4/2/15
by Salynn Boyles

Action Points

Mouse studies may help explain the reported increased risk of osteoporosis and related fractures among long-term users of proton pump inhibitors, which are among the most widely used drugs on the planet.

Researchers from the Forsyth Institute in Cambridge, Massachusetts, showed that stomach acid helps the intestines absorb and transfer calcium to the skeletal system. By dramatically reducing stomach acid, proton pump inhibitors (PPIs) appear to block this pathway, researcher Ricardo Battaglino, PhD, toldMedPage Today.

The researchers published their findings online, in the March 26 issue of the journal PLOS Genetics.

“Studies from our research team and others suggest that the main source of calcium in the blood is not from bone, as we used to think, but from calcium that comes from the intestine,” he said.

Snx10 Deficiency Linked to Bone Disorder

Battaglino and colleagues used transgenic mice deficient in the protein-coding gene Snx10 to test the hypothesis. Global Snx10 deficiency led to a condition in mice mimicking, which is a very rare, inherited disease in humans characterized by the abnormal bone growth disorder osteopetrosis and, paradoxically, rickets, Battaglino explained.

Mutations in the sorting nexin of the Snx10 gene, which interacts with the proton pump, have recently been shown to play a key role in a subset of human osteopetrosis, accounting for roughly 4% of cases.

The newly published research revealed that the process of cell entry, or endocytosis, was severely defective in Snx10-deficient osteoclasts, along with extracellular acidification, ruffled border formation, and bone resorption.

“We also discovered that Snx10 is highly expressed in stomach epithelium, with mutations leading to high stomach pH and low calcium solubilization,” the researchers wrote.

The only effective treatment for osteopetrosis — bone marrow transfer — does not work as well in babies with osteorickets, and they typically die very early in life. The Snx10 knock-0ut mice typically live only 2 or 3 weeks and exhibit severe osteopetrosis with a superimposed mineralization defect consistent with rickets, Battaglino said.

When the researchers injected calcium gluconate into the Snx10-deficient mice, the mice lived longer, “suggesting that this may be a life-saving component of the clinical approach to Snx10-dependent human osteopetrosis that has previously gone unrecognized,” the researchers wrote.

Bone and Acid-Producing Systems May Have Evolved Together

The studies also provided more evidence of a “shared molecular machinery” for the production of acid in the stomach and in osteoclasts, they continued.

“TreeFam, a database of phylogenetic trees from animal genomes that can be used to infer the evolutionary history of genes, shows that Snx10appears first in (the bony fishes) Osteichthyes,” the researchers wrote. “The acid-secreting stomach also evolved in bony fishes. This raises the intriguing prospect that the osteoclastic and gastric acid producing systems evolved simultaneously during vertebrate evolution, together with emergency of a mineralized skeleton, utilizing some of the same genes.”

Although this is just a hypothesis, Battaglino said it is increasingly clear that different systems within the body are more interconnected than previously thought.

“Until recently it has not been recognized that the skeletal system is regulated by many other systems, including the gastrointestinal tract, and that intestinal calcium that gets into the blood is required for many things, including skeletal formation,” he said.

The finding that gastric acidification plays a key role in calcium absorption, and that this regulatory pathway can be disrupted by treatment with PPIs, suggests a mechanism to explain the observed impact of proton pump inhibiting treatments on bone.

“Our findings underscore the relationship between gastric acidification and calcium absorption and its impact on bone health in the general population, and provide novel insights into the mechanisms governing the regulation of bone accrual via the gastrointestinal tract,” the researchers wrote.

The finding that calcium supplementation partly ameliorated this impact in the transgenic mice suggests a potential therapeutic strategy to reduce the risk to bone, Battaglino said.

According to supporting material published with the study, 100 million Americans use over-the-counter and prescription antacids to treat gastrointestinal reflux disease and related conditions.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner

last updated 04.03.2015