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

Odense University Hospital, Steno Diabetes Center Copenhagen, Rigshospitalet, Denmark, Aalborg University Hospital

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.

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.

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

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.

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.

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.

All participants must undergo a physical examination and deliver blood and urine samples in order to participate in the study.

The difference between treated and controls in changes from baseline to 18 months in bone specific alkaline phosphatase

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.

Changes between baseline and 18 months as well as differences between treated and controls. The HR-pQCT scan is a voluntary procedure.

Changes between baseline and 18 months as well as differences between treated and controls. The HR-pQCT scan is a voluntary procedure.

Changes between baseline and 18 months as well as differences between treated and controls. The HR-pQCT scan is a voluntary procedure.

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.

P-ionised calcium. Changes between baseline and 18 months as well as differences between treated and controls.

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.

Changes between baseline and 18 months as well as differences between treated and controls. These are voluntary procedures.

Changes between baseline and 18 months as well as differences between treated and controls. These are voluntary procedures.

Detailed histology of underlying cellular mechanisms using a combination of immunostainings and advanced in situ hybridizations on the bone biopsy

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