Alendronate vs Zoledronic Acid: Which Bisphosphonate Is Right for You?

What is the actual difference between the two drugs?

Both are bisphosphonates that slow bone resorption by osteoclasts. Alendronate binds to bone mineral and inhibits osteoclast activity without interfering with osteoclast recruitment or attachment, so bone formation exceeds resorption at remodeling sites [1]. Zoledronic acid also inhibits osteoclast-mediated resorption, concentrates at sites of high bone turnover, and its main molecular target is farnesyl pyrophosphate synthase [2].

The two labels cover the same four areas: postmenopausal osteoporosis (treatment and prevention), osteoporosis in men, glucocorticoid-induced osteoporosis, and Paget's disease of bone [1][2].

Doses differ by route. Alendronate for postmenopausal osteoporosis and for osteoporosis in men is 70 mg once weekly or 10 mg daily; prevention is 35 mg weekly or 5 mg daily; glucocorticoid-induced osteoporosis is 5 mg daily, or 10 mg daily in postmenopausal women not taking estrogen; Paget's disease is 40 mg daily for six months [1]. Reclast is 5 mg intravenously over at least 15 minutes once a year for treatment of postmenopausal osteoporosis, for osteoporosis in men, and for treatment and prevention of glucocorticoid-induced osteoporosis. It is given once every 2 years for prevention of postmenopausal osteoporosis, and Paget's disease is a single 5 mg infusion [2].

One name trap: zoledronic acid comes as two different products. Reclast 5 mg is the osteoporosis and Paget's product. The 4 mg product, sold as Zometa and as generics, is for cancer-related uses: a single infusion for hypercalcemia of malignancy, and an infusion every 3 to 4 weeks for multiple myeloma and bone metastases. The Reclast label says a patient being treated with Zometa should not be treated with Reclast [2][5].

Do they prevent the same fractures?

The evidence for each drug comes from a separate placebo-controlled trial in a different population, so the percentages below are not a ranking.

In FIT-1, 2,027 postmenopausal women aged 55 to 81 with low femoral neck bone density and at least one vertebral fracture took alendronate (5 mg daily, raised to 10 mg at 24 months) or placebo for 36 months [3]. New morphometric vertebral fractures occurred in 8.0% versus 15.0% (relative risk 0.53, a 47% reduction), clinically apparent vertebral fractures in 2.3% versus 5.0%, and any clinical fracture in 13.6% versus 18.2%; the relative hazard for hip fracture was 0.49 [3].

In HORIZON-PFT, 7,765 women with a mean age of 73 and osteoporosis received 5 mg zoledronic acid or placebo at baseline, 12 months and 24 months [4]. Morphometric vertebral fractures occurred in 3.3% versus 10.9% (70% lower), hip fractures in 1.4% versus 2.5% (41% lower), with nonvertebral fractures 25% lower, clinical fractures 33% lower and clinical vertebral fractures 77% lower [4].

A second zoledronic acid trial enrolled 2,127 men and women within 90 days of surgery for a hip fracture: new clinical fractures occurred in 8.6% versus 13.9%, and death from any cause in 9.6% versus 13.3% over a median follow-up of 1.9 years [6].

Which side effects are more likely?

The two profiles differ in kind: alendronate's main concern is the upper gut, and zoledronic acid's is the days after the infusion and the kidneys.

Alendronate and the esophagus. The label describes esophagitis, esophageal ulcers and erosions, occasionally with bleeding and rarely followed by stricture or perforation, some severe enough to require hospitalization. Risk appears greater in people who lie down after the dose, do not swallow it with the full 6 to 8 ounces of water, or keep taking it after symptoms start [1]. In the two 3-year US and multinational studies, drug-related abdominal pain occurred in 6.6% on alendronate 10 mg daily versus 4.8% on placebo, and esophageal ulcer in 1.5% versus 0% [1]. In the larger FIT cohort, abdominal pain was 1.5% versus 1.5% [1], and FIT-1 reported no significant difference in adverse experiences, including upper gastrointestinal disorders [3].

Zoledronic acid and the days after the infusion. An acute-phase reaction is common after the first dose: fever 18%, myalgia 9%, flu-like symptoms 8%, headache 7% and arthralgia 7%, mostly within the first three days and usually resolving within three days [2]. Symptoms are less frequent with later doses, and the label notes that acetaminophen after the infusion may reduce them [2]. In the 3-year trial, a transient rise in serum creatinine within 10 days occurred in 1.8% versus 0.8% on placebo, and adjudicated serious atrial fibrillation in 1.3% versus 0.4% [2]. Eye inflammation (iritis, uveitis, episcleritis) occurred in up to 0.2% [2].

What do both labels warn about?

Osteonecrosis of the jaw. An international consensus review estimated ONJ incidence at 0.001% to 0.01% in osteoporosis patients, against 1% to 15% in cancer patients on high-dose intravenous therapy [7]. The Reclast label calls for a routine oral examination before treatment [2]; the alendronate label lists invasive dental procedures, cancer, chemotherapy, corticosteroids, poor oral hygiene and ill-fitting dentures as risk factors, and says stopping the bisphosphonate may reduce risk for patients who need invasive dental work, with the treating physician and oral surgeon deciding [1].

Atypical femoral fractures. An ASBMR task force put absolute risk at 3.2 to 50 cases per 100,000 person-years, up to about 100 per 100,000 with long-term use [8]. Among 196,129 women aged 50 and older on bisphosphonates, 277 atypical femur fractures occurred; the hazard ratio was 8.86 for 3 to under 5 years of use and 43.51 for 8 years or more, compared with under 3 months, and risk fell quickly after stopping [9]. After 3 years of use, about 149 hip fractures were prevented for every 2 atypical fractures in White women, and 91 prevented for every 8 in Asian women [9]. Both labels say new thigh or groin pain should prompt evaluation for a femoral fracture [1][2].

Bone, joint and muscle pain. Severe, occasionally incapacitating pain has been reported from one day to several months after starting. The alendronate label says to discontinue if severe, and the Reclast label says to withhold future doses [1][2].

Low calcium and pregnancy. The labels say hypocalcemia must be corrected before either drug [1][2]. Both labels say to discontinue when pregnancy is recognized, and bisphosphonates stay in bone for years [1][2].

How long is each drug taken?

Neither label fixes a course. The Fosamax label says the optimal duration has not been determined, that its efficacy and safety data cover four years, and that patients at low risk of fracture should be considered for discontinuation after 3 to 5 years [1]. The Reclast label says its osteoporosis data cover three years, that optimal duration is undetermined, and that low-risk patients should be considered for discontinuation after 3 to 5 years [2].

The American Society for Bone and Mineral Research suggests reassessing risk after 5 years of oral bisphosphonate or 3 years of intravenous bisphosphonate. Patients at high risk, such as older women, those with a low hip T-score, a previous major osteoporotic fracture, or a fracture on therapy, may continue up to 10 years orally or 6 years intravenously; for women not at high fracture risk after 3 to 5 years, a drug holiday of 2 to 3 years may be considered [10].

What happens off treatment has been measured for each drug. In FLEX, 1,099 women who had taken alendronate for a mean of 5 years were randomized to continue (n=662) or switch to placebo (n=437) for 5 more years. Stopping lowered total hip bone density by 2.4% and spine bone density by 3.7% relative to continuing, though levels stayed at or above pretreatment values. Nonvertebral fractures were the same (19% continuing versus 18.9% stopping), and clinical vertebral fractures were 2.4% with continuing versus 5.3% with placebo [11]. In the HORIZON-PFT extension, 1,233 women were randomized to 3 more years of zoledronic acid (n=616) or placebo (n=617); femoral neck bone density held steady on treatment and fell slightly off it, a 1.04% difference, remaining above pretreatment levels, and new morphometric vertebral fractures were 14 with continued treatment versus 30 after stopping, with other fractures no different [12].

Weekly pill or yearly infusion?

The Fosamax label gives strict instructions, and they matter for absorption: take it on arising, at least 30 minutes before the first food, drink or medication of the day, with 6 to 8 ounces of plain water, and do not lie down for at least 30 minutes and until after the first food of the day [1]. Coffee or orange juice taken with the tablet reduced bioavailability by about 60%, and bioavailability was negligible when it was taken with or up to 2 hours after a standardized breakfast [1].

Zoledronic acid replaces that with one appointment. The Reclast label says the infusion must run over at least 15 minutes, that patients must be hydrated beforehand, that creatinine clearance should be calculated before each dose, and that the prescriber should perform a routine oral examination before starting [2].

Adherence to oral bisphosphonates has been studied. In a claims analysis of 35,537 women aged 45 and older who received an alendronate or risedronate prescription, 43% were refill compliant and 20% persistent over 24 months; patients who were compliant or persistent had 20% to 45% lower relative risk of total, vertebral, nonvertebral and hip fractures [13]. This was an observational association, and the study did not include zoledronic acid.

Who should not take each?

Alendronate is contraindicated in esophageal abnormalities that delay emptying such as stricture or achalasia, in people who cannot stand or sit upright for at least 30 minutes, in hypocalcemia, and in hypersensitivity to any component; the oral solution is not for people at increased risk of aspiration [1]. It is not recommended when creatinine clearance is below 35 mL/min, and the label advises caution with active upper gastrointestinal problems such as Barrett's esophagus, dysphagia, gastritis, duodenitis or ulcers [1].

Reclast is contraindicated in hypocalcemia, in creatinine clearance below 35 mL/min or evidence of acute renal impairment, and in hypersensitivity to zoledronic acid [2]. The label also advises caution with loop diuretics and aminoglycosides, which can lower serum calcium, and with nephrotoxic drugs such as NSAIDs [2].

Matching the drug to the situation