Favorable “Break”through Data for Proton Pump Inhibitors and Bone Density

Franklin Roosevelt’s secretary of state, Cordell Hull, wrote: “A lie will gallop halfway round the world before the truth has time to pull its breeches on.”

This saying came to my mind as I read a recent study (KE Hansen et al. Gastroenterol 2019; 156: 926-34) titled: “Dexlansoprazole and esomeprazole do not affect bone homeostasis in healthy postmenopausal women.”

In this study, the authors performed a prospective double-blind study with 115 healthy postmenopausal women who were treated with one of these two PPIs or placebo daily for 26 weeks.

Key findings:

  • PPI therapy did not reduce true fractional calcium absorption
  • There were no significant difference between groups in serum or urine levels of minerals, bone mineral density, or parathyroid hormone

Previous studies have found conflicting results of PPIs on bone density.  Studies suggesting that PPIs could affect bone density have been questioned due to “low odds ratios (<2), lack of dose response, biological implausibility, and uncontrolled potential confounders.”  The authors note that they chose bone turnover rather than changes in BMD as a primary outcome as bone turnover precede changes in BMD and should serve as an early marker of adverse effects.

My take: This study, while short in duration and with limited numbers of participants found no harmful effects of PPIs on skeletal health.

Related blog posts:

Tajo River, Toledo Spain

Long-term Bone Health of Children with Celiac Disease

In a recent study (C Canova et al. J Pediatr 2018; 198: 117-20) from Padua, Italy compared 1233 individuals with celiac disease to a comparison group of 6167 (from a population-based cohort of >200,000 individuals).  In this longitudinal study with a maximum followup of up to 23 years, the authors found no increase risk of fractures in youths diagnosed with celiac disease (HR of 0.87).


  • 22 individuals had fractures compared to 128 in the reference population
  • Median age of celiac diagnosis was 6 years


  • While celiac disease is linked to osteoporosis, “the vast majority of individuals with childhood celiac disease are likely to heal shortly after the introduction of a gluten-free diet.”

My take: Institution of a gluten-free diet for children with celiac disease likely removes the risk of osteoporosis.

Related blog posts:

  • Good News for Celiac Disease  –Gastroenterology 2010; 139: 763. Mortality NOT worsened in undiagnosed celiac disease (identified by review of serology) in Olmstead County, though bone density decreased. n=129 of 16,847. (?milder cases undiagnosed)
  • Common to be ‘D-ficient

Amelia Island -Restaurant Greeting

Cumberland Island 2018

Bone Health, Especially for IBD and Short Gut

Several colleagues with birthdays this week and next–Happy Birthday!

At our ICN population management meeting (as well as at a recent nutrition colloquium), Dr. Karen Loechner provided a timely update on bone health for our group.  Some of her slides are pictured below and a link to full slides follows.

Some of the points that I found interesting:

  • New hologic scans are much quicker (as little as 15 secs for some images) than typical DXA scans
  • While sodas have been associated with weaker bones, the main mechanism is likely displacement of milk from diet rather than direct effects
  • Adjust DXA results for height age
  • Think about vertebral compression fractures in children with mobility problems and painful symptoms



Full Link: Sticks and Stones Pediatric Osteoporosis


Will Vitamin D Prevent Osteoporosis –Probably Not

A recent excerpt from the NY Times regarding a study published online in The Lancet.  nyti.ms/1gnT1vz 

In a large review of studies, researchers have found almost no evidence that taking vitamin D supplements has any effect in preventing osteoporosis in middle-aged adults.

The analysis…included 23 randomized trials that measured the effect of vitamin D on bone density at four sites — spine, neck, hip and forearm — and included more than 4,000 generally healthy participants whose average age was 59.

The studies used dosages that varied from 500 units a day to 800 or more, given on varying schedules. In some studies, the subjects were given calcium as well.

Neither the pooled data nor any single study showed a significant increase in bone density across all four sites….The authors write that the widely believed idea that vitamin D promotes bone mineralization is probably incorrect.

“We’re not talking about people who are really vitamin D deficient,” said the lead author, Dr. Ian R. Reid, a professor of medicine at the University of Auckland in New Zealand. “But for healthy people focused on osteoporosis prevention, vitamin D does not make a positive contribution.”

Related posts:

PPI Side Effects: “Dissecting the Evidence”

While proton pump inhibitors (PPIs) are used extensively for acid-related diseases and have been around for nearly 25 years, there have been a number of reports about potential side effects.  As a drug class, PPIs have a very good safety profile.  A recent article reviews some controversial adverse effects and summarizes the evidence for and against (Clin Gastroenterol Hepatol 2013; 11: 458-64).

I. Calcium/bone effects.  After reviewing a number of studies, the authors conclude: “There is no good evidence to establish that PPI use has a significant risk for bone density loss or osteroporotic-related fractures….Supplemental calcium is not recommended or justified solely because of PPI use.”

II. Iron. “Although it is conceivable that PPI therapy may reduce absorption of nonheme iron and retard iron pool replenishment, this effect has not been well-studied or evident from widespread use in clinical practice.

III.  Magnesium.  “The FDA recommendation to consider checking magnesium levels before starting is not practical, in particular for the over-the-counter market. In patients who may be predisposed to …ongoing magnesium loss…it may be reasonable to follow…Given the rarity of the reports and no controlled studies to delineate the mechanisms, it is important for health care providers to be aware of this” (rare reports of profound hypomagnesemia).

IV. Pneumonia. “Small relative risk associated with short-term and high-dose PPI use.  These relationships, however, do not offer a definitive explanation for the relative risk” due to the studies and confounding factors.

V. Clostridium difficile.  “To date, there is insufficient evidence to conclude that there is a definitive relationship between PPI use and C difficile infection…clinicians should be aware of this potential relationship.”

VI. Traveler’s diarrhea.  “The data…were overall supportive of no associated risk, albeit there were a few specific case reports suggesting a remote causal association.”

VII. Small intestinal bacterial overgrowth. “The relationship between PPI use and the development of SIBO is still not understood.”

VIII. Interstitial nephritis.  Extremely rare. “Investigators…did not find enough evidence to support a causative relationship.”

IX. Methotrexate.  “Coadministration of PPIs with high-dose methotrexate appears to be correlated with delayed methotrexate elimination.”

Also discussed: Vitamin B12, Clopidogrel, Spontaneous bacterial peritonitis

The authors conclude that the above reported associations have received considerable attention.  “Because PPIs are overprescribed in many patients, …the clinical effects always should be reviewed and attempts should be justified to stop any therapy that may not be needed.”

Related blog entries:

Expert review: Celiac disease

A recent article gives a concise expert update on Celiac disease (NEJM 2012; 367: 2419-26).

As this is an area that has been covered several times by this blog and is familiar to most of the followers, I will comment on a few issues that were particularly interesting to me.  Though, the review is thorough and a helpful reference on most aspects of celiac disease..

What is the gluten threshold?  In patients with celiac disease, a minimal degree of gluten contamination is difficult to avoid.  “The lowest amount of daily gluten that causes damage to the celiac intestinal mucosa over (the gluten threshold) is 10 to 50 mg per day (a 25-g slice of bread contains approximately 1.6 g of gluten).”  New regulations propose that foods which are labeled as gluten free have less than 20 ppm of gluten contamination.

When are intraepithelial lymphocytes increased in the duodenum?  The abnormal threshold is considered >25 per 100 enterocytes.

What proportion of celiac disease patients have been diagnosed?  According to a recent European study, only a small proportion (21%) of celiac patients are clinically recognized.

Best screening test currently? Anti-tissue transglutaminase (TTG) IgA antibody –both sensitivity and specificity are >95%.  Consider TTG IgG in patients with IgA deficieny or possibly deamidated gliadin IgG.

Potential complications of untreated celiac disease? Osteoporosis, impaired splenic function, neurologic disorders, infertility or recurrent abortion, ulcerative jejunoileitis, and cancer.

Biopsy needed? Usually, “although recent guidelines suggest that biopsy may not be necessary in selected children with strong clinical and serologic evidence of celiac disease.”

Population-based screening or case-finding?  At this time, population-based screening is not recommended.  Case-finding based on symptoms and screening of at-risk groups is recommended though this is likely to miss >50% of cases.

Related blog posts:

Bone health in pediatrics

Due to the survival of chronically ill children, exposure to skeletal toxic treatments, and wider availability of bone health measurement technology, osteoporosis in pediatrics has become a widespread problem.  A useful concise review is available (J Pediatr 2012; 161: 983-88).

One of the biggest problems is the limited pediatric evidence on which to base treatment decisions.

Specific points regarding osteoporosis and bone health:

  1. Bone accretion: most of one’s bone mass is reached by late adolescence or early adulthood
  2. Frequency of bone fractures: in the general population, 1/2 of boys and 1/3rd of girls have sustained a fracture by 16 years of age.  Thus, bone pathology should be suspected in those with unusual fractures.
  3. Pathological fractures: “meaningful” history of fracture history includes a lower extremity long bone fracture, 2 or more upper extremity long bone fractures and/or vertebral compression fracture.
  4. Testing: due to cost and precision, dual-energy x-ray absorptiometry (DXA) remains most widely used measurement tool. However, quantitative computed tomography (QCT) has some advantages.  It is less biased by bone size and directing generates a measurement of volumetric bone mineral density.
  5. Primary osteoporosis: osteogenesis imperfecta (OI), idiopathic juvenile osteoporosis (IJO), and osteoporosis-pseudoglioma syndrome (related to loss of function in low-density lipoprotein receptor-related protein 5 [LRP5]).
  6. Secondary osteoporosis: neuromuscular diseases, malabsorption syndromes, medication-induced (glucocorticoids, diuretics), chemotherapy, and radiation treatments.
  7. 1st line treatment: adequate nutrition –especially adequate calcium and vitamin D and exercise (especially weight-bearing exercise).  It is noted that with cystic fibrosis patients there has been a better response to vitamin D3 (cholecalciferol) than D2 (ergocalciferol); as a consequence, the CF Foundation recommends all CF patients receive vitamin D3.  With regard to weight-bearing exercise, the data are conflicting regarding its efficacy.
  8. 2nd line treatment: treat underlying disorder.  For example, with inflammatory bowel disease (IBD), treatment of chronic inflammation with infliximab has been shown to improve markers of bone formation.  Inflammation in IBD has been shown to play a more important role than glucocorticoid dosing in terms of predicting bone health.
  9. 3rd line treatment ??? a) “Currently, teriparatide is the only available treatment with anabolic actions on bone.” But, a black box warning has cautioned against its use in pediatric patients   b) bisphosphonates: pamidronate, aleondronate, and zoledronic acid. A review of the small pediatric studies, primarily in OI patients, have shown some improvement in fractures, skeletal pain, and mobility.  Optimal dose, frequency, and duration remain unknown.
  10. Safety of bisphosphonates: potential problems include ‘acute phase reaction,’ hypocalcemia, musculoskeletal pain, gastrointestinal side effects, and many other adverse reactions. Atypical fractures and jaw osteonecrosis have been reported in adults.

Related blog posts:

Common to be “D-ficient”

Many of the children that a pediatric gastroenterologist sees are at risk for Vitamin D deficiency, including children with inflammatory bowel disease, cystic fibrosis, celiac disease, and liver diseases.  In addition, vitamin D deficiency is widespread: in U.S. 50% of children aged 1-5 years and 70% 6-11 years are vitamin D deficient or insufficient. A thorough review on this “D-lightful” vitamin was in a recent JPEN (JPEN J Parenter Enteral Nutr 2012; 9S-19S).

History: In 1822 Sniadecki recognized children in urban but not rural Poland developed rickets. He postulated the effects of the sun as the reason for rickets; his idea was dismissed.  In 1920s, the concept of irradiating milk to prevent rickets emerged. In 1950s, outbreak of hypercalcemia in infants in Great Britain was thought to be related to vitamin D fortification and curtailed this practice in Europe.  However, these cases were likely due to Williams syndrome.

Sources of vitamin D: oily fish (salmon), cod liver oil, some mushrooms, egg yolk, & sunlight. Exposure of an adult in a bathing suit to one minimal erythemal dose (MED) is equivalent to ingesting 20,000 IUs of Vitamin D. (The minimal dose that induces any visible reddening at that point is defined as one MED.)

Effect of sunscreen: A sun protection factor (SPF) of 30 absorbs approximately 98% of solar ultaviolet radiation & thus lowers vitamin D production by 98%.

Ethnicity: Melanin is an effective SPF.  A person of african-american descent, on average, has an SPF of 15, which reduces vitamin D production by 90%.

Age: Aging decreases 7-dehydrocholesterol in human skin.  Due to this, the elderly produce much less vitamin D.  For example, a 70 year old has a 75% reduction compared to a 20 year old.

Forms of vitamin D:  25-hydroxyvitamin D (25OH-D) is the major circulating form of vitamin D & physicians measure 25OH-D. 25OH-D is metabolized in kidney to 1,25-dihydroxyvitamin D (1,25OH-D), also called calcitriol.  This is the most biologically-active and is responsible for increasing intestinal calcium absorption and mobilizing calcium from bone.  However, 1,25OH-D provides no information vitamin D deficiency; it can be elevated or normal in deficiency states.

  • Cholecalciferol (vitamin D-3) is formed in the skin from 5-dihydrotachysterol.
  • Ergocalciferol (Vitamin D-2) is the form in Drisdol (8000 IU/mL) & Ergocalciferol Capsules (1.25 mg =50,000 USP Units)

Vitamin D deficiency:  The exact numbers are debated.  The institute of medicine (IOM) has considered individuals deficient if 25OH-D is <20 ng/mL.  The Endocrine Society and the author suggest vitamin D deficiency as <20 ng/mL & insufficiency as <30 ng/mL.  The author recommends ideal levels between 40-60 ng/mL.

Consequences of deficiency:

Osteoporosis, Osteopenia, Rickets (see references below): Bone weakening occurs due to loss of phosphorus from the kidneys.  Vitamin D deficiency lowers accrual of calcium in skeleton and leads to osteoporosis, osteopenia, and rickets. Imaging for rickets: the best single radiographic view for infants and children younger than 3 years is an anterior view of the knee that reveals the metaphyseal end and epiphysis of the femur and tibia. This site is best because growth is most rapid in this location, thus the changes are accentuated.

Nonskeletal consequences: vitamin D deficiency is associated with increased risk for preeclampsia, URIs, asthma, diabetes (type 1), multiple sclerosis, hypertension, and schizophrenia.


  • Infants who are breastfed should be receiving supplemental vitamin D, 400 IU/day.
  • Adults/children (>1 year) RDA 600 IU/day –mostly from diet per IOM. Yet author states, “it is unrealistic to believe that diet alone can ….provide this requirement.”
  • In vitamin D deficient patients: (initial treatment) 2000 IU/day or 50,000 IU/week for 6 weeks.
Toxicity from vitamin D (from NEJM 2010; 364: 248-254.): “Toxicity from vitamin D supplementation is rare and consists principally of acute hypercalcemia, which usually results from doses that exceed 10,000 IU per day; associated serum levels of 25-hydroxyvitamin D are well above 150 ng per milliliter (375 nmol per liter). The tolerable upper level of daily vitamin D intake recently set by the Institute of Medicine (IOM) is 4000 IU.”

Additional references:

  • -Pediatrics 2008; 122: 398. Should give 400 IU/day to breastfed babies. Consequences of Vit D deficiency: increased risk for DM, multiple sclerosis, cancer (breast, prostate,colon), rickets, and schizophrenia. Article lists vit D content of foods (high in cod liver oil, shrimp, fortified milk, many fish). Severe deficiency when < 5ng/mL, deficient if < 15 ng/mL; probably should be >32 ng/mL. Causes of vit D deficiency: decreased synthesis (due to lack of sun -skin pigmentation, sunscreen/clothing, geography, clouds), decreased intake, decreased maternal stores & breastfeeding, malabsorption (eg celiac, CF, EHBA, cholestasis), increased degradation; treatment of rickets: double-dose of vitamin d (~1000 IU/day for babies & 5000 for older kids) x 3-4 months along with calcium (30-75/mg/kg/day). Follow Ca/phos/alk phos monthly. Alternatively, give ~100,000 units over 1-5 days.
  • -JPEN J Parenter Enteral Nutr. 2011;35:308-316-Results: The study included 504 IBD patients (403 Crohn’s disease [CD] and 101 ulcerative colitis [UC]) who had a mean disease duration of 15.5 years in CD patients and 10.9 years in UC patients; 49.8% were vitamin D deficient, with 10.9% having severe deficiency. Vitamin D deficiency was associated with lower HRQOL (regression coefficient –2.21, 95% confidence interval [CI], –4.10 to –0.33) in CD but not UC (regression coefficient 0.41, 95% CI, –2.91 to 3.73). Vitamin D deficiency was also associated with increased disease activity in CD (regression coefficient 1.07, 95% CI, 0.43 to 1.71). Conclusions: Vitamin D deficiency is common in IBD and is independently associated with lower HRQOL and greater disease activity in CD. There is a need for prospective studies to assess this correlation and examine the impact of vitamin D supplementation on disease course.
  • -JPGN 2011;53: 361. similar prevalence of low Vitamin D as general population –58% with less than 32.
  • -JPGN 2011; 53: 11. Guidelines for bone disease with inflammatory bowel disease.
  • -Pediatrics 2010; 125: 633. Increasing Vit D deficiency noted in minority children. n=290. 22% w levels <20, 74% <30.
  • -Hepatology 2011; 53: 1118. Good vitamin D levels are another favorable predictive factor in antiviral response to Hep C along with IL28B.
  • -NEJM 2010; 364: 248-254. Vitamin D insufficiency. Levels between 20-30 may be OK -not enough evidence to determine conclusively whether this level is detrimental
  • -J Pediatr 2010; 156: 948. High rate among african americans with asthma, 86%. n=63.
  • -Pediatrics 2009; 124:e362. n=6275. 9% of pediatric patients vit D deficient & 61% were insufficient.
  • -Pediatrics 2009; 124:e371. n=3577. low 25OH-D levels inversely assoc with SBP/metabolic syndrome.
  • -NEJM 2009; 360: 398. case report of rickets
  • -J Pediatr 2003; 143: 422 & 434
  • -Pediatrics 2003; 111: 908. 200 IU Vit D recommended for all breastfed infants.
  • -J Pediatr 2000;137: 153 & 143.. Nutritional rickets–primarily in blacks; rec vitamin D 400 IU per day.