Always have an exit plan when starting patients on denosumab for osteoporosis, a leading endocrinologist has advised a meeting of rheumatologists.

Speaking to delegates at the Australian Rheumatology Association’s 2023 Annual Scientific Meeting in Hobart on 7 May, Associate Professor Frances Milat said denosumab could be an effective therapy, especially in the geriatric population, but urged clinicians to think ahead when prescribing the agent.

She said studies showed discontinuation led to accelerated bone loss and increased risk of multiple vertebral fractures, most of which occurred within one year of stopping.

However, denosumab cessation was recommended in certain circumstances, such as for patients with atypical femoral fracture (AFF), where continuation might lead to a worsening of the AFF or to a new contralateral AFF.

“Within a month [of stopping denosumab], [bone turnover markers] start their way upwards and… actually overshoot the placebo so that bone markers go higher than we would expect,” said Associate Professor Milat, deputy director of endocrinology and head of the Metabolic Bone Services at Monash Health.

“And with that we get those huge bone losses that occur very quickly.

“Typically within two years – all the bone is lost within two years, but most of the bone is lost within six months. I tell my registrars all the time that this is the critical time that you have to get in there and you have to do something.”

Associate Professor Milat, who is also head of the Metabolic Bone Research Group at the Hudson Institute, Melbourne, said most guidelines suggested transitioning to another antiresorptive agent like bisphosphonates, however the optimal regimen – such as whether to use oral alendronate acid or zoledronic acid and the optimal dosing schedule – remained unclear.

She referred to a clinical trial, published in the Journal of Bone and Mineral Research [link here] in 2020, led by Danish researcher Anne Sophie Sølling, of 61 participants (mean age 68), who discontinued denosumab after a mean 4.6 years of treatment.

Single intravenous infusion of zoledronate 5 mg given six or nine months after the last denosumab injection or when bone turnover was increased was not sufficient to maintain suppressed bone turnover markers or completely prevent bone loss but very high levels of bone markers and rapid bone loss were avoided.

Associate Professor Milat said zoledronate infusion six months after the last denosumab injection appeared the most attractive of the investigated options and there was potential for benefit from a second infusion 3-6 months later.

She also referred to the European Calcified Tissue Society position statement [link here] published in 2021, which suggested patients on denosumab for a short duration (up to 2.5 years) and with low fracture risk switch to oral bisphosphonates for 12-24 months or administer zoledronate for 1-2 years depending on re-evaluation of bone turnover markers and bone mineral density.

For denosumab treatment of a long duration (more than 2.5 years) and/or a high fracture risk, the recommendation was to continue denosumab for up to 10 years or switch patients to zoledronate, beginning six months after last denosumab injection with measurements of bone turnover markers three and six months later.

Repeat doses of zoledronate should be considered if markers were persistently increased, and where markers were not available, zoledronate administration should occur six and 12 months after last denosumab injection, she added.

In terms of other therapies, Associate Professor Milat said osteoanabolic agents reduced vertebral fracture risk by about 65-86% compared with placebo over 12-18 months of treatment as early as six months and were recommended as initial therapy for those classed as at “very high risk” of fracture in some guidelines.

Guidelines on denosumab cessation: 

Endocrine Society 2019 

• Denosumab administration should not be delayed or stopped without subsequent therapy.

American Association of Clinical Endocrinology 2020

• Continue denosumab for as long as clinically appropriate.
• Transition to another antiresorptive if denosumab therapy is discontinued.

Korean Endocrine Society 2021

• High-fracture-risk individuals are recommended to continue denosumab or continue with an alternative therapy (romosozumab) if necessary.
• All other patients patients should transition to one to two years of bisphosphonate use if denosumab is stopped.