We studied the effect of proton pump inhibitors, histamine H(2) receptor antagonists, and other types of antacid drugs on fracture risk. All cases were subjects with any fracture sustained during the year 2000 (n = 124,655). For each case, three controls (n = 373,962) matched on age and gender were randomly drawn from the background population. The primary exposure variables were use of proton pump inhibitors, histamine H(2) antagonists, and other antacid drugs. Adjustments were made for several confounders, including diagnosis of an ulcer, nonsteroidal anti-inflammatory drug use, use of histamine H(1) antagonists, stomach resection, previous fracture, and use of corticosteroids. The effect of dose was examined by stratifying for cumulated dose (defined daily dose). Use of proton pump inhibitors was associated with an increase in fracture risk for use within the last year [odds ratio (OR) = 1.18, 95% confidence interval (CI) 1.12-1.43 for overall fracture risk; OR = 1.45, 95% CI 1.28-1.65 for hip fractures; and OR = 1.60, 95% CI 1.25-2.04 for spine fractures). Histamine H(2) antagonists were associated with a decreased fracture risk if they had been used within the last year (OR = 0.88, 95% CI 0.82-0.95 for any fracture, OR = 0.69, 95% CI 0.57-0.84 for hip fractures). Other antacids were not associated with overall fracture risk but were associated with hip and spine fractures. Proton pump inhibitors appeared to be associated with a limited increase in fracture risk, in contrast to histamine H( 2 ) antagonists, which seemed to be associated with a small decrease in fracture risk. In all cases, the changes in risk estimates were small and the clinical significance was limited.

Proton pump inhibitors, histamine H2 receptor antagonists, and other antacid medications and the risk of fracture.

http://www.jbc.org/content/277/24/21971.full.pdf

Transcriptional Program of Mouse Osteoclast Differentiation Governed by the Macrophage Colony-stimulating Factor and the Ligand for the Receptor Activator of NFκB

Proton pump inhibitors are taken by millions of patients for prevention and treatment of gastroesophageal diseases Case-control studies have suggested that use of omeprazole is associated with an increased risk of hip fractures The aim of this prospective study was to assess the risk of vertebral fractures in postmenopausal women using omeprazole We studied 1,211 postmenopausal women enrolled in the Osteoporosis and Ultrasound Study from the general population Information on omeprazole and other risk factors for fractures including prevalent fractures and bone mineral density was obtained at baseline Vertebral fractures were assessed on X-rays obtained at baseline and at the end of the 6-year follow-up and analyzed centrally At baseline, 5% of this population was using omeprazole Age-adjusted rates for vertebral fractures were 189 and 060 for 100 person-years for omeprazole users and nonusers, respectively (P = 0009) In the multivariate analysis, omeprazole use was a significant and independent predictor of vertebral fractures (RR = 350, 95% CI 114–844) The other predictors were age higher than 65 years (RR = 234, 95% CI 102–534), prevalent vertebral fractures (RR = 362, 95% CI 163–808), and lumbar spine T score ≤ −25 (RR = 238, 95% CI 103–549) Omeprazole use is associated with an increased risk of vertebral fractures in postmenopausal women Further studies are required to determine the mechanism of the association between the underlying gastric disease, omeprazole use, and risk of osteoporotic fractures

Increase in Vertebral Fracture Risk in Postmenopausal Women Using Omeprazole

A novel pathophysiological mechanism for osteoporosis suggested by an in vivo gene expression study of circulating monocytes

PURPOSE Previous studies have reported inconsistent findings regarding the association between the use of acid-suppressive drugs such as proton pump inhibitors (PPIs) and histamine 2 receptor antagonists (H2RAs) and fracture risk. We investigated this association using meta-analysis.

METHODS We searched MEDLINE (PubMed), EMBASE, and the Cochrane Library from inception through December 2010 using common key words. We included case-control, nested case-control, and cohort studies. Two evaluators independently reviewed and selected articles. We determined pooled effect estimates by using random-effects meta-analysis, because of heterogeneity.

RESULTS Of 1,809 articles meeting our initial inclusion criteria, 5 case-control studies, 3 nested case-control studies, and 3 cohort studies were included in the final analyses. The pooled odds ratio (OR) for fracture was 1.29 (95% confidence interval [CI], 1.18–1.41) with use of PPIs and 1.10 (95% CI, 0.99–1.23) with use of H2RAs when compared with nonuse of the respective medications. Long-term use of PPIs increased the risk of any fracture (adjusted OR = 1.30; 95% CI, 1.15–1.48) and hip fracture risk (adjusted OR = 1.34; 95% CI, 1.09–1.66), whereas long-term H2RA use was not significantly associated with fracture risk.

CONCLUSIONS We found possible evidence linking PPI use to an increased risk of fracture, but no association between H2RA use and fracture risk. Widespread use of PPIs with the potential risk of fracture is of great importance to public health. Clinicians should carefully consider their decision to prescribe PPIs for patients already having an elevated risk of fracture because of age or other factors.

https://www.annfammed.org/content/annalsfm/9/3/257.full.pdf

Use of Acid-Suppressive Drugs and Risk of Fracture: A Meta-analysis of Observational Studies

We have previously postulated that mast cells (MC) may act as accessory cells in bone resorption. In this study we obtained evidence that histamine, the most abundant mediator released upon MC degranulation, is one of many factors modulating resorption. As the effect of histamine is mediated through different receptors, we tested the effects of mepyramine (1.5 mg/kg/day) and cimetidine (125 mg/kg/day), that antagonize H1 and H2 receptors, respectively. These effects were assessed morphometrically in a well-defined rat model of synchronized resorption at different stages of the process. On day 4 after induction (i.e., at the peak of resorption in this model), both agents reduced resorption significantly. Mepyramine acted by disturbing osteoclast activation and by reducing osteoclast activity (P < 0.01), while cimetidine principally reduced the size of the osteoclast population (P < 0.01). On day 6 (stage of declining resorption), the same resorption score as on day 4 was maintained in the mepyramine group, mainly through a marked increase in osteoclast activity (P < 0.01). In contrast, cimetidine continued to strongly reduce resorption (P < 0.01) and led to a further drop in the osteoclast population (P < 0.01). One day after induction, nonspecific esterase (NSE)-positive cells (putative osteoclast precursors) were significantly less numerous after treatment with the two agents. Significant changes in the MC population in the vicinity of the zone undergoing resorption occurred on days 4 and 6. The periosteal microvasculature adjacent to the reference bone zone was also markedly modified, especially in the cimetidine group. These results show that histamine intervenes in resorption through both H1 and H2 receptors. However, the mechanisms triggered by these receptors were quite different: H2 receptors appeared to be more strategic, as no replenishment of the osteoclast population occurred after the initial depletion in precursors. Histamine also appears to influence other neighbouring compartments, in which disturbances are probably linked to defective resorption. These findings support our hypothesis by which MC are accessory cells of resorption in this model.

H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: Evidence obtained by using receptor antagonists in a rat synchronized resorption model

Christine Dobigny

Papers

H1 and H2 histamine receptors modulate osteoclastic resorption by different pathways: Evidence obtained by using receptor antagonists in a rat synchronized resorption model