Proton-pump inhibitor-induced bone loss is preventable by concomitant use of a long-acting somatostatin analogue

Document Type : Original Article

Authors

Endocrine and Metabolism Research Center, Shiraz University of Medical Science, Shiraz, Iran

Abstract

Objective(s): Long-term consumption of pump inhibitors causes osteoporosis. Some possible mechanisms are gastrin over-secretion and hypochlorhydria. Octreotide is a somatostatin analog that inhibits the secretion of many hormones such as gastrin. This study aimed to assess the effects of pantoprazole on the bone when used with octreotide in an animal model. 
Materials and Methods: Forty-eight male Wistar rats were randomly assigned into 4 groups: A) pantoprazole 3 mg/Kg/day orally; B) Sandostatin LAR 1 mg/month intramuscular injection; C) Pantoprazole and Sandostatin LAR; and D) Control group. After 90 days of the experiment, bone densitometry was done and serum and urine samples were collected for analysis. 
Results: The results indicated a significant decrease in the global, spine, femur, and tibia bone mineral density (BMD) and bone mineral content (BMC) in the pantoprazole group compared to the control group (P<0.05). There was a significant increase in the levels of PTH, gastrin, and alkaline phosphatase (ALP) in the pantoprazole group compared to the control group (P<0.05). There was no significant difference in the serum levels of gastrin, PTH, ALP, and also BMD in the rats that received sandostatin+ pantoprazole or sandostatin alone, compared to the control group.
Conclusion: This study showed that the pantoprazole-induced bone loss, through elevation of serum gastrin and PTH, was preventable by concomitant use of a long-acting somatostatin analog.

Keywords

Main Subjects


1. Johnell O, Kanis J. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006;17:1726-1733.
2. Kim JJ, Jang EJ, Park J, Sohn HS. Association between proton pump inhibitor use and risk of fracture: A population-based case-control study. PLoS One 2020;15:e0235163.
3. Wang Y-H, Wintzell V, Ludvigsson JF, Svanström H, Pasternak B. Association Between Proton Pump Inhibitor Use and Risk of Fracture in Children. JAMA pediatrics. 2020; 174: 543-551.
4. Fattahi MR, Niknam R, Shams M, Anushiravani A, Taghavi SA, Omrani GR, et al. The association between prolonged proton pump inhibitors use and bone mineral density. Risk Manag Healthc Policy 2019; 12: 349-355.
5. Lespessailles E, Toumi H. Proton pump inhibitors and bone health: An update narrative review. Int J Mol Sci 2022; 23:10733.
6. da Maia TF, de Camargo BG, Pereira ME, de Oliveira CS, Guiloski IC. Increased Risk of Fractures and Use of Proton Pump Inhibitors in Menopausal Women: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health 2022;19:13501.
7. Thong BKS, Ima-Nirwana S, Chin K-Y. Proton pump inhibitors and fracture risk: a review of current evidence and mechanisms involved. Int J Environ Res Public Health 2019;16:1571.
8. Poly T, Islam M, Yang H-C, Wu C, Li YJ. Proton pump inhibitors and risk of hip fracture: a meta-analysis of observational studies. Osteoporos Int 2019; 30:103-114.
9. Wang L-T, Chen L-R, Chen K-H. Hormone-related and drug-induced osteoporosis: a cellular and molecular overview. Int J Mol Sci 2023; 24:5814.
10.    Koyyada A. Long-term use of proton pump inhibitors as a risk factor for various adverse manifestations. Therapie 2021; 76:13-21.
11. Linder L, Tamboue C, Clements JN. Drug-induced vitamin B12 deficiency: A focus on proton pump inhibitors and histamine-2 antagonists. J Pharm Pract 2017; 30:639-642.
12. De Martinis M, Sirufo MM, Nocelli C, Fontanella L, Ginaldi L. Hyperhomocysteinemia is associated with inflammation, bone resorption, vitamin B12 and folate deficiency and MTHFR C677T polymorphism in postmenopausal women with decreased bone mineral density. Int J Environ Res Public Health 2020; 17:4260.
13. Liu S, Huang Y, Tian S, Zhang W, Xu Y, Ge J. Hyperhomocysteinemia inhibits tibial fracture healing in rats through PI3K/AKT signaling pathway. Exp Ther Med 2020; 19:2083-2088.
14. Mester A, Apostu D, Ciobanu L, Piciu A, Lucaciu O, Campian RS, et al. The impact of proton pump inhibitors on bone regeneration and implant osseointegration. Drug Metab Rev 2019; 51:330-339.
15. Brazeau P, Vale W, Burgus R, Ling N, Butcher M, Rivier J, et al. Hypothalamic polypeptide that inhibits the secretion of immunoreactive pituitary growth hormone. Science 1973; 179:77-79.
16. Lamberts SW, Van der Lely A-J, de Herder WW, Hofland LJ. Octreotide. N Engl J Med. 1996; 334:246-254.
17. Arnold R, Frank M, Kajdan U. Management of gastroenteropancreatic endocrine tumors: the place of somatostatin analogues. Digestion 1994; 55(Suppl. 3):107-113.
18. Hofland LJ, Lamberts SW. Novel subtype specific and universal somatostatin analogues: clinical potential and pitfalls. Curr Pharm Des 2005; 11:1573-1592.
19. Fan M, Huang Y, Zhu X, Zheng J, Du M. Octreotide and Octreotide-derived delivery systems. J Drug Target 2023; 31:569-584.
20. Karp NA, Meehan TF, Morgan H, Mason JC, Blake A, Kurbatova N, et al. Applying the ARRIVE guidelines to an in vivo database. PLoS Biol 2015; 13:e1002151.
21. Matuszewska A, Nowak B, Rzeszutko M, Zduniak K, Szandruk M, Jędrzejuk D, et al. Effects of long-term administration of pantoprazole on bone mineral density in young male rats. Pharmacol Rep 2016; 68:1060-1064.
22. Perry IE, Sonu I, Scarpignato C, Akiyama J, Hongo M, Vega KJ. Potential proton pump inhibitor–related adverse effects. Ann N Y Acad Sci 2020; 1481:43-58.
23. Park J-H, Lee J, Yu S-Y, Jung J-H, Han K, Kim D-H, et al. Comparing proton pump inhibitors with histamin-2 receptor blockers regarding the risk of osteoporotic fractures: A nested case-control study of more than 350,000 Korean patients with GERD and peptic ulcer disease. BMC Geriatr 2020; 20:1-11.
24. Zhao L, Liu G, Jing W, Meng X, Zhu X. Effects of elderly patients with long-term use of proton pump inhibitors for osteoporosis. Chongqing Med 2017; 46:1768-1772.
25. Abtahi S, Driessen JH, Burden AM, Souverein PC, van den Bergh JP, van Staa TP, et al. Concomitant use of oral glucocorticoids and proton pump inhibitors and risk of osteoporotic fractures among patients with rheumatoid arthritis: A population-based cohort study. Ann Rheum Dis 2021; 80:423-431.
26. Ghebre YT. Proton pump inhibitors and osteoporosis: is collagen a direct target? Front Endocrinol (Lausanne) 2020; 11:473.
27. Kim GH. Proton pump inhibitor-related gastric mucosal changes. Gut liver 2021; 15:646-652.
28. Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell. Physiol Rev 2020; 100:573-602.
29. Waldum HL, Sørdal ØF, Mjønes PG. The enterochromaffin-like [ECL] cell—Central in Gastric physiology and pathology. Int J Mol Sci 2019; 20:2444.
30. Matuszewska A, Nowak B, Jędrzejuk D, Landwójtowicz M, Sadanowicz E, Sozański T, et al. Effect of long-term administration of ranitidine, a histamine H2 receptor antagonist, on bone metabolism in young growing rats. Pharmacol Rep 2018; 70:951-954.
31. Al Menhali A, Keeley TM, Demitrack ES, Samuelson LC. Gastrin induces parathyroid hormone-like hormone expression in gastric parietal cells. Am J Physiol Gastrointest Liver Physiol 2017; 312:G649-G657.
32. Gomes-Porras M, Cárdenas-Salas J. Somatostatin Analogs in Clinical Practice: A Review. Int J Mol Sci 2020; 21:1682.
33. Botana M, Castillo L, Pesquera C, Freijanes J, Amado J, Gonzalez-Macias J. Lack of effect of octreotide on parathyroid hormone levels and urinary excretion of epidermal growth factor. Horm Metab Res 1993; 25:37-39.
34. Clowes JA, Allen HC, Prentis DM, Eastell R, Blumsohn A. Octreotide abolishes the acute decrease in bone turnover in response to oral glucose. J Clin Endocrinol Metab 2003; 88:4867-4873.
35. Zapf Jr, Gosteli-Peter M, Weckbecker G, Hunziker EB, Reinecke M. The somatostatin analog octreotide inhibits GH-stimulated, but not IGF-I-stimulated, bone growth in hypophysectomized rats. Endocrinology 2002; 143:2944-2952.
36. Gagnemo-Persson R, Håkanson R, Sundler F, Persson P. Growth of the parathyroid glands in omeprazole-treated chickens. Scand J Gastroenterol 1994; 29:493-497.
37. Gagnemo-Persson R, Samuelsson A, Håkanson R, Persson P. Chicken parathyroid hormone gene expression in response to gastrin, omeprazole, ergocalciferol, and restricted food intake. Calcif Tissue Int 1997; 61:210-215.
38. Grimelius L, Johansson H, Lundqvist G, Olazabal A, Polak J, Pearse A. The parathyroid glands in experimentally induced hypergastrinemia in the rat. Scand J Gastroenterol 1977; 12:739-744.