Effect of Anti-osteoporotic Medications on Nonalcoholic Fatty Liver Disease

NCT05493761 | Active Not Recruiting Phase 4 FDA Drug

• 1 other identifier: 88235
• Study Type: interventional
• Target: 72
• Locations: 1 country
• Sites: 3

Brief Summary

Nonalcoholic fatty liver disease (NAFLD) is a chronic, metabolic liver disease that is closely related to obesity, type 2 diabetes mellitus (T2DM) and metabolic syndrome (MetS) in a bidirectional mode. NAFLD affects approximately 25% of the worldwide population. NAFLD refers to a phenotypic spectrum, including steatosis, inflammation and fibrosis, which can lead to cirrhosis and hepatocellular carcinoma in a minority of patients. However, despite its high prevalence, morbidity and mortality, as well as the extensive research in the field, there is not to-date a licensed medication specifically for NAFLD. Emerging evidence supports a potential association between NAFLD and osteoporosis; the prevalence of osteoporosis is probably higher in patients with NAFLD and, vise versa, the prevalence of NAFLD may be higher in patients with osteoporosis. In this context, it has been proposed that certain medications for osteoporosis may also prove to be beneficial to NAFLD. Denosumab, a human monoclonal IgG2 antibody against the receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL), is currently an established treatment for osteoporosis and other metabolic bone diseases. The axis RANKL-receptor activator of nuclear factor NF-κB (RANK)-osteoprotegerin (OPG) has been demonstrated as a key regulator of bone metabolism and, when dysregulated, it contributes to the pathogenesis of osteoporosis and other metabolic bone diseases. Interestingly, experimental studies have shown that circulating and hepatic RANKL may be upregulated in mice with diet-induced NAFLD, rendering RANKL a potential contributor to the pathogenesis of NAFLD, and ideally, a promising pharmacological target. On the other hand, bisphosphonates, another established, first-line treatment for osteoporosis, are expected to have no significant effect on hepatic metabolism in patients with NAFLD due to their pharmacokinetics and mechanism of action. This is a prospective non-randomized study which aims to investigate the comparative effect of denosumab versus bisphosphonates on hepatic steatosis and fibrosis in women with postmenopausal osteoporosis and concomitant NAFLD.

Conditions

Nonalcoholic Fatty Liver; Osteoporosis, Postmenopausal

Keywords

nonalcoholic fatty liver disease; hepatic steatosis; hepatic fibrosis; bisphosphonates; denosumab; postmenopausal osteoporosis; treatment; alendronate; nonalcoholic steatohepatitis; NAFLD; NASH; elastography; metabolic dysfunction-associated steatotic liver disease; metabolic dysfunction-associated steatohepatitis

Outcome Measures

Primary Outcomes (1)

• Hepatic steatosis: Ultrasound-Guided Attenuation Parameter (UGAP) measured on an ultrasound machine GE Logiq E10s.

  1. Between-within group interactions in UGAP (baseline to endpoint) 2. Between groups difference in change in UGAP (baseline to endpoint) UGAP is a non-invasive index based on the attenuation quantification of the ultrasound beam through the hepatic parenchyma, thus used for hepatic steatosis quantification. Cut-off values of \> 0.53 dB/cm/MHz, \>0.60 dB/cm/MHz, and \>0.65 dB/cm/MHz have been proposed for the diagnosis of steatosis grade S1, S2, and S3, respectively.

  12 months

Secondary Outcomes (15)

• Hepatic fibrosis: liver stiffness (LS) measured with 2D Shear Wave Elastography (2D SWE) on an ultrasound machine GE Logiq E10s.

  12 months

• Hepatic steatosis non-invasive index: Fatty Liver Index (FLI).

  12 months

• Hepatic steatosis non-invasive index: Hepatic Steatosis Index (HSI).

  12 months

• Hepatic fibrosis non-invasive index: NAFLD fibrosis score (NFS).

  12 months

• Hepatic fibrosis non-invasive index: Fibrosis-4 index (FIB-4).

  12 months

Study Arms (2)

"Denosumab"

EXPERIMENTAL

35 postmenopausal women with low bone mineral density (BMD) and NAFLD will receive denosumab.

Drug: Denosumab

"Alendronate"

ACTIVE COMPARATOR

35 postmenopausal women with low bone mineral density (BMD) and NAFLD will receive alendronate.

Drug: Alendronate Sodium

Interventions

Denosumab DRUG

60 mg (1ml) administered subcutaneously once every 6 months for 12 months (totally 2 injections). Patients will also be supplemented with calcium carbonate (1000 mg/d) and cholecalciferol (800 IU/day), according to the recent guidelines.

Also known as: Prolia

"Denosumab"

Alendronate Sodium DRUG

70 mg (1 tablet) administered per os once weekly for 12 months. Patients will also be supplemented with calcium carbonate (1000 mg/d) and cholecalciferol (800 IU/day), according to the recent guidelines.

Also known as: Fosamax

"Alendronate"

Eligibility Criteria

• Age: 40 Years+
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• postmenopausal women aged \> 40 years
• diagnosis of osteoporosis, or osteopenia and Fracture Assessment Risk (FRAX) score indicative for initiation of anti-osteoporotic treatment, or osteopenia and history of low-energy fracture. Evaluation of osteopenia and osteoporosis will be based on bone mineral density (BMD) of the lumbar spine and/or the femoral neck of the non-dominant hip measured with dual energy X-ray absorptiometry (DXA)
• diagnosis of NAFLD based on non-invasive indices of hepatic steatosis
• written informed consent

You may not qualify if:

• mean ethanol consumption \>10 g/day
• a history of other chronic liver disease (e.g., viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cholangitis and overlap syndromes, drug-induced liver injury, hemochromatosis, Wilson's disease, α1-antitrypsin deficiency)
• liver cirrhosis
• any malignancy
• chronic kidney disease
• uncontrolled hypothyroidism or hyperthyroidism
• use of the following medications within a 12-month period before baseline associated with drug-induced fatty liver: interferon, tamoxifen, amiodarone, aloperidin, glucocorticosteroids, anabolic steroids, any medication against tuberculosis, epilepsy or viruses, methotrexate, parenteral nutrition
• use of the following medications within a 12-month period before baseline associated probably with improvement in fatty liver: vitamin E, pioglitazone, insulin, glucagon-like peptide-1 receptor agonists (GLP-1RAs), sodium-glucose co-transporter-2 inhibitors (SGLT-2), orlistat, ursodeoxycholic acid
• use of any anti-osteoporotic medication within a 12-month period before baseline, except for calcium and vitamin D

Sponsors & Collaborators

• Aristotle University Of Thessaloniki: lead
• 424 General Military Hospital: collaborator

Study Sites (3)

Department of Endocrinology, "Hippokration" General Hospital of Thessaloniki

Thessaloniki, 54642, Greece

Location

1st Department of Obstetrics and Gynecology, School, of Medicine, Aristotle University of Thessaloniki

Thessaloniki, 56403, Greece

Location

424 General Military Hospital

Thessaloniki, 56429, Greece

Location

Related Publications (7)

• Makri E, Goulas A, Polyzos SA. Epidemiology, Pathogenesis, Diagnosis and Emerging Treatment of Nonalcoholic Fatty Liver Disease. Arch Med Res. 2021 Jan;52(1):25-37. doi: 10.1016/j.arcmed.2020.11.010. Epub 2020 Dec 14.

  PMID: 33334622 BACKGROUND

• Polyzos SA, Goulas A. Treatment of nonalcoholic fatty liver disease with an anti-osteoporotic medication: A hypothesis on drug repurposing. Med Hypotheses. 2021 Jan;146:110379. doi: 10.1016/j.mehy.2020.110379. Epub 2020 Nov 7.

  PMID: 33208241 BACKGROUND

• Filip R, Radzki RP, Bienko M. Novel insights into the relationship between nonalcoholic fatty liver disease and osteoporosis. Clin Interv Aging. 2018 Oct 4;13:1879-1891. doi: 10.2147/CIA.S170533. eCollection 2018.

  PMID: 30323574 BACKGROUND

• Anastasilakis AD, Polyzos SA, Makras P. THERAPY OF ENDOCRINE DISEASE: Denosumab vs bisphosphonates for the treatment of postmenopausal osteoporosis. Eur J Endocrinol. 2018 Jul;179(1):R31-R45. doi: 10.1530/EJE-18-0056. Epub 2018 Apr 24.

  PMID: 29691303 BACKGROUND

• Zhong L, Yuan J, Huang L, Li S, Deng L. RANKL Is Involved in Runx2-Triggered Hepatic Infiltration of Macrophages in Mice with NAFLD Induced by a High-Fat Diet. Biomed Res Int. 2020 May 25;2020:6953421. doi: 10.1155/2020/6953421. eCollection 2020.

  PMID: 32596356 BACKGROUND

• Rinotas V, Niti A, Dacquin R, Bonnet N, Stolina M, Han CY, Kostenuik P, Jurdic P, Ferrari S, Douni E. Novel genetic models of osteoporosis by overexpression of human RANKL in transgenic mice. J Bone Miner Res. 2014;29(5):1158-69. doi: 10.1002/jbmr.2112.

  PMID: 24127173 BACKGROUND

• Vachliotis ID, Anastasilakis AD, Goulas A, Goulis DG, Polyzos SA. Nonalcoholic fatty liver disease and osteoporosis: A potential association with therapeutic implications. Diabetes Obes Metab. 2022 Sep;24(9):1702-1720. doi: 10.1111/dom.14774. Epub 2022 Jun 14.

  PMID: 35589613 BACKGROUND

MeSH Terms

Conditions

Non-alcoholic Fatty Liver Disease; Osteoporosis, Postmenopausal; Fatty Liver; Liver Cirrhosis

Interventions

Denosumab; Alendronate

Condition Hierarchy (Ancestors)

Liver Diseases; Digestive System Diseases; Osteoporosis; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases; Fibrosis; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals

Study Officials

• Ilias D Vachliotis, MD, PhDc

  School of Medicine, Aristotle University of Thessaloniki

  STUDY DIRECTOR

• Athanasios D Anastasilakis, MD, PhD

  424 General Military Hospital, Thessaloniki, Greece

  STUDY DIRECTOR

• Antonis Goulas, MD, PhD

  School of Medicine, Aristotle University of Thessaloniki

  STUDY DIRECTOR

• Dimitrios G Goulis, MD, PhD

  School of Medicine, Aristotle University of Thessaloniki

  STUDY DIRECTOR

• Stergios A Polyzos, MD, PhD

  School of Medicine, Aristotle University of Thessaloniki

  PRINCIPAL INVESTIGATOR

• Zoe A Efstathiadou, MD, PhD

  Department of Endocrinology, "Hippokration" General Hospital of Thessaloniki

  STUDY DIRECTOR

• Vasileios Rafailidis, MD, PhD

  School of Medicine, Aristotle University of Thessaloniki

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Masking Details: No masking
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Pharmacology

Model Details: Multicenter, non-randomized, non-blinded, parallel group, one-year clinical trial

Study Record Dates

• First Submitted: July 24, 2022
• First Posted: August 9, 2022
• Study Start: December 23, 2022
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): September 1, 2026
• Last Updated: July 18, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: 12 months after the publication of the study.
• Access Criteria: Yet unknown

Locations

GR (3)