From the Journals

Zoledronate maintains bone loss after denosumab discontinuation



Women with postmenopausal osteoporosis who discontinued denosumab treatment after achieving osteopenia maintained bone mineral density at the spine and hip with a single infusion of zoledronate given 6 months after the last infusion of denosumab, according to results from a small, multicenter, randomized trial published in the Journal of Bone and Mineral Research.

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The cessation of the monoclonal antibody denosumab is typically followed by a “rebound phenomenon” often attributed to an increase in bone turnover above pretreatment values caused by the up-regulation of osteoclastogenesis, according to Athanasios D. Anastasilakis, MD, of 424 General Military Hospital, Thessaloníki, Greece, and colleagues. Guidelines recommend that patients take a bisphosphonate to prevent this effect, but the optimal bisphosphonate regimen is unknown and evidence is inconsistent.

To address this question, the investigators randomized 57 postmenopausal women with osteoporosis who had received six monthly injections of denosumab (for an average of 2.2 years) and had achieved nonosteoporotic bone mineral density (BMD) T scores greater than –2.5 but no greater than –1 at the hip or the spine. A total of 27 received a single IV infusion of zoledronate 5 mg given 6 months after the last denosumab injection with a 3-week window, and 30 continued denosumab and received two additional monthly 60-mg injections. Following either the zoledronate infusion or the last denosumab injection, all women received no treatment and were followed until 2 years from randomization. All women were given vitamin D supplements and were seen in clinic appointments at baseline, 6, 12, 15, 18, and 24 months.

Areal BMD of the lumbar spine and femoral neck of the nondominant hip were measured at baseline, 12, and 24 months by dual-energy x-ray absorptiometry, and least significant changes were 5% or less at the spine and 4% or less at the femoral neck, based on proposals from the International Foundation for Osteoporosis and the National Osteoporosis Foundation USA.

At 24 months, lumbar spine BMD (LS‐BMD) returned to baseline in the zoledronate group, but decreased in the denosumab group by 4.82% from the 12‐month value (P less than .001).

The difference in LS-BMD changes between the two groups from month 12 to 24, the primary endpoint of the study, was statistically significant (–0.018 with zoledronate vs. –0.045 with denosumab; P = .025). Differences in changes of femoral neck BMD were also statistically significant (–0.004 with zoledronate vs. –0.038 with denosumab; P = .005), the researchers reported.

The differences in BMD changes between the two groups 24 and 12 months after discontinuation of denosumab (6 months after the last injection) for the zoledronate and denosumab group respectively were also statistically significant both at the lumbar spine (–0.002 with zoledronate vs. –0.045 with denosumab; P = .03) and at the femoral neck (–0.004 with zoledronate vs. –0.038 with denosumab; P = .007).

The authors observed no relationship between the number of denosumab injections and LS-BMD changes in either group of women; however, they noted that responses of individual patients to zoledronate were variable. For example, three women who took zoledronate experienced decreases of LS-BMD greater than the least significant change observed at 24 months, a finding which could not be explained by the timing of the infusion, baseline rate of bone turnover, or baseline BMD.

“It appears that intrinsic factors that still need to be defined may affect the response of a few individuals,” they wrote.

This was further illustrated by one patient in the zoledronate group who sustained clinical vertebral fractures associated with significant, unexplained decreases of BMD that could not be prevented with the zoledronate infusion.

“In clinical practice, it is, therefore, advisable to measure BMD at 12 months after the zoledronate infusion and decide whether additional treatment may be required,” the authors wrote.

Another significant finding reported by the authors was that neither baseline nor 12‐month bone turnover marker (BTM) values were associated with BMD changes in either group of women during the entire study period.

“Particularly important for clinical practice was the lack of a relationship in zoledronate-treated women; even when women were divided according to baseline median BTM values (below or above) there were no significant difference in BMD changes at 12 or 24 months,” they wrote.

“In a substantial number of women in the denosumab group BTMs were still above the upper limit of normal of the postmenopausal age 18 months after the last Dmab [denosumab] injection but also in 7.4% of patients treated with zoledronate at 2 years,” they added.

“Whether in the latter patients BTMs were also increased before the start of Dmab treatment, as it is known to occur in some patients with osteoporosis, or are due to a prolonged effect of Dmab withdrawal on bone metabolism could not be prevented by zoledronate, is not known because pretreatment data were not available,” the study authors noted.

For adverse events, in addition to the one patient in the zoledronate group with clinical vertebral fractures, three patients in the denosumab group sustained vertebral fractures.

“Prevalent vertebral fractures have been previously reported as the most important risk factor for clinical vertebral fractures following cessation of Dmab therapy [which] strongly suggest that spine x-rays should be performed in all patients in whom discontinuation of Dmab treatment is considered,” the authors wrote.

“In most women with postmenopausal osteoporosis treated with [denosumab] in whom discontinuation of treatment is considered when a nonosteoporotic BMD is achieved, a single intravenous infusion of zoledronate 5 mg given 6 months after the last Dmab injection prevents bone loss for at least 2 years independently of the rate of bone turnover. Follow-up is recommended, as in a few patients treatment might not have the expected effect at 2 years for currently unknown reasons,” they concluded.

The study was funded by institutional funds and the Hellenic Endocrine Society. Several authors reported receiving consulting or lecture fees from Amgen, which markets denosumab, as well as other pharmaceutical companies.

SOURCE: Anastasilakis A et al. J Bone Miner Res. 2019 Aug 21. doi: 10.1002/jbmr.3853.

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