Interventions to prevent and treat corticosteroid-induced osteoporosis and prevent osteoporotic fractures in Duchenne muscular dystrophy

Bell, Jennifer M.; Shields, Michael; Watters, Janet; Hamilton, Ashley; Beringer, T. R. O.; Elliott, Mark T.; Quinlivan, R.; Tirupathi, Sandya; Blackwood, Bronagh

doi:10.1002/14651858.cd010899.pub2

Cited by 46 publications

(44 citation statements)

References 232 publications

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“…5). Bone morbidity due to chronic treatment of glucocorticoids are among the chief safety concerns of families and physicians [33,34], and prednisone causes both acute and chronic changes of bone turnover markers at doses of 0.2 mg/kg/day [5,6]. The lack of any changes in bone turnover markers in vamorolone-treated volunteers through 20 mg/kg/day is particularly promising regarding potential improved safety of this dissociative steroid.…”

Section: Discussionmentioning

confidence: 99%

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

Hoffman

Riddle²,

Siegler

et al. 2018

Steroids

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Background Glucocorticoid drugs are highly effective anti-inflammatory agents, but chronic use is associated with extensive pharmacodynamic safety concerns that have a considerable negative impact on patient quality of life. Purpose Vamorolone (VBP15) is a first-in-class steroidal multi-functional drug that shows potent inhibition of pro-inflammatory NFkB pathways via high-affinity binding to the glucocorticoid receptor, high affinity antagonism for the mineralocorticoid receptor, and membrane stabilization properties. Pre-clinical data in multiple mouse models of inflammation showed retention of anti-inflammatory efficacy, but loss of most or all side effects. Experimental approach We report first-in-human Phase 1 clinical trials (86 healthy adult males), with single ascending doses (0.1–20.0 mg/kg), and multiple ascending doses (1.0–20 mg/kg/day; 14 days treatment). Key results Vamorolone was well-tolerated at all dose levels. Vamorolone showed pharmacokinetic and metabolism profiles similar to prednisone. Biomarker studies showed loss of side effects of traditional glucocorticoid drugs (bone fragility, metabolic disturbance, immune suppression). Suppression of the adrenal axis was 10-fold less than prednisone. The crystallographic structure of vamorolone was solved, and compared to prednisone and dexamethasone. There was overlap in structure, but differences in conformation at the C-ring where glucocorticoids interact with Asn564 of the glucocorticoid receptor. The predicted loss of Asn564 binding to vamorolone may underlie the loss of gene transcriptional activity. Conclusions and interpretations Vamorolone is a dissociative steroid that retains high affinity binding and nuclear translocation of both glucocorticoid (agonist) and mineralocorticoid (antagonist) receptors, but does not show pharmacodynamic safety concerns of existing glucocorticoid drugs at up to 20 mg/kg/day.

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Section: Discussionmentioning

confidence: 99%

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

Hoffman

Riddle²,

Siegler

et al. 2018

Steroids

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“…Further small case-control studies, with limited follow-up, of bisphosphonate use in inflammatory conditions, while heterogeneous, all support the positive effect of treatment. 40 Although limited in number and design, studies have shown maintenance/improvement in BMD, 41,42 increased survival, 43 improved vertebral body shape and reduced pain. 40 Although limited in number and design, studies have shown maintenance/improvement in BMD, 41,42 increased survival, 43 improved vertebral body shape and reduced pain.…”

Section: Other Forms Of Secondary Osteoporosismentioning

confidence: 99%

“…[36][37][38][39] All published studies on Duchenne muscular dystrophy are observational in nature, with a recent Cochrane review concluding that there was no high-quality RCT evidence to guide management. 40 Although limited in number and design, studies have shown maintenance/improvement in BMD, 41,42 increased survival, 43 improved vertebral body shape and reduced pain. 44 However, there is some evidence that bone quality may be affected, with a reduction in the trabecular number on bone biopsy.…”

Section: Other Forms Of Secondary Osteoporosismentioning

confidence: 99%

Consensus guidelines on the use of bisphosphonate therapy in children and adolescents

Simm

Biggin

Zacharin

et al. 2018

J Paediatrics Child Health

118

116

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Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence-based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.

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“…Limited published data exist on the use of BPs for GIO in children. GIO is prevalent in children with Duchene muscular dystrophy treated with long term GCs and many studies have reported positive outcome (28,29). It is important to note that there is potential for recovery of bone density with reduced fracture risk to expected for age in children once GCs are discontinued (30,31).…”

Section: Steroids-induced Osteoporosismentioning

confidence: 99%

Zoledronic acid in pediatric metabolic bone disorders

Bowden¹,

Mahan²

2017

Transl. Pediatr

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Zoledronic acid (ZA), a highly potent intravenous bisphosphonate (BP), has been increasingly used in children with primary and secondary osteoporosis due to its convenience of shorter infusion time and less frequent dosing compared to pamidronate. Many studies have also demonstrated beneficial effects of ZA in other conditions such as hypercalcemia of malignancy, fibrous dysplasia (FD), chemotherapy-related osteonecrosis (ON) and metastatic bone disease. This review summarizes pharmacologic properties, mechanism of action, dosing regimen, and therapeutic outcomes of ZA in a variety of metabolic bone disorders in children. Several potential novel uses of ZA are also discussed. Safety concerns and adverse effects are also highlighted.

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Interventions to prevent and treat corticosteroid-induced osteoporosis and prevent osteoporotic fractures in Duchenne muscular dystrophy

Cited by 46 publications

References 232 publications

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

Phase 1 trial of vamorolone, a first-in-class steroid, shows improvements in side effects via biomarkers bridged to clinical outcomes

Consensus guidelines on the use of bisphosphonate therapy in children and adolescents

Zoledronic acid in pediatric metabolic bone disorders

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