Denosumab

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Denosumab Brand Names- Prolia | XGEVA

What is Denosumab

Denosumab is a subcutaneous fully human, highly specific, monoclonal antibody against receptor activator of nuclear factor kappa-beta ligand (RANKL).

Denosumab (Prolia) is a monoclonal antibody directed against RANK-L. This interferes with the ability of osteoblasts (and other cells with RANK-L on their surface) to bind to RANK and stimulate osteoclastic bone resorption. Denosumab is given in clinic or an infusion center at a dose of 60 mg SC every 6 months. This medication is well tolerated although there is a concern that infections could be increased since RANK-L is also on T helper cells and involved in dendritic cell activation. Notably, examination of large databases has failed to show an increased risk of serious infections in patients on denosumab who are also receiving immunosuppressive medications. In trials, denosumab increased lumbar spine bone mass by 6.5% and hip mass by 3.5%. This was accompanied by a 68% reduction in vertebral and 40% reduction in hip fractures over 3 years. Denosumab is cleared by the reticuloendothelial system and can, therefore, be used in osteoporotic patients with Class 4 CKD (CrCl 15–30 cc/minute) although there is an increased risk of hypocalcemia. As with the bisphosphonates, any planned invasive dental work (extractions, implants) should be done prior to starting denosumab, if possible, to reduce the risk for ONJ. It is also recommended that providers do an oral examination before starting therapy with denosumab. In patients already on denosumab, it is recommended that any elective invasive dental procedures be scheduled for 6 months after an injection and the next injection given after the dental procedure has fully healed.

The protein is produced in genetically engineered mammalian (Chinese hamster ovary) cells.

Denosumab blocks osteoclast activation, thereby resulting in decreased bone resorption (less bone breakdown) and modification of the release of calcium from the bone.

The drug lowers serum calcium via this mechanism. Denosumab decreases bone resorption in patients at high risk for osteoclast-mediated bone loss, including certain patients with bone metastases due to malignancy, and postmenopausal women with osteopenia.

In a phase 3 clinical trial conducted in women with postmenopausal osteoporosis, patients receiving denosumab had increases in bone mineral density of 9.2% in the lumbar spine and 6% in the total hip, and decreased relative risk of fracture of 68% for new vertebral fractures (RR = 0.32, 95% CI, 0.26 to 0.41, p less than 0.001), 20% for non-vertebral fractures (RR = 0.8, 95% CI, 0.67 to 0.95, p = 0.01), and 40% for hip fractures (RR = 0.6, 95% CI, 0.37 to 0.97, p = 0.04).

Due to the potential for serious adverse events associated with denosumab, the approved use in osteoporosis is limited to postmenopausal women with a history of fractures, a high risk of fractures, or intolerance to or failure of other osteoporosis therapy.

Denosumab delays the time to a first skeletal event (e.g., surgery, fracture, spinal cord compression, or radiation to the bone) in oncology patients with multiple myeloma or in patients with bone metastases due to solid tumors.

Denosumab was first approved by the FDA in June 2010; two products are available and it is essential that clinicians choose the right product for use.

Prolia is used for osteoporosis treatment and prophylaxis in selected patients.

Xgeva is used for prevention of skeletal-related events in patients with multiple myeloma or with bone metastases due to solid tumors, for the treatment of refractory hypercalcemia of malignancy, and for adults and skeletally mature adolescents with giant cell tumor of bone that is unresectable or where surgical resection is likely to result in severe morbidity.

Indications

  1. bone metastases
  2. giant cell tumor of bone
  3. hypercalcemia
  4. multiple myeloma
  5. osteoporosis
  6. osteoporosis prophylaxis

NOTE: Denosumab is available in two different products, Prolia and Xgeva, which are indicated for different therapeutic uses and are available in different strengths. Patients receiving Prolia should not receive Xgeva and vice versa.

For the treatment of osteoporosis in men and postmenopausal women at high risk for fracture, as well as for glucocorticoid-induced osteoporosis

Side Effects

  1. abdominal pain
  2. alopecia
  3. anaphylactoid reactions
  4. anemia
  5. angina
  6. angioedema
  7. anorexia
  8. arthralgia
  9. asthenia
  10. atopic dermatitis
  11. atrial fibrillation
  12. back pain
  13. bone fractures
  14. bone pain
  15. chills
  16. constipation
  17. cough
  18. cystitis
  19. dental pain
  20. diarrhea
  21. dyspnea
  22. erythema
  23. fatigue
  24. fatigue
  25. fever
  26. flatulence
  27. flushing
  28. gastroesophageal reflux
  29. headache
  30. hypercalcemia
  31. hypercholesterolemia
  32. hypocalcemia
  33. hypocalcemia
  34. hypomagnesemia
  35. hypophosphatemia
  36. hypophosphatemia
  37. hypotension
  38. infection
  39. laryngeal edema
  40. lichen planus-like eruption
  41. muscle cramps
  42. musculoskeletal pain
  43. myalgia
  44. nausea
  45. neuropathic pain
  46. neutropenia
  47. new primary malignancy
  48. oral ulceration
  49. osteonecrosis
  50. pancreatitis
  51. paresthesias
  52. peripheral edema
  53. pharyngitis
  54. pruritus
  55. rash
  56. tetany
  57. urticaria
  58. vertigo
  59. vomiting
  60. wheezing

What happens when denosumab is stopped, and what precautions are recommended?

Discontinuation of denosumab has been reported to result in rapid bone loss and, in some patients, the development of multiple vertebral fractures. Therefore, if denosumab therapy is stopped after at least two denosumab doses, it is recommended that bisphosphonate therapy be started; if an oral bisphosphonates is used, it should be started 6 months after the last denosumab injection, whereas if IV zoledronic acid is chosen, it should be given 9 months after the last denosumab injection.

Monitoring Parameters

  • serum calcium
  • serum creatinine/BUN
  • serum magnesium
  • serum phosphate

Contraindications

  • angioedema
  • bone fractures
  • breast-feeding
  • chemotherapy
  • children
  • contraception requirements
  • corticosteroid therapy
  • dental disease
  • dental work
  • diabetes mellitus
  • dialysis
  • eczema
  • hypocalcemia
  • immunosuppression
  • infants
  • infection
  • latex hypersensitivity
  • neoplastic disease
  • pancreatitis
  • pregnancy
  • pregnancy testing
  • renal failure
  • renal impairment
  • reproductive risk
  • surgery
  • tuberculosis
  • urticaria
  • vitamin D deficiency

Interactions

  • Azelastine; Fluticasone
  • Beclomethasone
  • Betamethasone
  • Budesonide
  • Budesonide; Formoterol
  • Calcitonin
  • Ciclesonide
  • Cinacalcet
  • Corticosteroids
  • Corticotropin, ACTH
  • Cortisone
  • Deflazacort
  • Dexamethasone
  • Etelcalcetide
  • Fludrocortisone
  • Flunisolide
  • Fluticasone
  • Fluticasone; Salmeterol
  • Fluticasone; Umeclidinium; Vilanterol
  • Fluticasone; Vilanterol
  • Formoterol; Mometasone
  • Hydrocortisone
  • Lenalidomide
  • Methylprednisolone
  • Mometasone
  • Palifermin
  • Penicillamine
  • Pomalidomide
  • Prednisolone
  • Prednisone
  • Thalidomide
  • Triamcinolone
  • Tuberculin Purified Protein Derivative, PPD

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