Prevalence and risk of bone fractures in patients with chronic pancreatitis: meta-analysis

Aim: to systematize data on the frequency and risk of bone fractures in patients with chronic pancreatitis.

Methods. MEDLINE/PubMed, EMBASE, Cochrane, Google Scholar through October 2020 were searched to identify studies evaluating the prevalence of bone fractures in chronic pancreatitis. For the final analysis, publications with detailed descriptive statistics (total sample size, number of patients with chronic pancreatitis, number of control persons, number of patients with fractures in groups) were selected, allowing the resulting data to be included in the meta-analysis.

Results. The final analysis included 6 studies involving 2 025 918 people (18 844 patients with chronic pancreatitis; 2 007 074 – control subjects). The generalized incidence of fractures in patients with chronic pancreatitis was 14.09% (95% CI: 5.877–25.098). There was significant heterogeneity between the results (p<0.0001; I2=99.58%). Chronic pancreatitis significantly increases the risk of fractures in comparison with control subjects with OR 2.819 (95% CI: 1.855–4.282; I2=97.14%). With the exclusion from the analysis of 2 studies with a wide 95% CI (less than 150 patients with chronic pancreatitis in each), the pooled fracture frequency was 9.25% (95% CI: 1.930–21.221; I2=99.74%).

Conclusion. This meta-analysis demonstrated that CP is a risk factor for fractures. Considering this association, it is advisable to include densitometry in the routine examination algorithms for patients with chronic pancreatitis, as well as to correct osteoporosis in this category of patients in time.

chronic pancreatitis, osteoporosis, fractures, nutritional status, vitamin D, enzyme replacement therapy

1. Beyer G, Habtezion A, Werner J, Lerch MM, Mayerle J. Chronic pancreatitis. Lancet. 2020;396(10249):499−512. doi: 10.1016/S0140-6736(20)31318-0

2. Gardner TB, Adler DG, Forsmark CE, Sauer BG, Taylor JR, Whitcomb DC. ACG Clinical Guideline: Chronic pancreatitis. Am J Gastroenterol. 2020;115(3):322−339. doi: 10.14309/ajg.0000000000000535

3. Yadav D, Lowenfels AB. The epidemiology of pancreatitis and pancreatic cancer. Gastroenterology. 2013;144(6):1252−1261. doi: 10.1053/j.gastro.2013.01.068

4. Xiao AY, Tan ML, Wu LM, Asrani VM, Windsor JA, Yadav D, et al. Global incidence and mortality of pancreatic diseases: A systematic review, meta-analysis, and meta-regression of population-based cohort studies. Lancet Gastroenterol Hepatol. 2016;1(1):45−55. doi: 10.1016/S2468-1253(16)30004-8

5. Petrov MS, Yadav D. Global epidemiology and holistic prevention of pancreatitis. Nat Rev Gastroenterol Hepatol. 2019;16(3):175−184. doi: 10.1038/s41575-018-0087-5

6. Kucheryavyy YuA, Andreev DN. Nutritional status in patients with chronic pancreatitis. J Nutritional Therapeutics. 2014;3(3):122−132. doi: 10.6000/1929-5634.2014.03.03.3

7. Maev IV, Kucheryavyi YA, Andreev DN, Bideeva TV. Nutritional status in patients with chronic pancreatitis. Terapevticheskiy arkhiv = Therapeutic archive. 2016;88(2):81−89 (In Russ.). doi: 10.17116/terarkh201688281-89

8. Rasmussen HH, Irtun O, Olesen SS, Drewes AM, Holst M. Nutrition in chronic pancreatitis. World J Gastroenterol. 2013;19: 7267−7275. doi: 10.3748/wjg.v19.i42.7267

9. Sikkens EC, Cahen DL, Koch AD, Braat H, Poley JW, Kuipers EJ, et al. The prevalence of fat-soluble vitamin deficiencies and a decreased bone mass in patients with chronic pancreatitis. Pancreatology. 2013;13(3):238−242. doi: 10.1016/j.pan.2013.02.008

10. Bideyeva TV, Andreev DN, Kucheryavyy YA, Maev IV. Dynamics of vitamin D level in patients with chronic pancreatitis on the background of enzyme replacement therapy. Meditsinskiy sovet = Medical Council. 2019;3:156−160 (In Russ.). doi: 10.21518/2079-701X-2019-3-156-160

11. Martínez-Moneo E, Stigliano S, Hedström A, Kaczka A, Malvike M, Waldthaler A, et al. Deficiency of fat-soluble vitamins in chronic pancreatitis: A systematic review and meta-analysis. Pancreatology. 2016;16(6):988−994. doi: 10.1016/j.pan.2016.09.008

12. Hoogenboom SA, Lekkerkerker SJ, Fockens P, Boermeester MA, van Hooft JE. Systematic review and meta-analysis on the prevalence of vitamin D deficiency in patients with chronic pancreatitis. Pancreatology. 2016;16(5):800−806. doi: 10.1016/j.pan.2016.07.010

13. National Osteoporosis Foundation. Physicians guide to prevention and treatment of osteoporosis. 2014. doi: 10.1007/s00198-014-2794-2

14. Winzenberg T, Jones G. Vitamin D and bone health in childhood and adolescence. Calcif Tissue Int. 2013;92(2):140−150. doi: 10.1007/s00223-012-9615-4

15. Compston JE, McClung MR, Leslie WD. Osteoporosis. Lancet. 2019;393(10169):364−376. doi: 10.1016/S0140-6736(18)32112-3

16. Melnichenko GA, Belaya ZhE, Rozhinskaya LYa, Toroptsova NV, Alekseeva LI, Biryukova EV, et al. Federal clinical guidelines for the diagnosis, treatment and prevention of osteoporosis. Problemy endokrinologii = Problems of Endocrinology. 2017; 63(6): 392−426. (In Russ.). doi: 10.14341/probl2017636392-426

17. Adams AL, Shi J, Takayanagi M, Braghin D, Gatti D, Vilei MT, et al. Ten-year hip fracture incidence rate trends in a large California population, 1997−2006. Osteoporos Int. 2013;24(1):373−376. doi: 10.1007/s00198-012-1938-5

18. Gheita TA, Hammam N. Epidemiology and awareness of osteoporosis: a viewpoint from the Middle East and North Africa. Int J Clin Rheumatol. 2018;13(3):134−147.

19. Duggan SN, Smyth ND, Murphy A, Macnaughton D, O’Keefe SJ, Conlon KC. High prevalence of osteoporosis in patients with chronic pancreatitis: a systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2014;12(2):219−228. doi: 10.1016/j. cgh.2013.06.016

20. Vijayakumar R, Busselberg D. Osteoporosis: An under-recognized public health problem. J Local Glob Health Sci. 2016;(1). doi: 10.5339/jlghs.2016.2

21. Tignor AS, Wu BU, Whitlock TL, Lopez R, Repas K, Banks PA, et al. High prevalence of low-trauma fracture in chronic pancreatitis. Am J Gastroenterol. 2010;105(12):2680−2686. doi: 10.1038/ajg.2010.325

22. Bang UC, Benfield T, Bendtsen F, Hyldstrup L, Beck Jensen J-E. The risk of fractures among patients with cirrhosis or chronic pancreatitis. Clin Gastroenterol Hepatol. 2014;12(2):320−326. doi: 10.1016/j.cgh.2013.04.031

23. Haas S, Krins S, Knauerhase A, Löhr M. Altered bone metabolism and bone density in patients with chronic pancreatitis and pancreatic exocrine insufficiency. JOP. 2015;16(1):58−62. doi: 10.6092/1590-8577/2898

24. Munigala S, Agarwal B, Gelrud A, Conwell DL. Chronic pancreatitis and fracture: A retrospective, population-based veterans administration study. Pancreas. 2016;45(3):355−361. doi:10.1097/MPA.0000000000000381

25. Rana F, Bekkali N, Charnley R, et al. Is metabolic bone disease routinely tested for in chronic pancreatitis? Gut. 2018;67:A157.

26. Kanakis A, Vipperla K, Papachristou GI, Brand RE, Slivka A, Whitcomb DC, et al. Bone health assessment in clinical practice is infrequenty performed in patients with chronic pancreatitis. Pancreatology. 2020;20(6):1109−1114. doi: 10.1016/j.pan.2020.07.396

27. Sietsema DL. Fighting the epidemic: Bone health and osteoporosis. Nurs Clin North Am. 2020;55(2):193–202. doi: 10.1016/j.cnur.2020.02.002

28. Somersalo A, Paloneva J, Kautiainen H, Lönnroos E, Heinänen M, Kiviranta I. Increased mortality after lower extremity fractures in patients <65 years of age. Acta Orthop. 2016;87(6):622– 625. doi: 10.1080/17453674.2016.1210533

29. Ahmed A, Deep A, Kothari DJ, Sheth SG. Bone disease in chronic pancreatitis. World J Clin Cases. 2020;8(9):1574−1579. doi: 10.12998/wjcc.v8.i9.1574

30. Oh HJ, Ryu KH, Park BJ, Yoon BH. Osteoporosis and osteoporotic fractures in gastrointestinal disease. J Bone Metab. 2018;25(4):213−217. doi: 10.11005/jbm.2018.25.4.213

31. Barkin JA, Barkin JS. Chronic pancreatitis and bone disease. J Clin Densitom. 2020;23(2):237−243. doi: 10.1016/j.jocd.2019.08.004

32. Stigliano S, Waldthaler A, Martinez-Moneo E, Lionetto L, Robinson S, Malvik M, et al. Vitamins D and K as factors associated with osteopathy in chronic pancreatitis: A prospective multicentre study (P-BONE Study). Clin Transl Gastroenterol. 2018;9(10):197. doi: 10.1038/s41424-018-0066-8

33. Duggan SN, Purcell C, Kilbane M, O’Keane M, McKenna M, Gaffney P, et al. An association between abnormal bone turnover, systemic inflammation, and osteoporosis in patients with chronic pancreatitis: a case-matched study. Am J Gastroenterol. 2015;110(2):336−345. doi: 10.1038/ajg.2014.430

34. Lips P, van Schoor NM. The effect of vitamin D on bone and osteoporosis. Best Pract Res Clin Endocrinol Metab. 2011;25(4):585−591. doi: 10.1016/j.beem.2011.05.002

35. Palermo A, Tuccinardi D, D’Onofrio L, Watanabe M, Maggi D, Maurizi AR, et al. Vitamin K and osteoporosis: Myth or reality? Metabolism. 2017;70:57−71. doi: 10.1016/j.metabol.2017.01.032

36. Dominguez-Munoz JE, Drewes AM, Lindkvist B, Ewald N, Czakó L, Rosendahl J, et al. Recommendations from the United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis. Pancreatology. 2018;18(8):847−854. doi: 10.1016/j.pan.2018.09.016

37. Khatkov IE, Maev IV, Abdulkhakov SR, Alekseenko SA, Alieva EI, Alikhanov RB, et al. The Russian consensus on the diagnosis and treatment of chronic pancreatitis. Terapevticheskiy arkhiv = Therapeutic archive. 2017;89(2):105−113. (In Russ.). doi: 10.17116/terarkh2017892105-113

38. Maev IV, Bideeva ТВ, Kucheryavyy YA, Andreev DN, Bueverov AO. Pharmacotherapy of chronic pancreatitis in terms of current clinical recommendations. Terapevticheskiy arkhiv = Therapeutic archive. 2018;90(8):81−85 (In Russ.). doi: 10.26442/terarkh201890881-85

39. De la Iglesia-García D, Huang W, Szatmary P, Baston-Rey I, Gonzalez-Lopez J, Prada-Ramallal G, et al; Efficacy of pancreatic enzyme replacement therapy in chronic pancreatitis: systematic review and meta-analysis. Gut. 2017;66(8):1354−1355. doi: 10.1136/gutjnl-2016-312529.

40. Gan C, Chen YH, Liu L, Gao JH, Tong H, Tang CW, et al. Efficacy and safety of pancreatic enzyme replacement therapy on exocrine pancreatic insufficiency: a meta-analysis. Oncotarget. 2017;8(55):94920−94931. doi: 10.18632/oncotarget.21659

41. Bideeva TV, Maev IV, Kucheryavyy YuA, Andreev DN, Shah YS, Lobanova EG, et al. The effectiveness of pancreatic enzyme replacement therapy using microencapsulated pancreatin preparations in the correction of nutritional status in patients with chronic pancreatitis: a prospective observational study. Terapevticheskiy arkhiv = Therapeutic archive. 2020;92(1):30−35 (In Russ.). doi:10.26442/00403660.2020.01.000488

42. Maev IV, Kucheryavyy YuA, Samsonov AA, Andreev DN. Difficulties and errors in the management tactics of patients with chronic pancreatitis. Terapevticheskiy arkhiv = Therapeutic archive. 2013;85(2):65−72 (In Russ.).