Class III evidence is the key to really understanding this. I agree with Sue’s comment that the media’s writing about research results is often misleading. The use of the word “linked” in the title is quite inflammatory.
Thanks Sue, I’m glad you agree (as a retired RN, too). I know the nuance doesn’t make for a good read, but the devil is always in the details. I was glad to be reminded of all the higher quality evidence to the contrary, and that the AGA specifically delegated the task of PPI nuance review to primary care! 😏
It’s a valid concern, no pressure to read this really long reply, but I’m going to cut and paste from an article on UpToDate ( a reference for clinicians that I subscribe to) about this subject:
Proton pump inhibitors — Insoluble calcium, such as calcium carbonate, requires an acid environment for optimal absorption. As a result, drugs that reduce stomach acid secretion (proton pump inhibitors [PPIs] and H2 blockers) may reduce calcium absorption. Because calcium absorption decreases with aging, a further reduction in calcium absorption with the addition of such drugs may have an adverse impact on skeletal health, particularly in older individuals.
Some [60], but not all [61,62], studies with PPIs show that fractional absorption of calcium is reduced in postmenopausal women. A possible explanation for the different results among studies is a difference in study conditions, including selection of isotope-labeled calcium (calcium carbonate capsules versus calcium chloride solution), method of measurement (fasting serum isotope-labeled calcium levels versus dual isotope measurements with a meal), duration (eg, 7 versus 30 days), type of PPI treatment (omeprazole versus a different PPI), and patient characteristics (mean age 76 versus 58 years). Dietary calcium (milk and cheese) absorption was not reduced in healthy individuals treated with omeprazole [63,64], suggesting that a meal induces a sufficient amount of acid secretion for calcium absorption despite PPI therapy.
The more important clinical question is whether PPIs affect fracture risk. In meta-analyses of case-control and cohort studies, the risk of hip, spine, and any-site fractures was modestly but significantly increased in patients taking PPIs (RRs 1.30, 1.56, and 1.16, respectively) [65-68]. In some studies [67,69], but not another [70], the risk was highest in long-term users of high-dose PPI therapy. In one analysis, the risk was confined to patients with at least one other risk factor for hip fracture [71], and in another, to current or former smokers [67].
The largest prospective cohort study (the WHI Study) did not find an association between PPI use and hip fracture (HR 1.00, 95% CI 0.71-1.40) [72]. However, PPI use was associated with an increased risk of clinical vertebral (HR 1.47, 95% CI 1.18-1.82), wrist, and total fractures. There was a smaller number of hip fracture events compared with wrist, clinical spine, or total fractures. The lower number of events, combined with the fact that PPI users were more likely than nonusers to be taking hormone therapy, may have reduced the ability of the study to detect an increased risk of hip fracture in PPI users.
H2 blockers were associated with an increased risk of hip fracture in some reports (adjusted odds ratio [AOR] 1.23, 95% CI 1.14-1.39) [69,71,73] but decreased [70] or unchanged [68,72] risk in others.
In a subsequent analysis of a national prescription database, concurrent use of PPIs and alendronate compared with alendronate alone was associated with loss of protection against hip fracture (fracture risk reduction with alendronate 39 versus 19 percent in non-PPI versus PPI users) [74]. Concurrent treatment with H2 blockers did not modify the treatment response to alendronate.
Although the association between PPIs and fracture is plausible, these observational studies do not prove causality. One possible mechanism by which PPIs and H2 blockers adversely affect bone is through impaired absorption of calcium carbonate due to achlorhydria, which increases bone loss and reduces BMD. In a prospective cohort study, chronic PPI use was associated with lower baseline BMD at the femoral neck and total hip, but use over 10 years was not associated with accelerated BMD decline [75]. In addition, other studies have not found a decrease in BMD in PPI users compared with nonusers [76,77], albeit in one of these there was an increased risk of falls and fractures in PPI users [76]. Thus, factors independent of BMD (eg, frailty) may contribute to fracture risk, and PPI use may be a marker of frailty since PPI users are, as a group, sicker than controls [75]. Further studies investigating the relationship between PPIs and fracture are required.
In the interim, because omeprazole was shown to reduce the fractional absorption of calcium carbonate in fasting postmenopausal women in some studies [60], we advise that postmenopausal women taking long-term PPI or H2 blocker therapy increase dietary calcium and, when necessary, use calcium supplements that do not require acid for absorption, such as calcium citrate. The treatment of postmenopausal women with or at risk for osteoporotic fracture is reviewed separately.
Bravo on this piece. Too often MSM articles are not written by scientists. While some media are better than others, always ask yourself, where's the science? While we do need follow ups with long term PPI usage, this paper was not it. We are still seriously looking at causation factors in dementia. This is a complicated area. There are some writers that I follow, Catherine Wu, Alan Dove and Helen Branswell are a few. Always keep a critical eye on it.
Bottom line, do not treat an article as medical advice.
Such a good bottom line quote - do not treat an article as medical advice. And always check the author’s credentials, and hold on to good brains like the ones you mentioned. Wish Helen Branswell would hop over here on Substack! Catherine Wu is great too. Will keep an eye out for Dove.
An excellent testimonial, and for the vast majority of people these meds have much greater benefit than harm in my experience too. And I hope 84 is the new 64 ☺️. Thanks for stopping by.
This posts rocks! A little skepticism, a little education, a little humor, a lot of scientific literacy, and hopefully a John’s Roast pork sandwich someday soon! Will forward this to some relatives who probably saw these headlines and got worried…
Hi Grace, I’ll do another post soon about medical journal/study basics, since few of us are statisticians, myself included. But there are a couple basics that help see through the veil of these types of headlines. And I don’t think the roast pork will disappoint 🤞
Good news, lll read more than the headline later… usually told people their risk was about that of eating grilled food with zantac impurities at worst. Encouraging headline thanks!
Excellent breakdown. I hate that the media so often gets it wrong when they write about the results of recent studies.
Me too, and the echo chamber gets so loud that original analyses are few and far between. Thanks for the feedback :)
Class III evidence is the key to really understanding this. I agree with Sue’s comment that the media’s writing about research results is often misleading. The use of the word “linked” in the title is quite inflammatory.
Thanks Sue, I’m glad you agree (as a retired RN, too). I know the nuance doesn’t make for a good read, but the devil is always in the details. I was glad to be reminded of all the higher quality evidence to the contrary, and that the AGA specifically delegated the task of PPI nuance review to primary care! 😏
Several years ago, I worried (and still do) about PPIs interfering with calcium absorption…particularly for women.
It’s a valid concern, no pressure to read this really long reply, but I’m going to cut and paste from an article on UpToDate ( a reference for clinicians that I subscribe to) about this subject:
Proton pump inhibitors — Insoluble calcium, such as calcium carbonate, requires an acid environment for optimal absorption. As a result, drugs that reduce stomach acid secretion (proton pump inhibitors [PPIs] and H2 blockers) may reduce calcium absorption. Because calcium absorption decreases with aging, a further reduction in calcium absorption with the addition of such drugs may have an adverse impact on skeletal health, particularly in older individuals.
Some [60], but not all [61,62], studies with PPIs show that fractional absorption of calcium is reduced in postmenopausal women. A possible explanation for the different results among studies is a difference in study conditions, including selection of isotope-labeled calcium (calcium carbonate capsules versus calcium chloride solution), method of measurement (fasting serum isotope-labeled calcium levels versus dual isotope measurements with a meal), duration (eg, 7 versus 30 days), type of PPI treatment (omeprazole versus a different PPI), and patient characteristics (mean age 76 versus 58 years). Dietary calcium (milk and cheese) absorption was not reduced in healthy individuals treated with omeprazole [63,64], suggesting that a meal induces a sufficient amount of acid secretion for calcium absorption despite PPI therapy.
The more important clinical question is whether PPIs affect fracture risk. In meta-analyses of case-control and cohort studies, the risk of hip, spine, and any-site fractures was modestly but significantly increased in patients taking PPIs (RRs 1.30, 1.56, and 1.16, respectively) [65-68]. In some studies [67,69], but not another [70], the risk was highest in long-term users of high-dose PPI therapy. In one analysis, the risk was confined to patients with at least one other risk factor for hip fracture [71], and in another, to current or former smokers [67].
The largest prospective cohort study (the WHI Study) did not find an association between PPI use and hip fracture (HR 1.00, 95% CI 0.71-1.40) [72]. However, PPI use was associated with an increased risk of clinical vertebral (HR 1.47, 95% CI 1.18-1.82), wrist, and total fractures. There was a smaller number of hip fracture events compared with wrist, clinical spine, or total fractures. The lower number of events, combined with the fact that PPI users were more likely than nonusers to be taking hormone therapy, may have reduced the ability of the study to detect an increased risk of hip fracture in PPI users.
H2 blockers were associated with an increased risk of hip fracture in some reports (adjusted odds ratio [AOR] 1.23, 95% CI 1.14-1.39) [69,71,73] but decreased [70] or unchanged [68,72] risk in others.
In a subsequent analysis of a national prescription database, concurrent use of PPIs and alendronate compared with alendronate alone was associated with loss of protection against hip fracture (fracture risk reduction with alendronate 39 versus 19 percent in non-PPI versus PPI users) [74]. Concurrent treatment with H2 blockers did not modify the treatment response to alendronate.
Although the association between PPIs and fracture is plausible, these observational studies do not prove causality. One possible mechanism by which PPIs and H2 blockers adversely affect bone is through impaired absorption of calcium carbonate due to achlorhydria, which increases bone loss and reduces BMD. In a prospective cohort study, chronic PPI use was associated with lower baseline BMD at the femoral neck and total hip, but use over 10 years was not associated with accelerated BMD decline [75]. In addition, other studies have not found a decrease in BMD in PPI users compared with nonusers [76,77], albeit in one of these there was an increased risk of falls and fractures in PPI users [76]. Thus, factors independent of BMD (eg, frailty) may contribute to fracture risk, and PPI use may be a marker of frailty since PPI users are, as a group, sicker than controls [75]. Further studies investigating the relationship between PPIs and fracture are required.
In the interim, because omeprazole was shown to reduce the fractional absorption of calcium carbonate in fasting postmenopausal women in some studies [60], we advise that postmenopausal women taking long-term PPI or H2 blocker therapy increase dietary calcium and, when necessary, use calcium supplements that do not require acid for absorption, such as calcium citrate. The treatment of postmenopausal women with or at risk for osteoporotic fracture is reviewed separately.
Thank you for this. 🙂 I’ll stick to getting calcium in my diet: milk, cottage cheese, cheese, yogurt.
Bravo on this piece. Too often MSM articles are not written by scientists. While some media are better than others, always ask yourself, where's the science? While we do need follow ups with long term PPI usage, this paper was not it. We are still seriously looking at causation factors in dementia. This is a complicated area. There are some writers that I follow, Catherine Wu, Alan Dove and Helen Branswell are a few. Always keep a critical eye on it.
Bottom line, do not treat an article as medical advice.
Such a good bottom line quote - do not treat an article as medical advice. And always check the author’s credentials, and hold on to good brains like the ones you mentioned. Wish Helen Branswell would hop over here on Substack! Catherine Wu is great too. Will keep an eye out for Dove.
I am now 84 years old and have been taking Nexium/Prilosec for over 25 years, one pill in the AM. I have not noticed any problems with dementia!
An excellent testimonial, and for the vast majority of people these meds have much greater benefit than harm in my experience too. And I hope 84 is the new 64 ☺️. Thanks for stopping by.
This posts rocks! A little skepticism, a little education, a little humor, a lot of scientific literacy, and hopefully a John’s Roast pork sandwich someday soon! Will forward this to some relatives who probably saw these headlines and got worried…
Hi Grace, I’ll do another post soon about medical journal/study basics, since few of us are statisticians, myself included. But there are a couple basics that help see through the veil of these types of headlines. And I don’t think the roast pork will disappoint 🤞
Seen this on H2RAs? https://www.medpagetoday.com/gastroenterology/gerd/106396?xid=nl_mpt_morningbreak2023-09-20&eun=g2007433d0r&utm_source=Sailthru&utm_medium=email&utm_campaign=MorningBreak_092023&utm_term=NL_Gen_Int_Daily_News_Update_active
Good news, lll read more than the headline later… usually told people their risk was about that of eating grilled food with zantac impurities at worst. Encouraging headline thanks!