Denosumab In Addition To Intense Urate-Lowering Therapy for Bone Erosions

The University of Alabama at Birmingham

Status and phase

Completed

Phase 2

Conditions

Gout

Treatments

Drug: Denosumab

Study type

Interventional

Funder types

Other

Identifiers

NCT02903446

F160315004

Details and patient eligibility

About

Bone erosions are a common manifestation and feature of structural damage in severe/chronic tophaceous gout. Management of this destructive and often debilitating gout complication has focused exclusively on urate-lowering therapy (ULT) to reduce frequency of gout attacks, but little attention has been given to prevention or reversal of gout related bone erosions and other structural damage to bone caused by gout. Since there is no known effective treatment to attenuate or improve structural damage caused by gout, we propose a pilot, controlled, proof-of-concept study in which denosumab, an FDA approved medication for the treatment of bone loss, will be added to standard ULT in 20 patients with erosive gout.

Full description

A recently published clinical trial with zoledronic acid failed to show an effect in improving bone erosions among individuals with chronic tophaceous gout, despite improvements in bone mineral density (BMD) and bone turnover markers. However, it is known that increased numbers of osteoclasts (cells that absorb bone tissue during growth and healing) in patients with tophaceous gout are most likely a result of enhanced osteoclast activity as these patients also have higher circulating levels of the protein receptor activator of nuclear factor kappa-B ligand (RANKL). RANKL has been identified to affect the immune system and control bone regeneration and remodeling.

Furthermore, peripheral blood cells and synovial fluid cells taken from patients with erosive gout preferentially formed osteoclast-like cells in the presence of RANKL. The number of osteoclasts formed significantly correlates with the number of tophi in gout patients.

Denosumab (Prolia®) is a fully human monoclonal antibody with a high affinity for RANKL that can bind and neutralize the activity of human RANKL. Given the relevance of RANKL in the mechanism of gouty erosions,a central hypothesis of this pilot study is that denosumab is more likely to precisely target RANKL and the mechanism of gouty erosions than zoledronic acid.

Enrollment

20 patients

Sex

All

Ages

30+ years old

Volunteers

No Healthy Volunteers

Inclusion criteria

Age 30 years or older and able to provide informed consent
Diagnosis of gout according to the American College of Rheumatology (ACR) / European League Against Rheumatism (EULAR) classification criteria
Radiographic foot bone erosion attributable to gout and confirmed by a radiologist
Serum urate of ≤ 5 mg/dL (300 µmol/L) or less*

Exclusion criteria

Treatment with bisphosphonates in the preceding 2 years
Any prior treatment with denosumab
Women of childbearing potential, who are not currently using birth control, are pregnant, planning to become pregnant, or are breast-feeding
Men planning to conceive in the next 12 months
Unstable systemic medical condition
Uncontrolled hyperthyroidism
Uncontrolled hypothyroidism
History of Addison disease
History of osteomalacia
History of osteonecrosis of the jaw (ONJ)
History of atypical femur fracture
History of tooth extraction, jaw surgery, dental implants, or other dental surgery within the prior 6 months
History of anorexia nervosa, bulimia (by history or physical) or obvious malnutrition.
Invasive dental work planned in the next 2 years
History of Paget's disease of bone
Other bone diseases which affect bone metabolism
Vitamin D deficiency [25(OH) vitamin D level < 20 ng/mL (<49.9 nmol/L)]†
Hypercalcemia
Elevated transaminases ≥ 2.0 x upper limit of normal (ULN)
Elevated total bilirubin > 1.5x ULN
History of any solid organ or bone marrow transplant
Malignancy within the last 5 years (except cervical carcinoma in situ or basal cell carcinoma)
Hypocalcemia
Poorly tolerant of ULT including allopurinol, febuxostat, or probenecid
Estimated glomerular filtration rate < 30 mL/minute/1.73 m^2
Current use of any biological therapy (eg. infliximab, etanercept, adalimumab, etc.)
Treatment history with pegloticase or another recombinant uricase
Recipient of an investigational drug within 4 weeks prior to study drug administration or plans to take an investigational agent during the study