U.S.

Pharmacist

Long-term Consequences of Chronic Proton Pump

Inhibitor Use

LeAnn W. O'Neill, PharmD; Benjamin L. Culpepper, PharmD; John A.

Galdo, PharmD, BCPS
DISCLOSURES
US Pharmacist. 2013;38(12):38-42.

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IN THIS ARTICLE

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Malabsorption

The first potential long-term consequence of chronic PPI use is

malabsorption of key minerals in the body, namely calcium and
magnesium. The loss of these minerals could lead to bone fractures or
cardiac abnormalities.
Decreased Calcium Absorption (Hypocalcemia)
Long-term PPI use has been associated with an increased risk of
osteoporosis and decreased bone mineral density (BMD), with a 35%
increased risk of fractures.[14] Calcium serves an important role in bone
health and formation, as it is a key component of hydroxyapatite (the main
structural element of bone). Bone material is a major reservoir for calcium
and may contain greater than 99% of a body's calcium.[15] The hypothesis
for the mechanism of PPI-induced bone fractures is that dietary calcium
absorption is dependent upon an acidic environment in the gastrointestinal
(GI) tract. Due to the decrease in acidity from the pharmacologic effect of
PPIs, a potential loss of calcium absorption occurs. This reduction in
calcium absorption leads to decreased osteoclastic activity and thus
decreases in BMD, thereby increasing fracture risk.[1]
The 2013 ACG guidelines on GERD state that existing osteoporosis is not
a contraindication to PPI therapy.[13] Patients with osteoporosis may remain
on PPI therapy unless another risk factor for hip fracture
exists.[13] Furthermore, in March 2011, the FDA modified its osteoporosis
and fracture warning. It was concluded that OTC products do not warrant
label changes to include warnings of fracture risk.[16]
However, several studies have demonstrated an association between long-
term PPI use and risk of fractures, but they contain numerous confounders.
Common risk factors for fractures such as a sedentary lifestyle and
concomitant use of certain medications (e.g., thiazide diuretics, hormone
replacement therapy, corticosteroids) are often observed in patients who
routinely take PPIs.[14]Additionally, patients who take high doses of PPIs are
at higher fracture risk versus patients who take lower OTC doses.[17] Finally,
patients who take PPIs for extended periods of time (>1 year) are more
likely to experience a fracture.[18]
An analysis of the data obtained from the Canadian Multicentre
Osteoporosis Study revealed that the use of PPIs was associated with
lower BMD, particularly at the hip and femoral neck, when compared to
non-PPI use.[19] However, long-term PPI use was not associated with an
accelerated decline in BMD. Targownik et al reported that patients using
PPIs did have lower BMD; however, these patients were significantly older
(66.3 vs. 60.9 years; P <.001) and had a higher mean body mass index
(BMI) (28.3 vs. 26.9; P <.001).[19]
Data remain relatively inconclusive and conflicting regarding the magnitude
of the PPI and fracture association in the absence of additional risk factors.
According to the 2013 ACG guidelines, there is insufficient evidence to
warrant routine BMD tests, calcium supplementation, or other routine
precautions because of PPI use.[13] In contrast, Health Canada issued an
alert in April 2013 stating that patients with existing risk factors for
osteoporosis should be monitored closely and should also receive short-
term PPI therapy at the lowest effective dose.[20] This is parallel to current
recommendations from the FDA despite the lack of recommendations from
the ACG.[16] If calcium supplementation is indicated, use of calcium citrate is
the preferred calcium supplement in patients taking PPIs, as it can be
absorbed in the absence of an acidic environment.[1]
Decreased Magnesium Absorption (Hypomagnesemia)
In March 2011, the FDA released a warning regarding low serum
magnesium levels associated with long-term use of PPIs.[21] An analysis of
reports from the FDA's Adverse Event Reporting System (AERS) states
that approximately 1% of patients who experienced an adverse effect while
on a PPI experienced hypomagnesemia.[21] The mechanism behind the
changes in absorption is unknown. Symptoms of hypomagnesemia include
seizures, arrhythmias, hypotension, and tetany. Hypomagnesemia is also
potentially fatal.[22] Hypomagnesemia related to chronic PPI use was not
addressed in the 2013 ACG guidelines.[13]
All PPIs are associated with decreased magnesium
absorption.[21] Hypomagnesemia was more common in older patients taking
a PPI (mean age 64.4 years).[21] Mean time to onset of hypomagnesemia
was 5.5 years after initiation of therapy.[21] Similarly, a systematic review of
case reports found that patients who presented with hypomagnesemia in
association with PPI use also presented with other electrolyte disturbances,
specifically hypokalemia and hypocalcemia.[23] Hypomagnesemia generally
resolved with the discontinuation of the PPI and recurred soon after the PPI
was rechallenged.[24]
Concurrent use of medications that also decrease magnesium increases
the risk of significant hypomagnesemia. Danziger et al reported that
patients who take a PPI with a diuretic have nearly a 55% greater risk of
hypomagnesemia than patients who take only a PPI.[22]
An FDA Drug Safety Communication warns of the risks of
hypomagnesemia and recommends that providers monitor serum
magnesium levels in patients taking PPIs.[21] The FDA suggests that
providers obtain serum magnesium levels prior to initiation of therapy and
periodically thereafter for patients who will continue prolonged treatment
and for patients who take medications that also cause hypo-magnesemia.
Patients who present with clinically significant hypomagnesemia may
require discontinuation of PPI therapy, magnesium replacement via oral or
IV methods, and treatment with an alternative class of drugs for GI
conditions such as an H2RA.[1]