We used the University of Wisconsin cohort to determine the extent to which the EULAR Sjögren’s syndrome disease activity index (ESSDAI) was associated with comorbidities that contribute to mortality. Our University of Wisconsin, Madison cohort had 111 patients with Sjögren’s Disease (SjD) by 2016 ACR/EULAR criteria and 194 control patients with sicca. Our study was performed from March 1st, 2020 through April 1st, 2023. We collected data using a standardized collection tool, including components of the Charlson Comorbidity Index (CCI). Stratifying our SjD patients by ESSDAI < 5 and ESSDAI ≥ 5, we assessed differences in comorbidities associated with mortality. At time of SjD diagnosis, the ESSDAI ≥ 5 group had increased odds of peripheral vascular disease compared to controls (OR 10.17; 95

ObjectiveThe objective is to update recommendations for prevention and treatment of glucocorticoid‐induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily.MethodsAn updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations.ResultsFor adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x‐ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision‐making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high‐dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included.ConclusionThis guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

Background: Obesity with metabolic syndrome is highly prevalent and shortens lifespan.Objectives: In a dose-finding crossover study, we evaluated the effect of glycomacropeptide (GMP) on satiety, glucose homeostasis, amino acid concentrations, inflammation, and the fecal microbiome in 13 obese women.Methods: Eligible women were <10 yr past menopause with a body mass index [BMI (in kg/m2)] of 28 to 35 and no underlying in-flammatory condition affecting study outcomes. Participants consumed GMP supplements (15 g GMP + 10 g whey protein) twice daily for 1 wk and thrice daily for 1 wk, with a washout period between the 2 wk. Women completed a meal tolerance test (MTT) on day 1 (soy MTT) and day 7 (GMP MTT) of each week. During each test, subjects underwent measures of glucose homeostasis, satiety, cytokines, and the fecal microbiome compared with that of usual diet, and rated the acceptability of consuming GMP supplements. Results: The mean & PLUSMN; SE age of the 13 women was 57 & PLUSMN; 1 yr, with a median of 8 yr (range: 3-9 yr) past menopause and a BMI of 30 (IQR: 29-32). GMP was highly acceptable to participants, permitting high adherence. Metabolic effects were similar for twice or thrice daily GMP supplementation. Glucose, insulin, and cytokine concentrations were no different. The postprandial area under the curve (AUC) for glucagon concentrations was significantly lower, and the insulin-glucagon ratio was significantly higher with GMP than that with the soy MTT. Postprandial AUC amylin concentration was significantly higher with GMP than that with the soy MTT and correlated with C-peptide (P < 0.001; R2 = 0.52) and greater satiety. Ingestion of GMP supplements twice daily reduced members of the genus Streptococcus (P = 0.009) and thrice daily consumption reduced overall & alpha; diversity.Conclusions: GMP is shown to increase amylin concentrations, improve glucose homeostasis, and alter the fecal microbiome. GMP can be a helpful nutritional supplement in obese postmenopausal women at risk for metabolic syndrome. Further investigation is warranted. This trial was registered at clinicaltrials.gov as NCT05551091.

Copyright © 2022 The Korean Society for Bone and Mineral Research This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Concerns about Race and Ethnicity within the United States Fracture Risk Assessment Tool

Obesity is a risk factor for chronic diseases and moderate weight loss is generally recommended. Energy restriction results in the loss of hip bone mineral density (BMD) in older adults, but there is no consistent decline at the lumbar spine (LS), possibly due to vertebral abnormalities although this may also be dependent on the amount of weight loss. In this secondary analysis of weight loss trials investigating BMD and trabecular bone score (TBS) changes over 12–18 months, 92 postmenopausal women (60.8 ± 5.8 years; body mass index 32.7 ± 4.4 kg/m2) without osteoporosis, were divided into two groups: those who lost < 5% body weight (minimal) or ≥ 5% (moderate). Hip and LS–BMD and TBS were measured at baseline, 6 and 12–18 months. Exclusion of vertebral abnormalities (VE) was used to calculate BMD at the spine (LS–BMD–VE) using standard guidelines. Women lost 2.3 ± 2.4% and 8.5 ± 4.7% weight in the minimal and moderate weight loss groups, respectively. Over one third of the women had at least one vertebral abnormality or partially degraded TBS at baseline that worsened after weight loss, increasing to over 50% in this population (p < 0.05). TBS and hip BMD decreased with weight loss (p < 0.05), but LS–BMD did not decrease significantly. However, after excluding vertebral abnormalities, the LS–BMD–VE decreased in the entire population (p < 0.01), and by 1.7 ± 4.3% in the moderate weight loss group. This study suggests that older women without osteoporosis have vertebral abnormalities that obfuscated declines in BMD with weight loss, indicating that bone at the spine is further compromised.

Introduction and hypothesis Sacrocolpopexy is considered mainstay treatment for apical or vaginal vault prolapse and is currently most often performed via a minimally invasive approach. Although mesh-related complications after this procedure are uncommon, mesh exposure can have an important impact on the patient's quality of life. Our objective is to perform a literature review on this complication post laparoscopic or robotic sacrocolpopexy. Methods Web of Science and MEDLINE databases were searched for relevant articles published between 2005 and 2021. We retrieved 272 articles of which 83 ultimately were withheld. Results Minimally invasive sacrocolpopexy (MISC) implies a low risk of mesh exposure, which is currently estimated at 3.5%. Literature however is marked by substantial methodological heterogeneity. Controversy remains in the debate over prevention of mesh exposure after MISC. Performing a concomitant total hysterectomy is associated with an increased risk compared to subtotal hysterectomy or hysteropexy. Treatment of mesh exposure is challenging as guidelines are lacking. Although supported by few prospective data, patients with asymptomatic mesh exposure are managed conservatively. Surgical intervention, preferentially performed by an experienced pelvic surgeon, is indicated in symptomatic patients. Conclusions Mesh exposure is often undiagnosed and remains untreated. There is a gap in evidence exploring risk factors for mesh-related complications and efficient measures for reducing them. Choosing the best treatment option is still difficult. Management should be individualized and optimized at the time of diagnosis. Lack of acknowledgement and experience can result in increased morbidity.

OBJECTIVE:Lupus nephritis (LN) predicts a 9-fold higher atherosclerosis cardiovascular disease (ASCVD) risk, highlighting the urgent need to target ASCVD prevention. Studies in IgA nephropathy reported that severe renal arteriosclerosis (r-ASCL) in diagnostic biopsies strongly predicted ASCVD risk. We recently found that 50% of LN pathology reports overlooked r-ASCL reporting, which could explain prior negative LN ASCVD risk studies. The present study was undertaken to examine associations between a composite of reported and overread r-ASCL and ASCVD events in LN.METHODS:Data were abstracted from all LN patients who underwent diagnostic biopsy between 1994 and 2017, including demographic information, ASCVD risk factors, and pathology reports at the time of LN diagnosis. We manually validated all incident ASCVD events. We overread 25% of the biopsies to grade r-ASCL using the Banff criteria. We supplemented the overread r-ASCL grade, when available, to determine the composite of reported and overread r-ASCL grade.RESULTS:Among 189 incident LN patients, 78% were female, 73% White, and the median age was 25 years. Overall, 31% had any reported r-ASCL, and 7% had moderate-to-severe r-ASCL. After incorporating systematically re-examined r-ASCL grade, the prevalence of any and moderate-to-severe r-ASCL increased to 39% and 12%, respectively. We found 22 incident ASCVD events over 11 years of follow-up. Using a composite of reported and overread r-ASCL grade, we found that severe r-ASCL in diagnostic LN biopsies was associated with 9-fold higher odds of ASCVD.CONCLUSION:Severe r-ASCL can predict ASCVD in LN; therefore, larger studies are required to systematically report r-ASCL and examine ASCVD associations.

Background: Preclinical data suggest that tofacitinib would protect bone health in patients with rheumatoid arthritis (RA). Objective: To assess fracture risk in tofacitinib RA clinical trials. Design: Post hoc analysis. Methods: We analyzed pooled data of phase I/II/III and long-term extension studies (‘ P123LTE cohort’), pooled data of placebo-controlled portions of phase III studies ( phase III placebo-controlled cohort), and data from ORAL Surveillance [phase IIIb/IV randomized, open-label trial evaluating tofacitinib 5/10 mg twice daily (BID) vs tumor necrosis factor inhibitor (TNFi) in patients ⩾ 50 years with ⩾ 1 additional cardiovascular risk factor]. Results: In the phase III placebo-controlled cohort, incidence rates (IRs) [95% confidence interval (CI)] of fracture were 2.11 (1.09–3.68), 2.56 (1.23–4.71), and 4.43 (1.78–9.12) per 100 patient-years (PYs) for tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively [tofacitinib 5 mg BID vs placebo: hazard ratio (HR) (95% CI) = 0.55(0.18–1.65); tofacitinib 10 mg BID vs placebo: HR (95% CI) = 0.72 (0.26–2.01)]. In P123LTE , IRs (95% CI) were 2.62 (2.29–2.99) and 2.26 (2.02–2.52) per 100 PY for average tofacitinib 5 and 10 mg BID, respectively. In ORAL Surveillance, IRs (95% CI) were 2.79 (2.34–3.30), 2.87 (2.40–3.40), and 2.27 (1.87–2.74) per 100 PY for tofacitinib 5 mg BID, tofacitinib 10 mg BID, and TNFi, respectively. In ORAL Surveillance, the risk of fracture was numerically higher than TNFi for tofacitinib 5 mg BID [HR (95% CI) = 1.23 (0.96–1.58)] and tofacitinib 10 mg BID [HR (95% CI) = 1.26 (0.97–1.62)]. In ORAL Surveillance, independent predictors of all and osteoporotic fractures with tofacitinib or TNFi included age ⩾ 65, female sex, history of fracture/osteoporosis, and baseline oral corticosteroid use. Conclusion: This post hoc analysis showed numerically lower fracture risk with tofacitinib versus placebo and numerically greater risk versus TNFi. We did not identify any tofacitinib-specific predictors of fractures, and predictors of fracture were generally aligned with prior literature in the general population and patients with RA. Patients with fracture risk factors should be adequately monitored and treated. Clinical trial registration: NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02187055, NCT02831855, NCT00413699, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT00661661, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT01262118, NCT01484561, NCT02281552, NCT02147587, NCT02092467

Objective Despite the pivotal role that hydroxychloroquine (HCQ) plays in treating systemic lupus erythematosus (SLE), less than 50% of patients take HCQ as prescribed. Measurement of HCQ blood levels can help clinicians distinguish nonadherence versus lack of efficacy of HCQ. Our objective was to systematically review publications and perform a meta-analysis to examine the correlation between HCQ levels and 1) nonadherence and 2) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, in SLE. Methods A comprehensive search was performed. We included observational and interventional studies that measured HCQ levels and assessed adherence or SLEDAI scores in adults with SLE. Forest plots compared pooled estimates of correlations between HCQ levels and reported nonadherence or SLEDAI scores. Results Among 604 studies screened, 17 were reviewed. We found 3-times higher odds of reported nonadherence in patients with low HCQ levels (odds ratio 2.95 [95% confidence interval (95% CI) 1.63, 5.35], P < 0.001). The mean SLEDAI score was 3.14 points higher in groups with below-threshold HCQ levels on a priori analysis (delta = 3.14 [95% CI -0.05, 6.23], P = 0.053), and 1.4 points higher in groups with HCQ levels of <500 ng/ml (delta = 1.42 [95% CI 0.07, 2.76], P = 0.039). Among 1,223 patients, those with HCQ levels >= 750 ng/ml had a 58% lower risk of active disease, and their SLEDAI score was 3.2 points lower. Conclusion We found a strong association between low HCQ levels and reported nonadherence. Our results suggest that HCQ levels of >= 750 ng/ml might be a potential therapeutic target.

In the field of human nutrition, randomized controlled trials (RCTs) are considered the gold standard for establishing causal relations between exposure to nutrients, foods, or dietary patterns and prespecified outcome measures, such as body composition, biomarkers, or event rates. Evidence-based dietary guidance is frequently derived from systematic reviews and meta-analyses of these RCTs. Each decision made during the design and conduct of human nutrition RCTs will affect the utility and generalizability of the study results. Within the context of limited resources, the goal is to maximize the generalizability of the findings while producing the highest quality data and maintaining the highest levels of ethics and scientific integrity. The aim of this document is to discuss critical aspects of conducting human nutrition RCTs, including considerations for study design (parallel, crossover, factorial, cluster), institutional ethics approval (institutional review boards), recruitment and screening, intervention implementation, adherence and retention assessment, and statistical analyses considerations. Additional topics include distinguishing between efficacy and effectiveness, defining the research question(s), monitoring biomarker and outcome measures, and collecting and archiving data. Addressed are specific aspects of planning and conducting human nutrition RCTs, including types of interventions, inclusion/exclusion criteria, participant burden, randomization and blinding, trial initiation and monitoring, and the analysis plan.

Objective Cardiovascular disease (CVD) is accelerated in patients with systemic lupus erythematosus and lupus nephritis (LN). Despite the literature suggesting that renal arteriosclerosis predicts CVD in other glomerulonephritis diseases, arteriosclerosis grading and reporting might be particularly overlooked in LN biopsies. Our objective was to examine the burden of renal arteriosclerosis in LN and to assess whether arteriosclerosis is underreported in LN biopsies. Methods We identified all patients with LN undergoing kidney biopsy between 1994 and 2017 at an academic center. We interpreted LN biopsy reports to classify the Banff categories of absent, mild, moderate, or severe renal arteriosclerosis. The prevalence of renal arteriosclerosis was compared with the prevalence published for age-matched healthy peers, and predictors of arteriosclerosis were examined. We overread biopsies for Banff renal arteriosclerosis grading and compared to pathology reports. Results Among 189 incident patients with LN, renal arteriosclerosis prevalence was 2 decades earlier compared to their healthy peers, affecting 40% of patients ages 31-39 years with LN compared to 44% of healthy peers ages 50-59 years. A multivariable analysis showed a 3-fold higher odds of renal arteriosclerosis in patients ages >= 30 years with LN. LN chronicity on biopsy results predicted a 4-fold higher odds of renal arteriosclerosis. The overreads determined that 50% of standard LN biopsy reports missed reporting the presence or absence of renal arteriosclerosis. Conclusion Renal arteriosclerosis is accelerated by 2 decades in patients with LN compared to their healthy peers and is overlooked by pathologists in half of the routine biopsy reports. We propose incorporating Banff renal arteriosclerosis grading in all LN biopsy reports.

BACKGROUND:Fractures are a common and burdensome problem among kidney transplant recipients (KTRs). Proton pump inhibitors (PPIs) are frequently used after kidney transplantation and have been associated with increased fracture risk in the general population. This study aimed to determine whether PPI use is associated with incidence of major fractures in KTRs.METHODS:Using the Wisconsin Allograft Recipient Database, we identified 155 KTRs with a major fracture that occurred at least 12 months after transplantation. Controls were selected using incidence-density sampling. Use of PPIs and histamine 2-receptor antagonists (H2RA) during the year before the index date were identified.RESULTS:A total of 155 cases were matched to 685 controls. Within 1 year before the index date, 68% of cases and 52% of controls used a PPI, and 16% of cases and 11% of controls used an H2RA. PPI use was associated with higher incidence of major fractures in unadjusted analysis (odds ratio [OR], 2.4; 95% CI, 1.6-3.5) and in adjusted analyses controlling for demographic and transplant-related covariates and use of corticosteroids, bisphosphonates, vitamin D and calcium supplements (OR, 1.9; 95% CI, 1.2-3.1). H2RA use was not associated with incidence of major fractures in adjusted analyses (OR, 1.0; 95% CI, 0.5-1.8). The associations between PPI use and fractures remained similar in analyses limited to spine and hip fractures.CONCLUSIONS:Use of PPIs, but not H2RAs, is associated with a higher risk of major fractures among KTRs. Clinicians should individualize PPI use in KTRs, evaluating the risks and benefits of prescribing and continuing PPIs in KTRs.

Background: In the general population, use of proton pump inhibitor (PPI) has been linked to higher risk of osteoporotic fractures. PPI is commonly prescribed in kidney transplant recipients (KTRs). However, the effect of PPI on osteoporosis in KTRs is largely unstudied. Methods: A total of 1,774 adult KTRs in the Wisconsin Allograft Recipient Database with at least one eligible bone mineral density (BMD) measurement at least 3 months after transplantation were included in the analyses. Associations between use of PPI and histamine-2 receptor antagonist (H2RA) at 3 months after transplantation and subsequent slope of T-score were assessed. Results: A total of 1,478 (83.3%) participants were using a PPI at 3 months after transplantation. Compared to the use of H2RA, use of PPI was not significantly associated with annualized slope of hip T-score (β = –0.0039, 95% CI –0.00497 to 0.0021) or annualized slope of spine T-score (β = –0.017, 95% CI –0.049 to 0.083) after adjustment for potential confounders. Similarly, no significant association between use of PPI and slope of T-score was observed when defining PPI/H2RA exposure as use within 6 months of the initial BMD measurement, or only including participants with at least 2 BMD measurements, or stratified by different age and sex. Conclusions: Use of PPI was not associated with an increased rate of BMD loss in KTRs. Our results support previous findings that PPI use does not have a significant effect on bone mineral loss.

Background/aim: Cost-efficient methods are essential for successful participant recruitment in clinical trials. Patient portal messages are an emerging means of recruiting potentially eligible patients into trials. We assessed the response rate and complaint rate from direct-to-patient, targeted recruitment through patient portals of an electronic medical record for a clinical trial, and compared response rates by differences in message content. Methods: The Study to Understand Fall Reduction and Vitamin D in You (STURDY) trial is a National Institutes of Health–sponsored, community-based study of vitamin D supplementation for fall prevention in older adults conducted at Johns Hopkins. Potential participants were identified using the Epic electronic medical record at the Johns Hopkins Health System based on age (≥70 years), ZIP code (30-mile radius of study site), and prior activation of a patient portal account. We prepared a shorter message and a longer message. Both had basic information about study participation, but the longer message also contained information about the significance of the study and a personal invitation from the STURDY principal investigator. The Hopkins Institutional Review Board did not require prior consent from the patient or their providers. We calculated the response rate and tracked the number of complaints and requests for removal from future messages. We also determined response rate according to message content. Results: Of the 5.5 million individuals receiving care at the Johns Hopkins Health System, a sample of 6896 met our inclusion criteria and were sent one patient portal recruitment message between 6 April 2017 and 3 August 2017. Assessment of enrollment by this method ended on 1 December 2017. There were 116 patients who expressed interest in the study (response rate: 1.7%). Twelve (0.2%) recipients were randomized. There were two complaints (0.03%) and one request to unsubscribe from future recruitment messages (0.01%). Response rate was higher with the longer message than the shorter message (2.1% vs 1.2%; p = 0.005). Conclusion: Patient portal messages inviting seniors to participate in a randomized controlled trial resulted in a response rate similar to commercial email marketing and resulted in very few complaints or opt-out requests. Furthermore, a longer message with more content enhanced response rate. Recruitment through patient portals might be an effective strategy to enroll trial participants.

Background Despite the pivotal role hydroxychloroquine (HCQ) plays in treating SLE, less than 50% of patients take HCQ as prescribed. Non-adherence versus lack of effect to HCQ are difficult to distinguish, underscoring the importance of measuring HCQ blood levels to assess adherence. Despite this, information and consensus on the clinical impact of incorporating routine testing of HCQ blood levels is lacking. Therefore, we systematically reviewed publications examining the correlation between 1) HCQ levels and adherence, and 2) HCQ levels and SLEDAI scores, in SLE patients. We hypothesized that low HCQ levels would correlate with non-adherence and higher SLEDAI scores. Methods A comprehensive search was performed using MeSH heading and keywords in Medline, Embase, CINHL and Web of Science databases. We selected observational and interventional studies that measured HCQ levels and assessed adherence and/or SLEDAI scores in adults with SLE. Newcastle Ottawa Scale and Cochrane Collaboration Risk Assessment tools were used to rate the quality of observational and intervention studies, respectively. We used Forest plots to compare pooled estimates (95% CI) of correlations between HCQ levels and patient or physician reported nonadherence and SLEDAI scores. Heterogeneity was assessed using I2. Results From 306 manually reviewed studies, four studies analyzing correlation between HCQ levels and adherence, and five studies examining the correlation between SLEDAI and HCQ blood levels, met inclusion criteria. The odds of nonadherence measured by physician or reported by the patient was 3 times higher in patients with below threshold HCQ levels, compared to those with higher HCQ levels (OR 2.95, 95% CI 1.63, 5.35, p<0.001, I2 49%) (figure 1, panel A). The mean SLEDAI score was 3.33 points higher in groups with HCQ levels below threshold, but this trend was not statistically significant (3.33, 95% CI −0.60, 7.26, p=0.097, I2 99%) (figure 1, panel B). Risk of bias assessment revealed three poor quality studies which were excluded in sensitivity analysis which did not change results. Limitations of our analysis include study heterogeneity and lack of consensus on HCQ level interpretations. Conclusions We found good correlation between HCQ levels and non-adherence. Low HCQ levels showed higher mean SLEDAI scores but due to the limited number of studies and heterogeneity we did not find significant correlation. Findings support the clinical utility of measuring HCQ levels in SLE patients. Future larger studies should investigate standards for HCQ level interpretation and target levels needed to minimize SLEDAI scores. Funding Source(s): n/a

Hansen et al1Hansen K.E. et al.Gastroenterology. 2019; 156: 926-934Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar performed a randomized, double-blind, placebo-controlled trial that assessed skeletal effects of treatment with dexlansoprazole (60 mg/d) or esomeprazole (40 mg/d), 2 potent proton pump inhibitors (PPIs), for 26 weeks among a total of 115 healthy postmenopausal women (mean age, 62 years; mean body mass index, 25 kg/m2). Although the treatment with dexlansoprazole or esomeprazole caused small increases in circulating markers of bone turnover, the authors found no clinically meaningful impact on areal bone mineral density (aBMD) in the lumbar spine, total hip, or femoral neck. To the best of my knowledge, this is the first report of a randomized clinical trial on this topic. Importantly, the finding of no clinically meaningful effect of PPI use on aBMD1Hansen K.E. et al.Gastroenterology. 2019; 156: 926-934Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar agrees with several independent meta-analyses of observational studies that showed no significant association of PPI therapy with aBMD.2Sugiyama T. Am J Gastroenterol. 2019; 114: 360-361Crossref PubMed Scopus (4) Google Scholar, 3Liu J. et al.Life Sci. 2019; 218: 213-223Crossref PubMed Scopus (41) Google Scholar The treatment period of 26 weeks might be too short to sufficiently evaluate the effects of agents on aBMD, as the authors discussed. However, the finding of no clinically meaningful impact of the treatment with dexlansoprazole or esomeprazole on aBMD1Hansen K.E. et al.Gastroenterology. 2019; 156: 926-934Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar still supports the finding of no clear causal relationship between PPI use and increased fracture risk,2Sugiyama T. Am J Gastroenterol. 2019; 114: 360-361Crossref PubMed Scopus (4) Google Scholar because the meta-analyses indicate that short-term (<1 year) and long-term (≥1 year) exposure of PPIs were similarly linked to increased fracture risk in observational studies.2Sugiyama T. Am J Gastroenterol. 2019; 114: 360-361Crossref PubMed Scopus (4) Google Scholar, 3Liu J. et al.Life Sci. 2019; 218: 213-223Crossref PubMed Scopus (41) Google Scholar, 4Poly T.N. et al.Osteoporos Int. 2019; 30: 103-114Crossref PubMed Scopus (69) Google Scholar It seems that reports of potential PPI-related complications have caused considerable confusion among clinicians and patients, even after recent publication of excellent reviews.5Freedberg D.E. et al.Gastroenterology. 2017; 152: 706-715Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar, 6Vaezi M.F. et al.Gastroenterology. 2017; 153: 35-48Abstract Full Text Full Text PDF PubMed Scopus (267) Google Scholar Therefore, it is important to note that the latest evidence1Hansen K.E. et al.Gastroenterology. 2019; 156: 926-934Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar, 2Sugiyama T. Am J Gastroenterol. 2019; 114: 360-361Crossref PubMed Scopus (4) Google Scholar, 3Liu J. et al.Life Sci. 2019; 218: 213-223Crossref PubMed Scopus (41) Google Scholar, 4Poly T.N. et al.Osteoporos Int. 2019; 30: 103-114Crossref PubMed Scopus (69) Google Scholar is consistent with clinical practice advice from the American Gastroenterological Association that long-term PPI users should not routinely screen or monitor aBMD using dual-energy x-ray absorptiometry.5Freedberg D.E. et al.Gastroenterology. 2017; 152: 706-715Abstract Full Text Full Text PDF PubMed Scopus (433) Google Scholar Here, to decrease the ongoing confusion on PPI use and fracture risk, I would like to offer a reasonable hypothesis as to why many observational studies have shown an association of PPI therapy with increased fracture risk.2Sugiyama T. Am J Gastroenterol. 2019; 114: 360-361Crossref PubMed Scopus (4) Google Scholar, 3Liu J. et al.Life Sci. 2019; 218: 213-223Crossref PubMed Scopus (41) Google Scholar, 4Poly T.N. et al.Osteoporos Int. 2019; 30: 103-114Crossref PubMed Scopus (69) Google Scholar In contrast with healthy participants of the authors’ randomized clinical trial, many PPI-treated patients investigated in observational studies would generally have various chronic diseases. Physical activity plays a fundamental role in skeletal health,7Sugiyama T. Int J Epidemiol. 2018; 47: 669-670Crossref PubMed Scopus (16) Google Scholar and physical activity levels in most patients with a chronic disease are lower than in healthy people.8Barker J. et al.Int J Epidemiol. 2019; (Feb 5 [Epub ahead of print])https://doi.org/10.1093/ije/dyy294Crossref Scopus (58) Google Scholar Consequently, lower physical activity seems to be a possible key word that can explain the noncausal relationship between PPI use and increased risk of fractures as well as falls.2Sugiyama T. Am J Gastroenterol. 2019; 114: 360-361Crossref PubMed Scopus (4) Google Scholar Dexlansoprazole and Esomeprazole Do Not Affect Bone Homeostasis in Healthy Postmenopausal WomenGastroenterologyVol. 156Issue 4PreviewEpidemiological studies have associated proton pump inhibitor (PPI) therapy with osteoporotic fractures, but it is not clear if PPIs directly cause osteoporosis. We evaluated the effect of dexlansoprazole and esomeprazole on bone turnover, bone mineral density (BMD), true fractional calcium absorption (TFCA), serum and urine levels of minerals, and levels of parathyroid hormone (PTH) in healthy postmenopausal women. Full-Text PDF ReplyGastroenterologyVol. 157Issue 2PreviewWe thank Dr Sugiyama for his comments on our recent publication of a randomized, double-blind, placebo-controlled trial that assessed skeletal effects of treatment with dexlansoprazole (60 mg/d) or esomeprazole (40 mg/d), 2 potent proton pump inhibitors (PPIs), in 115 healthy postmenopausal women.1 The finding that there was no clinically meaningful effect of PPI use on areal-bone mineral density, albeit at 26 weeks, in conjunction with no meaningful impact of PPIs on bone turnover, intestinal calcium absorption, or serum or urine mineral levels, led to our conclusion that neither dexlansoprazole or esomeprazole seem to harm the skeleton. Full-Text PDF