Denosumab Therapy Associated With Poorer Bone Mineral Density Outcomes

DEXA scan for bone mineral density (BMD)
Female patient undergoing a DEXA (DXA) scan for bone mineral density.
Researchers analyzed bone mineral density changes following denosumab therapy for osteoporosis.

Treatment with denosumab for a medium duration of 4 to 6 years is associated with inferior bone mineral density gains and higher rebound-associated bone loss following continuation compared with short-duration (up to 3 years) or long duration (>7 years) treatment, according to study results published in Bone.

Researchers conducted a retrospective observational study that included 282 women with postmenopausal osteoporosis, all of whom discontinued denosumab (short duration [5±2 injections] n=144; medium duration [10±2 injections] n=84; long duration [15±2 injections] n=54) and received zoledronate 6 months later. Bone turnover markers (BTMs) were measured every 3 months among patients with longer therapy duration (at least 5 years), and patients with an at least 2-fold BTM level increase received a second zoledronate dose.

Measurement of BMD was performed at baseline before denosumab initiation, at the final dose, and 1 to 2 years after zoledronate initiation. The primary endpoint was fracture rate after discontinuing denosumab. Secondary endpoints included the growth of BMD and BTMs as well as identifying risk factors for bone loss and/or vertebral fractures.

After switching to zoledronate, bone loss was highest among patients in the medium-duration group compared with those in the short-duration group (P <.001 each for total hip, lumbar spine, and femoral neck), but there was no significant difference between medium and long durations (P =.54 for total hip; P =.35 for lumbar spine; P =.20 for femoral neck). Among patients who received at least 10 denosumab injections, some experienced elevated BTMs 6 months after initiating zoledronate.

A second zoledronate dose was administered to 24 patients who showed lower subsequent BTMs 3 months after the first infusion. Twelve months after denosumab discontinuation, women who received 2 doses of zoledronate showed comparable lumbar spine (P =.37) and hip (P =.97) bone loss with those who received a single dose.

Limitations to this study include possible confounding factors and selection bias.

The study authors conclude, “[D]enosumab treatment durations are ideally short (up to 3 years) or long (>7 years), but not medium (4-6 years),” as those “with medium-duration treatment did not achieve the best possible BMD gains under denosumab, and experienced the maximal rebound-associated bone loss after its discontinuation.” They indicated that further studies should focus on “the frequency and timing of [repeated] zoledronate infusions.”

Disclosure: This clinical trial was supported by OsteoRheuma Bern, Sandoz, and Novartis. Please see the original reference for a full list of authors’ disclosures.


Everts-Graber J, Reichenbach S, Gahl B, et al. Effects of zoledronate on bone mineral density and bone turnover after long-term denosumab therapy: observations in a real-world setting. Bone. Published online July 23, 2022. doi:10.1016/j.bone.2022.116498