Averting Complications of Proton Pump Inhibitor Therapy by Effervescent Calcium Magnesium Citrate

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.

Inclusion Criteria:

- Must have taken PPI (omeprazole or equivalent ≥ 20 mg/day, ≥ three times per week, for
at least 2 months)

- Expected to continue at a similar dosage

- Stage 1 hypertension (with systolic blood pressure <140 and diastolic <90)

- controlled diabetes mellitus Type II with HbA1C less than 7%

Exclusion Criteria:

- 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%

- treatment with adrenocorticosteroids, diuretics, non-steroidal anti-inflammatory
agents

- regular dose of magnesium supplements, bisphosphonate, teriparatide, denosumab or
selective estrogen receptor modulators.

Inclusion/exclusion of other drugs or conditions will be considered on an individual basis.