Are there any studies or evidence to show that PPIs may cause vitamin D deficiency?

Comment by InpharmD Researcher

Recent studies, with limitations, suggest a potential association between long-term PPI use and vitamin D deficiency. In a 2023 study with pantoprazole use for 12 months, 100% of patients developed vitamin D deficiency compared to a control group (Table 1). Another study including patients with 6 months of PPI use, however, did not show a significant difference between PPI exposure and non-exposure but did observe PPI exposure to be associated with hyperparathyroidism (Table 2). The exact mechanism of vitamin D deficiency is unclear but could involve gastric pH, hypomagnesemia, or unaccounted factors affecting vitamin D absorption. Additionally, PPIs may have complex effects on bone health, impacting calcium absorption and bone metabolism, with potential links to osteoporotic fractures and gut microbiome changes.

Background

In a recent 2023 study, the authors found that long-term proton pump inhibitor (PPI) use with pantoprazole for at least 12 months led to significant vitamin D deficiency in 100% of patients (n= 30) compared to the control group without PPI use (See Table 1). However, another noted study where PPI was administered for at least 6 months did not find a significant difference in vitamin D levels versus control (See Table 2). While the mechanism of effect is not known, the author’s hypothesis includes potential influence on gastric pH, inducing hypomagnesemia which is involved in several steps in vitamin D metabolism, or being of advanced age. Vitamin D is also fat-soluble which could be influenced by body weight, a characteristic not accounted for within the study. There may also be drug interactions unaccounted for. [1], [2]

A 2022 review article discusses recent findings pertaining to the risk of osteoporotic fracture associated with PPIs, particularly with prolonged use. The article discussed the plausibility of the association between fragility fracture and PPI use, where the likelihood of causality was mostly based on observational studies. A possible mechanism is reduced calcium absorption in the intestines, potentially causing negative calcium balance, secondary hyperparathyroidism, increased bone loss, and fractures. However, findings on PPIs’ effects on calcium absorption vary. In vitro studies revealed that omeprazole may inhibit bone resorption by selectively targeting osteoclasts’ vacuolar H+Atpase. In humans, omeprazole was used to investigate the potential of PPIS to reduce bone resorption. Similar results were observed in ovariectomized rats, suggesting that PPIs might prevent osteoporosis by inhibiting osteoclast vacuolar-type H+ATPases. Additionally, PPIs were found to dose-dependently inhibit human osteoclasts, affecting osteoblast cell activity. [3]

Other factors explaining PPIs’ impact on bone health could include PPI-induced hypergastrinemia, leading to parathyroid levels. Impaired vitamin B12 absorption may also affect homocysteine levels, potentially increasing fracture risk among PPI users by altering collagen quality. Another explanation is long-term PPI use affects the gut microbiome, including hypomagnesemia and hypocalcemia. PPI use is linked to low magnesium levels, which can reduce muscle function as shown in recent reviews. As a result, hypomagnesemia can impact bone health by influencing key factors in bone metabolism, such as calcium and vitamin D. Magnesium serves as a natural calcium antagonist and plays a crucial role in vitamin D metabolism, as both 25-hydroxylase and 1-alpha hydroxylase enzymes depend on magnesium. [3]

References:

[1] Losurdo G, Caccavo NLB, Indellicati G, et al. Effect of Long-Term Proton Pump Inhibitor Use on Blood Vitamins and Minerals: A Primary Care Setting Study. J Clin Med. 2023;12(8):2910. Published 2023 Apr 17. doi:10.3390/jcm12082910
[2] Hinson AM, Wilkerson BM, Rothman-Fitts I, Riggs AT, Stack BC Jr, Bodenner DL. Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults. J Am Geriatr Soc. 2015;63(10):2070-2073. doi:10.1111/jgs.13661
[3] Lespessailles E, Toumi H. Proton Pump Inhibitors and Bone Health: An Update Narrative Review. Int J Mol Sci. 2022;23(18):10733. Published 2022 Sep 14. doi:10.3390/ijms231810733
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Are there any studies or evidence to show that PPIs may cause vitamin D deficiency?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-2 for your response.

 

Effect of Long-Term Proton Pump Inhibitor Use on Blood Vitamins and Minerals: A Primary Care Setting Study

Design

Transversal case-control study

N= 66

Objective

 To investigate possible alterations in micronutrients in chronic proton pump inhibitor (PPI) users in a general practitioner setting

Study Groups

PPI (n= 30)

Control (n= 36)

Inclusion Criteria

 Age 18 years and older, taking pantoprazole for at least 12 months, attending the general practitioner

Exclusion Criteria

Oral or parenteral supplement use containing iron, folate, vitamin B12 or D; other medications such as corticosteroids that could influence micronutrient levels; disease (e.g., atrophic gastritis, celiac disease, inflammatory bowel disease, and hematological disease) that could alter micronutrient levels

Methods

There is limited information regarding the treatment aside from pantoprazole use in the PPI group versus a control group that did not take any PPI in the last 12 months. Patients were recruited from the general practitioner setting. Vitamin D deficiency was determined by estimating a difference in prevalence of 35% between the two groups.

Duration

 January 2020 to December 2020

Outcome Measures

 Patients determined to be vitamin D deficient

Baseline Characteristics

  

PPI (n= 30)

Control (n= 36)

 p-value

Age, years

 75.6 63.2  < 0.001

Vitamin D, ng/mL

15.5 ± 6.8

 36.6 ± 21.2 < 0.001

Results

Endpoint

PPI (n= 30)

Control (n= 36)

p-value

Vitamin D deficiency

30 (100%)

9 (25%)

< 0.001

Adverse Events

 N/A

Study Author Conclusions

 Vitamin D deficit was observed more frequently in the PPI group (100%) than in controls (30%, p < 0.001), with blood levels lower in pantoprazole consumers.

InpharmD Researcher Critique

 Information on the baseline patient population, comorbidities, concomitant drug use, GI and organ status, etc. were not mentioned within the study. Other factors that could influence the vitamin D deficiency were not assessed.



References:

Losurdo G, Caccavo NLB, Indellicati G, et al. Effect of Long-Term Proton Pump Inhibitor Use on Blood Vitamins and Minerals: A Primary Care Setting Study. J Clin Med. 2023;12(8):2910. Published 2023 Apr 17. doi:10.3390/jcm12082910

 

Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults

Design

Retrospective chart review

N= 80

Objective

To measure the effect of proton pump inhibitors (PPIs), with and without concurrent bisphosphonates (BP), on parathyroid hormone (PTH), vitamin D, and calcium

Study Groups

Taking PPI (+PPI; n= 20)

Not taking PPI (-PPI; n= 20)

Taking PPI and BP (+PPI/BP; n= 20)

Not taking PPI but taking BP (-PPI/BP; n= 20)

Inclusion Criteria

Individuals aged 60 and older with concurrent calcium, PTH, vitamin D, and creatinine laboratory measurements  

Exclusion Criteria

Reduced renal function (creatinine >1.3 mg/dL) and low vitamin D (<30 ng/mL)

Methods

Calcium, PTH, vitamin D, creatinine, and age of the +PPI group were compared with those of the -PPI group, and those of the +PPI/BP group were compared with those of the -PPI/BP group using a t-test to establish statistical significance. PPIs included omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole. BPs included were alendronate, ibandronate, zoledronate, and risedronate.

Duration

Treatment duration with PPI/BP: at least 6 months 

Outcome Measures

 Serum calcium, PTH, vitamin D, and creatinine

Baseline Characteristics

 See Result

Results

Endpoint

 

PPI without Concurrent BP Therapy

p-value

 PPI with Concurrent BP Therapy

p-value
+PPI (n= 20) -PPI (n= 20) -- +PPI/BP (n= 20) -PPI/BP (n= 20)  --

Age, years

 73.0 ± 10.4  64.7 ± 16.7 0.08 77.2 ± 7.3 73.0 ± 10.0 0.20

Vitamin D levels, ng/mL

 36.6 ± 6.6 ng/mL 41.5 ± 9.5  0.06 37.6 ± 7.4 37.7 ± 7.4 0.80

Creatinine, mg/dL

 0.9 ± 0.2 mg 0.8 ± 0.02 0.10 0.9 ± 0.2 0.9 ± 0.2 0.80

Serum calcium, mg/dL

 9.1 ± 0.4 9.4 ± 0.4 0.02 9.2 ± 0.6 9.6 ± 0.6 0.04 

PTH, pg/mL

 65.5 ± 31.7 30.3 ± 18.0 <0.001 65.2 ± 36.3 43.4 ± 31.1 0.05

There was no statistically significant difference in calcium (p = 0.22) or PTH (p = 0.11) between the -PPI/BP and -PPI groups.

Adverse Events

See results

Study Author Conclusions

Based on the present study, chronic PPI exposure in elderly adults is associated with mild hyperparathyroidism regardless of concurrent oral BP administration.

InpharmD Researcher Critique

The retrospective chart review design of this study has limitations. It lacks investigation into key variables such as medical history, physical activity, concurrent medications, and medication adherence, all of which can influence PPI pharmacokinetics, skeletal homeostasis, and serum markers. Additionally, the exclusion of inpatients may limit the generalizability of findings, and reliance solely on serum calcium, vitamin D, and creatinine measurements doesn't adequately screen for early-stage renal disease. The high PTH levels observed in PPI groups may not represent the broader elderly population. 



References:

Hinson AM, Wilkerson BM, Rothman-Fitts I, Riggs AT, Stack BC Jr, Bodenner DL. Hyperparathyroidism Associated with Long-Term Proton Pump Inhibitors Independent of Concurrent Bisphosphonate Therapy in Elderly Adults. J Am Geriatr Soc. 2015;63(10):2070-2073. doi:10.1111/jgs.13661