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| Name | Class |
|---|---|
| 424 General Military Hospital | OTHER |
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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| "Denosumab" | Experimental | 35 postmenopausal women with low bone mineral density (BMD) and NAFLD will receive denosumab. |
|
| "Alendronate" | Active Comparator | 35 postmenopausal women with low bone mineral density (BMD) and NAFLD will receive alendronate. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Hepatic steatosis: Ultrasound-Guided Attenuation Parameter (UGAP) measured on an ultrasound machine GE Logiq E10s. |
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 |
| Measure | Description | Time Frame |
|---|---|---|
| Hepatic fibrosis: liver stiffness (LS) measured with 2D Shear Wave Elastography (2D SWE) on an ultrasound machine GE Logiq E10s. |
2D SWE is a non-invasive tool measuring the hepatic parenchyma stiffness, thus indirectly suggesting fibrosis stage (F). Cut-offs values of <8.27 kPa, 8.27-9.39 kPa, 9.40-11.88 kPa and >11.88 kPa have been proposed for F0-F1, F2, F3, and F4, respectively. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| 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 |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Endocrinology, "Hippokration" General Hospital of Thessaloniki | Thessaloniki | 54642 | Greece | |||
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 33334622 | Background | 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. | |
| 33208241 | 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. |
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There is a plan to make IPD and related data dictionaries available
12 months after the publication of the study.
Yet unknown
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| ID | Term |
|---|---|
| D065626 | Non-alcoholic Fatty Liver Disease |
| D015663 | Osteoporosis, Postmenopausal |
| D005234 | Fatty Liver |
| D008103 | Liver Cirrhosis |
| ID | Term |
|---|---|
| D008107 | Liver Diseases |
| D004066 | Digestive System Diseases |
| D010024 | Osteoporosis |
| D001851 | Bone Diseases, Metabolic |
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| ID | Term |
|---|---|
| D000069448 | Denosumab |
| D019386 | Alendronate |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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Multicenter, non-randomized, non-blinded, parallel group, one-year clinical trial
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No masking
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| 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. |
|
|
| 12 months |
| Hepatic steatosis non-invasive index: Fatty Liver Index (FLI). |
FLI is a non-invasive hepatic steatosis index, which is based on BMI, waist circumference, GGT and triglycerides. FLI ≥60 is associated with the presence of steatosis, while FLI <30 rules out the presence of steatosis. | 12 months |
| Hepatic steatosis non-invasive index: Hepatic Steatosis Index (HSI). |
HSI is a non-invasive hepatic steatosis index, which is based on AST, ALT, BMI, gender and the presence or not of T2DM. HSI ≥36 is associated with the presence of steatosis, while HSI <30 rules out the presence of steatosis. | 12 months |
| Hepatic fibrosis non-invasive index: NAFLD fibrosis score (NFS). |
NFS is a non-invasive hepatic fibrosis index, which is based on age, BMI, AST, ALT, platelets, albumin and the presence or not of T2DM. NFS >0.675 is associated with high probability of advanced hepatic fibrosis (F3-F4), while NFS <-1.455 is associated with low probability of advanced hepatic fibrosis (F3-F4). | 12 months |
| Hepatic fibrosis non-invasive index: Fibrosis-4 index (FIB-4). |
FIB-4 is a non-invasive hepatic fibrosis index, which is based on age, AST, ALT and platelets. FIB-4 ≥2.67 is associated with high probability of advanced hepatic fibrosis (F3-F4), while FIB-4 <1.3 (when age <65 years) or <2.0 (when age ≥65 years) is associated with low probability of advanced hepatic fibrosis (F3-F4). | 12 months |
| Hepatic fibrosis non-invasive index: AST-to-Platelet Ratio Index (APRI). |
APRI is a non-invasive hepatic fibrosis index, which is based on AST, ALT and platelets. APRI ≥1 is associated with high probability of advanced hepatic fibrosis (F3-F4), while APRI <0.5 is associated with low probability of advanced hepatic fibrosis (F3-F4). | 12 months |
| Liver function tests: alanine aminotransferase (ALT). | Between-within group interactions in ALT (baseline to endpoint) The normal range for ALT is 4-36 U/L, but it may be different in different laboratories. Higher values may indicate hepatocellular injury. | 12 months |
| Liver function tests: aspartate aminotransferase (AST) | Between-within group interactions in AST (baseline to endpoint) The normal range for AST is 8-33 U/L, but it may be different in different laboratories. Higher values may indicate hepatocellular injury. | 12 months |
| Insulin resistance index: Homeostasis Model Assessment - Insulin Resistance (HOMA-IR) | Between-within group interactions in HOMA-IR (baseline to endpoint) HOMA-IR is calculated by the formula: fasting glucose (mg/dl) × insulin (mU/L)/405, and indicates the degree of insulin resistance; higher scores indicate greater insulin resistance. A HOMA-IR value ≥2.5 is indicative of insulin resistance. | 12 months |
| Lipid profile: total cholesterol | Between-within group interactions in total cholesterol (baseline to endpoint) Total cholesterol levels <200mg/dl are considered acceptable, 200-239 mg/dl are borderline high, and ≥240 mg/dl are considered high; however, these cut-offs differentiate according to other cardiovascular risk factors. | 12 months |
| Lipid profile: triglycerides | Between-within group interactions in triglycerides (baseline to endpoint) Triglycerides levels <150mg/dl are considered acceptable, 150-199 mg/dl are borderline high, and ≥200 mg/dl are considered high. | 12 months |
| Lipid profile: low-density lipoprotein cholesterol (LDL-C) | Between-within group interactions in LDL-C (baseline to endpoint) LDL-C levels <100mg/dl are considered optimal, 100-129 mg/dl are borderline high, and >130 mg/dl are considered high; however, these cut-offs differentiate according to other cardiovascular risk factors. | 12 months |
| Lipid profile: high-density lipoprotein cholesterol (HDL-C) | Between-within group interactions in HDL-C (baseline to endpoint) For women, the normal range for HDL-C is 50-90 mg/dl. Higher HDL-C are regarded as better. | 12 months |
| Serum adipokines: leptin | Between-within group interactions in leptin (baseline to endpoint) For women, the normal range for leptin is 5-15 ng/ml, but it may be different for different ELISA kits. | 12 months |
| Serum adipokines: adiponectin | Between-within group interactions in adiponectin (baseline to endpoint) The normal range for adiponectin is 5-30 μg/ml, but it may be different for different ELISA kits. | 12 months |
| 1st Department of Obstetrics and Gynecology, School, of Medicine, Aristotle University of Thessaloniki |
| Thessaloniki |
| 56403 |
| Greece |
| 424 General Military Hospital | Thessaloniki | 56429 | Greece |
| 30323574 | 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. |
| 29691303 | 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. |
| 32596356 | 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. |
| 24127173 | 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. |
| 35589613 | 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. |
| D001847 |
| Bone Diseases |
| D009140 | Musculoskeletal Diseases |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D005355 | Fibrosis |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |
| D004164 | Diphosphonates |
| D063065 | Organophosphonates |
| D009943 | Organophosphorus Compounds |
| D009930 | Organic Chemicals |