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

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.

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