Rebound effect after denosumab discontinuation in a patient with lung cancer

Denosumab in oncology patients

Denosumab is an important part of treatment for patients with bone metastases. This monoclonal antibody inhibits osteoclasts and is more effective in patients with solid tumors than zoledronic acid in prolonging the time to bone-related events (pathologic fracture, radiation or surgery to the bone, or spinal cord compression). Denosumab is also indicated for osteoporosis treatment, but higher doses are used in oncological indications (120 mg once a month) compared to osteoporosis (60 mg every 6 months).

Due to the higher dosage and probably also because of the more vulnerable patient population, the rate of osteonecrosis of the jaw is higher, at 1.7% compared to 0.1% in osteoporosis patients. To reduce this risk, denosumab treatment is interrupted before invasive dental procedures. In osteoporosis cases, literature describes rebound vertebral fractures after discontinuing denosumab. This phenomenon is not widely described among oncology patients.

Case description

A 55-year-old woman with stage IV lung adenocarcinoma, previously treated with denosumab, presented for endocrine evaluation with 7 vertebral fractures that occurred over 4 months.

The patient was diagnosed with lung cancer in 2013, underwent surgery, and then four cycles of chemotherapy with cisplatin and pemetrexed followed by a negative positron emission tomography (PET) scan. Repeated PET/CT scans in December 2014 showed multiple hypermetabolic lymph nodes and a destructive rib lesion. Treatment with erlotinib at a dose of 150 mg daily and denosumab at a dose of 120 mg once a month was initiated. After 8 doses (December 2014 to September 2015), denosumab administration was interrupted due to necessary dental procedures. In May 2016, the woman received another dose of denosumab, but no subsequent doses due to ongoing dental issues. Repeat examinations in 2015 and 2016 showed a favorable therapeutic response to anti-tumor therapy until February 2017 when new lung lesions appeared on CT.

In August 2017, a chest CT showed a new compressive deformity of the thoracic vertebra T9. In October 2017, the patient lifted a heavy object and developed acute thoracic spine pain. Imaging revealed new fractures of the vertebral bodies T6, T12, and L1 with no identified bone metastases. New compression fractures of lumbar vertebrae L2, L3, and L4 were shown on a December 2017 CT. Due to persistent pain, kyphoplasty of vertebrae T6, T9, T12, and L1 through L4 was performed. Biopsies of these 7 vertebral bodies were negative for malignancy.

The patient had no previous osteoporotic fractures or height loss. There was a family history of osteoporosis in her aunt. The patient had been taking 2000 IU of vitamin D daily for many years, with a plasma 25-hydroxyvitamin D concentration of 94.9 nmol/L (within normal limits). Her only other risk factors included mild secondary hyperparathyroidism (parathyroid hormone range 5.3–11.9 pmol/L; norm up to 6.0 pmol/L) likely related to chronic kidney disease (estimated glomerular filtration range 30–40 mL/min) or inadequate calcium intake/absorption. Investigations for secondary causes of osteoporosis were otherwise negative. Bone densitometry in January 2018 showed a T score of the left femur of –1.7 with a Z score of –1.0 and a T score of the upper third of the radius of –0.6. Lumbar spine densitometry was unassessable due to kyphoplasty.

Discussion

Based on bone density and the absence of major secondary risk factors, this patient did not have an increased risk for compressive vertebral fractures. Although she had a rib metastasis, there were no signs of vertebral lesions, and her primary disease was responding to therapy. Thorough evaluation did not reveal a secondary cause that could explain 7 vertebral fractures over 4 months.

Since denosumab does not incorporate into the bone matrix like bisphosphonates, bone turnover is no longer suppressed once denosumab use is discontinued, and studies suggest subsequent accelerated bone resorption. Rebound fractures have not been described after the discontinuation of bisphosphonates. The patient in this case report did not experience vertebral fractures until 15 months after the last dose, which aligns with previous case studies of patients with vertebral fractures occurring 9–16 months after the last injection. Several studies have noted that 1–2 years after stopping denosumab therapy, markers of bone turnover and osteoclastogenesis rise to above-normal levels.

There is also some evidence that the increase in bone turnover markers and decrease in bone density after denosumab discontinuation correlate with the length of previous treatment. However, it is unclear if this is due to the duration of therapy or the cumulative dose. Patients taking oncology doses of denosumab (12 times the dose for osteoporosis) may have a higher risk of rebound fractures, so systematic review recommends not discontinuing denosumab in high-risk patients or potentially transitioning to another therapy, such as bisphosphonates. It is still uncertain whether it is safe to temporarily interrupt denosumab treatment in oncology patients for short periods (< 6 months, which is the common dosing interval for osteoporosis).

Conclusion

Although rebound fractures after denosumab discontinuation have been described in the literature for osteoporosis patients, this is the first published case of multiple vertebral fractures occurring in a patient treated with denosumab for oncology indications. It is likely that many cancer patients treated with denosumab succumb to their primary disease without interrupting denosumab treatment, hence the lack of reports on this phenomenon.

Patients receiving denosumab should be repeatedly educated on proper and effective oral hygiene, and invasive dental procedures should be performed before initiating this antibody treatment. Implementing such recommendations in a population with serious illness and urgent therapy needs is, of course, challenging. Similar to the importance of considering the risks and benefits of denosumab therapy in relation to osteonecrosis of the jaw before starting treatment, it is essential to consider the possibility of rebound vertebral fractures when planning to discontinue this therapy, or alternatively, to consider other treatments.

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Source: Tyan A., Patel S. P., Block S. et al. Rebound vertebral fractures in a patient with lung cancer after oncology-dose denosumab discontinuation: a cautionary tale. Mayo Clin Proc Innov Qual Outcomes 2019; 3 (2): 235–237, doi: 10.1016/j.mayocpiqo.2019.02.003.