Review of Zoledronic Acid (RECLAST) for the Treatment of Osteoporosis

In 2001 the Food and Drug Administration (FDA) approved zoledronic acid (RECLAST and generics) for the treatment and prevention of osteoporosis in postmenopausal women, a condition that occurs when bone mass and bone mineral density decline.[1] The FDA has also approved the drug to increase bone mass in men with osteoporosis, for the treatment and prevention of osteoporosis induced by glucocorticoid use, and for the treatment of Paget’s disease of bone in men and women. Zoledronic acid is administered as an intravenous infusion (5 milligrams in 100 milliliters [mL] of solution) once or every one or two years, depending on the indication.

Zoledronic acid is a bisphosphonate drug, which are often recommended as the first-line treatment for osteoporosis.[2] However, Public Citizen’s Health Research Group recommends only three oral bisphosphonates: alendronate (BINOSTO, FOSAMAX and generics), ibandronate (generics only) and risedronate (ACTONEL, ATELVIA and generics). Because these drugs are associated with serious adverse events, discussed in more detail below, we have designated them as Limited Use and recommend that they should only be used to treat patients at high risk of fractures.

Public Citizen’s Health Research Group has warned about zoledronic acid since 2005. In 2015, we designated it as a Do Not Use drug for osteoporosis treatment. In addition to adverse events associated with oral bisphosphonates, zoledronic acid increases the risk of kidney damage.[3]

Based on a review of new evidence, we now designate zoledronic acid as a Limited Use drug for osteoporosis in postmenopausal women who are at high risk of fractures but cannot tolerate oral bisphosphonates.

Efficacy and safety of zoledronic acid for osteoporosis

FDA approval of zoledronic acid for the treatment of osteoporosis was based on two clinical trials.[4] Both trials showed that, compared with placebo, zoledronic acid significantly increased bone mineral density and significantly reduced the incidence of fractures.

The first trial was a three-year placebo-controlled study of 7,736 postmenopausal women with osteoporosis who were randomized to receive zoledronic acid or placebo once a year.[5] The incidence of serious adverse events (29.2% vs. 30.1%) and all-cause mortality (3.4% vs. 2.9%) was comparable between participants in the zoledronic acid and placebo groups, respectively.

The second trial randomized 2,127 women and men with osteoporosis who had a hip fracture following a minor trauma to receive either zoledronic acid or placebo once a year.[6] The incidence of serious adverse events (38.3% vs. 41.3%) and all-cause mortality (9.6% vs. 13.3%) was lower in the zoledronic acid-treated participants than in those who received placebo.

Efficacy and safety of oral versus intravenous bisphosphonates

Bisphosphonates, including zoledronic acid, are effective in preventing fractures, including hip fractures, in postmenopausal women who are at high risk of fractures.[7],[8] Several studies have found that the efficacy and safety of bisphosphonates are generally comparable.[9],[10]

However, all bisphosphonates are associated with serious adverse events, including hypocalcemia (low blood calcium levels); kidney disease; severe muscle, bone and joint pain; and atypical femur (thigh bone) fractures.[11],[12] Another rare but serious adverse event is osteonecrosis (bone loss) of the jaw. For oral bisphosphonates, the risk is about 1 in 10,000 to 1 in 100,000 patient-years.

Intravenous zoledronic acid has additional adverse effects.[13] These include flu-like symptoms, usually within the first three days after the infusion, such as fever, headache, and muscle and joint pain,[14] as well as nausea, diarrhea and vomiting.

The timing of adverse events also differs between oral and intravenous bisphosphonates.[15] A systematic review and meta-analysis of eight trials including a total of 1,863 participants compared yearly injections with zoledronic acid to oral alendronate once a week for osteoporosis. The study found that in the first three days after the bisphosphonate dose, alendronate was associated with significantly lower rates of adverse events overall than zoledronic acid. After three days, however, patients who received alendronate had a significantly higher incidence of gastrointestinal adverse events than those who received zoledronic acid. These gastrointestinal adverse events can persist throughout treatment.

For people with osteoporosis at high risk of fractures who cannot tolerate oral bisphosphonates, zoledronic acid can be an alternative.[16]

Bisphosphonates are stored in bones for long periods and are released slowly over time.[17],[18] For this reason, continuous treatment beyond a few years doesn’t appear to offer additional benefits and may instead increase the risk of adverse events.

Public Citizen’s Health Research Group therefore recommends that treatment with oral bisphosphonates should generally be limited to five years. According to the prescribing information, treatment with zoledronic acid should be discontinued after three to five years, although the optimal treatment duration is not known.[19]

To provide more information about the duration of treatment, a 2025 study investigated whether infusions with zoledronic acid every five or ten years instead of yearly were effective for the prevention of vertebral fractures.[20] Funded by the Health Research Council of New Zealand, the trial included 1,003 postmenopausal women between the ages of 50 and 60 years not previously diagnosed with osteoporosis. The participants were divided into three groups; those in the first group received zoledronic acid both at the start of the trial and at five years, those in the second group received zoledronic acid at the start of the trial and placebo at five years, and those in the third group received only placebo.

The study found that treatment with zoledronic acid only once or twice over 10 years was effective in preventing vertebral fractures. In the study, 6.3% of participants who received two infusions of zoledronic acid and 6.6% of those who received one infusion had a vertebral fracture, compared with 11.1% of those in the placebo group.

Kidney disease

Zoledronic acid has been associated with impaired kidney function and kidney failure that may lead to hospitalization or dialysis; these serious adverse events can occur even after a single infusion.[21] A 2022 study that was based on a review of the electronic health records of 327 osteoporosis patients aged 75 or older who collectively received a total of 558 infusions, found that acute kidney injury occurred in 1.4% of these patients.[22]

Zoledronic acid should not be used by people with a creatinine clearance of less than 35 mL/min, an indicator of decreased kidney function.[23] Kidney function and the use of other drugs with kidney risks should be assessed prior to treatment, and patients should be well hydrated before receiving a zoledronic acid infusion.

What You Can Do

If you have osteoporosis, speak to your clinician. Certain lifestyle approaches not only help prevent osteoporosis but also can be used to treat it. These include weight-bearing and balance-maintaining exercises, adequate calcium and vitamin D intake, low or no alcohol consumption, and smoking cessation.

If drug treatment is needed, bisphosphonates such as alendronate, ibandronate and risedronate are recommended as initial treatments but should be limited to patients with high fracture risk. Although zoledronic acid does not appear to be more beneficial than oral bisphosphonates, the drug is an alternative for those who do not tolerate oral bisphosphonates.
 

References

[1] Sandoz. Label: zoledronic acid (RECLAST). November 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5a9b3737-9ce6-4a89-b76e-6aab79eba9cf&type=display. Accessed August 13, 2025.

[2] New research shows bisphosphonates prevent osteoporosis-related hip fractures. Worst Pills, Best Pills News. April 2021. https://www.worstpills.org/newsletters/view/1391. Accessed August 13, 2025.

[3] Ibid.

[4] Sandoz. Label: zoledronic acid (RECLAST). November 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5a9b3737-9ce6-4a89-b76e-6aab79eba9cf&type=display. Accessed August 13, 2025.

[5] Ibid.

[6] Ibid.

[7] New research shows bisphosphonates prevent osteoporosis-related hip fractures. Worst Pills, Best Pills News. April 2021. https://www.worstpills.org/newsletters/view/1391. Accessed August 13, 2025.

[8] Rosen H.R. Bisphosphonate therapy for the treatment of Osteoporosis. UpToDate. Updated March 10, 2025.

[9] Wang Q, Yu Q, Zeng P, et al. Efficacy and safety of annual infusion of zoledronic acid and weekly oral alendronate in the treatment of primary osteoporosis: A meta-analysis. J Clin Pharmacol. 2023 Apr;63(4):455-465.

[10] Uehara M, Nakamura Y, Suzuki T, et al. Efficacy and safety of oral ibandronate versus intravenous zoledronic acid on bone metabolism and bone mineral density in postmenopausal Japanese women with osteoporosis. J Clin Med. 2021 Nov 20;10(22):5420.

[11] Sandoz. Label: zoledronic acid (RECLAST). November 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5a9b3737-9ce6-4a89-b76e-6aab79eba9cf&type=display. Accessed August 13A, 2025.

[12] Rosen H.R. Risks of bisphosphonate therapy in patients with osteoporosis. UpToDate. Updated January 9, 2025.

[13] Ibid.

[14] Sandoz. Label: zoledronic acid (RECLAST). November 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5a9b3737-9ce6-4a89-b76e-6aab79eba9cf&type=display. Accessed August 13 2025.

[15] Wang Q, Yu Q, Zeng P, et al. Efficacy and safety of annual infusion of zoledronic acid and weekly oral alendronate in the treatment of primary osteoporosis: A meta-analysis. J Clin Pharmacol. 2023 Apr;63(4):455-465.

[16] Rosen H.R. Bisphosphonate therapy for the treatment of osteoporosis. UpToDate. Updated March 10, 2025.

[17] A guide to treatments for osteoporosis. Worst Pills, Best Pills News. May 2015. https://www.worstpills.org/newsletters/view/960. Accessed August 13, 2025.

[18] Rosen H.R. Bisphosphonate therapy for the treatment of osteoporosis. UpToDate. Updated March 10, 2025.

[19] Sandoz. Label: zoledronic acid (RECLAST). November 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5a9b3737-9ce6-4a89-b76e-6aab79eba9cf&type=display. Accessed August 13, 2025.

[20] Bolland MJ, Nisa Z, Mellar A, et al. Fracture prevention with infrequent zoledronate in women 50 to 60 years of age. N Engl J Med. 2025 Jan 16;392(3):239-248.

[21] Sandoz. Label: zoledronic acid (RECLAST). November 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5a9b3737-9ce6-4a89-b76e-6aab79eba9cf&type=display. Accessed August 13, 2025.

[22] Fixen CW, Fixen DR. Renal safety of zoledronic acid for osteoporosis in adults 75 years and older. Osteoporos Int. 2022 Nov;33(11):2417-2422.

[23] Sandoz. Label: zoledronic acid (RECLAST). November 2023. https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=5a9b3737-9ce6-4a89-b76e-6aab79eba9cf&type=display. Accessed August 13, 2025.