BACKGROUND:

Acid suppression therapy (AST), including proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs), is frequently prescribed to treat symptomatic gastroesophageal reflux in otherwise healthy infants. PPI use has been associated with increased fracture risk in older adults; 2 preliminary studies in children have conflicting results.

METHODS:

A retrospective cohort of children born 2001 to 2013 who were followed for ≥2 years was formed. Those with osteogenesis imperfecta, cholestasis, or child maltreatment were excluded. Prescription data were used to identify AST prescription before age 1 year. International Classification of Diseases, Ninth Revision, Clinical Modification codes identified fractures after age 1 year. A Cox proportional hazard analysis assessed fracture hazard and was adjusted for sex, prematurity, low birth weight, previous fracture, anti-epileptics, and overweight or obesity.

RESULTS:

Of 851 631 included children, 97 286 (11%) were prescribed AST in the first year of life; 7998 (0.9%) children were prescribed PPI, 71 578 (8%) were prescribed H2RA, and 17 710 (2%) were prescribed both a PPI and H2RA. Infants prescribed AST had an earlier median first fracture age (3.9 vs 4.5 years). After adjustment, increased fracture hazard was associated with PPI use (21%) and PPI and H2RA use (30%), but not H2RA use alone. Longer duration of AST treatment and earlier age of first AST use was associated with increased fracture hazard.

CONCLUSIONS:

Infant PPI use alone and together with H2RAs is associated with an increased childhood fracture hazard, which appears amplified by days of use and earlier initiation of ASTs. Use of AST in infants should be weighed carefully against possible fracture.

What’s Known on This Subject:

Proton pump inhibitors (PPIs) are used frequently in the treatment of symptomatic gastroesophageal reflux. Studies in adults have revealed an association between PPIs and increased fracture risk, but this has not been well studied in infants and children.

What This Study Adds:

This study included young children without known serious medical conditions prescribed acid suppression therapy during the first year of life, likely for symptomatic treatment of reflux. A positive association was found between PPI use and childhood fracture incidence.

Acid suppressants, including proton pump inhibitors (PPIs) and histamine H2-receptor antagonists (H2RAs), are commonly prescribed for the treatment of gastroesophageal reflux (GER) disease, erosive esophagitis, gastric and duodenal ulcers, eosinophilic esophagitis, and Helicobacter pylori gastritis. Although these diseases have remained relatively stable over the past decades, the use of PPIs and H2RAs has increased dramatically, doubling from 2004 to 20081 and tripling from 2002 to 2009.2 This increase has occurred not only in the adult population but also in pediatrics, with use in infants quadrupling from 1999 to 2003, and doubling from 2004 to 2008.3,4 This increase may reflect overtreatment of physiologic newborn reflux and misinterpretation of normal newborn crying.5,6 Newborn reflux and crying are normal newborn behaviors, and placebo-controlled trials have revealed that PPIs do not relieve symptoms related to GER in infants.7,8 

Although PPIs were initially thought to be safe,9 a growing body of research is uncovering several short- and long-term negative effects of PPI therapy.10 Long-term PPI use in adults has been associated with negative outcomes, including gastric cancers, infection, gastric polyps,11 chronic kidney disease,12 and overall increased mortality.13 In adult studies, PPI use has also been associated with decreased bone mass14,15 and an increased rate of fractures.16 Emerging research is revealing risks with PPI use in the pediatric population as well, with PPI use increasing the risk for gastroenteritis, community-acquired pneumonia, and Clostridium difficile infections.17,18 

Authors of few studies have looked specifically at bone health19 in children on PPIs, and the results have been limited and contradictory. A small study of 34 children (ages 5–9 and 12–15 years) revealed that PPIs were not associated with alterations in biochemical indicators of bone turnover.20 A larger study revealed that PPI use was associated with fracture in young adults (ages 18–24 years) but not in children (ages 4–18 years).21 In an earlier study, authors exploring the impact of preterm birth on fracture found that first-year PPI use may be associated with an increased fracture rate during the first 5 years of life, although they did not examine the effect of age at time of initiation or duration of exposure.22, Studies also have not been focused on acid suppression therapy (AST) use and fracture risk in otherwise healthy infants despite high prescription rates in this population.23 

In this study, we sought to explore the relationship between AST use in the first year of life and childhood fracture, accounting for duration of exposure and age at initiation. In the study, we hypothesize that prescription use of AST, specifically PPIs, in otherwise healthy infants will be associated with increased incidence of fracture in young children.

A retrospective cohort of children born in the Military Healthcare System (MHS) who received continuous MHS care for at least the first 2 and up to 14 years of life was formed. The MHS provides health care to military members, retirees, and dependent family members. Care is provided around the world at military treatment facilities and by civilian providers. Records are maintained for all inpatient and outpatient medical care and outpatient prescription medications.

Children born in the MHS between October 1, 2001, and September 30, 2013, were included. Children with diagnoses that included osteogenesis imperfecta, cholestasis, or child maltreatment, identified via International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, were excluded because these conditions independently predispose a child to fractures.22 Cholestasis is oftentimes associated with prolonged parenteral nutrition or chronic liver disease, both of which can increase the risk of metabolic bone disease.24 Birth hospitalizations of ≥7 days were used as a surrogate for admission to the NICU, and children with these extended birth hospitalizations were excluded in an attempt to limit the study population to otherwise lower-risk infants.

Data extracted from civilian and military outpatient pharmacy records were used to identify the days supply and refills of all AST prescriptions in the first 5 years of life. Children were classified as having been prescribed either a PPI, an H2RA, or both if they had ≥1 outpatient prescription for these medications during the first year of life. For children who started AST before 1 year of age, prescription data were followed for 5 years to track total length of treatment. These children were compared with children who were not prescribed any AST during the first 5 years of life. Those who initiated AST between the ages of 1 and 5 years were excluded from the primary analysis because later AST prescriptions are uncommon and are more likely related to chronic disease. Children who initiated AST at 12 to 24 months of age were included in a secondary analysis. Pharmacy records were also used to identify any children prescribed an anti-epileptic medication at any point in the study because anti-epileptics have been linked with increased fracture risk.25,26 

ICD-9-CM codes were used to identify fractures in the outpatient record that occurred both before and after the age of 1 year by using the Agency for Healthcare Research and Quality Clinical Classification System category for fractures.27 Any child with a fracture before 1 year of age was categorized as having a previous fracture, because previous fractures can be associated with increased fracture risk.28 Visits for the same fracture type within 6 months were excluded because they were likely follow-up visits and not visits for new fractures. ICD-9-CM codes were used to identify preterm birth (<37 + 0/7 weeks’ gestation) and low birth weight (LBW) (weight ≤2500 g) in the inpatient record of any children who were not already excluded for a birth hospitalization of ≥7 days. ICD-9CM codes were also used to identify obesity or overweight status in the outpatient record, because increased BMI has been linked to increased fracture risk and decreased bone mineral density.29,30 

Group differences were compared by using the Wilcoxon rank test and χ2 analysis. A Cox proportional hazard model was used to assess the hazard ratio (HR) of fracture by AST use. An adjusted analysis was used to control for sex, preterm birth, LBW, obesity and/or overweight, anti-epileptics, and history of fracture before 12 months of age. When Schoenfeld residual testing revealed a violation of the proportionality assumption, an interaction with time was added to the model.

Two secondary analyses were used to explore the impact of duration of prescription AST use and age of AST medication initiation. Length of prescription use was divided into quartiles for both H2RA and PPI groups and for the combination group. Each quartile was compared with controls who were not treated. A Cox proportional hazard model was used to assess the hazard of fracture by days on PPIs, H2RAs, and both medications; adjusted analyses were used to control for sex, preterm birth, LBW, obesity and/or overweight, anti-epileptics, fracture before 1 year of age, and time. By using 2 models, a sensitivity analysis was performed to explore whether previous fracture affected the relationship between AST and fracture.

Prescription patterns were next grouped by age at initiation. To fully explore age at AST initiation, the final analysis population was expanded to include children who initiated an AST from age 0 to 24 months. Children were classified as being prescribed AST in the first 6 months of life, at 6 to 12 months, and at 12 to 24 months and were compared with controls not prescribed any AST in the first 5 years. An analysis of variance with Tukey comparison was used to examine the impact of AST age of initiation on length of use. A Cox proportional hazard model was used to assess the relative incidence of fracture by days on PPIs, H2RAs, and both medications; adjusted analyses were used to control for male sex, preterm birth, LBW, obesity and/or overweight, anti-epileptics, fracture before 1 year of age, and time when indicated.

Stata Intercooled 13 (Stata Corp, College Station, TX) software was used for the statistical analysis. P <.05 was considered statistically significant. The study was reviewed and approved by the Uniformed Services University Institutional Review Board.

A total of 1 190 544 infants were born in the MHS between 2002 and 2015. Infants were excluded if they were classified as being at increased risk for facture because of an extended birth hospitalization of >7 days (40 099; 3.3%), maltreatment (9005; 0.74%), cholestasis (407; 0.03%), or osteogenesis imperfecta (174; 0.01%). Children also were excluded if they received MHS care for <2 years (266 309; 22%) or if they initiated AST after 1 year of age (22 919; 2%). Of the remaining 851 631 infants, 754 345 (89%) did not initiate AST and were study controls, and 97 286 (11%) initiated AST in the first year of life. Of those on AST, 7998 (9%) were prescribed a PPI, 71 578 (73%) were prescribed an H2RA, and 17 710 (18%) were prescribed both (Supplemental Fig 2). Compared with those not prescribed an acid suppressant in the first 5 years, children who initiated AST by 1 year of age were enrolled and followed in the MHS for a shorter period of time and were less likely to have overweight or obesity. They were more likely to be male, born preterm, and born with LBW. AST was not associated with anti-epileptic prescription medication use (Table 1).

TABLE 1

Demographics of Children Prescribed and Not Prescribed AST in the First Year of Life

All Children (N = 851 631)AST in the First Year of Life (n = 97 286)No AST in the First Year of Life (n = 754 345)P
Median age enrolled (IQR), y 5.8 (3.6–9.1) 5.2 (3.4–8.0) 5.9 (3.6–9.3) <.001 
Total fractures before 1 y of age (per 1000 person-years) 16 050 (16) 2144 (19) 13 906 (16) <.001 
Total fracture after 1 y of age (per 1000 person-years) 124 414 (22) 13 941 (24) 110 473 (21) <.001 
Median age of first fracture (IQR), y 4.4 (2.3–7.3) 3.9 (2.1–6.5) 4.5 (2.3–7.3) <.001 
Sex, n (%)     
 Male 435 102 (51.1) 53 764 (55.3) 381 338 (50.7) <.001 
 Female 416 529 (48.9) 43 534 (44.7) 372 995 (49.6) <.001 
Preterm birth, n (%) 32 319 (3.8) 6201 (6.4) 26 118 (3.5) <.001 
LBW, n (%) 19 952 (2.3) 3626 (3.7) 16 326 (2.2) <.001 
Anti-epileptic prescription, n (%) 9919 (1.2) 1124 (1.2) 8795 (1.2) .77 
Overweight or obesity, n (%) 49 450 (5.8) 5307 (5.5) 44 143 (5.9) <.001 
All Children (N = 851 631)AST in the First Year of Life (n = 97 286)No AST in the First Year of Life (n = 754 345)P
Median age enrolled (IQR), y 5.8 (3.6–9.1) 5.2 (3.4–8.0) 5.9 (3.6–9.3) <.001 
Total fractures before 1 y of age (per 1000 person-years) 16 050 (16) 2144 (19) 13 906 (16) <.001 
Total fracture after 1 y of age (per 1000 person-years) 124 414 (22) 13 941 (24) 110 473 (21) <.001 
Median age of first fracture (IQR), y 4.4 (2.3–7.3) 3.9 (2.1–6.5) 4.5 (2.3–7.3) <.001 
Sex, n (%)     
 Male 435 102 (51.1) 53 764 (55.3) 381 338 (50.7) <.001 
 Female 416 529 (48.9) 43 534 (44.7) 372 995 (49.6) <.001 
Preterm birth, n (%) 32 319 (3.8) 6201 (6.4) 26 118 (3.5) <.001 
LBW, n (%) 19 952 (2.3) 3626 (3.7) 16 326 (2.2) <.001 
Anti-epileptic prescription, n (%) 9919 (1.2) 1124 (1.2) 8795 (1.2) .77 
Overweight or obesity, n (%) 49 450 (5.8) 5307 (5.5) 44 143 (5.9) <.001 

IQR, interquartile range.

In the unadjusted analysis, the hazard of fracture after 1 year of age was associated with being prescribed a PPI (HR 1.23; 95% CI 1.15–1.32), being prescribed an H2RA (HR 1.13; 95% CI 1.10–1.15), and being prescribed both an H2RA and a PPI in the first year of life (HR 1.32; 95% CI 1.26–1.38; Table 2). An increased hazard of fracture was associated with male sex, overweight or obesity, and previous fracture; a decreased fracture hazard was associated with LBW (Table 2). Preterm birth and anti-epileptic medication were not associated with fracture (Table 2). A sensitivity analysis revealed that previous fracture did not affect the association between AST and fracture.

TABLE 2

Unadjusted and Adjusted HRs by AST Use in the First Year of Life

Unadjusted HR of Fracture (95% CI)Adjusted HR of Fracture (95% CI)
Male sex 1.08 (1.07–1.10) 1.08 (1.06–1.09) 
Preterm birth 0.98 (0.95–1.02) 1.01 (0.97–1.05) 
LBW 0.90 (0.86–0.95) 0.90 (0.85–0.94) 
Previous fracture 1.85 (1.75–1.96) 3.59 (3.22–4.00)a 
Anti-epileptic medication 0.98 (0.92–1.04) 0.99 (0.93–1.05) 
Overweight or obesity 1.12 (1.09–1.14) 0.99 (0.95–1.04)b 
PPI use 1.23 (1.15–1.32) 1.23 (1.14–1.31) 
H2RA use 1.13 (1.10–1.15) 1.04 (0.99–1.09)c 
PPI and H2RA use 1.32 (1.26–1.38) 1.31 (1.25–1.37) 
Previous fracture and time — 0.99 (0.99–0.99)a 
H2RA and time — 1.00004 (1.00002–1.0006)c 
Overweight or obesity and time — 1.00001 (1.00003–1.00007)b 
Unadjusted HR of Fracture (95% CI)Adjusted HR of Fracture (95% CI)
Male sex 1.08 (1.07–1.10) 1.08 (1.06–1.09) 
Preterm birth 0.98 (0.95–1.02) 1.01 (0.97–1.05) 
LBW 0.90 (0.86–0.95) 0.90 (0.85–0.94) 
Previous fracture 1.85 (1.75–1.96) 3.59 (3.22–4.00)a 
Anti-epileptic medication 0.98 (0.92–1.04) 0.99 (0.93–1.05) 
Overweight or obesity 1.12 (1.09–1.14) 0.99 (0.95–1.04)b 
PPI use 1.23 (1.15–1.32) 1.23 (1.14–1.31) 
H2RA use 1.13 (1.10–1.15) 1.04 (0.99–1.09)c 
PPI and H2RA use 1.32 (1.26–1.38) 1.31 (1.25–1.37) 
Previous fracture and time — 0.99 (0.99–0.99)a 
H2RA and time — 1.00004 (1.00002–1.0006)c 
Overweight or obesity and time — 1.00001 (1.00003–1.00007)b 

—, not applicable.

a

Interaction with time reveals that the impact of previous fracture decreases with time.

b

Interaction with time reveals that the impact of overweight or obesity status on fracture slightly increases with time.

c

Interaction with time reveals that the impact of H2RA use on fracture slightly increases with time.

After adjustment for covariates, including time, the association between AST prescriptions and fracture remained. Fracture hazard increased 23% in children prescribed a PPI (HR 1.23; 95% CI 1.14–1.31) and 31% in children prescribed both an H2RA and a PPI in the first year of life (HR 1.31; 95% CI 1.25–1.37; Table 2, Fig 1). The adjusted fracture hazard was increased with male sex and previous fracture, was decreased with LBW, and was not associated with overweight or obesity, with anti-epileptic use, or with preterm birth (Table 2). H2RA initiation in the first year of life was not associated with increased fracture.

FIGURE 1

Cumulative incidence of fracture estimates by first year of life acid suppression use.

FIGURE 1

Cumulative incidence of fracture estimates by first year of life acid suppression use.

Close modal

An adjusted analysis used to explore effects of prescription length in days suggests that fracture hazard increases with duration of AST exposure. Medication days were divided into quartiles for each medication class. The median prescription length was 60 days for monotherapy with PPIs or H2RAs and 192 days for combination therapy (Table 3). Children prescribed a PPI for 0 to 30 days had a 19% increased fracture hazard, and those prescribed PPIs for >150 days had a 41% increased fracture hazard (Table 3). Children prescribed a combination of PPIs and H2RAs for 0 to 120 days had a 17% increased fracture hazard compared with controls with no AST use in the first 5 years of life (Table 3). Use of PPIs and H2RAs was associated with increased fracture hazard for medication use for 120 to 192 days (31%), 192 to 338 days (20%), and >338 days (50%; Table 3). Use of H2RAs alone was associated with increased fracture hazard in those prescribed the medications for 0 to 30 days (14%), 60 to 120 days (16%), and >120 days (22%; Table 3).

TABLE 3

Adjusted Hazard of Fracture Associated With AST Started Before Age 1 by Duration of Exposure

PPIs (n = 7998)H2RAs (n = 71 578)Both H2RAs and PPIs (n = 17 710)
Days on MedicationAdjusted HR (95% CI)Days on MedicationAdjusted HR (95% CI)Days on MedicationAdjusted HR (95% CI)
0–30 1.19 (1.11–1.29) 0–30 1.14 (1.09–1.18) 0–120 1.17 (1.06–1.29) 
30–60 1.20 (1.09–1.33) 30–60 0.99 (0.90–1.08)a 120–192 1.31 (1.18–1.47) 
60–150 1.23 (1.13–1.33) 60–120 1.16 (1.11–1.21) 192–338 1.20 (1.08–1.32) 
>150 1.41 (1.32–1.52)b >120 1.22 (1.17–1.27)c >338 1.50 (1.37–1.65)d 
PPIs (n = 7998)H2RAs (n = 71 578)Both H2RAs and PPIs (n = 17 710)
Days on MedicationAdjusted HR (95% CI)Days on MedicationAdjusted HR (95% CI)Days on MedicationAdjusted HR (95% CI)
0–30 1.19 (1.11–1.29) 0–30 1.14 (1.09–1.18) 0–120 1.17 (1.06–1.29) 
30–60 1.20 (1.09–1.33) 30–60 0.99 (0.90–1.08)a 120–192 1.31 (1.18–1.47) 
60–150 1.23 (1.13–1.33) 60–120 1.16 (1.11–1.21) 192–338 1.20 (1.08–1.32) 
>150 1.41 (1.32–1.52)b >120 1.22 (1.17–1.27)c >338 1.50 (1.37–1.65)d 

Models were adjusted for male sex, preterm birth, LBW, anti-epileptic medication use, overweight or obesity, previous fracture, and time.

a

Interaction with time reveals that the impact of H2RA use on fracture slightly increases with time.

b

Differed significantly from 0–30, 30–60, and 60–150 d.

c

Differed significantly from 0–30 and 30–60 d.

d

Differed significantly from 0–120 and 192–338 d.

Compared with controls with no AST prescriptions before age 5, PPI initiation at 0 to 6 months of life was associated with a 23% increased fracture hazard, PPI initiation at 6 to 12 months was associated with a 21% increase, and PPI initiation at 12 to 24 months was not associated with an increased fracture hazard in the adjusted analysis (Table 4). Children prescribed an H2RA did not have an increased hazard of fracture regardless of when medication was initiated (Table 4). Fracture hazard was increased in children prescribed both a PPI and an H2RA, compared with controls with no AST use; PPI and H2RA initiation at 0 to 6 months was associated with a 32% increase, at 6 to 12 months a 23% increase, and at 12 to 24 months a 38% increase in adjusted analysis (Table 4). Duration of AST exposure decreased with age of initiation (P < .001), with the mean length of use differing for all 4 groups.

TABLE 4

Adjusted Hazard of Childhood Fracture Associated With Early AST, Stratified by Age of Prescription Initiation

Initiated in First 6 mo (n = 84 845)Initiated at Ages 6–12 mo (n = 12 441)Initiated at Ages 12–24 mo (n = 8390)
Unadjusted HR (95% CI)Adjusted HR (95% CI)Unadjusted HR (95% CI)Adjusted HR (95% CI)Unadjusted HR (95% CI)Adjusted HR (95% CI)
Male sex 1.08 (1.07–1.09) 1.08 (1.06–1.09) 1.08 (1.07–1.10) 1.08 (1.06–1.09) 1.08 (1.07–1.10) 1.08 (1.07–1.10) 
Preterm birth 0.97 (0.94–1.01) 0.99 (0.96–1.04) 0.98 (0.95–1.02) 1.03 (0.98–1.07) 0.98 (0.94–1.02) 1.02 (0.97–1.06) 
LBW 0.90 (0.86–0.94) 0.90 (0.85–0.95) 0.89 (0.85–0.94) 0.89 (0.84–0.94) 0.89 (0.85–0.94) 0.89 (0.84–0.94) 
Previous fracture 1.85 (1.74–1.96) 3.57 (3.20–3.98)a 1.85 (1.74–1.96) 3.52 (3.14–3.95)a 1.85 (1.74–1.97) 3.50 (3.13–3.93)a 
Overweight or obesity 1.12 (1.09–1.14) 0.99 (0.94–1.04)b 1.12 (1.09–1.15) 0.99 (0.94–1.05)b 1.12 (1.09–1.15) 0.99 (0.94–1.04)b 
Anti-epileptics 0.98 (0.92–1.04) 0.98 (0.92–1.05) 0.98 (0.92–1.05) 0.98 (0.92–1.05) 0.98 (0.92–1.05) 0.98 (0.92–1.05) 
PPI use 1.24 (1.14–1.34) 1.23 (1.14–1.33) 1.21 (1.05–1.40) 1.21 (1.05–1.39) 1.13 (0.98–1.30) 1.06 (0.91–1.24) 
H2RA use 1.12 (1.09–1.15) 1.04 (0.99–1.10)c 1.15 (1.08–1.22) 1.04 (0.92–1.17)c 1.10 (1.01–1.19) 0.91 (0.75–1.11) 
PPI and H2RA use 1.33 (1.27–1.39) 1.32 (1.26–1.38) 1.24 (1.08–1.42) 1.23 (1.07–1.41) 1.42 (1.20–1.68) 1.38 (1.16–1.65) 
Previous fracture and time — 0.9996 (0.9996–0.9997)a — 0.9996 (0.9996–0.9997)a — 0.9996 (0.9996–0.9997)a 
H2RA and time — 1.00004 (1.00002–1.00007)c — — — — 
Overweight or obesity and time — 1.00005 (1.00003–1.00007)b — 1.00005 (1.00003–1.00007)b — 1.00006 (1.00004–1.00008)b 
Initiated in First 6 mo (n = 84 845)Initiated at Ages 6–12 mo (n = 12 441)Initiated at Ages 12–24 mo (n = 8390)
Unadjusted HR (95% CI)Adjusted HR (95% CI)Unadjusted HR (95% CI)Adjusted HR (95% CI)Unadjusted HR (95% CI)Adjusted HR (95% CI)
Male sex 1.08 (1.07–1.09) 1.08 (1.06–1.09) 1.08 (1.07–1.10) 1.08 (1.06–1.09) 1.08 (1.07–1.10) 1.08 (1.07–1.10) 
Preterm birth 0.97 (0.94–1.01) 0.99 (0.96–1.04) 0.98 (0.95–1.02) 1.03 (0.98–1.07) 0.98 (0.94–1.02) 1.02 (0.97–1.06) 
LBW 0.90 (0.86–0.94) 0.90 (0.85–0.95) 0.89 (0.85–0.94) 0.89 (0.84–0.94) 0.89 (0.85–0.94) 0.89 (0.84–0.94) 
Previous fracture 1.85 (1.74–1.96) 3.57 (3.20–3.98)a 1.85 (1.74–1.96) 3.52 (3.14–3.95)a 1.85 (1.74–1.97) 3.50 (3.13–3.93)a 
Overweight or obesity 1.12 (1.09–1.14) 0.99 (0.94–1.04)b 1.12 (1.09–1.15) 0.99 (0.94–1.05)b 1.12 (1.09–1.15) 0.99 (0.94–1.04)b 
Anti-epileptics 0.98 (0.92–1.04) 0.98 (0.92–1.05) 0.98 (0.92–1.05) 0.98 (0.92–1.05) 0.98 (0.92–1.05) 0.98 (0.92–1.05) 
PPI use 1.24 (1.14–1.34) 1.23 (1.14–1.33) 1.21 (1.05–1.40) 1.21 (1.05–1.39) 1.13 (0.98–1.30) 1.06 (0.91–1.24) 
H2RA use 1.12 (1.09–1.15) 1.04 (0.99–1.10)c 1.15 (1.08–1.22) 1.04 (0.92–1.17)c 1.10 (1.01–1.19) 0.91 (0.75–1.11) 
PPI and H2RA use 1.33 (1.27–1.39) 1.32 (1.26–1.38) 1.24 (1.08–1.42) 1.23 (1.07–1.41) 1.42 (1.20–1.68) 1.38 (1.16–1.65) 
Previous fracture and time — 0.9996 (0.9996–0.9997)a — 0.9996 (0.9996–0.9997)a — 0.9996 (0.9996–0.9997)a 
H2RA and time — 1.00004 (1.00002–1.00007)c — — — — 
Overweight or obesity and time — 1.00005 (1.00003–1.00007)b — 1.00005 (1.00003–1.00007)b — 1.00006 (1.00004–1.00008)b 

—, not applicable.

a

Interaction with time reveals that the impact of previous fracture decreases with time.

b

Interaction with time reveals that the impact of overweight or obesity on fracture increases slightly with time.

c

Interaction with time reveals that the impact of H2RA use on fracture increases slightly with time.

AST medication use during the first year of life was associated with increased fracture hazard in children. The greatest fracture hazard was associated with combination PPI and H2RA use during the first year of life. PPI use alone was associated with an increased fracture hazard, whereas H2RA use alone did not significantly impact fracture hazard. Fracture hazard increased with duration of AST use, which suggests a possible dose-dependent response, and with younger age of AST initiation with PPIs, alone or in combination with H2RAs.

These findings are consistent with adult studies linking AST with increased risk for osteoporotic fracture.31,32 Results are also consistent with research linking fracture with early PPI use in infants who were sick and healthy,22, and with findings that PPIs did not increase fracture risk in older children,21 because AST initiation after age 1 was not associated with fracture.

Similar to adult studies,33 fracture hazard increased with prescription duration. The median prescription length for combined therapy (192 days) was considerably longer than that for PPIs (60 days) or H2RAs (60 days; Table 3), possibly suggesting that the increased fracture hazard is related to duration of medication use, or perhaps an unidentified confounding disease, rather than a synergistic effect of combined AST.

Fracture hazard increased with younger age of initiation, with children starting at <6 months of age having greater fracture hazard than those starting at 12 to 24 months of age. Results are consistent with the limited previous studies that revealed an increased fracture rate in infants but not in older children.21 This may be due to rapid bone turnover that occurs in the first year of life,34 or this may be because infants who start earlier may continue AST treatment for longer periods of time. Although diagnostic codes indicating prescription rationale could not be linked, results may be related to different indications for medications in older versus younger children. Previous studies infer AST initiation at age ≤6 months is for treatment of symptoms of GER or GER disease,35 which is difficult to diagnose in infants, and that the majority of children outgrow symptoms by age 1.

The exact mechanism linking AST with bone health is unclear; however, biologically plausible hypotheses exist. It was previously postulated that PPIs could impair calcium absorption because of their effect on gastric acid secretion,36 leading to compensatory hyperparathyroidism and increased osteoclast activity.37 Adult studies, however, revealed no significant difference in bone density or blood calcium levels in patients on long-term PPI therapy versus none.38,39 Another theory is that PPIs change osteoclast activity and viability.40 Osteoclasts have a proton pump on their surface, which, if inhibited, could lead to osteoclast dysfunction and unopposed osteoblast activity resulting in a disorganized and potentially more fragile bone matrix.2 One study of pantoprazole on human osteoclasts in vitro revealed that exposed osteoclasts had significantly lower viability and activity, although no change was seen in osteoclast-specific gene expression.41 

The effect of H2RAs on bone development has been less studied compared with that of PPIs and is less strongly associated with fracture. Older adult users of H2RAs showed decreased bone mineral density on dual-energy radiograph absorptiometry scans, but this was seen only in those not taking calcium supplements.32 One adult study revealed no association between H2RAs and fracture,42 and another revealed reduced fractures in adults on combination H2RA and PPI therapy, compared with PPI use alone.43 The authors of these studies, however, explored the effect of AST on the adult bone, which may react differently to PPI and H2RA exposure than the rapidly growing and remodeling bone of young children.

Although an association between AST use in infancy and increased fracture risk was found, findings do not explore fracture patterns or mechanism of injury. Children with ICD-9-CM codes for child maltreatment were excluded; however, the incidence of recorded maltreatment in this study population was low, likely indicating that all children who were maltreated were not excluded. Only more severe maltreatment is regularly coded in the electronic health record. In addition, infant victims of maltreatment often present with symptoms that include fussiness and GER or vomiting, which could result in an AST prescription.44,45 

Study findings do not establish a causal relationship between PPI exposure and fracture. Practitioners should continue to take appropriate actions when they evaluate children with histories, injuries, or fracture patterns that cause concern for potential abuse, regardless of AST exposure.

This study is additionally limited by use of prescriptions as a proxy for taking medication; researchers were unable to assess if children consistently used the medication for the full prescription period and were unable to account for different dosing methods or prescribing patterns over time. In the study, we also excluded appointments for the same type of fracture within 6 months as follow-up appointments; this determination may have resulted in misclassification of some new cases of fracture as follow-up. Although factors most known to be associated with fracture in young children were accounted for, other potential confounders, including socioeconomic status, geographic region, breastfeeding status, use of other medications, or comorbid conditions besides those in this study’s exclusion criteria, were not captured or included. Finally, the use of such a large sample may have overpowered our analyses.

This study has multiple strengths, including a large population and the ablity to identify and exclude children with conditions that place them at highest risk for fractures. The MHS provides free health care and free or low-cost prescriptions, reducing access-to-care and ascertainment bias. Finally, in this study, we examined the impact of AST prescribed during infancy on fracture risk over a longer time period (compared with that in previously reported studies).

AST used in the first year of life, especially PPIs, are associated with increased fracture hazard in children. Results should not be interpreted to suggest that PPIs or H2RAs alone explain fractures, which is important in suspected cases of nonaccidental trauma. Results indicate longer AST use and earlier initiation may increase fracture hazard. Practitioners should be aware of the potential for fracture when considering treatment with AST versus lifestyle changes and watchful waiting. If AST use is necessary, providers should limit prescriptions to a single drug and limit their duration when possible.

Drs Malchodi and Wagner conceptualized and designed the study, drafted the initial manuscript, and reviewed and substantially revised the manuscript; Dr Hisle-Gorman conceptualized and designed the study, analyzed the data, drafted the initial manuscript, and reviewed and substantially revised the manuscript; Ms Susi was responsible for acquisition of data, data analysis, and interpretation of data and reviewed and substantially revised the manuscript; Dr Gorman was responsible for study design and analysis of data and reviewed and substantially revised the manuscript; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the Department of the Navy, Department of Defense, nor the US Government. Some authors are a military service member or a US Government employee. This work was prepared as part of their official duties. Title 17 US Code §105 provides that “copyright protection under this title is not available for any work of the United States Government.” Title 17 US Code §101 defines a United States Government work as a work prepared by a military service member or employee of the United States Government as part of that person’s official duties.

FUNDING: No external funding.

COMPANION PAPER: A companion to this article can be found online at www.pediatrics.org/cgi/doi/10.1542/peds.2019-0909.

     
  • AST

    acid suppression therapy

  •  
  • GER

    gastroesophageal reflux

  •  
  • H2RA

    histamine H2-receptor antagonist

  •  
  • HR

    hazard ratio

  •  
  • ICD-9-CM

    International Classification of Diseases, Ninth Revision, Clinical Modification

  •  
  • LBW

    low birth weight

  •  
  • MHS

    Military Healthcare System

  •  
  • PPI

    proton pump inhibitor

1
Illueca
M
,
Alemayehu
B
,
Shoetan
N
,
Yang
H
.
Proton pump inhibitor prescribing patterns in newborns and infants.
J Pediatr Pharmacol Ther
.
2014
;
19
(
4
):
283
287
[PubMed]
2
Uzoigwe
OF
.
Proton pump inhibitors and fracture: do they do what it says on the tin?
Osteoporos Int
.
2016
;
27
(
4
):
1671
1672
[PubMed]
3
Illueca
M
,
Alemayehu
B
,
Shoetan
N
,
Yang
H
.
Proton pump inhibitor prescribing patterns in newborns and infants
.
J Pediatr Pharmacol Ther
.
2014
;
19
(
4
):
283
287
[PubMed]
4
Barron
JJ
,
Tan
H
,
Spalding
J
,
Bakst
AW
,
Singer
J
.
Proton pump inhibitor utilization patterns in infants.
J Pediatr Gastroenterol Nutr
.
2007
;
45
(
4
):
421
427
5
Harris
BR
,
Bennett
WE
.
Infant reflux in the primary care setting: a brief educational intervention and management changes.
Clin Pediatr (Phila)
.
2018
;
57
(
8
):
920
926
[PubMed]
6
Fiedorek
S
,
Tolia
V
,
Gold
BD
, et al
.
Efficacy and safety of lansoprazole in adolescents with symptomatic erosive and non-erosive gastroesophageal reflux disease.
J Pediatr Gastroenterol Nutr
.
2005
;
40
(
3
):
319
327
[PubMed]
7
Orenstein
SR
,
Hassall
E
,
Furmaga-Jablonska
W
,
Atkinson
S
,
Raanan
M
.
Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease.
J Pediatr
.
2009
;
154
(
4
):
514
520.e4
[PubMed]
8
Moore
DJ
,
Tao
BS
,
Lines
DR
,
Hirte
C
,
Heddle
ML
,
Davidson
GP
.
Double-blind placebo-controlled trial of omeprazole in irritable infants with gastroesophageal reflux.
J Pediatr
.
2003
;
143
(
2
):
219
223
[PubMed]
9
Gunasekaran
TS
,
Hassall
EG
.
Efficacy and safety of omeprazole for severe gastroesophageal reflux in children.
J Pediatr
.
1993
;
123
(
1
):
148
154
[PubMed]
10
Waldum
HL
,
Brenna
E
,
Sandvik
AK
.
Long-term safety of proton pump inhibitors: risks of gastric neoplasia and infections.
Expert Opin Drug Saf
.
2002
;
1
(
1
):
29
38
[PubMed]
11
Tran-Duy
A
,
Spaetgens
B
,
Hoes
AW
,
de Wit
NJ
,
Stehouwer
CD
.
Use of proton pump inhibitors and risks of fundic gland polyps and gastric cancer: systematic review and meta-analysis.
Clin Gastroenterol Hepatol
.
2016
;
14
(
12
):
1706
1719.e5
[PubMed]
12
Xie
Y
,
Bowe
B
,
Li
T
,
Xian
H
,
Balasubramanian
S
,
Al-Aly
Z
.
Proton pump inhibitors and risk of incident CKD and progression to ESRD.
J Am Soc Nephrol
.
2016
;
27
(
10
):
3153
3163
[PubMed]
13
Costarino
AT
,
Dai
D
,
Feng
R
,
Feudtner
C
,
Guevara
JP
.
Gastric acid suppressant prophylaxis in pediatric intensive care: current practice as reflected in a large administrative database.
Pediatr Crit Care Med
.
2015
;
16
(
7
):
605
612
[PubMed]
14
Arj
A
,
Razavi Zade
M
,
Yavari
M
,
Akbari
H
,
Zamani
B
,
Asemi
Z
.
Proton pump inhibitors use and change in bone mineral density.
Int J Rheum Dis
.
2016
;
19
(
9
):
864
868
[PubMed]
15
Ozdil
K
,
Kahraman
R
,
Sahin
A
, et al
.
Bone density in proton pump inhibitors users: a prospective study [published correction appears in Rheumatol Int. 2016;36(10):1479].
Rheumatol Int
.
2013
;
33
(
9
):
2255
2260
[PubMed]
16
Yu
EW
,
Bauer
SR
,
Bain
PA
,
Bauer
DC
.
Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies.
Am J Med
.
2011
;
124
(
6
):
519
526
[PubMed]
17
Canani
RB
,
Cirillo
P
,
Roggero
P
, et al;
Working Group on Intestinal Infections of the Italian Society of Pediatric Gastroenterology, Hepatology and Nutrition (SIGENP)
.
Therapy with gastric acidity inhibitors increases the risk of acute gastroenteritis and community-acquired pneumonia in children.
Pediatrics
.
2006
;
117
(
5
). Available at: www.pediatrics.org/cgi/content/full/117/5/e817
[PubMed]
18
Nylund
CM
,
Eide
M
,
Gorman
GH
.
Association of Clostridium difficile infections with acid suppression medications in children.
J Pediatr
.
2014
;
165
(
5
):
979
984.e1
19
Golden
NH
,
Abrams
SA
;
Committee on Nutrition
.
Optimizing bone health in children and adolescents.
Pediatrics
.
2014
;
134
(
4
). Available at: www.pediatrics.org/cgi/content/full/134/4/e1229
[PubMed]
20
Kocsis
I
,
Arató
A
,
Bodánszky
H
, et al
.
Short-term omeprazole treatment does not influence biochemical parameters of bone turnover in children.
Calcif Tissue Int
.
2002
;
71
(
2
):
129
132
[PubMed]
21
Freedberg
DE
,
Haynes
K
,
Denburg
MR
, et al
.
Use of proton pump inhibitors is associated with fractures in young adults: a population-based study.
Osteoporos Int
.
2015
;
26
(
10
):
2501
2507
[PubMed]
22
Wagner
K
,
Wagner
S
,
Susi
A
,
Gorman
G
,
Hisle-Gorman
E
.
Prematurity does not increase early childhood fracture risk.
J Pediatr
.
2019
:
207
:
148
153
[PubMed]
23
Faden
HS
,
Ma
CX
.
Trends in oral antibiotic, proton pump inhibitor, and histamine 2 receptor blocker prescription patterns for children compared with adults: implications for clostridium difficile infection in the community.
Clin Pediatr (Phila)
.
2016
;
55
(
8
):
712
716
[PubMed]
24
Rouillard
S
,
Lane
NE
.
Hepatic osteodystrophy.
Hepatology
.
2001
;
33
(
1
):
301
307
[PubMed]
25
Gniatkowska-Nowakowska
A
.
Fractures in epilepsy children.
Seizure
.
2010
;
19
(
6
):
324
325
[PubMed]
26
Petty
SJ
,
Wilding
H
,
Wark
JD
.
Osteoporosis associated with epilepsy and the use of anti-epileptics-a review.
Curr Osteoporos Rep
.
2016
;
14
(
2
):
54
65
[PubMed]
27
Healthcare Cost and Utilization Project Clinical Classifications Software
. Clinical Classifications Software (CCS) for ICD-9-CM. 2010. Available at: https://www.hcup-us.ahrq.gov/toolssoftware/ccs/ccs.jsp. Accessed December 12, 2018
28
Goulding
A
.
Risk factors for fractures in normally active children and adolescents.
Med Sport Sci
.
2007
;
51
:
102
120
[PubMed]
29
Goulding
A
,
Jones
IE
,
Taylor
RW
,
Williams
SM
,
Manning
PJ
.
Bone mineral density and body composition in boys with distal forearm fractures: a dual-energy x-ray absorptiometry study.
J Pediatr
.
2001
;
139
(
4
):
509
515
[PubMed]
30
Kelley
JC
,
Crabtree
N
,
Zemel
BS
.
Bone density in the obese child: clinical considerations and diagnostic challenges.
Calcif Tissue Int
.
2017
;
100
(
5
):
514
527
[PubMed]
31
Yanagihara
GR
,
de Paiva
AG
,
Neto
MP
, et al
.
Effects of long-term administration of omeprazole on bone mineral density and the mechanical properties of the bone.
Rev Bras Ortop
.
2015
;
50
(
2
):
232
238
[PubMed]
32
Kinjo
M
,
Setoguchi
S
,
Solomon
DH
.
Antihistamine therapy and bone mineral density: analysis in a population-based US sample.
Am J Med
.
2008
;
121
(
12
):
1085
1091
[PubMed]
33
Laine
L
.
Proton pump inhibitors and bone fractures?
Am J Gastroenterol
.
2009
;
104
(
suppl 2
):
S21
S26
[PubMed]
34
Hlaing
TT
,
Compston
JE
.
Biochemical markers of bone turnover - uses and limitations.
Ann Clin Biochem
.
2014
;
51
(
pt 2
):
189
202
[PubMed]
35
Barron
JJ
,
Tan
H
,
Spalding
J
,
Bakst
AW
,
Singer
J
.
Proton pump inhibitor utilization patterns in infants.
J Pediatr Gastroenterol Nutr
.
2007
;
45
(
4
):
421
427
36
Metz
DC
.
Examining the potential relationship between proton pump inhibitor use and the risk of bone fracture.
Gastroenterol Hepatol (N Y)
.
2011
;
7
(
12
):
831
833
[PubMed]
37
Safe
M
,
Chan
WH
,
Leach
ST
,
Sutton
L
,
Lui
K
,
Krishnan
U
.
Widespread use of gastric acid inhibitors in infants: are they needed? Are they safe?
World J Gastrointest Pharmacol Ther
.
2016
;
7
(
4
):
531
539
[PubMed]
38
Targownik
LE
,
Lix
LM
,
Leung
S
,
Leslie
WD
.
Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss.
Gastroenterology
.
2010
;
138
(
3
):
896
904
[PubMed]
39
Yang
YX
.
Chronic proton pump inihibitor therapy and calcium metabolism.
Curr Gastroenterol Rep
.
2012
;
14
(
6
):
473
479
[PubMed]
40
Rzeszutek
K
,
Sarraf
F
,
Davies
JE
.
Proton pump inhibitors control osteoclastic resorption of calcium phosphate implants and stimulate increased local reparative bone growth.
J Craniofac Surg
.
2003
;
14
(
3
):
301
307
[PubMed]
41
Prause
M
,
Seeliger
C
,
Unger
M
,
Rosado Balmayor
E
,
van Griensven
M
,
Haug
AT
.
Pantoprazole decreases cell viability and function of human osteoclasts in vitro.
Mediators Inflamm
.
2015
;
2015
:
413097
[PubMed]
42
Kwok
CS
,
Yeong
JK
,
Loke
YK
.
Meta-analysis: risk of fractures with acid-suppressing medication.
Bone
.
2011
;
48
(
4
):
768
776
[PubMed]
43
Abrahamsen
B
,
Vestergaard
P
.
Proton pump inhibitor use and fracture risk - effect modification by histamine H1 receptor blockade. Observational case-control study using national prescription data.
Bone
.
2013
;
57
(
1
):
269
271
[PubMed]
44
Kondis
JS
,
Muenzer
J
,
Luhmann
JD
.
Missed fractures in infants presenting to the emergency department with fussiness.
Pediatr Emerg Care
.
2017
;
33
(
8
):
538
543
[PubMed]
45
Orenstein
SR
.
Crying in infant GERD: acid or volume? Heartburn or dyspepsia?
Curr Gastroenterol Rep
.
2008
;
10
(
5
):
433
436
[PubMed]

Competing Interests

POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.

FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.

Supplementary data