Bisphosphonate Use Before Denosumab Reduces Rebound Risk

Prescribing a bisphosphonate after discontinuing denosumab could prevent rebound of bone decay symptoms, a new study shows.

Denosumab, which was approved by the US Food and Drug Administration (FDA) in 2018, strengthens bones in adverse circumstances—such as protecting bones in patients with cancer or reversing bone loss and improving BMD in postmenopausal women with osteoporosis.

IT is a human monoclonal antibody that binds to and inhibits NF-kB ligand (RANKL), a central regulator of bone metabolism, and by doing so prevents the maturation of osteoclasts.

Past studies have shown denosumab to be as effective as alendronate in preventing hip fracture in osteoporosis, and even superior to zoledronic acid in delaying skeletal-related events in advanced cancer. Unfortunately, studies have also indicated a persistent rebound problem in bone damage after a patient discontinues denosumab treatment, particularly in children.

The Rebound Effect Observatory in Lausanne (ReoLaus) Bone Project tracked bone turnover markers (BTMs), bone mineral density (BMD), and risk of spontaneous vertebral fractures in 71 patients for >1 year after their denosumab treatments ended.

Any lumbar spine BMD loss over 3.96% at 1 year after denosumab discontinuation (DD) categorized a patient as having suffered significant rebound, placing them in the 'losers' group. Investigators defined DD as beginning 18 months after a patient’s last denosumab injection.

The 71 patients studied were post-menopausal women, ages 63.8±8.1 years, who discontinued denosumab after 7.7±2.2 injections. These patients’ BMI varied from 23.8±4.5, with an average of 0.96 prevalent fractures per patient; 8.45% had been previously exposed to corticoids and 22.54% to anti-aromatases.

Thirty patients were classified as losers, as compared to 41 as 'stable,' 17.25 months after each patient’s last denosumab injection.

The losers group had several defining characteristics other than their rebound bone damage. First, they’d been younger than the stable patients when beginning denosumab injection treatment (61.4±7.3 versus 65.5±8.2 years, P= .034) and had higher spinal cervical traction (STCx) levels (644.7 versus 474.1 ng/ml, P= .005).

There was no difference between the losers and the stable in the rate of bisphosphonates (BP) given under 2 years before denosumab. The occurrence of fresh fractures was low (0.18/patient) in both groups. Initial BTM values, measured a median of 7.5 months after last injection, were comparable between groups (sCTX: losers, 592 ng/ml; stable, 379 ng/ml, P= .06).

Nevertheless, there were some key differences. Losers had never received zoledronate, while 12% of the Stable had (P= .047). At discontinuation in both groups combined, 59% received zoledronate, 24% alendronate, 3% others, and 14% nothing (P= .39 between groups). By nearly 13 months post-BP, losers had higher BTMS than stable (sCTX 537 vs. 336 ng/ml, P= .009).

Altogether, the study determined that low BMTs, receiving zoledronate prior to denosumab introduction, and younger patient age all reduce the risk of BMD loss.

“Our study suggests that being younger, having higher bone turnover markers and not having received zoledronate before denosumab introduction increase the risk of bone mineral density loss following discontinuation of denosumab,” said lead investigator Dr. Bérengère Aubry-Rozier, of the Rheumatology Unit at Lausanne University Hospital, Switzerland, in a statement.

Even if a bisphosphonate such as zoledronate was introduced at DD, this couldn’t counteract the losses caused by not receiving a bisphosphonate prior to initial denosumab.

“Our results support the use of denosumab after a bisphosphonate to reduce the bone mineral density loss at its discontinuation, and close monitoring of sCTX to maintain levels below the upper limit of the normal range for premenopausal women,” Aubry-Rozier said.

The study was presented at 2019’s Annual European Congress of Rheumatology (EULAR) in Madrid, Spain.