Treating Idiopathic Inflammatory Myopathies Related Reduced Bone Mineral Density With Denosumab or Zoledronic Acid
Treating Idiopathic Inflammatory Myopathies Related Reduced Bone Mineral Density With Denosumab or Zoledronic Acid
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.
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.
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