Impaired gastric acidification negatively affects calcium homeostasis and bone mass

Schinke, Thorsten; Schilling, Arndt F.; Baranowsky, Anke; Seitz, Sebastian; Marshall, Robert P.; Linn, Tilman; Blaeker, Michael; Huebner, Antje K.; Schulz, Ansgar; Simon, Ronald; Gebauer, Matthias; Priemel, Matthias; Kornak, Uwe; Perkovic, Sandra; Barvencik, Florian; Beil, Frank Timo; Fattore, Andrea Del; Frattini, Annalisa; Streichert, Thomas; Pueschel, Klaus; Villa, Anna; Debatin, Klaus‐Michael; Rueger, Johannes M.; Teti, Anna; Zustin, Jozef; Sauter, Guido; Amling, Michael

doi:10.1038/nm.1963

Cited by 179 publications

(148 citation statements)

References 45 publications

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“…This CaR-dependent gastrin response to Ca 2+ forms the basis for the diagnostic Ca 2+ stimulation test in patients with Zollinger-Ellison (ZES) syndrome, whose gastrinomas express CaR, and this also explains the observed exacerbation of acid hypersecretion in multiple endocrine neoplasia type 1 patients with hyperparathyroidism and ZES (15). Because acid promotes Ca 2+ absorption, the CaR-expressing G cell behaves like a Ca 2+ regulatory cell, as evidenced by the fact that gastrin receptor null mice become hypocalcemic (22).…”

Section: Low Basal Gastrin and Absent Gastrin Response To Luminal Nutmentioning

confidence: 99%

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

Feng

Petersen²,

Coy³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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The calcium-sensing receptor (CaR) is the major sensor and regulator of extracellular Ca 2+ , whose activity is allosterically regulated by amino acids and pH. Recently, CaR has been identified in the stomach and intestinal tract, where it has been proposed to function in a non-Ca 2+ homeostatic capacity. Luminal nutrients, such as Ca 2+ and amino acids, have been recognized for decades as potent stimulants for gastrin and acid secretion, although the molecular basis for their recognition remains unknown. The expression of CaR on gastrin-secreting G cells in the stomach and their shared activation by Ca 2+ , amino acids, and elevated pH suggest that CaR may function as the elusive physiologic sensor regulating gastrin and acid secretion. The genetic and pharmacologic studies presented here comparing CaR-null mice and wild-type littermates support this hypothesis. Gavage of Ca 2+ , peptone, phenylalanine, Hepes buffer (pH 7.4), and CaR-specific calcimimetic, cinacalcet, stimulated gastrin and acid secretion, whereas the calcilytic, NPS 2143, inhibited secretion only in the wild-type mouse. Consistent with known growth and developmental functions of CaR, G-cell number was progressively reduced between 30 and 90 d of age by more than 65% in CaR-null mice. These studies of nutrient-regulated G-cell gastrin secretion and growth provide definitive evidence that CaR functions as a physiologically relevant multimodal sensor. Medicinals targeting diseases of Ca 2+ homeostasis should be reviewed for effects outside traditional Ca 2+ -regulating tissues in view of the broader distribution and function of CaR.

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Section: Low Basal Gastrin and Absent Gastrin Response To Luminal Nutmentioning

confidence: 99%

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

Feng

Petersen²,

Coy³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

123

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“…Moreover, IL-11 is key in gastric damage, mucosal repair and gastric cancer progression (27,28). Since the detected osteoclastogenesis did not correlate with the presence of bone metastases, we suggested an alternative hypothesis to explain it, considering a potential relationship between an increased osteoclastogenesis and the gastric acid levels, which are known to affect OC activity (29). We observed that some patients with increased osteoclastogenesis also showed chronic gastritis and referred to taking proton-pump inhibitors (data not shown).…”

Section: Discussionmentioning

confidence: 89%

Bone metastases in gastric cancer follow a RANKL-independent mechanism

et al. 2013

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Abstract. Gastric cancer is one of the most common and lethal malignancies worldwide. Bone metastases in gastric cancer are less common than in other solid tumors, but when they occur the prognosis is generally poor. Increased osteoclastogenesis and osteoclast activity are common features in bone metastases caused by different osteotropic cancer. We investigated osteoclastogenesis and its mechanisms in gastric cancer by enrolling 31 newly diagnosed gastric cancer patients and 45 healthy controls. We studied in vitro osteoclastogenesis in the peripheral blood mononuclear cell cultures of patients and controls, showing spontaneous osteoclastogenesis for half of the patients. This osteoclastogenesis was RANKL-and TNF-α-independent. We analyzed primary tumor and bone metastatic tissues of gastric cancer for the expression of genes involved in osteoclastogenesis. The expression of transforming growth factor-β (TGF-β), osteoprotegerin (OPG), IL-7 and dickkopf-1 (DKK-1) was higher in primary tumors than in bone metastases. RANKL was not detectable in primary tumor or in bone metastatic tissue. The serum RANKL level was significantly higher in healthy controls than in patients, and it was not related to osteoclastogenesis, thereby suggesting that RANKL is not involved in the bone metastatic mechanisms in gastric cancer. We hypothesized a role of RANKL in angiogenesis, thus we compared the serum levels of RANKL to those of VEGF, since VEGF is directly related to angiogenesis. Different from RANKL, the VEGF serum levels were higher in gastric patients than in controls, suggesting a block of the angiogenesis inhibition due to RANKL. RANKL and VEGF serum levels were not predictive of overall survival in our cohort of gastric patients.

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“…In addition, the widespread use of PPI among elderly patients has recently been linked to increased fracture risk and disrupted calcium absorption [37,38]. Yang and coworkers found an association between long-term PPI therapy and an increased risk of hip fracture, which led us to investigate this issue within our study cohort.…”

Section: Discussionmentioning

confidence: 93%

Stress fractures in elderly patients

Breer

Krause

Marshall

et al. 2012

International Orthopaedics (SICOT)

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Purpose The purpose of this study was to investigate specific risk factors, common fracture locations and possible sexspecific differences in elderly patients with stress fractures. Methods This analysis enrolled 105 patients (83 women, 22 men) with stress fractures. For the analysis of possible risk factors related to increasing age, data from 82 patients (67 women, 15 men) aged 40 years and older (mean age of 57.4 ± 11.0 years) were compared with that from a younger control group [23 patients (16 women, seven men), mean age 28.4±6.7 years]. Bone mineral density (BMD) was determined using dual-energy X-ray absorptiometry bone densitometry (DXA) and blood samples were taken. Results A total of 211 stress fractures were found. Of these, 177 were found in the study group, of which 90.4 % were located in the lower limb. Lumbar and femoral BMD was significantly lower in elderly patients; however, the BMD of most patients was within the osteopenic or normal range. Within the study group, a total of 83.8 % had a vitamin D insufficiency (<30 μg/ l); 75.5 % were not engaged in regular physical activity more than once a week. Overweight patients within the study group had significantly more stress fractures compared to normal weight patients (2.6±1.7 vs. 1.9±1.1, p<0.05). Conclusions A similar contribution of risk factors has been found for stress fractures in elderly patients and younger controls of the general population. Stress fracture incidence seems to be rather multifactorial and not based on osteoporotic changes alone. A balanced calcium and vitamin D metabolism seems to be of paramount importance for stress fracture prevention in elderly patients.

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Impaired gastric acidification negatively affects calcium homeostasis and bone mass

Cited by 179 publications

References 45 publications

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

Calcium-sensing receptor is a physiologic multimodal chemosensor regulating gastric G-cell growth and gastrin secretion

Bone metastases in gastric cancer follow a RANKL-independent mechanism

Stress fractures in elderly patients

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