Fosamax vs Reclast (Zoledronic Acid): Switching Between Them

Is switching from Fosamax to Reclast a defined procedure?

The Reclast label sets the osteoporosis dose at 5 mg infused over no less than 15 minutes once a year and does not describe a transition from an oral bisphosphonate [1].

What the Reclast label does settle is what has to be in place before a first infusion. Reclast is contraindicated in hypocalcemia and in creatinine clearance below 35 mL/min or acute renal impairment, and the label states that creatinine clearance should be calculated with the Cockcroft-Gault formula using actual body weight before each dose [1]. It also states that hypocalcemia and mineral disturbances must be corrected before treatment [1].

How the two are taken

Alendronate is an oral bisphosphonate. The Fosamax label gives 70 mg once weekly for osteoporosis treatment, taken on arising at least 30 minutes before the first food, drink or medication of the day, with 6 to 8 ounces of plain water, staying upright for at least 30 minutes.

Reclast is given as a 5 mg intravenous infusion over no less than 15 minutes: once a year for treatment of postmenopausal osteoporosis, osteoporosis in men, and glucocorticoid-induced osteoporosis, or once every 2 years for prevention of postmenopausal osteoporosis [1]. The Reclast prescribing information states that the infusion is followed by a 10 mL normal saline flush and that patients should be appropriately hydrated before administration [1]. Reclast is not metabolized and is eliminated unchanged by the kidney, with a terminal elimination half-life of 146 hours [1].

Both drugs act on the osteoclast. Zoledronic acid inhibits osteoclast-mediated bone resorption, with farnesyl pyrophosphate synthase as its main molecular target in the osteoclast and high binding affinity to bone mineral accounting for its long action [1].

What the fracture trials show, and what they do not

The Fracture Intervention Trial enrolled 2,027 postmenopausal women with low femoral-neck bone density and at least one vertebral fracture, randomized to alendronate 5 mg daily (raised to 10 mg at 24 months) or placebo and followed for 36 months. New morphometric vertebral fractures occurred in 8.0% on alendronate versus 15.0% on placebo (relative risk 0.53, 95% CI 0.41 to 0.68); any clinical fracture occurred in 13.6% versus 18.2%, and the relative hazard for hip fracture was 0.49 (95% CI 0.23 to 0.99) [3].

HORIZON-PFT randomized 3,889 women to zoledronic acid 5 mg and 3,876 to placebo, given as three annual infusions. Morphometric vertebral fractures were 3.3% versus 10.9% (relative risk 0.30, 95% CI 0.24 to 0.38) and hip fractures 1.4% versus 2.5% (hazard ratio 0.59, 95% CI 0.42 to 0.83); nonvertebral, clinical and clinical vertebral fractures fell by 25%, 33% and 77% [4].

Neither trial compared the drugs with each other, and in FIT every woman had a prevalent vertebral fracture [3][4]. The two percentages describe each drug against placebo in different populations, not a head-to-head result.

What changes in the side-effect profile

Reclast's warnings are renal toxicity, osteonecrosis of the jaw, atypical femoral fractures, severe bone, joint and muscle pain, and hypocalcemia [1]. Its most common reactions, above 10%, are pyrexia, myalgia, headache, arthralgia and pain in extremity [1]. In the 3-year trial of 7,736 women, pyrexia occurred in 17.9% on Reclast versus 4.6% on placebo, myalgia 11.7% versus 3.7%, influenza-like illness 8.8% versus 2.7%, headache 12.4% versus 8.1% and arthralgia 23.8% versus 20.4% [1]. The acute phase reaction itself (fever 18%, myalgia 9%, flu-like symptoms 8%, headache 7%, arthralgia 7%) mostly appeared within the first 3 days and usually resolved within 3 days, up to 7 to 14 days, and was less frequent with later doses; when acetaminophen was given at the infusion and for 72 hours in the hip-fracture trial, fever was 7% and arthralgia 3% [1].

In the 3-year trial, serious atrial fibrillation was reported in 1.3% (50 patients) on Reclast versus 0.4% (17 patients) on placebo, with all atrial fibrillation events at 2.5% versus 1.9%; more than 90% occurred more than a month after the infusion, and an ECG substudy of 559 patients found no difference 9 to 11 days after dosing [1]. In the 2,127-patient hip-fracture trial, serious atrial fibrillation was 1.0% versus 1.2% [1].

Bisphosphonates carry rare class risks. Osteonecrosis of the jaw is estimated at 0.001% to 0.01% in osteoporosis patients, against 1% to 15% in cancer patients on high-dose intravenous therapy [5]; in the Reclast osteoporosis trial, one placebo patient and one Reclast patient had symptoms consistent with it [1]. The Reclast label says a routine oral examination should be performed before treatment begins [1]. Atypical femoral fractures carry an absolute risk of 3.2 to 50 cases per 100,000 person-years, up to about 100 with long-term use [6]; among 196,129 women on bisphosphonates, 277 atypical fractures occurred, with a hazard ratio of 8.86 for 3 to under 5 years of use and 43.51 for 8 years or more compared with under 3 months [7]. The Reclast label says patients with new thigh or groin pain should be evaluated [1].

Calcium and vitamin D around a switch

Reclast has an explicit daily target: an average of at least 1,200 mg calcium and 800 to 1,000 international units of vitamin D for osteoporosis, and for Paget's disease 1,500 mg elemental calcium in divided doses plus 800 international units of vitamin D, particularly in the 2 weeks after the infusion [1]. The Reclast label says preexisting hypocalcemia and mineral disturbances must be effectively treated before therapy starts [1].

How long to continue

The Reclast label says the optimal duration of use has not been determined, that its osteoporosis efficacy and safety data cover three years, that the need for continued therapy should be re-evaluated periodically, and that low-risk patients should be considered for discontinuation after 3 to 5 years [1].

The ASBMR task force put the reassessment point at 5 years of oral bisphosphonate or 3 years of intravenous bisphosphonate, suggested continuing for up to 10 years orally or 6 years intravenously in high-risk patients such as older women with a low hip T-score or a previous major osteoporotic fracture, and suggested a 2-to-3-year holiday for women not at high risk after 3 to 5 years [2].

What stopping looks like on each drug has been measured. In FLEX, 1,099 women who had taken alendronate for a mean of 5 years were randomized to continue or switch to placebo for 5 more years; stopping lowered total hip bone density by 2.4% and spine density by 3.7% relative to continuing, though levels stayed at or above pre-treatment values, nonvertebral fractures were the same (19% versus 18.9%) and clinical vertebral fractures were fewer with continuing (2.4% versus 5.3%) [8]. In the HORIZON extension, 1,233 women who had received 3 annual infusions were randomized to 3 more years or placebo; femoral neck density held steady with continued treatment and dropped slightly after stopping (between-group difference 1.04%), new morphometric vertebral fractures were 14 versus 30, and other fractures did not differ [9].

Switching back from Reclast to Fosamax

Zoledronic acid leaves the blood quickly but stays in bone. Plasma concentrations fall below 1% of peak within 24 hours [1], yet in the HORIZON extension bone density remained above pretreatment levels after treatment stopped, while bone-turnover markers remained well below pretreatment levels [9]. After stopping alendronate, mean bone density in FLEX remained at or above pretreatment levels five years later [8].