How to Stop Bone Loss After Denosumab? No Easy Answers

Patients who discontinue treatment with the osteoporosis drug denosumab, despite transitioning to zoledronate, show significant losses in lumbar spine bone mineral density (BMD) within a year, according to the latest findings to show that the rapid rebound of bone loss after denosumab discontinuation is not easily prevented with other therapies — even bisphosphonates.

“When initiating denosumab for osteoporosis treatment, it is recommended to engage in thorough shared decision-making with the patient to ensure they understand the potential risks associated with discontinuing the medication,” senior author Shau-Huai Fu, MD, PhD, Department of Orthopedics, National Taiwan University Hospital Yunlin Branch, Douliu, Taiwan, told Medscape Medical News.

Furthermore, “integrating a case manager system is crucial to support long-term adherence and compliance,” he added.

The results are from the Denosumab Sequential Therapy prospective, open-label, parallel-group randomized clinical trial, published online on November 11 in JAMA Network Open.

In the study, 101 patients were recruited between April 2019 and May 2021 at a referral center and two hospitals in Taiwan. The patients, including postmenopausal women and men over the age of 50, had been treated with regular denosumab for at least 2 years and had no previous exposure to other antiosteoporosis medication.

They were randomized to treatment either with continuous denosumab at the standard dose of 60 mg twice yearly or to discontinue denosumab and receive the standard intravenous dose of the bisphosphonate zoledronate at 5 mg at the time when the next dose of denosumab would have been administered.

There were no differences between the two groups in serum bone turnover markers at baseline.

The current results, reflecting the first year of the 2-year study, show that, overall, those receiving zoledronate (n = 76), had a significant decrease in lumbar spine BMD, compared with a slight increase in the denosumab continuation group (−0.68% vs 1.30%, respectively; P = .03).

No significant differences were observed between the groups in terms of the study’s other measures of total hip BMD (median, 0% vs 1.12%; P = .24), and femoral neck BMD (median, 0.18% vs 0.17%; P = .71).

Additional findings from multivariable analyses in the study also supported results from previous studies showing that a longer duration of denosumab use is associated with a more substantial rebound effect: Among 15 of the denosumab users in the study who had ≥ 3 prior years of the drug, the reduction in lumbar spine BMD was even greater with zoledronate compared with denosumab continuation (−3.20% vs 1.30%; P = .003).

Though the lack of losses in the other measures of total hip and femoral neck BMD may seem encouraging, evidence from the bulk of other studies suggests cautious interpretation of those findings, Fu said.

“Although our study did not observe a noticeable decline in total hip or femoral neck BMD, other randomized controlled trials with longer durations of denosumab use have reported significant reductions in these areas,” Fu said. “Therefore, it cannot be assumed that non-lumbar spine regions are entirely safe.”

Fracture Risk Is the Overriding Concern

Meanwhile, the loss of lumbar spine BMD is of particular concern because of its role in what amounts to the broader, overriding concern of denosumab discontinuation — the risk for fracture, Fu noted.

“Real-world observations indicate that fractures caused by or associated with discontinuation of denosumab primarily occur in the spine,” he explained.

Previous research underscores the risk for fracture with denosumab discontinuation — and the greater risk with longer-term denosumab use, showing an 11.8% annual incidence of vertebral fracture after discontinuation of denosumab used for less than 2 years, increasing to 16.0% upon discontinuation after more than 2 years of treatment.

Randomized trials have shown sequential zoledronate to have some benefit in offsetting that risk, reducing first-year fracture risk by 3%-4% in some studies.

In the current study, 3 of 76 participants experienced a vertebral fracture in the first year of discontinuation, all involving women, including two who had been receiving denosumab for ≥ 4 years before medication transition.

If a transition to a bisphosphonate is anticipated, the collective findings suggest doing it as early on in denosumab treatment as possible, Fu and his colleagues noted in the study.

“When medication transition from denosumab is expected or when long-term denosumab treatment may not be suitable, earlier medication transition with potent sequential therapy should be considered,” they wrote.

Dosing Adjustments?

The findings add to the evidence that “patients who gain the most with denosumab are likely to lose the most with zoledronate,” Nelson Watts, MD, who authored an editorial accompanying the study, told Medscape Medical News.

Furthermore, “denosumab and other medications seem to do more [and faster] for BMD in the spine, so we expect more loss in the spine than in the hip,” said Watts, who is director of Mercy Health Osteoporosis and Bone Health Services, Bon Secours Mercy Health in Cincinnati.

“Studies are needed but not yet done to see if a higher dose or more frequent zoledronate would be better for BMD than the ‘usual’ yearly dose,” Watts added.

The only published clinical recommendations on the matter are discussed in a position paper from the European Calcified Tissue Society (ECTS).

“Pending additional robust data, a pragmatic approach is to begin treatment with zoledronate 6 months after the last denosumab injection and monitor the effect with bone turnover markers, for example, 3 and 6 months after the zoledronate infusion,” they recommended.

In cases of increased bone turnover markers, including above the mean found in age- and sex-matched cohorts, “repeated infusion of zoledronate should be considered,” the society added.

If bone turnover markers are not available for monitoring the patients, “a pragmatic approach could be administrating a second infusion of zoledronate 6 months after the first infusion,” they wrote.

Clinicians Need to Be Proactive From the Start

Bente Langdahl, MD, of the Medical Department of Endocrinology, Aarhus University Hospital in Aarhus, Denmark, who was a co-author on the ECTS position statement, added that clinicians should also be proactive on the other side of treatment — before it begins — to prevent problems with discontinuation, in commenting to Medscape Medical News.

“I think denosumab is a very good treatment for some patients with high fracture risk and very low BMD, but both patients and clinicians should know that this treatment is either lifelong or there needs to be a plan for discontinuation,” Langdahl said.

Langdahl noted that denosumab is coming off patent soon; hence, issues with cost could become more manageable.

But until then, “I think [cost] should be considered before starting treatment because if patients cannot afford denosumab, they should have been started on zoledronate from the beginning.”

Discontinuation Reasons Vary

Research indicates that, broadly, adherence to denosumab ranges from about 45% to 72% at 2 years, with some reasons for discontinuation including the need for dental treatment or cost, Fu and colleagues reported.

Fu added to Medscape Medical News, however, that other reasons for discontinuing denosumab “are not due to “need” but rather factors such as relocating, missing follow-up appointments, or poor adherence.”

Lorenz Hofbauer, MD, who is head of the Division of Endocrinology, Diabetes, and Bone Diseases, Department of Medicine III at the Technical University Medical Center in Dresden, Germany, noted that another issue contributing to some hesitation by patients about remaining on, or even initiating denosumab, is the known risk for osteonecrosis of the jaw (ONJ).

Though reported as being rare, research continuing to stir concern for ONJ with denosumab use includes one recent study of patients with breast cancer showing those treated with denosumab had a fivefold higher risk for ONJ vs those on bisphosphonates.

“About 20% of my patients have ONJ concerns or other questions, which may delay treatment with denosumab or other therapies,” Hofbauer told Medscape Medical News.

“There is a high need to discuss risk versus benefits towards a shared decision-making,” he said.

Conversely, however, Hofbauer noted that adherence to denosumab at his center is fairly high — at 90%, which he says is largely credited to an electronically supported recall system in place at the center.

Denosumab maker Amgen also offers patient reminders via email, text, or phone through its Bone Matters patient support system, which also provides access to a call center for questions or to update treatment appointment information.

In terms of the ongoing question of how to best prevent fracture risk when patients do wind up discontinuing denosumab, Watts concluded in his editorial that more robust studies are needed.

“The dilemma is what to do with longer-term users who stop, and the real question is not what happens to BMD, but what happens to fracture risk,” he wrote.

“It is unlikely that the fracture risk question can be answered due to ethical limitations, but finding the best option, [whether it is] oral or intravenous bisphosphonate, timing, dose, and frequency, to minimize bone loss and the rebound increase in bone resorption after stopping long-term denosumab requires larger and longer studies of better design.”

The authors had no disclosures to report. Watts has been an investigator, consultant, and speaker for Amgen outside of the published editorial. Hofbauer is on advisory boards for Alexion Pharmaceuticals, Amolyt Pharma, Amgen, and UCB. Langdahl has been a primary investigator on previous and ongoing clinical trials involving denosumab.