Lix LM, Metge CJ, et al. Use of Targownik LE, Lix LM, Metge CJ, et al. Use of proton pump inhibitors and risk of osteoporosis-proton pump inhibitors and risk of osteoporosis-related fractures. related fractures. CMAJCMAJ 2008;179:319-326. 2008;179:319-326.

George M, Stein B, Muller O, et al. Metabolic George M, Stein B, Muller O, et al. Metabolic activation stimulates acid secretion and activation stimulates acid secretion and expression of matrix degrading proteases in expression of matrix degrading proteases in human osteoblasts. human osteoblasts. Ann Rheum DisAnn Rheum Dis 2004;63;67- 2004;63;67-70. 70.

Straub D. Calcium Supplementation in Clinical Straub D. Calcium Supplementation in Clinical Practice: A Review of Forms, Doses, and Practice: A Review of Forms, Doses, and Indications Indications Nutr Clin PractNutr Clin Pract 2007; 22:286-296. 2007; 22:286-296.

Yang, Y.-X., Lewis, J. D., Epstein, S., Metz, D. C. Yang, Y.-X., Lewis, J. D., Epstein, S., Metz, D. C. Long-term Proton Pump Inhibitor Therapy and Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture. Risk of Hip Fracture. JAMAJAMA 2006;296:2947-2953. 2006;296:2947-2953.

ReferencesReferences

Ilich J, Kerstetter J. Nutrition in Bone Health Ilich J, Kerstetter J. Nutrition in Bone Health Revisited: A Story Beyond Calcium. Revisited: A Story Beyond Calcium. Am J Clin Am J Clin NutrNutr 2000;19:715-737. 2000;19:715-737.

Heaney R, Dowell S, Bierman J, et al. Heaney R, Dowell S, Bierman J, et al. Absorbability and Cost Effectiveness in Absorbability and Cost Effectiveness in Calcium Supplementation. Calcium Supplementation. Am J Clin NutrAm J Clin Nutr 2001;20:239-246.2001;20:239-246.

NIH Consensus Developmental Panel on NIH Consensus Developmental Panel on Optimal Calcium Intake. Optimal Calcium Intake. JAMAJAMA 1994;272:1942-1948.1994;272:1942-1948.

Recker RR. Calcium absorption and Recker RR. Calcium absorption and achlorhydria. achlorhydria. N Engl J MedN Engl J Med. 1985;313:70-73.. 1985;313:70-73.

ReferencesReferences

Heller H, Greer L, Poindexter J, et al. Heller H, Greer L, Poindexter J, et al. Pharmacokinetic and Pharmacodynamic Pharmacokinetic and Pharmacodynamic Comparison of Two Calcium Supplements in Comparison of Two Calcium Supplements in Postmenopausal Women. Postmenopausal Women. Journ Clin PharmJourn Clin Pharm 2000;40:1237-1244.2000;40:1237-1244.

Gokce C, Cokce O, Baydinc C, et al. Use of Gokce C, Cokce O, Baydinc C, et al. Use of random urine samples to estimate total urinary random urine samples to estimate total urinary calcium and phosphate excretion. calcium and phosphate excretion. Arch Intern Arch Intern MedMed 1991;151:1587-1588. 1991;151:1587-1588.

National Osteoporosis Foundation. National Osteoporosis Foundation. www.nof.org. Last accessed May 26, 2009.www.nof.org. Last accessed May 26, 2009.

Renal Transport of Calcium, Magnesium, and Renal Transport of Calcium, Magnesium, and PhosphorusPhosphorus. . The KidneyThe Kidney. Suki W, Rouse D. . Suki W, Rouse D. 1991. 380-393.1991. 380-393.

QUESTIONSQUESTIONS