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denosumab (Prolia, Xgeva)

Indications: - osteoporosis a) elderly women b) hypogonadism - men on anti-androgen therapy (GnRH analog) c) effective in patients with renal impairment [10] d) modest efficacy [18]# - prevention of cancer-related bone injury - bone metastases from solid tumors [5,11] - giant cell tumor of bone [6] - hypercalcemia of malignancy [15,16]* - reduces risk of type 2 diabetes, foot ulcers & mortalty vs alendronate [28] * not indicated for treatment of hypercalcemia of malignancy (GRS9) [7] # disproportionate adverse effects including back pain & serious infections [18] (on list of medications to avoid) Contraindications: - prevention of cancer-related bone injury from bone metastases due to prostate cancer (NGC) Dosage: - 60 mg, 1-3 doses SQ every 3-6 months - recommended injection sites include upper arm, upper thigh, or abdomen - duration of therapy - bone resorption transiently increases dramatically upon cessation of therapy, increasing risk of vertebral fractures [2,22,24] - no established duration of therapy [19] - duration of therapy 5 years [20] - safe for 10 years of therapy [23] - continued increases in bone mineral density without plateau - if discontinued, use bisphosphonate to reduce osteoclastic activity & bone resorption [19] prefilled syringe: 1 mL 60 mg/mL (single use) vial: 1 mL 60 mg/mL (single use) * No dosage adjustment with renal failure Monitor: - serum calcium in patients on hemodialysis Adverse effects: - back pain - musculoskeletal pain, - pain in the extremities - hyperlipidemia - cystitis - osteonecrosis of the jaw [11] - pancreatitis has been reported in clinical trials - possible excess risk for cellulitis [12] - hypocalcemia in hemodialysis patients [25] * Boxed Warning: - increased risk of severe hypocalcemia in patients with advanced chronic kidney disease [27] - patients on dialysis or with mineral & bone disorder at highest risk Drug interactions: - may not increase risk of infection with used in combination with biological response modifier [12] Mechanism of action: 1) antibody to RANKL 2) reduces osteoclasts & bone resorption 3) may have beneficial effects on glycemic control [26] Notes: - cost 2010: $825 per injection - cost of $46,000 per vertebral fracture prevented [21] - insurance approval generally requires renal failure (creatinine clearance < 30 mL/min) [7]

Interactions

drug adverse effects of pharmaceutical monoclonal antibodies

General

pharmaceutical monoclonal antibody

References

  1. McClung MR et al, Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006; 354:821 PMID: 16495394
  2. Smith MR et al Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer N Eng J Med Aug 11, 2009 PMID: 19671656 http://content.nejm.org/cgi/content/full/NEJMoa0809003 - Cummings SR et al Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis N Eng J Med Aug 11, 2009 PMID: 19671655 http://content.nejm.org/cgi/content/full/NEJMoa0809493 - Khosla S Increasing Options for the Treatment of Osteoporosis N Eng J Med Aug 11, 2009 PMID: 19671654 http://content.nejm.org/cgi/content/full/NEJMe0905480 - FDA briefing document for advisory committee meeting http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM176595.pdf
  3. FDA Medwatch, June 1, 2010 FDA Approves New Injectable Osteoporosis Treatment for Postmenopausal Women http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm214150.htm
  4. Prescriber's Letter 17(8): 2010 COMMENTARY: New Drug: Prolia (Denosumab) MEDGUIDE: Drug Products with Medication Guides GUIDELINES: Diagnosis and Treatment of Osteoporosis (ICSI) GUIDELINES: Prevention and Treatment of Osteoporosis (NOF) GUIDELINES: Management of Osteoporosis in Postmenopausal Women (NAMS) Detail-Document#: 260803 (subscription needed) http://www.prescribersletter.com
  5. FDA NEWS RELEASE, Nov. 19, 2010 FDA approves Xgeva to help prevent cancer-related bone injury http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm234346.htm
  6. Deprecated Reference
  7. Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013 - Geriatric Review Syllabus, 9th edition (GRS9) Medinal-Walpole A, Pacala JT, Porter JF (eds) American Geriatrics Society, 2016
  8. Genant HK, Libanati C, Engelke K, Improvements in hip trabecular, subcortical, and cortical density and mass in postmenopausal women with osteoporosis Bone. 2013 Oct;56(2):482-8. PMID: 23871852
  9. Keaveny TM, McClung MR, Genant HK Femoral and vertebral strength improvements in postmenopausal women with osteoporosis treated with denosumab. J Bone Miner Res. 2014 Jan;29(1):158-65. PMID: 23794225
  10. Jamal SA, Ljunggren O, Stehman-Breen C et al Effects of denosumab on fracture and bone mineral density by level of kidney function. J Bone Miner Res. 2011 Aug;26(8):1829-35 PMID: 21491487
  11. Stopeck AT, Lipton A, Body JJ et al Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol. 2010 Dec 10;28(35):5132-9. PMID: 21060033
  12. Curtis JR et al. Risk of hospitalized infection among rheumatoid arthritis patients concurrently treated with a biologic agent and denosumab. Arthritis Rheumatol 2015 Jun; 67:1456 PMID: 25708920
  13. Orwoll E, Teglbjerg CS, Langdahl BL et al A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density. J Clin Endocrinol Metab. 2012 Sep;97(9):3161-9. PMID: 22723310
  14. Sidlauskas KM, Sutton EE, Biddle MA. Osteoporosis in men: epidemiology and treatment with denosumab. Clin Interv Aging. 2014 Apr 8;9:593-601. Review. PMID: 24748777 Free PMC Article
  15. Mirrakhimov AE.3. Hypercalcemia of Malignancy: An Update on Pathogenesis and Management. N Am J Med Sci. 2015 Nov;7(11):483-93. Review. PMID: 26713296 Free PMC Article
  16. Sternlicht H, Glezerman IG. Hypercalcemia of malignancy and new treatment options. Ther Clin Risk Manag. 2015 Dec 4;11:1779-88. Review. PMID: 26675713 Free PMC Article
  17. Diab DL, Watts NB. Denosumab in osteoporosis. Expert Opin Drug Saf. 2014 Feb;13(2):247-53. PMID: 24289327
  18. Therapeutics Letter #108. Therapeutics Initiative Drugs to Avoid. http://www.ti.ubc.ca/2018/01/04/108-drugs-avoid/
  19. Medical Knowledge Self Assessment Program (MKSAP) 18, 19 American College of Physicians, Philadelphia 2018, 2022
  20. Qaseem A, Forciea MA, McLean RM et al Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians. Ann Intern Med. 2017. May 9. PMID: 28492856 http://annals.org/aim/article/2625385/treatment-low-bone-density-osteoporosis-prevent-fractures-men-women-clinical - Orwoll ES Clinical Practice Guidelines for Osteoporosis: Translating Data to Patients? Ann Intern Med. 2017. May 9. PMID: 28492858 http://annals.org/aim/article/2625389/clinical-practice-guidelines-osteoporosis-translating-data-patients
  21. Albert SG, Reddy S CLINICAL EVALUATION OF COST EFFICACY OF DRUGS FOR TREATMENT OF OSTEOPOROSIS: A META-ANALYSIS. Endocr Pract. 2017 Jul;23(7):841-856 PMID: 28448754
  22. Anastasilakis AD, Polyzos SA, Makras P et al. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systemic review and additional cases. J Bone Miner Res. 2017;32(6):1291-1296 PMID: 28240371 Free article https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3110
  23. Bone HG, Wagman RB, Brandi ML et al.10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomized FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol. 2017;5(7):513-523 PMID: 28546097 https://www.thelancet.com/journals/landia/article/PIIS2213-8587(17)30138-9/fulltext
  24. Cummings SR, Ferrari S, Eastell R et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res. 2018;33(2):190-198 PMID: 29105841 Free article https://asbmr.onlinelibrary.wiley.com/doi/10.1002/jbmr.3337
  25. Prolia Postmarketing Active Safety Surveillance Program http://www.proliasafety.com - Monaco K Watch for Severe Hypocalcemia in Dialysis Patients on Prolia, FDA Warns. Agency said potential risk may require more frequent blood calcium monitoring. https://www.medpagetoday.com/nephrology/generalnephrology/101872 - US Food & Drug Administration FDA investigating risk of severe hypocalcemia in patients on dialysis receiving osteoporosis medicine Prolia (denosumab). FDA Drug Safety Communication. Nov 22, 2022 https://www.fda.gov/drugs/drug-safety-and-availability/fda-investigating-risk-severe-hypocalcemia-patients-dialysis-receiving-osteoporosis-medicine-prolia
  26. Lyu H et al. Denosumab and incidence of type 2 diabetes among adults with osteoporosis: Population based cohort study. BMJ 2023 Apr 18; 381:e073435. PMID: 37072150 PMCID: PMC10111187 Free PMC article https://www.bmj.com/content/381/bmj-2022-073435
  27. FDA MedWatch - Prolia (denosumab): Drug Safety Communication. Jan 19, 2024 FDA adds Boxed Warning for increased risk of severe hypocalcemia in patients with advanced chronic kidney disease taking osteoporosis medicine Prolia (denosumab). https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease
  28. Henney AE, Riley DR, O'Connor B et al Denosumab, for osteoporosis, reduces the incidence of type 2 diabetes, risk of foot ulceration and all-cause mortality in adults, compared with bisphosphonates: An analysis of real-world, cohort data, with a systematic review and meta-analysis Diabetes Obes Metab. 2024 Jun 20. doi: 10.1111/dom.15708. Online ahead of print. PMID: 38899553 https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.15708