Altered Osteoprotegerin/RANKL Ratio and Low Bone Mineral Density in Celiac Patients on Long-term Treatment with Gluten-free Diet

 

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Abstract

Skeletal demineralization and mineral metabolism derangement are well-recognized features of untreated celiac disease (CD). Although treatment with a gluten-free diet appears to prevent bone loss while correcting skeletal demineralization in childhood, there is evidence that bone mineral density does not return to normal in celiacs diagnosed in adulthood. Osteoprotegerin (OPG), a member of the tumor necrosis factor receptor family, and ligand of receptor activator of NFkB (RANKL) are involved in the process of bone turnover and have been implicated in the pathogenesis of osteoporosis and other metabolic bone diseases. We measured OPG, RANKL, bone mineral density (BMD), and biochemical markers of bone turnover in 32 adult female premenopausal celiac patients on a gluten-free diet, and thirty age-matched healthy women. We correlated the OPG/RANKL ratio with the severity of bone loss. Celiac patients had a mean BMD lower than controls in lumbar spine and in the femoral neck. Serum levels of bone alkaline phosphatase (BAP, marker of bone formation), and urinary excretion of telopeptides of type I collagen (a marker of bone resorption) were significantly higher than in controls. Serum OPG and RANKL levels were significantly higher in CD patients than in controls, while the OPG/RANKL ratio was significantly lower in CD patients than in controls and was positively correlated with BMD at the spine. The role of elevated OPG in CD patients is unclear, but it might represent a compensatory mechanism against other factors that promote bone damage. Further studies are required to assess a possible therapeutic potential of osteoprotegerin in optimally treated celiacs with persistent osteopenia.

References

• 1 Alaedini A, Green P H. Narrative review: celiac disease: understanding a complex autoimmune disorder.  Ann Intern Med. 2005;  142 289-298
  PubMedGoogle Scholar
• 2 Bianchi M L, Bardella M T. Bone and celiac disease.  Calcif Tissue Int. 2002;  71 465-471
  CrossrefPubMedGoogle Scholar
• 3 Corazza G R, Di Stefano M, Maurino E, Bai J C. Bones in coeliac disease: diagnosis and treatment.  Best Pract Res Clin Gastroenterol. 2005;  19 453-465
  CrossrefPubMedGoogle Scholar
• 4 Pistorius L R, Sweidan W H, Purdie D W, Steel S A, Howey S, Bennett J R, Sutton D R. Coeliac disease and bone mineral density in adult female patients.  Gut. 1995;  37 639-642
  PubMedGoogle Scholar
• 5 Vogelsang H, Suk E K, Janisiw M, Stain C, Mayr W R, Panzer S. Calcaneal ultrasound attenuation and vitamin-D-receptor genotypes in celiac disease.  Scand J Gastroenterol. 2000;  35 172-176
  CrossrefPubMedGoogle Scholar
• 6 Valdimarsson T, Toss G, Ross I, Lofman O, Strom M. Bone mineral density in coeliac disease.  Scand J Gastroenterol. 1994;  29 457-461
  PubMedGoogle Scholar
• 7 Juergens J L, Scholz D A, Wollaeger E E. Severe osteomalacia associated with occult steatorrhea due to nontropical sprue; report of five cases.  Arch Intern Med. 1956;  98 774-782
  PubMedGoogle Scholar
• 8 Molteni N, Bardell M T, 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 2025-2028
  PubMedGoogle Scholar
• 9 Ciacci C, Marelli L, Klain M, Savino G, Salvatore M, Mazzacca G, Cirillo M. Effects of dietary treatment on bone mineral density in adults with celiac disease: factors predicting response.  Am J Gastroenterol. 1997;  92 992-996
  PubMedGoogle Scholar
• 10 Selby P L, Davies M, Adams J E, Mawer E B. Bone loss in celiac disease is related to secondary hyperparathyroidism.  J Bone Miner Res. 1999;  14 652-657
  PubMedGoogle Scholar
• 11 Taranta A, Fortunati D, Longo M, Rucci N, Iacomino E, Aliberti F, Facciuto E, Migliaccio S, Bardella M T, Dubini A, Borghi M O, Saraifoger S, Teti A, Bianchi M L. Imbalance of osteoclastogenesis-regulating factors in patients with celiac disease.  J Bone Miner Res. 2004;  19 1112-1121
  CrossrefPubMedGoogle Scholar
• 12 Lemieux B, Boivin M, Brossard J H, Lepage R, Picard D, Rousseau L, D’Amour P. Normal parathyroid function with decreased bone mineral density in treated celiac disease.  Can J Gastroenterol. 2001;  15 302-307
  PubMedGoogle Scholar
• 13 Pazianas M, Butcher G P, Subhani J M, Finch P J, Ang L, Collins C, Heaney R P, Zaidi M, Maxwell J D. Calcium absorption and bone mineral density in celiacs after long term treatment with gluten-free diet and adequate calcium intake.  Osteoporos Int. 2005;  16 56-63
  CrossrefPubMedGoogle Scholar
• 14 Fornari M C, Pedreira S, Niveloni S, Gonzales D, Diez R A, Vazquez H, Mazure R, Sugai E, Smecuol E, Boerr L, Maurino E, Bai J C. Pre- and post-treatment serum levels of cytokines IL-1beta, IL-6, and IL-1 receptor antagonist in celiac disease. Are they related to the associated osteopenia?.  Am J Gastroenterol. 1998;  93 413-418
  PubMedGoogle Scholar
• 15 Hofbauer L C. Osteoprotegerin ligand and osteoprotegerin: novel implications for osteoclast biology and bone metabolism.  Eur J Endocrinol. 1999;  141 195-210
  CrossrefPubMedGoogle Scholar
• 16 Lacey D L, Timms E, Tan H L, Kelley M J, Dunstan C R, Burgess T, Elliott R, Colombero A, Elliott G, Scully S, Hsu H, Sullivan J, Hawkins N, Davy E, Capparelli C, Eli A, Qian Y X, Kaufman S, Sarosi I, Shalhoub V, Senaldi G, Guo J, Delaney J, Boyle W J. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation.  Cell. 1998;  17;93 (2) 165-176
  PubMedGoogle Scholar
• 17 Hofbauer L C, Khosla S, Dunstan C R, Lacey D L, Boyle W J, Riggs B L. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption.  J Bone Miner Res. 2000;  15 2-12
  CrossrefPubMedGoogle Scholar
• 18 Coen G, Ballanti P, Balducci A, Calabria S, Fischer M S, Jankovic L, Manni M, Morosetti M, Moscaritolo E, Sardella D, Bonucci E. Serum osteoprotegerin and renal osteodystrophy.  Nephrol Dial Transplant. 2002;  17 233-238
  PubMedGoogle Scholar
• 19 Feuerherm A J, Borset M, Seidel C, Sundan A, Leistad L, Ostensen M, Faxvaag A. Elevated levels of osteoprotegerin (OPG) and hepatocyte growth factor (HGF) in rheumatoid arthritis.  Scand J Rheumatol. 2001;  30 229-234
  CrossrefPubMedGoogle Scholar
• 20 Ueland T, Bollerslev J, Godang K, Muller F, Froland S S, Aukrust P. Increased serum osteoprotegerin in disorders characterized by persistent immune activation or glucocorticoid excess - possible role in bone homeostasis.  Eur J Endocrinol. 2001;  145 685-690
  CrossrefPubMedGoogle Scholar
• 21 Szalay F, Hegedus D, Lakatos P L, Tornai I, Bajnok E, Dunkel K, Lakatos P. High serum osteoprotegerin and low RANKL in primary biliary cirrhosis.  J Hepatol. 2003;  38 395-400
  CrossrefPubMedGoogle Scholar
• 22 Morabito N, Gaudio A, Lasco A, Atteritano M, Pizzoleo M A, Cincotta M, La Rosa M, Guarino R, Meo A, Frisina N. Osteoprotegerin and RANKL in the pathogenesis of thalassemia-induced osteoporosis: new pieces of the puzzle.  J Bone Miner Res. 2004;  19 722-727
  CrossrefPubMedGoogle Scholar
• 23 Stilgren L S, Rettmer E, Eriksen E F, Hegedus L, Beck-Nielsen H, Abrahamsen B. Skeletal changes in osteoprotegerin and receptor activator of nuclear factor-kappab ligand mRNA levels in primary hyperparathyroidism: effect of parathyroidectomy and association with bone metabolism.  Bone. 2004;  35 256-265
  CrossrefPubMedGoogle Scholar
• 24 Maimoun L, Couret I, Mariano-Goulart D, Dupuy A M, Micallef J P, Peruchon E, Ohanna F, Cristol J P, Rossi M, Leroux J L. Changes in osteoprotegerin/RANKL system, bone mineral density, and bone biochemicals markers in patients with recent spinal cord injury.  Calcif Tissue Int. 2005;  76 404-411
  CrossrefPubMedGoogle Scholar
• 25 Ciacci C, Cirillo M, Cavallaro R, Mazzacca G. Long-term follow-up of celiac adults on gluten-free diet: prevalence and correlates of intestinal damage.  Digestion. 2002;  66 178-185
  CrossrefPubMedGoogle Scholar
• 26 Marsh M N. Gluten, major histocompatibility complex, and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (“celiac sprue”).  Gastroenterology. 1992;  102 330-354
  CrossrefPubMedGoogle Scholar
• 27 Wahab P J, Meier J WR, Mulder C JJ. Histologic follow-up of people with Coeliac Disease on a gluten-free diet: slow and incomplete recovery.  Am J Clin Pathol. 2002;  118 459-463
  CrossrefPubMedGoogle Scholar
• 28 Tursi A, Brandimarte G, Giorgetti G M, Gigliobianco A. Endoscopic features of celiac disease in adults and the correlation with age, histological damage, and clinical form of the disease.  Endoscopy. 2002;  34 787-792
  Article in Thieme ConnectPubMedGoogle Scholar
• 29 Paffenbarger R S Jr, Wing A L, Hyde R T. Physical activity as an index of heart attack risk in college alumni.  Am J Epidemiol. 1978;  108 161-175
  PubMedGoogle Scholar
• 30 Ireland P, Jolley D, Giles G, O’Dea K, Powkes J, Ritishauer I, Wahlquist M L, Williams J. A food frequency questionnaire for use in Australian prospective study involving an ethnically diverse cohort.  Asia Pac J Clin Nutr. 1994;  3 19-31
  PubMedGoogle Scholar
• 31 WHO Study Group .Assessment of fracture risk and its application to screening for post-menopausal osteoporosis. WHO Tech Rep Ser 1994 n° 843
  Google Scholar
• 32 McFarlane X A, Balla A K, Robertson D AF. Effect of a gluten-free diet on osteopenia in adults with newly diagnosed coeliac disease.  Gut. 1996;  39 180-184
  CrossrefPubMedGoogle Scholar
• 33 Kemppainen T, Kroger H, Janatuinen E, Arnala I, Lamberg-Allardt C, Karkkainen M, Kosma V M, Julkunen R, Jurvelin J, Alhava E, Uusitupa M. Bone recovery after a gluten-free diet: a 5-year follow-up study.  Bone. 1999;  25 355-360
  CrossrefPubMedGoogle Scholar
• 34 Keaveny A P, Freaney R, McKenna M J, Masterson J, O’Donoghue D P. Bone remodeling indices and secondary hyperparathyroidism in celiac disease.  Am J Gastroenterol. 1996;  91 1226-1231
  PubMedGoogle Scholar
• 35 Kontakou M, Przemioslo R T, Sturgess R P, Limb A G, Ciclitira P J. Expression of tumour necrosis factor-alpha, interleukin-6, and interleukin-2 mRNA in the jejunum of patients with coeliac disease.  Scand J Gastroenterol. 1995;  30 456-463
  PubMedGoogle Scholar
• 36 Little R D, Carulli J P, Del Mastro R G, Dupuis J, Osborne M, Folz C, Manning S P, Swain P M, Zhao S C, Eustace B. et al . A mutation in the LDL receptor-related protein 5 gene results in the autosomal dominant high-bone-mass trait.  Am J Hum Genet. 2002;  70 (1) 11-19
  PubMedGoogle Scholar
• 37 Gong Y, Slee R B, Fukai N, Rawadi G, Roman-Roman S, Reginato A M, Wang H, Cundy T, Glorieux F H. et al . LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.  Cell. 2001;  107 513-523
  CrossrefPubMedGoogle Scholar
• 38 Hofbauer L C, Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases.  JAMA. 2004;  292 490-495
  CrossrefPubMedGoogle Scholar
• 39 Fiore C E, Riccobene S, Mangiafico R, Santoro F, Pennisi P. Hepatitis C-associated osteosclerosis (HCAO): report of a new case with involvement of the OPG/RANKL system.  Osteoporos Int. 2005;  16 2180-2184
  CrossrefPubMedGoogle Scholar

C. E. Fiore, M. D., Ph. D.

Department of Internal Medicine

University of Catania OVE · Via Plebiscito 628 · 95124 Catania · Italy

Phone: +39 (095) 7435386

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Email: carmelo.fiore@tin.it