Circulating Molecular Drivers of Bone Remodeling in Pancreatitis

Rachel L. Hill; Dhiraj Yadav; Phil A. Hart; David C. Whitcomb; Kristen J. McQuerry; Kelsey N. Karnik; Kimberly M. Stello; Darwin L. Conwell; Madhumathi Rao; Samer AlKaade; Stephen T. Amann; Michelle A. Anderson; Peter Banks; Darwin Conwell; Adam Slivka; Randall E. Brand; Gregory A. Cote; Joseph Romagnuolo; Christopher E. Forsmark; Timothy Gardner; Andres Gelrud; Nalini Guda; Michele Lewis; Thiruvengadam Muniraj; Bimaljit S. Sandhu; Vikesh Singh; C. Mel Wilcox

doi:10.14309/ctg.0000000000000926

Circulating Molecular Drivers of Bone Remodeling in Pancreatitis

Rachel L. Hill
, Dhiraj Yadav
, Phil A. Hart
, David C. Whitcomb
, Kristen J. McQuerry
, Kelsey N. Karnik
, Kimberly M. Stello
, Darwin L. Conwell
, Madhumathi Rao
, Samer AlKaade
, Stephen T. Amann
, Michelle A. Anderson
, Peter Banks
, Darwin Conwell
, Adam Slivka
, Randall E. Brand
, Gregory A. Cote
, Joseph Romagnuolo
, Christopher E. Forsmark
, Timothy Gardner

Andres Gelrud, Nalini Guda, Michele Lewis, Thiruvengadam Muniraj, Bimaljit S. Sandhu, Vikesh Singh, C. Mel Wilcox

Research output: Contribution to journal › Article › peer-review

Abstract

INTRODUCTION: – Pancreatitis-associated osteopathy is a clinically significant but mechanistically underexplored complication of pancreatic disease. We aimed to characterize stage-specific alterations in bone remodeling biomarkers across the spectrum of disease: recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP).METHODS: – In a cross-sectional analysis of North American Pancreatitis Study 2 participants, we measured serum mechanistic (sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin), hormonal (fibroblast growth factor 23, insulin, and leptin), and modulatory (osteopontin, oncostatin, and osteoactivin) markers in controls (n = 30), RAP (n = 40), and CP (n = 40) using a multiplex assay. Group differences were assessed with ANOVA, Fisher exact test, and Kruskal-Wallis; multivariable regression identified predictors of biomarker variation.RESULTS: – Eight of 10 biomarkers differed significantly among groups. Sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin were elevated in RAP and CP vs controls, with the highest values in CP. The RANKL/OPG ratio was greatest in CP. Fibroblast growth factor 23 was increased in RAP, while insulin was reduced in CP. Osteopontin and oncostatin were elevated in pancreatitis groups, with osteopontin increasing progressively from control to RAP to CP. Several bone biomarker patterns varied by sex, tobacco, and alcohol use. Stepwise regression identified several significant predictors.DISCUSSION: – These findings represent the most comprehensive bone metabolism biomarker profiling in pancreatitis to date, revealing stage-specific dysregulation of bone remodeling. Findings suggest a shift toward increased bone resorption and impaired formation with disease progression. Larger longitudinal studies are needed for marker validation, to clarify mechanisms, and guide targeted interventions to reduce bone loss and fracture risk in this high-risk population.

Original language	English
Pages (from-to)	e00926
Journal	Clinical and Translational Gastroenterology
DOIs	https://doi.org/10.14309/ctg.0000000000000926
State	Published - Dec 1 2025

Bibliographical note

Publisher Copyright:
© 2025

Funding

Financial support: This research was partly supported by the National Cancer Institute and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH) under the following awards: T32 DK063922, DK061451, R21 DK098560, U01 DK108327, and U01 DK108306. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. National Institute of Diabetes and Digestive and Kidney Diseases T32 DK063922 David Whitcomb National Institute of Diabetes and Digestive and Kidney Diseases DK061451 David Whitcomb National Institute of Diabetes and Digestive and Kidney Diseases R21 DK098560 David Whitcomb National Institute of Diabetes and Digestive and Kidney Diseases U01 DK108327 Phil Hart National Institute of Diabetes and Digestive and Kidney Diseases U01 108306 Dhiraj Yadav

Funders	Funder number
National Childhood Cancer Registry – National Cancer Institute
National Institute of Diabetes and Digestive and Kidney Diseases	T32 DK063922
National Institutes of Health (NIH)	R21 DK098560, DK061451, U01 DK108306, U01 DK108327

Keywords

biomarkers
bone remodeling
chronic pancreatitis
osteopathy
recurrent acute pancreatitis

ASJC Scopus subject areas

Gastroenterology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.14309/ctg.0000000000000926

Cite this

Hill, R. L., Yadav, D., Hart, P. A., Whitcomb, D. C., McQuerry, K. J., Karnik, K. N., Stello, K. M., Conwell, D. L., Rao, M., AlKaade, S., Amann, S. T., Anderson, M. A., Banks, P., Conwell, D., Slivka, A., Brand, R. E., Cote, G. A., Romagnuolo, J., Forsmark, C. E., ... Wilcox, C. M. (2025). Circulating Molecular Drivers of Bone Remodeling in Pancreatitis. Clinical and Translational Gastroenterology, e00926. https://doi.org/10.14309/ctg.0000000000000926

@article{7a08f4798716425bb47c74c0db923ef9,

title = "Circulating Molecular Drivers of Bone Remodeling in Pancreatitis",

abstract = "INTRODUCTION: – Pancreatitis-associated osteopathy is a clinically significant but mechanistically underexplored complication of pancreatic disease. We aimed to characterize stage-specific alterations in bone remodeling biomarkers across the spectrum of disease: recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP).METHODS: – In a cross-sectional analysis of North American Pancreatitis Study 2 participants, we measured serum mechanistic (sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin), hormonal (fibroblast growth factor 23, insulin, and leptin), and modulatory (osteopontin, oncostatin, and osteoactivin) markers in controls (n = 30), RAP (n = 40), and CP (n = 40) using a multiplex assay. Group differences were assessed with ANOVA, Fisher exact test, and Kruskal-Wallis; multivariable regression identified predictors of biomarker variation.RESULTS: – Eight of 10 biomarkers differed significantly among groups. Sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin were elevated in RAP and CP vs controls, with the highest values in CP. The RANKL/OPG ratio was greatest in CP. Fibroblast growth factor 23 was increased in RAP, while insulin was reduced in CP. Osteopontin and oncostatin were elevated in pancreatitis groups, with osteopontin increasing progressively from control to RAP to CP. Several bone biomarker patterns varied by sex, tobacco, and alcohol use. Stepwise regression identified several significant predictors.DISCUSSION: – These findings represent the most comprehensive bone metabolism biomarker profiling in pancreatitis to date, revealing stage-specific dysregulation of bone remodeling. Findings suggest a shift toward increased bone resorption and impaired formation with disease progression. Larger longitudinal studies are needed for marker validation, to clarify mechanisms, and guide targeted interventions to reduce bone loss and fracture risk in this high-risk population.",

keywords = "biomarkers, bone remodeling, chronic pancreatitis, osteopathy, recurrent acute pancreatitis",

author = "Hill, \{Rachel L.\} and Dhiraj Yadav and Hart, \{Phil A.\} and Whitcomb, \{David C.\} and McQuerry, \{Kristen J.\} and Karnik, \{Kelsey N.\} and Stello, \{Kimberly M.\} and Conwell, \{Darwin L.\} and Madhumathi Rao and Samer AlKaade and Amann, \{Stephen T.\} and Anderson, \{Michelle A.\} and Peter Banks and Darwin Conwell and Adam Slivka and Brand, \{Randall E.\} and Cote, \{Gregory A.\} and Joseph Romagnuolo and Forsmark, \{Christopher E.\} and Timothy Gardner and Andres Gelrud and Nalini Guda and Michele Lewis and Thiruvengadam Muniraj and Sandhu, \{Bimaljit S.\} and Vikesh Singh and Wilcox, \{C. Mel\}",

note = "Publisher Copyright: {\textcopyright} 2025",

year = "2025",

month = dec,

day = "1",

doi = "10.14309/ctg.0000000000000926",

language = "English",

pages = "e00926",

journal = "Clinical and Translational Gastroenterology",

issn = "2155-384X",

publisher = "Lippincott Williams and Wilkins",

}

Hill, RL, Yadav, D, Hart, PA, Whitcomb, DC, McQuerry, KJ, Karnik, KN, Stello, KM, Conwell, DL , Rao, M, AlKaade, S, Amann, ST, Anderson, MA, Banks, P, Conwell, D, Slivka, A, Brand, RE, Cote, GA, Romagnuolo, J, Forsmark, CE, Gardner, T, Gelrud, A, Guda, N, Lewis, M, Muniraj, T, Sandhu, BS, Singh, V & Wilcox, CM 2025, 'Circulating Molecular Drivers of Bone Remodeling in Pancreatitis', Clinical and Translational Gastroenterology, pp. e00926. https://doi.org/10.14309/ctg.0000000000000926

TY - JOUR

T1 - Circulating Molecular Drivers of Bone Remodeling in Pancreatitis

AU - Hill, Rachel L.

AU - Yadav, Dhiraj

AU - Hart, Phil A.

AU - Whitcomb, David C.

AU - McQuerry, Kristen J.

AU - Karnik, Kelsey N.

AU - Stello, Kimberly M.

AU - Conwell, Darwin L.

AU - Rao, Madhumathi

AU - AlKaade, Samer

AU - Amann, Stephen T.

AU - Anderson, Michelle A.

AU - Banks, Peter

AU - Conwell, Darwin

AU - Slivka, Adam

AU - Brand, Randall E.

AU - Cote, Gregory A.

AU - Romagnuolo, Joseph

AU - Forsmark, Christopher E.

AU - Gardner, Timothy

AU - Gelrud, Andres

AU - Guda, Nalini

AU - Lewis, Michele

AU - Muniraj, Thiruvengadam

AU - Sandhu, Bimaljit S.

AU - Singh, Vikesh

AU - Wilcox, C. Mel

PY - 2025/12/1

Y1 - 2025/12/1

N2 - INTRODUCTION: – Pancreatitis-associated osteopathy is a clinically significant but mechanistically underexplored complication of pancreatic disease. We aimed to characterize stage-specific alterations in bone remodeling biomarkers across the spectrum of disease: recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP).METHODS: – In a cross-sectional analysis of North American Pancreatitis Study 2 participants, we measured serum mechanistic (sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin), hormonal (fibroblast growth factor 23, insulin, and leptin), and modulatory (osteopontin, oncostatin, and osteoactivin) markers in controls (n = 30), RAP (n = 40), and CP (n = 40) using a multiplex assay. Group differences were assessed with ANOVA, Fisher exact test, and Kruskal-Wallis; multivariable regression identified predictors of biomarker variation.RESULTS: – Eight of 10 biomarkers differed significantly among groups. Sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin were elevated in RAP and CP vs controls, with the highest values in CP. The RANKL/OPG ratio was greatest in CP. Fibroblast growth factor 23 was increased in RAP, while insulin was reduced in CP. Osteopontin and oncostatin were elevated in pancreatitis groups, with osteopontin increasing progressively from control to RAP to CP. Several bone biomarker patterns varied by sex, tobacco, and alcohol use. Stepwise regression identified several significant predictors.DISCUSSION: – These findings represent the most comprehensive bone metabolism biomarker profiling in pancreatitis to date, revealing stage-specific dysregulation of bone remodeling. Findings suggest a shift toward increased bone resorption and impaired formation with disease progression. Larger longitudinal studies are needed for marker validation, to clarify mechanisms, and guide targeted interventions to reduce bone loss and fracture risk in this high-risk population.

AB - INTRODUCTION: – Pancreatitis-associated osteopathy is a clinically significant but mechanistically underexplored complication of pancreatic disease. We aimed to characterize stage-specific alterations in bone remodeling biomarkers across the spectrum of disease: recurrent acute pancreatitis (RAP) and chronic pancreatitis (CP).METHODS: – In a cross-sectional analysis of North American Pancreatitis Study 2 participants, we measured serum mechanistic (sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin), hormonal (fibroblast growth factor 23, insulin, and leptin), and modulatory (osteopontin, oncostatin, and osteoactivin) markers in controls (n = 30), RAP (n = 40), and CP (n = 40) using a multiplex assay. Group differences were assessed with ANOVA, Fisher exact test, and Kruskal-Wallis; multivariable regression identified predictors of biomarker variation.RESULTS: – Eight of 10 biomarkers differed significantly among groups. Sclerostin, dickkopf-1, receptor activator of nuclear factor κβ ligand, and osteoprotegerin were elevated in RAP and CP vs controls, with the highest values in CP. The RANKL/OPG ratio was greatest in CP. Fibroblast growth factor 23 was increased in RAP, while insulin was reduced in CP. Osteopontin and oncostatin were elevated in pancreatitis groups, with osteopontin increasing progressively from control to RAP to CP. Several bone biomarker patterns varied by sex, tobacco, and alcohol use. Stepwise regression identified several significant predictors.DISCUSSION: – These findings represent the most comprehensive bone metabolism biomarker profiling in pancreatitis to date, revealing stage-specific dysregulation of bone remodeling. Findings suggest a shift toward increased bone resorption and impaired formation with disease progression. Larger longitudinal studies are needed for marker validation, to clarify mechanisms, and guide targeted interventions to reduce bone loss and fracture risk in this high-risk population.

KW - biomarkers

KW - bone remodeling

KW - chronic pancreatitis

KW - osteopathy

KW - recurrent acute pancreatitis

UR - https://www.scopus.com/pages/publications/105026262443

UR - https://www.scopus.com/pages/publications/105026262443#tab=citedBy

U2 - 10.14309/ctg.0000000000000926

DO - 10.14309/ctg.0000000000000926

M3 - Article

C2 - 41036802

AN - SCOPUS:105026262443

SN - 2155-384X

SP - e00926

JO - Clinical and Translational Gastroenterology

JF - Clinical and Translational Gastroenterology

ER -

Circulating Molecular Drivers of Bone Remodeling in Pancreatitis

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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