Reclast (Zoledronic Acid): What to Expect Week-by-Week in Your First Month

What does the first month actually look like?

Reclast is zoledronic acid 5 mg, given as an intravenous infusion over no less than 15 minutes and followed by a 10 mL normal saline flush [1]. For osteoporosis it is dosed once a year, or once every 2 years for prevention in postmenopausal women [1].

Most of the short-term trouble falls in the first three days after the dose. Most fever and aches resolve within 3 days, although they can last 7 to 14 days, and a temporary rise in creatinine was observed within 10 days in the osteoporosis trial [1]. The sections below go through those windows and then the rest of the month.

Days 1 to 3: fever, aches and the acute-phase reaction

In the three-year osteoporosis trial of 7,736 women, fever was reported by 17.9% of women on Reclast versus 4.6% on placebo, myalgia by 11.7% versus 3.7%, flu-like illness by 8.8% versus 2.7%, headache by 12.4% versus 8.1%, nausea by 8.5% versus 5.2%, and arthralgia by 23.8% versus 20.4% [1].

The label's acute phase reaction figures from that trial were fever (18%), muscle aches (9%), flu-like symptoms (8%), headache (7%) and joint aches (7%) [1]. Most of these symptoms occurred within the first 3 days after the infusion and usually resolved within 3 days, with resolution sometimes taking 7 to 14 days [1].

An allergic reaction is different. Known hypersensitivity to zoledronic acid or any Reclast component is a contraindication, and hives, swelling and anaphylaxis have been reported [1].

Acetaminophen is the one measure the label names: administration of acetaminophen following Reclast administration may reduce the incidence of acute-phase reaction symptoms [1]. When patients in the hip-fracture trial received acetaminophen at the time of the infusion and for 72 hours afterward, fever was reported in 7% and arthralgia in 3% [1].

For pain relief with an NSAID, the label advises caution with potentially nephrotoxic drugs such as NSAIDs [1], and it lists diuretics, advanced age and dehydration among the factors that raise renal risk [1].

Days 4 to 7: the reaction winds down

The label says the acute-phase symptoms usually resolve within 3 days, and in some patients up to 7 to 14 days [1]. It also states that these symptoms decrease with later doses [1].

The kidney data the label reports are tied to a 10-day window: a transient increase in serum creatinine occurred within 10 days of dosing in 1.8% of Reclast-treated patients versus 0.8% of placebo patients, and it resolved without specific therapy [1].

Kidney function and calcium around the infusion

Before each infusion, creatinine clearance is calculated with the Cockcroft-Gault formula using actual body weight, and the label contraindicates the drug at a creatinine clearance below 35 mL/min or with evidence of acute renal impairment [1]. Acute renal failure has been reported after a single dose, with rare hospitalization, dialysis or fatal outcomes in patients who had moderate to severe renal impairment or risk factors such as dehydration, diuretics or nephrotoxic drugs [1].

On the calcium side, hypocalcemia is a contraindication to Reclast, the label warns that hypocalcemia may worsen during treatment and is a significant risk after administration in Paget's disease, and it directs that patients be instructed about calcium and vitamin D supplementation [1]. For osteoporosis, an average of at least 1,200 mg calcium and 800 to 1,000 international units of vitamin D daily is recommended [1]. For Paget's disease the label specifies 1,500 mg elemental calcium daily in divided doses and 800 international units of vitamin D, particularly in the 2 weeks following the infusion [1].

Weeks 3 and 4: after the usual reaction window

By this point the usual flu-like reaction has typically resolved [1]. One timing detail matters for this window. In the three-year trial, adjudicated serious atrial fibrillation occurred in 1.3% of Reclast patients versus 0.4% on placebo, but more than 90% of these events happened more than a month after the infusion, and an ECG substudy of 559 patients found no difference between groups 9 to 11 days after dosing [1].

Other warnings on the label

These problems are not part of the ordinary flu-like reaction:

• Osteonecrosis of the jaw. The label says a routine oral examination should be performed by the prescriber before treatment starts, and that patients with risk factors should avoid invasive dental procedures if possible [1]. In the 7,736-woman osteoporosis trial, one Reclast patient and one placebo patient had symptoms consistent with osteonecrosis of the jaw; there were none in the 2,127-patient hip-fracture trial [1]. Most reported cases have been in cancer patients receiving intravenous bisphosphonates who had dental procedures [1].
• Atypical femoral fracture. The label states that patients with thigh or groin pain should be evaluated to rule out a femoral fracture, and that interrupting bisphosphonate therapy should be considered if one is found [1].
• Severe bone, joint and muscle pain. This is a separate warning from the ordinary acute-phase aches; the label says to withhold future doses if severe symptoms occur [1].
• Eye inflammation. Iritis, uveitis and episcleritis are reported with bisphosphonates; in the Reclast trials these occurred in up to 0.2% of patients [1].

When does fracture protection begin?

The fracture benefit is measured over years, not weeks. In HORIZON-PFT, 3,889 postmenopausal women were randomized to yearly zoledronic acid 5 mg and 3,876 to placebo for 3 years. Morphometric vertebral fractures occurred in 3.3% versus 10.9% (70% lower, relative risk 0.30), hip fractures in 1.4% versus 2.5% (41% lower, hazard ratio 0.59), and nonvertebral, clinical and clinical vertebral fractures were reduced by 25%, 33% and 77% respectively [2].

In the hip-fracture trial, 2,127 patients were randomized to yearly zoledronic acid (n=1,065) or placebo (n=1,062) within 90 days of fracture repair. Over a median follow-up of 1.9 years, new clinical fractures occurred in 8.6% versus 13.9% (35% lower) and deaths from any cause in 9.6% versus 13.3% [3].

What happens after three years

The label states that the optimal duration of Reclast has not been determined and that patients at low risk of fracture should be considered for discontinuation after 3 to 5 years, with periodic fracture risk re-evaluation if they stop [1]. In the extension study, 1,233 women who had already received 3 years of treatment were randomized to 3 more years of zoledronic acid (n=616) or placebo (n=617): femoral neck bone mineral density stayed level with continued treatment and dropped slightly after stopping, a between-group difference of 1.04%, though it remained above pre-treatment levels. New morphometric vertebral fractures were 14 versus 30 (odds ratio 0.51); other fractures did not differ [4].