Single Shot of Zoledronate Doesn't Preserve BMD After Denosumab

Pam Harrison

August 04, 2017

A single dose of the bisphosphonate zoledronate does not adequately prevent loss of bone-mineral density (BMD) typically seen after discontinuation of denosumab, a new case series report suggests.

The research was published in Calcified Tissue International by Prof Ian R Reid, of the University of Auckland, New Zealand, and colleagues.

Denosumab is a monoclonal antibody that acts as a potent antiresorptive agent and is now widely used in the treatment of osteoporosis.

However, when treatment is discontinued, bone resorption resumes rapidly and reaches twice baseline levels within 12 months after the last injection. As a result, over the first year off therapy, BMD declines significantly and fracture risk increases.

Oral Bisphosphonates More Effective After Stopping Denosumab?

Six patients involved in the phase 3 FREEDOM trial evaluating denosumab for the treatment of osteoporosis received 7 years of continuous denosumab, after which they received a single infusion of 5 mg of zoledronate 6 months after the last dose of denosumab.

At baseline, patients were 82.6 years of age and their spinal T score was -1.69. Total baseline hip T score was -1.96.

Over the course of the 7 years of denosumab treatment, spine BMD increased by 18.5% (= .006) while total hip BMD increased by 6.9% (= .03).

BMD was again measured 18 to 23 months after patients received the single infusion of zoledronate, at which point the researchers observed "significant declines" in BMD at both the spine (= .043) and at the hip (= .005).

BMD at the spine was still 9.3% higher post–zoledronate infusion than BMD levels prior to initiation of denosumab (= .003), the researchers point out.

However, the same was not true of BMD of the hip, which was not significantly different from BMD levels of the hip at baseline.

"At the time of postzoledronate BMD measurements, serum PINP levels were between 39 and 60 µg/L (mean, 52 µg/L), suggesting that the zoledronate treatment had not adequately inhibited bone turnover," the investigators observe.

PINP is one of the many markers of bone turnover currently in use and refers to serum type 1 procollagen.

As the authors observe, it's not clear whether more intensive dosing with zoledronate might better preserve BMD gains made with long-term treatment of denosumab.

However, evidence suggests that a single infusion of zoledronate suppresses bone resorption for a good 5 years, so investigators chose not to repeat the dose.

Others have reported that BMD remained stable after patients were crossed over from denosumab to oral weekly alendronate, although follow-up was limited to a single year (Osteoporos Int. 2012;23:317-326).

This might be because denosumab significantly reduces bone turnover, and therefore uptake of any subsequent bisphosphonate would be expectedly low until such time as bone turnover increases, thereby allowing greater skeletal uptake of an oral agent.

Thus, the researchers suggest that oral bisphosphonates might be more effective in the setting of denosumab discontinuation.

Alternatively, if an intravenous bisphosphonate is being considered to preserve BMD gains following treatment with denosumab, "their administration should be delayed until bone turnover markers have risen into the normal range," they advise.

It has also been reported that after the first year off denosumab, all gains in BMD made while on treatment are lost (J Clin Endocrinol Metab. 2011;96:972-980).

Dr Reid reports having received research grants and honoraria from Amgen, Novartis, Merck, and Lilly. The coauthors report no relevant financial relationships.

Calcif Tissue Int. Published online May 13, 2017. Abstract

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