Reclast (Zoledronic Acid) Rebound Effects When Stopping

Does stopping zoledronic acid cause a rebound?

A rebound means bone turnover overshoots after a drug is stopped, so bone resorption runs higher than it did before treatment began. That pattern is documented for denosumab. After a scheduled dose is omitted, bone turnover markers rise by 3 months and reach above baseline by 6 months, bone mineral density falls back to baseline by 12 months, and in a post hoc analysis of the FREEDOM trial and its extension the vertebral fracture rate rose from 1.2 per 100 participant-years on treatment to 7.1 per 100 participant-years off treatment [3].

The zoledronic acid extension data look different. Women who stopped after three annual infusions in the HORIZON extension trial showed a slow drift rather than a surge: over the next three years their bone turnover markers rose slightly and stayed well below pre-treatment levels, and their femoral neck bone density stayed above where it started [1].

Binding to bone

Zoledronic acid is not metabolized and is excreted unchanged by the kidneys [2]. The Reclast label attributes the drug's long duration of action to its high binding affinity to bone mineral, and notes that bisphosphonates are incorporated into the bone matrix and gradually released over a period of years [2].

What the extension trial measured

HORIZON-PFT randomized 7,765 postmenopausal women with osteoporosis to yearly zoledronic acid 5 mg or placebo for three years, and found morphometric vertebral fractures in 3.3% vs 10.9% (relative risk 0.30) and hip fractures in 1.4% vs 2.5% [4]. Women who completed that trial could enter an extension: 1,233 were randomized to three more years of yearly 5 mg zoledronic acid (n=616) or to placebo (n=617), so the second group effectively stopped after three doses [1].

• Bone density. Femoral neck bone mineral density stayed constant during continued treatment and dropped slightly after stopping. The difference between the two groups across years 3 to 6 was 1.04% (95% CI 0.4 to 1.7; p=0.0009), and density in both groups remained above pre-treatment values [1].
• Turnover markers. Biochemical markers stayed constant with continued treatment and rose slightly in the women who stopped, remaining well below pre-treatment levels in both groups [1].
• Fractures. New morphometric vertebral fractures were less frequent with continued treatment: 14 vs 30 (odds ratio 0.51; p=0.035). Other fractures did not differ between the groups [1].

The investigators concluded that after three annual doses many patients may stop for up to three years, while patients at high fracture risk, particularly for vertebral fracture, may benefit from continuing [1].

Who may benefit from continuing

The 2016 American Society for Bone and Mineral Research task force reviewed the extension data and reported that a low hip T-score predicted who benefited from continued treatment: between -2 and -2.5 in the alendronate extension trial (FLEX) and below -2.5 in the zoledronic acid extension [5]. The task force suggested reassessing fracture risk after 3 years of intravenous bisphosphonate therapy, and continuing for up to 6 years with periodic evaluation in women at high risk, such as older women, those with a low hip T-score or high fracture risk score, those with a previous major osteoporotic fracture, or those who fracture on treatment [5].

For women who are not at high fracture risk after 3 to 5 years of bisphosphonate treatment, the same report says a drug holiday of 2 to 3 years can be considered [5].

What the Reclast label says about how long to treat

The Reclast label states that the optimal duration of use has not been determined, that low-fracture-risk patients should be considered for drug discontinuation after 3 to 5 years of use, and that patients who stop need periodic fracture risk re-evaluation [2].

What is not known

The extension trial followed women for three years after their last infusion, so it does not describe what happens to bone density, turnover or fracture risk beyond that point [1]. The ASBMR task force described its approach as based on limited evidence, mostly vertebral fracture reduction in white postmenopausal women, and noted that it may be applicable to men and to glucocorticoid-induced osteoporosis with some adaptations [5].