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Published on 4 June 2009

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Review of zoledronic acid in the treatment of postmenopausal osteoporosis

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Intravenous zoledronic acid 5mg every 12 months reduces the risk of vertebral fractures, hip fractures and nonvertebral fractures in women with postmenopausal osteoporosis

Lina E Aguirre
MD MS

E Michael Lewiecki
MD FACP FACE

New Mexico
Clinical Research &
Osteoporosis Center
Albuquerque
New Mexico
USA

Osteoporosis is characterised by low bone mineral density (BMD) and poor bone quality, resulting in reduced bone strength and increased risk of fracture. Osteoporotic fractures are associated with adverse clinical outcomes that include disability and increased risk of death. Oral bisphosphonates, the first-line therapy for most patients with postmenopausal osteoporosis (PMO), increase BMD and reduce risk of fracture; however, bioavailability is low, the dosing regimen is complex, some patients experience gastrointestinal intolerance, and compliance and persistence are poor.

Intravenous (IV) zoledronic acid (ZOL), a bisphosphonate that is approved as a yearly treatment for PMO, has 100% bioavailability, no concerns with gastrointestinal intolerance, and provides effective treatment for at least 12 months with a single dose. We review the evidence for the therapeutic effect of IV ZOL for the treatment of PMO and its potential role in the management of PMO in clinical practice.

Osteoporosis is a systemic skeletal disease that affects over 200 million people worldwide. About 30% of all postmenopausal women have osteoporosis in the United States (US) and European Union (EU), and 40% of these women will sustain one or more fragility fractures in their remaining lifetime,[1] with the incidence of fractures increasing with advancing age.[2] Osteoporosis is diagnosed by measuring a patient’s BMD by dual-energy X-ray absorptiometry (DXA) and applying criteria established by the World Health Organization (WHO): BMD 2.5 standard deviations or more below the mean BMD of a young-adult reference population (T-score≤–2.5) or occurrence of a fragility fracture. Risk factors for fractures that are independent of BMD include advancing age, previous fracture, family history of osteoporosis, cigarette smoking and chronic use of glucocorticoids.

Osteoporosis is underdiagnosed and undertreated.[3] Treated patients commonly take their medication incorrectly or for too short a time to benefit from fracture risk reduction.[4] A study of a large US pharmacy claims database showed that one-year adherence was better with weekly dosing compared with daily (45% versus 33%, respectively), but still suboptimal.[5] Poor adherence to therapy is associated with increased fracture risk, with fractures resulting in excess morbidity and mortality and high healthcare expenses.[4,6,7]

Treatment of PMO
The aim of treatment is to prevent development of osteoporosis and decrease the risk of fracture. Universal recommendations from the National Osteoporosis Foundation for all adults include a daily intake of at least 1,200mg elemental calcium with diet plus supplements, if needed; vitamin D3 800–1,000 International Units (IU) per day; regular weight-bearing exercise; and avoidance of cigarette smoking and excessive alcohol use.[8]

Oral bisphosphonates (alendronate, ibandronate, risedronate) are first-line therapy for most patients with PMO. These drugs increase bone strength and reduce fracture risk by reducing bone resorption and increasing BMD.[9] However, oral bisphosphonates have low bioavailability and require daily, weekly or monthly administration after an overnight fast with a glass of plain water, followed by a postdose fast of 30–60 minutes while maintaining an upright position. The complex dosing regimen and gastrointestinal intolerance that sometimes occur in clinical practice are factors that may reduce compliance and persistence to therapy.

IV bisphosphonates (ibandronate, ZOL) for the treatment of PMO are given at intervals of 3 and 12 months, respectively, providing a simple dosing regimen that assures 100% bioavailability, no concern of gastrointestinal adverse effects and prolonged suppression of bone turnover. These may be considered for first-line therapy of PMO, and are especially useful for patients with malabsorption, gastrointestinal intolerance or contraindications with oral bisphosphonates.

IV ZOL is the newest IV bisphosphonate to be approved as treatment for PMO in the EU, US and other countries.

Dosage and use in PMO
ZOL is administered as a 5 mg IV infusion over at least 15 minutes every 12 months. ZOL should be used with caution in patients taking other nephrotoxic drugs,[10] and is not recommended in patients with creatinine clearance <35ml/min, history of hypersensitivity to bisphosphonates, or hypocalcaemia.

Efficacy of ZOL for treatment of PMO
Evidence for the role of ZOL in the treatment of PMO comes from two large phase III randomised, doubleblind, placebo-controlled clinical trials: Health Outcomes and Reduced Incidence with ZOL Once Yearly (HORIZON) Pivotal Fracture Trial (PFT)[11] and HORIZON– Recurrent Fracture Trial (HORIZON-RFT).[12] Both studies excluded patients with previous use of anabolic agents, sodium fluoride or strontium; hypocalcaemia or hypercalcaemia; or creatinine clearance less than 30.0 ml/min.

HORIZON-PFT, an international study enrolling 7,765 postmenopausal women (age 65–89 years, mean 73 years) with PMO, found that yearly IV ZOL infusions significantly reduced the incidence of fractures over a period of 3 years. Subjects were randomised to receive a 15-minute IV infusion of ZOL 5 mg (n=3,889) or placebo (n=3,876) at baseline, 12 months and 24 months. All subjects received supplemental calcium 1,000–1,500 mg and vitamin D 400–1,200 IU per day. Primary endpoints were new vertebral fractures and hip fractures. Overall, 3- year use of ZOL significantly increased BMD and reduced bone turnover markers, with a 70% decrease in the risk of morphometric vertebral fractures (absolute risk reduction [ARR] 7.6%), 41% decrease in hip fractures (ARR 1.1%) and 25% decrease in nonvertebral fractures (ARR 2.7%).

HORIZON-RFT evaluated the efficacy and safety of a yearly 15-minute IV infusion of ZOL 5mg (n=1,065) or placebo (n=1,062) in ambulatory women and men (mean age, 74.5 years), with the first dose administered within 90 days after surgical repair of a low-trauma hip fracture. The duration of the study was event-driven, with 211 clinical fractures required to have a power of 90% to detect a 35% reduction in the rate of clinical fracture in the ZOL group compared with the placebo
group. All patients received daily supplementation with oral calcium (1,000–1,500mg) and vitamin D (800–1,200IU).

The median follow-up was 1.9 years. The primary endpoint was a new clinical fracture, excluding fractures of the face and digits, and fractures in abnormal bone, such as those seen with metastatic cancer. The main findings of the HORIZON-RFT study were that use of IV ZOL 5 mg within 90 days of low-trauma hip fracture was associated with a significant 35% decrease in the risk of clinical fractures (ARR 5.3%), 46% decrease in the risk of clinical vertebral fractures (ARR 2.1%) and 27% decrease in the risk of nonvertebral fractures (ARR 3.1%) compared with placebo. Also, for the first time in any randomised controlled clinical trial of a treatment for osteoporosis, a significant reduction in all-cause mortality of 28% was reported with the use of ZOL compared with placebo.

Tolerability and safety
Once-yearly IV infusion of ZOL 5mg for the treatment of PMO is safe and well tolerated.[11,12] The most commonly reported adverse event is an acute phase reaction, with symptoms that include pyrexia, myalgias, arthralgias and headache. These influenza-like symptoms typically begin in the first 24 hours after infusion and last no more than 3 days. This is rarely seen in patients previously treated with a bisphosphonate; the risk may be reduced and the symptoms controlled with over-the-counter anti-inflammatory agents.

A mild, transient, clinically insignificant decrease in serum calcium and increase in serum creatinine have also been reported.[10] To reduce the risk of adverse metabolic effects, all patients should have adequate calcium and vitamin D intake, and be well hydrated before and after the IV infusion. Osteonecrosis of the jaw (ONJ) has been associated with bisphosphonate use, most often in patients with multiple myeloma or breast carcinoma who are given much larger cumulative doses than used for osteoporosis.[13]

In HORIZON-PFT, there no spontaneous reports of ONJ, with two potential cases, one in the ZOL group and one in the placebo group, identified after further review and expert adjudication. No cases of ONJ were reported in HORIZON-RFT. There is no evidence that the risk of ONJ is greater with IV bisphosphonates compared with oral bisphosphonates when used for the treatment of osteoporosis. ZOL was associated with an increased incidence of serious atrial fibrillation (but not the total atrial fibrillation) compared with placebo in HORIZON-PFT,[11] but other studies examining  the relationship between bisphosphonate use and atrial fibrillation have shown mixed results.[14,15]

It is not known whether any bisphosphonate increases the risk of atrial fibrillation, and the limited evidence suggests that this theoretical concern should not alter treatment decisions in any way.

Clinical value
Osteoporosis is a major public health problem with serious clinical and economic consequences. The use of a once-yearly IV ZOL offers the potential to improve effectiveness in clinical practice by providing 100% bioavailability, eliminating concern of malabsorption of oral bisphosphonates due to intestinal disease or incorrect administration, and providing drug that reduces bone turnover for at least one year after a single infusion.

Conclusion
IV ZOL 5mg has been shown to significantly decrease the risk of vertebral, hip and other fractures in women with PMO and to reduce the risk of new clinical fractures and all-cause mortality in women and men after hip fractures. The assured adherence over the 1-year period may translate into greater real-world fracture protection than has been available in the past. Further
studies are needed to evaluate the efficacy and safety of IV ZOL beyond 3 years, and its benefits, risks and cost-effectiveness in comparison with other therapeutic agents.

References
1. Melton LJ 3rd, Chrischilles EA, Cooper C, Lane AW, Riggs BL. Perspective. How many women have osteoporosis? J Bone Miner Res 1992 Sep;7(9):1005-10.
2. Wasnich RD. Epidemiology of osteoporosis in the United States of America. Osteoporos Int 1997;7 Suppl 3:S68-72.
3. Nguyen TV, Center JR, Eisman JA. Osteoporosis: underrated, underdiagnosed and undertreated. Med J Aust 2004 Mar 1;180(5 Suppl):S18-22.
4. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc 2006 Aug;81(8):1013-22.
5. Recker RR, Gallagher R, MacCosbe PE. Effect of dosing frequency on bisphosphonate medication adherence in a large longitudinal cohort of women. Mayo Clin Proc 2005 Jul;80(7):856-61.
6. McCombs JS, Thiebaud P, McLaughlin-Miley C, Shi J. Compliance with drug therapies for the treatment and prevention of osteoporosis. Maturitas 2004 Jul 15;48(3):271-87.
7. Bliuc D, Nguyen ND, Milch VE, Nguyen TV, Eisman JA, Center JR. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women. JAMA 2009 Feb 4;301(5):513-21.
8. National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2008.
9. Rodan GA, Reszka AA. Bisphosphonate mechanism of action. Curr Mol Med 2002 Sep;2(6):571-7.
10. Lewiecki EM, Miller PD. Renal safety of intravenous bisphosphonates in the treatment of osteoporosis. Expert Opin Drug Saf 2007 Nov;6(6):663-72.
11. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007 May 3;356(18):1809-22.
12. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007 Nov 1;357(18): 1799-809.
13. Khosla S, Burr D, Cauley J, et al. Bisphosphonateassociated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2007 Oct;22(10):1479-91.
14. Heckbert SR, Li G, Cummings SR, Smith NL, Psaty BM. Use of alendronate and risk of incident atrial fibrillation in women. Arch Intern Med 2008 Apr 28;168(8):826-31.
15. Sorensen HT, Christensen S, Mehnert F, et al. Use of bisphosphonates among women and risk of atrial fibrillation and flutter: population based case-control study. BMJ 2008 Apr 12;336(7648):813-6.



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