Treatment of Adynamic Bone Disorder With Parathyroid Hormone in Chronic Kidney Disease

Study Overview
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Brief Summary
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This study is a 1:1 randomized controlled trial with an intervention for 18 months and a follow up period of 12 months. The purpose of the study is to assess the safety and efficacy of recombinant human parathyroid hormone for treatment of adynamic bone disorder in patients with chronic kidney disease.

Detailed Description
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This study is a 1:1 randomized controlled trial with an intervention for 18 months and a follow up period of 12 months. The study will explore if treatment with recombinant human parathyroid hormone (PTH) improves bone turnover and bone mineral density (BMD), and thereby prevents the high risk of fracture in patients with chronic kidney disease (CKD). Disturbed bone metabolism is related to increased risk of cardiovascular disease in patients with CKD. This study also wishes to examine of treatment with recombinant PTH improves cardiovascular parameters.

Official Title
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Treatment of Adynamic Bone Disorder With Parathyroid Hormone in Patients With Chronic Kidney Disease

Conditions
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Adynamic Bone Disease, Chronic Kidney Diseases, Cardiac Disease, Chronic Kidney Disease-Mineral and Bone Disorder

Intervention / Treatment
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* Drug: Teriparatide
* Diagnostic Test: DXA,VFA, X-ray, HR-pQCT, 18-F NAF PET/CT
* Procedure: Bone biopsy
* Diagnostic Test: Cardiac tests
* Other: Blood and urine samples and physical examination


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years CKD stage 4-5D (eGFR ≤29 ml/min) according to Kidney Disease Improving Global Outcomes(KDIGO) definition DXA scan with a T-score at the total hip, femoral neck or lumbar spine (L1-4) ≤-2 (or Z-score ≤-2) in a minimum of 2 vertebraes and/or former fragility fracture (vertebral, hip, for- or upper arm, ankle) assessed with VFA or x-ray of the columna Patients with expected adynamic bone disorder, based on BSAP≤21 µg/l or biopsy-verified low bone turnover Exclusion Criteria: Hypercalcemia defined as sustained ionized calcium >1.35 mmol/l Previous fracture withon the last 6 months *Patients may be rescreened after the 6 months Previous calciphylaxis Thyroid disturbances not adequately treated based on the opinion by the clinician Treatment with digoxin Paget's disease or other metabolic bone disorders Antiresorptive or bone anabolic medication during the last 24 months (for bisphosphonates it is only during the last 12 months) Former or present malignant disease (except skin basal or planocellular carcinoma) Previous external beam or implant radiation therapy to the skeleton Kidney transplanted patients Oral prednisolone treatment exceeding a total of 450 mg during the last 6 months or active oral prednisolone treatment with a daily dose of > 5 mg 25 hydroxyvitamin D2 and D3 <50 nmol/l *Patients may be rescreened after correction Inability to administer teriparatide Reduced liver function *Alanine Aminotransferase (ALAT) >3x upper limit of normal or bilirubin > 2x upper limit of normal Pregnancy, lactation or fertile women (post-menopausal females are not considered fertile) not using safe anticonception (the following contraceptive methods are considered appropriate: Intrauterine device (IUD) or hormonal anticontraceptive (oral contraceptives, implant, transdermal patches, vaginal ring or depot injection)). Hypersensitivity to the active substance in teriparatide or to any of the excipients or content Inability to provide informed consent Medical conditions or treatments that may interfere with assessments of the outcomes of the trial Drug or alcohol abuse Unable to participate in a clinical study based on the judgement by the local investigator For those participating in the bone biopsy procedure: 1) Hypersensitivity to any of the tetracyclines or to any of the excipients or content, 2) Treatment with anticoagulants (vitamin K antagonists, Non-vitamin K Antagonist Oral Anticoagulants (NOAC), unfractionated or low-molecular heparin or antiplatelet agents that, due to clinical indication can't be paused, 3) Disturbances in thrombosis and/or haemostasis For those participating in pulse wave measurements: 1) Atrial fibrillation, 2) Aorta stenosis

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Teriparatide<br>Patients receive teriparatide 20 micrograms once daily for 18 months | Drug: Teriparatide<br>* 20 micrograms<br>* Other names: Terrosa;Diagnostic Test: DXA,VFA, X-ray, HR-pQCT, 18-F NAF PET/CT<br>* All participants undergo DXA and VFA or X-ray scans 3 times during the study. Some participants (those connected to Herlev) are offered 18F NAF PET/CT scans at baseline and after 18 months and some participants (those connected to Odense University Hospital and Aalborg University Hospital) are offered HR-pQCT scans at baseline and after 18 months. The 18F-NAF PET/CT and HR-pQCT are optional, so it is not a must to have these procedures done to participate in the study.<br>Procedure: Bone biopsy<br>* All participants are invited to undergo a bone biopsy after 18 months, but it is not a must to have the procedure done to participate in the study.<br>Diagnostic Test: Cardiac tests<br>* All participants are invited to undergo 24-hour blood pressure measurements and pulse wave measurements at baseline and after 18 months, but it is not a must to have these procedures done to participate in the study.<br>Other: Blood and urine samples and physical examination<br>* All participants must undergo a physical examination and deliver blood and urine samples in order to participate in the study.<br>|
| Other: Controls<br>Controls receive no treatment with teriparatide | Diagnostic Test: DXA,VFA, X-ray, HR-pQCT, 18-F NAF PET/CT<br>* All participants undergo DXA and VFA or X-ray scans 3 times during the study. Some participants (those connected to Herlev) are offered 18F NAF PET/CT scans at baseline and after 18 months and some participants (those connected to Odense University Hospital and Aalborg University Hospital) are offered HR-pQCT scans at baseline and after 18 months. The 18F-NAF PET/CT and HR-pQCT are optional, so it is not a must to have these procedures done to participate in the study.<br>Procedure: Bone biopsy<br>* All participants are invited to undergo a bone biopsy after 18 months, but it is not a must to have the procedure done to participate in the study.<br>Diagnostic Test: Cardiac tests<br>* All participants are invited to undergo 24-hour blood pressure measurements and pulse wave measurements at baseline and after 18 months, but it is not a must to have these procedures done to participate in the study.<br>Other: Blood and urine samples and physical examination<br>* All participants must undergo a physical examination and deliver blood and urine samples in order to participate in the study.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in bone specific alkaline phosphatase (BSAP) | The difference between treated and controls in changes from baseline to 18 months in bone specific alkaline phosphatase | Baseline and 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients who no longer has adynamic bone disorder based on a BSAP >21 µg/l | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. It is also measured through study completion, an average of 30 months | 
| BMD at the lumbar spine, antebrachium, femoral neck and total hip | Changes between baseline and 18 months as well as differences between treated and controls | Baseline and 18 months. The scan is also performed at 30 months | 
| Incidence of fragility fractures and vertebral fractures assessed using x-ray of columna | Changes between baseline and 18 months as well as differences between treated and controls | Baseline and 18 months. The scan is also performed at 30 months | 
| Bone microarchitecture assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) | Changes between baseline and 18 months as well as differences between treated and controls. The HR-pQCT scan is a voluntary procedure. | Baseline and 18 months | 
| Volumetric BMD assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) | Changes between baseline and 18 months as well as differences between treated and controls. The HR-pQCT scan is a voluntary procedure. | Baseline and 18 months | 
| Bone geometry assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) | Changes between baseline and 18 months as well as differences between treated and controls. The HR-pQCT scan is a voluntary procedure. | Baseline and 18 months | 
| Bone strength assessed using high-resolution peripheral quantitative computed tomography (HR-pQCT) | Changes between baseline and 18 months as well as differences between treated and controls. The HR-pQCT scan is a voluntary procedure. | Baseline and 18 months | 
| Regional bone formation using 18F-Sodium Fluoride Positron Emission Tomography/Computed Tomography (18F-NAF PET/CT) | Changes between baseline and 18 months as well as differences between treated and controls. The 18F-NAF PET/CT is a voluntary procedure. | Baseline and 18 months | 
| Changes in p-PTH | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. Some of them are also measured during follow up. | 
| Changes in p-phosphate | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. Some of them are also measured during follow up. | 
| Changes in p-magnesium | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. Some of them are also measured during follow up. | 
| Changes in calcium | P-ionised calcium. Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. Some of them are also measured during follow up. | 
| Bone histomorphometry | Static and dynamic bone histomorphometry classified by the bone Turnover Mineralization Volume (TMV) classification assessed by bone biopsy. Performed after 18 months. This is a voluntary procedure. | 18 months | 
| Changes in Intact Procollagen type 1 N-terminal Propeptide (P1NP) | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. They are also measured during follow up | 
| Changes in total P1NP | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. They are also measured during follow up | 
| Changes in Tartrate-Resistant Acid Phosphatase 5b (TRAP5b) | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. They are also measured during follow up | 
| Changes in sclerostin | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. They are also measured during follow up | 
| Changes in Receptor Activator of Nuclear factor Kappa-B Ligand (RANKL) | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. They are also measured during follow up | 
| Changes in Osteoprotegerin (OPG) | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. They are also measured during follow up | 
| Changes in Fibroblast Growth Factor 23 (FGF-23) | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months. They are also measured during follow up | 
| 24-hour blood pressure | Changes between baseline and 18 months as well as differences between treated and controls. These are voluntary procedures. | Baseline and 18 months | 
| Pulse wave measurements including velocity | Changes between baseline and 18 months as well as differences between treated and controls. These are voluntary procedures. | Baseline and 18 months | 
| Changes in cardiovascular marker Calciprotein Particles (CPP)/T50 | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months | 
| Changes in cardiovascular marker N-Terminal pro B-type Natriuretic Peptide (NT-proBNP) | Changes between baseline and 18 months as well as differences between treated and controls. | Baseline and 18 months | 
| Adverse reactions | The incidence of adverse reactions in treated patients. This is examined during the entire study. | From baseline to 18 months | 
| Bone microstructure | Bone mictrostructure by micro-compyter tomography of the bone biopsy | 18 months | 
| Bone histology | Detailed histology of underlying cellular mechanisms using a combination of immunostainings and advanced in situ hybridizations on the bone biopsy | 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Fracture risk, Teriparatide