Table 2.
Long-term studies of effects of PPIs on calcium absorption/metabolism and/or bone fractures)
| Author(Yr) Study | Number. Pts(Pt) | Type Patient | Type Study | Study Design | Results | Ref |
|---|---|---|---|---|---|---|
| Wright (2010, in press) | 12 healthy volunteers | Healthy volunteers | Placebo- controlled, double blind, cross-over study | Purpose; to evaluate the acute effect of OMEP on intestinal calcium absorption | 1. Neither calcium absorption nor urinary calcium levels differed between PPI use (3 days) and placebo group, despite marked difference in gastric acid suppression | [47] |
| Gray (2010) | 130,487 females, enrolled in WHI Observations study with mean F/U of 7.8 yrs | Age 50–79 | Prospective | F/u 7.8 yrs, compare drug information with main outcomes self-reported fractures, and for subsample 3 year change in BMD | 1. Multivariate adjusted hazard ratios for current PPI use were 1.00 (95% CI, 1.18–1.82) for hip fractures; 1.47 (CI 1.05–1.51) for spine; 1.26, CI, 1.15–1.36 for total fractures. 2. Use of PPIs associated with marginal effect on 3 yr BMD change at hip (p=0.05), but not other sites. |
[••19] |
| Targownik (2010) |
1. 2193 pts (hip)[3956 spine] with dec BMD compared to 5527 (hip)[10257 spine] controls without. 2.2193 longitudinal BMD study |
Pts from Manitoba Bone Mineral Density Database (MBMDD) | Cross sectional and longitudinal study | 1. Pts in MBMDD with hip/lumbar dec BMD (t score ≤-2.5) compare 3 controls 2. Compare all pts who had 2 BMD between 2001-6 (n=2549). |
1. PPI usage not associated with having osteoporosis at the hip (OR, 0.84 95% CI-0.55–1.34) or lumbar spine (OR, 0.79, CI-0.59–1.06) for PPI use of >1500 doses over 5 yrs 2. In the longitudinal study PPIs did not cause significant decrease in BMD at either the hip or lumbar spine |
[16] |
| Corley (2009) | 33,592 pts with hip fracture matched to 130,741 control (Kaiser database) | All patients with hip fracture matched to control (age, gender, ethnicity | Nested control study | Identified all cases hip fracture in Kaiser database and then matched to 4 controls with similar age, gender, ethnicity. Analyzed PPI/H2R use | 1. Pts using PPI≥2yrs had 30% inc risk of hip fracture (OR, 1.3, 95% CI-1.21–1.39) and H2R 18% inc 2. Higher doses for longer time had greater risk (>1.5 pills PPI for 8–10 yrs, OR39, CI 1.4–4.08. 3. Greatest risk for pt 50–59 yrs of age, OR, 2.31, CI 1.67–3.19. 4. Risk of hip fracture inc with time /dose of PPI |
[56] |
| Roux (2009) | 1211 postmenopausal women | Postmenopausal women in Osteoporosis and Ultrasound study | Prospective study | At baseline and end of 6yr F/u vertebral fractures assessed by X-Ray and correlated with PPI use | 1. At baseline 5%were using omeprazole. 2. Age-adjusted rates for vertebral fractures were 1.89 (omeprazole users) and 0.60 per 100 person yrs for nonusers (RR 3.41)(p=0.009) 3. Multivariate analysis risk factors include omeprazole use (RR 3.10, p=0.027l), age>65(RR2.34, p=0.44), low lumber spine BMD (RR-2.38, p=0.04) |
[••57] |
| Kirkpantur (2009) | 68 maintenance hemodialysis pts (Group 1–36 PPI users, Group 2 (32, PPI nonusers) | Maintenance hemodialysis pts | Cohort study | Radius, hip, and spine BMD assessment and correlated with PPI use and other variables | 1. Mean duration of PPI use was 27 ± 5 mos. 2. PPI users had lower BMD at all sites(p=0.019–0.04) 3. Serum Ca, PTH, phosphate similar two groups 4. Multivariable analysis for >18 mos PPI use, was 1.31 for low BMD in the radius, 0.98 femoral neck, 0.94 trochanter, 1.19 in lumbar spine |
[15] |
| Kaye (2008) | 1. Phase 1: 4414 pts each matched to up to 10 controls 2. Phase 2: 1098 cases vs. 10923 controls |
Aged 50–79 from United Kingdom General Practice Research Database (GPRD) | Two phase, matched, nested control study | Phase 1: Match cases with hip fracture between 1995– 2005 to controls Phase 2: match cases and control without major risk factors for hip fracture |
1. Phase 1; PPIs usage did not increase risk of hip fracture (OR, 0.9, 95% CI 07–1.1) 2. No evidence for association of hip fracture with increased PPI dose or with a specific PPI |
[20] |
| Targownik (2008) | 15,792 cases of osteoporosis-related fracture matched with 47,289 controls for age, gender, and comorbidities. | In Population Health Research Data Repository (Manitoba) identified all with hip, vertebra wrist fracture from 199–2004 | Retrospective, matched cohort study | Compared PPI use and other variables in those with or without fractures | 1. PPI use ≤6 yrs not associated with inc fractures 2. PPI use >6 yrs associated with inc risk of fractures (AOR, 1.92 95% CI-1.16–3.18, p=0.011). 3. PPI use ≥5 yrs associated with inc risk hip fracture (AOR, 1.62, CI-.02–2.58, p=0.04) and after ≥7yrs even higher risk (AOR, 4.55, CI-1.68–12.39, P=0.002) |
[58] |
| Yu (2008) | 5,755 men and 5,339 women >65 from the Osteoporotic Fractures of Men study (MrOS) and Study of Osteoporotic fractures (SOF) study | Age >65 with SOF women recruited 1986– 1988, men 2000-2 community dwelling. | Cohort study and prospective | Compared PPI use and other variables to BMD and BMB change with time | 1. On multivariate analysis men, not women, using either PPIs/H2R had lower BMD (hip, femur)(P<0.01) 2. PPIs in women inc nonspinal fracture rate (RH.1.34, Ci-1.10–1.64) 3. PPIs in men not taking calcium supplements had inc nonspinal fracture rate (RH.1.49, CI-1.04–2.14 4. No inc rate of bone loss with time in PPI/H2R users (p=0.09) |
[46] |
| Yang (2006) | 13,556 hip fracture cases and 13,5386 controls from GPRD UK database | Age>50 yrs | Nested case control study | Compared characteristics including PPI/H2R use in patients with/without hip fractures | 1. Overall adjusted OR for hip fracture on PPIs>1 yr was increased at 1.44 (95% CI-1.30–1.59) 2. Risk hip fracture increased in both H2R (OR 1.23) and PPI users > 1 yr (OR 1.44) 3. Risk increased with duration of PPI use and higher with high PPPI dose (>1.75 average) (AOR 2.65). |
[•8] |
| Vestergaard (2006) | 124,655 with fracture and 373,962 controls from Danish population for the years 2000 | All cases with any fracture and controls (age/gender matched) | Case control study | Compared characteristics with primary endpoint. Use of PPI/H2R/ antacids | 1. PPIs associated with increased risk of fracture (OR 1.18 95% CI 1.12–1.43); OR 1.45, CI 1.28–1.65 for hip; and OR-1.60, CI 1.25–2.04 for spine fracture. 2. H2R associated with a decreased risk if used within last year. 3. Antacids did not change risk overall, but increased risk for hip and spine fractures 4. No dose-response was seen with PPIs |
[•42] |
Abbreviations. See Table 1. Inc-increase; dec-decrease; RR-relative risk; WHI-women’s Health Initiative Observation Study and Clinical Trials; F/u-follow-up; BMD-bone mineral density measured by densitometry; MBMDD -Manitoba Bone Mineral Density Database ; OR-Odds ratio, CI-confidence interval; AOR-adjusted Odds ratio;