Abstract
Summary
Chronic inflammation and malabsorption in celiac disease (CD) can cause bone metabolism alterations and bone mineral loss in children and adults. Bone status before and after gluten-free diet, epidemiology of fractures, and possible treatment options for CD-related osteoporosis are presented. Controversial aspects of this complication of CD are discussed.
The relationship between bone derangements and celiac disease (CD) was recognized almost 50 years ago, but many questions are still open. We are now aware that osteoporosis is a relatively frequent atypical presentation of CD, especially in adults, and that undiagnosed CD can be the cause of osteoporosis and related fractures. Chronic inflammatory intestinal diseases, including CD, can affect bone and mineral metabolism because of alterations in both systemic and local regulatory factors. The pathogenetic processes are still controversial, but two main mechanisms seem to be involved: intestinal malabsorption and the presence of chronic inflammation. This review analyzes the published data on bone involvement in children, adolescents, and adults either before or after a gluten-free diet. Special attention is paid to the epidemiology of fractures in celiac patients, considering that fractures are a major complication of osteoporosis and an important problem in the management of a chronic disease like CD. The usefulness of screening osteoporotic patients systematically for CD is still an open question, but some rules can be given. Finally, the current treatment options for children and adults are discussed. Recommendations for future clinical research are proposed.
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Notes
A short comment, not specific for celiac disease, on the use of the T- or Z-score to evaluate bone density in adults (in adults only, since in children and adolescents the Z-score must be used) may be useful at this point, to better understand the differences in bone density reported by different authors. By definition, the Z-score virtually coincides with the T-score in the 25–39 years age range. In older adults, the use of the T-score is universally accepted to define osteoporosis, osteopenia, or normality, according to the recommendations of a WHO Study Group [58]. There are strong scientific evidences of a clear relationship between the decrease of the T-score value and the increase of fragility fractures at any age. Thus, the T-score helps to evaluate the current risk of fractures, as well as the future risk. The Z-score, being the comparison with the mean value of healthy controls matched for both sex and age, is less useful in older adults, because some degree of bone loss is prevalent even among the apparently healthy subjects used as controls. However, the Z-score may help to understand how much the bone density of an individual affected by a disease is different from that of the healthy population of the same gender and age, and this may be the main reason why many studies on celiac patients with a wide age range used the Z-score.
References
Dube C, Rostom A, Sy R et al (2005) The prevalence of celiac diseases in average-risk and at-risk Western European populations: A systematic review. Gastroenterology 128:S57–S67
Holtmeier W, Caspary WF (2006) Celiac disease: review. Orph J Rare Dis 1:3 (DOI 10.1186/1750-1172-1-3)
Rampertab SD, Pooran N, Brar P et al (2006) Trends in the presentation of celiac disease. Am J Med 19:9–14
Esteve M, Rosinach M, Fernández-Bañares F et al (2006) Spectrum of gluten-sensitive enteropathy in first-degree relatives of patients with celiac disease: clinical relevance of lymphocytic enteritis. Gut 55:1739–1745
Shaoul R, Lerner A (2007) Associated autoantibodies in celiac disease. Autoimmun Reviews 6:559–565
Trier JS (1998) Diagnosis of celiac sprue. Gastroenterology 115:211–216
Dieterich W, Laag B, Schopper H (1998) Autoantibodies to tissue transglutaminase as predictors of celiac disease. Gastroenterology 115:1317–1321
Bardella MT, Trovato C, Cesana BM et al (2001) Serological markers for celiac disease: is it time to change? Dig Liver Dis 33:426–431
Marsh MN (1992) Gluten, major histocompatibility complex, and the small intestine. A molecular and immunologic approach to the spectrum of gluten sensitivity (celiac sprue). Gastroenterology 102:330–354
Green P, Jabri B (2003) Coeliac disease. Lancet 362:383–391
Alaedini A, Green PHR (2005) Narrative review: Celiac disease: Understanding a complex autoimmune disorder. Ann Int Med 142:289–298
Green PHR, Cellier C (2007) Celiac disease. N Engl J Med 357:1731–1743
Salvensen HA, Böe J (1953) Osteomalacia in sprue. Acta Med Scand 466:290–299
Melvin KEW, Hepner GW, Bordier P et al (1970) Calcium metabolism and bone pathology in adult coeliac disease. Q J Med 39:83–113
Caraceni MP, Molteni N, Bardella MT et al (1988) Bone and mineral metabolism in adult celiac disease. Am J Gastroenterol 83:274–277
Meyer D, Stavropolous S, Diamond B et al (2001) Osteoporosis in a North American adult population with celiac disease. Am J Gastroenterol 96:112–119
Ng DPK, Stone M, Hosking DJ, Long RG (1992) Calcium malabsorption in celiac sprue in not the result of vitamin D deficiency. Gastroenterology 102:A229
Corazza GR, Di Sario A, Cecchetti L et al (1995) Bone mass and metabolism in patients with celiac disease. Gastroenterology 109:122–128
Selby PL, Davies M, Adams JE, Mawer EB (1999) Bone loss in celiac disease is related to secondary hyperparathyroidism. J Bone Miner Res 14:652–657
Lemieux B, Bolvin M, Brossard JH et al (2001) Normal parathyroid function with decreased bone mineral density in treated celiac disease. Can J Gastroenterol 15:302–307
Clements MR, Davies M, Hayes ME et al (1992) The role of 1,25-dihydroxyvitamin D in the mechanism of acquired vitamin D deficiency. Clin Endocrinol (Oxf) 37:17–27
Colston KW, Mackay AG, Finlayson C et al (1994) Localisation of vitamin D receptor in normal human duodenum and in patients with coeliac disease. Gut 35:1219–1225
Staun M, Jarnum S (1998) Measurement of the 10,000-molecular weight calcium-binding protein in small-intestinal biopsy specimens from patients with malabsorption syndromes. Scand J Gastroenterol 23:827–832
Vogelsang H, Suk EK, Janlsiw M et al (2000) Calcaneal ultrasound attenuation and vitamin-D-receptor genotypes in celiac disease. Scand J Gastroenterol 35:172–176
Valdimarsson T, Arnqvist HJ, Toss G et al (1999) Low circulating insulin-like growth factor I in coeliac disease and its relation to bone mineral density. Scand J Gastroenterol 34:904–908
Jameson S (2000) Coeliac disease, insulin-like growth factor, bone mineral density and zinc. Scand J Gastroenterol 35:894–896
Jansson UHG, Kristiansson B, Magnusson P et al (2001) The decrease of IGF-I, IGF-binding protein-3 and bone alkaline phosphatase isoforms during gluten challenge correlates with small intestinal inflammation in children with coeliac disease. Eur J Endocrinol 144:417–423
Bardella MT, Bianchi ML, Teti A (2005) Chronic inflammatory intestinal diseases and bone loss. Gut 54:1508
Moreno ML, Crusius JBA, Cherñavsky A et al (2005) The IL-1 gene family and bone involvement in celiac disease. Immunogen 57:618–620
Taranta A, Fortunati D, Longo M et al (2004) Imbalance of osteoclastogenesis-regulating factors in patients with celiac disease. J Bone Miner Res 19:1112–1121
Di Stefano M, Veneto G, Corrao G, Corazza GR (2000) Role of lifestyle factors in the pathogenesis of osteopenia in adult coeliac disease: a multivariate analysis. Eur J Gastroenterol Hepatol 12:1195–1199
McFarlane XA, Bhalla AK, Reeves DE et al (1996) Osteoporosis in treated adult coeliac disease. Gut 36:710–714
Kaukinen K, Peräaho M, Lindfors K et al (2007) Persistent small bowel mucosal villous atrophy without symptoms in coeliac disease. Aliment Pharmacol Ther 25:1237–1245
Fasano A, Catassi C (2005) Coeliac disease in children. Best Pract Res Clin Gastrenterol 19:467–478
Mora S, Weber G, Barera G et al (1993) Effect of gluten-free diet on bone mineral content in growing patients with celiac disease. Am J Clin Nutr 57:224–228
Scotta MS, Salvatore S, Salvatoni A et al (1997) Bone mineralization and body composition in young patients with celiac disease. Am J Gastroenterol 92:1331–1334
Barera G, Mora S, Brambilla P et al (2000) Body composition in children with celiac disease and the effects of a gluten-free diet: a prospective case-control study. Am J Clin Nutr 72:71–75
Sdepanian VJ, De Miranda Carvalho CN, De Morais B et al (2003) Bone mineral density of the lumbar spine in children and adolescents with celiac disease on a gluten-free diet in Sao Paulo, Brazil. J Ped Gastroenterol Nutr 37:571–576
Exner GU, Sacher M, Shmerling DH et al (1978) Growth retardation and bone mineral status in children with coeliac disease recognized after the age of 3 years. Helv Paediatr Acta 33:497–507
Hansen D, Bennedback FN, Hansen LK et al (2001) High prevalence of celiac disease in Danish children with type I diabetes mellitus. Acta Paediatr 90:1238–1243
Diniz-Santos DR, Brandão F, Adan L et al (2007) Bone mineralization in young patients with type I diabetes mellitus and screening-identified evidence of celiac disease. Dig Dis Sci DOI 10.1007/s10620-007-9988-9
Bozzola M, Giovenale D, Bozzola E et al (2005) Growth hormone deficiency and coeliac disease: an unusual association? Clin Endocrinol 62:372–375
Hamrick MW, Ferrari SL. Leptin and the sympathetic connection of fat to bone. Osteoporos Int. 2007 Oct 9; [Epub ahead of print]
Patel MS, Elefteriou F (2007) The new field of neuroskeletal biology. Calcif Tissue Int 80:337–347
Ertekin V, Orbak Z, Selimoglu MA, Yildiz L (2006) Serum leptin levels in childhood celiac disease. J Clin Gastroenterol 40:906–909
Mora S, Barera G, Ricotti A et al (1998) Reversal of low bone density with a gluten-free diet in children and adolescents with celiac disease. Am J Clin Nutr 67:477–481
Mora S, Barera G, Beccio S et al (1999) Bone density and bone metabolism are normal after long-term gluten-free diet in young celiac patients. Am J Gastroenterol 94:398–403
Molteni N, Caraceni MP, Bardella MT et al (1990) Bone mineral density in adult celiac patients and the effect of gluten-free diet from childhood. Am J Gastroenterol 85:51–53
Challa A, Moulas A, Cholevas V et al (1998) Vitamin D metabolites in patients with coeliac disease. Eur J Pediatr 157:262–263
Tau C, Mautalen C, De Rosa S et al (2006) Bone mineral density in children with celiac disease. Effect of a gluten-free diet. Eur J Clin Nutr 60:358–363
Cellier C, Flobert C, Cormier C et al (2000) Severe osteopenia in symptom-free adults with a childhood diagnosis of coeliac disease. Lancet 355:806
Butcher GP, Banks LM, Walters JFR (1992) Reduced bone mineral density in coeliac disease - the need for bone densitometry estimations. Gut 33:S54
McFarlane XA, Bhalla A, Morgan L et al (1992) Osteoporosis: a frequent finding in treated adult coeliac disease. Gut 33(Suppl 2):S48
Valdimarsson T, Löfman O, Toss G, Ström M (1996) Reversal of osteopenia with diet in adult coeliac disease. Gut 38:322–327
Bardella MT, Fredella C, Prampolini L et al (2000) Body composition and dietary intakes in adult celiac disease patients consuming a strict gluten-free diet. Am J Clin Nutr 72:937–939
Pistorius LR, Sweidan WH, Purdie DW et al (1995) Coeliac disease and bone mineral density in adult female patients. Gut 37:639–642
Corazza GR, Di Stefano M, Mauriño E, Bai JC (2005) Bones in coeliac disease: diagnosis and treatment. Best Pract Res Clin Gastrenterol 19:453–465
WHO Study Group. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis (WHO Technical Report Series no. 843). Geneva: World Health Organization 1994
Walters JRF, Banks LM, Butcher GP, Fowler CR (1995) Detection of low bone mineral density by dual energy x ray absorptiometry in unsuspected suboptimally treated coeliac disease. Gut 37:220–224
Corazza GR, Di Sario A, Cecchetti L et al (1996) Influence of pattern of clinical presentation and of gluten-free diet on bone mass and metabolism in adult coeliac disease. Bone 18:525–530
Mazure R, Vazquez H, Gonzalez D et al (1994) Bone mineral affection in asymptomatic adult patients with celiac disease. Am J Gastroenterol 89:2130–2134
Mustalahti K, Collin P, Sievãnen H et al (1999) Osteopenia in patients with clinically silent coeliac disease warrants screening. Lancet 354:744–745
Bai D, Brar P, Holleran S et al (2005) Effect of gender on the manifestation of celiac disease: evidence for greater malabsorption in men. Scand J Gastroenterol 40:183–187
Bai JC, Gonzalez D, Mautalen C et al (1997) Long-term effect of gluten restriction on bone mineral density in coeliac disease. Aliment Pharmacol Ther 11:157–164
Sategna-Guidetti C, Grosso SB, Grosso S et al (2000) The effects of 1-year gluten withdrawal on bone mass, bone metabolism and nutritional status in newly-diagnosed adult coeliac disease patients. Aliment Pharmacol Ther 14:35–43
Valdimarsson T, Toss G, Löfman O, Strõm M (2000) Three years’ follow-up of bone density in adult coeliac disease: significance of secondary hyperparathyroidism. Scand J Gastroenterol 35:274–280
Kemppainen T, Kroger H, Janatuinen E et al (1999) Bone recovery after a gluten-free diet: a 5-year follow-up study. Bone 25:355–360
Ciacci C, Maurelli L, Klain M et al (1997) Effects of dietary treatment on bone mineral density in adults with celiac disease: factors predicting response. Am J Gastroenterol 92:992–996
Matysiak-Budnik T, Malamut G, Patey-Mariaud de Serre N et al (2007) Long-term follow-up of 61 coeliac patient diagnosed in childhood: evolution toward latency is possible on a normal diet. Gut 56:1376–1386
Ciacci C, Cirillo M, Mellone M et al (1995) Hypocalciuria in overt and subclinical celiac disease. Am J Gastroenterol 90:1480–1484
Molteni N, Bardella MT, Vezzoli G et al (1995) Intestinal calcium absorption as shown by stable strontium test in celiac disease before and after gluten-free diet. Am J Gastroenterol 90:2025–2208
Corazza GR, Di Sario A, Sacco G et al (1994) Subclinical coeliac disease: an anthropometric assessment. J Int Med 236:183–187
Kozanoglu E, Basaran S, Goncu MK (2005) Proximal myopathy as an unusual presenting feature of celiac disease. Clin Rheumatol 24:76–78
Salvesen HA, Boe J (1953) Osteomalacia in sprue. Acta Med Scand 1466:290–299
Landolsi H, Bouajina E, Mankaï A et al (2006) Severe osteomalacia due to undiagnosed coeliac disease: three case reports of Tunisian women. Rheumatol Int 26:261–263
Harzy T, Benbouazza K, Amine B et al (2005) An unusual case of osteomalacia as the presenting feature of coeliac disease. Rheumatol Int 26:90–91
Byrne MF, Razak AR, Leader MB et al (2002) Disabling osteomalacic myopathy as the only presenting feature of coeliac disease. Eur J Gastroenterol Hepatol 14:1271–1274
Basu RA, Elmer K, Babu A, Kelly CA (2000) Coeliac disease can still present with osteomalacia!. Rheumatology (Oxford) 39:335–336
Viljamaa M, Collin P, Huhtala H et al (2005) Is coeliac diseases screening risk groups justified? A fourteen-year follow-up with special focus on compliance and quality of life. Aliment Pharmacol Ther 22:317–324
Fritzsch J, Hennicke G, Tannapfel A (2005) 10 frakturen in 21 jahren. Unfallchirurg 108:994–997
Vazquez H, Mazure R, Gonzalez D et al (2000) Risk of fractures in celiac disease patients: a cross-sectional, case-control study. Am J Gastroenterol 95:183–189
Fickiling WE, McFarlane XA, Bhalla AK, Robertson DA (2001) The clinical impact of metabolic bone disease in coeliac disease. Postgrad Med J 77:33–36
Moreno ML, Vazquez H, Mazure R et al (2004) Stratification of bone fracture risk in patients with celiac disease. Clin Gastroenterol Hepatol 2:127–134
Thomason K, West J, Logan RF et al (2003) Fracture experience of patients with celiac disease: a population-based study. Gut 52:518–522
Vestergaard P, Mosekilde L (2002) 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 156:1–10
West J, Logan RFA, Card TR et al (2003) Fracture risk in people with celiac disease: a population-based cohort study. Gastroenterology 125:429–436
Davie MW, Gaywood I, George EJ et al (2005) Excess non-spine fractures in women over 50 years with celiac disease: a cross-sectional, questionnaire-based study. Osteoporos Int 16:1150–1155
Jafri MR, Nordstrom CW, Murray JA et al (2007) Long-term fracture risk in patients with celiac disease: a population-based study in Olmted County, Minnesota. DOI 10.1007/s10620-007-9976-0
Ludvigsson JF, Michaelsson K, Ekbom A, Montgomery SM (2007) Coeliac disease and the risk of fractures - a general population-based cohort study. Aliment Pharmacol Ther 25:273–285
Olmos M, Antelo M, Vazquez H et al (2008) Systematic review and meta-analysis of observational studies on the prevalence of fractures in coeliac disease. Dig Liver Dis 40:46–53
National Institute of Health (2005) Consensus Development Conference Statement on Celiac Disease; June 28–30, 2004. Gastroenterology 128(4 Supp 1):S1-S9
Lindh E, Ljunghall S, Larsson K, Lavö B (1992) Screening for antibodies against gliadin in patients with osteoporosis. J Int Med 231:403–406
Eastell R (1998) Practical management of the patient with osteoporotic fracture. In: Meunier PJ (ed) Osteoporosis: diagnosis and management. Martin Dunitz, London, pp 175–190
Mather KJ, Meddings JB, Beck PL et al (2001) Prevalence of IgA-antiendomysial antibody in asymptomatic low bone mineral density. Am J Gastroenterol 96:120–125
Armagan O, Uz T, Tascioglu F et al (2005) Serological screening for celiac disease in premenopausal women with idiopathic osteoporosis. Clin Rheumatol 24:239–243
Drummond FJ, Annis P, O’Sullivan K et al (2003) Screening for asymptomatic celiac disease among patients referred for bone densitometry measurement. Bone 33:970–974
O’Leary C, Feighery C, Feighery A et al (2002) The prevalence of coeliac disease among female subjects having bone densitometry. Ir J Med Sci 171:145–147
Sanders DS, Patel D, Khan FB et al (2005) Case-finding for adult celiac disease in patients with reduced bone mineral density. Dig Dis Sci 50:587–592
Stenson WF, Newberry R, Lorenz R et al (2005) Increased prevalence of celiac disease and need for routine screening among patients with osteoporosis. Arch Intern Med 165:393–399
Lupatelli G, Fuscaldo G, Castellucci G et al (1994) Severe osteomalacia due to gluten-sensitive enteropathy. Ann Ital Med Int 9:40–43
Gannage MH, Abikaram G, Nasr F, Awada H (1998) Osteomalacia secondary to celiac disease, primary hyperparathyroidism, and Graves’ disease. Am J Med Sci 315:136–139
Bianchi ML, Bardella MT (2002) Bone and celiac disease. Calcif Tissue Int 71:465–471
Scott EM, Gaywood I, Scott BB, for the British Society of Gastroenterology (2000) Guidelines for osteoporosis in coeliac disease and inflammatory bowel disease. Gut 46(Suppl I)i1-i8
Hepner GW, Jowsey J, Arnaud C et al (1978) Osteomalacia and celiac disease: response to 25-hydroxyvitamin D. Am J Med 65:1015–1020
Mautalen C, Gonzalez D, Mazure R et al (1997) Effect of treatment on bone mass, mineral metabolism and body composition in untreated celiac disease patients. Am J Gastroenterol 92:313–318
Walters JRF (1994) Bone mineral density in coeliac disease. Gut 35:150–151
Pazianas M, Butcher GP, Subhani JM et al (2005) Calcium absorption and bone mineral density in celiacs after long term treatment with gluten-free diet and adequate calcium intake. Osteoporos Int 16:56–63
Kupper C (2005) Dietary guidelines and implementation for celiac disease. Gastroenterology 128:S121–S127
Meek SE, Nix K (2007) Hypocalcemia after alendronate therapy in patients with celiac disease. Endoc Pract 13:403–407
Hill ID, Dirks MH, Liptak GS et al (2005) Guideline for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 40:1–19
Lewis NR, Scott BB (2005) Should patients with coeliac disease have their bone mineral density measured? Eur J Gastroenterol Hepatol 17:1065–1070
McGough N, Cummings JH (2005) Coeliac disease: a diverse clinical syndrome caused by intolerance of wheat, barley and rye. Proc Nutr Soc 64:434–450
Murray JA (2006) Celiac disease in patients with an affected member, type 1 diabetes, iron-deficiency, or osteoporosis? Gastroenterology 128:S52–S56
Bianchi ML, Bardella MT. Celiac disease: its effects on bone. (DOI 10.1138/20060212) IBMS BoneKEy - Osteovision 2006 3:30–38
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Bianchi, ML., Bardella, M.T. Bone in celiac disease. Osteoporos Int 19, 1705–1716 (2008). https://doi.org/10.1007/s00198-008-0624-0
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DOI: https://doi.org/10.1007/s00198-008-0624-0