A fully humanized Ig G2 monoclonal antibody that binds specifically to the receptor acitvator of the nuclear factor kB ligand, a key mediator of osteoclast formation, function and survival (Lacey).

It inhibits the receptor activator of RANKL.

This monoclonal antibody binds to RANK, ligand, preventing  RANK login interacting with RANK receptors.

It  binds to RANKL, and prevents it from binding onto the receptor activator of nuclear factor  kB, on osteoclast, precursors and mature osteoclasts.

It inhibits the formation, differentiation, activation, and function of osteoclasts greatly reducing bone resorption.

An anti-reorptive agent approved for the management of metastatic bone disease in patients with solid tumors and is also indicated for the prevention of bone loss and/or fragility fractures associated with cancer therapyies.

Denosumab is a monoclonal antibody that binds avidly to RANKL, preventing its interaction with its receptor RANK17 and causing rapid suppression of bone resorption. 

It inhibits the maturation of osteoclast precursors and subsequent promotion of apoptosis of mature osteoclasts.
Its use results in the accumulation of osteoclast precursors, and a decline in mature osteoclast number and activity.

Mimics the activity of a naturally occurring protein, osteoprotegerin.

Inhibits binding of the receptor activator of nuclear factor kappa-B LIGAND (RANKL} to RANK receptors located on the surface of osteoclasts and their precursors: preventing formation, function, and survival of osteoclasts, which then reduces bone resorption, allowing for growth in cortical and trabecular bone.

It is not incorporated into the bone matrix, and its effects wear off quickly post discontinuation, leading to rapid maturation of the readily available, preformed, pre-osteoclasts, and a high bone remodeling state-rebound phenomenon.

Discontinuation of the drug is associated with significant bone structure compromise with decreased cortical bone thickness, decreased trabecular bone volume, increased unmineralized, bone, and high levels of bone turnover markers and manifests with multiple vertebral fractures.

Trade name Prolia.

Binds and inactivates RANKL.

Unlike bisphosphonates, it is not incorporated into sites of bone remodeling, explaining its reversible mechanism of action.

RANKL inhibition may also exert antitumour effects.

Prevents osteoclast activation by preventing interaction of osteoclast precursors with RANK ligand.

Reduce high risk of vertebral and nonvertebral fractures, including hip fractures.

Hypocalcemia and vitamin D deficiency must be corrected prior to initiation of therapy.

Associated with increased bone mineral density in women receiving aromatase inhibitor therapy for breast cancer (Ellis).

Administered subcutaneously.

Pregnancy must be ruled out prior to administration of Prolia

Prolia should be administered by a healthcare professional.

Administer 60 mg every 6 months as a subcutaneous injection in the

upper arm, upper thigh, or abdomen.

Instruct patients to take calcium 1000 mg daily and at least 400 IU

vitamin D daily.

Associated with increased bone mineral density in postmenopausal women with low bone mass, and decreased levels of bone turnover markers (Miller PD).

Indicated for the treatment of postmenopausal women with osteoporosis at high risk for fracture, with a history of osteoporotic fracture, or multiple risk factors for fracture, or for patients who have failed or are intolerant to other osteoporosis treatments.

In post-menopausal women with osteoporosis its use reduces the incidence of vertebral, non-vertebral and hip fractures.

Denosumab produces a very rapid fall in resorption bone turnover markers.

Unlike bisphosphonates treatment results in bone mineral density gains that rapidly wane after discontinuation of treatment.

Higher rates of fractures are reported when the drug is discontinued, so the treatment should be continued indefinitely or transitioned to alternative anti-resorptive medications upon discontinuation.

The preferred parenteral formulation of bisphosphonates for patients with chronic kidney disease.

It is  not cleared by the kidney and has no renal toxicity, making it useful in patients with impaired renal function.

Indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors, but is not indicated for the prevention of skeletal-related events in patients with multiple myeloma.

Contraindicated in patients with hypocalcemia.

Effective in reducing skeletal related events in multiple myeloma.

In patients with predisposition to hypocalcemia and in patients with disturbed mineral metabolism monitoring of calcium and mineral levels is highly recommended.

Patients with a creatinine clearance less than 30mL/min or receiving dialysis are at greater risk for severe hypocalcemia compared to patients with normal renal function.

In patients with hypocalcemia supplements with calcium and vitamin D are indicated.

Female patients on dialysis have a higher incidence of severe hypocalcemia.

Serious infections are more frequent in patients than in placebo patients.

Dermatitis, eczema and rashes occur at a significantly higher rate than in placebo treated patients.

Osteonecrosis of the jaw has been reported, and oral examinations should be performed prior to initiation of this drug with appropriate preventive dentistry.

2.2% of patients develop jaw osteonecrosis and 79% had tooth extraction, poor oral hygeine, or use of a dental appliance.

With increases in survival trends, patients with metastatic cancer have more time to experience a skeletal-related event.

Has superior prevention of skeletal related events vs zoledronic acid in patients with breast cancer metastatic to bone: Denosumab was shown to significantly delay time to first skeletal related eventhh by 18% as compared to zoledronic acid..

Among patients with advanced cancers, it has been documented to prevent skeletal associated events, hypercalcemia, pathologic fracture, spinal cord compression, and radiation or surgery for the treatment of bone metastasis.

Reduced calcium levels and 70% of patients with cancer associated hypercalcemia.

Pre-existing hypocalcemia must be corrected prior to initiating therapy.

Can cause severe symptomatic hypocalcemia, and fatal cases have been reported.

Calcium levels should be monitored and calcium, magnesium, and vitamin D should be administered as necessary.

Patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function.

Anaphylaxis has been reported with use.

Osteonecrosis of the jaw (ONJ) can occur, manifesting as jaw pain, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion.

Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestation of ONJ.

Preventive dentistry is required prior to initiation of therapy and oral examinations should be periodically reevaluated.

Dental procedures should be avoided during treatment.

Atypical femoral fracture has been reported with denosumab and can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution.

Atypical femoral fractures commonly occur with minimal or no trauma at the affected area.

Atypical femoral fractures may be bilateral.

Atypical femoral fractures frequently associated with prodromal pain in the affected area, weeks to months before a complete fracture occurs.

Patients receiving treatment with glucocorticoids are at higher risk of atypical femoral fractures.

Patients on denosumab with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture.

Can cause fetal harm when administered to a pregnant woman.

Adverse reactions include: fatigue, asthenia, hypophosphatemia, nausea, and dyspnea.

The most common adverse reactions resulting in discontinuation of therapy are osteonecrosis and hypocalcemia.

Osteonecrosis of the jaw occurs in about 2% of patients compared to 1.4% of patients treated with zoledronic acid.

Osteonecrosis of the jaw may be recognized as early as six months after initiation of therapy.

The cumulative incidence of osteoporosis of the jaw was 0.8% at one year, 1.9% at two years and 2% at three years for denosumb, and 0.5% at one year 1.2% at two years and 1.4% at three years (Stopeck A et al).

Adverse reactions are more common than placebo and include back pain, extremity pain, musculoskeletal pain, hypercholesterolemia, and cystitis.

Most frequent adverse reactions are fatigue, asthenia, hypophosphotemia and nausea.

Dyspnea most common serious adverse reaction.

Most common adverse reactions resulting in discontinuation of the drug are osteonecrosis and hypocalcemia.

Can suppress bone turnover in patients refractory to zoledronic acid.

In a phase three study in men receiving androgen-deprivation therapy for prostate cancer Denosumab increased bone mineral density at all sites and was associated with a reduction in incidence of new vertebral fractures in patients with nonmetastatic disease (Smith MR et al).

Treatment with bone-protecting agents (BPAs) zoledronic acid or denosumab entirely eliminated the risk of fracture as seen in a study of men with metastatic castration-resistant prostate cancer (CRPC) treated with enzalutamide alone or in combination with radium-223.

In this study of 1432 patients with non-metastatic castration resistant prostate cancer treated with denosumab vs placebo a delay of 4.2 months in time to detection of metastases with the inhibition of RANLK but no effect on survival ().

In the above study survival was not increased in the denosumab group compared to placebo, but the rate of osteonecrosis of the jaw (5%), and hypocalcemia (2%) were.

In phase three study of patients treated with androgen deprivation therapy there was a significant decrease in vertebral fractures compared to placebo at 12, 24 and 36 months (Smith MR).

In a randomized study of denosumab vs zoledronic acid in breast cancer patients (2,046) and bone metastases: deonosumab superior to zoledronic acid in delaying time to first skeletal related event and to successive events, and to the delay in time to the first radiation , and time to to first hypercalcemic event (Stopeck A et al).

In the above phase 3 double-blind study denosumab significantly delayed the time to first SRE by 18% compared to the zoledronic acid, with a median time to first SRE 26.4 months for the zoledronic group and this was not yet reached for the denosumab group.

In the above study denosumab reduce the risk of first and subsequent SREs by 23%.

Serum type I C-telopeptide(CTx) is a bone resorption marker, denosumab activity.

Denosumb associated with greater reductions in bone turnover markers thn observed with zoledronic acid: the median reduction in urinary N-telopeptide was 80% versus 68%, respectively.

Three days following a single injection of denosumab CTx levels are reduced by more than 80%, with maximum reduction in 1 month.

In metastatic CRPC (castrate resistant prostate cancer) 2.3% denosumab treated patients develpoed osteonecrosis of the jaw vs. 1.3% with zoledronic acid arm, hypocalcemia 13% with denosumab vs. 6% with zoledronic acid.

Acute phase reactions such as flulike syndrome within the first three days of treatment occurred in 10.4% of denosumab patients and 27.3% of zoledronic acid patients (Stpck A et al).

Adverse renal toxicity occurred in 4.9% of denosumab patients versus 8.5% of the zoledronic acid patients in the above study.

In a phase III study of denosumab versus zoledronic acid in patients with bone metastases from advanced solid tumors were multiple myeloma showed that denosumab was not an inferior in reducing the risk for first SRE (Henry D et al).

In the above study denosumab was associated with a significant delay in time to pain worsening among all patients.

Every three month treatment may be as good as every month treatment in suppressing bone turnover (Lipton A et al).

Dose reductions not required for renal or hepatic impairment.

FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis Every six Months) trial: 60 mg subcutaneous vs. placebo every six months for 36 months with 1000 mg of calcium and vitamin D supplementation with osteoporosis in 7868 women-the risk reduction for vertebral fractures for that denosumab group similar to IV zoledronic acid, and greater than oral bisphosphonates.

In the above study the denosumab group there was 2.3% new fractures compared to 7.2% for placebo.

Clearance of the drug occurs through reticuloendothelial system with subsequent renal filtration and excretion.

In a study with early-stage breast cancer it did not improve disease related outcomes for women with high-risk early breast cancer-D-CARE phase 3 trial (Coleman R)

In the above study 5% of the patients had osteoporosis of the jaw.

The drug is not incorporated into bone and accumulation is not a factor.

Withdrawal of denosumab may cause increased osteoclastic activity and hypercalcemia.

Withdrawl of denosumab may cause a rebound phenomenon and increase osteoporosis and cause multiple vertebral fractures.

Its use is recommended for long-term, or transition to another anti-resorptive agent.

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