New Drug Update 2009-2010 - LAFP

alendronate (mean prior exposure, 4 years) were randomized to receive zoledronic acid 5 mg as a single
infusion plus 52 weeks of oral placebo (113 patients) or placebo infusion plus 52 weeks of oral
alendronate 70 mg (112 patients). Bone biopsy revealed nearly identical effects on static and dynamic
histomorphometric measures. BMD values did not differ between groups. Annual infusion was preferred
overall by 78.7% of patients; the once-a-week oral dosing was preferred by 9%. Substantially more
patients expressed the preference that the infusion was more convenient (79.2% vs 7.2%), the infusion
fits their lifestyle better (72.4% vs 8.1%), and they would be willing to take it for a longer period of time
(71.5% vs 9%). 28th Annual Meeting of the American Society for Bone and Mineral Research; September
15–19, 2006; Philadelphia, PA. Abstract SA357.and Abstract SU329.
The efficacy of zoledronic acid injection administered annually in the prevention of new clinical fracture is
also being assessed in a randomized, double-blind, placebo-controlled study enrolling 2,128 patients 50
years of age and older who have undergone surgical repair of a low-trauma hip fracture in the preceding
90 days (HORIZON-Recent Hip Fracture Trial RFT).N Engl J Med 2007;357: online 9/17/07.Mean age
was 74.4 years, and 76.1% were female. A prior osteoporotic fracture was reported for 45.3% of patents.
Patients received IV zoledronic acid 5 mg annually or placebo infusion annually. All patients received
vitamin D orally as a loading dose, followed by 800 units vitamin D3 and calcium carbonate 1,000 mg
daily. Concomitant therapy with calcitonin, hormone replacement therapy, selective estrogen receptor
modulators, tibolone, and external hip protectors was permitted. The primary study end point was
subsequent skeletal fractures; patients will be followed until 211 fractures have been reported. Secondary
outcomes included changes in BMD and health resource utilization. The rates of any new clinical fracture
were 8.6% in the zoledronic acid group and 13.9% in the placebo group, a 35% risk reduction with
zoledronic acid (P = 0.001); the respective rates of a new clinical vertebral fracture were 1.7% and 3.8%
(P = 0.02), and the respective rates of new nonvertebral fractures were 7.6% and 10.7% (P = 0.03). In the
safety analysis, 101 of 1054 patients in the zoledronic acid group (9.6%) and 141 of 1057 patients in the
placebo group (13.3%) died, a reduction of 28% in deaths from any cause in the zoledronic acid group (P
= 0.01). The most frequent adverse events in patients receiving zoledronic acid were pyrexia, myalgia,
and bone and musculoskeletal pain. No cases of osteonecrosis of the jaw were reported, and no adverse
effects on the healing of fractures were noted. The rates of renal and cardiovascular adverse events,
including atrial fibrillation and stroke, were similar in the two groups.
CONTRAINDICATIONS: The contraindications, warnings, and precautions for zoledronic acid are similar
to those of IV ibandronate and pamidronate. Zoledronic acid is contraindicated in patients with clinical
hypersensitivity to zoledronic acid monohydrate or other bisphosphonates, or any of the excipients in the
injectable formulation (mannitol, sodium citrate). When used in the treatment of osteoporosis and Paget
disease, zoledronic acid is also expected to be contraindicated in patients with uncorrected
hypocalcemia. Table 4 compares the contraindications associated with injectable ibandronate,
pamidronate, and zoledronic acid.
Table 4. Comparison of Contraindications Associated With Ibandronate, Pamidronate and
Zoledronic Acid Therapy
Contraindications Ibandronate Pamidronate Zoledronic Acid
Hypersensitivity to the product X X X
Hypersensitivity to other bisphosphonates X X
Uncorrected hypocalcemia
X
WARNINGS AND PRECAUTIONS: Because of the potential for renal toxicity, zoledronic acid should not
be administered at doses higher than the approved dosage, and the duration of infusion should be no
less than 15 minutes. In clinical trials, the risk of renal function deterioration was increased in patients
who received zoledronic acid over 5 minutes, compared with patients who received the same dose over
15 minutes. The risk of renal function deterioration and renal failure was also increased in patients
receiving an 8 mg dose, even when it was administered over 15 minutes.
The FDA reviewed spontaneous post-marketing reports of atrial fibrillation reported in association with
oral and intravenous bisphosphonates and did not identify a population of bisphosphonate users at
increased risk of atrial fibrillation. In addition, as part of the data review for the recent approval of onceyearly
Reclast for the treatment of postmenopausal osteoporosis, the FDA evaluated the possible
association between atrial fibrillation and the use of Reclast. Most cases of atrial fibrillation occurred more
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