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Prolia, risk of hypocalcemia, osteonecrosis of the jaw


Prolia ( Denosumab ) is designed to inhibit RANKL ( RANK ligand ), a protein that acts as the primary signal for bone removal.
Activation of RANK by RANKL promotes the maturation of pre-osteoclasts into osteoclasts. Denosumab inhibits this maturation of osteoclasts by binding to and inhibiting RANKL. This mimics the natural action of osteoprotegerin, an endogenous RANKL inhibitor.

Prolia may affect the immune system. People who have weakened immune system or take medicines that affect the immune system may have an increased risk for developing serious infections.

The most common side effects of Prolia in women are: back pain, pain in arms and legs, high cholesterol, muscle pain, bladder infection.

Hypocalcemia

Denosumab decreases bone resorption. Bone resorption plays an important role in calcium homeostasis. It is physiologically plausible that Denosumab administration and associated suppressed bone remodeling may lead to with a higher incidence of hypocalcemia.
Hypocalcaemia was evaluated in several clinical trials.
Hypocalcaemia is a known class effect of antiresorptive drugs. Denosumab induced hypocalcemia appears to be transient ( in first month after dosing, nadir at day 8-11 ) with spontaneous resolution without any serious sequelae observed in this study. In this clinical trial, hypocalcemia was an exclusion criterion and subjects were given 1 gm calcium as a concomitant medication.

Osteonecrosis of the jaw

Osteonecrosis, or avascular necrosis of the jaw ( ONJ ) is a pathological process associated with pain, swelling, exposed bone, local infection, and pathologic fracture of the jaw. Postmarketing experience with bisphosphonates has raised concerns about the potential for bone remodeling inhibition and osteonecrosis of the jaw.
Risk factors for bisphosphonate associated ONJ include long-term use ( greater than 3 years ), patients with malignancy, poor oral hygiene, dental procedures, concomitant therapies ( radiation, chemotherapy, corticosteroids ), and IV use of bisphosphonates ( Ruggiero et al, Annu.Rev Med 2008 ) The mechanism by which osteonecrosis develops in relationship to treatment with bisphosphonates is not well understood.
ONJ presents as exposed necrotic bone typically involving the maxilla or mandible and an infection. It is especially common in patients with malignancies being treated with intravenous bisphosphonates. It is not known whether ONJ is the primary process that becomes secondarily infected, if ONJ represents primary osteomyelitis, exacerbated by the use of bisphosphonates, or if it is the consequence of a combination of events, including the use of bisphosphonates, poor dental hygiene, and/or a dental procedure or condition. It is also uncertain if the presence of actinomyces, noted commonly in ONJ lesions, is actively contributing to the development or progression of ONJ, or is simply related to the presence of necrotic bone in an anaerobic environment.
The true incidence and risk of ONJ related to treatment with denosumab is unknown; however, based on its antiresorptive effects, there is a recognized risk that patients treated with Denosumab have the potential to develop ONJ.

Source: FDA, 2009

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