Table 1.

Prior Longitudinal Studies Examining the Adjusted Relationship Between Proton Pump Inhibitors (PPI) and Bone Mineral Density (BMD)

Author (year)	Study population	PPI assessment	BMD assessment	Adjusted resultsa,b
Yu (2008)(5)	n = 4230 men aged ≥65 years	PPI use defined as taking medication for previous 4 weeks to clinic visit.	SOF: baseline and 4.9 years later.	PPIs had no significant effect on change in BMD at total hip.
	n = 2856 women aged ≥65 years	SOF: baseline and 4.9 years later. MrOS: baseline and 4.6 years later.	MrOS: baseline and 4.6 years later.	Annual change in BMD:
	Subjects in the Osteoporotic Fractures in Men Study (MrOS) or women from the Study of Osteoporotic Fractures (SOF)		Assessed at the hip. Annualized % change.	Total hip: −0.70 (p = 0.08) (women) Total hip: −0.38 (p = 0.39) (men)
Targownik (2010)(6)	N = 2549 subjects	Drug history for 5 years before baseline. PPI user if subject with use of PPI on ≥50% of the days (standard dose).	Change assessed for the lumbar spine and the total hip.	PPIs had no significant effect on change in BMD at standard or high-intensity doses.
	Subjects from the Manitoba Bone Mineral Density Database		Assessments separated by 1 to 3 years.	Annualized change in BMD:
			Annualized % change.	Spine: 0.03%±0.22% (p > 0.2) (standard dose PPI)
				Total hip: −0.17%±0.18% (p > 0.2) (standard dose PPI)
Gray (2010)(8)	n = 6695 (hip); n = 6629 (spine)	Assessed at baseline and year 3. Duration of PPI use described as <1 year, 1 to 3 years, or >3 years.	Assessed at baseline and years 3 and 6	PPIs had no significant effect on change in BMD when time- varying PPI use was included.
	Women aged 50 to 79 years from Women’s Health Initiative.		Assessed for total hip and spine.	Three-year changes in BMD including women on Ca/Vit D (PPI not considered as time-varying):
			Three-year % change.	Hip: 0.62 (PPI use) versus 1.36 (PPI non-use) (p = 0.05)
				Spine: 2.30 (PPI use) versus 1.34 (PPI non-use) (p = 0.94)
Targownik (2012)(7)	n = 8340 completed baseline; n = 6458 completed 5-year assessment; n = 4512 completed 10-year assessment	Assessed at baseline, year 5, and year 10. PPI user if reported PPI use at all time points included in the analysis.	Assessed at baseline and years 5 and 10.	PPIs had no significant effect on change in BMD.
	Population-based stratified random sample of Canadian population (CaMOS) aged ≥25 years.		Assessed for femoral neck, total hip, and spine.	10-year change in BMD:
			10-year % change.	Hip: 0.9% (−1.0 to 2.9%) (p = NS)
				Femoral neck: −0.5% (−2.9 to 1.8%) (p = NS)
				Spine: −0.7% (−3.3 to 1.9%) (p = NS)

Note: Studies without a non-user group were excluded.

^aCovariates differed by study. Yu (2008) included age, race, BMI, alcohol use, exercise, corticosteroids, NSAIDs, calcium supplements, osteoporosis medications, self-reported health, concurrent weight change, initial total hip BMD, caffeine intake, smoking, and history of stomach surgery. Targownik (2010) included age, sex, BMI, cardiovascular disease, diabetes, hypertension, COPD, renal disease, cirrhosis, thyroid disease, alcohol abuse, inflammatory bowel disease, celiac disease, oral ERT, SERMs, calcitonin, bisphosphonates, systemic corticosteroids (>5mg prednisone per day), anti-androgens, tamoxifen, anti-epileptics, SSRIs, and thiazide diuretics. Targownik (2012) included age, sex, age-sex interactions, BMI, history of minimal trauma fracture, family history of minimal trauma fracture, presence of RA, IBD, CLD, CKD, thyroid disease, smoking, heavy alcohol use (≥14 drinks per week), history of falls, use of concomitant medications that may influence BMD (corticosteroids, thiazides β-blockers, nitrates, anti-epileptics, SSRIs, tamoxifen, and osteoporosis medications, total calcium intake, and vitamin D intake). Gray (2010) included age, race/ethnicity, BMI, smoking, physical activity level, self-reported health, parental history of hip fractures, diabetes mellitus, history of fractures, corticosteroid use, physical function construct, history of myocardial infarction or angina, history of asthma or emphysema, arthritis, osteoporosis, psychoactive medications use, past or current use of hormone therapy or bisphosphonates, moderate or severe stomach ulcers, moderate or severe heartburn, WHI trial participation, and intervention arms.

^bOnly results from adjusted longitudinal analyses are presented.