Clinical trial NCT05493761: Effect of Anti-osteoporotic Medications on Nonalcoholic Fatty Liver Disease
Official title: Effect of Anti-osteoporotic Medications on Hepatic Steatosis and Fibrosis of Women with Postmenopausal Osteoporosis and Nonalcoholic Fatty Liver Disease
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
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
Lead sponsor: Aristotle University Of Thessaloniki
Sponsor class: OTHER
Collaborators: name: 424 General Military Hospital
First posted: 2022-08-09
Enrollment: 70
Sex: FEMALE
Minimum age (years): 40
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicenter, non-randomized, non-blinded, parallel group, one-year clinical trial
Primary purpose: TREATMENT

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.


Eligibility criteria: Inclusion Criteria:

* 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

Exclusion Criteria:

* 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

Primary outcomes:
measure: Hepatic steatosis: Ultrasound-Guided Attenuation Parameter (UGAP) measured on an ultrasound machine GE Logiq E10s.
timeFrame: 12 months
Secondary outcomes:
measure: Hepatic fibrosis: liver stiffness (LS) measured with 2D Shear Wave Elastography (2D SWE) on an ultrasound machine GE Logiq E10s.
timeFrame: 12 months
measure: Hepatic steatosis non-invasive index: Fatty Liver Index (FLI).
timeFrame: 12 months
measure: Hepatic steatosis non-invasive index: Hepatic Steatosis Index (HSI).
timeFrame: 12 months
measure: Hepatic fibrosis non-invasive index: NAFLD fibrosis score (NFS).
timeFrame: 12 months
measure: Hepatic fibrosis non-invasive index: Fibrosis-4 index (FIB-4).
timeFrame: 12 months
measure: Hepatic fibrosis non-invasive index: AST-to-Platelet Ratio Index (APRI).
timeFrame: 12 months
measure: Liver function tests: alanine aminotransferase (ALT).
timeFrame: 12 months
measure: Liver function tests: aspartate aminotransferase (AST)
timeFrame: 12 months
measure: Insulin resistance index: Homeostasis Model Assessment - Insulin Resistance (HOMA-IR)
timeFrame: 12 months
measure: Lipid profile: total cholesterol
timeFrame: 12 months
measure: Lipid profile: triglycerides
timeFrame: 12 months
measure: Lipid profile: low-density lipoprotein cholesterol (LDL-C)
timeFrame: 12 months
measure: Lipid profile: high-density lipoprotein cholesterol (HDL-C)
timeFrame: 12 months
measure: Serum adipokines: leptin
timeFrame: 12 months
measure: Serum adipokines: adiponectin
timeFrame: 12 months
Other outcomes:
Locations:
city: Thessaloniki
country: Greece
facility: 1st Department of Obstetrics and Gynecology, School, of Medicine, Aristotle University of Thessaloniki
city: Thessaloníki
country: Greece
facility: Department of Endocrinology, "Hippokration" General Hospital of Thessaloniki
city: Thessaloníki
country: Greece
facility: 424 General Military Hospital
Study officials:
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Ilias D Vachliotis, MD, PhDc
role: STUDY_DIRECTOR
affiliation: 424 General Military Hospital, Thessaloniki, Greece
name: Athanasios D Anastasilakis, MD, PhD
role: STUDY_DIRECTOR
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Antonis Goulas, MD, PhD
role: STUDY_DIRECTOR
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Dimitrios G Goulis, MD, PhD
role: STUDY_DIRECTOR
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Stergios A Polyzos, MD, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Department of Endocrinology, "Hippokration" General Hospital of Thessaloniki
name: Zoe A Efstathiadou, MD, PhD
role: STUDY_DIRECTOR
affiliation: School of Medicine, Aristotle University of Thessaloniki
name: Vasileios Rafailidis, MD, PhD
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.