Clinical trial NCT03027557
Conditions: Primary Hyperparathyroidism Parathyroid Adenoma Parathyroid Hyperplasia
Keywords: Primary Hyperparathyroidism Parathyroid Adenoma Parathyroid Hyperplasia Cinacalcet Denosumab Drug Therapy Bone Mineral Density Calcium
Sponsor: Peter Vestergaard
Start date: 2017-03-01; Completion date: 2019-09-12
Enrollment: 46 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The only known cure for primary hyperparathyroidism is surgical removal of one or more parathyroid glands. Some patients however, do not fulfill criteria for surgery or do not want to undergo a procedure due to fear of the associated risks. Therefore a medical alternative is warranted.

This study aims to evaluate the effects of Denosumab alone, and in combination with Cinacalcet, as a medical treatment for patients suffering from primary hyperparathyroidism, with mild osteoporosis. To the best of our knowledge no previously reported randomized controlled trial has investigated the use of denosumab in primary hyperparathyroidism.

60 patients will be enrolled in three different treatment-groups: 20 receiving both Denosumab and Cinacalcet, 20 Denosumab and placebo and 20 placebo and placebo. Patients included do not meet the criteria for, or have no wish for a surgical procedure.

By combining the two drugs, this study could possibly contribute to the discovery of a realistic medical alternative to surgery. It is expected that the therapy will be able to both control s-calcium and s-intact parathyroid hormone (iPTH), and simultaneously enhance bone-structure. The therapy thus has the potential of preventing fractures and possibly other long-term effects of primary hyperparathyroidism such as formation of kidney stones, and coronary calcification. Another objective of this project is to investigate whether the combined therapy can facilitate an actual reset of the Calcium-sensing receptor, and thereby de facto cure the disease.

Detailed description:
Background/Context:

This project deals with medical treatment of primary hyperparathyroidism. The only cure currently available is surgical removal of one or more parathyroid glands, but this option is neither feasible, nor desirable in all patients with the diagnosis.

Today a major group of patients are being diagnosed by coincidence with biochemical blood-screening, and are therefore in an asymptomatic state of the disease at the time of diagnosis. Long term studies show that these patients over time often have progression in their disease, and develop complications such as osteoporosis. Thus a medical alternative is warranted.

Previous studies have investigated the effects of well known antiresorptive drugs such as bisphosphonates, as well as estrogen-related compounds. These drugs have had effects on particularly bone mineral density (BMD) and biochemical bone-turnover markers, but have been able only transiently to lower blood-calcium levels. Combined with too many unwanted side-effects and a high prevalence of contraindications for a large proportion of the patients needing treatment, these drugs have not provided a realistic alternative to surgery.

Treatment today generally follows the international consensus for treatment of asymptomatic patients with primary hyperparathyroidism. Briefly this includes watchful waiting with biannual control-sessions for indication of surgery, screening for kidney stones/nephrolithiasis, osteoporosis and s-calcium - and s-iPTH levels.

This randomized controlled trial involves the drugs Cinacalcet og Denosumab. Denosumab has previously been shown to greatly improve BMD, lower s-calcium, lower the rate of bone-turnover and prevent osteoporotic fractures in several populations with different diseases, but has never been tested in a published randomized controlled trial in patients with primary hyperparathyroidism.

Cinacalcet has been proved able to lower s-iPTH, lower s-Calcium and thereby relieve symptoms of hypercalcaemia caused by primary hyperparathyroidism. It does not however, lower the rate of bone turnover, and it has not been show to improve BMD.

By combining the two drugs, this study could possibly contribute to the discovery of a realistic medical alternative to surgery. It is expected that the therapy will be able to both control s-calcium and s-iPTH, and simultaneously enhance bone-structure. The therapy thus has the potential of preventing fractures and possibly other long-term effects of primary hyperparathyroidism such as formation of kidney stones, and coronary calcification. Another objective of this project is to investigate whether the combined therapy can facilitate an actual reset of the Calcium-sensing receptor, and thereby de facto cure the disease.

Arms: arm 1: 20 subjects will be treated with combined 60mg denosumab bi-annually , 30 mg cinacalcet daily and 50 micrograms vitamin-D daily. arm 2: 20 subjects will receive 60mg denosumab bi-annually, placebo and 50 micrograms vitamin-D daily. arm 3: 20 subjects will receive a saline injection bi-annually (blinded), placebo-tablets and 50 micrograms vitamin-D daily.
Interventions: intervention 1: Cinacalcet 30 mg Tablet intervention 2: Denosumab Inj 60 mg/ml intervention 3: Placebo tablets intervention 4: Saline Injection (Placebo)
Intervention descriptions: intervention 1: Participants in one arm will receive 30 mg cinacalcet each day. intervention 2: Participants in two arms will receive 60 mg Denosumab biannually. intervention 3: Participants in two arms will receive one placebo-tablet each day. intervention 4: Participants in one arm will receive saline injections as placebo for denosumab.

Protocol documents:
Prot_SAP_000.pdf: 
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Treatment of Primary Hyperparathyroidism with Denosumab and 
Cinacalcet.  
  
EudraCT number: 2016-001510-20  
NTC: 03027557  
Sponsor Protocol number: 180987  
  
Subinvestigator:  
Julius Simoni Leere, Cand. Med.  
Registrar, Region Nordjylland  
Autorisation-ID: 0BKC2  
  
Sponsor and Investigator:   
Peter Vestergaard, MD, Professor, Ph.d., Dr.med.   
Endokrinologisk Afdeling, Aalborg Universitetshospital, Mølleparkvej 4,  
9000 Aalborg   
  
  
Single-center study.  
  
  
  
  
  
  
  
  
  
  
  


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Studyprotocol  
Treating Primary Hyperparathyroidism with Denosumab and Cinacalcet.  
1. Generel provisions.  
Trialcenter:  
Endokrinologisk Afdeling, Aalborg Universitetshospital, Mølleparkvej 4, 9000 Aalborg,  
Tlf. 97 66 36 00  
Collaborationpartners:  
Radiologisk Afdeling, Aalborg Universitetshospital, Mølleparkvej 4, 9000 Aalborg  
Klinisk Biokemisk Afdeling, Aalborg Universitetshospital, Mølleparkvej 4, 9000 Aalborg  
Sygehusapoteket, Aalborg Universitetshospital, Porsvej 1, 9000 Aalborg   
GCP monitoring by:  
The trial will be monitored by: GCP-enheden ved Aalborg og Aarhus Universitetshospitaler, Institut 
for Klinisk Medicin Aarhus Universitet, Brendstrupgårdsvej 100, 8200 Aarhus N.  
Contact:   
Forskningens Hus i Aalborg, Søndre Skovvej 15, 9000 Aalborg, Telephone: 9766 6266  
  
The trial will be conducted according to the trial protocol, ICH-GCP guidelines and 
applicable legislation.  
  
Date of trial initiation: 01-09-2016  
Date of end of trial: 01-04-2019  
  
Signature by sponsor and investigator:  
Date: 26-04-16  
Peter Vestergaard
  
  
Signature by Subinvestigator:  
Date: 27-04-16 
  
  
Julius Simoni Leere   
 


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Table of contents  
2. .................................................................................................... Background  
2.1. ................................................................................................................... Drugs 
2.2. ............................................................. Resultats of non-clinical and clinical 
trials 
2.3. ...............Summary of side effects, risks and advantages for the trial subjects  
2.4. .......................................Dose, dosing, dosefrequency and treatment period   
2.5. .................................................................................................. Trial population 
3 ............................................................................................................. Trial aims 
4 .................................................................................................................... Trialplan  
4.1 ....................................................................... Primary and secondary endpoints 
4.2 ............................................................................................................. Trialdesign 
4.3 ......................................... measures for reducing or elimination of bias 
4.4+4.5. ............................................................................................. Treatment  
4.6 ................................................................................................ End of trial  
4.7 .............................................................................................. Drug registration 
4.8 ...........................................................................................................................CRF 
4.9 .............................................................................................Randomisation codes 
5 ................................................... Selection and exclusion of trial subjects  
5.1 ............................................................ Selection and screening of trial subjects 
5.2 ..................................................................................................... Inclusion criteria 
5.3 ................................................................................................... Exclusion criteria 
5.4 ..................................................................... Procedures for trial exit 
6 ..................................................................................... Treatment of trial subjects  
6.1 .......................................................................................... Treatment description 
6.2 ................................................................... Examinations of trial subjects  
6.3 ........................................................ Other medications used by trial subjects 
6.4 .................................................................................................................Adherence  
6.5 ...........................Control of trial end  
7 ............................................................................................................. Evaluation of effect 


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7.1+7.2 .................................................................................................. Effectparameters  
8 ........................ Monitoring of safety and handling of side effects and adverse events   
8.1+8.2. ...................................... Side effects, risks and side effects for trial subjects  
8.3+8.4 .......................................................................................... Safety parameters  
8.5 ................................................................... Registration of events/side effects  
8.6+8.7 ........................ Measures to prevent and treat complications  
8.8+8.9 .......................................................... Reporting of events/side effects  
8.10+8.11. Procedure for reporting to the National Board of Health and the Science 
Ethics Committee  
9. .......................................................................................................................... Statistics 
9.1 .....................................................................................Statistical considerations 
9.2 ...............................................................................................Power calculations 
9.3 ...................................................................................... Significance levels  
9.4 ........................................................................... Criteria for end of trial  
9.5 ............................................................................. Missing and unused data  
9.6 ............................................................ Deviations from the statistical plan 
9.7 Trial subjects for whom data will be included in the statistical analyses 
10. .................................................................... Access to source data/source documents  
11. ......................................................................... Quality control 
12. ............................................................................................................................... Ethics 
12.1 .........................................................................................Ethical considerations 
12.2 ............Reecruitment and obtaining of informed consent from trial subjects 
12.3 ............................................................................... Privacy protection  
12. 4...…………………………… Use of data from patient files 
12.5. ......................................... Access to trial information for trial subjects  
13. .......................................Handling and filing of data and biological material  
13. 1.. ....................................................................................................... Datahandling  
13.2+13.3. ................................................................... Rresearch biobank 
14. ......................................................................................... Financing and insurance  
15. ........................................................................................................... Publication  


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16……………………………………………………………………….Reeferences  
Abbreviations………………………………………………………….…….  
 
2. Background information.  
List of abreviations is at the end of the document.  
Background.  
Primary Hyperparathyroidism (pHPT) is the most common disease in gl. parathyroidea, and the 
most common cause of hypercalcaemia. Today, approx. 900-1000 patients a year in Denmark. 1 
The etiology is only partially elucidated, and there are several subtypes of the disease - both 
adenomas (85-90%), multiglandular hyperplasia, less common carcinomas and very rare hereditary 
mutations can give the diagnostic biochemical picture with high s-Ca2 + and at the same time 
elevated, or highly normal s-intact parathyroid hormone (s-iPTH). Common is a pathologically 
elevated secretion of PTH, which in turn directly and indirectly increases intestinal absorption, bone 
resorption and renal reabsorption of Ca2 +. 2  
The disease expresses itself symptomatically very variable according to severity, and patients can 
debut with everything from pronounced hypercalcemic symptoms with severely affected general 
condition, to a completely asymptomatic random biochemically detected condition. The effects of 
pHPT are manifold and affect multiple organ systems. These include decalcification of the bones, 
which leads to osteoporosis and fractures, increased excretion of calcium from the kidneys, which 
leads to a negative calcium balance, as well as increased risk of nephrocalcinosis, formation of 
kidney stones. kidney failure. There is also an increased risk of cardiovascular disease, ulcer 
disease, pancreatitis and pancreatic insufficiency, confusion, memory loss, psychosis, joint and 
muscle pain and fatigue, etc. 2  
More and more patients (80%) are diagnosed at an early (asymptomatic) stage by biochemical 
screening of s-calcium. Several studies indicate that this group of patients is also exposed to the 
effects of pHPT. Patients have increased bone remodeling3,4, which in turn has been shown by 
histomorphological analyzes, DXA and micro-CT to increase the cortical porosity of the bones and 
dilute the cortical width, while the trabecular bone thickness in mild pHPT may remain 
unaffected.5. The latter is controversial, however, as HRqCT analyzes show microstructural 
changes in the trabecular bone, which are considered to be able to lower its strength as well.6–10 
Long-term studies suggest that the disease progresses over time, leading to an increase in scalcium 
and a decrease in BMD11,12. The increased bone turnover thus forms a rationale for treatment. 
Whether the fracture risk in asymptomatic primary hyperparathyroidism is elevated is not yet fully 
elucidated, but cohort and population studies suggest that fracture risk is increased in both cortical 
and trabecular bone for up to 10 years before diagnosis and treatment of pHPT. A brand new 
prospective study of patients referred to a highly specialized center has shown that there is no 
difference in the incidence of vertebral fractures (VF), and densitometric osteoporosis between 
asymptomatic and symptomatic patients referred to a highly specialized center with pHPT (VFs, 
34.4 vs 34.7%; osteoporosis at DXA, 59.4 vs 65.8%) 13. 
 
Translation types 


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Text translation 
Source text 
 
1148 / 5000 
Translation results 
Curative treatment for pHPT is found today exclusively in the form of parathyroidectomy. 
Surgery is often not desirable in asymptomatic patients, just as a larger group of those 
diagnosed due to comorbidity, or for other reasons, meet the surgical criteria (found later in 
this document). However, over time, these patients are at high risk of developing 
complications of pHPT. An effective medical treatment alternative for those patients who 
are not surgery candidates would therefore be desirable. Thus, over time, several different 
solutions have been tried without finding an actual alternative to surgery. Medication is used 
today primarily in symptomatic patients while waiting for surgery, in severe symptomatic 
hypercalcaemia, or as a supplement to surgery e.g. in case of continued hypercalcaemia, or 
severe osteoporosis. Today, standard treatment for asymptomatic patients, often merely 
biochemical and radiological observation for signs of osteoporosis, renal involvement and 
calcium levels, is for the purpose of emergence of surgical indication. In the meantime, 
patients are often treated only with calcium and vitamin D.14  
 
2.1 Drugs  
  
The purpose of this study is to investigate whether treatment with Denosumab (ATC code: 
M05BX04) alone, or in combination with Cinacalcet (ATC code: H05BX01), may be an 
effective medical alternative for patients with low BMD pHPT who are not surgery 
candidates. Particular emphasis is placed on the treatment of hypercalcaemia, the prevention 
of osteoporosis and the effect of the treatment on bone structure and circulation. The 
medicine included in the trial is listed below. Cinacalcet and Denosumab will be the 
registered trial drug, and will be notified as such. Preparation name: Prolia® Generic Name: 
Denosumab ATC Code: M05BX04 Manufacturer: Amgen AB (Denmark). Strandvejen 70, 
2900 Hellerup, Denmark Appearance: Green-white pen Dose: 1 syringe contains 60 mg (1 
ml) of denosumab. Svt a dose. Description of the drug substance: Prolia is a recombinant 
human IgG2 monoclonal antibody with osteoclast inhibitory activity. The antibody is 
directed against RANKL. Decreased stimulation of the RANK receptor on preosteoclastic 
cells results in inhibited osteoclast formation and activity, thereby decreasing bone 
resorption, increasing bone mineral density, and reducing the risk of fracture. Rationale for 
dose use and duration of treatment: The usual dose for the treatment of osteoporosis is 60 
mg x 1 every 6 months. V. prevention of fractures, and reduction of severe hypercalcemia in 


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malignant disease, doses as high as 120 mg at 8-day intervals may be used. For this study 
we will use: 60 mg, semi-annually for 1 year. Packing in the experiment: Experimental 
name. Subinvestigator's name. Randomization number. Lot number. The text "Prolia® / 
Placebo". Preparation name: Mimpara® Generic name: Cinacalcet ATC code: H05BX01 
Manufacturer: Amgen AB (Denmark). Strandvejen 70, 2900 Hellerup, Denmark Method of 
administration: Oral, green oval tablets without notch. Dosage: 1 tablet (film-coated) 
contains 30 mg, 60 mg or 90 mg of cinacalcet (as hydrochloride). Description of the drug 
substance: Increases the sensitivity of the calcium-sensitive receptor (CaSR) to extracellular 
calcium, leading to decreased parathyroid hormone secretion. Rationale for dose use and 
duration of treatment: Treated for 1 year with 30 mg x 1 daily, for comparability with other 
clinical studies in the field, and to avoid the risk of hypocalcaemia. Packing for this 
experiment: Experiment name. Subinvestigator's name. Randomization number. Lot 
number. The text "Mimpara® / Placebo". Placebo 1 (placebo for prolia): Generic Name: 
Isotonic Saline (NaCl 0.9%), Fresenius Kabi, 10/20 ml vial. Manufacturer: Fresenius Kabi, 
Islands Brygge 57, 2300 København S ATC code: B05BB01, V07AB Method of 
administration: Subcutaneous, administered on the back of the arm. Contents: Physiological 
dose of saline. Dosage: 1 ml semi-annually at control visits. Packaging: 10 / 20ml vial with 
label applied, 1 ml drawn into clear, sterile disposable plastic syringe by blinded healthcare 
professionals immediately prior to injection. Packing: Eudract No. Subinvestigator contact 
information. ID number. Lot number. The text "Prolia® / Placebo". For NaCl, the labels are 
provided by the hospital pharmacy so that the blinded staff knows which patients need 
placebo. Batch no. on the given vial (which is also supplied by the hospital pharmacy), 
which is found in the ward, is registered on the label as well as in TMF. Placebo 2 (placebo 
for mimpara): Generic Name: Placebo (Placebo Centyl) Manufacturer: Jemopharm, 
Hasselvej 1, 4780 Stege Contents: Physiological dose of inactive minerals. 6.8x17 mm. 
Method of administration: Oral, green oval tablets with scored notch. Dosage: 1 pc daily. 
Packing: Eudract no. Subinvestigator contact information. ID number. Lot number. The text 
"Mimpara® / Placebo". Placebo for Mimpara: "Placebo Centyl" was originally produced for 
a similar experiment focusing on bone turnover, with Centyl as an intervention agent, where 
it has also been used as a placebo. Mimpara's color and size are comparable to placebo, as 
they are both green, measuring 6 x 10 mm and 7 x 17 mm respectively. Placebo has division 
notches and is thus not completely identical to the intervention preparation. We currently 
hold “Placebo Centyl” for a population of 50 patients. If more patients are included (up to 
60 patients), additional Placebo Centyl will be purchased. Placebo has no effect on bone 
turnover. Placebo is packaged by the pharmacy staff in white, opaque Duma cans, and the 
counting and registration of experimental medication is done by blinded staff who are not 
investigators or sub-investigators, so the trial supervisor or delegated evaluating physician 
will be blinded. Trial participants are naturally not informed about the appearance of 
Mimpara / Placebo, which is why they will also be blinded in relation to the treatment. D 
vitamin. Supplied by D3 Pharmacy ApS, Bispensgade 22, 9000 Aalborg, Denmark as tablets 
of 25 micrograms each. Everyone is given a supplement of 50 micrograms daily unless they 
receive> 25 micrograms in advance. Vitamin D supplementation is given as vitamin D 
deficiency exacerbates primary hyperparathyroidism, may in itself lead to secondary (and 


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tertiary) hyperparathyroidism, and is included as standard in the treatment guidelines for 
patients with primary hyperparathyroidism.  
  
Litterature review:  
As previously mentioned, various pharmacological solutions to pHPT and their consequences have 
been tried over time. Particular focus has been on mitigating the effect on bone impact, and the 
genes due to the high s-calcium. Overall, the treatment can be divided into traditional antiresorptive 
drugs, as well as calcimimetics. Good effect on BMD, and lowering of S-Ca2 + and bone markers 
has been demonstrated for antiresorptive treatment with e.g. bisphosphonates15–17, estrogens and 
selective estrogen receptor modulators18–21 in previous studies. However, the effect on S-Ca2 + is 
temporary as one does not modulate parathyroid disease CaSR, so after a period one sees a rebound 
effect due to increasing amounts of PTH. 
  
2.2 Resultats of non-clinical and clinical trials.   
Cinacalcet:  
Translation types 
Text translation 
Source text 
 
2703 / 5000 
Translation results 
Administration of Cinacalcet is currently permitted in most countries for secondary HPT 
related to chronic kidney disease, as well as pHPT for parathyroid carcinoma. Cinacalcet has 
been shown in several studies to be effective in significantly lowering and normalizing s-
Ca2 +, normalizing s-phosphate and, to a lesser extent, significantly lowering s-iPTH in 
patients with varying degrees of pHPT. 22–31 This effect has been shown in extension 
studies to the performed RCTs and retrospective studies to remain effective even over 
longer treatment periods (years) .28,32 The effect apparently does not depend on the 
etiology of the condition, and thus it has been shown that the same dose is required for effect 
in sporadic pHPT and MEN1 patients.22,33,34 Similarly, the drug has been found to be 
effective in lowering s-Ca2 + in patients with parathyroid carcinoma 31. The present studies 
suggest a slight increase in bone turnover assessed on bone formation and degradation 
markers, and BMD, u-calcium and creatinine remain unchanged during cinacalcet treatment. 
Thus, in cinacalcet treatment of primary hyperparathyroidism, additional treatment of these 


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endpoints will be required. The effect of cinacalcet on hypercalcemic symptoms or on hard 
endpoints such as fractures, kidney stones or cardiovascular complications has not been 
elucidated in RCT for patients with pHPT. The treatment triggers side effects relatively 
often (in about 25% of those treated), but these are by far the most mild - moderate, 
relatively rarely lead to discontinuation of treatment and increase with dose increase. A 
single study has systematically evaluated improved quality of life when taking Cinacalcet, 
suggesting this 25, but this needs to be confirmed by further studies. Faggiano et al found in 
a retrospective study of 23 patients with pHPT in cinacalcet treatment, of which 10 in 
combination with the bisphosphonate alendronate, that all treated patients received 
stabilized and controlled s-calcium, s-phosphate and u-calcium. Similarly, PTH decreased 
significantly. There was no difference in these parameters between the two groups. In 
patients with alendronate supplementation, BMD was assessed v. T-score increased by 9.6% 
in lumbar vertebrae and 3.9% in femur (p <0.01). In patients treated with Cinacalcet alone, 
BMD remained unchanged.35. No other studies are known with cinacalcet in combination 
with antiresorptives currently with pHPT. In combination with alendronate, BMD increases, 
and combination therapy thus appears to be attractive to all patients with the combination of 
hypercalcaemia and osteoporosis based on pHPT. Additional studies with combination 
therapy of pHPT, including with Denosumab are requested in it 4th international workshop 
for medical treatment of asymptomatic pHPT.14  
    
Denosumab:  
Denosumab is a recombinant human IgG2 monoclonal antibody that inhibits RANKL. 
Decreased stimulation of the RANK receptor leads to inhibited osteoclast formation. The 
drug was first studied as a remedy in the treatment of osteoporosis in postmenopausal 
women. In the large 3rd phase FREEDOM trial, 7868 postmenopausal women with 
osteoporosis were randomized to treatment with subcutaneous 60 mg denosumab every 6 
months, or placebo. After 3 year, denosumab had improved BMD (9.2% (95% CI, 8.2 to 
10.1) in the lumbar spine, and 6.0% (95% CI, 5.2 to 6.7) in the hip) compared with placebo. 
Bone turnover markers were reduced (after 36 months CTx: 72% and P1NP: 76% according 
to placebo) and the incidence for vertebral, hip and nonvertebral fractures was significantly 
reduced (relative to placebo 68%, 40% and 20%, respectively). 36.37 In a substudy, vBMD 
was assessed by qCT increasing relative to the placebo group by 21.8%, 7.8%, and 5.9%, 
respectively, for the lumbar spine, hip, and femoral neck after 36 months (all p <0.0001). 
Compared with placebo and baseline, a similarly significant increase in bone mineral 
content (BMC) was seen at the hip (p <0.0001) and a significant BMC improvement in the 
trabecular, subcortical and cortical part of the bone (p <0.0001) .38,39. Also the strength of 
the bone is shown improved, v. Finite element analysis (v. QCT), the bone strength is thus 
increased in the hip by 8.6% p <0.0001 and in the vertebrae by 18.2% p <0.0001 after 36 
months compared to baseline .40 A follow-up extension study showed that long-term 
treatment (up to 8 years) maintains a still constructive effect in relation to BMD, and that the 
substance maintains bone markers for turnover at a low level. The incidence of vertebral and 
nonvertebral fractures also remained low with respect to placebo.41 This trend has been 


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confirmed by histological / histomorphological examination of bone biopsies in a total of 41 
of the included patients who had been in treatment for up to 5 years at the time of biopsy.42 
Another 2363 substudy of study participants examined a possible prophylactic effect of 
denosumab on aortic calcification, as well as on the incidence of cardiovascular events. 
Denosumab was not shown to have a significant effect over 3 years.43 A large number of 
studies have been performed confirming the above effects on aBMD, vBMD, bone markers 
(CTx and P1NP) and fractures in postmenopausal osteoporotic women.44–51 These effects 
have been shown in extension studies to continue to improve almost linearly over several 
years by continued treatment52–54. This is further substantiated in a recently published 
meta-analysis which, based on 4 of the above-mentioned RCTs with denosumab vs. Placebo 
finds a pooled effect with significant increase in BMD on lumbar spine (7.58%), hip 
(4.86%), and distal 1/3 of radius (2.92%) relative to placebo-treated (all, P <0.001). Patients 
treated with denosumab had a significant and very rapid decrease in CTx (-66.16%) and 
P1NP (-64.65%) compared to placebo-treated patients (both P <0.001). Adverse events were 
similar between the 2 groups (pooled odds ratio = 1.04, P = 0.625) .55 Another meta-
analysis showed a slightly increased risk of infections with denosumab treatment according 
to placebo RR = 1.23 (1.00, 1.52), but no difference according to bisphosphonates RR = 
1.13 (0.63, 2.03), and no other increased risks.56 Compared to bisphosphonates in patients 
with postmenopausal osteoporosis, denosumab has shown superiority in effect on both BMD 
and bone markers in a number of RCTs and open-label studies. 57–62, just as denosumab 
has been shown to be better at reducing cortical porosity in relation to alendronate, rated v 
qCT.63 Denosumab has also been studied in osteoporotic men64, in glucocorticoid 
treatment-associated osteoporosis60,65 and in bone loss associated with anti-hormone-based 
therapy in breast and prostate cancer, which is associated with increased fracture risk66–69. 
Here, too, denosumab has shown good efficacy in increasing BMD, lowering skeletal 
related events, lowering bone turnover measured by bone markers, and alleviating 
malignancy-associated hypercalcaemia. Denosumab has been shown in a single small open-
label study to be able to increase BMD significantly in patients with secondary 
hyperparathyroidism. Denosumab has been shown to be effective in lowering s-calcium 
significantly. This effect can be exploited in hypercalcemic conditions .: In a small single-
arm, open-label, proof-of-concept study in 15 patients with severe malignancy-induced 
treatment-refractory hypercalcaemia, Hu et al. Showed that denosumab in intensive therapy 
was able to lower s-calcium to endpoint (≤11.5 mg / dL) in 64% of patients within 10 days 
of first dose. Median uNTx / uCr decreased as expected. 70 This is supported by a number 
of case reports that primarily describe that Denosumab may be effective in treating 
refractory hypercalcemia in parathyroid carcinoma.71–75 However, the decreases in s-
calcium have been shown to trigger a compensatory increase in s-iPTH in postmenopausal 
women osteoporosis76, which is why we in patients with pHPT predict a similar rebound 
effect of denosumab monotherapy.  
 
Regarding side effects, the FREEDOM study using the same dose as in this trial did not find 
a significant difference in the incidence of adverse effects, mild to severe, between the 3900 
who received denosumab and those who received placebo. Most commonly reported were 


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eczema and extremity pain. Likewise, there was no difference in the number who chose to 
stop treatment on the basis of side effects. The total amount of infection-related side effects 
was low and not significant, but numerically slightly higher than in the placebo group 
(especially cellulitis and eczema). The infections were heterogeneous in etiology and could 
not be related to the administration or duration of denosumab exposure.77 There was no 
increase in the risk of cancer, cardiovascular disease, delayed healing of fractures, or 
hypocalcaemia, and there were no cases of jaw osteonecrosis. In the extension study, 8 cases 
of jaw osteonecrosis and two cases of atypical fractures were added, which, considering the 
size of the study population, must be considered to be low.41 To sum up, one can briefly say 
that denosumab has shown superiority over bisphosphonates when it comes to increasing 
BMD, and lowering the risk of fractures in i.a. postmenopausal women with osteoporosis, as 
well as cancerous women and men in aromatase inhibitor and antiandrogen treatment, 
respectively. Likewise, it is more effective in lowering scalcium in malignant 
hypercalcaemia with solid bone metastases, and has also been shown to be effective in 
several case reports of refractory hypercalcaemia in patients with metastatic parathyroid 
cancer. Based on the known studies and meta-analyzes, Denosumab has been shown to be 
safe and without unacceptable side effects. There are no published studies in which 
denosumab has been tested in a controlled study in patients with primary 
hyperparathyroidism. Based on the above experiences from other patient groups, we believe 
that denosumab in combination with cinacalcet may be an effective medical treatment 
alternative to achieve good disease control in patients with pHPT, while improving BMD, 
lowering bone turnover and significantly reducing fracture risk in these patients. 
 
Detrimental effects of pHPT:  
Cardiovascular:  
Increased cardiovascular mortality and morbidity are well described in classical primary 
hyperparathyroidism, just as it has been shown that this excess mortality decreases after 
parathyroidectomy.78–81 Increased s-iPTH has been shown in larger population studies to be 
associated with increased mortality and degree and risk of developing arteriosclerosis. 82.83 
Limited and divergent data are available on cardiovascular outcome in asymptomatic pHPT. While 
some population studies suggest that there is no increased mortality associated with the 
condition84, others find a significantly increased cardiovascular morbidity and mortality.85. 
Several small studies have been performed on cardiovascular risk factors, such as hypertension, 
ventricular hypertrophy, coronary and valve calcification in asymptomatic pHPT. It is i.a. 
demonstrated that there is an association between high s-iPTH and aortic valve calcification, which 
has been shown to occur more frequently in patients with mild pHPT than in controls.86,87 The 
same authors conducted another small study in patients with mild pHPT, examining the effect of 
parathyroidectomy on signs of cardiovascular disease (carotis intima-media thickness, and stiffness, 
and aortic valve calcification), and found a modest positive effect on this 88. A small study has 
shown increased pulse wave velocity, indicative of incipient arteriosclerosis, in 24 patients with 
mild pHPT vs . matched control group.89 Conversely, a small study of 31 patients with mild pHPT 
compared to control group, by evaluation by MDCT could not demonstrate increased frequency of 


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coronary calcification.90 Overall, the studies suggest a subclinical impact, with increased vascular 
stiffness as the most consistent finding . Studies have been performed on the preventive effect of 
cinacalcet for cardiovascular morbidity and mortality secondary hyperparathyroidism due to chronic 
renal failure. These suggest a possible effect of Cinacalcet on the development of cardiovascular 
disease in secondary hyperparathyroidism in chronic renal disease91–94. There are no studies on 
the effect of Cinacalcet on cardiovascular disease or hard endpoints such as coronary calcification 
in pHPT. In this study, we want, although it is not the main focus of the study, to contribute to the 
evidence in this area. Many of the patients included in this trial are expected to belong to the group 
of patients with asymptomatic pHPT. Therefore, at CT we will examine the presence of coronary 
calcification, monitor blood pressure and record cardiovascular co-morbidity, and later examine 
whether there is a difference at baseline based on symptomatology and whether there is a difference 
in the development at the end of the study based on the treatment subgroups. 
  
Kidneys and pancreas:  
Asymptomatic hypercalciuria occurs in approx. 40% of patients with primary HPT.95. 
Hypercalciuria has been shown to be part of the background for stone formation in patients 
with symptomatic pHPT, as it contributes to the saturation of the urine with stone-forming 
calcium salts such as calcium phosphate and calcium oxalate.96 Cipriani et al found in a 
prospective study that kidney stones were found more often in symptomatic patients than in 
patients with asymptomatic pHPT (78% vs. 35.5%), this is a higher prevalence of kidney 
stones than retrospective studies have previously shown in patients with detected pHPT (eg 
7% in asymptomatic patients 97 and in symptomatic patients 25.4% in 98 and 60% 96), and 
the study may be subject to selection bias. Nevertheless, the finding underscores the 
importance of monitoring for kidney stones in patients with asymptomatic pHPT. Brardi et 
al find in a small pilot study with ten patients with pHPT that cinacalcet in combination with 
calcium-normalized diet is able to significantly reduce the size and number of kidney stones 
shown by ultrasound and biochemistry.99 We will further elucidate this finding , by CT 
examine the presence of kidney stones and nephrocalcinosis, and evaluate prevalence in 
relation to symptoms, and possibly. effect of interventional pharmacies. The association 
between pHPT and acute and chronic pancreatitis is much debated. A systematic review 
reviewed the last 30 years of studies, and found a prevalence of pancreatitis of between 
1.5% and 15% in a total of 10 studies on each of more than 50 trial participants.100 In this 
study, we want to examine patients with CT for prevalence of pancreatic calcifications and 
lesions, and see if necessary. development after 1 year of treatment. In this trial, in 
connection with qCT v. Baseline and after 1 year, we will co-scan the coronary artery, 
kidneys and pancreas to assess the incidence of calcifications, and progression thereof 
between treatment groups over time, including the difference in incidence in asymptomatic 
and symptomatic patients. 
 
Literature search strategy:  
Pubmed and embase were used. In pubmed the following MESH-terms were used ”Primary  


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Hyperparathyroidism*” combined with Mesh-synonyms for ”Denosumab” and ”Cinacalcet” 
combined and alone and furthermore using synonyms found in Embase. The following 
combinations of the terms Mesh- Denosumab and Cinacalcet, Denosumab and osteoporosis,  
Denosumab and hypercalcemia, PHPT and CT, -Cardiovascular Disease/Vascular  
Calcification/Coronary Artery Disease, - Chronic-/Calcific-/Acute Pancreatitis, and  
Nephrocalcinosis/Nephrolithiasis/Kidney Calculi were also used.  In Embase the following 
combinations were used Primary Hyperparathyroidism combined with Cinacalcet and Denosumab, 
and Denosumab alone. All non-English literature was deselected.  Original clinical trials with the 
following prioritation were selected RCT, prospectivc cohortstudies and retrospective 
cohortestudies. Chain-searching of reference lists of identified literature was performed in order to 
find any missed studies.  
2.3 Summary of potential side effects, risks and potential benefits for the trial subjects.  
  
Side effects and risks for the trial subjects:  
  
Mimpara  
Known side effects associated with treatment with Mimpara, see the manufacturer's package 
leaflet:  
 
Very common: may affect more than 1 in 10 people  
Nausea and vomiting. These side effects are usually quite mild and are not persistent.  
 
Common: can affect up to 1 in 10 people  
Dizziness, numbness or tingling sensation (paraesthesia), loss of appetite or decreased 
appetite, muscle pain (myalgia), fatigue (asthenia), rash, decreased testosterone levels, high 
potassium levels in the blood (hyperkalaemia), allergic reactions (hypersensitivity, or 
headache, cramps) low blood pressure, upper respiratory tract infection, difficulty breathing 
(dyspnoea), cough, indigestion (dyspepsia), diarrhea, abdominal pain - pain in the upper 
abdomen, constipation, muscle spasms, back pain, low calcium levels in the blood 
(hypocalcaemia). Not known: frequency cannot be estimated from the available data 
Urticaria, swelling of the face, lips, mouth, tongue or throat, which may cause difficulty 
swallowing or breathing (angioedema), abnormally fast or throbbing heartbeat, which may 
be associated with low levels of calcium in your blood (QT prolongation and ventricular 
arrhythmia secondary to hypocalcaemia).  
 
Prolia:  
Known side effects with Prolia:  
 
Very common side effects (may affect more than 1 in 10 people):  
Pain in bones, joints and / or muscles that can sometimes be severe, pain in the arms or legs 
(pain in the extremities).  
 


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Common side effects (may affect up to 1 in 10 people):  
Painful urination, frequent urination, blood in the urine, involuntary urination 
(incontinence), upper respiratory tract infection, pain, tingling or numbness going down the 
legs (sciatica), blurred area of the lens of the eye (cataracts), constipation, stomach 
discomfort , rash, skin condition with itching, redness and / or dryness (eczema).  
 
Uncommon side effects (may affect up to 1 in 100 people):  
Fever, vomiting, abdominal pain or discomfort (diverticulitis), ear infection.  
 
Rare side effects (may affect up to 1 in 1,000 people):  
Allergic reactions (eg swelling of the face, lips, tongue, throat or other parts of the body, 
rash, itching or hives, wheezing or difficulty breathing). Patients receiving Prolia may 
develop skin infections in rare cases. As Prolia inhibits bone turnover, in very rare cases 
atypical fractures of bones and degradation of bone tissue in the jaw are seen. Radiation 
dose in connection with CT scan is associated with a well-known slightly increased risk of 
cancer. (see under the section on ethics). In addition, discomfort / inconvenience / time 
consumption in connection with blood sampling, clinical checks and completion of 
questionnaires. Benefits and possible benefits for the trial participant: The project provides 
new information on treatment options and prevalence of sequelae for patients with pHPT, as 
well as knowledge about the effect of denosumab on calcium metabolism and bone status in 
this group of patients. The project can thus contribute to the development of an effective 
medical treatment alternative for patents with pHPT. When studied with qCT, it will be 
possible to gain a more basic and detailed understanding of the impact on bone structure in 
patients with pHPT. We expect that the beneficial effects demonstrated in the studies 
reviewed above will benefit the trial participants in this study. Thus, we hope to be able to 
reduce / eliminate symptoms triggered by hypercalcaemia, increase BMD, and thus prevent 
and treat osteoporosis, bone fractures and possibly reduce the risk of developing kidney 
stones. By participating in the project, there is a theoretical possibility that the participants 
avoid progression in their condition in the long term, and thus they may avoid having to 
remove one or more parathyroid glands at a later operation. Risks associated with surgery 
are rare, but include complete or partial paralysis of the vocal cords, swallowing problems, 
permanent low calcium in the blood, bleeding, pain and infection.  
 
2.4 Description and justification of dose, dosing, dosefrequency and treatment period.  
Prolia:   
Rationale for dose use and duration of treatment: The usual dose for the treatment of osteoporosis is 
60 mg x 1 every 6 months. for the prevention of fractures. For the reduction of severe 
hypercalcaemia in malignant disease, doses as high as 120 mg at 8-day intervals may be used. For 
this study we will use: 60 mg, semi-annually for 1 year, svt a total of 2 injections. This dose is 
consistent with what has been used in trials in populations with other disorders.  
 
Mimpara:  


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Rationale for dose use and duration of treatment: Treated for 1 year with 30 mg x 1 daily, for 
comparability with other clinical trials in the field, and to avoid the risk of hypokalemia.  
 
D vitamin:  
The vitamin D supplement is given to all participants, as a lack of vitamin D exacerbates primary 
hyperparathyroidism, can in itself lead to secondary (and tertiary) hyperparathyroidism, and is 
included as standard in the treatment guidelines for patients with primary hyperparathyroidism. 
 
2.5 Description of the trial population:  
  
The population will consist of patients who during the recruitment period (1 February 2017 - 1 
April 2018) are diagnosed or monitored for primary hyperparathyroidism in the North Jutland 
Region, who have a reduced BMD with a T-score between -1.0 and -3.5, and who are not 
candidates for surgery or who waive an otherwise indicated surgery. (See further under the section 
on recruitment.) 
 
3. Trial aims.  
  
The aim of this randomized, double-blind, placebo-controlled study is to investigate whether 
treatment with Denosumab (ATC code: M05BX04) alone, or in combination with Cinacalcet (ATC 
code: H05BX01), may be an effective medical alternative for patients with low BMD pHPT who do 
not are surgery candidates. Particular emphasis is placed on the treatment of hypercalcaemia, the 
prevention of osteoporosis and the effect of the treatment on bone structure and circulation. 
 
 
Fokusareas:  
Primary aims:  
Effect of intervention therapy on bone density, turnover and microstructure: To elucidate the effect 
of Denosumab, Cinacalcet or placebo with DXA of hip and spine, VFA of spine and q-CT of spine 
and distal 1/3 of radius v. Baseline and after 1 year in patients with pHPT, and decreased BMD. 
 
Secondary aims:  
-The effect of intervention treatment on biochemical disease control: Disease control and bone 
impact are continuously monitored by measuring s-ionized - and total Ca2 +, s- iPTH, s-phosphate, 
as well as bone markers in blood and urine over time (1 year). Occurrence and possible effect of 
treatment on other side effects of pHPT: In the course, s-amylase (pancreatic effect), s-creatinine 
(kidney effect), hs-crp, blood pressure, and ECG (cardiovascular effect) are measured. In 
connection with baseline and final qCT scan, the coronary artery (cardiovascular effect), kidneys 
and urinary tract (kidney effect) and the pancreas (pancreatic effect) are co-scanned. Thus, several, 
and ongoing, biochemical and imaging measurements of possible pancreatic, renal and 
cardiovascular effects are included. - Any reset of Ca-SR during prolonged treatment? To assess 


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whether prolonged suppression of s-Ca2 + and s-PTH can produce a reset of CaSR's sensitivity to 
S-Ca2 +, treatment is stopped after 1 year. 2 weeks after stopping treatment, s-Ca2 + and s-PTH are 
measured.  
 
Trial hypotheses:  
1. Treatment with a combination of denosumab and cinacalcet is more effective than monotherapy 
with denosumab and / or placebo in improving BMD and bone structure in patients with pHPT.  
2. The CT part of a qCT can be used to detect coronary, pancreatic calcification, and 
nephrocalcinosis / lithiasis in patients with both symptomatic and asymptomatic pHPT.  
3. The combination of denosumab and cinacalcet lowers Ca2 +, iPTH and bone markers –  
4. Combination therapy with denosumab and cinacalcet may reset Ca-SR, thereby “curing” the 
disease. 
 
4. Trial plan.  
4.1 Primary and secondary endpoints.  
  
Primary endpoint:  
-Percent change in BMD after 1 year of treatment from baseline and between intervention groups 
and placebo. 
 
Secondary endpoints:   
-Change in vBMD, BMC, cortical and trabecular thickness and ratio between them. 
-Changes in s-calcium and s-PTH continuously and after 1 year of treatment.  
-Percentage change in serum and urine bone markers  
-Incidence / changes in the prevalence of coronary calcification assessed by agate tone score (and 
Ca2 + volume score).  
- Development in possible nephrolithiasis / nephrocalcinosis assessed by CT - Development in 
possible pancreatic calcifications assessed by CT  
-Possibly. reset of Ca-SR: measured by effect on p. Ca2 + and PTH at break (end) in treatment.  
-A lateral DXA scan of the back (Vertebral Fracture Assessment (VFA) assesses the occurrence of 
osteoporotic collapses, including the relationship between anterior, middle and posterior 
compression. 
 
4.2 Trial design   
  
Et rand A randomized double-blind controlled single-center study.  
  
Figure 1. Project flow diagram.  


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4.3 Measures for reducing or eliminating bias.  
  
Bias is reduced by strict implementation of double-blindness and placebo control.  
 
Medicine:  
In this trial, denosumab is used in the form of Prolia, and cinacalcet in the form of Mimpara, both 
produced by Amgen and supplied by Sygehusapoteket, Aalborg University Hospital. Masking is 
planned so that both Prolia and placebo for Prolia (saline injection) will be administered without the 
patient or the person in charge of the trial seeing the syringe. The injections are thus planned to be 
performed by health personnel delegated by the person responsible for the experiment, who have 
thus been blinded. Tablets (Mimpara / Placebo) will be handed out in white plastic Duma cans, 
which will be delivered and packed by the hospital pharmacy, Aalborg, which will only be opened 
after the patient's return home. The patient will not be informed about the appearance of either 
placebo or Mimpara. Counting and registration of trial drugs will be performed by blinded 
healthcare professionals. The content of placebo will be resp. saline and mineral supplements 
without effect on bone turnover. During treatment visits in week 1, 1 treatment is submitted by the 
therapist (delegated). syringe s.c. containing either Prolia® or Placebo (saline). Duma cans are also 
handed out to each participant with tablets bearing the test name, subinvestigator's name, ID 
number, dose number, lot number and that the content is either "Mimpara®" or "Placebo". Sponsor 
guarantees that it is possible to blind at individual patient level without compromising the blindness 
of the other patients.  
 
Randomization:  
Randomization for intervention and placebo is performed at the hospital pharmacy, and is 
performed by number-based lottery. Each participant is randomized to one number, which is known 
by the participant and subinvestigator, but where group membership is unknown to both, thus both 
experimenters and participants are blinded. Information about group affiliation is stored on a 
randomization list at the hospital pharmacy and in locked rooms with the unblinded staff where the 
person responsible for the trial does not have access. The list can only be handed out to 


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experimenters after the experiment has ended. In the event of an urgent need for blinding of one or 
more participants, this will take place by the hospital pharmacy's 24-hour staff. 
 
4.4 + 4.5 Trial treatment.  
The trial will for the individual participant last 54 weeks from inclusion to final visit. 2 weeks 
before the final visit, the medication will be terminated, to measure any. continuously re-set by Ca-
SR. There will be no inflow period. Extension of the study can be considered, framed for scientific 
and logistical reasons. In that case, this eventual case will then be notified in a separate protocol 
submission. Treatment in the trial consists of the intervention drugs denosumab (Prolia®), 
cinacalcet (Mimpara®) and vitamin D, as well as inactive placebo drugs. The dose of the 
intervention preparations is 60 mg denosumab / half-year, 30 mg cinacalcet / dgl. The placebo 
preparations may contain physiological doses of minerals or saline. Vitamin D contains 25 
micrograms / tablet. Packing and labeling for dispensing placebos and intervention funds is handled 
by the hospital pharmacy, Aalborg University Hospital. The HDPE-Duma cans with intervention 
and placebo medicine are labeled with the experimental name, subinvestigator's name, 
randomization number, lot number and the text “Mimpara® / Placebo”. For Mimpara® and vitamin 
D as well as for placebo, oral dosing is taken with one tablet daily for morning administration. 
Prolia® and placebo injections are given at check-ups by healthcare professionals delegated by the 
investigator. The syringes will be either a Prolia syringe from the manufacturer (green / white) or a 
disposable plastic syringe with 1 ml of isotonic saline drawn up immediately before the test. The 
trial participant will not see the syringe administered by blinded delegated healthcare professionals. 
The treatment period for both intervention drugs and placebo is 1 year. Blood sample control is 
planned with attendance in the endocrinology department for the first time 1 week after entering the 
trial. Subsequent weeks 2, and 4 and thereafter check every 4 weeks. There will be a final interview 
and control at the termination of the experiment, where with the participant's consent, clarification 
of group placement and review of trial results at participant level will take place. 2 weeks after 
discontinuation of experimental medication, participants will be called in for an additional check-up 
in order to measure a possible increase in iPTH, and advice on further treatment.  
 
4.6 Rules for stopping the entire trial and for the individual participant 
Rules for stopping the entire trial:  
  
In case of high incidence (more than 10 independent subjects), of predefined serious adverse events 
related to the pharmacology of the trial (serious adverse events); particularly severe and 
symptomatic hypocalcaemia, QT interval changes, aseptic bone necrosis, severe infections or 
atypical stress fractures. A similarly high incidence of unexpectedly serious side effects will of 
course lead to consideration of discontinuation of the trial, in which case the trial manager and 
sponsor will be discussed immediately.  
 
Rules for stopping the experiment in the individual participant:  
The following serious side effects have been assessed to be theoretical in relation to the treatment. 
When developing one or more of these, the experiment will be stopped for the individual. • Severe 
hypocalcaemia (ionized calcium <0.9 mmol / l; total calcium <1.45 mmol / l) Significant 
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l) • Severe infection • Aseptic bone necrosis • Atypical stress fractures • QT interval extension • 
Development of Angioedema The established exclusion criteria (see the section on this) with regard 
to medical treatment so far, and during the commencement of the trial for the individual participant, 
also apply during the course of the trial. Initiation of medical treatment, which is covered by the 
means on the exclusion criteria list, by a doctor treating at any given time, results in exclusion from 
the trial. Procedure for withdrawal of the experiment: If you wish to withdraw from the trial from 
the trial participant, a subsequent final visit is offered, with an agreement on further course, 
requisition of final tests and clarification of any. questions. In case of treatment need, a 
randomization number will be requested from the randomization list at the hospital pharmacy, 
which is staffed 24 hours a day, and affiliation with the intervention or placebo group will be 
revealed to the trial participant and subinvestigator. In the case of SAEs, the participant will be 
followed for development and clarification of causation in the event of withdrawal. If the reason for 
withdrawal is not of a therapeutic nature, the randomization number will be revealed to those 
responsible for the trial and will participate at the end of the trial in its entirety. Upon withdrawal, 
trial participants will be asked for a request for future updates regarding the trial's results, will 
receive the subinvestigator's contact information, and will be contacted during development in the 
trial that may have future treatment consequences for the resigned participant. 
 
4.7 Procedures for trial drug accounting.  
Dispensed trial drug is listed in a separate medicine folder of the unblinded staff to whom the 
person responsible for the trial does not have access. During monthly control visits, the trial 
participants are asked to bring all study-related drug packaging, including any remaining tablets 
since last visit. The trial participant is also asked about side effects of the trial drug and regularity in 
the intake of the preparations. Non-ingested tablets are indicated in the table whereby the total drug 
intake can be calculated. Furthermore, participants of the trial withdraw in the event of non-validity 
of participation, hereby defined as more than four days of consecutive failure to take the 
preparation, verified by the participant's information and brought medication. Similarly, absence 
from controls with subcutaneous drug administration will be grounds for withdrawal from the 
project. 
 
4.8 CRF: Source data registered in the CRF are described in detail under the item 
”Effectparameters”.  
4.9 Randomisation code.  
Code storage rules:  
Linking between code and affiliation handed out to the subinvestigator and trial participant in either 
the intervention or placebo groups is stored exclusively on paper in the form of a randomization list 
with the unblinded staff, in rooms where trial managers do not have access, and at the hospital 
pharmacy which is staffed 24 hours a day. urgent need.  
 
Code Breaking Rules:  
Test code must be obtained by: • End of the experiment Development of serious side effects, where 
the trial participant withdraws from the trial, and where knowledge of affiliation in the intervention 


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or placebo group is revealed to the participant and subinvestigator with regard to categorization and 
statistical processing. Development of serious adverse reactions where an arbitrary treating 
physician treating the serious adverse reaction considers it necessary to obtain knowledge of 
affiliation in the intervention or placebo group and where the participant withdraws from the 
clinical trial. 
 
5. Selection and exclusion of trial subjects.  
  
5.1 Selection and screening of trial subjects.  
Inclusion of up to 60 participants is sought according to the inclusion and exclusion criteria below. 
The participants will be patients who have been diagnosed with primary hyperparathyroidism at 
Endocrinology Departments in the North Jutland Region, by virtue of elevated sCa2 +, 
simultaneously elevated s-iPTH and exclusion of differential diagnoses. Participants will have a 
Tscore of between -1.0 and -3.5 for DXA scanning performed in connection with their assessment 
or monitoring. Participants will be patients who due to their comorbidity, own desire or other 
reasons do not meet the criteria for curative treatment in the form of surgery. These are thus 
patients with a disease requiring treatment, or a condition which in the long run will give rise to 
significant side effects, for which there is currently no satisfactory medical treatment offer. 
Pregnant or breastfeeding women are not involved. Participating women are asked if they are 
menstruating and are divided into fertile premenopausal women and infertile postmenopausal 
women. Fertile premenopausal women should submit to a negative pregnancy test prior to 
participation in the trial and use safe contraception throughout the study period as well as five 
times the blood half-life of the trial drug after the end of the trial. Safe contraception is defined as 
birth control pills, IUDs, depot injection of progestogen, subdermal implantation, hormonal 
vaginal ring and transdermal transdermal patches. 
  
5.2 Inclusion criteria.  
• Women and men over 18 years. • T-score rated by DXA between -1.0 and -3.5. • Patients from all 
over North Jutland examined and diagnosed with primary hyperparathyroidism at endocrinology 
outpatient clinics / wards, at hospitals in the North Jutland Region. This means persistent 
hypercalcaemia over at least two separate measurements with concomitantly elevated or 
inappropriately high normal s-iPTH and exclusion of differential diagnoses. (Regarding pregnancy - 
see exclusion criteria.) 
  
5.3 Exclusion criteria.  
 
Exclusion criteria summarized: • History of diseases that cause hypercalcaemia in addition to 
pHPT. • Patients treated with Prolia (denosumab) or Mimpara (Cinacalcet) • Patients previously 
treated with Mimpara • Moderate to severe hepatic impairment assessed by liver enzymes (ALT> 
250u / l, GGT> 150u / l) and bilirubin> 30 micromol / l. • AMI or stroke within the last 3 months. • 
Known heart failure. • Risk factors for extended QTc interval. • Unhealed lesions from dental or 


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oral surgery. Primary bone diseases other than osteoporosis. • Patient with renal disease and renal 
insufficiency, including eGFR <30 mmol / L / 1.73m2, found at first biochemical requisition. • 
Patients on ongoing thiazide or lithium therapy. • Anamnesis with generalized seizures and 
epilepsy. • Active malignant disease. • Known allergy to intervention agents. • Pregnancy or breast-
feeding. (positive pregnancy test v. inclusion) • Fertile women who do not want to use safe 
contraception. (By this is meant IUD or hormonal contraception (birth control pills, implants, 
transdermal transdermal patches, vaginal ring or transdermal injection). Conditions which, in the 
opinion of the subinvestigators and sponsors, make the participant unsuitable for carrying out the 
experiment, including a lack of understanding of the experiment or a lack of physical ability to 
participate. 
  
Safety rules:   
  
As cinacalcet is metabolised by the enzyme CYP3A4, patients will be orally and in writing advised 
against concomitant treatment with ketoconazole, macrolides, grapefruit juice, itraconazole, 
protease inhibitors, norfluoxetine, and voriconazole. Cinacalcet inhibits the enzyme CYP2D6 
therefore patients should be advised against concomitant treatment with flecainide, mexiletine, 
propafenone, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, zuclopenthixol, 
atenolol, metoprolol, propanolol, timolol, mipramin, mapitrile, amipriptin, amipriptin , codeine, 
dextromorphan, tramadol, fluoxetine, and paroxetine. Patients who are or during the trial period are 
being treated with the above preparations will be excluded from the trial in the development of side 
effects. From clinical experience, we know that these interactions are very rare. All patients who are 
potential participants will be discussed with regard to meeting the applicable inclusion and 
exclusion criteria between subinvestigator and sponsor. 
   
5.4 Procedures for exiting the trial.  
Upon the emergence of the safety parameters mentioned in section 8.3, the trial participant will 
withdraw from the trial immediately after its discovery. In the event of the occurrence of 
unexpected serious adverse reactions or conditions that may be suspected to be adverse events that 
will require hospitalization, the patient will, after discussion between the sponsor, sub-investigator 
and subject, withdraw from the trial. In the event of a serious illness requiring treatment in addition 
to those included in the trial (eg treatment-requiring cancer or AMI / stroke - which is also included 
in the exclusion criteria), the patient will be excluded from the trial. In other cases of diseases and 
side effects, any. Withdrawal depends on the overall assessment of the subinvestigators, sponsors / 
supervisors and trial participants. In case of withdrawal: Safety parameters that are objectively 
verified by biochemical values, radiological findings or clinically will be disclosed to the 
subinvestigator, who will then be responsible for telephone contact with the participant for the 
purpose of the trial, and requisition of final biochemical analysis package, which must be taken as 
soon as possible (when practical) possible. The subinvestigator will also record values obtained for 
research purposes. In the event of serious adverse events requiring hospitalization in the trial, the 
treatment will be handled by the treating physician at all times. Doctors who are delegated in the 
trial will be made aware in writing of incidents that lead to withdrawal from the project. Additional 
data will not be collected without renewed permission from the resigned participant after the end of 


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the trial. The participant is offered follow-up information regarding the results of the experiment 
and the outcome, if the participant is interested in this. Upon commencement of medical treatment 
by the physician in charge of treatment in primary, secondary and tertiary sectors, which at any time 
by the physician in charge of treatment is considered essential for the participants' further health and 
well-being, which are covered by exclusion criteria for the trial, the participant will withdraw from 
the trial. Resigned participants will only be reimbursed to the extent that recruitment is ongoing and 
the target number of participants of 45 has not yet been reached. In the case of 45 recruited 
participants, there will be no replacement of resigned participants. Further treatment and follow-up 
for retired trial participants will be handled by the relevant therapists in both the primary sector and 
the hospital sector. 
 
6. Treatment of trial subjects.  
  
6.1 Description of the treatment  
For the individual participant, the trial will last 52 weeks from inclusion to the final visit + 2 weeks 
thereafter to the measurement of any. re-set by Ca-SR. There will be no inflow period. Extension of 
the study is considered, framed for scientific and logistical reasons. This possible case will then be 
notified in a separate protocol submission. Treatment in the trial consists of the intervention drugs 
denosumab (Prolia®), cinacalcet (Mimpara®) and vitamin D, as well as inactive placebo drugs. The 
dose of the intervention preparations is 60 mg denosumab / half year, 30 mg cinacalcet / dgl, and for 
vitamin D 50 micrograms / dgl. The placebo preparations may contain physiological doses of 
minerals without affecting bone and saline. Packaging for dispensing placebo and intervention 
funds is handled by the hospital pharmacy. Packaging with intervention and placebo medicine is 
labeled with the experimental name, subinvestigator's name, randomization number, lot number and 
the text “Mimpara® / Placebo”. For Mimpara® and vitamin D as well as for placebo, oral dosing is 
taken with one tablet daily for morning administration. Prolia® and placebo injections are given at 
check-ups by healthcare professionals delegated by the investigator. The syringes will be imprinted 
with “Prolia® / Placebo” and will either be a Prolia syringe from the manufacturer (Amgen) or a 
clear disposable plastic syringe with isotonic saline. The treatment period for both intervention 
drugs and placebo is 1 year. Blood test monitoring is planned with attendance in the endocrinology 
department 1st time 1 week after entering the trial. Subsequent weeks 2, and 4 and thereafter check 
every 4 weeks. There will be a final interview and control at the termination of the experiment, 
where with the participant's consent, clarification of group placement and review of trial results at 
participant level will take place. 2 weeks after the end of the trial and discontinuation of the trial 
drug, participants will be called in for an additional check-up in order to measure a possible 
increase in iPTH, and advice on further treatment.  
  
6.2  Interventions on the trial subjects.  
  
Biological material is requested in the form of blood samples, which require puncture of a vein on 
the forearm. No invasive procedures are performed in connection with imaging studies, and no 
requisition of biological material other than urine and blood samples is planned. When 


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administering prolia, the medicine is administered subcutaneously, which will take place once every 
six months, and is considered harmless from a procedural point of view. 
 
6.3 Other drugs used by the trial subjects.  
  
The trial participants' medication, in addition to the trial medication, is registered at each control 
visit in CRF. It is assessed here whether medication has been started up which may lead to 
exclusion from the trial, just as patients will be made aware of any risks of interactions. The 
responsibility for treatment other than that framed in the trial will be imposed on the relevant 
therapist who may start the treatment. Trial participants are allowed and instructed in, upon entering 
the trial, to bring information sheets regarding the trial treatment at all contacts with the health 
service. 
 
 6.4 Adherence.  
  
Dispensed trial drug is listed in a separate medicine folder at the unblinded staff. During monthly 
control visits, the trial participants are asked to bring all study-related drug packaging, including 
any remaining tablets since last visit. This is also reviewed by the blind staff. The trial participant is 
also asked about side effects of the trial drug and regularity in the intake of the preparations. Non-
ingested tablets are indicated in the table whereby the total drug intake can be calculated. 
Furthermore, participants of the trial withdraw in the event of non-validity of participation, hereby 
defined as more than four days of consecutive failure to take the preparation, verified by the 
participant's information and brought medication. Similarly, absence from controls with 
subcutaneous drug administration will be grounds for withdrawal from the project. 
 
6.5 Check ups at the end of the trial and after the trial.  
  
At the end of the trial for the individual participant, counseling and management of further 
treatment of the condition framed in the trial, (primary hyperparathyroidism) and complications 
thereof (osteoporosis, hypercalcemia) is handled by the Department of Endocrinology, Aalborg 
University Hospital. Other complications in the form of kidney stones, coronary stenoses, fractures, 
etc. will be handled under relevant auspices as well as the primary sector. 
  
7. Evaluation of effect.  
  
7.1 + 7.2 Effect parameters.  
  
 
Radiological, biochemical and clinical markers are used to assess the treatment effect of both 
interventional drugs and placebo. Main radiological endpoint is percentage change in BMD and 
BMC in bone svt. distal radius, hip and lumbar spine after 52 weeks. For quantification of this, 
DXA scanning and VFA are used, with calculation of Z- and T-scores. T-score indicates, based on 
the BMD measured for the patient, the number of standard deviations above or below the mean for 


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a healthy 30-year-old of the same sex and ethnicity as the patient. Also assessed by qCT parameters 
such as vBMD, cortical and trabecular thickness, ratio between them, porosity and column collapse. 
This svt distal radius as well as the lumbar spine. These effect parameters have been chosen, as this 
allows information on bone architecture and strength to be obtained, which cannot be assessed by 
more traditional scanning methods. Thus, the application of qCT can contribute to a deeper 
understanding of the treatment's impact on bone structure, also for comparison with future similar 
projects. In connection with q-CT, the coronary area, kidneys and urinary tract, as well as the 
pancreas will also be scanned at baseline and after 1 year for examination of prevalence and 
development of coronary calcification, nephrocalcinosis, nephrolithiasis and for pancreatic 
calcification during the treatment period. This is quantified by Agatston scoring of coronary 
calcification, and radiological assessment of kidneys and pancreas. Thus, the incidence of, and a 
possible preventive effect on the development of side effects of primary hyperparathyroidism of 
treatment is assessed. The course duration of 1 year is decided for reasons of regularity between 
blood sampling and assessment of treatment effect for comparison with other studies and with 
regard to power calculation, where percentage change in BMD after 1 year is the starting point. 
Primary biochemical endpoints are absolute changes in values for blood sample packs termed 
“immediate analyzes” and “frost samples”. The content is listed below. For each session, control of 
"Immediate analyzes" in the form of ionized and total, alb corr. Calcium, s-phosphate, s-PTH, Hgb 
with EVF, acid-base status (T-CO2), infection parameters (CRP, leukocytes with diff. ), electrolytes 
(Na + and K +), liver (ALT) and renal function (creatinine and eGFR) for the development of side 
effects and for understanding physiological changes due to the interventional drug. These are 
registered in the CRF. All other samples are frozen for later analysis called "Frost samples", these 
are only analyzed at the end of the experiment. The time horizons for the visits have been chosen on 
the basis of existing knowledge of the pharmacological agents. For the package "Bone markers", 
markers for bone breakdown and construction are used, for which the majority have been initiated 
at the Department of Clinical Biochemistry, Aalborg University Hospital, at the time of application. 
"Baseline" is divided into 2 visits, preliminary study and start visit as stated in the participant 
information. 
 
Week 
Base- 
line  
1  
  
2  4  8  12  16  20  24  
28  32  36  40  44  48  52  54  
Analysed 
immediately 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Samples for freezing 
  
  
  
  
  
x  
  
  
  
  
  
  
  
  
  
  
  
QCT  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DXA-scan  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
VFA  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical end 
epidemiological data 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


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Biochemical markers:  
• “Immediate analyzes” Na +, K +, ALT, (hs) -CRP, differential count leukocytes, creatinine 
(eGFR), hemoglobin, hematocrit (EVF), albumin, T-CO2, Ca2 + ion-free, Ca2 + total (albumin-
corrected), s-iPTH after drug-fasting, phosphate, at 1st visit further sedimentation reaction. • "Frost 
samples" Blood tests: urate, urea, GGT, bilirubin, amylase, lipid status, FSH, LH, free testosterone 
in men, bioavailable estradiol, 1,25 and 25-OH vitamin-D, magnesium, TSH, bone-specific alkaline 
phosphatase and methaneephrines. In addition, bone markers in the form of p-CTX, p-Trap5b, 
P1NP, bone-specific alkaline phosphatase, osteocalcin., FGF-23, and sclerostin. For urine frozen: 
Ucalcium, u-creatinine and u-phosphate on daily urine, which are collected at diagnosis, 24 weeks 
and 48 weeks. Time windows for controls: In general, control times are aimed at being as close as 
possible to what is stated schematically. For visits to control weeks 1, 2 and 4, the generally 
accepted time window will be +/- 3 days. For the inspections week 8 and onwards, the acceptable 
window will be +/- 10 days. Clinical data: Height, weight, BMI - Blood pressure and heart rate - 
Smoking status and alcohol consumption - Daily calcium intake - Dispositions, phpt, osteoporosis - 
Comorbidity - Medical treatment: Prednisolone, osteoporosis treatment, antihypertensives, 
hormonal treatment -EKG at 0.6, and 12 months. -MDI / HAMD depression score v. 0.6 and 12 
months. Side effects are registered by form in CRF - see appendix. Requisition and analysis: 
Sampling, analysis and forwarding to the analytical department are handled at the Endocrinology 
Laboratory, Aalborg University Hospital. Samples are ordered by subinvestigator / delegates in the 
hospital's existing system (“Labka II”), where sampling from the printed PTB note of requisitioned 
samples is handed in on arrival at the Endocrinology Laboratory on given dates. A uniform 
sampling time is sought. Answers are returned to the subinvestigator in paper form for manual entry 
based on the code number in the data processing tool. Especially about selection and use of control 
group: In the experiment, a control group of up to 20 participants (1/3 of the participants) is used for 
comparison with the intervention groups m. Resp. Prolia and Prolia combined with Mimpara, in 
circumstances that would be quite similar to the traditional ones for patients with newly diagnosed 
primary hyperparathyroidism with a BMD within the stated framework, which is considered non-
operable, as such patients today are basically simply observed on an ongoing basis. The control 
group is selected by lottery among all included patients. Addition or omission of surveys: If during 
the implementation of the study new biochemical parameters emerge which turn out to be better at 
characterizing the bone turnover than those mentioned above, the biochemical analyzes can be 
replaced / supplemented with these. Likewise, the subinvestigator reserves the right not to perform 
one or more of the above analyzes if it proves difficult to carry out for technical or economic 
reasons. Biochemical analyzes can only be omitted, replaced or changed after acceptance by the 
Science Ethics Committee. 
 
8. Safety evaluation and handling of side effects and adverse events.  
  
8.1 + 8.2 Known side effects, discomfort etc. 
 The disadvantages for the patients when participating in the trial are, in addition to inconvenience, 
time spent, and thus possibly lost earnings, primarily any side effects to the experimental drug. 
Known side effects of the intervention medication: Mimpara Known side effects associated with 
treatment with Mimpara, see package leaflet: Very common: may affect more than 1 in 10 people 
Nausea and vomiting. These side effects are usually quite mild and are not persistent. Common: can 


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hit up to 1 in 10 people Dizziness, numbness or tingling sensation (paraesthesia), loss of appetite or 
decreased appetite, muscle pain (myalgia), fatigue (asthenia), rash, decreased testosterone levels, 
high potassium levels in the blood (hyperkalaemia), allergic reactions (hypersensitivity, or 
headache, cramps) low blood pressure, upper respiratory tract infection, difficulty breathing 
(dyspnoea), cough, indigestion (dyspepsia), diarrhea, abdominal pain - pain in the upper abdomen, 
constipation, muscle spasms, back pain, low calcium levels in the blood (hypocalcaemia). Not 
known: frequency cannot be estimated from the available data Urticaria, swelling of the face, lips, 
mouth, tongue or throat, which may cause difficulty swallowing or breathing (angioedema), 
abnormally fast or throbbing heartbeat, which may be associated with low levels of calcium in your 
blood (QT prolongation and ventricular arrhythmia secondary to hypocalcaemia). Prolia: Known 
side effects with Prolia: Very common side effects (may affect more than 1 in 10 people): Pain in 
bones, joints and / or muscles that can sometimes be severe, pain in the arms or legs (pain in the 
extremities). Common side effects (may affect up to 1 in 10 people): Painful urination, frequent 
urination, blood in the urine, involuntary urination (incontinence), upper respiratory tract infection, 
pain, tingling or numbness going down the legs (sciatica), blurred area of the lens of the eye 
(cataracts), constipation, stomach discomfort , rash, skin condition with itching, redness and / or 
dryness (eczema). Uncommon side effects (may affect up to 1 in 100 people): Fever, vomiting, 
abdominal pain or discomfort (diverticulitis), ear infection. Rare side effects (may affect up to 1 in 
1,000 people): Allergic reactions (eg swelling of the face, lips, tongue, throat or other parts of the 
body, rash, itching or hives, wheezing or difficulty breathing). Patients receiving Prolia may 
develop skin infections in rare cases. As Prolia inhibits bone turnover, in very rare cases atypical 
fractures of bones and degradation of bone tissue in the jaw are seen. Radiation dose in connection 
with CT scan and DXA scan is associated with a well-known slightly increased risk of cancer. (see 
under the section on ethics). In addition, discomfort / inconvenience / time consumption in 
connection with blood sampling, clinical checks and completion of questionnaires. 
 
8.3 + 8.4 Safety parameters.  
 
On the basis of proven, as well as theoretically possible, side effects for cinacalcet and denosumab, 
the trial is operated with the following safety parameters, which lead to withdrawal from the trial: 
As stated in section 4.6: "Rules for stopping the trial of the individual participant:" • Severe 
hypocalcaemia (ionized calcium <0.9 mmol / l; total calcium <1.45 mmol / l) Significant 
symptomatic and persistent hypocalcaemia (ionized calcium <1.10 mmol / l; total calcium <2.0 
mmol / l). • Severe hospitalization infection • Aseptic bone necrosis • Atypical stress fractures • 
Development of extended QT interval • Development of severe renal insufficiency (GFR <30) • 
Development of Angioedema associated with ingestion of intervention drugs. Blood samples are 
taken to evaluate infection (CRP and leukocytes with differential count), acid-base status (T-CO2), 
kidney (Creatinine and eGFR), liver (ALT), electrolytes (Na + and K +), and calcium status (Ca2 + 
ion, Ca2 + total and albumin corr., S-phosphate and s-PTH) as well as Hemoglobin with hematocrit 
at each control visit for early biochemical detection of adverse events. At each follow-up visit, side 
effects, hospitalizations and treatments in the intervening period are asked. In relation to the drug 
denosumab, hypocalcaemia and its consequences are given priority in the selection of safety 
parameters. The development of hypocalcaemia, which has been shown to occur during treatment 
with denosumab, particularly in renal disease, and the theoretically possible but clinically very rare 


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side effects: increased tendency to infection (and therefore severe / recurrent infections), jaw 
osteonecrosis and stress fractures are defined as safety parameters withdrawal from the experiment, 
while relevant biochemical analyzes are requested. Similarly, in relation to the drug cinacalcet, 
electrolyte ranking and its consequences, especially within the spectrum of dyscalcaemia, are 
prioritized in the selection of safety parameters. The development of hypokalcaemia, as well as the 
very rare side effects of prolonged QT interval, and angioedema are defined as safety parameters 
and result in their onset withdrawal from the trial, while relevant biochemical analyzes are 
requested. The time frame for requisition is as soon as possible upon arrival at the relevant 
biochemistry department. The ECG is checked at the start of interventional medicine, after 6 and 12 
months of treatment. Hypocalcaemia due to denosumab treatment has been reported to be 
particularly pronounced in renal disease, where treatment with calcium gluconate and vitamin d has 
been shown to be necessary. Therefore, patients with severe renal insufficiency (eGFR <30) will 
not be able to participate in the trial. In the case of new-onset hypocalcaemia, the condition will, if 
possible, be attempted with oral calcium supplementation. If s-ionized calcium can be brought to 
level, the experiment is continued. If this is not possible, the patient will be treated according to 
generally accepted guidelines (typically with calcium and vitamin D), and will be excluded from the 
trial as indicated. As cinacalcet is metabolised by the enzyme CYP3A4, patients will be orally and 
in writing advised against concomitant treatment with ketoconazole, macrolides, grapefruit juice, 
itraconazole, protease inhibitors, norfluoxetine, and voriconazole. Cinacalcet inhibits the enzyme 
CYP2D6 therefore patients should be advised against concomitant treatment with flecainide, 
mexiletine, propafenone, haloperidol, olanzapine, perphenazine, risperidone, thioridazine, 
zuclopenthixol, atenolol, metoprolol, propanolol, timolol, mipramin, mapitrile, amipriptin, 
amipriptin , codeine, dextromorphan, tramadol, fluoxetine, and paroxetine. Osteonecrosis of the jaw 
and possibly atypical fractures have been shown, as with bisphosphonates, to occur sporadically 
during treatment with denosumab. This is probably a class effect for all substances that effectively 
inhibit osteoclast function, and the incidence has been on a par with zoledronic acid and other 
bisphosphonates in reports and direct head-to-head studies. The incidence of jaw osteonecrosis 
overall for denosumab and bisphosphonates is by international consensus estimated at between 
0.001% to 0.01%, at doses for the treatment of osteoporosis, which is marginally higher than the 
incidence in the general population (<0.001%). with denosumab has been associated with 
oncological doses (120mg / month) not used in this study. However, patients with non-healing 
wounds after tooth or jaw surgery will be excluded from the study. As RANKL is expressed in a 
number of tissues in addition to bone, including synovial, dendritic cells, T and B cells, there is a 
theoretical possibility that denosumab may be immunosuppressive. In the clinical trials reviewed, 
there has generally not been a statistically significant or clinically significant effect on the immune 
system. Long-term safety studies are still ongoing.102 
 
8.5 Recording of adverse events/side effects.  
  
Both serious and less serious adverse events are recorded in the patient record, and via CRF in the 
trial master file with information on whether the subinvestigator attributes association to trial 
medication. The symptoms that have arisen in this context, based on a medical assessment, will be 
compared with the product summaries for the drugs used. The events will be recorded indicating the 
affected organ system, as well as the severity of the event (mild, moderate, severe). Likewise, the 


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time relationship in relation to the intervention funds submitted will be registered. At any national 
level, any serious incident will be reported to the institution legally responsible for it at any time, 
whether it is pre-defined side effects or symptoms described by the trial participant, whether or not 
it is attributed to the trial drug by the subinvestigator / investigator. SAEs are thus reported 
immediately, and no later than within 24 hours by the subinvestigator to the sponsor who handles 
the further reporting, cf. 8.8. Admission will always be registered as SAE. Incidents / side effects 
are recorded in the patient record. 
  
8.6 Measures to prevent and treat adverse effects.  
  
Guideline in the event of a serious adverse event: Based on knowledge of existing adverse reactions 
to the interventional medicine, frequent checks on relevant biochemical variables are planned 
during the first 12 weeks of the trial with a view to early detection of inappropriate adverse 
reactions. In the event of the development of serious adverse events (both defined and undefined 
safety parameters), the trial participant will be instructed by the subinvestigator to discontinue the 
trial as soon as possible, potentially reversing several of the side effects, including hypocalcaemia, 
hyperkalaemia, hyperkalaemia. In the event of adverse reactions without reversibility of treatment 
discontinuation, treatment will follow current local and national guidelines and is expected to 
require hospitalization. In case of conditions requiring hospitalization, pt. of written information to 
the attending physician about conditions for withdrawal from the trial and immediate cessation of 
taking the trial drug. This experimental information is provided upon entry into the experiment. 
(See appendix "important information for doctors and other healthcare professionals"). A 
participant card will also be handed out with the trial name and information corresponding to that 
stated on the medicine labels, as well as the subinvestigator's name and contact information. At each 
control visit, participants will be asked about known symptoms and side effects of the intervention 
funds. (See Appendix Side Effect Questionnaire). In the event of side effects or other serious 
events, participants are informed to contact a physician, and then the person responsible for the trial. 
(see participant information). Upon withdrawal from the trial, the patient will be followed until the 
reason for withdrawal is noted and the biochemical termination analysis package is requested, as 
well as in the case of side effects, whether the outcome of the side effect will be fatal. In the event 
of the occurrence of non-exclusion-demanding side effects, where the investigator / delegate 
initiates any treatment, the participant will be followed up with closer checks for a period, 
depending on the given condition. 
 
8.8 +8.9  Reporting of adverse events/side effects  
  
The sponsor will immediately notify the National Board of Health if unexpected and serious 
suspected side effects occur during the trial. Sponsor shall ensure that all information about 
unexpected and serious suspected adverse reactions that are fatal or life-threatening is recorded and 
reported to The National Board of Health and the Ethics Committee of the North Jutland Region as 
soon as possible and no later than 7 days after the sponsor has become aware of such a suspected 
side effect. No later than 8 days after the report, the sponsor must notify the National Board of 
Health and the Science Ethics Committee North Jutland of all relevant information about the 
sponsor's and subinvestigator's follow-up on the report. All other unexpected and serious suspected 


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side effects must be reported to the National Board of Health and the Science Ethics Committee 
North Jutland no later than 15 days after the sponsor has become aware of these. Any report must 
be accompanied by comments on any consequences for the trial. All side effects and events are 
reported at the end of the trial in the final report to the National Board of Health and the Science 
Ethics Committee North Jutland. Subinvestigator must immediately report any serious incident to 
sponsor. The report must be followed up by a detailed written report, and in both the immediate 
report and the subsequent report, the subinvestigator must identify the subjects with a personal code 
number. The sub-investigator must also report to the sponsor incidents and / or abnormal analysis 
results that are stated in the trial protocol as being critical to the safety of the subjects. When 
reporting deaths, the subinvestigator must provide any additional information that the sponsor may 
request. The definitions are as follows, cf. the Executive Order for Clinical Trials: • incident: any 
adverse event in a patient or subject in a clinical trial after treatment with a medicinal product, 
without any connection between that treatment and the adverse event; • side effect: any harmful and 
unwanted reaction to a trial drug regardless of dose • unexpected side effect: a side effect whose 
nature or severity does not match the product information • serious incident or serious adverse 
reaction: an event or adverse event that, regardless of dose, results in death, is life-threatening, 
results in hospitalization or prolongation of hospital stay, results in significant or persistent 
disability or incapacity for work, or leads to a congenital anomaly or malformation. Reporting will 
be directed electronically to the SUSAR database (EudraVigilance Clinical Trial Module, E2B) 
using the e-form. A SUSAR is a Suspected Unexpected Serious Adverse Reaction: unexpected and 
serious suspected side effect. An adverse reaction is a SUSAR and must be reported when the 
following criteria are met: • severe, ie. result in death, be life-threatening, result in hospitalization or 
extension of hospital stay, • result in significant or permanent disability or incapacity for work or • 
lead to a congenital anomaly or malformation. • The side effect must be related to the test drug. 
That is, there is presumed to be a causal link between taking the drug and the side effect that 
occurred. Both the subinvestigator and the sponsor must assess causality. Sponsor must not 
disapprove of subinvestigator's assessment, and reports where sponsor does not agree with 
subinvestigator must be reported. • The side effect must be unexpected, ie a side effect whose 
nature or severity does not match the product information described in the SPC. As this is a blinded 
trial, the assessment of the adverse reaction must be carried out before blinding, but data must be 
blinded before reporting to the Danish Medicines Agency. As previously stated, sections on adverse 
reactions in the SPC for interventional medicine will be used as a reference in assessing the adverse 
reactions reported by trial participants, the causality assessment will always be based on a medical 
assessment. 
 
8.10 Procedure for annual safety reports to the National Board of Health and the 
Science Ethics Committee.  
  
Once a year during the entire trial period, a report is prepared listing all suspected serious adverse 
reactions that have occurred during the trial period. This is submitted to the Danish Medicines 
Agency and the Science Ethics Committee. To design this, a Form for reporting side effects is used, 
with an attached list. As mentioned above, SUSARS will also be reported immediately.  
 
8.11 Procedure for reporting side effects/adverse events at the end of trial.  
  


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Upon termination of the trial, final reporting of adverse reactions to SST and VEK will be submitted 
within 90 days of the end of the trial, together with notification of the termination of the trial. The 
reporting of side effects here will be similar to the annual reports. 
 
9. Statistics.  
9.1 Statistical considerations:  
 
When statistically calculating the data obtained, the use of different methods for the individual parts 
of the project is expected. No analysis is planned during the collection period, as in the controls, 
ongoing evaluation of biochemical signs of any serious side effects for the individual trial 
participant. All other data processing will take place exclusively after the end of the experiment. 
The following evaluations are planned to be carried out after the collection period: Intervention 
groups vs. Placebo and each other; All groups individually; development of effect goals; 
Symptomatic vs. Asymptomatic patients. Descriptive statistical methods are used for these 
populations; absolute values, mean, SD, SE, medians, quartiles (Q1, Q3), and range (Min, Max). 
For significance of difference between the groups, t-tests and wilcoxon signed rank according to 
indication can be used. Multiple regression analysis can be used in relation to confounder 
correction. Additional static methods will be considered in the course. 
  
9.2 Power calculation.  
The power calculation is based on the primary power measure BMD v. DXA scanning. With a risk 
of type 1 error of 5% and a risk of type 2 error of 20% (svt. A power of 80%) and an increase of 1% 
in BMD at DXA after 1 year with a Standard deviation on the BMD measurements of 1%, 15 
participants must be used in each group. This calculation does not take into account dropouts, but 
since an SD of 1% is set high (in reality closer to 0.8), and in that case only 10 participants are 
needed in each group, it is expected to be sufficient in the calculated population size. Based on this, 
up to 60 trial participants will be included. 
  
9.3 Applied significance level.  
  
A statistical significance level of 5%, P < 0,05 will be used.  
  
9.4 Criteria for end of trial.  
  
Participants' completion of the final sample collection, DXA and QCT scanning as well as full 
attendance and for predetermined requisitions are considered completed trial participation if the 
medicine has been taken as agreed. The experiment ends at the notified date, or at the last 
participant's (60 in total) last final visit before that. Should the trial be extended, a separate request 
will be submitted.  
 
9.5 Missing or unused data.  
  
 


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Missing data, including analysis errors, coagulation defective samples, will be considered missing 
values and not included in the analysis. In that case, the number of samples requested will be 
applied in each analysis (N). In the case of reference interval ultimate samples, which cannot be 
calculated in numerical value, these will also be categorized as missing values. 
  
9.6 Deviations from the original statistical plan.  
Deviations from the original statistical plan will be reported to the relevant authorities. 
 
9.7 Trial subjects whose data will be used for the statistical analyses.  
All subjects who have started treatment will be able to be included in the statistical analyzes.  
 
10. Access to source data/source documents.  
Upon request, full and unrestricted access to source data is provided to the local Science Ethics 
Committee, the National Board of Health, the Danish Data Protection Agency and the GCP unit, 
during prior consultation on ethical aspects regarding information attributable to specific 
individuals. Requests for access to source data for other countries' health authorities will depend on 
specific assessment and prior consultation with national Danish health authorities. Exchange of data 
with foreign and national research groups will only take place after concrete assessment and by 
anonymisation of sensitive personal information. 
 
11. Quality controls.  
  
The test will be performed according to the present test protocol, ICH-GCP guidelines and 
applicable legislation. The trial will be monitored at the GCP unit at Aalborg and Aarhus University 
Hospitals, Department of Clinical Medicine Aarhus University, Brendstrupgårdsvej 100, 8200 
Aarhus N. Contact: Forskningens Hus in Aalborg, Søndre Skovvej 15, 9000 Aalborg, Main number: 
9766 6266 The project follows general procedures for quality control and assurance. 
  
12. Ethics  
12.1 Ethical considerations.  
The study will be conducted in accordance with the protocol and applicable legislation in the field. 
The experiment will be performed according to the Helsinki Declaration of Biomedical Research 
involving subjects. The primary ethical considerations in the trial relate to radiation hygiene in 
performing DXA and qCT scans, as well as the use of placebo in the presence of mild osteoporosis. 
Radiation hygiene: According to Chief Physician Jens Brøndum Frøkjær [1], from previous 
experiments at the Radiology Department, the radiation dose is known for the following studies: 
CT-KAG svt 0.5mSv, CT-upper abdomen 1 mSv qCT 3 vertebrae: 1.5 mSV Radiation dose at qCT 
of forearm is not known, but is stated in the international literature to <0.01mSv He estimates that 
the radiation dose at CT-KAG as well as CT-upper abdomen corresponds to the applied dose in the 
reported experiment with scanning of heart, pancreas and kidneys, with renal pelvis for 
calcifications. Total with a radiation dose of 1.5 mSV per study. qCT of the column loads as 
indicated with 1.5 mSv per scan. Each patient is thus expected to have a total radiation dose of 
approx. 6 mSv at the two scanning sessions. Corresponding to an overall increased risk of fatal 


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cancer of 0.03%, and thus an increase in overall risk from 25.0% to 25.03%. This is based on 
concrete calculations at the Department of Radiology, Aalborg University Hospital, and is 
consistent with findings in international publications. [2] Radiation dose at DXA, VFA and qCT of 
radius is so low that it is of negligible risk. The radiation dose corresponds to that measured in other 
Danish research projects, which have been approved by regional science ethics committees. 
 
[1] Jens Brøndum Frøkjær, Overlæge, Radiologisk Afd., Aalborg  
Universitetshospital  
[2] Damilakis J, Adams JE, Guglielmi G, Link TM. Radiation exposure in X-raybased imaging 
techniques used in osteoporosis. Eur Radiol. 2010;20(11):2707-14  
  
Placebo, osteoporosis and fractures.  
Upon entering the trial, participants have verified cheesepene or mild osteoporosis from previous 
DXA scans performed for control or diagnostic purposes. Patients with moderate to severe 
osteoporosis (T-score <-3.5) will not be able to participate. Participants will all receive vitamin D 
supplements, and will also be randomized to treatment with either Prolia or placebo. Treatment with 
Vitamin D and Lime is standard treatment in people with osteopenia. Only people with mild 
osteoporosis (T-score between -2.5 and -3.5) can participate, and the treatment period is relatively 
short compared to the usual annual bone loss. Thus, we assess that the watchful waiting regime with 
vitamin D, which is standard in monitoring patients with primary hyperparathyroidism, and is 
actually what the patients in the placebo group are offered, can be justified in the listed setup. 
Should patients incur bone fractures during the treatment period, their continued participation in the 
trial will be reconsidered and discussed with the patient.  
 
Benefits of participating in the trial.  
The project adds new information about treatment options and prevalence of sequelae for patients 
with pHPT, as well as knowledge about the effect of denosumab on calcium metabolism and bone 
status in the studied group of patients. The project can thus contribute to the development of an 
effective medical treatment alternative for patents with pHPT. By examination with qCT, it will be 
possible to gain a new and more basic and detailed understanding of the impact of both the disease 
and the treatment on the bone structure in patients with pHPT, than what more traditional scanning 
methods can produce. We expect that the beneficial effects demonstrated in the studies reviewed in 
the background section will benefit the trial participants in this study. Thus, we hope to be able to 
reduce / eliminate symptoms triggered by hypercalcaemia, increase BMD, and thus prevent and 
treat osteoporosis, bone fractures and possibly reduce the risk of developing kidney stones. By 
participating in the project, there is a theoretical possibility that the participants avoid progression in 
their condition in the long term, and thus they may avoid having to surgically remove one or more 
parathyroid glands at a later operation. Risks associated with surgery are rare, but include complete 
or partial paralysis of the vocal cords, swallowing problems, permanent low calcium in the blood, 
bleeding, pain and infection. 
  
12.2 Recruitment of trial participants and informed consent  
  
 


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Participants are recruited in several ways: via. day section and outpatient clinic in connection with 
control visits or assessment here, Department of Endocrinology, Aalborg University Hospital. Other 
possible candidates, all known in the department, are scheduled to be contacted by mail. 
Participants will be from the primary sector, or hospitals in the North Jutland Region referred for 
investigation and treatment of hypercalcaemia / pHPT. The assessment program typically includes 
blood tests, UL scan of the neck, DXA scan, and possibly scintigraphs and CT scans in search of 
focus. Upon detection of elevated PTH, as well as exclusion of differential diagnoses (including 
tertiary hyperparathyroidism, lithium treatment, pheochromocytoma, and familial hypercalcemic 
hypocalcury), the diagnosis of primary hyperparathyroidism is determined. Potential participants in 
their study were found to have a low BMD v. DXA scan with a T-score between -1.0 and -3.5. If 
the patient does not want or meet the criteria * for surgery, they are offered inclusion in the study. 
This will be offered by determining the diagnosis or by one of the patient's visits to the ward, or by 
positive feedback by letter. Materials regarding the study are submitted, with general information 
about the project's purpose, method and involvement of the patient (see cover letters and participant 
information). The pamphlets "Subjects' Rights" and "Before you decide" are also handed out. 
Interested parties will be invited to a visit per. letter and will receive oral information regarding the 
study. It will be possible for the person in question to contact the subinvestigator by telephone and 
via electronic and traditional text by agreeing to participate in an inclusion interview. (see appendix 
Participant information., Cover letters. Notice letters.) * Criteria for operation: Hypercalcemic 
symptoms • Nephrolithiasis, nephrocalcinosis or renal impairment • Age <50 years • Osteoporosis 
Serum calcium 10% above upper normal range (ionized plasma calcium> 1.45 mmol / l or albumin-
corrected plasma calcium> 2.80 mmol / l)) Information call: Interested parties will be summoned 
for an interview with the possibility of a co-chair, which is mentioned in the summons letter, where 
the investigations and the course of study will be reviewed. The information interview takes place 
at Aalborg University Hospital in an undisturbed room (office) without switched on mobile phones 
/ pagers, and is handled by Subinvestigator, Investigator or one of them delegated with the 
necessary professional knowledge. During the interview, the trial participant will be made aware of 
the possibility of a reflection period of up to 14 days prior to giving informed consent. Consent can 
be withdrawn at any time, and without justification. Only when the informed consent is available 
with the signatures of both the trial participant and the person responsible for the trial will the 
investigations be started. (consent form and package leaflets attached). Consent is registered on 
paper, and registered in the patient's electronic medical record. Package leaflets will be provided for 
the preparations Prolia® and Mimpara® and jointly side effects will be reviewed. In this context, 
information material is also handed out to health professionals. Predefined known serious side 
effects and the risk thereof will be informed, as well as for treatments, follow-up and convalescence 
at their onset. Participants will be instructed in the procedure for contacting the person responsible 
for the trial and the doctor at the onset of symptoms / side effects. The oral information interview is 
conducted by one of the medically trained experimenter, ie. Peter Vestergaard, Julius Simoni Leere, 
or one of the delegates responsible. 
  
12.3 Privacy protection.  
   
Forsøget er anmeldt til Datatilsynet og der er givet godkendelse for perioden 2016 – 2026.   


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The experiment has been notified to the Danish Data Protection Agency and approval has been 
given for the period 2016 - 2026. The information about the subjects is protected by the Personal 
Data Processing Act and the Health Act. External partners are not involved in EU or non-EU 
countries, and all biological material is stored and analyzed in Denmark. All trial contacts are 
registered in the EHR, where all information relevant to the patients' treatment is noted. The 
patients' other health information will be followed up via EHR, including documentation of adverse 
events, information on deaths and verification of information on existing diseases for analytical use. 
The requisition will be made with informed, written consent from participating patients. The trial 
will, after approval from the Science Ethics Committee, be notified to the Danish Medicines 
Agency. 
 
12.4 Information from patient files.  
Information on participants' health status, medication, and co-morbidity will be obtained upon 
enrollment in the study. This is to assess suitability in relation to inclusion, exclusion criteria 
and safety parameters. The information as well as demographic data can later be used for 
comparison between the subgroups in anonymised form. All information will be retrieved with 
your consent. 
 
12.5 Trial subjects access to information on the project.  
  
All participants receive contact information for the subinvestigator, who if they are interested will 
give them information regarding development in the project, publications, etc. An email list is 
created for this, which interested parties will provide contact information in connection with 
enrollment in the experiment. Possibly. info meeting about the result will be agreed at t later time. 
     
13. Handling and acrhiving of data and biological material.  
  
13.1 Datahandling.  
Archiving of data will take place both manually and mechanically on a computer system. For each 
participant, paper responses received by inclusion interviews, questionnaires, X-ray scanning and 
biochemical analysis are saved. Responses from these requisitions are entered by the 
subinvestigator on personal computer with storage thereon and secondary as a backup on locally 
connected drive. There will be no storage on internet media. There will be password protection on 
computer and used storage media known only by subinvestigator and sponsor. Third party review 
and tampering will not be permitted without the agreement of the subinvestigator and sponsor. Data 
will be stored for the period notified to the Danish Data Protection Agency, and will be re-notified 
in the event of a request for an extension for permission to do so.  
  
  
13.2 + 13.3 Biobank.  
  
A biobank will be set up for the experiment. Collected biological material will be urine and blood 
taken in connection with planned control samples in the experiment. The biobank is used for 


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continuous freezing of urine and blood for analysis at the end of the experiment. Participants will be 
asked in advance to give their consent and including authorizing that the material may also be used 
for future research projects or further research in connection with the project, including the 
emergence of new markers for bone turnover. The storage will take place until 01 / 04-2026, when 
the material will be destroyed, or until the trial participant wants the material destroyed. Further 
permission for storage will be applied for if the material is to be used for projects after the specified 
time. Future research will require a new application and approval by Scientific Ethics Committee. 
There will be stored approx. 5-10 ml of blood, approx. 5-10 ml of urine pr. participant per. 
examination. There are no risks associated with taking samples to the biobank. The biobank will be 
notified to the Danish Data Protection Agency in accordance with current legislation. 
  
14. Financing and insurance  
  
14.1 Economy.  
The trial is funded by existing research funds in the possession of sponsors from the North Jutland 
Region and Aalborg University. Fundraising is also planned, including funds from the Augustinús 
Foundation, AP Møller-Mærsk, Velux, Aase and Einar Danielsen's Foundation, as well as the 
Beckett Foundation. Funds allocated to the project will be deposited in a research account with the 
support of a sponsor. The initiative for the experiment was taken by the sponsor and subinvestigator 
without comment or amendments made by supporting parties. No agreement has been reached and 
will not be paid directly or indirectly for each participant. At the Department of Clinical Medicine, 
Aalborg University, the sponsor is in possession of research funds that are largely expected to be 
used for biochemical analyzes involved in the trial. The execution of radiological examinations is 
framed by the DRG tariff at the Department of Radiology, Aalborg University and will thus not 
directly or indirectly affect the operation of the experiment. Any excess support amount will be kept 
in the sponsor's custody under the Clinical Institute to finance future projects and analyzes, congress 
participants during which presentation of results can take place, or for future PhD projects. From 
Peter Vestergaard's professorship, we have the necessary funds for salaries, (1 part-time bioanalyst 
in 3 years - DKK 550,000; 1 PhD student for 3 years - DKK 1,548,000; 3 part-time supervisors - 
DKK 300,000), blood and urine samples (DKK 500,000), and scans (DKK 100,000 - ie a total of 
DKK 3,003,000). Funding for intervention medicine and placebo (Total approx.: DKK 535,000) is 
currently being sought from the above-mentioned funds. Should the fund applications fail, Sponsor, 
Peter Vestergaard has additional funds from an EU agency.er finansieret af eksisterende 
forskningsmidler i sponsors besiddelse fra Region Nordjylland og Aalborg Universitet. 
 
14.2 Insurance  
The trial is covered by insurance at Aalborg University and the patient insurance. Patients are 
covered by ordinary health insurance. Involved personnel are covered by resp. North Jutland 
Region and Aalborg University. 
 
14.3 Payment of participants  
 


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No remuneration is given, but participants can receive transportation allowance according to current 
rules. The amount will reimburse specific petrol costs for car driving or train travel 2. class. 
  
15. Publication  
15.1 Publications  
Results are planned to be published in international scientific journals. All results are given in 
anonymised form. Results will be published regardless of whether they are published in 
international journals or not, and whether their character is positive, negative or inconclusive. 
Subinvestigator will act as 1st author, sponsor and investigator as supervisor. 
 
15.2 Reporting on trial end.  
The trial will be completed at the last participant's last visit. This will be notified to the National 
Board of Health and the Science Ethics Committee North Jutland after 90 days from completion. 
 
16. References:  
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Christiansen, P. et al. Primary hyperparathyroidism: biochemical markers and bone mineral 
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Valdemarsson, S., Lindergard, B., Tibblin, S. & Bergenfelz, A. Increased biochemical 
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Dempster, D. W. et al. Preserved three-dimensional cancellous bone structure in mild 
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Stein, E. M. et al. Primary hyperparathyroidism is associated with abnormal cortical and 
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Vu, T. D. T. et al. New insights into the effects of primary hyperparathyroidism on the 
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Chen, Q. et al. Effects of an Excess and a Deficiency of Endogenous Parathyroid Hormone 
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26. 
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27. 
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39. 
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40. 
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42. 
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43. 
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progression of aortic calcification or incidence of adverse cardiovascular events in 
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29, 450–7 (2014).  
44. 
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sclerostin and dickkopf-1 levels of naive postmenopausal women with low bone mass: A 
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Human Monoclonal Antibody to RANKL, in Postmenopausal Women. J. Bone Miner. Res. 
19, 1059– 1066 (2004).  
46. 
Bone, H. G. et al. Effects of denosumab on bone mineral density and bone turnover in 
postmenopausal women. J Clin Endocrinol Metab 93, 2149–2157 (2008).  
47. 
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Lewiecki, E. M. et al. Two-year treatment with denosumab (AMG 162) in a randomized 
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49. 
McClung, M. R. Denosumab in postmenopausal women with low bone mineral density - 
Reply. N. Engl. J. Med. 354, 2391 (2006).  
50. 
Nakamura, T., Matsumoto, T., Sugimoto, T. & Shiraki, M. Dose-response study of 
denosumab on bone mineral density and bone turnover markers in Japanese postmenopausal 
women with osteoporosis. Osteoporos. Int. 23, 1131–40 (2012).  
51. 
Nakamura, T. et al. Clinical trials express: Fracture risk reduction with denosumab in 
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Sugimoto, T. et al. Three-year denosumab treatment in postmenopausal Japanese women and 
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Zhou, Z. et al. Safety of denosumab in postmenopausal women with osteoporosis or low 
bone mineral density: A meta-analysis. Int. J. Clin. Exp. Pathol. 7, 2113–2122 (2014).  
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Body, J.-J. et al. Effects of denosumab in patients with bone metastases with and without 
previous bisphosphonate exposure. J. Bone Miner. Res. 25, 440–446 (2010).  
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Brown, J. P. et al. Denosumab significantly increases bone mineral density and reduces bone 
turnover compared with monthly oral ibandronate and risedronate in postmenopausal women 
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Mok, C. C., Ho, L. Y. & Ma, K. M. Switching of oral bisphosphonates to denosumab in 
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Recknor, C. et al. Denosumab Compared With Ibandronate in Postmenopausal Women 
Previously Treated With Bisphosphonate Therapy. Obstet. Gynecol. 121, 1291–1299 (2013).  
62. 
Roux, C. et al. Denosumab compared with risedronate in postmenopausal women 
suboptimally adherent to alendronate therapy: Efficacy and safety results from a randomized 
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Zebaze, R. M. et al. Differing effects of denosumab and alendronate on cortical and 
trabecular bone. Bone 59, 173–179 (2014).  
64. 
Langdahl, B. L. et al. A 24-Month Study Evaluating the Efficacy and Safety of Denosumab 
for the Treatment of Men With Low Bone Mineral Density: Results From the ADAMO 
Trial. J. Clin. Endocrinol. Metab. 100, 1335–1342 (2015).  
65. 
Petranova, T., Sheytanov, I., Monov, S., Nestorova, R. & Rashkov, R. Denosumab improves 
bone mineral density and microarchitecture and reduces bone pain in women with 
osteoporosis with and without glucocorticoid treatment. Biotechnol. Biotechnol. Equip. 28, 
1127–1137 (2014).  
66. 
Ellis, G. K. et al. Randomized trial of denosumab in patients receiving adjuvant aromatase 
inhibitors for nonmetastatic breast cancer. J. Clin. Oncol. 26, 4875–4882 (2008).  
67. 
Martin, M. et al. Bone-related complications and quality of life in advanced breast cancer: 
Results from a randomized phase III trial of denosumab versus zoledronic acid. Clin. Cancer 
Res. 18, 4841–4849 (2012).  
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Gnant, M. et al. Adjuvant denosumab in breast cancer ( ABCSG-18 ): a multicentre , 
randomised , double-blind , placebo- controlled trial. Lancet 6736, 1–11 (2015).  
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Planas Morin, J. et al. Bone mass behavior after 1 year of different treatment strategies in 
prostate cancer patients subjected to androgen deprivation therapy. Rheumatol. Int. 34, 1419– 
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Hu, M. I. et al. Denosumab for patients with persistent or relapsed hypercalcemia of 
malignancy despite recent bisphosphonate treatment. J. Natl. Cancer Inst. 105, 1417–1420 
(2013).  
71. 
Bech, A. & de Boer, H. Denosumab for tumor-induced hypercalcemia complicated by renal 
failure. Ann. Intern. Med. 156, 906–7 (2012).  
72. 
Karuppiah, D. et al. Refractory hypercalcaemia secondary to parathyroid carcinoma: 
Response to high-dose denosumab. Eur. J. Endocrinol. 171, K1–K5 (2014).  
73. 
Nadarasa, K. et al. Denosumab for management of refractory hypercalcaemia in recurrent 
parathyroid carcinoma. Eur. J. Endocrinol. 171, L7–8 (2014).  
74. 
Tong, C. V, Hussein, Z., Noor, N. M., Mohamad, M. & Ng, W. F. Use of denosumab in 
parathyroid carcinoma with refractory hypercalcemia. QJM 108, 49–50 (2015).  
75. 
Vellanki, P., Lange, K., Elaraj, D., Kopp, P. a & El Muayed, M. Denosumab for management 
of parathyroid carcinoma-mediated hypercalcemia. J. Clin. Endocrinol. Metab. 99, 387–90 
(2014).  
76. 
Makras, P. et al. Parathyroid hormone changes following denosumab treatment in 
postmenopausal osteoporosis. Clin. Endocrinol. (Oxf). 79, 499–503 (2013).  
77. 
Watts, N. B. et al. Infections in postmenopausal women with osteoporosis treated with 
denosumab or placebo: Coincidence or causal association? Osteoporos. Int. 23, 327–337 
(2012).  
78. 
Agarwal, G. et al. Cardiovascular dysfunction in symptomatic primary hyperparathyroidism 
and its reversal after curative parathyroidectomy: results of a prospective case control study. 
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Hedbäck, G. M. & Odén, A. S. Cardiovascular disease, hypertension and renal function in 
primary hyperparathyroidism. J. Intern. Med. 251, 476–483 (2002).  
80. 
Osto, E. et al. Coronary microvascular dysfunction induced by primary hyperparathyroidism 
is restored after parathyroidectomy. Circulation 126, 1031–9 (2012).  
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Vestergaard, P. et al. Cardiovascular events before and after surgery for primary 
hyperparathyroidism. World J. Surg. 27, 216–222 (2003).  
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atherosclerotic disease in 2 community-based cohorts. Arterioscler. Thromb. Vasc. Biol. 34, 
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Anderson, J. L. et al. Parathyroid hormone, vitamin D, renal dysfunction, and cardiovascular 
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Iwata, S. et al. Aortic valve calcification in mild primary hyperparathyroidism. J. Clin. 
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88. 
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Schillaci, G. et al. Large-artery stiffness: A reversible marker of cardiovascular risk in 
primary hyperparathyroidism. Atherosclerosis 218, 96–101 (2011).  
90. 
Kepez, A. et al. Evaluation of subclinical coronary atherosclerosis in mild asymptomatic 
primary hyperparathyroidism patients. Int. J. Cardiovasc. Imaging 25, 187–93 (2009).  
91. 
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Undergoing Dialysis. N. Engl. J. Med. 367, 2482–2494 (2012).  
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Parfrey, P. S. et al. The Effects of Cinacalcet in Older and Younger Patients on 
Hemodialysis: The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events 
(EVOLVE) Trial. Clin. J. Am. Soc. Nephrol. 10, 791–799 (2015).  
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Raggi, P. et al. The ADVANCE study: A randomized study to evaluate the effects of 
cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. 
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Urena-Torres, P. A. et al. Protocol adherence and the progression of cardiovascular 
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Odvina, C. V et al. Biochemical characterization of primary hyperparathyroidism with and 
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calcifications in patients with primary hyperparathyroidism: Associations with biochemical 
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List of abbreviations:  
  
BMC: Bone Mineral Content  
BMD: Bone Mineral Density   
BSAP: Bone Specific Alkaline Phosphatase (formations markør) CaSR: 
Calcium sensing receptor.  
CTx: Carboxy-terminal collagen crosslinks (resorption marker)  
DXA: Dual-energy X-ray absorptiometry   
FGF-23: Fibroblast growth factor 23   
HRqCT: High Resolution Quantitative Computed Tomography  
MDCT: Multidetector Computed Tomography  
MEN1: Multiple Endocrine Neoplasia type 1  
Osteocalcin: Formationsmarker 
pHPT: Primary Hyperparathyroidism  
P1NP: Serum type 1 procollagen (N-terminal) 
 qCT: Quantitative Computed Tomography  
RANKL: Receptor activator of nuclear factor kappa-B ligand  
Sclerostin: Inhibition of bone formation.  
sHPT: Secondary Hyperparathyriodism  
s-iPTH: serum – intakt parathyroidhormon  
uNTx: Urinary collagen type 1 cross-linked N-telopeptid 
VF: Vertebral Fractures  
VFA: Vertebral Fracture Assessment   
T-score: Deviation from BMD of a 30 year old subject of the same gender  


 
 
  
Final statistical analysis plan  
(from the final protocol)  
  
  
4. Study Plan:  
  
4.1 Primary and Secondary Endpoints.   
Primary endpoint:  
-Percentage change in BMD (by DXA) after one year of treatment from baseline.  
Secondary endpoints:   
-Changes in volumetric BMD, BMC, cortical and trabecular width as well as ratio between these.   
-Changes in s-calcium and s-PTH at each visit and after one year of treatment.  
-Percentage change in serum- and urine- bone turnover markers  
- Prevalence/changes in coronary calcifications by Agatston-score (and Ca2+-volume score).   
-Development in nephrolithiasis/nephrocalcinose by CT  
-Development in pancreatic calcifications by CT  
-Possible reset of the Calcium sensing receptor: measured by effect on serum-Ca2+ and PTH after the 
termination of the study-treatment.  
-Prevalence of osteoporotic vertebral frectures by Vertebral Fracture Assessment (VFA), including the 
relationship between anterior, mid- and posterior compressions.  
  
  
7. Impact Assessment  
  
7.1 + 7.2. Efficacy Endpoints  
For the evaluation of efficacy of the study-treatment (active as well as placebo) radiological, biochemical and 
clinical endpoints will be investigated. The most important radiological endpoints are percentage change in 
BMD and BMC in at the distal radius, hip and lumbar column at 52 weeks. To quantify this, DXA-scans 
with VFA, including calculations of Z- and T-scores will be used. The T-score indicate, based on the 
individual BMD, the number of standard-deviations above or below the mean for a healthy person of the 
same sex and ethnicity at 30 years of age. Similarly QCT-parameters such as vBMD, cortical and trabecular 
width (and ratio between these), porosity, and vertebral fractures will be investigated (at the distal radius and 
lumbar column). These endpoints (QCT) have been chosen because they allow for evaluation of 
bonearchitecture and strength, which cannot be investigated by more traditional scan-methods (DXA). 
Hence, the use of QCT can contribute to the achievement of a deeper understanding of the impact of the 
treatment on bone-structure.  
  
In relation to the QCT-scans at baseline and after one year, images of the coronary arteries, kidneys, and the 
pancreas will be obtained for evaluation of prevalence and development of  coronary calcifications, 
nephrocalcinosis, nephrolithiasis and pancreatic calcifications in the treatment-period. These endpoints will 
be quantified by Agatston-scoring of coronary calcifications, and radiological assessment of the kidneys and 
the pancreas. This allows for assessment of a potential preventive effects of the treatment on the development 
of known sequlae/targets of primary hyperparathyroidism.  
  
The duration of the intervention-period (1 year) has been chosen to standardize the regularity of 
bloodsampling and powercalculation (based on the percentage changes in BMD over one year) and to allow 
for comparison of treatment effect with previous trials.   
  


 
 
The biochemical endpoints are measured by absolute change in blood-test-parameters for the following 
collections of tests: “immediate analyses” and “frozen samples”. The contents are listed below.  
  
  
  
At each session control of “immediate analyses” are planned.These include ionized calcium, total albumin 
adjusted calcium, s-phosphate, s-PTH, hemoglobin and erythrocyte volume fraction, acid-base status (TCO2), 
infection-parameters (CRP, WBC w. diff.), electrolytes (Na+ and K+), liver (ALAT), and 
kidneyfunction(creatinine and eGFR). These tests are measured at each visit for safety purposes and to gain a 
better understanding of the physiological changes induced by the study-treatment. These parameters are 
registered in the individual case report forms.       
   
All additional blood-samples are frozen for later analysis after the end of the study. The timeframe for the 
included control-visits has been chosen based on the available knowledge on the effects of the 
studymedicine.  
For analysis of “Bone-turnover markers”, markers of bone resorption and –formation will be used of which 
the majority are available at the Department of Clinical Biochemistry, Aalborg University Hospital, at the 
time of application.  
  
  
”Baseline” is divided in 2 separate visits, preliminary examination and start-visit.  
  
Week  
Base- 
line  
1  
  
2  4  8  12  16  20  24  
28  32  36  40  44  48  52  54  
”Immediate 
analyses”  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
”Frozen Samples”  
  
  
  
  
  
x  
  
  
  
  
  
  
  
  
  
  
  
QCT  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
DXA-scanning  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
VFA  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Clinical and 
epidemiological 
data  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Biochemical markers:  
• ”Immediate analyses”  
Na+, K+, ALAT, (hs)-CRP, WBC w. diff, creatinine(eGFR), hemoglobin, erythrocyte volume fraction, 
albumin, T-CO2, Ionized Calcium, total albumin adjusted calcium, s-PTH after pausing study medicine, 
phosphate, and at baseline, additionally erythrocyte sedimentation rate.  
  
• ”Frozen Samples”  
Blood-tests: urate, carbamid, GGT, bilirubin, amylase, lipid-status, FSH, LH, free testosterone, estradiol, 
1,25 and 25-OH-vitamin-D, magnesium, TSH, bone specific alkaline phosphatase and metanephrines. In 
addition to these, bone turnover markers in the form of p-CTX, p-Trap5b, P1NP, bone-specific alkaline 


 
 
phosphatase, osteocalcin ,FGF-23, and sclerostin. Furthermore (24hr) urine samples are frozen: U-calcium, 
u-creatinine and u-phosphate collected at baseline, 24 weeks and 48 weeks.   
  
Timeframe for control-visits:  
Generally control-visits are planned carried out as accurately as possible according to the plan above. For 
visits at weeks 1, 2 and 4 from start, the acceptable timeframe will be +/-3 days. For the remaining visits 
(weeks 8 and onward) the acceptable timeframe will be +/-10 days.  
  
Clinical data:  
-Height, weight, BMI  
-Bloodpressure and pulse  
-Smoking status and alcohol consumption  
-Daily calcium-intake  
-Familial dispositions, PHPT, osteoporosis  
-Co-morbidities  
-Pharmacological history: Prednisolone, osteoporosis treatment, anti-hypertensives, hormonal treatment -
EKCG at 0,6, and12 mths.  
-MDI/HAMD depression-scores at 0,6 og 12 mths.  
- Adverse events are registered by questionnaire in the CRF.  
  
9. Statistics:   
9.1 Statistical considerations:  
The collected data from the different parts of the project is planned to be analyzed by different methods. No 
analyses of data is planned to be carried out prior to the end of the study, except for evaluation of potential 
reported and biochemical adverse events on an individual level.  All other data management will take place 
after the end of data collection.   
  
The following evaluations are planned to take place after the end of the study:  
Comparisons of the variables listed above, between the three groups (by study-treatment);  Development 
in endpoints within all groups.   
Symptomatic vs. Asymptomatic patients (Symptoms of PHPT).  
  
For these comparisons descriptive statistical methods will be applied; absolute values, means, standard 
deviations and standard errors, medians, quartiles(Q1, Q3), and range (Min, Max).   
For testing of significance of differences between groups, t-tests and wilcoxon signed rank tests (parametric 
and non-parametric tests) per indication can be applied. Multiple regression-analysis can be applied in 
relation to investigation of confounder-correction. Further statistical methods will be considered before the 
analysis.  
  
9.2 Power calculation.   
The power-calculation is based on the primary endpoint BMD by DXA-scan.   
With a risk of type 1 errors of 5% and a risk of type 2 errors of 20% (a power of 80%) and an expected 
increase of 1% in BMD by DXA after 1 year with a standard-deviation for the BMD-measurements at 1%,  
15 are needed in each group.  
This calculation does not account for dropouts, but since a SD of 1% is a high estimate (in reality closer to 
0.8%, in which case only 10 participants in each group are needed), the calculated population-size is 
expected to be adequate.   
Based on this, up to 60 participants will be sought to be included.  
  
9.3 Significance level applied.  
 P-values <0.05 are considered significant  


 
 
  
9.5 Missing data.  
Missing data, including analysis errors and faulty blood-tests, will not be included in the analyses. In case of 
missing data, the number of analyzed results (n) will be reported. Reference interval-ultimate results, that 
cannot be converted to a numerical value similarly will be categorized as missing data. All participants that 
have initiated study-treatment will be included in the statistical analyses.