Table 1.

Characteristics of the included studies.

Study	Study design	Study population	Mean age	No. of cases	No. of controls	PPI use	Outcome
Ozdil et al. (2013)	Prospective cohort	Males & females	37.7 ± 8.8	114	110	PPI doses & type: Lansoprazole 30 mg/day, Pantoprazole 40 mg/day, or Esomeprazole 40 mg/day.The duration was 8.5 ± 2.3 months	PPI results in a statistically significant reduction in BMD of the vertebra and femur.
Gray et al. (2010)	Prospective cohort	Females	PPI users 64.8 ± 7.1, PPI non-users 63.1 ± 7.3	3396	148,394	PPI classes include: Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, Rabeprazole. The duration (<1Y, 1–3Y, >3Y)	PPI use was associated with only a marginal effect on 3-year BMD change at the hip but not at other site & this association was not present in longer follow up 6 years
Elaine et al. (2008)	Prospective cohort	Females	79.3	234	4574	The type and dose of PPI were not recorded. The average follows up 4.6 years.	No significant BMD differences were observed
Solomon et al. (2015)	Prospective cohort	Females	PPI users 50.7 ± 4.2, PPI non-users 50.2 ± 3.9	207	1605	The PPI type, dose was not recorded. The duration was 9.9 years.	No difference in the adjusted model in the annualized BMD change at the lumbar spine, femoral neck or total hip in the PPI users compared with non-users.
Bahtiri et al. (2016)	Prospective cohort	Males & females	50.59 ± 10.61	167	42	PPI doses & type: Omeprazole at 20 mg/day, Esomeprazole at 20 mg/day, Lansoprazole at 30 mg/day, and Pantoprazole at 40 mg/day. The duration was 1 year	PPI treatment for 12 months resulted in lower femur neck & total hip BMD T scores
Roux et al. (2012)	Prospective cohort	Females	PPI users 65.9 ± 6.3, PPI non-users 65.8 ± 6.6	61	1150	Omeprazole recorded as a type and no dose recorded. The duration 6 years	Patient using omeprazole had lower lumbar spine and hip BMD T scores at baseline but after follow up there was no difference in hip BMD between users & non-users
Targownik et al. (2012)	Prospective cohort	Males & females	Y0 61.0 ± 13.0, Y5 59.9 ± 12.1, Y10 58.0 ± 11.6	228	8112	The dose & indication for PPI use were not recorded followed after baseline at 5 years and 10 years	PPI users had lower BMD at baseline than PPI non-users, but PPI use over 10 years did not appear to be associated with accelerated BMD loss
Targownik et al. (2017)	Prospective cohort	Males & females	PPI users 65.1 ± 9.1, PPI non-users 64.9 ± 7.9	52	52	The dose & type of PPI were not recorded. The duration was 5 years	Long term PPI use is not associated with any changes in BMD or bone strength that would predispose to an increased risk of fracture.
Shin et al. (2019)	Retrospective cohort	Females	64.3 ± 10.4	223	223	The dose & type of PPI were not recorded. Exposure to PPI was 30 D, 31–90 Ds, >90 Ds.	Total hip BMD was significantly lower in the PPI exposure groups regardless of the exposure timing. However, the association of BMD with the PPI exposure timing was inconsistent for the lumbar or femoral neck
Xuan et al. (2014)	Retrospective cohort	Males & females	63 ± 10	79	47	The dose & type of PPI were not recorded. The duration was less than one year	Long term use of PPI is associated with decrease in hip joint BMD.