Zoledronic acid

Zoledronic acid, also known as zoledronate and sold under the brand name Zometa[4] by Novartis among others, is a medication used to treat a number of bone diseases.[3] These include osteoporosis, high blood calcium due to cancer, bone breakdown due to cancer, Paget's disease of bone[3] and Duchenne muscular dystrophy (DMD). It is given by injection into a vein.[3]

Zoledronic acid
Clinical data
Trade namesReclast, Zometa, others[1]
Other nameszoledronate
AHFS/Drugs.comMonograph
MedlinePlusa605023
License data
Pregnancy
category
Routes of
administration		Intravenous
Drug classBisphosphonate[3]
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding22%
MetabolismNil
Elimination half-life146 hours
ExcretionKidney (partial)
Identifiers
IUPAC name
  • [1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid)
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC5H10N2O7P2
Molar mass272.090 g·mol−1
3D model (JSmol)
SMILES
  • O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
InChI
  • InChI=1S/C5H10N2O7P2/c8-5(15(9,10)11,16(12,13)14)3-7-2-1-6-4-7/h1-2,4,8H,3H2,(H2,9,10,11)(H2,12,13,14)
  • Key:XRASPMIURGNCCH-UHFFFAOYSA-N
 NY (what is this?)  (verify)

Common side effects include fever, joint pain, high blood pressure, diarrhea, and feeling tired.[3] Serious side effects may include kidney problems, low blood calcium, and osteonecrosis of the jaw.[3] Use during pregnancy may result in harm to the baby.[3] It is in the bisphosphonate family of medications.[3] It works by blocking the activity of osteoclast cells and thus decreases the breakdown of bone.[3]

Zoledronic acid was patented in 1986 and approved for medical use in the United States in 2001.[3][5] It is on the World Health Organization's List of Essential Medicines.[6][7]

Medical uses

Bone complications of cancer

Zoledronic acid is used to prevent bone fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis.[8] It can also be used to treat hypercalcaemia of malignancy and can be helpful for treating pain from bone metastases.[9]

It can be given at home rather than in hospital. Such use has shown safety and quality-of-life benefits in people with breast cancer and bone metastases.[10]

Osteoporosis

Zoledronic acid, in brand name products Aclasta and Reclast among others,[11] may be given as a 5 mg infusion once per year for treatment of osteoporosis in men and post-menopausal women at increased risk of fracture.[12]

In 2007, the U.S. Food and Drug Administration (FDA) also approved it for the treatment of postmenopausal osteoporosis.[13][14]

Other

Zoledronic acid may be used for treatment of osteogenesis imperfecta.[15]

A single 5 mg dose of zoledronic acid is used for the treatment of Paget's disease.[16]

Contraindications

Side effects

Side effects can include fatigue, anemia, muscle aches, fever, and/or swelling in the feet or legs. Flu-like symptoms are common after the first infusion, although not subsequent infusions, and are thought to occur because of its potential to activate human gamma delta T cell (γδ T cells).

Kidneys

There is a risk of severe renal impairment. Appropriate hydration is important before administration, as is adequate calcium and vitamin D intake before Aclasta therapy in patients with hypocalcaemia, and for ten days following Aclasta in patients with Paget's disease of the bone. Monitoring for other mineral metabolism disorders and the avoidance of invasive dental procedures for those who develop osteonecrosis of the jaw is recommended.[18]

Zoledronate is rapidly processed via the kidneys; consequently its administration is not recommended for patients with reduced renal function or kidney disease.[19] Some cases of acute kidney injury either requiring dialysis or having a fatal outcome following Reclast use have been reported to the U.S. Food and Drug Administration (FDA).[20] This assessment was confirmed by the European Medicines Agency (EMA), whose Committee for Medicinal Products for Human Use (CHMP) specified new contraindications for the medication on 15 December 2011, which include hypocalcaemia and severe renal impairment with a creatinine clearance of less than 35 ml/min.[21]

Osteonecrosis of the jaw

A rare complication that has been recently observed in cancer patients being treated with bisphosphonates is osteonecrosis of the jaw. This has mainly been seen in patients with multiple myeloma treated with zoledronic acid who have had dental extractions.[22]

Atypical fractures

After approving the drug on 8 July 2009, the European Medicines Agency conducted a class review of all bisphosphonates, including zoledronic acid, after several cases of atypical fractures were reported.[23] In 2008, the EMA's Pharmacovigilance Working Party (PhVWP) noted that alendronic acid was associated with an increased risk of atypical fracture of the femur that developed with low or no trauma. In April 2010, the PhVWP noted that further data from both the published literature and post-marketing reports were now available which suggested that atypical stress fractures of the femur may be a class effect. The European Medicines Agency then reviewed all case reports of stress fractures in patients treated with bisphosphonates, relevant data from the published literature, and data provided by the companies which market bisphosphonates. The Agency recommended that doctors who prescribe bisphosphonate-containing medicines should be aware that atypical fractures may occur rarely in the femur, especially after long-term use, and that doctors who are prescribing these medicines for the prevention or treatment of osteoporosis should regularly review the need for continued treatment, especially after five or more years of use.[23]

Pharmacology

As a nitrogenous bisphosphonate, Zoledronic acid is a potent inhibitor of bone resorption, allowing the bone-forming cells time to rebuild normal bone and allowing bone remodeling.[24] [25]

Relative potency[26]
Bisphosphonate Relative potency
Etidronate 1
Tiludronate 10
Pamidronate 100
Alendronate 100-500
Ibandronate 500-1000
Risedronate 1000
Zoledronate 5000

Research

Zoledronic acid has been found to have a direct antitumor effect and to synergistically augment the effects of other antitumor agents in osteosarcoma cells.[27]

Zoledronic acid has shown significant benefits versus placebo over three years, with a reduced number of vertebral fractures and improved markers of bone density.[28][14] An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture.[12]

Zoledronic acid also attenuates accumulation of DNA damage in mesenchymal stem cells and protects their function.[29]

With hormone therapy for breast cancer

An increase in disease-free survival (DFS) was found in the ABCSG-12 trial, in which 1,803 premenopausal women with endocrine-responsive early breast cancer received anastrozole with zoledronic acid.[30] A retrospective analysis of the AZURE trial data revealed a DFS survival advantage, particularly where estrogen had been reduced.[31]

In a meta-analysis of trials where upfront zoledronic acid was given to prevent aromatase inhibitor-associated bone loss, active cancer recurrence appeared to be reduced.[32]

As of 2010 "The results of clinical studies of adjuvant treatment on early-stage hormone-receptor-positive breast-cancer patients under hormonal treatment – especially with the bisphosphonate zoledronic acid – caused excitement because they demonstrated an additive effect on decreasing disease relapses at bone or other sites. A number of clinical and in vitro and in vivo preclinical studies, which are either ongoing or have just ended, are investigating the mechanism of action and antitumoral activity of bisphosphonates."[33]

A 2010 review concluded that "adding zoledronic acid 4 mg intravenously every 6 months to endocrine therapy in premenopausal women with hormone receptor-positive early breast cancer ... is cost-effective from a US health care system perspective".[34]

References
  1. Drugs.com International trade names for zoledronic acid Page accessed Jan 14, 2015
  2. "Zoledronic acid Use During Pregnancy". Drugs.com. 1 June 2020. Retrieved 19 October 2020.
  3. "Zoledronic Acid". The American Society of Health-System Pharmacists. Retrieved 8 December 2017.
  4. "PRESS RELEASE: Novartis's Reclast Receives FDA Approval FOR Women With Postmenopausal Osteoporosis". FierceBiotech. 20 August 2007. Retrieved 2021-09-02.
  5. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 524. ISBN 9783527607495.
  6. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  7. World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
  8. National Prescribing Service (2009). "Zoledronic Acid for Osteoporosis". Medicines Update, Available at "Zoledronic acid (Aclasta) for osteoporosis: National Prescribing Service Ltd NPS". Archived from the original on April 23, 2010. Retrieved January 20, 2010.
  9. http://www.health.gov.il/units/pharmacy/trufot/alonim/533.pdf Zomera prescribing information
  10. Wardley A, Davidson N, Barrett-Lee P, Hong A, Mansi J, Dodwell D, et al. (May 2005). "Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: a randomised, crossover study of community vs hospital bisphosphonate administration". Br. J. Cancer. 92 (10): 1869–76. doi:10.1038/sj.bjc.6602551. PMC 2361764. PMID 15870721.
  11. Dhillon, S. (2016). "Zoledronic Acid (Reclast®, Aclasta®): A Review in Osteoporosis". Drugs. 76 (17): 1683–1697. doi:10.1007/s40265-016-0662-4. PMID 27864686. S2CID 22079489.
  12. Lyles K, et al. (2007). "Zoledronic Acid and Clinical Fractures and Mortality after Hip Fracture". N. Engl. J. Med. 357 (18): 1799–809. doi:10.1056/NEJMoa074941. PMC 2324066. PMID 17878149.
  13. "Biotech PRESS RELEASE: Novartis's Reclast Receives FDA Approval FOR Women With Postmenopausal Osteoporosis" (Press release). FierceBiotech, A Division of Questex A FierceMarkets Publication. August 20, 2007. Retrieved 2018-03-27.
  14. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. (May 2007). "Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis". N Engl J Med. 356 (18): 1809–22. doi:10.1056/nejmoa067312. PMID 17476007. S2CID 71443125.
  15. Dwan, K; Phillipi, CA; Steiner, RD; Basel, D (19 October 2016). "Bisphosphonate therapy for osteogenesis imperfecta". The Cochrane Database of Systematic Reviews. 10: CD005088. doi:10.1002/14651858.CD005088.pub4. PMC 6611487. PMID 27760454.
  16. "Paget's Disease of Bone". www.rheumatology.org. Retrieved 2015-07-09.
  17. Vondracek, S. F. (2010). "Managing osteoporosis in postmenopausal women". American Journal of Health-System Pharmacy. 67 (7 Suppl 3): S9–19. doi:10.2146/ajhp100076. PMID 20332498.
  18. "NPS MedicineWise" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2014-01-25.
  19. "Zometa 4mg/5ml Concentrate for Solution for Infusion". medicines.org.uk. Archived from the original on 2010-02-24. Retrieved 2010-02-24.
  20. "FDA Alert: Reclast (zoledronic acid): Drug Safety Communication - New Contraindication and Updated Warning on Kidney Impairment". drugs.com.
  21. "European Medicines Agency - Human medicines". europa.eu.
  22. Durie BG, Katz M, Crowley J (2005). "Osteonecrosis of the jaw and bisphosphonates". N. Engl. J. Med. 353 (1): 99–102, discussion 99–102. doi:10.1056/NEJM200507073530120. PMID 16000365.
  23. "European Medicines Agency - Human medicines". europa.eu.
  24. "Aclasta label- Australia" (PDF). Archived from the original (PDF) on 2016-03-04. Retrieved 2014-01-25.
  25. "Bisphosphonates". International Osteoporosis Foundation. International Osteoporosis Foundation. Retrieved 30 July 2022.
  26. D., Tripathi, K. (2013-09-30). Essentials of medical pharmacology (Seventh ed.). New Delhi. ISBN 9789350259375. OCLC 868299888.
  27. Koto K, Murata H, Kimura S, et al. (July 2010). "Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents". Oncol. Rep. 24 (1): 233–9. doi:10.3892/or_00000851. PMID 20514467.
  28. Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, Widmer A, Devogelaer JP, Kaufman JM, Jaeger P, Body JJ, Brandi ML, Broell J, Di Micco R, Genazzani AR, Felsenberg D, Happ J, Hooper MJ, Ittner J, Leb G, Mallmin H, Murray T, Ortolani S, Rubinacci A, Saaf M, Samsioe G, Verbruggen L, Meunier PJ (2002). "Intravenous zoledronic acid in postmenopausal women with low bone mineral density". N. Engl. J. Med. 346 (9): 653–61. doi:10.1056/NEJMoa011807. PMID 11870242.
  29. Misra, Juhi; Mohanty, Sindhu T.; Madan, Sanjeev; Fernandes, James A.; Hal Ebetino, F.; Russell, R. Graham G.; Bellantuono, Ilaria (2016). "Zoledronate Attenuates Accumulation of DNA Damage in Mesenchymal Stem Cells and Protects Their Function". Stem Cells. 34 (3): 756–767. doi:10.1002/stem.2255. PMC 4832316. PMID 26679354.
  30. Gnant M, Mlineritsch B, Schippinger W, Luschin-Ebengreuth G, Pöstlberger S, Menzel C, et al. (February 2009). "Endocrine therapy plus zoledronic acid in premenopausal breast cancer". N. Engl. J. Med. 360 (7): 679–91. doi:10.1056/NEJMoa0806285. PMID 19213681.
  31. Coleman RE, Winter MC, Cameron D, et al. (March 2010). "The effects of adding zoledronic acid to neoadjuvant chemotherapy on tumour response: exploratory evidence for direct anti-tumour activity in breast cancer". Br. J. Cancer. 102 (7): 1099–105. doi:10.1038/sj.bjc.6605604. PMC 2853093. PMID 20234364.
  32. Brufsky A, Bundred N, Coleman R, et al. (May 2008). "Integrated analysis of zoledronic acid for prevention of aromatase inhibitor-associated bone loss in postmenopausal women with early breast cancer receiving adjuvant letrozole". Oncologist. 13 (5): 503–14. doi:10.1634/theoncologist.2007-0206. PMID 18515735.
  33. Tonyali O, Arslan C, Altundag K (November 2010). "The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives". Expert Opin Pharmacother. 11 (16): 2715–25. doi:10.1517/14656566.2010.523699. PMID 20977404. S2CID 26073229.
  34. Delea TE, Taneja C, Sofrygin O, Kaura S, Gnant M (August 2010). "Cost-effectiveness of zoledronic acid plus endocrine therapy in premenopausal women with hormone-responsive early breast cancer". Clin. Breast Cancer. 10 (4): 267–74. doi:10.3816/CBC.2010.n.034. PMID 20705558.
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