Editorial

Effects and management of denosumab discontinuation

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) have been characterized with the use of oral bisphosphonates in osteoporosis and zoledronate in oncology. Uncertainties remain, though, with the occurrence of BRONJ related to the use of zoledronate in osteoporosis.

We aimed to estimate the incidence and characterize the risk factors of zoledronate-associated BRONJ in osteoporosis as compared with oral bisphosphonates in real life setting.

Cases of BRONJ associated with zoledronate, alendronate or risedronate were extracted from the French pharmacovigilance database up to 2020. The incidence of BRONJ was estimated as their respective numbers related to cases of BRONJ in patients treated with bisphosphonates for osteoporosis, over the same period, according to the Medic’AM database.

Between 2011 and 2020, BRONJ incidence with zoledronate was 9.6/100,000 patient-year (PY), significantly higher than with alendronate (5.1/100,000 PY, P < 0.001), and risedronate (2.0/100,000 PY, P < 0.001). The number of patients treated with bisphosphonates has steadily decreased by 44.5% over 10 years. Meanwhile, the incidence of BRONJ decreased (5.8/100,000 PY in 2011; 1.5/100,000 in 2020), although a rebound was observed in 2018, including 47.6% of BRONJ following denosumab. Apart from classical risk factors, recent dental cares stood out in more than 40% of BRONJ, and zoledronate had a shorter exposure time than oral bisphosphonates.

In a real-life setting, our data confirm that zoledronate-associated BRONJ in osteoporosis is scarce, seeming slightly more common compared with oral bisphosphonates. We also raise awareness of dental care guidelines and greater vigilance when using bisphosphonates in patients with previous exposure to denosumab.

A Fracture Liaison Service (FLS) was set up at Lille University Hospital in 2016. The purpose of this study was to assess persistence with osteoporosis treatment in patients from the FLS over a period of 1 year, and to determine predictors of discontinuation.

The study population comprised adults of both genders, aged 50 or over, admitted to Lille University Hospital between January 2016 and January 2019 for a low-trauma fracture and managed in our FLS. Outcomes included (1) persistence rate at 1 year after treatment initiation, (2) persistence rate at 2 years after treatment initiation, (3) persistence rate at 1 and 2 years after treatment initiation according to type of treatment, (4) predictors of non-persistence, and (5) reasons for discontinuing treatment over 1 year after initiation. Persistence was determined using the Kaplan–Meier method.

In all, 1224 patients (≥50 years old) with a recent history of low-trauma fracture (≤12 months) were identified. Of these, 380 patients – 79.2% female; mean (SD) age 76 (11) years – were seen at the FLS. In those 380 patients, 410 fractures were found and 360 of them (87.8%) were major fractures, breaking down as follows: vertebra (44%), hip (19%), proximal humerus (10%), and pelvis (8%). Osteoporosis treatment was prescribed for 367 (96.6%) patients and 275 of them began the prescribed treatment. The following anti-osteoporosis drugs were prescribed: zoledronic acid (n=150, 54.5%), teriparatide (n=63, 22.9%), and denosumab (n=39, 14.2%). Oral bisphosphonates were prescribed for a few patients (n=23, 8.4%). Persistence with osteoporosis medication (any class) was estimated at 84.1% (95% CI: 79.1% to 88.1%) at 12-month follow-up, and dropped to 70.3% (95% CI: 63.7% to 75.9%) at 24 months. When drug-specific analyses were performed using the Kaplan–Meier method, persistence rates at 12 and 24 months were found to be higher with denosumab than with any other treatment. Independent predictors of non-persistence at 12 months were ‘follow-up performed by a general practitioner (GP)’ – Odds Ratio (OR) for GP vs. FLS = 3.68; 95% CI, 1.52 to 8.90, p=0.004 – and ‘treatment with zoledronic acid’ – OR for zoledronic acid vs. denosumab = 3.39; 95% CI, 1.21 to 9.50, p=0.019; OR for zoledronic acid vs. teriparatide = 8.86; 95% CI, 1.15 to 68.10, p=0.035.

This study provides evidence of the success of our FLS in terms of long-term persistence with osteoporosis treatments. However, osteoporosis treatment initiation still needs to be improved.

Recent reviews by the clinical bone research community suggest caution with prescription of drug holidays for patients with postmenopausal osteoporosis (PMO) treated with denosumab for an extended period of time. Main reasons for this suggestion are based on the fact that discontinuation of denosumab treatment leads to a relapse of osteoclastic bone resorption and a loss of bone mineral density (BMD) to pre-treatment levels at only 12–28 months. The question remains what is the best treatment option for cases where it is required to discontinue and/or reduce the drug dose and what are the consequences on BMD and bone turnover markers (BTMs). The latter questions are difficult to be addressed using clinical trials alone given the large number of parameter combinations involved to answer this problem.

In this paper, we apply a recently developed in silico mechanistic pharmacokinetic–pharmacodynamic (PK–PD) model of the effect of denosumab on bone remodelling in PMO. To address the above clinical relevant questions, we design a wide range of current and virtual treatment regimens to study the effect of drug holiday duration and therapy resumption on the evolution of BTMs, BMD and mineral content. Our numerical simulation results indicate the symptomatic effect of denosumab, which is lost once treatment is stopped. This effect is most clearly seen on rapid loss of BMD to pre-treatment levels 12 months after the last injection (8% and 3.6% per year in the lumbar spine and femoral neck, respectively). Also, we identify that independently of the duration of drug holiday (i.e. 12, 16 or 18 months) resuming treatment can restore BMD quite effectively. However, the latter result does not consider the possibility of potential fractures that can occur during the drug holiday. Finally, we identify a treatment case most promising for achieving maintenance of BMD and mineral content, while moderately increasing BTMs. The latter case uses no drug holiday, but reduces the most commonly prescribed denosumab dose (60 mg every 6 months) by half at same interval.

Denosumab is an antiresorptive drug with demonstrated efficacy in the treatment of osteoporosis. However, discontinuation of this agent is associated with increased bone turnover and rapid bone loss, and more recently, with the development of vertebral fractures (VF) in some patients. Therefore, the aim of the study was to analyze the clinical characteristics, bone metabolism parameters and evolution of a group of patients who developed vertebral fractures after denosumab discontinuation. In addition, we reviewed the literature on this subject.

During a period of 28 months (September 2015–January 2018) 7 women presenting spontaneous vertebral fractures after denosumab discontinuation were attended in the Rheumatology Department of our centre. We analyzed their clinical characteristics, bone metabolism parameters and evolution and reviewed the literature related to this subject.

The patients had received denosumab during 24–58 months (median 38), and developed a median of 5 VF per patient at 8–20 months (median 10) since the last dose of denosumab. Only 2 patients presented previous VF, and most (5 patients) received previous bisphosphonate treatment. After VF all restarted antiosteoporotic treatment with no further fractures during follow-up (median 19 months).

In this short series, previous bisphosphonate treatment does not seem to be a protective factor for the development of VF. The possible development of VF following discontinuation of denosumab must be taken into account in the clinical practice of physicians and dentists. Nonetheless, further studies are needed to improve the identification of patients at risk and the most adequate sequential treatment options.