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1 This supplement contains the following items: 1. Original protocol, final protocol, summary of changes 2. Original statistical analysis plan, final statistical analysis plan, summary of changes Original protocol VERTOS IV trial ClinicalTrials.gov Identifier: NCT Purpose The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), is a new minimally invasive technique for pain treatment in which bone cement is injected in the fractured vertebra. Recent RCTs provide conflicting results: two sham-controlled studies show no benefit of PV while an unmasked but controlled RCT found significantly better pain relief after PV at acceptable costs. Study Type: Study Design: Interventional Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Single Blind (Subject) Primary Purpose: Treatment Objectives To evaluate the efficacy of bone cement injection in PV for patients with acute painful osteoporotic compression fractures, as compared with a simulated placebo procedure without injection of bone cement. We hypothesize that patients who had undergone PV would report less pain at 1 day, 1 week and 1, 3, 6 and 12 months (the primary outcomes) than those in the sham control group. Study design VERTOS IV is a multicenter RCT concerning the treatment of patients with a painful osteoporotic VCF. Patients are recruited on the Radiology departments of the participating hospitals and randomized to PV or a simulated procedure. Upon obtaining informed consent an independent central telephone operator completes the randomization procedure, using a computer program. The maximum allowed unbalance (block size) is six, with a maximum sample size of 84 for each participating center. A total of 180 patients will be enrolled, 90 in each group. This is based on the assumption of a 1.5 point difference in pain relief (VAS Score) and a 20% withdrawal rate (α=0.05 and β=0.20, 7 measurement points). The enrolment of patients will take place in four centres in The Netherlands: St. Elisabeth Ziekenhuis in Tilburg, Catharina Ziekenhuis in Eindhoven, Medisch Spectrum Twente in Enschede and Albert Schweitzer Ziekenhuis in Dordrecht. Randomization will start January 2011 with an expected completion of enrolment by January There is a one-year follow-up, with the possibility of an extended follow-up at two years. The overall Institutional Review Board is approval is obtained at the St. Elisabeth Hospital in Tilburg. In addition, each participating center will obtain a local Institutional Review Board Approval. This study is registered at ClinicalTrials.gov., NCT Osteoporosis- and pain medication. All patients receive osteoporosis medication, such as bisphosphonates together with supplemental calcium and vitamin D. Pain medication demanded by the patient is recorded. Analgesics are classified following the WHO classification: (1) Paracetamol (acetaminophen), (2) Tramadol, (3) Tramadol and Paracetamol, (4) Morphine. Non Steroid Anti Inflammatory Drugs (NSAID) are only

2 prescribed if patients are intolerant for opiate- derivatives or when already used. Corrections in dose and classification of pain medication are made if necessary. Clinical follow-up An experienced nurse-practitioner requests patients to fill out a standard questionnaire before and at 1 day, 1 week, and 1, 3, 6 and 12 months after the procedure. The questionnaire consist of the VAS score and questions about use of pain medication, pain location, and pain type. The VAS score is a pain score ranging from 0 (no pain) to 10 (worst pain ever. Other medical treatment and visits to alternative medical specialists, GP's and physical therapists are recorded and compared between groups. Secondary outcomes are back pain related disability and QOL as measured with the Roland Morris Disability (RMD) Questionnaire and the Questionnaire of the European Foundation for Osteoporosis (Qualeffo), respectively. The Qualeffo is developed specifically for patients with osteoporosis. This questionnaire consists of 41 questions about: pain, physical function, social function, general health perception, and mental function. The Qualeffo score ranges from 0 (best quality of life) to 100 (worst quality of life). This questionnaire will be completed at five measurement moments (before and at 1, 3, 6, and 12 months after the procedure). The RMD questionnaire is a disability questionnaire that measures the functional status of patients with back pain. The RMD will be completed at all measurement points. All patients visit the internist at 1,3,6 and 12 months follow-up. All patients receive a pain diary. Patients are asked to fill out the VAS score and use of analgesics is recorded on a daily basis during the first month after randomization. Sample size considerations Assuming a 1.5 point difference in pain relief as measured by VAS score and a withdrawal rate of 20% (α=0.05 and β=0.20, 7 measurement points), a total of 180 patients will be enrolled, 90 in each group. Criteria Inclusion Criteria: VCF on X-ray of the spine (minimal 15% loss of height) level of VCF Th5 or lower back pain 6 weeks at time of X-ray 50 years of age bone edema on MRI of the fractured vertebral body focal tenderness on VCF level decreased bone density T-scores -1 Exclusion Criteria: severe cardio-pulmonary condition untreatable coagulopathy systemic or local infection of the spine (osteomyelitis, spondylodiscitis) suspected alternative underlying disease (malignancy) radicular and/or cauda compression syndrome contra-indication for MRI Randomization Arms

3 Experimental: vertebroplasty Using fluoroscopic guidance, the practitioner infiltrates the skin and subcutaneous tissues overlying the pedicle of the target vertebra or vertebrae with 1% lidocaine and infiltrates the periosteum of the pedicles with 0.25% bupivacaine (marcaine). For the vertebroplasty procedure, 11-gauge or 13-gauge needles are passed into the central aspect of the target vertebra or vertebrae. Bone cement is prepared on the bench and injected under constant fluoroscopy into the vertebral body. Injection is stopped when the cement reaches to the posterior aspect of the vertebral body or leaks into an extraosseous space, such as the intervertebral disk or an epidural or paravertebral vein. Sham Comparator: sham procedure Using fluoroscopic guidance, the practitioner infiltrates the skin and subcutaneous tissues overlying the pedicle of the target vertebra or vertebrae with 1% lidocaine and infiltrates the periosteum of the pedicles with 0.25% bupivacaine (marcaine). During the sham intervention, verbal and physical cues, such as pressure on the patient's back, are given, and the bone cement is prepared to simulate the odor associated with mixing of polymethacrylate, but the needle is not placed and cement is not injected. Primary outcome measures: pain relief [ Time Frame: 12 months ] Primary outcome will be pain relief at 1 day, 1 week, and 1,3, 6 and 12 months. The questionnaire consist of the VAS score and questions about use of pain medication, pain location, and pain type. Other medical treatment and visits to alternative medical specialists, GP's and physical therapists are recorded and compared between groups. Patients are asked to fill out the VAS score and use of analgesics is recorded on a daily basis during the first month after randomization. Secondary Outcome Measures back pain related disability [ Time Frame: 0, 1day, 1 week, 1,3,6,12 months ] Back pain related disability as measured with the Roland Morris Disability (RMD) Questionnaire. The Qualeffo is developed specifically for patients with osteoporosis. This questionnaire consists of 41 questions about: pain, physical function, social function, general health perception, and mental function. The RMD questionnaire is a disability questionnaire that measures the functional status of patients with back pain! Quality of Life [ Time Frame: 1 week, 1,3,6,12 months ]! QOL as measured with the Questionnaire of the European Foundation for Osteoporosis (Qualeffo). The Qualeffo is developed specifically for patients with osteoporosis. This questionnaire consists of 41 questions about: pain, physical function, social function, general health perception, and mental function. The Qualeffo score ranges from 0 (best quality of life) to 100 (worst quality of life). This questionnaire will be completed at five measurement moments (before and at 1, 3, 6, and 12 months after the procedure). Final protocol VERTOS IV trial ClinicalTrials.gov Identifier: NCT

4 Purpose The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), is a new minimally invasive technique for pain treatment in which bone cement is injected in the fractured vertebra. Recent RCTs provide conflicting results: two sham-controlled studies show no benefit of PV while an unmasked but controlled RCT found significantly better pain relief after PV at acceptable costs. Study Type: Study Design: Interventional Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Single Blind (Subject) Primary Purpose: Treatment Objectives To evaluate the efficacy of bone cement injection in PV for patients with acute painful osteoporotic compression fractures, as compared with a simulated placebo procedure without injection of bone cement. We hypothesize that patients who had undergone PV would report less pain at 1 day, 1 week and 1, 3, 6 and 12 months (the primary outcomes) than those in the sham control group. Study design VERTOS IV is a multicenter RCT concerning the treatment of patients with a painful osteoporotic VCF. Patients are recruited on the Radiology departments of the participating hospitals and randomized to PV or a simulated procedure. Upon obtaining informed consent an independent central telephone operator completes the randomization procedure, using a computer program. The maximum allowed unbalance (block size) is six, with a maximum sample size of 84 for each participating center. A total of 180 patients will be enrolled, 90 in each group. This is based on the assumption of a 1.5 point difference in pain relief (VAS Score) and a 20% withdrawal rate (α=0.05 and β=0.20, 7 measurement points). The enrolment of patients will take place in four centres in The Netherlands: St. Elisabeth Ziekenhuis in Tilburg, Catharina Ziekenhuis in Eindhoven, Medisch Spectrum Twente in Enschede and Albert Schweitzer Ziekenhuis in Dordrecht. Randomization will start January 2011 with an expected completion of enrolment by January There is a one-year follow-up, with the possibility of an extended follow-up at two years. The overall Institutional Review Board is approval is obtained at the St. Elisabeth Hospital in Tilburg. In addition, each participating center will obtain a local Institutional Review Board Approval. This study is registered at ClinicalTrials.gov., NCT Osteoporosis- and pain medication All patients receive osteoporosis medication, such as bisphosphonates together with supplemental calcium and vitamin D. Pain medication demanded by the patient is recorded. Analgesics are classified following the WHO classification: (1) Paracetamol (acetaminophen), (2) Tramadol, (3) Tramadol and Paracetamol, (4) Morphine. Non Steroid Anti Inflammatory Drugs (NSAID) are only prescribed if patients are intolerant for opiate- derivatives or when already used. Corrections in dose and classification of pain medication are made if necessary. Clinical follow-up An experienced nurse-practitioner requests patients to fill out a standard questionnaire before and at 1 day, 1 week, and 1, 3, 6 and 12 months after the procedure. The questionnaire consist of the VAS score and questions about use of pain medication, pain location, and pain type. The VAS score is a pain score ranging from 0 (no pain) to 10

5 (worst pain ever. Other medical treatment and visits to alternative medical specialists, GP's and physical therapists are recorded and compared between groups. Secondary outcomes are back pain related disability and QOL as measured with the Roland Morris Disability (RMD) Questionnaire and the Questionnaire of the European Foundation for Osteoporosis (Qualeffo), respectively. The Qualeffo is developed specifically for patients with osteoporosis. This questionnaire consists of 41 questions about: pain, physical function, social function, general health perception, and mental function. The Qualeffo score ranges from 0 (best quality of life) to 100 (worst quality of life). This questionnaire will be completed at five measurement moments (before and at 1, 3, 6, and 12 months after the procedure). The RMD questionnaire is a disability questionnaire that measures the functional status of patients with back pain. The RMD will be completed at all measurement points. All patients visit the internist at 1,3,6 and 12 months follow-up. All patients receive a pain diary. Patients are asked to fill out the VAS score and use of analgesics is recorded on a daily basis during the first month after randomization. Sample size considerations Assuming a 1.5 point difference in pain relief as measured by VAS score and a withdrawal rate of 20% (α=0.05 and β=0.20, 7 measurement points), a total of 180 patients will be enrolled, 90 in each group. Criteria Inclusion Criteria: VCF on X-ray of the spine (minimal 15% loss of height) level of VCF Th5 or lower back pain 6 weeks at time of X-ray, extended up to maximum of 9 weeks 50 years of age bone edema on MRI of the fractured vertebral body focal tenderness on VCF level decreased bone density T-scores -1 Exclusion Criteria: severe cardio-pulmonary condition untreatable coagulopathy systemic or local infection of the spine (osteomyelitis, spondylodiscitis) suspected alternative underlying disease (malignancy) radicular and/or cauda compression syndrome contra-indication for MRI Randomization Arms Experimental: vertebroplasty Using fluoroscopic guidance, the practitioner infiltrates the skin and subcutaneous tissues overlying the pedicle of the target vertebra or vertebrae with 1% lidocaine and infiltrates the periosteum of the pedicles with 0.25% bupivacaine (marcaine). For the vertebroplasty

6 procedure, 11-gauge or 13-gauge needles are passed into the central aspect of the target vertebra or vertebrae. Bone cement is prepared on the bench and injected under constant fluoroscopy into the vertebral body. Injection is stopped when the cement reaches to the posterior aspect of the vertebral body or leaks into an extraosseous space, such as the intervertebral disk or an epidural or paravertebral vein. Sham Comparator: sham procedure Using fluoroscopic guidance, the practitioner infiltrates the skin and subcutaneous tissues overlying the pedicle of the target vertebra or vertebrae with 1% lidocaine and infiltrates the periosteum of the pedicles with 0.25% bupivacaine (marcaine). During the sham intervention, verbal and physical cues, such as pressure on the patient's back, are given, and the bone cement is prepared to simulate the odor associated with mixing of polymethacrylate, but the needle is not placed and cement is not injected. Primary outcome measures: pain relief [ Time Frame: 12 months ] Primary outcome will be pain relief at 1 day, 1 week, and 1,3, 6 and 12 months. The questionnaire consist of the VAS score and questions about use of pain medication, pain location, and pain type. Other medical treatment and visits to alternative medical specialists, GP's and physical therapists are recorded and compared between groups. Patients are asked to fill out the VAS score and use of analgesics is recorded on a daily basis during the first month after randomization. Secondary Outcome Measures back pain related disability [ Time Frame: 0, 1day, 1 week, 1,3,6,12 months ]! Back pain related disability as measured with the Roland Morris Disability (RMD) Questionnaire. The Qualeffo is developed specifically for patients with osteoporosis. This questionnaire consists of 41 questions about: pain, physical function, social function, general health perception, and mental function. The RMD questionnaire is a disability questionnaire that measures the functional status of patients with back pain Quality of Life [ Time Frame: 1 week, 1,3,6,12 months ]! QOL as measured with the Questionnaire of the European Foundation for Osteoporosis (Qualeffo). The Qualeffo is developed specifically for patients with osteoporosis. This questionnaire consists of 41 questions about: pain, physical function, social function, general health perception, and mental function. The Qualeffo score ranges from 0 (best quality of life) to 100 (worst quality of life). This questionnaire will be completed at five measurement moments (before and at 1, 3, 6, and 12 months after the procedure). Summary of all amendments: One inclusion criteria was modified during the study due to a scarce inclusion: Back pain 6 weeks at time of X-ray was extended up to 9 weeks Original Statistical analysis The data will be analyzed according to the intention-to-treat principle. Standard statistical techniques will be used to describe characteristics of patients in both groups. We will compare baseline characteristics in the two treatment groups and if incomparability appears, we will in secondary analysis adjust for differences. The primary outcome, significant pain relief will be compared with the analysis of variance for repeated measures. If adjustment for possible baseline incomparability is needed, analysis of covariance will be done. Since we

7 expect the difference between the two groups will particularly become evident at 3, 6 and 12 months, the analysis will also be performed at these time points. Final Statistical analysis Analyses were performed using IBM SPSS statistics 23 and the R programming software (R development Core Team, 2008)16. P-values< 0.05 were considered to indicate statistical significance. G-Power was used to calculate the sample size. Based on Klazen et al.7, assuming a 2 point VAS difference, a pooled standard deviation of 4.23 and 20% withdrawal (α= 0.05 and β= 0.20 at 7 time points), 90 patients needed to be included in each group. Analysis was by intention to treat, meaning that we have analysed our patients based on their initial treatment assignment. Proportions of adverse events, drugs, and baseline fractures were compared using 2 tests. In Table 1 (baseline characteristics), for continuous and normally distributed variables, means and standard deviation were computed whereas for non-normally distributed variables the median and interquartile range were reported. Our primary endpoint (difference between groups in mean reduction of VAS during 12 months follow-up) and secondary endpoints (difference between groups in mean reduction of QUALEFFO & RMDQ during 12 months follow-up) were analysed using a mixed modelling approach. The statistical interaction between treatment and time was used to evaluate the primary and secondary endpoints. Tests for differences between the groups at specific time points were derived directly from the mixed model by making use of the custom hypothesis test command in the SPSS syntax. A mixed model analysis makes use of all available data for each participant, thereby accounting for data missing at random. Model estimates were adjusted based on the covariates age, gender, vertebral level, pain treatment, osteonecrosis, new fractures after baseline and progressive vertebral height loss. A first-order autoregressive covariance structure was used to model the repeated measurements. The extent to which patients reached significant pain relief over time was analysed with Cox regression analysis. Differences between the survival curves of the two groups were assessed using the log-rank test. Following the analysis of our primary objective, exploratory post-hoc analyses were done to determine whether progressive vertebral height loss interacted with treatment in predicting the pain intensity during one-year follow-up. Chi-square tests were used to assess the difference between groups in the occurrence of new fractures and to examine the difference in proportion of patients in each group with a VAS score of 5 or higher at 12 months follow-up. Generalized mixed modelling was used to investigate differences between groups in the use of pain medication during 12 month follow-up. Summary of all amendments: No intention-to-treat principle was applicable as there were no cross- over cases. One inclusion criteria was modified during the study due to a scarce inclusion: Back pain 6 weeks at time of X-ray was extended up to 9 weeks. Following the analysis of our primary objective, exploratory post-hoc analyses were done to determine whether progressive vertebral height loss interacted with treatment in predicting the pain intensity during one-year follow-up. Chi-square tests were used to assess the difference between groups in the occurrence of new fractures and to examine the difference in proportion of patients in each group with a VAS score of 5 or higher at 12 months

8 follow-up. Generalized mixed modelling was used to investigate differences between groups in the use of pain medication during 12 month follow-up.