Zoledronic acid

Zoledronic acid

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Systematic (IUPAC) name
[1-hydroxy-2-(1H-imidazol-1-yl)ethane-1,1-diyl]bis(phosphonic acid)
Clinical data
AHFS/Drugs.com	monograph
MedlinePlus	a605023
Licence data	EMA:Link, US FDA:link
Pregnancy category	D (U.S.)
Legal status	℞-only (U.S.)
Routes of administration	Intravenous
Pharmacokinetic data
Protein binding	22%
Metabolism	Nil
Biological half-life	146 hours
Excretion	Renal (partial)
Identifiers
CAS Number	118072-93-8
ATC code	M05BA08 (WHO)
PubChem	CID: 68740
IUPHAR/BPS	3177
DrugBank	DB00399
ChemSpider	61986
UNII	70HZ18PH24 Y
KEGG	D08689 N
ChEMBL	CHEMBL924 Y
PDB ligand ID	ZOL (PDBe, RCSB PDB)
Chemical data
Formula	C5H10N2O7P2
Molecular mass	272.09 g/mol
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)

Zoledronic acid (INN) or zoledronate is a bisphosphonate given intravenously. Marketed by Novartis under the trade names Zometa, Zomera, Aclasta and Reclast), it is also available as a generic.

Mechanism of action

Zoledronic acid slows down bone resorption, allowing the bone-forming cells time to rebuild normal bone and allowing bone remodeling.

Approvals and indications

In all cases administration is by intravenous infusion over a minimum of five minutes.

Bone complications of cancer

Zometa is used to prevent skeletal fractures in patients with cancers such as multiple myeloma and prostate cancer, as well as for treating osteoporosis. It can also be used to treat hypercalcemia of malignancy and can be helpful for treating pain from bone metastases.

It can be administered at home rather than in hospital. Such administration has shown safety and quality-of-life benefits in breast cancer patients with bone metastases.

Osteoporosis

Marketed as Aclasta (in Australia) or Reclast (in the US), zoledronic acid 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.

In 2007, the U.S. Food and Drug Administration (FDA) also approved Reclast for the treatment of postmenopausal osteoporosis.

Paget's disease

As Reclast a single dose of 5 mg is used for the treatment of Paget's disease.

Side-effects

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

There is a risk of severe renal impairment. Appropriate hydration is important prior to administration, as is adequate calcium and vitamin D intake prior to Aclasta therapy in patients with preexisting 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.

Zoledronate is rapidly processed via the kidneys; consequently its administration is not recommended for patients with reduced renal function or kidney disease. Some cases of acute renal failure either requiring dialysis or having a fatal outcome following Reclast use have been reported to the U.S. Food and Drug Administration (FDA). 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.

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 zoledronate who have had dental extractions.

After approving the drug on 8 July 2009, the European Medicines Agency conducted a class review of all bisphosphonates, including Zoledronate, after several cases of atypical fractures were reported. 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.

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.

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

Zoledronate also attenuates accumulation of DNA damage in mesenchymal stem cells and protects their function. Given this characteristic, its potential to affect conditions arising from stem-cell dysfunction makes it a promising medicine for a range of age-related diseases

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. A retrospective analysis of the AZURE trial data revealed a DFS survival advantage, particularly where estrogen had been reduced.

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. 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. Ongoing large trials testing bisphosphonates as adjuvant treatment in breast cancer include NSABP B-34, the NATAN trial, and SWOG-S0307. 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".

Contraindications

• Poor renal function (e.g. CrCl<30 mL/min)
• Hypocalcaemia
• Pregnancy
• Paralysis

External links

• http://www.multiplemyeloma.org/treatments/3.06.html
• http://www.us.zometa.com/info/index.jsp
• http://www.zometa.com/index.jsp
• http://www.reclast.com/