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
Formation
240mg/d
900mg/d
Absorbed
180 mg/d
Ca ECF
Resorption
240mg/d
Secreted
420mg/d
Feces
660mg/d
URINE CALCIUM /
CREATININE RATIO
Excreted in
urine 240mg/d
URINE
N-TELOPEPTIDE
Reinforced Concrete:
Steel Lattice + Cement
Matrix
Bone
Type 1 Collagen
Calcified Matrix
+
Bone
Type 1
Collagen
+
Calcified
Matrix
Osteoclast Phagocytizes 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
31 patients
16 Calcium citrate
15 Calcium carbonate
4 weeks
4 weeks
Pt excluded
Citrate + PPI
Carbonate + PPI
4 weeks
4 weeks
Carbonate + PPI
Citrate + PPI
4 weeks
4 weeks
Data analysis

paired t-test with a p-value of <0.05
deemed statistically significant
Results
Results

Urinary Ca/Cr ratio
– No statistically significant difference of
the calcium absorption as reflected in the
ratio after addition of the PPI
Urinary Calcium / Creatinine Ratio Following
Addition of PPI
2.5
2.223
2.075
2
1.642
1.5
1
P=
P=
0.1462
0.7883
0.5
0
Calcium
alone
Ca citrate + Ca carbonate
PPI
+ PPI
Mean Ca/Cr ratio
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
Urinary NTX Following Addition of PPI
50
45
40
40
40
35
30
25
29
P=
P=
0.0003
0.0011
20
15
10
5
0
Calcium alone Ca citrate +
PPI
Ca carbonate
+ PPI
Mean Urinary NTX
nmol/mmol Cr
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 osteoporosisrelated 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.
QUESTIONS