Bisphosphonate Prior to Parathyroidectomy in Primary Hyperparathyroidism

Aim The overall aim of this study is a physiological investigation of the effect of bisphosphonate treatment versus placebo at time of parathyroidectomy (PTX) in patients with primary hyperparathyroidism (PHPT) on bone, kidney and the cardiovascular system one-year post-surgery.

Hypothesis:

In patients with PHPT and low areal bone mineral density (aBMD), treatment at time of PTX with zoledronic acid (ZOL) compared to placebo:

1. does not improve aBMD 2. does not improve bone microarchitecture 3. does not improve volumetric bone mineral density (vBMD) 4. does not influence changes in BTM 5. does not improve coronary artery calcium score (CACS) 6. does not improve arterial stiffness (pulse wave velocity \[PWV\]) 7. does not improve degree of renal calcifications or urinary parameters

Background:

PHPT is a common endocrine disorder characterised by hypercalcemia and inappropriately high levels of parathyroid hormone (PTH). In most cases, PHPT is caused by hypersecretion of PTH from a single adenoma (80-90%). It is a chronic disease, which may lead to several complications such as osteoporosis, renal calcifications, cardiovascular disease, and neuropsychiatric symptoms. Surgical removal of the parathyroid gland/-s causing the hypersecretion of PTH is the only definitive cure for PHPT. It is a disease that mostly affects women with a ratio of 3:4 in the age group 40-70 years. Even though many patients are asymptomatic up to one third of the patients have osteoporosis at the time of diagnosis. Hypersecretion of PTH affects bone causing an increase in bone turnover markers (BTM), a decrease in BMD and an increased risk of fractures. Successful PTX normalises the calcium homeostasis and increases BMD one-year post-surgery at both lumbar spine and total hip, whereas the BMD increase at the distal forearm is minor. Accordingly, in Denmark, patients with PHPT and osteoporosis are most often treated with PTX only and "watchful waiting" is employed regarding BMD. If osteoporosis is sustained one year post surgery treatment (typically with a bisphosphonate) is, then initiated. To date, limited data on the effect of bisphosphonates if administrated at time of PTX is available. A retrospective study comparing 24 PHPT patients treated with PTX alone to 26 PHPT patients treated with both bisphosphonates and PTX found no beneficial effects on BMD of adding bisphosphonate to PTX. In another retrospective study however, co-treatment with bisphosphonate prior to PTX in patients with both PHPT and osteoporosis was associated with a decreased risk of fracture whereas, adding bisphosphonates after PTX did no reduce fracture risk. In contrast, a RCT in patients with PHPT comparing treatment with ZOL 1-3 months after PTX to PTX alone and found a significantly higher increase in BMD at the lumbar spine and femoral neck in the group treated with ZOL. At the total hip, however, BMD increased more in the group that only received PTX. Taken together the studies so far have shown conflicting results. Moreover, as the lumbar spine and femoral neck are sites relatively rich in trabecular bone with higher turn-over, whereas cortical bone is more prominent at the total hip, the effects of bisphosphonates and PTX may differ according to bone site. Therefore, it is unclear if treatment with bisphosphonate at time of PTX strengthens bone or impairs the natural recovery of bone during the first year after PTX. Only very few studies have addressed this issue. As up to one third of the patients with PHPT are diagnosed with osteoporosis, it is essential to clarify which treatment approach is optimal for the recovery of bone in this patient group. To clarify bisphosphonates effect on bone metabolism at the time of PTX, the investigators will perform a mechanistic study in patients with PHPT and either osteopenia or osteoporosis to study the pharmacodynamic effects on bone prior to PTX.

Several studies have reported an increased mortality compared to the general population in patients with classic PHPT with moderate to severely elevated ionized calcium levels whilst studies with focus on mild PHPT found no increased mortality. Overall death was reported from cardiovascular diseases (CVD) and malignancy. ZOL is a well-known drug used for decades to treat osteoporosis and malignancy-related bone disease. However, possible positive effects such as reduced mortality and cardiovascular events of ZOL used have been discussed. In a RCT study investigating the effects of ZOL infusion every 18 months on BMD in postmenopausal women observed a lower rate of myocardial infarction and composite cardiovascular outcomes (defines as myocardial infarction, need for coronary revascularization, stroke or sudden dead) but not stroke in the group receiving ZOL compared to placebo. In contrast, meta-analyses looking at cardiovascular safety of ZOL , found no beneficial effects on major cardiovascular events with ZOL used, however, in one meta-analysis an increased risk of arterial fibrillation was observed.\[22, 23\] In a large cohort study from Denmark and Sweden investigating the safety of ZOL against oral bisphosphonate also observed a higher risk of atrial fibrillation, other arrhythmias, and heart failure compared to untreated individuals whereas the cardiovascular mortality among ZOL users was lower. Studies investigating effects of ZOL on cardiovascular outcomes are all made in population with osteoporosis or in patients with low BMD. However, no one have investigated ZOLs effect on cardiovascular indices in patients with PHPT. Coronary artery calcium score (CACS) and pulse wave velocity (PWV) are strong predictors of CVD in healthy individuals. Only few studies have investigated the CACS in PHPT patients. A cross-sectional study of 130 PHPT patients compared to a cohort of population-based control subjects found a greater positive CACS in PHPT patients compared to controls. However, another cross-sectional study of only 20 PHPT patients found no increased CACS compared to healthy controls.\[28\] Central arterial stiffness measured as PWV has been established as a predictor of cardiovascular events and all-cause mortality in both the middle-aged and elderly population. A few prospective studies have reported an increased arterial stiffness in PHPT patients compared to healthy individual and a decreased arterial stiffness following PTX. A RCT study investigating short-term effect of PTX on arterial stiffness observed a significant decrease in PWV 3-month after PTX in PHPT with moderate-severe hypercalcemia. As patients with PHPT have increased CVD mortality is it of great interest to investigated if ZOL infusion in PHPT may have a proactive effect on the cardiovascular system as well as beneficial effects on bone architecture.

Renal calcifications are common in PHPT and in many studies the prevalence is determined to be around 20-25%. However, effects of PTX on the remission on renal calcifications are sparser. The risk of nephrolithiasis declines following PTX, although the risk remains increased compared to the general population. Hypercalciuria is of importance for the development of calcifications, however it does not fully explain the increased stone risk. Other metabolic factors in the urine may play a role in the increased risk of renal calcifications. One study with 51 PHPT patients found normalization of urinary calcium excretion following PTX but not on all other urinary metabolic parameters. As only few studies have evaluated the effect of PTX on urinary parameters and renal calcifications one-year post-surgery the investigators want to assess a metabolic urinary profile and a CT-scan of the kidneys and urinary tracts in PHPT with renal calcifications compared to PHPT without calcifications and effects of PTX as well as the potential effects of treatment with ZOL.

Methods Design: A randomized, double-blinded placebo-controlled trial

Patient flow: Patients referred to Aarhus University Hospital (AUH) for PTX due to PHPT will be included prospectively. The investigators aim to include 140 patients with PHPT - 70 patients in each group. Patients will be enrolled consecutively until the required number of participants have been achieved. The enrolment period will be approximately 1 years. Enrolled participants will be randomized to intervention- or placebo group and receive either ZOL or placebo (saline water) 2-4 weeks prior to PTX. Enrolled participants will be examined as detailed below (table 1). Participants who did not archive normocalcemia following PTX may not have to continue their participation in the study after (unsuccessful) PTX. One-year post-surgery a control visit will be held for all participants. The participants finish the study at the 12- month follow-up visit after PTX. Participants will be excluded from the study if a ionized calcium \>1,35 mmol/l is measured at day 28.

Intervention:

ZOL 4 mg vs. placebo (100 ml saline water) as a single intravenous (iv) infusion. Participants will receive ZOL or saline water at the outpatient clinic of Endocrinology, Aarhus University Hospital approximately two-four weeks prior to PTX (baseline). According to standard of care at the hospital, all patients will be recommended a daily oral supplement with 800 mg of elementary calcium in combination with 38 micrograms of cholecalciferol following PTX.

Double blinding: A nurse with no association to the project will mask both ZOL and saline water prior to randomisation with non-transparent bags so that both patients and investigators in the trial are blinded to the content of the infusion bags. At time of inclusion, participants will be randomised (double blinded) to receive either ZOL or placebo (saline) 2-4 weeks prior to PTX. ZOL and saline water will be administrated as an iv. infusion over 15 minutes by a study nurse without any other relation to the study. Randomization will be performed using a computer algorithm. Overall, participants will be stratified based on gender and ionized calcium ≤ or ≥ 1,45 mmol/l into 2 approximately equally sized groups. One of the groups will also have BTM performed at day 14 and at week 8, 16 and 24.

Overall medical records:

ZOL and placebo (saline water) are supplied by the hospital pharmacy and delivered to the investigation site. The investigators will document and keep a record of experimental drug delivered to the site with the following information: name, strength, amount received, date of receipt, batch number, expiration date, amount of experimental drug on the investigation site, date and initials on the person which has updated the records of the experimental drug delivered. The delivery note from the pharmacy may be used as documentations provided it contains the above information and will be signed upon receipt.

Individual medical records:

Medical records for each participant will be carried out thoroughly. A separate document will be used for the individual medical records to obtain blinding. Before the experimental drug is delivered to the investigator a second person with no association to the project will double check that is it the correct experimental drug delivered to the investigator according to the randomisation. The medical records will contain the following information: Patients ID, name, strength, and amount of the experimental drug, batch number, expiration date, amount of drug delivered and administered, date and initials of persons delivered and administrated the drug, amount of experimental drug returned, date and initial of person receiving returned experimental drug.

Unblinding:

The investigator has the responsibility and the possibility to unblind participants in case of emergency.

Measurements:

aBMD are measured by dual energy x-ray absorptiometry (DXA) and high-resolution peripheral computed tomography (HRpQCT) scans at baseline and end of study. Volumetric bone mineral density is

• Effects of ZOL at aBMD at distal forearm [Срок оценки: 12 months (one year)]
• Effects of ZOL at aBMD at femoral neck [Срок оценки: 12 months (one year)]
• Effects of ZOL at aBMD at total hip [Срок оценки: 12 months (one year)]
• Effects on microarchitecture measured by high-resolution peripheral computed tomography (HRpQCT). [Срок оценки: 12 months]
• Effects on biochemical bone turnover markers (BTM). [Срок оценки: 12 months]
• Effects on vBMD at the hip [Срок оценки: 12 months]
• Effects on vBMD at the lumbar spine. [Срок оценки: 12 months]
• Effects on coronary artery calcium score (CACS) [Срок оценки: 12 months]
• Effects on pulse wave velocity (PWV) [Срок оценки: 12 months]
• Effects of ZOL on renal calcifications [Срок оценки: 12 months]
• Effects of ZOL on urinary analytes [Срок оценки: 12 months]