Conditions: Osteoporosis Hypomagnesemia
Keywords: Bone mineral density
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 62
Healthy volunteers: yes

Brief summary:
Proton pump inhibitors (PPIs) are widely used for the control of gastric ulcer-gastritis, erosive esophagitis (gastroesophageal reflux disease), peptic ulcer disease (duodenal ulcer), and heartburn. Despite their efficacy, their use has been implicated in possibly causing fragility fractures (osteoporosis), hypomagnesemia (magnesium deficiency) and increased risk of chronic kidney disease (CKD). The current trial represents the investigators' ongoing effort to discern whether these complications could be averted by effervescent calcium magnesium citrate (EffCaMgCit).

Detailed description:
In a single-dose bioavailability study, the investigators showed previously that provision of calcium and magnesium in a soluble form as EffCaMgCit improved intestinal absorption of calcium and magnesium and suppressed parathyroid function during PPI treatment, compared with calcium carbonate. In a multidosing trial with esomeprazole 40 mg/day for 28 days, EffCaMgCit suppressed parathyroid function and bone turnover, and increased serum and urinary magnesium, compared with placebo. Moreover, EffCaMgCit co-administered with PPI conferred an alkali load, and averted apparent acid load conferred by PPI (when given with placebo).

In the current proposal, the investigators wish to conduct a 2-year treatment trial, directed at obtaining more definitive evidence that EffCaMgCit overcomes all three complications of PPI.

Aim 1. To test the hypothesis that EffCaMgCit would prevent/treat osteoporosis, by suppressing parathyroid function and bone resorption, thereby stabilizing bone mineral density (BMD). The critical endpoint will be BMD. Secondary endpoints will be serum PTH and C-terminal telopeptide (CTX).

Aim 2. To test the hypothesis that EffCaMgCit would prevent/treat hypomagnesemia/magnesium deficiency, by providing bioavailable magnesium. The critical endpoint will be fractional excretion of magnesium (FEMg) and free muscle magnesium by MRS. Secondary endpoints will be serum and urinary magnesium.

Aim 3. To test the hypothesis that EffCaMgCit would reduce the risk of CKD during PPI use by averting putative hypomagnesemia/magnesium deficiency and neutralizing acid load. The investigators propose that PPI causes hypomagnesemia/magnesium deficiency and confers an acid load, - factors implicated for incident CKD and its progression. EffCaMgCit is expected to avert incident CKD by providing bioavailable magnesium and alkali load. Critical endpoints will be endogenous creatinine clearance, FEMg, free muscle magnesium and acid-base status.

Arms:
arm 1: 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate; designed to be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit will contain 400 units of vitamin D. arm 2: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.

Interventions: intervention 1: EffCaMgCit intervention 2: Placebo
Intervention descriptions: intervention 1: Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) magnesium, and 50 meq total citrate. intervention 2: Each sachet of Placebo will contain microcrystalline cellulose, but no calcium, magnesium or citrate. Placebo will be added to 6 oz water for 1-2 minutes, to be dissolved/suspended before swallowing. The placebo will contain 400 units of vitamin D.

Protocol document:
Prot_SAP_000.pdf: 
Title of Project: Averting Complications of Proton Pump Inhibitor Therapy by 
Effervescent Calcium Magnesium Citrate  
NCT number:  NCT03812380 
IRB approved date: 09.01.2020 
 


 
 
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Title of Project: Averting Complications of Proton Pump Inhibitor Therapy by Effervescent 
Calcium Magnesium Citrate  
Principal Investigator: Khashayar Sakhaee, M.D., Center for Mineral Metabolism and Clinical 
Research (CMMCR), University of Texas Southwestern Medical Center (UTSW) 
Co-Investigator: Orson W. Moe, M.D., CMMCR, UTSW 
Specific Aims: Proton pump inhibitors (PPIs) are widely used for the control of gastric ulcer-
gastritis, erosive esophagitis (gastroesophageal reflux disease), peptic ulcer disease (duodenal 
ulcer), and heartburn. Despite their efficacy, their use has been implicated in possibly causing 
fragility fractures (osteoporosis), hypomagnesemia (magnesium deficiency) and increased risk of 
chronic kidney disease (CKD). The current trial represents our ongoing effort to discern whether 
these complications could be averted by effervescent calcium magnesium citrate (EffCaMgCit).  
In a single-dose bioavailability study, we showed previously that provision of calcium and 
magnesium in a soluble form as EffCaMgCit improved intestinal absorption of calcium and 
magnesium and suppressed parathyroid function during PPI treatment, compared with calcium 
carbonate. In a multidosing trial with esomeprazole 40 mg/day for 28 days, EffCaMgCit 
suppressed parathyroid function and bone turnover, and increased serum and urinary 
magnesium, compared with placebo. Moreover, EffCaMgCit co-administered with PPI conferred 
an alkali load, and averted apparent acid load conferred by PPI (when given with placebo).  
In the current proposal, we wish to conduct a 2-year treatment trial, directed at obtaining more 
definitive evidence that EffCaMgCit overcomes all three complications of PPI.  
Aim 1. To test the hypothesis that EffCaMgCit would prevent/treat osteoporosis, by suppressing 
parathyroid function and bone resorption, thereby stabilizing bone mineral density (BMD). The 
critical endpoint will be overall change in BMD T-Score and Z-Score from baseline to the end of 
study. Secondary endpoints will be the change in serum PTH and C-terminal telopeptide (CTX).  
Aim 2. To test the hypothesis that EffCaMgCit would prevent/treat hypomagnesemia/magnesium 
deficiency, by providing bioavailable magnesium. The critical endpoint will be the overall change 
in the fractional excretion of magnesium (FEMg) and free muscle magnesium by MRS from 
baseline to the end of study. Secondary endpoints will be the change in serum and urinary 
magnesium.  
Aim 3. To test the hypothesis that EffCaMgCit would reduce the risk of CKD during PPI use by 
averting putative hypomagnesemia/magnesium deficiency and neutralizing acid load. We 
propose that PPI causes hypomagnesemia/magnesium deficiency and confers an acid load, - 
factors implicated for incident CKD and its progression. EffCaMgCit is expected to avert incident 
CKD by providing bioavailable magnesium and alkali load. Critical endpoints will be the overall 
change in endogenous creatinine clearance, FEMg, free muscle magnesium and net acid 
excretion, a measure of acid-base status.  
Circumstances Leading to This IND:  Since 2012, our group has explored the therapeutic 
potential of EffCaMgCit in overcoming the complications of prolonged PPI use, namely 
osteoporosis, hypomagnesemia and risk of CKD. (Since adverse symptoms sometimes 
accompanied hypomagnesemia, the term magnesium deficiency more aptly defines this 


 
 
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complication.) The initial studies with EffCaMgCit were conducted without IND but with the 
approval of UTSW’s IRB, which decreed that calcium magnesium citrate is already available in 
the marketplace and would not require a special authorization from the FDA to conduct a research 
study. To make EffCaMgCit, we contracted Sterling Pharmaceutical Services, Inc (Dupo, IL), 
which followed all the FDA’s guidelines for Chemistry, Control and Manufacturing. However, 
Sterling did not use ingredients with drug master file (DMF) and letter of authorization (LOA).  
The first study was a single-dose bioavailability protocol (IRB #082012-030). In healthy subjects, 
intestinal absorption of calcium and magnesium was estimated from the rise in serum and urinary 
magnesium following a single oral load of calcium carbonate or EffCaMgCit while taking placebo 
or omeprazole (OMP) 20 mg bid for 1 week. Calcium absorption from calcium carbonate was 
much lower on OMP compared with placebo, and magnesium absorption from calcium carbonate 
was negligible on both OMP and placebo. In contrast, calcium absorption from EffCaMgCit was 
greater than from calcium carbonate on placebo; it was undiminished by OMP. EffCaMgCit also 
provided bioavailable Mg on both OMP and placebo. OMP attenuated parathyroid suppression 
(measured from changes in serum PTH) from calcium carbonate, but it did not affect parathyroid 
suppression from EffCaMgCit.  
The second study was a multidosing protocol (IRB # 112014-057). The effect of EffCaMgCit was 
compared with placebo in a crossover trial in 22 subjects taking PPI at twice the usual dose 
(esomeprazole 40 mg/day) for 28 days, representing the recommended treatment regimen for 
erosive esophagitis-gastritis. While on PPI, EffCaMgCit increased serum calcium, thereby 
reducing serum PTH and serum CTX, a bone resorption marker; it also raised serum and urinary 
magnesium.  
The preceding trials conducted without IND showed that EffCaMgCit provided bioavailable 
calcium and magnesium, reduced bone resorption, and increased serum and urinary magnesium 
in subjects taking PPI. However, we did not obtain evidence that osteoporosis was stabilized or 
prevented, or that magnesium deficiency was averted. To do so, we would have to show effects 
on bone mass and tissue content of magnesium. Moreover, the foregoing studies did not address 
another complication of PPI use - increased risk of CKD. Though theoretically possible, there is 
so far no evidence that EffCaMgCit prevents incident CKD.  
We envision that another trial (a long-term treatment, possibly considered as Phase III) would be 
required to more firmly establish the value of EffCaMgCit in the prevention/treatment of 
osteoporosis, magnesium deficiency and CKD during PPI use. We would like to conduct such a 
trial under IND, using ingredients with DMF and LOA.  
We have followed the same steps with another formulation of EffCaMgCit, with the same Mg 
content but lower Ca to accommodate special need of CKD. After acquiring promising data from 
single-dose bioavailability and feasibility multidosing study using IRB-approved protocols, we are 
now conducting a more definitive study under IND (#139613).  
Background and Significance: PPIs are effective inhibitors of gastric acid secretion. Thus, they 
are widely used for the control of gastric ulcer-gastritis, erosive esophagitis (gastroesophageal 


 
 
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reflux disease), peptic ulcer disease (duodenal ulcer), and heartburn. PPIs are among the most 
commonly used drugs worldwide, with annual sales in the USA alone exceeding $10 billion.  
However, several population-based studies have reported increased risk of skeletal fractures 
during prolonged PPI use (Roux, 2009). Moreover, hypomagnesemia has been reported during 
PPI treatment (Kuipers, 2009). The symptomatic presentation of some of the cases suggested 
that magnesium deficiency with tissue depletion of magnesium had occurred. The alert by the 
FDA of these complications led to their inclusion under Warnings & Precautions in the package 
inserts of PPIs (FDA, 2011; Tamura, 2012). More recently, PPI use has been associated with 
increased risk of CKD, defined by estimated glomerular filtration rate (eGFR) of less than 60 
ml/min (Wijarnpreecha, 2017; Xie, 2017). These reports led to a news alert by a leading 
nephrology society (ASN, 2017).  
For each complication, we shall review studies conducted to date on how EffCaMgCit might be 
useful in overcoming these disturbances. We shall then cite additional studies needed to obtain 
further validation.  
To discuss complication of osteoporosis first, a plausible explanation is the induction by PPI of 
hypo- or achlorhydria that impairs the solubility of calcium salts and hence the calcium 
bioavailability. The consequent stimulation of parathyroid function would cause bone loss leading 
eventually to fragility fractures. To prove this scheme, the inventors conducted a multi-dosing trial, 
in which the effect of EffCaMgCit was compared with placebo in a crossover trial in 22 subjects 
taking PPI at twice the usual dose (esomeprazole 40 mg/day) for 28 days, representing the 
recommended treatment format for erosive esophagitis-gastritis. Subjects took a dose of 
EffCaMgCit (containing 19 meq Ca and 10 meq Mg) or placebo twice per day, along with 
esomeprazole 40 mg per day.  
 Recognizing short t1/2 of EffCaMgCit, a venous blood sample was obtained at 4 hours after the 
morning dose of EffCaMgCit or placebo after 2 weeks and 4 weeks of treatment. Serum calcium 
was significantly higher after EffCaMgCit than placebo, with virtually every subject showing a 
higher value (Fig. 1). In the Placebo group (while on esomeprazole), a low or marginally low serum 
calcium (< 9 mg/dL) was encountered in 23% of subjects at 2 weeks and in 18% of subjects at 4 
weeks. After EffCaMgCit (with esomeprazole), none of the patients had low or marginally low 
serum calcium. Thus, not only did EffCaMgCit raise serum calcium, but it also corrected low or 
marginally low serum calcium; EffCaMgCit treated hypocalcemia or marginal hypocalcemia from 
PPI therapy. 


 
 
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In the same multi-dosing trial, serum PTH was significantly lower after 2 weeks and 4 weeks of 
treatment with EffCaMgCit (plus esomeprazole) compared with placebo (plus esomeprazole) (Fig. 
2). Prevalence of high serum PTH (> 65 pg/ml) was much lower during 2 weeks and 4 weeks of 
treatment with EffCaMgCit (plus esomeprazole) compared with placebo (plus esomeprazole). 
Thus, EffCaMgCit treated hypocalcemia from esomeprazole. While on placebo (esomeprazole 
alone), a higher number of subjects had high serum PTH at 2 weeks (n = 15) and 4 weeks (n = 
10), indicating that some subjects acquired secondary hyperparathyroidism on esomeprazole. On 
EffCaMgCit (plus esomeprazole), fewer subjects had high serum PTH at 2 weeks (n = 4) and at 
4 weeks (n = 3). Thus, EffCaMgCit prevented development of secondary hyperparathyroidism 
from PPI.  
At both 2 weeks and 4 weeks of treatment, serum CTX was significantly lower on EffCaMgCit 
(plus esomeprazole) compared with placebo (plus esomeprazole). Six subjects had high serum 
CTX at both 2 weeks and 4 weeks of placebo (on esomeprazole)(Fig. 3). On EffCaMgCit (plus 
Serum Calcium, mg/dL
8.0
8.5
9.0
9.5
10.0
10.5
2 Weeks
4 Weeks
p=0.0003
p=0.003
Placebo
EffCaMgCit
Placebo
EffCaMgCit
 
Fig. 1. Comparison of serum 
calcium between Placebo 
and EffCaMgCit after 2 
weeks and 4 weeks of 
treatment along with PPI. 
Solid square and vertical 
line indicate mean ± SD. 
Data from the completed 
multidosing trial with 
EffCaMgCit in 22 subjects.  
Fig. 2. Comparison of 
serum PTH between 
Placebo and EffCaMgCit 
after 2 weeks and 4 weeks 
of treatment along with PPI. 
Solid square and vertical 
line indicate mean ± SD. 
Data from the completed 
multidosing trial with 
EffCaMgCit in 22 subjects.  
 
Serum PTH, pg/mL
0
20
40
60
80
100
120
140
2 Weeks
4 Weeks
p<0.0001
p<0.0001
Placebo
EffCaMgCit
Placebo
EffCaMgCit
Fig. 2. Comparison of 
serum PTH between 
Placebo and EffCaMgCit 
after 2 weeks and 4 weeks 
of treatment along with 
PPI. Solid square and 
vertical line indicate mean 
± SD. Data from the 
completed multidosing 
trial with EffCaMgCit in 22 
subjects.  


 
 
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esomeprazole), high serum CTX was found in none of the subjects at 2 weeks and only one 
subject at 4 weeks. Thus, EffCaMgCit treated excessive bone loss from PPI.  
CTX is a degradation product of bone collagen; it is released into the circulation when bone is 
resorbed by osteoclasts. Serum CTX is an excellent biochemical marker for bone resorption. 
Serum CTX is used commonly to evaluate response to anti-osteoporosis drugs. However, CTX 
is a static measure of bone resorption; it does not reflect the amount of bone mass. BMD, a 
measure of bone mass, is strongly correlated inversely with the rate of fractures. BMD has been 
used to define osteoporosis from the degree of decline from the peak value. In the proposed trial, 
we plan to measure BMD in L2-L4, femoral neck and distal radius. 
We shall now discuss the second complication of PPI. In the FDA’s Adverse Event Reporting 
System in 2012, the odds ratio of hypomagnesemia was 2.76 between omeprazole use and non-
omeprazole use (Tamura, 2012). The risk increased with longer duration of PPI use.  
A prominent cause for the development of hypomagnesemia which we ourselves championed is 
the induction of hypo- or achlorhydria by PPI that impairs the solubility and hence the 
bioavailability of magnesium salts (Kuipers, 2009). PPI might also inhibit magnesium absorption 
by impairing passive absorption of magnesium (Thongon, 2011) or by promoting bicarbonate 
secretion (Mertz-Nielson, 1996).  
Serum CTX, ng/mL
0.0
0.2
0.4
0.6
0.8
1.0
1.2
2 Weeks
4 Weeks
p<0.0001
p<0.0001
Placebo
EffCaMgCit
Placebo
EffCaMgCit
Fig. 3. Comparison of 
serum CTX between 
Placebo and EffCaMgCit 
after 2 weeks and 4 weeks 
of treatment along with PPI. 
Solid square and vertical 
line indicate mean ± SD. 
Data from the completed 
multidosing trial with 
EffCaMgCit in 22 subjects.  
 


 
 
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By delivering magnesium in a soluble form, EffCaMgCit should overcome the low solubility of 
magnesium salts resulting from PPI-induced inhibition of gastric acid secretion or promotion of 
bicarbonate secretion; it might also accommodate inhibition of passive magnesium absorption by 
PPI. In our aforementioned multi-dosing study with esomeprazole 40 mg per day, serum 
magnesium (obtained at 4 hours after the morning dose) was significantly higher after EffCaMgCit 
than after placebo (Fig. 4). At baseline (before starting esomeprazole), 9% of subjects had 
hypomagnesemia or marginal hypomagnesemia (< 2 mg/dL). During treatment with Placebo with 
esomeprazole, hypomagnesemia or marginal hypomagnesemia was found in a higher 
percentage of subjects (14% at 2 weeks, and 23% at 4 weeks). During treatment with EffCaMgCit 
with esomeprazole, no one had hypomagnesemia or marginal hypomagnesemia. Thus, 
EffCaMgCit treated or prevented hypomagnesemia or marginal hypomagnesemia from PPI 
therapy. 
We acknowledge that hypomagnesemia is an inadequate gauge of magnesium deficiency, 
reflective of depletion of magnesium stores in tissues. It is magnesium deficiency that is 
responsible for neuromuscular disturbances, arrhythmia, cardiovascular death (Sakaguchi, 2014) 
and deterioration of renal function (van Laecke, 2013). Serum magnesium may be normal in some 
cases of magnesium deficiency. FEMg is a good biomarker of systemic Mg deficiency as it 
exploits the renal response to defend body Mg deficit. In addition, FEMg helps distinguish renal 
versus extrarenal losses of magnesium (Elisaf, 1997), although the likelihood of PPI inducing 
renal Mg wasting is very low. Free muscle magnesium might also be an excellent marker of 
intracellular magnesium deficiency (Irish, 1997). In the proposed trial, we plan to measure FEMg 
and free muscle magnesium by MRS, as well as serum magnesium.  
 We shall now discuss the last complication of PPI use, - increased risk of CKD. The evidence for 
this complication is based largely on observational, association studies. PPI use has been 
associated with increased incidence of CKD (eGFR < 60 ml/min, representing Stage III or higher), 
from a meta-analysis of published trials (Wijarnpreecha, 2017) and from a large VA database 
(Xie, 2017). The fact that PPIs cause acute kidney injury via acute interstitial nephritis is 
Serum Magnesium, mg/dL
1.6
1.8
2.0
2.2
2.4
2.6
2.8
2 Weeks
4 Weeks
p=0.01
p=0.01
Placebo
EffCaMgCit
Placebo
EffCaMgCit
Fig. 4. Comparison of 
serum Mg between Placebo 
and EffCaMgCit after 2 
weeks and 4 weeks of 
treatment along with PPI. 
Solid square and vertical 
line indicate mean ± SD. 
Data from the completed 
multidosing trial with 
EffCaMgCit in 22 subjects. 


 
 
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unequivocal, with a 3-fold risk in PPI users versus non-users. The increased risk for CKD is slightly 
lower (2-fold). The underlying pathology is not known (Moledinoa 2016, Toth-Manikowsli 2017). 
It is conceivable that PPI-induced CKD may be due to chronic interstitial nephritis.  
A detailed review of the literature and our own data suggests a causal role of 
hypomagnesemia/magnesium deficiency and acid load from PPI for the increased risk of CKD. 
Both factors are potentially correctible by EffCaMgCit.  
 Hypomagnesemia alone has been associated with impaired renal function (Sakaguchi, 2015; van 
Laecke, 2013). Magnesium deficiency has been associated with inflammation and magnesium 
supplementation has anti-inflammatory activities (Nielsen 2018). It is possible that the magnesium 
wasting can worsen chronic interstitial nephritis in chronic PPI users. In patients on hemodialysis, 
those on PPI have a reduced survival rate (Ago, 2016). Excessive acid load is associated with 
renal impairment (Banerjee, 2015), and progression of CKD slows while on alkali therapy in small 
clinical trials (Phisitkul, 2010; de Brito-Ashurst, 2009; Mahajan, 2010). It is commonly believed 
that PPI does not deliver an acid load, since the reduced proton secretion in the upper bowel by 
PPI is compensated by a commensurate fall in bicarbonate secretion by the pancreas (Cameron, 
2012). However, a contrary evidence has appeared, showing that PPI promotes duodenal 
bicarbonate secretion (Mertz-Nielson, 1996). If enhanced duodenal bicarbonate secretion in fact 
exceeds the reduction in gastric acid secretion, PPI will impart an acid load.  
 Our data from the multidosing trial indicate that PPI under certain circumstances might deliver an 
acid load (Fig. 5). 24-h urinary citrate and ammonium were determined at Baseline and after PPI 
+ Placebo or PPI + EfffCaMgCit. On PPI alone (with Placebo), urinary citrate was significantly 
lower than at Baseline, indicative of the kidneys’ response to a systemic acid load. In subjects on 
PPI with EffCaMgCit, urinary citrate was significantly higher than at Baseline.  
Urinary Citrate, mg/day
0
200
400
600
800
1000
1200
1400
Baseline
PPI +
Placebo
PPI +
EffCaMgCit
*
*
Fig. 5. 24-h urinary citrate 
during Baseline, PPI + 
Placebo, and PPI + 
EffCaMgCit. Data from the 
completed multidosing trial 
in 22 subjects. * p < 0.05 vs 
Baseline. 


 
 
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EfffCaMgCit. On PPI alone (with Placebo), urinary citrate was significantly lower than at Baseline, 
indicative of the kidneys’ response to a systemic acid load. In subjects on PPI with EffCaMgCit, 
urinary citrate was significantly higher than at Baseline.  
 On PPI alone (with Placebo), urinary ammonium was marginally higher than at Baseline, 
supportive of marginal delivery of acid load (Fig. 6). On PPI with EffCaMgCit, urinary ammonium 
was 
significantly 
lower 
than 
at 
Baseline. 
Thus, 
PPI 
might 
not 
only 
cause 
hypomagnesemia/magnesium deficiency, but it might also deliver an acid load. Both factors might 
contribute to renal impairment. Increased ammoniagenesis might also contribute to renal tubular 
injury by interacting with complement (Nath, 1985). EffCaMgCit should correct magnesium 
deficiency, acid load, and enhanced ammoniagenesis, thereby averting incident CKD. 
Our preliminary data from the multidosing trial indicated that PPI alone (with placebo) tended to 
increase, whereas EffCaMgCit (with PPI) tended to reduce serum FGF23. The difference between 
the two treatment phases was significant at 4 weeks of treatment. If verified, FGF23 might be 
another factor involved in the PPI-induced incident CKD, which is ameliorated by EffCaMgCit. In 
conclusion, we expect that:  
• 
EffCaMgCit should prevent/treat osteoporosis from PPI use.  
• 
PPI produces hypomagnesemia/magnesium deficiency and EffCaMgCit should abrogate 
this disturbance. 
• 
By delivering bioavailable Mg and alkali load, EffCaMgCit should retard or block renal 
impairment and progression of CKD during PPI therapy. 
The goals of the proposed trial are to conduct a two-year treatment trial instead of 4- week 
treatment, to:  
• 
Measure BMD (in addition to bone turnover markers), to show effectiveness of EffCaMgCit 
in prevention or treatment of osteoporosis. 
Urinary NH4
+, meq/day
0
10
20
30
40
50
Baseline
PPI +
Placebo
PPI +
EffCaMgCit
** (  )
†
Fig. 6. Urinary ammonium 
during Baseline, PPI + Placebo, 
and PPI + EffCaMgCit. Data 
from the completed multidosing 
trial in 22 subjects. ** p < 0.01 
from Baseline; (†) p < 0.001 
between PPI + Placebo vs. PPI + 
EffCaMgCit. P between Baseline 
and PPI + Placebo was 0.18. 
 


 
 
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• 
Obtain other measures of Mg status (FEMg and free muscle Mg), besides serum Mg, to 
demonstrate maintenance of Mg sufficiency or reversal of Mg deficiency by EffCaMgCit 
during PPI therapy. 
• 
Evaluate acid-base status (NAE, urinary citrate and ammonium), to show that acid load 
from PPI is abrogated by alkali load delivered by EffCaMgCit. 
• 
Measure renal function (endogenous creatinine clearance and eGFR), besides serum 
creatinine, to show that EffCaMgCit stabilizes or inhibits deterioration of renal function.  
 
Research Design and Methods: 
Materials 
  
EffCaMgCit and Placebo will be purchased by CMMCR from Sterling Pharmaceutical 
Services (Dupo, IL) as research drugs. EffCaMgCit and Placebo will be contained in sachets of 
identical appearance, identified by different lot numbers. To provide adequate blinding, each 
medication sachet will be labelled with the study name, IRB number, principal investigator’s name, 
expiration date and identification number of the study subject. Labels will be applied to the 
appropriate medication sachets once the subject has been randomized and assigned to a 
treatment group. Labelling of the sachets will be done by personnel who are not engaged in 
patient care.  
  
Each sachet of EffCaMgCit will contain 19 meq or 380 mg calcium, 10 meq (122 mg) 
magnesium, and 50 meq total citrate. Each sachet of Placebo will contain microcrystalline 
cellulose, but no calcium, magnesium or citrate. Both are designed to be added to 6 oz water for 
1-2 minutes, to be dissolved/suspended before swallowing. Each sachet of EffCaMgCit or placebo 
will contain 400 units of vitamin D.  
Conflict of Interest Statement 
  
UT Southwestern so far has not yet secured a pharmaceutical partner for EffCaMgCit. 
Despite lack of industrial sponsorship, the investigators feel that the proposed study is sufficiently 
meritorious scientifically to be pursued by them. Thus, this protocol is investigator-initiated and 
research-driven, and not industry-sponsored. The costs of the study will be borne by the 
Biotechnology Program of CMMCR. CMMCR will purchase test medications from Sterling 
Pharmaceutical Services.  
Study Subjects 
  
Ambulatory adult subjects (> 21 years of age) of either gender of any ethnicity will be 
recruited by advertisement at UTSW campus and Parkland Health & Hospital System as well as 
utilizing the UT Southwestern Clinical Research Information System (utCRIS) which pulls data 
from the UT Southwestern electronic medical record system. To be eligible for the study, subjects 
must have taken PPI (omeprazole or equivalent ≥ 20 mg/day, ≥ three times per week, for at least 
2 months) and expected to continue at a similar dosage in the foreseeable future. utCRIS will be 
used to search for subjects who have a known condition which justifies long term use of PPIs, 
such as GERD and NERD requiring long-term management, Barrett’s esophagus, Zollinger-
Ellison syndrome, and anti-platelet therapy[Scarpignato 2016 BMC 14:179].  utCRIS will also be 
used to identify subjects who have unsuccessfully attempted discontinuation of PPIs.  Patients 


 
 
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who are required to take calcium by their primary physician are excluded from the study.  Also 
excluded from the study will be those with end-stage renal failure on dialysis, hypercalcemia, 
hypophosphatemia (serum P < 2.5 mg/dL), hypertension stage 2 or higher, diabetes Type II with 
HbA1C ≥ 7%, and treatment with adrenocorticosteroids, diuretics, non-steroidal anti-inflammatory 
agents (≥ 2 doses per week), regular dose of magnesium supplements, bisphosphonate, 
teriparatide, denosumab or selective estrogen receptor modulators. Stage 1 hypertension (with 
systolic blood pressure <140 and diastolic <90) and controlled diabetes mellitus Type II with 
HbA1C less than 7% will be allowed. Inclusion/exclusion of other drugs or conditions will be 
considered on an individual basis. A careful record will be made for the type and dose of all 
medications.  
We plan to recruit 70 subjects at the primary site at UTSW and Parkland Health & Hospital 
System. We expect that 20% of subjects might have eGFR <65 ml/min at entry.  
Outline of Study 
 
Screening. Before enrollment into the trial, potential candidates will undergo screening, 
whereby a venous blood sample will be obtained for complete metabolic panel (including calcium, 
phosphorus, and creatinine), HbA1c, Mg and complete blood count (with differential). A 
pregnancy test will be done if applicable. Ambulatory blood pressure will be obtained. Those who 
meet the entry-exclusion criteria will be selected for consideration into the study. 
Randomization. Eligible patients will be randomized into two equal groups, stratified 
according to age (> or ≤ 50 years) and, dose (> or ≤ 20 mg three times/week). After baseline 
evaluation, one group (EffCaMgCit Group) will take EffCaMgCit, and the other group (Placebo 
Group) will take microcrystalline cellulose suspension for two years (Fig. 7). Both groups will take 
PPI at the prevailing dose. Both drugs will be taken 1 sachet each just before or along with 
breakfast and dinner. Thus, patients in the EffCaMgCit group will receive 38 meq (760 mg) Ca, 
20 meq (365 mg) Mg, and 100 meq total citrate per day. Those in the Placebo group will not take 
any calcium, magnesium or citrate.  
Diet and customary drugs. Customary ad lib diet will be taken throughout the study except 
for instructed breakfast on testing days. Customary drugs will be continued, except those 
specified under exclusions. It is expected that most patients at entry will be taking vitamin D. Each 
sachet of EffCaMgCit or placebo contains 400 units of vitamin D. During the trial, additional 
vitamin D judged to be needed by their physicians will be allowed. 


 
 
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Baseline evaluation (0 month, Table 1). Patients will stop their customary calcium or 
magnesium supplements on enrollment, and they will omit them throughout the study. After one 
week of stopping above, they will return to the clinic after eating a regular breakfast meal 
(instructed, low in calcium and magnesium). Two-4 hours later, a venous blood sample will be 
obtained. Patients will complete side effect 
questionnaire with the aid of a research nurse 
or study coordinator (Table 1).  
Test drug treatment. After baseline 
evaluation, patients will then take EffCaMgCit or 
Placebo 1 sachet bid (1 with breakfast and 1 
sachet with dinner) for two years, by adding 
contents of sachet to 6 oz water and drinking 
the solution. They will also take omeprazole (or 
similar PPI) delayed release upon awakening at 
a similar dose as prior to entry into the trial. Study participants will not be switched to a new PPI, 
a new dose, or a new delivery method solely for the purposes of the study. The tolerance to taking 
the medication will be evaluated by using the questionnaire (Table 1).  
Table 1. Side Effect Questionnaire
 
 
Fig. 7. Scheme of study. 
Baseline
(n = 70)
EffCaMgCit + PPI
(n = 35)
Placebo + PPI
(n = 35)


 
 
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Follow-up visits. Patients will be followed in an ambulatory setting every 3 months (Table 
2). At each visit, a venous blood sample will be collected 2-4 hours after breakfast and/or test 
drug. The meal will be a standard breakfast, low in calcium and magnesium. Patients will be 
instructed to collect 24-h urine under oil while kept cold in an ice chest or refrigerator the day 
preceding the visit and bring the sample to the clinic on the day of the visit. The side effect 
questionnaire will be completed. At Baseline and each follow-up visit, blood pressure will be 
measured after subjects sit quietly for at least 10 minutes. At Baseline, 12 months and 24 months 
of treatment, BMD of L2-L4 vertebrae, femoral neck and radial shaft, and free muscle Mg by MRS 
will be obtained. At Baseline, 12 months and 24 months, spinal fracture assessment will be 
determined by DEXA. 
 
 


 
 
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Table 2. Follow-up Visits 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
Venous blood 
  post-meal & load 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
24 h urine 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Bone mineral density 
✓ 
 
 
 
✓ 
 
 
 
✓ 
MRS, free muscle Mg 
✓ 
 
 
 
✓ 
 
 
 
✓ 
Side effect questionnaire 
  Blood pressure 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
 
Laboratory Tests. A venous blood sample obtained at each visit will be analyzed for 
metabolic panel (including calcium, and creatinine), magnesium, PTH, CTX, BSAP (bone specific 
alkaline phosphatase, a marker of bone formation), FGF23, Klotho, IL6 and isoprostane (Fig. 3). 
At 0, 12 and 24 months, HbA1c will be obtained. 24-h urine samples will be measured for stone 
risk profile (including Ca, Mg, P, Na, K, sulfate, uric acid, citrate, ammonium, creatinine and pH), 
pCO2, and markers for tubular damage (N-acetyl-β-D-glucosaminidase (NAG), microglobulin, and 
albumin). Titratable acid (TA) will be measured and FEMg calculated. BMD will be measured by 
dual photon absorptiometry. Free muscle Mg will be obtained in a calf muscle by MRS.  
Calculations. Net acid excretion will be calculated using the formula: NAE = (titratable 
acidity + ammonium) – (citrate – bicarbonate). Endogenous creatinine clearance will be obtained 
by using 24-h urinary creatinine and post-meal/load venous blood sample ((uCr, mg/24hr) / (sCr, 
mg/dL * 14.4)) as well as using the Cockcroft and Gault formula ([(140 - age) x TBW] / (Scr x 72) 
(x 0.85 for females)). FEMg is the ratio of magnesium clearance and creatinine clearance, using 
24-h urinary magnesium and creatinine and corresponding serum magnesium and creatinine 
obtained post meal/load.  
MRS for free muscle magnesium will be performed at UTSW’s Advanced Imaging Research 
Center. Intracellular Mg will be measured in a calf muscle, by using 31P magnetic resonance 
spectroscopy, based on the formula: [Mg] – kd(10.796-D)/(D-8.251), in which kd is the 
dissociation constant for MgATP complex (=50 µM) and D is the chemical shift difference between 
alpha- and beta-ATP 31P signals observed in 31P MR spectrum. 
 Metabolic panel will be obtained from Quest. All other tests will be performed or analyzed by 
CMMCR’s laboratory. Serum for inflammatory marker (such as IL6 or isoprostane) will be saved 
frozen. Urine samples will be saved frozen for NAG, macroglobulin and albumin (Mahajan, 2010). 
Upon study completion, the saved samples will be analyzed for specified tests if warranted.  
 
 


 
 
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Table 3. Laboratory Tests 
 
0 
3 
6 
9 
12 
15 
18 
21 
24 
Serum Ca, PTH 
  CTX, BSAP, IL6 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
BMD 
✓ 
 
 
 
✓ 
 
 
 
✓ 
Serum Mg 
  FEMg 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Free muscle Mg 
✓ 
 
 
 
✓ 
 
 
 
✓ 
24 h urinary citrate 
  NH4, TA, NAE, NAG 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
Serum Cr 
  End Cr Cl 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
✓ 
 
Expectations 
  
Skeletal status 
• 
In the EffCaMgCit + PPI group, BMD would slightly increase or be stabilized, and serum 
PTH and CTX would decline, 
• 
In the Placebo + PPI group (PPI alone), BMD would slightly decline, and serum PTH and 
CTX would slightly increase. 
 
Magnesium status 
• 
In the EffCaMgCit + PPI group, FEMg, free muscle Mg and serum Mg would be increased 
from Baseline. 
• 
In the Placebo + PPI group (PPI alone), FEMg, free muscle Mg and serum Mg would be 
slightly decreased from Baseline. 
 
Acid-base balance 
• 
In the EffCaMgCit + PPI group, urinary citrate would be increased, and urinary NAE and 
ammonium would be decreased from Baseline. 
• 
In the Placebo + PPI group (PPI alone), urinary citrate would be reduced, and urinary NAE 
and ammonium would be increased from Baseline. 
 
Renal function 
• 
In the EffCaMgCit + PPI group, endogenous creatinine clearance and eGFR would be 
unchanged or slightly increased from Baseline. 
• 
In the Placebo + PPI group (PPI alone), endogenous creatinine clearance and eGFR 
would be decreased from Baseline. One possible explanation for the decline in eGFR by 
PPI might be PPI-induced interstitial fibrosis, which continues to a chronic condition with 
continued PPI use. There is a possibility that EffCaMgCit may alleviate interstitial fibrosis, 


 
 
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by overcoming acid load, FGF23 excess, and inflammation worsened by magnesium 
deficiency. 
 
Potential Side Effects 
EffCaMgCit might cause loose bowel movements or diarrhea. Threshold magnesium dose for 
diarrhea is 40 meq/day; we will be using 20 meq/day. In general, even among few who initially 
develop diarrhea, the gastrointestinal tolerance improves with continued treatment.  
  
Very rarely, patients might develop hypophosphatemia (serum P < 2.5 mg/dL) from excessive 
intestinal phosphate binding by Ca and/or Mg contained in EffCaMgCit. Rare patients might 
develop hypercalcemia from oral calcium load during both treatments. If a patient presents with 
either a serum P < 2.5 mg/dL or grade   2 hypercalcemia, as defined as analbumin-corrected 
serum Ca > 11.5 mg/dL, in two consecutive follow-up visits, they will be withdrawn from the study. 
Statistical Considerations 
Sample size calculations. 
 Aim 1. To the best of our knowledge, there is no prospective report on the serial change 
in BMD during PPI. Hence, we used CTX to calculate sample size (Table 2). In the completed 
crossover 4 week trial, CTX was 0.47 ± 0.24 in the placebo + PPI, and 0.28 ± 0.13 in the 
EffCaMgCit + PPI. Assuming power of 0.8, 54 subjects would be needed. 
Aim 2. For magnesium status, the aforementioned trial revealed serum magnesium of 2.08 
± 0.15 in placebo + PPI, and 2.21 ± 0.15 in EffCaMgCit + PPI (Table 2). With power of 0.8, 34 
subjects would be needed.  
The same trial also revealed FEMg of 0.034 ± 0.013 for placebo + PPI, and 0.052 ± 0.018 
for EffCaMgCit + PPI (Table 2). For a power of 0.8, 34 subjects would be needed.  
Thus, 34-54 patients would be required. We plan to enroll 70 patients to accommodate 
20-30% attrition.  


 
 
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Table 2. Sample Size Calculations 
 
Placebo + PPI 
EffCaMgCit + PPI 
 
 
Variable 
Mean 
SD 
Mean 
SD 
Power 
N 
Bone CTX 
0.47 
0.24 
0.28 
0.13 
0.8 
54 
Mg Status 
 
 
 
 
 
 
  sMg 
2.08 
0.15 
2.21 
0.15 
0.8 
34 
  FEMg 
0.034 
0.013 
0.052 
0.018 
0.8 
34 
eGFR Decline  
14.5 
18 
0 
18 
0.8 
54 
 
Aim 3. We were unable to locate a publication which showed actual change in eGFR during PPI 
treatment; no histological description of the lesion has been reported. However, retrospective 
analysis of large database are available. Xie (2018) reported that 15% of subjects had incident 
CKD with eGFR less than 60 ml/min after 2 years of PPI therapy, and 12% in those not on PPI. 
The following assumptions were made. (a) eGFR was 95 ml/min before PPI therapy. (b) 15% had 
eGFR of 55 ml/min after 2 years of PPI treatment. The remaining 85% of subjects had a decline 
from 95 ml/min to 85. Thus, estimated decline in eGFR would be 14.5 ml/min over 2 years. (c) 
The SD of eGFR was assumed to be 25%, the same as in our trial among stone formers. (e) 
EffCaMgCit + PPI would maintain endogenous creatinine clearance and eGFR unchanged (0±18) 
during 2 years of treatment, but Placebo + PPI would produce a decline of 14±18%. Setting power 
at 0.8, 27 subjects in each group would be needed to detect a decline in eGFR of 14.5%. In 
addition to Xie, two other papers described similar increase in risk of CKD in PPI users (Lazarus 
2016, Peng 2016) 
Randomization. Allocation to EffCaMgCit or Placebo treatment will be determined with a 
stratified blocked randomization scheme, stratified according to age (> or ≤ 50 years) and, dose 
(> or ≤ 20 mg three times/week), and programmed using SAS Proc Plan.  
 
Statistical analysis. The statistical mean difference between PPI + Placebo and PPI + 
EffCaMgCit for variables (serum PTH, CTX and BMD T-Score; serum Mg, FEMg, and free 
muscle Mg; urinary citrate, ammonium and NAE; serum creatinine and endogenous creatinine 
clearance) will be assessed by mixed-effects model repeated measures analysis. For subjects 
50 years or older, the T-Score will be utilized. Those with T-Score < -2.5 will be excluded from 
the study.  For subjects < 50 years, the Z-Score will be utilized. Those with Z-Score < -2 will be 
excluded from the study.  The effect of duration of treatment (particularly at 1 year and 2 years) 
will be evaluated by including fixed effects factors for time in the repeated measures model; the 
study participant will be modeled as a random effect. For skewed variables, data 
transformations or nonparametric tests will be implemented as appropriate. Statistical analyses 
will be performed with SAS software (SAS Institute, Cary, NC). 
Data Safety and Monitoring:   
 
 


 
 
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The Research Personnel and PI now meet weekly to review and discuss patient safety, 
study data quality and timeliness, participant recruitment, accrual and retention, 
participant risk versus benefit, protocol adherence and other factors that affect study 
outcome. They will continue to monitor and ensure the safety of the patient, quality of 
the data, and success of the study. 
Interim analysis. An intent to treat analysis will be performed. Participants with at least one post-
randomization study visit will be included. Interim analysis might be performed at midpoint of the 
study (about one year of treatment). If a decision is made to conduct it, the type I error rate will 
be controlled using a Lan-Demets alpha-spending function with O-Brien-Fleming 
boundaries. The interim analysis will be performed by the study statistician for efficacy and 
reassessment of sample size; the sample size may be modified or the interim look can result in 
no action. To ensure trial integrity, efficacy results will not be disclosed to study investigators or 
personnel who are in contact with the participants. 
 A two-sided alpha <5% will be considered significant for all analyses. Power analysis 
assumptions will be reassessed and the adjustment for multiple looks will be based on O’Brien-
Fleming boundaries.  
 
  
 
 


 
 
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References: 
Ago R, Shindo T, Banshodani M, et. al. Hypomagnesemia as a predictor of mortality in 
hemodialysis patients and the role of proton pump inhibitors: A cross-sectional, 1-year, 
retrospective cohort study. Hemodial Int, 2016. 20(4): 580-588.  
ASN: Reflux medications linked to chronic kidney disease and kidney failure. 2017. 
Banerjee T, Crews DC, Wesson DE, et al. High dietary acid load predicts ESRD among adults 
with CKD. J Am Soc Nephrol, 2015. 26(7): 1693-6700.  
Cameron M, Maalouf NM, Poindexter J, et al. The diurnal variation in urine acidification differs 
between normal individuals and uric acid stone formers. Kidney Int, 2012. 81(11): 1123-1130.  
de Brito-Ashurst I, Varagunami M, Raftery MJ, et al. Bicarbonate supplementation slows 
progression of CKD and improves nutritional status. J Am Soc Nephrol, 2009. 20: 2075-2084. 
Elisaf M, Panteli K, Theodorou J, et al. Fractional excretion of magnesium in normal subjects and 
in patients with hypomagnesemia. Magnes Res, 1997. 10(4): 315-320.  
FDA drug safety communications: possible increased risk of fractures of the hip, wrist, and spine 
with the use of proton pump inhibitors. March 3, 2011.  
Irish AB, Thompson CH, Kemp GJ, et al. Intracellular free magnesium in skeletal muscle in chronic 
uremia. Nephron, 1997. 76: 20-25. 
Kuipers MT, Thang HD, Arntzenius AB. Hypomagnesaemia due to use of proton pump inhibitors 
– a review. Netherl J Med, 2009. 67: 169-172. 
Lazarus B, Chen Y, Wilson FP, et al. Proton pump inhibitor use and the risk of chronic kidney 
disease. JAMA Intern Med, 2016. 176(2):238-246.  
Mahajan A, Simoni J, Sheather SJ. Daily oral sodium bicarbonate preserves glomerular filtration 
rate by slowing its decline in early hypertensive nephropathy. Kidney Int, 2010. 78: 303-309.  
Mertz-Nielsen A, Hillingso J, Bukhave K, et al. Omeprazole promotes proximal duodenal mucosal 
bicarbonate secretion in humans. Gut, 1996. 38(1): 6-10.  
Moledina DG, Perazella MA. PPIs and kidney disease: from AIN to CKD. J Nephrol, 2016. 
29(5):611-616.  
Nath KA, Hostetter MK, Hostetter TH. Pathophysiology of chronic tubulo-interstitial disease in 
rats: interactions of dietary acid load, ammonia, and complement C3. J Clin Invest, 1985. 76: 667-
675.  
Nielsen FH. Magnesium deficiency and increased inflammation: current perspectives. J Inflamm 
Res, 2018. 11: 25-34.  


 
 
STU042018-078, Sakhaee, FormA-ResearchProtocol, Mod_6, 09-02-20 
 
IND #139613 EffCaMgCit.PPI 09.01.2020 
 
19 
Peng YC, Lin CL, Yeh HZ, et al. Association between the use of proton pump inhibitors and the 
risk of ESRD in renal diseases: A population-based, case-control Study. Medicine (Baltimore), 
2016. 95(15): e3363.  
Phisitkul S, Khanna A, Simoni J, et al. Amelioration of metabolic acidosis in patients with low GFR 
reduced kidney endothelial proliferation and kidney injury, and better preserved GFR. Kidney Int, 
2010. 77: 617-623.  
Roux C, Briot K, Gossec L, et al. Increase in vertebral fracture risk in postmenopausal women 
using omeprazole. Calcif Tissue Int, 1999. 84: 13–19.  
Sakaguchi Y, Iwatani H, Hamano T, et al. Magnesium modifies the association between serum 
phosphate and the risk of progression to end-stage kidney disease in patients with non-diabetic 
chronic kidney disease. Kidney Int, 2015. 88(4): 833-842.  
Tamura T, Sakaeda T, Kadoyama K, et al. Omeprazole- and esomeprazole-associated 
hypomagnesaemia: data mining of the public version of the FDA Adverse Event Reporting 
System. Int J Med Sci, 2012. 9(5): 322-326.  
Thongon N and Krishnamra N. Omeprazole decreases magnesium transport across Caco-2 
monolayers. World J Gastroenterol, 2011. 17(12): 1574-1583.  
Toth-Manikowski S, Grams ME. Proton pump inhibitors and kidney disease - GI upset for the 
nephrologist? Kidney Int Rep, 2017. 2(3): 297-301. 
Van Laecke S, Nagler EV, Verbeke F, et al. Hypomagnesemia and the risk of death and GFR 
decline in chronic kidney disease. Am J Med, 2013. 126(9): 825-831.  
Wijarnpreecha K, Thongprayoon C, Chesdachai S, et al. Associations of proton-pump inhibitors 
and H2 receptor antagonists with chronic kidney disease: A meta-analysis. Dig Dis Sci, 2017. 
62(10): 2821-2827.  
Xie Y, Bowe B, Li T, et al. Long-term kidney outcomes among users of proton pump inhibitors 
without intervening acute kidney injury. Kidney Int, 2017. 91(6): 1482-1494.