Clinical Features of 24 Patients With Rebound‐Associated Vertebral Fractures After Denosumab Discontinuation: Systematic Review and Additional Cases

Abstract

We aimed to study the clinical and imaging characteristics of patients sustaining vertebral fractures after denosumab discontinuation. For this purpose, we conducted a computerized advanced literature search that identified 13 published cases, and we additionally included another 11 new cases from our centers. Twenty-four postmenopausal women with vertebral fracture(s) after denosumab discontinuation, experiencing 112 fractures in total, were analyzed. The mean number of fractures per patient was 4.7. The most commonly affected vertebrae were T12 and L1. All fractures occurred 8 to 16 months after the last denosumab injection. Eighty-three percent of the patients were treatment naïve, whereas 33% had prevalent vertebral fractures. Five (23%) patients were on concurrent aromatase inhibitor treatment. When patients were divided according to treatment duration with an arbitrary cut-off of 2 years, those with ≤2 years of denosumab treatment had fewer fractures compared with those with >2 years (mean ± SEM fractures 3.2 ± 0.7 versus 5.2 ± 1.4, p = 0.055). Vertebroplasty was used in 5 patients, resulting in additional clinical vertebral fractures in all cases. We conclude that vertebral fracture(s) after denosumab discontinuation are in the majority of patients multiples, and they occur a few months after the effect of the last dose is depleted. Therefore, patients should not delay or omit denosumab doses. Fractures are typically osteoporotic, located at the lower thoracic and the upper lumbar spine. Vertebroplasty is an unsuccessful treatment strategy for such patients. © 2017 American Society for Bone and Mineral Research.

Denosumab Prevents Early Periprosthetic Bone Loss After Uncemented Total Hip Arthroplasty: Results from a Randomized Placebo-Controlled Clinical Trial

“…Before study start, reports indicated loss of gained BMD and a rebound effect on biochemical markers of bone metabolism in postmenopausal women with osteopenia or osteoporosis 12 months after discontinuation of a 24‐month treatment with denosumab . After the start of the present study, several case reports and post hoc analyses of the extension of the randomized controlled Freedom study reported increased incidences of vertebral fractures after discontinuation of treatment with denosumab, especially in patients with prevalent vertebral fractures . The growing awareness of this rebound effect and the incidence of vertebral fractures have led to reviews of the literature and position statements from the European Calcified Tissue Society and the European Menopause and Andropause Society regarding the potentially negative effect on bone health after discontinuation of denosumab treatment .…”

Zoledronate for the Prevention of Bone Loss in Women Discontinuing Denosumab Treatment. A Prospective 2-Year Clinical Trial

“…There was no relationship between the number of Dmab injections and LS‐BMD changes (month 12 to 24) in either group of women; in the Dmab group, the correlation coefficient ( rs ) between changes in LS‐BMD and number of denosumab injections (4 to 10) was −0.155 ( p = 0.415). In the ZOL group, the respective rs was −0.002 ( p = 0.991).…”

“…In the FREEDOM study and its Extension, Dmab was shown to increase BMD to such levels in a substantial number of women with postmenopausal osteoporosis that might lead in clinical practice to treatment discontinuation when the target is reached. However, the effect of Dmab, as of other antiosteoporotic medications with the exception of bisphosphonates, is rapidly reversible and may be also associated in a few patients with increased incidence of clinical vertebral fractures . A strategy to consolidate and maintain the Dmab‐induced BMD gains for longer periods of time is, therefore, desirable.…”

“…Denosumab (Dmab), a monoclonal antibody against the receptor activator of nuclear factor κB ligand (RANKL), substantially decreases bone resorption and turnover, increases bone mineral density (BMD), and reduces the risk of fractures in women with postmenopausal osteoporosis . Cessation, of treatment, however, is followed by rapid reversal of its favorable skeletal effects, associated in a few patients with multiple vertebral fractures . This is attributed to an increase in bone turnover above pretreatment values, a response described as “rebound phenomenon” probably due to upregulation of osteoclastogenesis .…”

Optimizing Sequential and Combined Anabolic and Antiresorptive Osteoporosis Therapy

“…The mechanism by which teriparatide exerts this extensive pro‐remodeling effect in patients is undefined but may relate to teriparatide stimulating a large pool of previously quiescent osteoclast precursors in a synchronized fashion. Given the recent suggestion that the accelerated bone remodeling which occurs when denosumab is discontinued (even in the absence of adding a pro‐remodeling drug) is associated with an increase risk of compound vertebral fractures, it seems prudent to suggest that physicians avoid prescribing this specific drug transition …”