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Zoledronic acid

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(Redirected from Zoledronate)

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
  • [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)
  • O=P(O)(O)C(O)(Cn1ccnc1)P(=O)(O)O
  • 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
 X markNcheckY (what is this?)  (verify)

Zoledronic acid, also known as zoledronate and sold under the brand name Zometa among others,[8] 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]

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][9] It is on the World Health Organization's List of Essential Medicines.[10]

Medical uses

[edit]

Zoledronic acid is indicated for the prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia) in people with advanced malignancies involving bone; the treatment of adults with tumor-induced hypercalcemia (TIH).[6]

Zoledronic acid is also indicated for the treatment and prevention of postmenopausal osteoporosis; the treatment to increase bone mass in men with osteoporosis; the treatment and prevention of glucocorticoid-induced osteoporosis; the treatment of Paget's disease of bone in men and women.[5][7]

Bone complications of cancer

[edit]

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.[11] It can also be used to treat hypercalcaemia of malignancy and can be helpful for treating pain from bone metastases.[12]

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.[13]

Osteoporosis

[edit]

Zoledronic acid is used for the treatment of osteoporosis in men and post-menopausal women at increased risk of fracture.[14][15]

In 2007, the US Food and Drug Administration (FDA) approved zoledronic acid for the treatment of postmenopausal osteoporosis.[8][16]

In post-menopausal women, zoledronic acid has shown significant benefits versus placebo over three years, with a reduced number of vertebral fractures and improved markers of bone density.[17][16] An annual dose of zoledronic acid may also prevent recurring fractures in patients with a previous hip fracture.[15]

Other

[edit]

Zoledronic acid may be used for treatment of osteogenesis imperfecta.[18]

Contraindications

[edit]

Side effects

[edit]

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

[edit]

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.[20]

Zoledronate is rapidly processed via the kidneys; consequently its administration is not recommended for patients with reduced renal function or kidney disease.[21] 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).[22] 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.[23]

Bone

[edit]

Osteonecrosis of the jaw

[edit]

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.[24]

Atypical fractures

[edit]

After approving the drug in July 2009, the European Medicines Agency conducted a class review of all bisphosphonates, including zoledronic acid, after several cases of atypical fractures were reported.[25] 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.[25]

Pharmacology

[edit]

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.[26] [27]

Zoledronic acid causes osteoclasts, the cells responsible for bone resorption, to undergo apoptosis (programmed cell death), while reducing apoptosis in the bone-building osteoblasts.[28] It also prevents macrophages from differentiating into osteoclasts. All of these contribute to reduced bone resorption.[29] The molecular mechanisms behind these effects have been outlined.[30]

Relative potency[31]
Bisphosphonate Relative potency
Etidronate 1
Tiludronate 10
Pamidronate 100
Alendronate 100-500
Ibandronate 500-1000
Risedronate 1000
Zoledronate 5000

Research

[edit]

Zoledronic acid has a direct antitumor effect in vitro, inducing cancer cells such as osteosarcoma cells to undergo apoptosis or to be stuck in the S phase of the cell cycle.[32] It also synergistically augments the effects of other antitumor agents in osteosarcoma cells.[33] One study attributes these two effects to the inhibition of Rab proteins and topoisomerase II.[32] It is also known to induce apoptosis by generating reaction oxygen species and opening up chloride channels in nasopharyngeal carcinoma cells, similar to how it causes apoptosis of osteoclasts.[34]

Zoledronic acid has an anti-cancer effect in animal models of osteosarcoma. A very small amount of data from a phase I study suggests possible efficacy in humans too.[35]

With hormone therapy for breast cancer

[edit]

Zoledronic acid may be a useful add-on treatment in 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.[36] A retrospective analysis of the AZURE trial data revealed a DFS survival advantage, particularly where estrogen had been reduced.[37]

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.[38]

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."[39]

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".[40]

References

[edit]
  1. ↑ "International trade names for zoledronic acid". Drugs.com. Archived from the original on 4 March 2016. Retrieved 14 January 2015.
  2. ↑ "Zoledronic acid Use During Pregnancy". Drugs.com. 1 June 2020. Archived from the original on 16 November 2021. Retrieved 19 October 2020.
  3. 1 2 3 4 5 6 7 8 9 10 "Zoledronic Acid". The American Society of Health-System Pharmacists. Archived from the original on 15 December 2017. Retrieved 8 December 2017.
  4. ↑ "Therapeutic Goods (Poisons Standard— June 2025) Instrument 2025" (pdf). Therapeutic Goods Administration (TGA). May 2025. Retrieved 31 August 2025.
  5. 1 2 "Reclast- zoledronic acid injection, solution". DailyMed. 7 July 2022. Retrieved 10 August 2024.
  6. 1 2 "Zometa EPAR". European Medicines Agency. 20 March 2001. Archived from the original on 7 June 2023. Retrieved 5 July 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  7. 1 2 "Aclasta EPAR". European Medicines Agency (EMA). 15 April 2005. Retrieved 10 August 2024. Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.
  8. 1 2 "Novartis's Reclast Receives FDA Approval for Women With Postmenopausal Osteoporosis". FierceBiotech (Press release). 20 August 2007. Archived from the original on 28 March 2018. Retrieved 2 September 2021.
  9. ↑ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 524. ISBN 978-3-527-60749-5. Archived from the original on 14 January 2023. Retrieved 2 June 2020.
  10. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl:10665/371090. WHO/MHP/HPS/EML/2023.02.
  11. ↑ 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 23 April 2010. Retrieved 20 January 2010.
  12. ↑ "Zomera prescribing information" (PDF). Novartis Pharmaceuticals Corporation. U.S. Food and Drug Administration. April 2014. Archived from the original (PDF) on 19 June 2022. Retrieved 10 October 2023.
  13. ↑ 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". British Journal of Cancer. 92 (10): 1869–1876. doi:10.1038/sj.bjc.6602551. PMC 2361764. PMID 15870721.
  14. ↑ Dhillon S (November 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.
  15. 1 2 Lyles KW, Colón-Emeric CS, Magaziner JS, Adachi JD, Pieper CF, Mautalen C, et al. (November 2007). "Zoledronic acid and clinical fractures and mortality after hip fracture". The New England Journal of Medicine. 357 (18): 1799–1809. doi:10.1056/NEJMoa074941. PMC 2324066. PMID 17878149.
  16. 1 2 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". The New England Journal of Medicine. 356 (18): 1809–1822. doi:10.1056/nejmoa067312. PMID 17476007. S2CID 71443125.
  17. ↑ Reid IR, Brown JP, Burckhardt P, Horowitz Z, Richardson P, Trechsel U, et al. (February 2002). "Intravenous zoledronic acid in postmenopausal women with low bone mineral density". The New England Journal of Medicine. 346 (9): 653–661. doi:10.1056/NEJMoa011807. PMID 11870242.
  18. ↑ Dwan K, Phillipi CA, Steiner RD, Basel D (October 2016). "Bisphosphonate therapy for osteogenesis imperfecta". The Cochrane Database of Systematic Reviews. 2016 (10) CD005088. doi:10.1002/14651858.CD005088.pub4. PMC 6611487. PMID 27760454.
  19. ↑ Vondracek SF (April 2010). "Managing osteoporosis in postmenopausal women". American Journal of Health-System Pharmacy. 67 (7 Suppl 3): S9–19. doi:10.2146/ajhp100076. PMID 20332498.
  20. ↑ "NPS MedicineWise" (PDF). Archived from the original (PDF) on 4 March 2016. Retrieved 25 January 2014.
  21. ↑ "Zometa 4mg/5ml Concentrate for Solution for Infusion". medicines.org.uk. Archived from the original on 24 February 2010. Retrieved 24 February 2010.
  22. ↑ "FDA Alert: Reclast (zoledronic acid): Drug Safety Communication - New Contraindication and Updated Warning on Kidney Impairment". drugs.com. Archived from the original on 3 March 2016. Retrieved 23 January 2018.
  23. ↑ "European Medicines Agency - Human medicines". europa.eu. Archived from the original on 25 September 2015. Retrieved 3 April 2012.
  24. ↑ Durie BG, Katz M, Crowley J (July 2005). "Osteonecrosis of the jaw and bisphosphonates" (PDF). The New England Journal of Medicine. 353 (1): 99–102, discussion 99–102. doi:10.1056/NEJM200507073530120. hdl:2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/357907. PMID 16000365. Archived (PDF) from the original on 21 August 2023. Retrieved 25 June 2023.
  25. 1 2 "European Medicines Agency - Human medicines". europa.eu. Archived from the original on 19 January 2013. Retrieved 3 April 2012.
  26. ↑ "Aclasta label- Australia" (PDF). Archived from the original (PDF) on 4 March 2016. Retrieved 25 January 2014.
  27. ↑ "Bisphosphonates". International Osteoporosis Foundation. Retrieved 30 July 2022.[permanent dead link]
  28. ↑ Cheng YT, Liao J, Zhou Q, Huo H, Zellmer L, Tang ZL, et al. (August 2021). "Zoledronic acid modulates osteoclast apoptosis through activation of the NF-κB signaling pathway in ovariectomized rats". Experimental Biology and Medicine. 246 (15). Maywood, N.J.: 1727–1739. doi:10.1177/15353702211011052. PMC 8719043. PMID 33926259.
  29. ↑ Wang L, Fang D, Xu J, Luo R (November 2020). "Various pathways of zoledronic acid against osteoclasts and bone cancer metastasis: a brief review". BMC Cancer. 20 (1) 1059. doi:10.1186/s12885-020-07568-9. PMC 7607850. PMID 33143662.
  30. ↑ Wang B, Zhan Y, Yan L, Hao D (2022). "How zoledronic acid improves osteoporosis by acting on osteoclasts". Frontiers in Pharmacology. 13 961941. doi:10.3389/fphar.2022.961941. PMC 9452720. PMID 36091799.
  31. ↑ Tripathi KD (30 September 2013). Essentials of medical pharmacology (Seventh ed.). New Delhi: Jaypee Brothers Medical Publishers, Ltd. ISBN 978-93-5025-937-5. OCLC 868299888.
  32. 1 2 Okamoto S, Jiang Y, Kawamura K, Shingyoji M, Tada Y, Sekine I, et al. (November 2014). "Zoledronic acid induces apoptosis and S-phase arrest in mesothelioma through inhibiting Rab family proteins and topoisomerase II actions". Cell Death & Disease. 5 (11): e1517. doi:10.1038/cddis.2014.475. PMC 4260733. PMID 25393473.
  33. ↑ Koto K, Murata H, Kimura S, Horie N, Matsui T, Nishigaki Y, et al. (July 2010). "Zoledronic acid inhibits proliferation of human fibrosarcoma cells with induction of apoptosis, and shows combined effects with other anticancer agents". Oncology Reports. 24 (1): 233–239. doi:10.3892/or_00000851. PMID 20514467.
  34. ↑ Wang L, Gao H, Yang X, Liang X, Tan Q, Chen Z, et al. (October 2018). "The apoptotic effect of Zoledronic acid on the nasopharyngeal carcinoma cells via ROS mediated chloride channel activation". Clinical and Experimental Pharmacology & Physiology. 45 (10): 1019–1027. doi:10.1111/1440-1681.12979. PMID 29884989.
  35. ↑ Conry RM, Rodriguez MG, Pressey JG (2016). "Zoledronic acid in metastatic osteosarcoma: encouraging progression free survival in four consecutive patients". Clinical Sarcoma Research. 6 (1) 6. doi:10.1186/s13569-016-0046-2. PMC 4848872. PMID 27127605.
  36. ↑ 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". The New England Journal of Medicine. 360 (7): 679–691. doi:10.1056/NEJMoa0806285. PMID 19213681.
  37. ↑ Coleman RE, Winter MC, Cameron D, Bell R, Dodwell D, Keane MM, 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". British Journal of Cancer. 102 (7): 1099–1105. doi:10.1038/sj.bjc.6605604. PMC 2853093. PMID 20234364.
  38. ↑ Brufsky A, Bundred N, Coleman R, Lambert-Falls R, Mena R, Hadji P, 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". The Oncologist. 13 (5): 503–514. doi:10.1634/theoncologist.2007-0206. PMID 18515735. S2CID 23710758.
  39. ↑ Tonyali O, Arslan C, Altundag K (November 2010). "The role of zoledronic acid in the adjuvant treatment of breast cancer: current perspectives". Expert Opinion on Pharmacotherapy. 11 (16): 2715–2725. doi:10.1517/14656566.2010.523699. PMID 20977404. S2CID 26073229.
  40. ↑ 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". Clinical Breast Cancer. 10 (4): 267–274. doi:10.3816/CBC.2010.n.034. PMID 20705558.
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