Proton Pump Inhibitors and Histamine-2 Receptor Antagonists are Associated with Hip Fractures among At-Risk Patients

Abstract

BACKGROUND & AIMS

Drugs that inhibit gastric acid might increase the risk of hip fracture. However, little long-term exposure data exist and no large studies have been conducted in the United States.

METHODS

We conducted a case-control study using data from an integrated health services organization. We evaluated 33,752 patients with incident diagnoses of hip/femur fractures (cases), 130,471 matched members without fractures (controls), prescription data for use of proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) (up to 10 years cumulative duration), and confounders.

RESULTS

Patients with hip fractures were more likely than controls to have previously received ≥2 years supply of PPIs (odds ratio [OR]=1.30, 95% confidence interval [CI]=1.21–1.39) or H2RAs (OR=1.18, 95% CI=1.08–1.29). The risk was reduced after medication discontinuation (OR=1.30, 95% CI 1.21–1.41 for current PPI users vs. OR=1.09, 95% CI 0.64–1.85 for patients who received their last prescription was 3–5 years ago). Higher dosages (but not increasing cumulative durations) were associated with increased risk (e.g. ≥1.5 pills/day OR=1.41, 95% CI 1.21–1.64; <0.74 pills/day OR=1.12, 95% CI 0.94–1.33). Excess fracture risk for PPI use was only present among persons with at least one other fracture risk factor.

CONCLUSION

Use of drugs that inhibit gastric acid is associated with an increased risk of hip fracture; however, this association was only found among persons with at least one other risk factor for hip fracture. Acid inhibition might therefore be associated with fracture risk in persons already at risk for osteoporosis, although other confounding cannot be excluded.

Hip fractures are a major cause of morbidity and mortality; over 329,000 persons are hospitalized annually with hip fractures in the United States.¹ The resultant disease burden is substantial, with a frequent need for invasive interventions (e.g. over 234,000 hip replacement surgeries in 2004 alone), prolonged rehabilitation, and a mortality rate of 5–10% within the first month.² Thus, identifying modifiable risk factors for hip fractures would be of substantial benefit to the public health.³

Acid inhibitors, which are among the most commonly used pharmaceuticals in the United States, may theoretically increase or decrease the risk of hip fractures.⁴ Proton pump inhibitors (PPIs) and histamine-2 receptor antagonists (H2RAs) could diminish bone density by decreasing calcium absorption⁵ or by inducing hyperparathyroidism through hypergastrinemia.^{6, 7} Alternatively, acid inhibitors may modify acid-related enzymes in bones that regulate bone remodeling, which could decrease (or increase) fracture risk.^{4, 8, 9}

Few human studies of the association between acid inhibition and hip fractures exist, the results are discordant (even between three studies within the same European data set)^10–12 and no large or long-term studies have been published from the United States. In addition, in prior studies, increased fracture risk was also associated with medications not clearly associated with osteoporosis, such as anti-cholesterol medications, aspirin, or nonsteroidal anti-inflammatory drugs (NSAIDS), raising the possibility of confounding.^{10, 13}

Thus, we performed a nested case-control study of the association between prescriptions for acid-suppressing medications (for up to 10 years) and the risk of hip fracture within a large, community-based population. We also evaluated whether fracture risk was generally associated with other commonly used medications, which would suggest confounding.

METHODS

Study Population

We conducted a case-control study among the approximately 3.3 million members of the Kaiser Permanente, Northern California (KPNC) integrated health care delivery system which provides comprehensive inpatient and outpatient services. The KPNC membership demographics closely approximate the region’s underlying census demographics. ¹⁴ Prescription drug benefits are utilized by >90% of members; pharmacy databases electronically record all dispensed prescriptions (including amount, directions for use, calculated days supply, and refills); their performance is validated for both as needed and daily medications.^{15, 16} Additional databases include information on membership, medical diagnoses assigned by the provider for each outpatient visit, hospitalization diagnoses, and procedures performed. Outpatient diagnoses are assigned by clinicians and are not linked with provider compensation. The analyses were approved by the institutional review board.

Case Definition

Cases were KPNC members who met the following criteria: an incident diagnosis of a hip fracture between January, 1995 and September, 2007, using International Classification of Disease, 9^th revision (ICD-9) codes 820.0 -821.20 (hip or femur fractures, excluding lower femoral condyle); at least 18 years of age at the index date; no prior hip/femur fracture diagnosis; and at least two years of membership prior to the index date. The index date was the fracture date. We evaluated the validity of electronic coding for hip fracture using a manual record review of 60 randomly selected patients from 1998–2007; we identified data supporting a fracture diagnosis in 90% of patients, indicating a high level of coding validity.

Control Definition

For each case, up to four matched controls (if available) were randomly selected from the KPNC membership using incidence density sampling. With this method, each control was chosen from among all eligible adult members who lacked a diagnosis of a hip fracture at the index date of the matched case and who had at least two years of membership prior to the index date.¹⁷

Controls were matched by sex, year of birth (3-year age groups), duration of membership (rounded to year), first year of membership, and race/ethnicity.

Exposure Status

Medication exposures used KPNC prescription pharmacy databases. All prescriptions were for prior to the index date and definitions were created a priori (i.e. prior to the analyses). The databases contain detailed information on dispensed medications since approximately January, 1994, the frequency of refills, and directions for use. The primary exposure for the analysis was the cumulative dose, defined as “days supply.” The “days supply” variable used the number of pills dispensed and their directions for use; e.g. 60 pills dispensed, with instructions to take one pill twice a day, equaled a 30 days supply. The “exposure duration” was the interval between the first and last prescriptions plus the number of days supplied for the last prescription. For subjects with a single prescription, the duration equaled the days supplied. We evaluated compliance and dose intensity using the “average daily dose” (dispensed pills divided by exposure duration) and three dose categories: occasional use (<0.75 pills per day); approximate daily use (0.75–1.49 pills per day) and twice a day use (≥1.5 pills per day).

For the proton pump inhibitors (PPIs), exposed subjects had all exposure PPI prescriptions dispensed prior to their index date; unexposed (reference) subjects had prescriptions for neither PPIs nor H2RAs.

For the H2RA analyses, exposed subjects had all exposure H2RA prescriptions dispensed prior to their index date; unexposed (reference) subjects had prescriptions for neither PPIs nor H2RAs. We excluded from all H2RA exposure categories subjects with PPI prescriptions.

Confounding and Effect Modification

In addition to the matched factors, we evaluated the following as potential confounders (using ICD coding): arthritis, cerebrovascular disease, hemiplegia, asthma, dementia, psychoses, diabetes mellitus, thyroid disease, ischemic heart disease, epilepsy, gait disorder, peptic ulcer disease, gastroesophageal reflux disease, visual impairment, and chronic kidney disease. We evaluated smoking (prior or current) and alcohol abuse/counseling using ICD codes and internal KPNC codes for substance use or treatment.

Persons with multiple health problems or healthcare seeking behavior may be more likely to receive common diagnoses (such as reflux) and to receive treatment for acid-related conditions (such as with a PPI). Thus, we also evaluated as potential confounders other diagnoses which indicate use of the health system including: essential hypertension and colon polyp (both diagnoses require screening tests); headaches; and diverticulosis (without diverticulitis).

We evaluated whether expected associations were present for other medications known to modify fracture risk (e.g. glucocorticoids, estrogen, thiazide diuretics, thyroid supplementation, bisphosphonates, and anxiolytics) and medications not known to be associated with fracture risk (e.g. angiotensin converting enzymes, calcium channel blockers, nonnarcotic analgesics).¹⁸ For glucocorticoids or bisphosphonates, which can modify fracture risk with few doses, subjects were “exposed” if they received ≥1 prescriptions. For other medications, patients were “exposed” if they received ≥365 days supply, unexposed if they received no prescriptions, and not included in these analyses if they had intermediate values.

Finally, we evaluated common indications for anti-secretory therapy (i.e. gastroesophageal reflux disease).

Statistical Analysis

Primary Analysis

The study utilized standard analytic techniques for evaluating case-control studies and conditional logistic regression.^{17, 19–21} All definitions and modeling strategies were planned a priori (i.e. prior to analysis). We evaluated confounding by contrasting odds ratios between models with and without potential confounders; using a priori criteria, the final model included factors which altered the odds ratio by approximately ≥10%.¹⁷ Of all the risk factors and medications, only smoking met these criteria; thus, the final model included the outcome, the exposure, and smoking. The “saturated” model contained all variables listed in the confounding section. Effect modification (e.g. differences in PPI effect across age strata) was evaluated using cross product terms in the logistic regression model and by evaluating stratum specific ratios.²¹ Comparable results were found for both conditional and unconditional logistic regression models; all main results used the conditional regression models. The attributable fraction calculations utilized maximum likelihood estimates from the unconditional logistic regression models.²²

RESULTS

We identified 33,864 members with a hip fracture diagnosis between 1995 and September, 2007. Of these, we excluded 112 cases (mainly elderly members) who lacked controls that fulfilled all the matching criteria, leaving 33,752 cases and 130,471 controls for the main analyses. The cases were predominantly women (65.7%), persons ≥70 years of age (69.4%), and non-Hispanic whites (79.6%) (Table 1). Of the cases, 20,498 (60.7%) had not received any prescriptions for PPIs or H2RAs. Among PPI users, 1558 (4.6%) were dispensed ≥2 years supply. Among H2RA users (without any PPI use), 875 (2.6%) were dispensed ≥2 years supply.

Table 1.

Demographic characteristics. Cases and controls were matched for sex, age, duration of membership, first year of membership, and race/ethnicity.

	Controls # (%)	Cases # (%)
Total Subjects	130,471	33,752
Gender
Female	84,550 (64.8)	22,183 (65.7)
Age at index date (years)
18–29	5230 (4.0)	1302 (3.9)
30–39	4369 (3.4)	1075 (3.2)
40–49	6109 (4.7)	1531 (4.5)
50–59	9880 (7.6)	2,452 (7.3)
60–69	16,026 (12.3)	3,963 (11.7)
70–79	35,316 (27.1)	8,890 (26.3)
80–89	43,322 (33.2)	11,332 (33.6)
>89	10,219 (7.8)	3207 (9.5)
Smoking1	29,473 (22.6)	9940 (29.5)
Alcohol abuse	4883 (3.7)	2261 (6.7)
Diabetes	19,607 (15.0)	6102 (18.1)
Arthritis	44,104 (33.8)	13,462 (39.9)
Kidney disease	2966 (2.3)	1399 (4.1)
Ethnicity
Non-Hispanic White	103,962 (79.7)	26,879 (79.6)
Hispanic White	8395 (6.4)	2183 (6.5)
Black	5952 (4.6)	1526 (4.5)
Asian/Pacific Islander	5522 (4.2)	1424 (4.2)
Other	3902 (3.0)	1051 (3.1)
Unknown	2738 (2.1)	689 (2.0)
Medication Days Supply
PPI use2
None	84,913 (65.1)	20,498 (60.7)
≥2 years	4806 (3.7)	1558 (4.6)
H2RA use2
None	84,913 (65.1)	20,498 (60.7)
≥2 years	3061 (2.4)	875 (2.6)

¹Prior or current smoking diagnosis

²“None” designates members with no PPI or H2RA use. Among users of acid suppression, H2RA users had no PPI use; PPI users could use H2RAs.

Analyses

Antisecretory Medication and Fracture Risk

We defined long-term users as those with ≥2 years supply of medication. The risk of fracture was 30% higher among persons with ≥2 years supply of PPI, compared with nonusers (OR=1.30, 95% CI 1.21–1.39). Fracture risk was also higher among persons with ≥2 years H2RA use (OR=1.18, 95% CI 1.08–1.29).

Dose Intensity and Fracture Risk

There was a general trend for increased fracture risk among subjects taking higher average daily doses (Tables 2 & 3). The fracture risk was not significantly elevated among persons who used <0.75 PPI pills/day for ≥2 years, compared with nonusers (OR=1.12, 95% CI 0.94–1.33). In contrast, risk was increased among persons taking 0.75–1.49 pills/day (OR=1.30, 95% CI 1.19–1.42) and ≥1.5 pills/day (OR=1.41, 95% CI 1.21–1.64; vs. nonusers).

TABLE 2.

Proton pump inhibitors and the risk of hip fracture, by increasing daily dose and cumulative duration of use

	Cumulative Duration (years)
	No use	<1	1–1.9	2–3.9	4–5.9	6–7.9	8–9.9	≥10
Pills per day		Adjusted Odds Ratios and 95% Confidence Intervals1
0.01–0.74	Reference2	1.08 (0.90–1.29)	1.21 (1.03–1.41)	1.23 (1.08–1.39)	1.10 (0.95–1.28)	1.35 (1.13–1.62)	0.99 (0.75–1.32)	2.07 (1.30–3.28)
0.75–1.49	Reference	1.30 (1.22–1.39)	1.36 (1.20–1.53)	1.43 (1.28–1.60)	1.18 (1.03–1.36)	1.18 (0.99–1.41)	1.36 (1.05–1.75)	1.64 (1.07–2.52)
>=1.5	Reference	1.21 (1.13–1.29)	1.51 (1.24–1.85)	1.23 (1.01–1.51)	1.59 (1.21–2.10)	1.59 (1.08–2.32)	2.39 (1.40–4.08)	1.39 (0.61–3.16)
All doses	Reference	1.25 (1.19–1.31)	1.31 (1.20–1.42)	1.34 (1.24–1.44)	1.21 (1.10–1.33)	1.33 (1.19–1.49)	1.33 (1.12–1.57)	1.85 (1.41–2.43)
Total numbers of cases and controls by duration category3
Cases	20,498	3359	863	1114	696	465	212	86
Controls	84,913	10,868	2591	3484	2317	1423	658	216

¹Cases and controls were individually matched for sex, age, duration of membership, first year of membership, and race/ethnicity; models were adjusted for a smoking diagnosis.

²Reference group for all comparisons consists of members with no PPI or H2RA use. Members in PPI user categories could also use H2RAs.

³Number of subjects for each cumulative duration category.

TABLE 3.

Histamine-2 receptor antagonists and the risk of hip fracture, by increasing daily dose and cumulative duration of use

	Cumulative Duration (years)
	No use	<1	1–1.9	2–3.9	4–5.9	6–7.9	8–9.9	10
Pills per day		Adjusted Odds Ratios and 95% Confidence Intervals1
0.01–0.74	Reference2	1.17 (1.02–1.35)	1.09 (0.98–1.21)	1.12 (1.02–1.22)	1.03 (0.93–1.14)	1.06 (0.94–1.19)	1.32 (1.14–1.53)	1.29 (1.02–1.62)
0.75–1.49	Reference	1.18 (1.10–1.27)	1.19 (1.06–1.34)	1.14 (1.03–1.27)	1.21 (1.05–1.39)	1.23 (1.04–1.47)	0.95 (0.76–1.19)	1.20 (0.89–1.62)
≥1.5	Reference	1.14 (1.09–1.19)	1.27 (1.12–1.45)	1.34 (1.18–1.51)	1.15 (0.97–1.36)	1.25 (1.01–1.55)	1.10 (0.83–1.46)	1.53 (1.09–2.14)
All doses	Reference	1.11 (1.06–1.15)	1.14 (1.04–1.24)	1.15 (1.06–1.24)	1.10 (0.99–1.22)	1.02 (0.89–1.18)	1.03 (0.86–1.24)	1.31 (1.03–1.66)
Total numbers of cases and controls by duration category3
Cases	20,498	3695	761	924	517	286	169	107
Controls	84,913	13,720	2747	3352	1913	1221	715	333

¹Cases and controls were individually matched for sex, age, duration of membership, first year of membership, and race/ethnicity; models were adjusted for a smoking diagnosis.

²Reference group for all comparisons consists of members with no PPI or H2RA use. PPI user categories could also use H2RAs.

³Number of subjects for each cumulative duration category.

Dose Duration and Fracture Risk

Fracture risk did not substantially increase with longer durations of use (Tables 2 & 3). Although there was a statistically significant increase in risk with longer durations (p-value trend <0.01 for both PPI duration and H2 duration), this was mainly due to the increase between nonusers and any use.

Fracture Risk After Discontinuation

The strength of the association between PPI use and hip fracture was strongest among current users and diminished after discontinuation of PPI use (Table 4). Among current users (≥2 years supply of PPI prior to the index date and at least one PPI prescription in the year prior to the index date), the fracture risk associated with PPI use was OR=1.30 (95% CI 1.21–1.41). The risk trended lower for persons whose most recent prescription was 1–1.9 years prior to the index date 1.24 (0.90 – 1.72) and 2–2.9 years prior to the index date (1.09 (0.64 – 1.85).

Table 4.

Association between ≥2 years supply of proton pump inhibitors and the risk of hip fracture, stratified by time since most recent prescription.

	User Status	Interval Since Last Prescription1	Cases	Controls	Adjusted Odds Ratios 95% Confidence Intervals2
No Use			84,913	20,498	Reference
≥2 years supply	All Users	All Persons with ≥2 years supply	1558	4806	1.30 (1.21 – 1.39)
Current vs. Former Users3	Current User	Prescription in last year	1288	3958	1.30 (1.21 – 1.41)
	Recent User	Last Prescription 1–1.9 years prior	73	220	1.24 (0.90 – 1.72)
	Former User	Last Prescription 2–2.9 years prior	23	84	1.09 (0.64 – 1.85)
	Former User	Last Prescription 3–5.9 years prior	15	87	0.69 (0.37 – 1.28)

¹Time between index date and last PPI prescription among persons with ≥2 years supply of proton pump inhibitors prior to their index date. A current user, for example, would have received at least one prescription in the year prior to hip fracture (or the comparable index date for controls)

²Cases and controls were individually matched for sex, age, duration of membership, first year of membership, and race/ethnicity; models were adjusted for a smoking diagnosis.

³Among subjects with ≥2 years supply

Attributable Fraction and Population Incidence

Approximately 1.78% (95% CI 1.39–2.17) of fractures in the population were theoretically independently attributable to ≥1 year of PPI use, if we assume the association was causal.

We calculated the crude fracture incidence rates for two groups matched by birth year, sex, health plan enrollment date and KPNC membership duration. For persons not exposed to proton pump inhibitors, the incidence of hip fractures was 2.14 per 1000 person years. For persons with at least a 365 day supply of proton pump inhibitors, the fracture incidence after this exposure period was 3.24 per 1000 person years. These estimates are within the range of prior population-based reports of fracture incidence.^{10, 23, 24}

Presence of Other Risk Factors for Hip Fracture

The association between ≥2 years PPI use and hip fracture was only present among subjects with at least one other risk factor for hip fracture (≥1 risk factor present OR=1.25, 95% CI 1.16–1.35; no risk factors present OR=0.66, 95% CI 0.38–1.12; p-value interaction=0.02; individual risk factors listed in Table 5 and methods section). At least one risk factor was present among 73% of persons ≥50 years of age and 36% of persons <50 years of age. Most of the 6364 members with ≥2 years of PPI use had at least one risk other risk factor for hip fracture (6006 subjects, 94.4%); in contrast, relatively few of the 112,437 subjects with ≥1 risk factor had ≥2 years of PPI use (6006 subjects, 5.3%).

Table 5.

≥2 years of proton pump inhibitor use and the risk of hip fracture, stratified by presence or absence of other specific risk factors for hip fracture.

Risk Factor	Risk Factor Absent	Risk Factor Present
	Odds Ratios (95% Confidence Intervals1)	Odds Ratios (95% Confidence Intervals1)
Fracture Risk Increased Among PPI users with Risk Factor
Alcohol abuse	1.29 (1.20 –1.39)	1.45 (0.71 – 2.96)
Arthritis	1.26 (1.10 – 1.45)	1.37 (1.22 – 1.54)
Diabetes	1.22 (1.12 – 1.33)	1.43 (1.12 – 1.82)
Kidney Disease	1.26 (1.17 – 1.36)	2.02 (0.80 – 5.06)
Glucocorticoids	1.11 (1.00 – 1.24)	1.51 (1.28 – 1.78)
Fracture Risk Similar or Lower Among PPI users with Risk Factor
Cerebrovascular Disease	1.32 (1.20 – 1.44)	1.06 (0.85 – 1.33)
Dementia	1.36 (1.26 – 1.48)	0.81 (0.58 – 1.14)
Epilepsy	1.30 (1.21 – 1.40)	Not Available2
Gait Disorder	1.18 (1.08 – 1.30)	0.90 (0.32 – 2.49)
Hemiplegia	1.30 (1.21 – 1.40)	1.04 (0.33 – 3.27)
Psychoses	1.30 (1.18 – 1.42)	1.06 (0.86 – 1.31)
Smoking	1.32 (1.19 – 1.47)	1.16 (1.00 – 1.35)
Visual Impairment	1.29 (1.20 – 1.39)	Not Available2
Anxiolytics	1.29 (1.14 – 1.44)	0.79 (0.39 – 1.60)
≥1 Risk Factor3	0.66 (0.38–1.12)	1.25 (1.16–1.35)

^*P-value interaction=0.02

¹Odds ratios contrast risk of hip fracture among persons with ≥2 years of PPI use vs. reference group. Reference group for all comparisons consists of members with no PPI or H2RA use. For example, for the diabetes strata, the odds ratio evaluates the association between PPI use and fracture risk among persons with a diabetes diagnosis (risk factor present) and the same association among persons without a diabetes diagnosis (risk factor absent). The fracture risk associated with PPI use was 21% greater among diabetics than among non-diabetics.

²Not available; too few matched cells available for calculation

³P-value interaction=0.02

We provide the fracture risk for ≥2 years of PPI use vs. nonusers for each risk factor, although the study is underpowered to evaluate each risk factor individually (Table 5). The risk associated with PPI use trended higher among persons with alcohol abuse, arthritis, diabetes, kidney disease, and glucocorticoid use than among persons without these risk factors (Table 6). The trends for increased risk were most notable for fracture risk factors associated with decreased bone density (e.g. diabetes,³ renal insufficiency,²⁵ and glucocorticoid use).

Table 6.

Diagnoses, other medication use, and fracture risk

	# Controls (%)	# Cases (%)	Odds Ratios (95% Confidence Intervals1)
Diagnoses2
Alcohol abuse	4883 (3.7)	2261 (6.7)	1.70 (95% CI 1.48–1.96)
Arthritis	44104 (33.8)	13462 (39.9)	1.49 (95% CI 1.38–1.60)
Cerebrovascular Disease	18643 (14.3)	6579 (19.5)	1.26 (95% CI 1.12–1.41)
Dementia	10431 (8.0)	4780 (14.2)	1.58 (95% CI 1.35–1.85)
Diabetes	19607 (15.0)	6102 (18.1)	1.18 (95% CI 1.03–1.34)
Epilepsy	375 (0.3)	169 (0.5)	2.03 (95% CI 1.45–2.84)
Gait Disorder	3210 (2.5)	1421 (4.2)	1.32 (95% CI 1.02–1.71)
Hemiplegia	3264 (2.5)	1372 (4.1)	1.63 (95% CI 1.29–2.06)
Kidney Disease	2966 (2.3)	1399 (4.1)	1.41 (95% CI 1.04–1.92)
Psychoses	18381 (14.1)	7969 (23.6)	1.42 (95% CI 1.25–1.61)
Smoking	29444 (22.6)	9936 (29.4)	1.45 (95% CI 1.34–1.56)
Visual Impairment	1990 (1.5)	730 (2.2)	1.51 (95% CI 1.15–1.98)
Medications3
Angiotensin converting enzyme inhibitors	25223 (19.3)	7132 (21.1)	1.05 (95% CI 0.94–1.16)
Anxiolytics	5234 (4.0)	1997 (5.9)	1.22 (95% CI 1.02–1.45)
Bisphosphonates3,4	10910 (8.4)	4277 (12.7)	1.46 (95% CI 1.27–1.68)
Calcium channel blockers	19672 (15.1)	5561 (16.5)	1.04 (95% CI 0.93–1.17)
Estrogen	20602 (15.8)	4613 (13.7)	0.68 (95% CI 0.61–0.76)
Glucocorticoids3	29144 (22.3)	8800 (26.1)	1.16 (95% CI 1.06–1.27)
Nonnarcotic analgesics	2390 (1.8)	853 (2.5)	1.22 (95% CI 0.95–1.57)
Thiazide diuretics	17478 (13.4)	4251 (12.6)	0.97 (95% CI 0.86–1.09)
Thyroid supplementation	16775 (12.9)	4557 (13.5)	1.11 (95% CI 0.94–1.31)

¹Odds ratios from saturated model, adjusted for use of other medications and risk factors (see methods section for details)

²Listed diagnoses are those associated with increased risk in the saturated regression model (see methods section for details). All listed diagnoses were included as risk factors in analyses of other risk factors for hip fracture.

³Medications are ≥1 year supply except for glucocorticoids and bisphosphonates, which are for any use (see methods). Glucocorticoids and anxiolytics were included as risk factors in analyses of other risk factors for hip fracture.

⁴Expected direction is increased risk since bisphosphonates are prescribed for persons with an increased fracture risk

Age, Sex, and Indication for Anti-Secretory Treatment

The association between ≥2 years of PPI use and fracture risk differed by age (p-value interaction term<0.01). Risk was significantly increased for all decades between ages 40–89; however, an association was still only present for persons with other fracture risk factors and the excess risk associated with PPI use trended stronger for younger age groups (e.g. for ages ≥50 years, ≥1 risk factor present OR=1.25, 95% CI 1.16–1.35; risk factors absent OR=0.75, 95% CI 0.43–1.31; for persons <50 years with ≥1 risk factor, OR=1.71, 95% CI 1.00–2.93).

The association between ≥2 years of PPI use and hip fracture was comparable between men (OR=1.34, 95% CI 1.18–1.51) and women (OR=1.28, 95% CI 1.17–1.39; p-value interaction=0.55). There was no significant interaction by race/ethnicity (p-value=0.38).

The association between ≥2 years PPI use and hip fracture was somewhat greater among the 103,123 persons without a GERD diagnosis (OR=1.66, 95% CI 1.41–1.96) than among the 8652 persons with a GERD diagnosis (OR=1.38, 95% CI 1.05–1.82; p-value interaction term <0.01). For ≥2 years H2RA use, an increased risk was found among patients without GERD (OR=1.22, 95% CI 1.08–1.38) but not for persons with GERD (OR=0.89, 95% CI 0.55–1.44).

Other Medications and Risk of Hip Fracture

The associations between other medication classes and the risk of hip fracture were generally in accordance with expected values (Table 6). For medications not known to be mechanistically linked with fracture risk (angiotensin converting enzyme inhibitors, calcium channel blockers, nonnarcotic analgesics), we found no significant associations. For medications/conditions with known associations (anxiolytics, bisphosphonates, estrogen, glucocorticoids, thiazide diuretics, thyroid supplementation),²⁶ associations were in the expected direction, although not all were statistically significant.

Confounding

The magnitude of the associations between ≥2 years of PPI use (vs. no use) and fracture risk were comparable between a saturated model containing all the listed risk factors and medications (OR=1.22, 95% CI 0.96–1.54), a simple bivariate model with only PPI use and case status (OR=1.36, 95% CI 1.27–1.46) and the final model with PPI use, case status, and smoking (OR=1.30, 95% CI 1.21–1.39). Similar findings were present for ≥1 year of use (final model with only smoking, OR=1.34, 95% CI 1.27–1.42). We did not include serum vitamin D levels or prescriptions for vitamin D as potential confounders since levels are often obtained after a diagnosis of osteoporosis has been made; however, inclusion of these variables also did not change the estimates (data not shown).

DISCUSSION

The usage of acid suppressing medications (H2 antagonists or proton pump inhibitors) was associated with an increased risk of hip fracture in a large, general population, the risk was higher among subjects taking the more potent proton pump inhibitors (compared with H2RAs), decreased after medication discontinuation, and it rose with increasing dose but not necessarily with longer durations. The increased risk was confined to persons with certain other risk factors for hip fracture.

These findings extend those of prior studies that evaluated acid inhibition and fracture risk, most of which found some association. A case-control study in the United Kingdom General Practice Database found an increased fracture risk among persons taking acid inhibitors (for both PPIs and H2RAs) for over a year, even after adjustment for multiple confounders and increased risk with a longer duration of use.¹⁰ A Canadian study, in contrast, found no increased risk for up to six years of use, but an association for over six years of use.¹³ However, both studies also found increased risk for other drugs not clearly associated with fracture risk, such as aspirin, nonsteroidal anti-inflammatory drugs and antidepressants, raising concerns about confounding. In addition, another study in the same United Kingdom database, restricted to persons without risk factors for hip fracture, found no association between PPIs and fracture risk (relative risk 0.9; 95% CI 0.7–1.1) and no escalations of risk with increased PPI use.¹¹ The authors suggested the differences between the studies may have been from “residual confounding or effect modification” in the former study. A Danish study found a small increase in fracture risk associated with proton pump inhibitor use in the year prior to fracture, but, paradoxically, a significantly decreased risk among H-2 antagonist users.²⁷

There are several mechanisms through which acid inhibition could theoretically alter fracture risk.²⁸ First, acid inhibition may directly impair calcium absorption, with a resultant decrease in bone density and increase in fracture risk.⁵ A randomized trial in 18 subjects indicated that omeprazole decreased the absorption of radiolabelled calcium pills by 61% compared with placebo.⁵ Other studies of acid secretion, dietary calcium, and calcium supplements have disparate results.^29–33 Second, acid inhibition may induce hyperparathyroidism, which directly decreases bone mineral density, through hypergastrinemia, although this is controversial. ^{6, 7} For either of these mechanisms, it is unclear whether brief periods of acid inhibition can change calcium balance sufficiently to increase the risk of fracture. A third potential mechanism is through an alteration of bone remodeling.^{8, 9} Proton pumps locally acidify bone at the level of the osteoclast; ³⁴ this local acidification is used in bone remodeling. Bone strength is influenced by a careful balance between bone formation and bone resorption. If proton pump inhibitors modify this acidity, fracture risk could change in unpredictable ways: fracture risk could decrease (by decreasing resorption) or increase (by altering density without increasing strength).^{8, 9, 35} Of note, none of these mechanisms are proven, minimal mechanistic data are extant, human studies have evaluated only selected populations,^{36, 37} and animal models suggest that osteoporosis may be induced after surgical removal of the acid-secreting portions of the stomach through a mechanism independent from calcium absorption and parathyroid hormone levels and which is not reproducible with PPIs.^{38, 39}

We found an increased risk of fracture associated with even short durations of acid inhibitor use (<1 year). Possibilities for this finding include a true association (with even short intervals causing decreased bone density or altered bone remodeling) or confounding. The short-term results could be confounded by indication: indications for short-term treatment (e.g. after periods of hospitalization or illness from other disorders) may differ from those for long-term treatment. Such persons may have different risk fracture profiles from longer-term users that are difficult to delineate.

These results raise the question: do acid inhibitors directly increase the risk of hip fractures? A causal association is supported by the presence of increased risk with greater acid suppression (PPI vs. H2RA), elevated risk with higher daily doses, decreased risk with discontinuation of acid suppression, and the presence of increased risk among persons with other risk factors for osteoporosis (if acid suppression decreases calcium absorption, it would be expected to increase fracture risk the most among persons with already diminished bone densities).¹⁷ The main result not supporting a causative association is the absence of a clear trend for increased risk with longer durations of use.

There are several potential limitations of this study. The databases started recording dispensed medications in approximately 1995; thus, more remote exposures were not evaluable. This might underestimate the exposure in both cases and controls, particularly for the first few years of the database. However, analyses confined to fractures diagnosed after Jan 1, 2000 provided similar results to those from the full data set (data not shown). Second, spurious associations may be seen with variables related to the utilization of medical services. Patients using medical services for other reasons may be more likely to have conditions recognized (such as GERD) that result in treatment with acid inhibitors. However, adjustment for other common medical conditions, and inclusion only of persons without a GERD diagnosis still demonstrated persistent positive associations. In addition, the finding that other frequently prescribed medications were not associated with fracture risk decreases the possibility that the associations between acid inhibitors and fracture risk were solely due to confounding from contacts with the health system. Third, a case-control design cannot completely control for unknown confounders and detailed data on some confounders (e.g. lifetime alcohol use, diet, body mass index for all persons, lifetime smoking histories, etc.) were not available. However, prior large surveys in KPNC population provided smoking and alcohol abuse rates within a reasonable range of those detected by the current study, analyses suggested little evidence for confounding even among those with alcohol abuse and tobacco use diagnoses (who likely represent heavier users) and analyses confined to persons with BMI data provided similar results (data not shown). We did not include bone density data. Falls are the most common mechanism for hip fractures; however, only some persons have falls and, among those with falls, only some have fractures. Osteoporosis may contribute to the risk of fracture among those with falls, but individual measurements of bone mineral density measurements are not generally available in large populations and are not randomly distributed, potentially biasing analyses using density data. Finally, misclassification of exposure status may influence the results. One type of proton pump inhibitors became available over-the-counter in 2003, and H2RAs were over-the-counter prior to that time, although members could receive both PPIs and H2RAs by prescription after that date (at reduced cost compared with over-the-counter).⁴⁰ Thus, some members who took PPIs or H2RAs over-the-counter may have been classified as “unexposed”; if present, this would be expected to decrease the strength of the association: a “bias towards the null”.

Strengths of this study include its large size (approximately five times more cases with ≥1 year of PPI use than the United Kingdom study), access to care for all members, over 10 years of exposure data, the ascertainment of all recorded diagnoses of hip fractures arising within a general population (thereby minimizing referral bias), detailed electronic data for dispensed medications (eliminating recall bias), data for multiple confounders, and the use of a control group that approximates the region’s underlying general population base.¹⁴ The large size permitted evaluation for small intervals of use and multiple potential confounders (including use of other medications, such as bisphosphonates).

In conclusion, this study found an association between the use of PPIs, H2- receptor antagonists and the risk of hip fracture. The risk was higher among PPI users than among H2RA users; however, the increased risk was confined to persons with at least one other fracture risk factor. If the association is causal, the overall increase in risk is small and the risk attributable to acid inhibition in the general population is low, although the exposed population is fairly large for a medication exposure. These findings do not recommend against acid suppression for persons with clear indications for treatment, but they do advise appropriate vigilance in prescribing these medications to persons with defined indications and at the lowest effective dose. The mechanism for the association is unknown; although diminished calcium absorption from acid inhibition is an intuitive explanation supported by a small trial, it is not a proven mechanism. Additional mechanistic information is needed regarding the effects of acid inhibition on calcium absorption, bone metabolism, and bone strength and whether interventions such as calcium and vitamin D supplements modify the associations between acid inhibition and fracture risk.