Bone Marrow Edema
Conditions
Keywords
bone marrow edema, Aclasta
Brief summary
The primary aim is to test the reduction of bone marrow edema syndrome after a singular intravenous treatment with Zoledronic Acid within 6 weeks compared to placebo. The volume of the edema is defined as biometric data measured by the use of MRT before and six weeks after treatment. The hypothesis has to be checked whether Zoledronic Acid is efficient in the treatment of painful bone marrow edema. A statistically significant reduction of the edema in the MRT is considered as evidence for efficacy.
Interventions
DRUGAclasta
1 x intravenous non-current drip (infusion)
DRUGPlacebo
NaCl Solution
Sponsors
Crolll Gmbh
University of Wuerzburg
Wuerzburg University Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Men: age over ≥ 18 years or women: age over ≥ 18 years with finished reproductivity according to the following definition: * ≥ 12 month persistent natural (spontaneous) amenorrhoea (women aged \<50: additionally: FSH \>40MIE/ml and estrogen deficiency of \<30pg/ml or a negative estrogen test) * status post hysterectomy and / or bilateral oophorectomy * finished reproduction planning * secure diagnosis of bone marrow edema using MRT * current osteologic basic laboratory values (≤ 4 weeks before V2) according to DVO criteria * presence of an personally signed informed consent for the participation in the study
Exclusion criteria
* \- subchondral bone loss or already occurred cartilage damage due to the bone marrow edema * reactive bone marrow edema with advanced arthrotic changes in the adjacent joint (grade III and IV according to Kellgren and Lawrence) * patients with edematous changes in bone marrow due to the diagnosis of M. Sudeck / algodystrophy / Complex Regional Pain Syndrome (CRPS) * patients with known hypo- and hyperparathyroidism, osteogenesis imperfecta, osteomalacia, M. Paget or another systemic skeletal diseases, except osteoporosis * patients with bone necrosis in the painful skeletal region * patients with infectious process at the affected bone or the adjacent joint and adjacent soft parts, respectively * patients with diagnosed or assumed rheumatoid arthritis, Lupus erythematodes, collagenosis or vasculitides * patients with advanced renal insufficiency (GFR according to Cockcroft / Gault ≤ 40 ml/min/KO) * patients with malignant diseases with osseous manifestation in anamnesis/history * status post malignant basic/primary disease with large dosed chemotherapy * current or massive dose therapy completed before less than 6 weeks (\>7.5mg prednisolon equivalent) with glucocorticoids * patients with a malignant tumor disease within the past 5 years, independent from the affected organ system and independent from the implemented treatment, the presence of a relapse or metastatic invasion, except basal cell carcinoma and squamous-cell carcinoma of the skin Current treatment due to uveitis * vague/ambiguous hyper- or hypocalcemia, hyper- or hypophosphatemia * etiological vague/ambiguous AP-increase * symptomatic renal calculus or nephrocalcinosis within 2 years before V2 * recent fracture within the last 3 months independent of the localisation * non consolidated fractures * previous treatment with i.v. bisphosphonates within the last 12 months * previous treatment with oral bisphosphonates within the last 12 months and longer than 3 months * pre-treatment with prostacyclin analogs (Ilomedin® / Iloprost®) within the past 6 months * Current treatment due to inflammatory diseases of the jaw area as well as planned tooth extractions or tooth extractions less than 6 months ago or oral surgery implant treatment * pregnancy or nursing period * patients immediately involved in the conduction of the trial and relatives * patients with current proceedings related to the bone marrow edema * patients for which the participation in the study carries an increased risk under consideration of the health condition due to the assessment of the investigator * participation in another clinical trial within 30 days before study start or during the trial * participation of patient who might be dependent on the investigator, also the spouse, parents or children
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Reduction of the Edema Area | Week 6 after administration of a single intravenous dose of zoledronic acid (5 mg) | The volume of the edema in cm³ is defined as biometric data measured by the use of MRI before and six weeks after treatment. Edema volume at screening was set to 100%. Edema volume six weeks after study drug administration was provdied as percentage reduction compared to the value at screening |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduction of Pain | Assessment at week 6 | Reduction of pain as measured by a visual analog scale (VAS). Range 0-100. Higher values indicating worse pain. |
| Quality of Life (Qualeffo-41 Questionnaire) | Assessment at week 3 | Quality of life as measured by the Qualeffo-41 questionnaire - a quality of life questionnaire in patients with fractures of the European Foundation for Osteoporosis Higher values indicate worse quality of life |
| Subjective Estimation of Medical Condition (PDI) | Assessment at week 3 | Subjective estimation of medical condition as assessed by PDI (Pain Disability Index). Range 0-70. The higher the index the greater the person's disability due to pain. |
| Reduction of Pain (VAS) | Assessment at week 3 | Reduction of pain as measured by a Visual Analog Scale (VAS). Range 0-100 with higher values indicating worse pain. |
| Number of Days of Illness | Assessment at week 6 | Aggregated number of days of illness i.e. sick leave from work, assessed until week 6 |
| Number of Aseptic Bone Necrosis and Fatigue Fractures | Baseline until end of study (week 12) | Assessment of number of patients withaseptic bone necrosis and/or fatigue fractures. |
| Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Week 3, 6 | including changes in the following parameters according to DVO guidelines: Calcium, Phosphate, Creatinin-Clearance (Cockcroft-Gault), Alkaline Phosphatase, γGT, CRP |
| Number of Additional Medicinal Visits | Assessment at week 3 | Number of additional medicinal visits until week 3 |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zoledronic Acid single-dose zoledronic acid (Aclasta) with vitamin D 1000IU/d - 5 mg i.v. | 34 |
| Placebo placebo with vitamin D 1000 IU/d (NaCl Solution) | 14 |
| Total | 48 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up (Until Week 12) | Adverse Event | 1 | 0 |
| Follow-up (Until Week 12) | Subsequent follow-up treatment required | 0 | 1 |
| Follow-up (Until Week 12) | Surgical intervention - not study related | 1 | 0 |
Baseline characteristics
| Characteristic | Placebo | Zoledronic Acid | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1 Participants | 5 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 13 Participants | 29 Participants | 42 Participants |
| Pain (VAS) | 34.1 units on a scale STANDARD_DEVIATION 21.1 | 36.9 units on a scale STANDARD_DEVIATION 27.4 | 34.9 units on a scale STANDARD_DEVIATION 24.8 |
| Qualeffo-41 | 2.2 units on a scale STANDARD_DEVIATION 0.6 | 2.1 units on a scale STANDARD_DEVIATION 0.5 | 2.1 units on a scale STANDARD_DEVIATION 0.5 |
| Severity of disease mild | 2 Participants | 4 Participants | 6 Participants |
| Severity of disease moderate | 10 Participants | 22 Participants | 32 Participants |
| Severity of disease severe | 2 Participants | 8 Participants | 10 Participants |
| Sex: Female, Male Female | 4 Participants | 12 Participants | 16 Participants |
| Sex: Female, Male Male | 10 Participants | 22 Participants | 32 Participants |
| Subjective estimation of medical condition (Paian Disability Index) | 21.3 units on a scale STANDARD_DEVIATION 6.4 | 20.8 units on a scale STANDARD_DEVIATION 6.8 | 20.8 units on a scale STANDARD_DEVIATION 13.5 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 14 |
| other Total, other adverse events | 34 / 34 | 11 / 14 |
| serious Total, serious adverse events | 4 / 34 | 1 / 14 |
Outcome results
Primary
Reduction of the Edema Area
The volume of the edema in cm³ is defined as biometric data measured by the use of MRI before and six weeks after treatment. Edema volume at screening was set to 100%. Edema volume six weeks after study drug administration was provdied as percentage reduction compared to the value at screening
Time frame: Week 6 after administration of a single intravenous dose of zoledronic acid (5 mg)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Reduction of the Edema Area | 64.53 percentage of edema volume | Standard Deviation 41.92 |
| Placebo | Reduction of the Edema Area | 23.97 percentage of edema volume | Standard Deviation 46.52 |
p-value: =0.006t-test, 2 sided
p-value: =0.015Wilcoxon (Mann-Whitney)
Secondary
Number of Additional Medicinal Visits
Number of additional medicinal visits until week 3
Time frame: Assessment at week 3
Population: Reporting group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Number of Additional Medicinal Visits | 1 Number of additional medicinal visits |
| Placebo | Number of Additional Medicinal Visits | 0 Number of additional medicinal visits |
Secondary
Number of Additional Medicinal Visits
Aggregated number of unscheduled medicinal visits
Time frame: Assessment at week 6
Population: Reporting Group
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Zoledronic Acid | Number of Additional Medicinal Visits | 0 Medicinal Visits |
| Placebo | Number of Additional Medicinal Visits | 0 Medicinal Visits |
Secondary
Number of Aseptic Bone Necrosis and Fatigue Fractures
Assessment of number of patients withaseptic bone necrosis and/or fatigue fractures.
Time frame: Baseline until end of study (week 12)
Population: Reporting group
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Zoledronic Acid | Number of Aseptic Bone Necrosis and Fatigue Fractures | 0 Participants |
| Placebo | Number of Aseptic Bone Necrosis and Fatigue Fractures | 0 Participants |
Secondary
Number of Days of Illness
Number of days of illness assessed until week 6
Time frame: Assessment at week 6
Population: Reporting group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Number of Days of Illness | 0.94 days | Standard Deviation 4.1 |
| Placebo | Number of Days of Illness | 3.14 days | Standard Deviation 4.1 |
Secondary
Number of Days of Illness
Aggregated number of days of illness i.e. sick leave from work, assessed until week 6
Time frame: Assessment at week 6
Population: Reporting group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Number of Days of Illness | 1.24 days | Standard Deviation 5.02 |
| Placebo | Number of Days of Illness | 3.00 days | Standard Deviation 7.63 |
Secondary
Number of Participants With Adverse Events as a Measure of Safety and Tolerability
including changes in the following parameters according to DVO guidelines: Calcium, Phosphate, Creatinin-Clearance (Cockcroft-Gault), Alkaline Phosphatase, γGT, CRP
Time frame: Week 3, 6
Population: Reporting Group
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Zoledronic Acid | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serum Calcium | 0 participants |
| Zoledronic Acid | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serum Phosphate | 0 participants |
| Zoledronic Acid | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serum Alkaline Phosphatase | 0 participants |
| Zoledronic Acid | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Gamma-GT | 0 participants |
| Zoledronic Acid | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serum Creatinine | 0 participants |
| Zoledronic Acid | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | C-reactives protein | 0 participants |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serum Creatinine | 1 participants |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serum Calcium | 0 participants |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Gamma-GT | 0 participants |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serum Phosphate | 0 participants |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | C-reactives protein | 0 participants |
| Placebo | Number of Participants With Adverse Events as a Measure of Safety and Tolerability | Serum Alkaline Phosphatase | 0 participants |
Secondary
Quality of Life (Qualeffo-41 Questionnaire)
Quality of life as measured by the Qualeffo-41 questionnaire - a quality of life questionnaire in patients with vertebral fractures of the European Foundation for Osteoporosis
Time frame: Assessment at week 6
Population: Reporting group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Quality of Life (Qualeffo-41 Questionnaire) | 2.0 units on a scale | Standard Deviation 0.5 |
| Placebo | Quality of Life (Qualeffo-41 Questionnaire) | 2.1 units on a scale | Standard Deviation 0.6 |
Secondary
Quality of Life (Qualeffo-41 Questionnaire)
Quality of life as measured by the Qualeffo-41 questionnaire - a quality of life questionnaire in patients with fractures of the European Foundation for Osteoporosis Higher values indicate worse quality of life
Time frame: Assessment at week 3
Population: Reporting group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Quality of Life (Qualeffo-41 Questionnaire) | 2.1 units on a scale | Standard Deviation 0.4 |
| Placebo | Quality of Life (Qualeffo-41 Questionnaire) | 2.1 units on a scale | Standard Deviation 0.6 |
Secondary
Reduction of Pain
Reduction of pain as measured by a visual analog scale (VAS). Range 0-100. Higher values indicating worse pain.
Time frame: Assessment at week 6
Population: Reporting group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Reduction of Pain | 25.0 units on a scale | Standard Deviation 28.7 |
| Placebo | Reduction of Pain | 38.5 units on a scale | Standard Deviation 30.2 |
Secondary
Reduction of Pain (VAS)
Reduction of pain as measured by a Visual Analog Scale (VAS). Range 0-100 with higher values indicating worse pain.
Time frame: Assessment at week 3
Population: Reporting group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Reduction of Pain (VAS) | 25.5 units on a scale | Standard Deviation 22.7 |
| Placebo | Reduction of Pain (VAS) | 25.6 units on a scale | Standard Deviation 24.4 |
Secondary
Subjective Estimation of Medical Condition (PDI)
Subjective estimation of medical condition as assessed by PDI (Pain Disability Index)
Time frame: Assessment at week 6
Population: Reporting group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Subjective Estimation of Medical Condition (PDI) | 13.1 units on a scale | Standard Deviation 6 |
| Placebo | Subjective Estimation of Medical Condition (PDI) | 18.8 units on a scale | Standard Deviation 7.7 |
Secondary
Subjective Estimation of Medical Condition (PDI)
Subjective estimation of medical condition as assessed by PDI (Pain Disability Index). Range 0-70. The higher the index the greater the person's disability due to pain.
Time frame: Assessment at week 3
Population: Reporting group
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zoledronic Acid | Subjective Estimation of Medical Condition (PDI) | 14.8 units on a scale | Standard Deviation 5.8 |
| Placebo | Subjective Estimation of Medical Condition (PDI) | 20.5 units on a scale | Standard Deviation 7.3 |