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Commentary and Observations from
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Novel Medication Sequencing for Treatment of Osteoporosis

Novel Medication Sequencing for Treatment of Osteoporosis

For the remainder of 2022, there are no new medications for osteoporosis expected to become available in the US. With more than 10 million Americans older than 50 years estimated to have osteoporosis, and close to 2 million suffering fragility fractures every year, where do we stand with the drugs we currently have in our arsenal? Is there anything we can do to simplify our regimens and decrease our costs while continuing to provide safe and effective fracture reduction care?

We know there is significant bone loss and increase in bone turnover markers (BTMs) and new vertebral fractures beginning as early as 7 months after a patient's last dose of denosumab (Dmab) for osteoporosis. This risk of new vertebral fractures is particularly high in those with compression fractures prior to treatment. An interesting Swiss study investigated the impact of Dmab followed by zoledronic acid (ZOL) on bone mineral density (BMD) and BTMs; the article is currently in press in the Journal of Clinical Densitometry. Patients in this study were mostly postmenopausal osteoporotic females, though a few men were included as well.

The aim of this Swiss study was to discern what would happen to BMD and BTMs in patients with osteoporosis after only 1 dose of Dmab followed by 1 dose of ZOL given 6 months later (n = 32). This group was compared to a group who received 2.5 years of Dmab, or 5 total doses, followed by 1 dose of ZOL 6 months later (n = 110). Both BMD and BTMs, when available, were measured before the treatment began and 18 months later.

The results were statistically significant and, at 18 months, showed BMD increase of 7.6% in the lumbar spine with the single dose of Dmab plus ZOL versus 5.6% with 5 doses of Dmab followed by ZOL. The same trend held true for BMD increases at the total hip and femoral neck at 18 months (See chart below).

% Change in BMD

Dmab (x1) plus ZOL (x1)

Dmab (x5) plus ZOL (x1)

P value

Lumbar Spine




Total Hip




Femoral Neck




The authors suggest that a rebound effect is seen with longer courses of Dmab, resulting in an overshoot of BTMs and increased risk of multiple vertebral fractures. They then suggest an "escape" of the rebound effect when only 1 dose of Dmab is used and followed by ZOL. The greater BMD increases at 18 months suggest that, with this treatment format, early postmenopausal osteoporotic females may reach a target goal of osteopenia (> –2.5 T-score) within a short treatment period.

It is important to note that this study included a small number of patients, did not provide fracture results, and was a retrospective analysis that may be subject to selection bias as reported by the authors. Hopefully, however, this study will serve as a format for future sequential treatment studies that meet reasonable costs and target goals for BMD gains.

  • Everts-Graber J, Lehmann T. Bone mass gains after one denosumab injection followed by zoledronate. J Clin Densitom. 2022;[Epub].
  • Cummings SR. 2018 Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Mineral Res. 2018;33:190.
  • Denosumab PI.

Filed under: Orthopedics, Rheumatology

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