Dose‐dependent inhibitory effects of proton pump inhibitors on human osteoclastic and osteoblastic cell activity

Abstract

Proton pump inhibitors (PPIs), a class of molecules that are used to decrease gastric acid production, might have adverse effects on bone metabolism. The aim of this study was to characterize the concentration-dependent and time-dependent effects of three PPIs (omeprazole, esomeprazole, and lansoprazole) on human osteoclast precursor cells isolated from peripheral blood, and on human mesenchymal stem cells (osteoblast precursors). Cell cultures were characterized for total protein content, apoptosis, and several osteoclastic/osteoblastic features, and also for the involvement of some intracellular signaling pathways. PPIs caused a dose-dependent decrease in cellular density, which correlated with an increase in the apoptosis rate, effects that became statistically significant at concentrations ≥ 10 À5 M. They also inhibited phenotype-related gene expression and functional parameters. For both cell types, cellular function, i.e. osteoclastic resorption and the formation of mineralized deposits by osteoblastic cells, was more affected than proliferation-related parameters. The three PPIs showed similar qualitative and quantitative effects, but displayed some differences in the underlying intracellular signaling pathways. These results suggest that PPIs might have a direct deleterious effect on bone cells, with the possibility of decreased bone turnover.

A Review of the Novel Application and Potential Adverse Effects of Proton Pump Inhibitors

“…A fall in the blood calcium concentration not only affects bone formation, which is regulated by osteoblasts, but also promotes bone resorption by osteoclasts, followed by a decrease in bone mineral density [81, 82]. Second, PPIs could inhibit the V-ATPase of osteoclasts in the same way that PPIs inhibit gastric H + /K + -ATPase, having a direct deleterious effect on bone cells, with the possibility of decreased bone turnover [83]. Third, long-term use of PPIs could cause a homocysteine concentration and parathyroid hormone increase, which interfere with collagen cross-linking and weaken bone [82].…”

Proton Pump Inhibitors and the Risk for Fracture at Specific Sites: Data Mining of the FDA Adverse Event Reporting System

“…Studies have explored the potential effects of PPIs on calcium absorption 40 , bone mineral density (BMD) 41–44 , bone metabolism 45, 46 , increased histamine release 47 , or their association with fall risk 16, 23 . In addition, it has been hypothesized that PPI use may be associated with hyperparathyroidism 48 , which has been recently reported in a cohort of elderly subjects 49 .…”

Hyperparathyroidism Associated with Long‐Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults

“…Efficient calcium absorption is an important determinant of long‐term skeletal integrity. PPI‐induced hypochlorhydria can decrease calcium absorption in elderly adults, who are less able to upregulate calcium absorption from the intestines . However, no studies have found an association between long‐term PPI exposure and low bone mineral density (BMD) or a decrease in BMD over time .…”

“…Data supporting any underlying disease mechanism(s) caused by PPIs and their effects on common laboratory parameters are limited . Increasing evidence suggests that PPIs may disrupt skeletal integrity through two primary and potentially synergistic mechanisms: PPI‐induced hypochlorhydria impairs calcium absorption and reduces calcium bioavailability for incorporation into bone, resulting in compensatory and potentially chronic hyperparathyroidism, which increases bone turnover; and PPIs can directly inhibit acid‐dependent osteoclasts and impair adequate bone resorption, which results in dense but fragile bones …”