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Proton Pump Inhibitors and the Treatment of Osteoporosis

By: Neal Shah

Osteoporosis is a disease of the bone characterized by decreased bone mineral density (BMD), which reduces the ability of bone to provide adequate structural support.  The main cause of this decreased BMD is inadequate calcium intake or absorption.  The decreased BMD can cause diffuse lesions throughout the skeletal system and can eventually lead to fractures.1

The most common places for fractures to occur are the wrist, hip, and spine, and femur.2,3 Dual-energy X-ray absorptiometry (DXA) scans determine the BMD of a patient by measuring and comparing the results of these body locations to a normal, matched population.  The measurement of BMD, a T-score, represents standard deviations from the mean.  Osteoporosis is defined as a T-score of < -2.5, whereas a milder form of osteoporosis (known as osteomalacia) is defined as a T-score between -2.5 to -1.0.2,4  Universally, women above the age of 65 and men above age 70 should receive screening for osteoporosis.2-4  Once a diagnosis of osteoporosis is established, the patient should increase physical activity and start a daily regimen of calcium and vitamin D, and the clinician should initiate prescription medication therapy.

Pharmacologic treatments of osteoporosis include bisphosphonates, teriparatide, denusomab, raloxifene, and calcitonin.3,5  Some drugs worth mentioning are raloxifene, bazedoxifene, and denusomab.  Raloxifene is a selective estrogen receptor modulator (SERM) used in the prevention of vertebral fractures and treatment of osteoporosis in postmenopausal patients, when there is an increased risk of breast cancer.2  Another SERM, bazedoxifene, exhibits favorable effects on lipid and bone profiles—both vertebral and non-vertebral, and provides protection against fractures for up to five years.  This drug is not currently available in the United States market.6 Denusomab is a monoclonal antibody that increases prevents RANKL from activating its receptor, thus decreasing bone resorption.  Patients receive a 60 mg subcutaneous injection of denusomab for osteoporosis every six months.7

A recent economic study of postmenopausal osteoporotic women in Belgium compared the cost effectiveness of three years of treatment with denosumab versus risedronate or alendronate.  The study found that denosumab was a cost-effective strategy compared to the two bisphosphonates, and it has the potential to become a first line therapy due to the relative ease of (and duration between) administration.8

Bisphosphonates are the most commonly used drugs in osteoporosis therapy because of easy, once-weekly or once-monthly oral administration and low cost, whereas the other therapies may be parenteral and are associated with increased costs.9  Patients usually take bisphosphonates in the morning, before any other food or liquids, with a full glass of water, remaining upright for at least half an hour (as seen with alendronate).  The 30-minute waiting period prevents any reflux from causing esophagitis.11

Patients who may have pre-existing gastroesophageal reflux disease (GERD) may also be on proton pump inhibitors (PPIs).  A recent report stated that PPIs decreased the efficacy of alendronate in preventing hip fractures.11  In 2010, the FDA issued a statement, warning that high dose and long-term PPI therapy may increase the risk of developing osteoporosis.  These results were not very clear: two studies cited in their statement used high dose PPIs in their trial, another two studies cited used long term PPI use in their trial, and three other studies have shown that there is no consistent association between osteoporosis and PPI use.12  The cause behind the purported decrease in efficacy is due to the pharmacologic effects of PPIs.

Calcium is traditionally absorbed in an acidic environment.  PPIs decrease acidity; so, one can logically assume that decreased calcium absorption in at-risk patients may accelerate bone resorption.  In one observational study, concurrent bisphosphonate (alendronate) and PPI use in elderly patients was associated with a dose-dependent loss of protection against hip fractures.  This study did not show any association between histamine-2 receptor antagonists (H2RA) and decreased protection against hip fractures.13

Another study at the Massachusetts General Hospital observed that PPI use was associated with an increased risk of non-spine fracture in men not taking calcium supplements, but H2RA use was not associated with non-spine fractures.14 A retrospective 10-year analysis by a research group in California found that both, PPIs and H2RAs, posed an increased risk of hip fracture.  However, this association was only found in those with at least one other risk factor for hip fractures.15  Another study analyzed the results from the Women’s Health Initiative (WHI), in terms of PPI and fracture risks, and concluded that the use of PPIs was not associated with hip fractures, but was modestly associated with clinical spine, forearm or wrist, and total fractures.16

One limit unaddressed in any study was the type of calcium supplementation.  There are two common, orally administered calcium products: calcium carbonate and calcium citrate.  Calcium carbonate requires an acidic environment, whereas calcium citrate does not.17  The daily allowance of calcium in males and females above the age of 50 is 1000-1200 mg per day.  Combinations of calcium and vitamin D increase the absorption of calcium.  Since the maximal absorption of calcium is roughly 500-600 mg, patients should separate their calcium intake to twice daily.  Hence, none of the studies addressed whether calcium supplementation was with calcium carbonate or calcium citrate.

Patients on concomitant bisphosphonates and PPIs should continue to take calcium citrate and vitamin D to reach their daily allowance of calcium.


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