Send letter to journal:
Re: Should we screen adults with osteoporotic fractures for coeliac disease?

Dear Editor

In the recently published debate in Gut regarding the utility of mass screening of European and North American populations for coeliac disease (CD), divergent conclusions were presented.[1,2] In this context, the increased utility of screening adults for CD in those presenting with concomitant morbidity (e.g. metabolic bone disease and fracture) was raised. To support such an hypothesis, evidence of either an increased fracture rate in those with CD or, alternatively, an increased incidence of CD in those presenting with fracture would be required.

Thomason et al,[3] in a study of 244 patients with CD and 161 age and sex matched controls have addressed the first of these possibilities. They found that patients with CD "as a whole do not represent a population of particularly high risk of osteoporotic fracture".

Available data regarding the prevalence of CD in older people with osteoporosis are limited and controversial. Several reports [4,5] have suggested an increased prevalence of CD among patients with idiopathic osteoporosis leading the authors to recommend screening for CD of all osteoporotic patients. However, these findings are not supported by other studies.[6,7] In a study aimed at determining the prevalence of previously undetected secondary contributors to osteoporosis in otherwise healthy older women (mean age 65.5years), the incidence of CD was 1.7%.[8]

Consequently, it seems important to know whether in older adults screening for CD in those presenting with osteoporotic fractures would yield a significant number of unsuspected cases. Osteoporotic hip fracture, a dramatic consequence of osteoporosis and a leading cause of morbidity and mortality in older people, has been reported in association with clinically silent CD.[9,10] However, to our knowledge, serological screening tests for CD have not been systematically studied in older adults with hip fracture.

We screened the serum of 347 consecutive older patients (> 60 years of age) with hip fracture (74% females, age range 60 - 101 years, mean age 81.5+7.3 (SD) years) for the presence of IgA endomysial antibodies (EMA), IgA and IgG gliadin antibodies (IgA-AGA and IgG-AGA) and total IgA. In 13% of patients the IgA-AGA test was positive (above 34 ELISA units) whilst in 11% of patients the titre of IgG-AGA was slightly elevated (above 46 ELISA units). However, none of the patients had a positive anti-endomysial antibody test which is known to have a high specificity (98-100%).[11] This negative finding is particularly noteworthy given that 86% of the screened population had a low body weight (<60kg), 79.1% had low serum 25-hydroxyvitamin D concentration (< 50nmol/L), 69% had secondary hyperparathyroidism (serum PTH > 5.5pmol/L) and 21.6% had anaemia (haemoglobin <110g/L). Such abnormalities are often associated with CD and are believed to contribute to the development of osteoporosis in CD. So, one might expect that investigation of a cohort of older adults with osteoporosis presenting with a hip fracture might yield a moderate number of people with subclinical CD. However, this was not the case in this analysis. Our findings indicate that CD appears not to be an important contributing pathogenic factor in an older hip fracture population with osteoporosis. It further suggests that routine screening for CD in a similar population, or even in those individuals with a hip fracture and accompanying hypovitaminosis D and/or secondary hyperparathyroidism, would have low yield and not be cost-effective.

Despite these findings, we would continue to encourage physicians evaluating older adults to consider, but not routinely screen for, CD when unexplained metabolic bone disease presents even in the absence of gastrointestinal complaints and/or dermatitis herpetiformis.

Alexander A Fisher
Department of Geriatric Medicine, The Canberra Hospital, ACT, Australia

Michael W Davis
Department of Geriatric Medicine, The Canberra Hospital, ACT, Australia

Marc M Budge
Department of Geriatric Medicine, The Canberra Hospital, ACT , Australia
and
Australian National University Medical School, Australia

References

(1) Fasano A. European and North American populations should be screened for coeliac disease. Gut 2003;52:168-9.

(2) Kumar PJ. European and North American populations should be screened for coeliac disease. Gut 2003;52:170-1.

(3) Thomason K, West J, Logan RFA, Coupland C et al. Fracture experience of patients with coeliac disease: a population based survey. Gut 2003;52:518 -522.

(4) Nuti R, Martini G, Valenti R, et al. Prevalence of undiagnosed coeliac syndrome in osteoporotic women. J intern Med 2001;250:361-6.

(5) Lindh E, Ljunghall S, Larsson K, et al. Screening for antibodies against gliadin in patients with osteoporosis. J Intern Med 1992;231:403-6.

(6) Mather KJ, Meddings JB, Beck PL, et al. Prevalence of IgA- antiendomysial antibody in asymptomatic low bone mineral density. Am J Gastroenterol 2001;96:120-5.

(7) Gonzalez D, Sugai E, Gomez, et al. Is it necessary to screen for celiac disease in postmenopausal osteoporotic women? Calcif Tissue Int 2002;71:141-4.

(8) Tannenbaum C, Clark J, Schwartzman K, et al. Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab 2002;87:4431-7.

(9) Fickling WE, McFarlane XA, Bhalla AK, et al. The clinical impact of metabolic bone disease in coeliac disease. Postgrad Med J 2001;77:33-6.

(10) Rubinstein A, Liron M, Bodner G, et al. Bilateral femoral neck fractures as a result of coeliac disease. Postgrad Med J 1982;58:61-2.

(11) Carroccio A, Vitale G, Di Prima L, et al. Comparison of anti- transglutaminase ELISAs and an anti-endomysial antibody assay in the diagnosis of celiac disease: a prospective study. Clin Chem 2002;48:1546-50.

Send letter to journal:
Re: Author's reply to Walters and van Heel

Dear Editor

We agree that the risk of fracture in coeliac disease needs to be estimated more precisely and that judicious use of DEXA scanning is appropriate in this group, as it is in the general population. However as Walters et al. and others have clearly shown, bone mineral density does improve following treatment with a gluten free diet, so recommendations to screen all newly diagnosed people with coeliac disease at diagnosis do not seem judicious.[1]

Larger studies are needed and one such is in progress. Nevertheless the small increases in risk which we found are similar to those found in the only other population-based study of fracture risk in people with coeliac disease.[2] In the absence of robust data showing a marked increase in the risk of fracture in people with coeliac disease, perhaps the onus should be on those making such recommendations [1] to provide evidence supporting their efficacy and cost effectiveness.

References

(1) Scott EM, Gaywood I, Scott BB. Guidelines for osteoporosis in coeliac disease and inflammatory bowel disease. British Society of Gastroenterology. Gut 2000;46:i1-8.

(2) Vestergaard P, Mosekilde L. Fracture risk in patients with celiac Disease, Crohn's disease, and ulcerative colitis: a nationwide follow-up study of 16,416 patients in Denmark. Am J Epidemiol 2002;156:1-10.

Send letter to journal:
Re: Detecting the risks of osteoporotic fractures in coeliac disease

Dear Editor

The recent report by Thomason et al.[1] which failed to detect a significant increase in fractures experienced by treated coeliacs might reassure many patients and physicians. However this study, and the accompanying commentary by Compston [2] need full and critical assessment before changes in practice are adopted and coeliacs are no longer targeted to be screened for osteoporosis.

It is not surprising that no significant increase in fracture could be detected in this population of well-treated coeliacs, given previous findings. The American Gastroenterology Association recently reviewed studies of osteoporosis in gastrointestinal diseases including coeliac disease, according to standard levels of evidence.[3] All such studies have shown low mean bone mineral density (BMD) around the time of diagnosis of untreated coeliac disease, with a pooled analysis showing very low bone mass (age and gender-adjusted Z-scores below -2) in 40% in the spine and 15% at the hip. However, many reports including our own [4] have shown normal, or near normal mean values after treatment. This reflects the great improvement in BMD [5] and calcium absorption [6] which occurs when enteropathy is reversed with a gluten-free diet. The real issues are how to recognise previously undiagnosed cases, and how to identify potential patient subgroups who might still be at risk due to suboptimal treatment.[4]

The study also did not have sufficient power to detect any increase in those fractures most typical of osteoporosis, which have a high prevalence late in life.[7] Such fractures typically include vertebral collapse and deformity, causing significant morbidity, but which commonly are undiagnosed unless looked for radiologically. In a 50-year old woman, there is a 32% life-time risk of subsequent vertebral fractures.[8] However, these were not recorded in either coeliacs or controls in this study, indicating that the questionnaire method employed led to marked under-reporting. Femoral neck (hip) fractures, the most serious complication of osteoporosis, have an population incidence less than 1% by the age of 65 but approaching 20% by the age of 90. In this study, only about one-third of the coeliacs were aged over 65 and only one-tenth (n=20) over 75. Approximately 400 cases and controls would be needed in a prospective study to detect a 50% increase in risk from 20% to 30% with 90% power. Hence the ability of this study is clearly limited to detect a significant life-time increase in fracture risk in the minority of coeliacs who are sub-optimally treated. Much larger groups are needed, in a prospective study which includes radiological ascertainment of vertebral fractures.

A relevant comparison can be made with the large US Study of Osteoporotic Fractures Research Group where over 9000 women greater than 65 years of age were studied. In 1814 subjects with a daily calcium intake less than 400mg, those below the median for fractional calcium absorption (so resembling untreated coeliacs) experienced an incidence of hip fractures of about 9 per 1000 person-years – 2.5-fold greater than those with absorption above the median.[9]

The absolute life-time risk of osteoporotic fractures is reasonably large in the ageing population, even if the relative risk in coeliacs is not that great. Patients will be reassured by the knowledge that BMD has improved with dietary treatment and that individual risk has decreased. We hold that as the true risk of fracture in treated and untreated elderly coeliacs is unknown at present, judicious use of DXA measurements, following appropriate guidelines, to monitor calcium homeostasis and the benefits of treatment, should continue.

References

(1) K Thomason, J West, R F A Logan, C Coupland, and G K T Holmes. Fracture experience of patients with coeliac disease: a population based survey. Gut 2003;52: 518-522

(2) J Compston. Is fracture risk increased in patients with coeliac disease? Gut 2003;52: 459-460.

(3) Bernstein CN, Leslie WD, Leboff MS. AGA technical review on osteoporosis in gastrointestinal diseases. Gastroenterology 2003;124:795-841.

(4) Walters JRF, Banks LM, Butcher GP, Fowler CR. Detection of low bone mineral density by dual energy X-ray absorptiometry in unsuspected suboptimally treated coeliac disease. Gut 1995; 37:220-24.

(5) Valdimarsson T, Lofman O, Toss G, Strom M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996; 38:322-7.

(6) Molteni N, Bardella MT, Vezzoli G, Pozzoli E, Bianchi P. Intestinal calcium absorption as shown by stable strontium test in celiac disease before and after gluten-free diet. Am J Gastroenterol 1995; 90:2025-28.

(7) Compston J. Osteoporosis. In: Oxford Textbook of Medicine. 4th edition. Volume 3. Warrell DA, Cox TM, Firth JD, Benz EJ, (Eds). Oxford: Oxford University Press, 2003: 185-9.

(8) Cummings SR, Black DM, Rubin SM. Lifetime risks of hip, Colles', or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 1989; 149:2445-8.

(9) Ensrud KE, Duong T, Cauley JA et al. Low fractional calcium absorption increases the risk for hip fracture in women with low calcium intake. Ann Intern Med 2000; 132:345-53.