Parathyroid Adenoma, Parathyroid Hyperplasia, Primary Hyperparathyroidism
Conditions
Keywords
Primary Hyperparathyroidism, Parathyroid Adenoma, Parathyroid Hyperplasia, Cinacalcet, Denosumab, Drug Therapy, Bone Mineral Density, Calcium
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.
Interventions
DRUGCinacalcet 30 mg Tablet
Participants in one arm will receive 30 mg cinacalcet each day.
Participants in two arms will receive 60 mg Denosumab biannually.
OTHERPlacebo tablets
Participants in two arms will receive one placebo-tablet each day.
OTHERSaline Injection (Placebo)
Participants in one arm will receive saline injections as placebo for denosumab.
Sponsors
Aalborg University
Peter Vestergaard
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men and women of 18 years of age or older. * T-score by Dual X-ray Absorptiometry (DXA) between -1,0 og -3,5 * Patients from The North Jutland Region diagnosed with primary hyperparathyroidism at the Department of Endocrinology, Aalborg University Hospital. (Hypercalcaemia measured at two different time-points and simultaneous elevated/inappropriately high PTH, and exclusion of differential diagnosis.)
Exclusion criteria
* Medical history of diseases leading to hypercalcaemia other than Primary Hyperparathyroidism. * Patients being treated with Denosumab or Cinacalcet prior to inclusion or previously treated with Denosumab or Cinacalcet. * Moderately - Severely decreased liver function (alanine aminotransferase \>250u/l, gamma-glutamyl transferase\>150u/l, Bilirubin \>30) * Acute myocardial infarction or apoplexia in the 3 months before inclusion. * Medical record of heart failure * Risk factors of prolonged corrected QT interval (QTc). * Open lesions from oral surgery. * Primary diseases of the bone other than osteoporosis. * Patients suffering from kidney disease or renal failure. * Patients under treatment with thiazide or lithium. * Medical record of generalized seizures or epilepsy. * Active malignant disease. * Known allergies towards the specified medicinal products (IMPs). * Pregnancy or breastfeeding. * Fertile women who do not agree to the usage of effective contraception. * Other circumstances, evaluated by the responsible investigator, making the subject unsuitable for participation.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in 1/3 Forearm Bone Mineral Density | Baseline,one year | Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan. |
| Change in Lumbar Spine Bone Mineral Density | Baseline,one year | Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan. |
| Change in Total Hip Bone Mineral Density | Baseline,one year | Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan. |
| Change in Femoral Neck Bone Mineral Density | Baseline,one year | Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan. |
| Change in 1/3 Forearm Bone Mineral Density | Baseline,one year | Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan. |
| Percentage Change in Lumbar Spine Bone Mineral Density | Baseline,one year | Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan. |
| Percentage Change in Total Hip Bone Mineral Density | Baseline,one year | Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan. |
| Percentage Change in Femoral Neck Bone Mineral Density | Baseline,one year | Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reset of the Calcium Sensing Receptor? | 2 weeks after termination of medication. | Measured from effect on s-calcium and PTH weeks after termination of IMP |
| Vertebral Fracture Assessment - Final Scan | Patients with vertebral fractures at one year reported. | Number of participants with vertebral fractures as assessed by VFA at final scan. |
| Change MDI-score | Baseline, 6 mths, one year. | Major Depression Inventory (MDI)-score, Baseline, 6 months, one year (week 52)., change between baseline and 1 year reported. The Major Depression Inventory (MDI) is a mood questionnaire developed by the World Health Organization. To calculate the total score, a sum of ten individual items (each with an individual score between 0-5, with 0 indicating absence of a symptom and 5 indicating constant presence of a given symptom) is used. A higher score signifies deeper depression with 50 being the maximum score. |
| Adverse Reactions. | Monthly up to one year. | All participants filled in questionnaires regarding symptoms related to the treatment. Results are reported in the Adverse Events section. |
| Bone Mineral Content | Baseline, one year | Measured at baseline and after one year at the lumbar spine and distal 1/3 of the non-dominant antebrachii. |
| Change in Cortical Width. | Baseline, one year. | Measured at baseline and after one year at the distal non-dominant antebrachii. |
| Change in Volumetric BMD for the Distal Forearm. | Baseline, one year | Measured at baseline and after one year by QCT. |
| Percentage Change in Volumetric BMD for the Lumbar Spine. | Baseline, one year | Measured at baseline and after one year by QCT. |
| Mean p-PTH During Treatment. | Monthly up to one year. | Blood samples were acquired once every 4 weeks for safety-purposes. |
| Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP). | Change from baseline at 48 weeks reported. | p-P1NP, change from baseline at 48 weeks. |
| Percent Change From Baseline in P-osteocalcin. | Change from baseline at 48 weeks reported. | p-osteocalcin, change from baseline at 48 weeks. |
| Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP). | Change from baseline at 48 weeks reported. | S-Bone specific alkaline phosphatase, change from baseline at 48 weeks. |
| Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b). | Change from baseline at 48 weeks reported. | P-Trap5b, change from baseline at 48 weeks. |
| Percent Change From Baseline in p-Sclerostin. | Change from baseline at 48 weeks reported. | P-Sclerostin, change from baseline at 48 weeks. |
| Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23). | Change from baseline at 48 weeks reported. | P-FGF23 , change from baseline at 48 weeks. |
| Changes in p-25-vitamin D | Change from baseline at 48 weeks reported. | P-25-vitD , change from baseline at 48 weeks. |
| Changes in s-1,25-vitamin D | Change from baseline at 48 weeks reported. | S-1,25-vitD, change from baseline at 48 weeks. |
| Patients With Nephrocalcinosis, Final Scan. | Baseline, one year | Number of subjects w. renal calcifications at final scan. |
| Mean p-Phosphate During Treatment. | Monthly up to one year. | Blood samples were acquired once every 4 weeks for safety-purposes. |
| Percentage Change in Volumetric BMD for the Distal Forearm. | Baseline, one year | Measured at baseline and after one year by QCT. |
| Change in Volumetric BMD for the Lumbar Spine. | Baseline, one year | Measured at baseline and after one year by QCT. |
| Mean P-calcium During Treatment. | Monthly up to one year. | Blood samples were acquired once every 4 weeks for safety-purposes. |
| Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX) | Change from baseline at 48 weeks reported. | p-CTX, change from baseline at 48 weeks. |
| Median Agatstons Score Final | Baseline, one year | Simultaneously with QCT-measurements coronary calcification was be assessed. Agatston score is a score based on the extent of coronary artery calcification calculated on the amount of plaque observed in a CT scan. A score of zero indicates absence of coronary calcium, 1-10: minimal calcification, 11-100 mild calcification, 101-400 moderate calcification, \>400 severe calcification. Thus the score increases with increasing level of calcification in the coronary vessels. |
| Patients With Nephrolithiasis Final Scan. | Patients with nephrolithiasis at one year reported. | Number of subjects w. renal stones at final scan. |
| Patients With Pancreas-calcifications Final Scan. | Patients with pancreas-calcifications at one year reported. | By QCT. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Safety Measures | Monthly up to one year. | Biochemical measures of changes in liver, infection, kidney and electrolyte-status and urinary excretion of calcium. |
Countries
Denmark
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Combined Treatment. 15 subjects were treated with combined 60mg denosumab every six months, 30 mg cinacalcet daily and 50 micrograms vitamin-D3 daily. | 15 |
| Denosumab Monotherapy 16 subjects received 60 mg denosumab every six months, placebo and 50 micrograms vitamin-D daily. | 16 |
| Placebo 15 subjects will receive a saline injection every six months(blinded), placebo-tablets and 50 micrograms vitamin-D daily. | 15 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Combined Treatment. | Denosumab Monotherapy | Placebo | Total |
|---|---|---|---|---|
| Agatston Score | 4.9 units on a scale | 10.1 units on a scale | 55.7 units on a scale | 15.5 units on a scale |
| Age, Continuous | 65.1 years STANDARD_DEVIATION 13.2 | 65.4 years STANDARD_DEVIATION 8.8 | 68.0 years STANDARD_DEVIATION 7 | 66.15 years STANDARD_DEVIATION 9.7 |
| Body Mass Index | 27.7 kg/m^2 STANDARD_DEVIATION 3.5 | 27.4 kg/m^2 STANDARD_DEVIATION 4.8 | 28.4 kg/m^2 STANDARD_DEVIATION 3.9 | 27.8 kg/m^2 STANDARD_DEVIATION 4 |
| Cortical width | 1.23 mm STANDARD_DEVIATION 0.5 | 1.19 mm STANDARD_DEVIATION 0.5 | 1.14 mm STANDARD_DEVIATION 0.4 | 1.2 mm STANDARD_DEVIATION 0.4 |
| Fracture by Vertebral Fracture Assessment (VFA) | 1 Participants | 3 Participants | 2 Participants | 6 Participants |
| Ionized Calcium | 1.39 mmol/l STANDARD_DEVIATION 0.08 | 1.39 mmol/l STANDARD_DEVIATION 0.078 | 1.39 mmol/l STANDARD_DEVIATION 0.08 | 1.39 mmol/l STANDARD_DEVIATION 0.06 |
| Major Depression Inventory score | 5 MDI-points | 5 MDI-points | 5 MDI-points | 5 MDI-points |
| Nephrocalcinosis | 2 Participants | 1 Participants | 3 Participants | 6 Participants |
| Nephrolithiasis | 0 Participants | 3 Participants | 1 Participants | 4 Participants |
| Pancreas calcifications | 0 Participants | 1 Participants | 2 Participants | 3 Participants |
| P-Parathyroid Hormone (PTH) | 12.1 pmol/l STANDARD_DEVIATION 6.2 | 13.1 pmol/l STANDARD_DEVIATION 6.4 | 11.2 pmol/l STANDARD_DEVIATION 4.3 | 12.1 pmol/l STANDARD_DEVIATION 5.7 |
| P-Phosphorous | 0.77 mmol/l STANDARD_DEVIATION 0.15 | 0.77 mmol/l STANDARD_DEVIATION 0.16 | 0.79 mmol/l STANDARD_DEVIATION 0.12 | 0.78 mmol/l STANDARD_DEVIATION 0.14 |
| Race and Ethnicity Not Collected | — | — | — | 0 Participants |
| Region of Enrollment Denmark | 15 participants | 16 participants | 15 participants | 46 participants |
| Sex: Female, Male Female | 14 Participants | 13 Participants | 12 Participants | 39 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 3 Participants | 7 Participants |
| T-score 1/3 FA (by DXA) | -2.4 T-score STANDARD_DEVIATION 1.2 | -2.4 T-score STANDARD_DEVIATION 1.2 | -2.8 T-score STANDARD_DEVIATION 0.9 | -2.5 T-score STANDARD_DEVIATION 1.1 |
| T-score FN (by DXA) | -2.0 T-score STANDARD_DEVIATION 0.7 | -1.9 T-score STANDARD_DEVIATION 0.7 | -1.7 T-score STANDARD_DEVIATION 0.6 | -1.88 T-score STANDARD_DEVIATION 0.6 |
| T-score Lumbar Spine (LS) by Dual X-ray Absorptiometry (DXA) | -1.9 T-score STANDARD_DEVIATION 0.93 | -2.0 T-score STANDARD_DEVIATION 0.68 | -1.3 T-score STANDARD_DEVIATION 0.85 | -1.7 T-score STANDARD_DEVIATION 0.87 |
| T-score TH (by DXA) | -1.4 T-score STANDARD_DEVIATION 0.5 | -1.4 T-score STANDARD_DEVIATION 0.6 | -1.1 T-score STANDARD_DEVIATION 0.5 | -1.3 T-score STANDARD_DEVIATION 0.5 |
| U-Calcium | 338 mg/d | 276 mg/d | 314 mg/d | 284 mg/d |
| U-Phosphorous | 28.5 mmol/d | 32.2 mmol/d | 35.2 mmol/d | 32.0 mmol/d |
| vBMD distal forearm | 183.5 mg/cm^3 STANDARD_DEVIATION 32 | 194.9 mg/cm^3 STANDARD_DEVIATION 37.6 | 181.4 mg/cm^3 STANDARD_DEVIATION 35.5 | 192.6 mg/cm^3 STANDARD_DEVIATION 34.6 |
| Volumetric Bone Mineral Density (vBMD) LS | 96.4 mg/cm^3 STANDARD_DEVIATION 28.1 | 99.7 mg/cm^3 STANDARD_DEVIATION 24 | 94.2 mg/cm^3 STANDARD_DEVIATION 25.4 | 96.9 mg/cm^3 STANDARD_DEVIATION 25.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 15 | 0 / 16 | 0 / 15 |
| other Total, other adverse events | 13 / 15 | 15 / 16 | 15 / 15 |
| serious Total, serious adverse events | 2 / 15 | 1 / 16 | 3 / 15 |
Outcome results
Primary
Change in 1/3 Forearm Bone Mineral Density
Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
Time frame: Baseline,one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group did not provide results for this analysis as he/she experienced a wrist fracture prior to the final scan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Change in 1/3 Forearm Bone Mineral Density | 0.005 g/cm^2 | Standard Error 0.003 |
| Denosumab Monotherapy | Change in 1/3 Forearm Bone Mineral Density | 0.005 g/cm^2 | Standard Error 0.003 |
| Placebo | Change in 1/3 Forearm Bone Mineral Density | -0.005 g/cm^2 | Standard Error 0.004 |
p-value: =0.096ANOVA
Primary
Change in Femoral Neck Bone Mineral Density
Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
Time frame: Baseline,one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the placebo group did not provide results for this analysis as he/she had had a hip-replacement performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Change in Femoral Neck Bone Mineral Density | 0.023 g/cm^2 | Standard Error 0.006 |
| Denosumab Monotherapy | Change in Femoral Neck Bone Mineral Density | 0.020 g/cm^2 | Standard Error 0.005 |
| Placebo | Change in Femoral Neck Bone Mineral Density | -0.007 g/cm^2 | Standard Error 0.006 |
p-value: =0.0019ANOVA
Primary
Change in Lumbar Spine Bone Mineral Density
Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
Time frame: Baseline,one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Change in Lumbar Spine Bone Mineral Density | 0.030 g/cm^2 | Standard Error 0.009 |
| Denosumab Monotherapy | Change in Lumbar Spine Bone Mineral Density | 0.042 g/cm^2 | Standard Error 0.009 |
| Placebo | Change in Lumbar Spine Bone Mineral Density | -0.016 g/cm^2 | Standard Error 0.007 |
p-value: <0.00001ANOVA
Primary
Change in Total Hip Bone Mineral Density
Change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
Time frame: Baseline,one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the placebo group did not provide results for this analysis as he/she had had a hip-replacement performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Change in Total Hip Bone Mineral Density | 0.027 g/cm^2 | Standard Error 0.006 |
| Denosumab Monotherapy | Change in Total Hip Bone Mineral Density | 0.021 g/cm^2 | Standard Error 0.003 |
| Placebo | Change in Total Hip Bone Mineral Density | -0.013 g/cm^2 | Standard Error 0.006 |
p-value: <0.00001ANOVA
Primary
Percentage Change in 1/3 Forearm Bone Mineral Density
Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
Time frame: Baseline,one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group did not provide results for this analysis as he/she experienced a wrist fracture prior to the final scan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Percentage Change in 1/3 Forearm Bone Mineral Density | 0.94 % change | Standard Error 0.7 |
| Denosumab Monotherapy | Percentage Change in 1/3 Forearm Bone Mineral Density | 0.88 % change | Standard Error 0.5 |
| Placebo | Percentage Change in 1/3 Forearm Bone Mineral Density | -0.91 % change | Standard Error 0.7 |
p-value: =0.081ANOVA
Primary
Percentage Change in Femoral Neck Bone Mineral Density
Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
Time frame: Baseline,one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the placebo group did not provide results for this analysis as he/she had had a hip-replacement performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Percentage Change in Femoral Neck Bone Mineral Density | 3.70 % change | Standard Error 0.98 |
| Denosumab Monotherapy | Percentage Change in Femoral Neck Bone Mineral Density | 3.03 % change | Standard Error 0.86 |
| Placebo | Percentage Change in Femoral Neck Bone Mineral Density | -0.78 % change | Standard Error 0.9 |
p-value: =0.0027ANOVA
Primary
Percentage Change in Lumbar Spine Bone Mineral Density
Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
Time frame: Baseline,one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Percentage Change in Lumbar Spine Bone Mineral Density | 3.6 % change | Standard Error 1.1 |
| Denosumab Monotherapy | Percentage Change in Lumbar Spine Bone Mineral Density | 5.1 % change | Standard Error 1.1 |
| Placebo | Percentage Change in Lumbar Spine Bone Mineral Density | -1.8 % change | Standard Error 0.8 |
p-value: =0.0001ANOVA
Primary
Percentage Change in Total Hip Bone Mineral Density
Percentage change of Bone Mineral Density after one year of treatment from baseline. Measured with Dual-energy X-ray absorptiometry (DXA)-scan.
Time frame: Baseline,one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the placebo group did not provide results for this analysis as he/she had had a hip-replacement performed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Percentage Change in Total Hip Bone Mineral Density | 3.45 % change | Standard Error 0.72 |
| Denosumab Monotherapy | Percentage Change in Total Hip Bone Mineral Density | 2.64 % change | Standard Error 0.41 |
| Placebo | Percentage Change in Total Hip Bone Mineral Density | -1.50 % change | Standard Error 0.72 |
p-value: <0.00001ANOVA
Secondary
Adverse Reactions.
All participants filled in questionnaires regarding symptoms related to the treatment. Results are reported in the Adverse Events section.
Time frame: Monthly up to one year.
Secondary
Bone Mineral Content
Measured at baseline and after one year at the lumbar spine and distal 1/3 of the non-dominant antebrachii.
Time frame: Baseline, one year
Population: Data were not collected
Secondary
Change in Cortical Width.
Measured at baseline and after one year at the distal non-dominant antebrachii.
Time frame: Baseline, one year.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group experienced a wrist fracture prior to the final scan and was excluded. 4 patients did not provide data for the analysis due to errors in the technique of the obtained images.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Change in Cortical Width. | -0.04 mm | Standard Error 0.1 |
| Denosumab Monotherapy | Change in Cortical Width. | 0.02 mm | Standard Error 0.08 |
| Placebo | Change in Cortical Width. | 0.04 mm | Standard Error 0.05 |
p-value: >0.05ANOVA
Secondary
Change in Volumetric BMD for the Distal Forearm.
Measured at baseline and after one year by QCT.
Time frame: Baseline, one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group experienced a wrist fracture prior to the final scan and was excluded. 5 patients did not provide data for the analysis due to errors in the technique of the obtained images.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Change in Volumetric BMD for the Distal Forearm. | 1.0 mg/cm^3 | Standard Error 2.1 |
| Denosumab Monotherapy | Change in Volumetric BMD for the Distal Forearm. | 9.6 mg/cm^3 | Standard Error 3.7 |
| Placebo | Change in Volumetric BMD for the Distal Forearm. | -1.1 mg/cm^3 | Standard Error 4.6 |
p-value: =0.0077ANOVA
Secondary
Change in Volumetric BMD for the Lumbar Spine.
Measured at baseline and after one year by QCT.
Time frame: Baseline, one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. Another scan could not be included due to a technical problems with the image analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Change in Volumetric BMD for the Lumbar Spine. | 4.93 mg/cm^3 | Standard Error 2.15 |
| Denosumab Monotherapy | Change in Volumetric BMD for the Lumbar Spine. | 5.35 mg/cm^3 | Standard Error 1.91 |
| Placebo | Change in Volumetric BMD for the Lumbar Spine. | -2.56 mg/cm^3 | Standard Error 1.6 |
p-value: =0.0071ANOVA
Secondary
Change MDI-score
Major Depression Inventory (MDI)-score, Baseline, 6 months, one year (week 52)., change between baseline and 1 year reported. The Major Depression Inventory (MDI) is a mood questionnaire developed by the World Health Organization. To calculate the total score, a sum of ten individual items (each with an individual score between 0-5, with 0 indicating absence of a symptom and 5 indicating constant presence of a given symptom) is used. A higher score signifies deeper depression with 50 being the maximum score.
Time frame: Baseline, 6 mths, one year.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final collection of MDI-questionnaires.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Change MDI-score | 0.0 MDI-score |
| Denosumab Monotherapy | Change MDI-score | -0.5 MDI-score |
| Placebo | Change MDI-score | 0.0 MDI-score |
p-value: =0.83Kruskal-Wallis
Secondary
Changes in p-25-vitamin D
P-25-vitD , change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Changes in p-25-vitamin D | 22.1 nmol/l |
| Denosumab Monotherapy | Changes in p-25-vitamin D | 16.0 nmol/l |
| Placebo | Changes in p-25-vitamin D | 21.2 nmol/l |
p-value: =0.22ANOVA
Secondary
Changes in s-1,25-vitamin D
S-1,25-vitD, change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Changes in s-1,25-vitamin D | 7.5 pmol/l |
| Denosumab Monotherapy | Changes in s-1,25-vitamin D | 4.5 pmol/l |
| Placebo | Changes in s-1,25-vitamin D | 26.0 pmol/l |
p-value: =0.18Kruskal-Wallis
Secondary
Mean P-calcium During Treatment.
Blood samples were acquired once every 4 weeks for safety-purposes.
Time frame: Monthly up to one year.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Mean P-calcium During Treatment. | 1.28 mmol/l | Standard Error 0.007 |
| Denosumab Monotherapy | Mean P-calcium During Treatment. | 1.38 mmol/l | Standard Error 0.006 |
| Placebo | Mean P-calcium During Treatment. | 1.40 mmol/l | Standard Error 0.004 |
p-value: =0.0001ANOVA
Secondary
Mean p-Phosphate During Treatment.
Blood samples were acquired once every 4 weeks for safety-purposes.
Time frame: Monthly up to one year.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Mean p-Phosphate During Treatment. | 0.83 pmol/l | Standard Error 0.013 |
| Denosumab Monotherapy | Mean p-Phosphate During Treatment. | 0.76 pmol/l | Standard Error 0.012 |
| Placebo | Mean p-Phosphate During Treatment. | 0.083 pmol/l | Standard Error 0.011 |
p-value: <0.00001ANOVA
Secondary
Mean p-PTH During Treatment.
Blood samples were acquired once every 4 weeks for safety-purposes.
Time frame: Monthly up to one year.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Mean p-PTH During Treatment. | 12.0 pmol/l |
| Denosumab Monotherapy | Mean p-PTH During Treatment. | 13.4 pmol/l |
| Placebo | Mean p-PTH During Treatment. | 9.9 pmol/l |
p-value: =0.0001Kruskal-Wallis
Secondary
Median Agatstons Score Final
Simultaneously with QCT-measurements coronary calcification was be assessed. Agatston score is a score based on the extent of coronary artery calcification calculated on the amount of plaque observed in a CT scan. A score of zero indicates absence of coronary calcium, 1-10: minimal calcification, 11-100 mild calcification, 101-400 moderate calcification, \>400 severe calcification. Thus the score increases with increasing level of calcification in the coronary vessels.
Time frame: Baseline, one year
Population: Some participant from the combined and placebo groups could not be included in the analysis because they had coronary stents.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Median Agatstons Score Final | 5.0 score on a scale |
| Denosumab Monotherapy | Median Agatstons Score Final | 24.3 score on a scale |
| Placebo | Median Agatstons Score Final | 117.8 score on a scale |
p-value: =0.38Kruskal-Wallis
Secondary
Patients With Nephrocalcinosis, Final Scan.
Number of subjects w. renal calcifications at final scan.
Time frame: Baseline, one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Treatment. | Patients With Nephrocalcinosis, Final Scan. | 2 Participants |
| Denosumab Monotherapy | Patients With Nephrocalcinosis, Final Scan. | 1 Participants |
| Placebo | Patients With Nephrocalcinosis, Final Scan. | 3 Participants |
Secondary
Patients With Nephrolithiasis Final Scan.
Number of subjects w. renal stones at final scan.
Time frame: Patients with nephrolithiasis at one year reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Treatment. | Patients With Nephrolithiasis Final Scan. | 0 Participants |
| Denosumab Monotherapy | Patients With Nephrolithiasis Final Scan. | 3 Participants |
| Placebo | Patients With Nephrolithiasis Final Scan. | 1 Participants |
Secondary
Patients With Pancreas-calcifications Final Scan.
By QCT.
Time frame: Patients with pancreas-calcifications at one year reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Treatment. | Patients With Pancreas-calcifications Final Scan. | 0 Participants |
| Denosumab Monotherapy | Patients With Pancreas-calcifications Final Scan. | 1 Participants |
| Placebo | Patients With Pancreas-calcifications Final Scan. | 2 Participants |
Secondary
Percentage Change in Volumetric BMD for the Distal Forearm.
Measured at baseline and after one year by QCT.
Time frame: Baseline, one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. One participant from the denosumab group experienced a wrist fracture prior to the final scan and was excluded. 5 patients did not provide data for the analysis due to errors in the technique of the obtained images.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Percentage Change in Volumetric BMD for the Distal Forearm. | 0.53 % change | Standard Error 1.2 |
| Denosumab Monotherapy | Percentage Change in Volumetric BMD for the Distal Forearm. | 5.2 % change | Standard Error 1 |
| Placebo | Percentage Change in Volumetric BMD for the Distal Forearm. | -0.74 % change | Standard Error 2.6 |
p-value: =0.011ANOVA
Secondary
Percentage Change in Volumetric BMD for the Lumbar Spine.
Measured at baseline and after one year by QCT.
Time frame: Baseline, one year
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan. Another scan could not be included due to a technical problems with the image analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Combined Treatment. | Percentage Change in Volumetric BMD for the Lumbar Spine. | 6.18 % change | Standard Error 3.14 |
| Denosumab Monotherapy | Percentage Change in Volumetric BMD for the Lumbar Spine. | 5.66 % change | Standard Error 1.85 |
| Placebo | Percentage Change in Volumetric BMD for the Lumbar Spine. | -2.94 % change | Standard Error 1.96 |
p-value: =0.011ANOVA
Secondary
Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX)
p-CTX, change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX) | -48.7 % change |
| Denosumab Monotherapy | Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX) | -58.2 % change |
| Placebo | Percent Change From Baseline in P-carboxy-terminal Collagen Crosslinks (CTX) | 11.8 % change |
p-value: =0.0001Kruskal-Wallis
Secondary
Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23).
P-FGF23 , change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23). | 35.8 % change |
| Denosumab Monotherapy | Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23). | 20.4 % change |
| Placebo | Percent Change From Baseline in P-fibroblast Growth Factor 23 (FGF23). | 28.0 % change |
p-value: =0.85ANOVA
Secondary
Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP).
p-P1NP, change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP). | -63.1 % change |
| Denosumab Monotherapy | Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP). | -66.1 % change |
| Placebo | Percent Change From Baseline in p-N-terminal Propeptide of Type I Procollagen (p-P1NP). | 17.8 % change |
p-value: =0.0001Kruskal-Wallis
Secondary
Percent Change From Baseline in P-osteocalcin.
p-osteocalcin, change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Percent Change From Baseline in P-osteocalcin. | -60.0 % change |
| Denosumab Monotherapy | Percent Change From Baseline in P-osteocalcin. | -58.9 % change |
| Placebo | Percent Change From Baseline in P-osteocalcin. | 7.0 % change |
p-value: =0.0001ANOVA
Secondary
Percent Change From Baseline in p-Sclerostin.
P-Sclerostin, change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Percent Change From Baseline in p-Sclerostin. | 10.0 % change |
| Denosumab Monotherapy | Percent Change From Baseline in p-Sclerostin. | 6.5 % change |
| Placebo | Percent Change From Baseline in p-Sclerostin. | 4.8 % change |
p-value: =0.5Kruskal-Wallis
Secondary
Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b).
P-Trap5b, change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b). | -27.8 % change |
| Denosumab Monotherapy | Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b). | -36.7 % change |
| Placebo | Percent Change From Baseline in p-Tartrate-resistant Acid Phosphatase 5b (Trap5b). | 2.3 % change |
Secondary
Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP).
S-Bone specific alkaline phosphatase, change from baseline at 48 weeks.
Time frame: Change from baseline at 48 weeks reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final blood-sampling.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Combined Treatment. | Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP). | -40.0 % change |
| Denosumab Monotherapy | Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP). | -46.3 % change |
| Placebo | Percent Change From Baseline in S-bone-specific Alkaline Phosphatase (BAP). | 9.7 % change |
p-value: =0.0001Kruskal-Wallis
Secondary
Reset of the Calcium Sensing Receptor?
Measured from effect on s-calcium and PTH weeks after termination of IMP
Time frame: 2 weeks after termination of medication.
Secondary
Vertebral Fracture Assessment - Final Scan
Number of participants with vertebral fractures as assessed by VFA at final scan.
Time frame: Patients with vertebral fractures at one year reported.
Population: One participant from the combined treatment-group was not included in the analysis due to withdrawal before the final scan.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Combined Treatment. | Vertebral Fracture Assessment - Final Scan | 1 Participants |
| Denosumab Monotherapy | Vertebral Fracture Assessment - Final Scan | 3 Participants |
| Placebo | Vertebral Fracture Assessment - Final Scan | 2 Participants |
Other Pre-specified
Safety Measures
Biochemical measures of changes in liver, infection, kidney and electrolyte-status and urinary excretion of calcium.
Time frame: Monthly up to one year.