Zoledronic acid

Zoledronic acid belongs to the bisphosphonate family. Its target in bone is the osteoclast, the cell responsible for breaking down old bone tissue. Inside this cell, it blocks a specific enzyme, farnesyl pyrophosphate synthase, which belongs to the mevalonate pathway. This enzyme makes molecules that the osteoclast needs to survive and to work.

By blocking this enzyme, the drug prevents the prenylation of small GTPase proteins that the osteoclast needs to function. Deprived of these proteins, the cell can no longer break down mineralised bone and eventually undergoes apoptosis, its programmed death. Bone resorption slows, bone loss reverses and the skeleton becomes stronger.

Zoledronic acid is indicated for the treatment and prevention of osteoporosis in postmenopausal women, to increase bone mass in men, in osteoporosis caused by corticosteroids and in Paget’s disease of bone. What these situations have in common is bone that breaks down faster than it rebuilds, which leaves it prone to fractures.

Its benefit was established by the HORIZON trial (Black et al., New England Journal of Medicine, 2007). In postmenopausal women with osteoporosis, a yearly 5 mg infusion reduces the risk of vertebral fractures by 70 percent and the risk of hip fractures by 41 percent over 3 years compared with placebo, with hip events falling from 2.5 to 1.4 percent.

Zoledronic acid is given as a 5 mg intravenous infusion, over at least 15 minutes, in a care setting. The schedule is one infusion per year to treat osteoporosis and one infusion every 2 years for prevention. Because it is given intravenously, the dose does not depend on meals or on a daily timing.

A single injection acts for a long time. Clearance from the blood occurs in three phases, with a terminal half-life of 146 hours, and 39 percent of the dose leaves unchanged in the urine within 24 hours. The rest binds to bone and is then released very slowly into the circulation, which explains the long duration of action and the spacing between infusions. The yearly schedule maintains this bone saturation from one infusion to the next.

The most common effect is a so-called acute phase reaction, which occurs in the days after the infusion and resembles a passing flu-like state: fever, joint and muscle pain, headache. It eases within a few days and lessens with later infusions. Over the whole 3-year follow-up, the adverse effects most often reported in the osteoporosis trial were arthralgia in 23.8 percent of patients, fever in 17.9 percent, headache in 12.4 percent, myalgia in 11.7 percent and a flu-like syndrome in 8.8 percent.

A marked drop in blood calcium, below 7.5 mg/dL, affected about 0.2 percent of patients, with no symptomatic form observed, which is why any hypocalcaemia should be corrected before the first infusion. Two rare but serious effects have been reported with bisphosphonates, including zoledronic acid: osteonecrosis of the jaw and atypical, low-energy femoral fractures. Thigh or groin pain should prompt an assessment for an incomplete femoral fracture.

The drug curbs the destruction of bone, but rebuilding calls for raw material. Supplementation is required during treatment: at least 1200 mg of calcium and 800 to 1000 IU of vitamin D per day in osteoporosis. Without these intakes, the benefit for bone strength cannot be fully expressed.

This foundation must be in place even before the first infusion. Hypocalcaemia and vitamin D deficiency must be corrected effectively before starting treatment, because zoledronic acid tends to lower blood calcium. Food is the simplest and most lasting way to maintain these reserves, alongside what the doctor may prescribe.

Kidney function is checked before each infusion, through a serum creatinine measurement and a clearance calculation using the Cockcroft-Gault formula. The drug is contraindicated in cases of hypocalcaemia, creatinine clearance below 35 mL/min and acute kidney failure. This check determines the go-ahead for each yearly injection.

Some combinations call for caution. Other drugs that are toxic to the kidney, such as non-steroidal anti-inflammatory drugs, add to the renal risk. Loop diuretics increase the risk of hypocalcaemia, and aminoglycosides can prolong the lowering of blood calcium. Reporting all of one’s treatments allows the doctor to adjust the laboratory monitoring.