Clinical trial NCT04034199: Treating Idiopathic Inflammatory Myopathies Related Reduced Bone Mineral Density With Denosumab or Zoledronic Acid
Official title: Efficacy of Denosumab and Zoledronic Acid in the Treatment of Idiopathic Inflammatory Myopathies Related Reduced Bone Mineral Density: a Prospective Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Idiopathic Inflammatory Myopathies
Osteoporosis, Osteopenia
Keywords: denosumab
zoledronic acid
Lead sponsor: Kwong Wah Hospital
Sponsor class: OTHER
Collaborators: name: Tung Wah Group of Hospitals
First posted: 2019-07-26
Enrollment: 40
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a prospective open-label controlled trial. All patients will continue calcium (1000mg daily) and vitamin D supplementation (at least 800 international unit daily). Patients with osteopenia or osteoporosis in a baseline DEXA scan will be randomized by computer-generated blocks in 1:1 ratio into receiving denosumab (treatment group) or zoledronic acid (controlled group). Denosumab is given at 60mg subcutaneously every 6 months, following the FDA approved dosage. Zoledronic acid is administered intravenously at 5mg yearly. DEXA scan will be repeated after 12 months of treatment.
Primary purpose: TREATMENT

Brief summary: Idiopathic inflammatory myopathies (IIM) patients are at high risk of development of reduced bone mineral density due to impairment of functional status due to the disease and a relatively high dose of glucocorticoid use for the treatment. Reduced bone mineral density is prevalent in local IIMs patients. Denosumab and zoledronic acid are established treatments for osteoporosis in postmenopausal women and glucocorticoid-induced osteoporosis. However, the role of these treatments in reduced bone mineral density including osteoporosis and osteopenia related to IIMs are lacking. There is also no evidence on comparing the efficacy of the two agents. Therefore, the investigators conducted this prospective randomized controlled study to compare the efficacies of denosumab and zoledronic acid in treating reduced bone mineral density in IIMs patients. The hypothesis in this study is that treatment by denosumab or zoledronic acid would improve bone mineral density in IIMs patients with reduced bone mineral density.

Detailed description: Background:

With recent advances in diagnoses and classification of idiopathic inflammatory myopathies (IIM), an increasing number of newly diagnosed cases of IIM is expected. These patients are vulnerable to the development of Glucocorticoid-induced osteoporosis (GIOP) due to impaired mobility related to musculoskeletal involvement and the relatively high doses of glucocorticoid (GC) required for disease control. Reduced bone mineral density is prevalent among IIM patients shown in the previous local study: osteoporosis and osteopenia are seen in 23.7% and 47.4% of IIM patients respectively. 10% of patients on long term GC treatment sustain a fracture and up to 30-40% of patients are found to have radiological vertebral fractures. Compared to GIOP, the treatment for patients with osteopenia is less well addressed in current guidelines for the management of GIOP. Treatment is usually indicated in patients with a previous history of prior low energy fracture and high fracture risks determined by FRAX score. However, IIMs remain a rare disease entity and IIMs patients are at particularly high risk for osteoporosis and its complications due to a relatively high dose of steroid use and functional impairment from the disease. Therefore, traditional fracture risks assessment tool might not be able to fully assess the fracture risks in this subgroup of patients.

Denosumab is a human monoclonal antibody against receptor activator of nuclear factor kappa-B ligand (RANKL) and its use is associated with a reduced risk of vertebral, non-vertebral and hip fracture in post-menopausal women. A recent randomized controlled trial has shown that denosumab is more efficacious than risedronate in the improvement of BMD in GIOP patients. Denosumab has been confirmed efficacious in GIOP patients but its efficacy in high-risk osteopenia patients are not well studied. On the other hand, zoledronic acid is licensed for the treatment of GIOP and trials found zoledronic acid improve bone mineral density at the lumbar spine or femoral neck at 12 months of treatment. Current evidence comparing the efficacy between denosumab and zoledronic acid is lacking.

In this prospective study, the investigators aimed to assess the efficacy of denosumab and zoledronic acid in the treatment of IIMs patients with reduced bone mineral density.

Study methods This is a prospective open-label controlled trial. All IIMs patients followed up in Kwong Wah Hospital are invited to participate in this study. Eligibility, inclusion, and exclusion criteria are described in details in subsequent sessions. All included patients will have dual-energy X-Ray absorptiometry (DEXA) scan performed at baseline. All participants will continue calcium (1000mg daily) and vitamin D supplementation (at least 800 international unit daily). Patients with osteopenia or osteoporosis in a baseline DEXA scan will be randomized by computer-generated blocks in 1:1 ratio into receiving denosumab (treatment group) or zoledronic acid (controlled group). Denosumab is given at 60mg subcutaneously every 6 months, following the FDA approved dosage. Zoledronic acid is administered intravenously at 5mg yearly. DEXA scan will be repeated after 12 months of treatment.

All participants will be interviewed and examined at the time of recruitment and at subsequent follow-up visits. Patients enrolled in the study will attend follow-up visits at least every 4 months with monitoring of adverse events associated with denosumab or zoledronic acid use. In case of severe adverse events, treatment will be terminated, and patients will be withdrawn from this study.

Demographic data including age, sex, ethnicity, body weight and height, menopausal status, parity, smoking and drinking history, and comorbidities will be recorded. Diagnosis and classification of IIM according to Bohan and Peter criteria (14) and duration of the disease will also be documented. Details of treatment regime including dosage of GCs at time of recruitment, cumulative GCs dosage, concomitant immunosuppressants, and medication history will be recorded. Personal history of previous vertebral or osteoporotic fracture and avascular necrosis will be screened. Complications related to IIMs which included interstitial lung disease, dysphagia and malignancy and Health assessment questionnaire disability index (HAQ-DI) at baseline will be documented. Blood results including serum albumin level, C reactive protein (CRP), erythrocyte sedimentation rate (ESR) and creatine kinase (CPK) will be measured at baseline and upon follow-up visits.

BMD results are recorded in terms of absolute value, T-score (Number of standard deviations above or below mean results of young adults) and Z-score (Number of standard deviations above or below mean results of the age-matched population). Radiographs of the thoracic and lumbar spine will be performed at enrolment and at the completion of the study to look for vertebral collapses. Vertebral collapse is defined as a loss of at least 25% height of vertebrae. Fractures and new vertebral collapse during the study period will be documented.

IIMs disease activity at baseline is measured by physician's and patient's global assessment by visual analog scale, manual muscle testing 8 (MMT8) and Myositis Disease Activity Assessment Visual Analogue Scale (MYOACT).

BMD at the lumbar spine (L1-4), hip and femoral neck are measured by DEXA scan using Hologic Discovery DXA system (Model: Discovery W, Hologic, Bedford, USA) The reference ranges for T-score for Male and Female are derived from a database from the University of Hong Kong, using matched Hong Kong Male and female data. The technicians responsible for reading DEXA images are blinded for the details of the study.

Patients are invited to join this study from August June 2019 to December 2019. Baseline DEXA scan and randomization will be performed within 1 month of study enrolment. Participants would receive 12 months of treatment and DEXA scan will be repeated within 1 month upon completion of treatment. The study and subsequent analyses will be completed by March 2021.

For the estimation in sample size, the mean baseline BMD in GIOP patients from local data is 0.87 g/cm2 with a standard deviation of 0.085 g/cm2. The expected increase in BMD after 12 months of denosumab treatment is 8% compared to placebo whereas zoledronic acid is associated with a 6-7% increase in BMD when compared to placebo. Sample size calculated is 23 patients in each group assuming 5% type I error and 80% power.

For statistical analysis, descriptive statistics for demographic and clinical data are expressed as mean +/- standard deviation if they are normally distributed or as median and range otherwise. Independent Student's t-test is used for analyzing continuous variables with normal distribution and Chi-square test for categorical variables. Differences in BMD between the two groups is compared with paired t-test. After adjustment of confounding factor, analysis of covariance method (general linear model) will be done. Covariates adjusted include age, sex, BMI, smoking and drinking status, duration of menopause in female patients, duration of GC and cumulative dosage of GC. For assessing risk factors associated with reduced BMD, associations between the continuous variables and BMD is assessed by Pearson's correlation test. Univariate analysis followed by multiple linear regression model is used to identify the independent variables for BMD. A P-value of \< 0.05 is considered as statistically significant. SPSS 25 will be used for statistical analysis.

This study is approved by the local ethical committee - Research Ethics Application (Kowloon Central/Kowloon East) and is conducted in full accordance with the Helsinki Declaration. Written consent is obtained from all participants. Serious adverse events will be reported to the research and ethics committee.

This is an investigator-initiated study not supported by any pharmaceutical company. The authors have no conflicts of interest to declare.

Outcome measures will be described in subsequent sessions.

Eligibility criteria: All idiopathic inflammatory myopathies (IIMs) patients under follow-up in Kwong Wah Hospital are invited to participate in this study.

IIMs are diagnosed by rheumatologist according to Bohan and Peter Criteria. Eligible patients will have dual-energy X-ray absorptiometry (DEXA) scan performed at baseline.

Inclusion Criteria:

1. Adult patients of at least 18 years of age and
2. Evidence of reduced BMD in osteopenia (defined by T-score of -0.1 to -2.5) or osteoporosis range (defined by T-score of \< -2.5) at baseline by dual-energy X-ray absorptiometry (DEXA) scan.

Exclusion Criteria:

1. Pregnant patients
2. Patients with juvenile onset of disease (\<18 years of age)
3. Patients with pre-existing metabolic bone conditions
4. Patients who are already on osteoporotic treatment other than calcium and vitamin D (including bisphosphonates, denosumab, teriparatide, raloxifene or strontium)
5. Patients who are contraindicated to denosumab or zoledronic acid including severe renal impairment and hypersensitivity
6. Patients who are not able to give informed consent

Primary outcomes:
measure: Change in bone mineral density at 12 months in denosumab and zoledronic acid group
timeFrame: 12 months
Secondary outcomes:
measure: Prevalence of osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Comparison of Change in Bone Mineral Density at lumbar spine and hip between the two treatment groups (denosumab and zoledronic acid)
timeFrame: 12 months
measure: Gender as a risk factor for osteoporosis and osteopenia in IIMs patients
timeFrame: at baseline
measure: Smoking status as a risk factor for osteoporosis and osteopenia in IIMs patients
timeFrame: at baseline
measure: Drinking status as a risk factor for osteoporosis and osteopenia in IIMs patients
timeFrame: at baseline
measure: Menopausal status as a risk factor for osteoporosis and osteopenia in IIMs patients
timeFrame: at baseline
measure: BMI as Risk factor for osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Age as Risk factor for osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: IIMs disease duration as Risk factor for osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Different subtypes of IIMs and risks for osteoporosis and osteopenia
timeFrame: at baseline
measure: Effect of medications on osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Serum albumin level as risk factor in osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Serum C reactive protein level as risk factor for osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Erythrocyte sedimentation rate as risk factor for osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Serum creatine kinase as risk factor for osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Disability as risk factor for osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Effect of IIMS disease activity on osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: Effect of IIMs disease activity on osteoporosis and osteopenia in idiopathic inflammatory myopathies patients
timeFrame: at baseline
measure: New fractures during study period
timeFrame: during study period (12 months)
measure: Adverse events associated with denosumab and zoledronic acid
timeFrame: throughout study period (12 months)
Other outcomes:
Locations:
city: Hong Kong
country: Hong Kong
facility: Kwong Wah Hospital
Study officials:
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