A single dose of zoledronic acid (Reclast) given after 15 months of combination therapy with teriparatide (Forteo) and denosumab (Prolia) largely maintained the bone mineral density (BMD) gains in postmenopausal women with osteoporosis, a researcher reported.
In the open-label phase IV DATA-HD trial, 76 women received either 20 or 40 µg of teriparatide subcutaneously each day for 9 months, and at 3 and 9 months, they all received subcutaneous denosumab, 60 mg. Women who completed the combination phase of the study were then invited to participate in an extension phase; 53 did so and received a single dose of 5 mg intravenous zoledronic acid 24 to 35 weeks after the last dose of denosumab. Their mean age was 66.
“In postmenopausal women with osteoporosis, combination therapy with teriparatide and denosumab produces rapid and large gains in bone mineral density compared to monotherapy,” said Sabashini K. Ramchand, MBBS, of Harvard University in Boston, in a presentation at the virtual American Society for Bone and Mineral Research meeting.
“However, cessation of denosumab leads to prompt bone loss, loss of antifracture efficacy, and increased risk of multiple vertebral fractures. The current expert recommendation is to transition to a bisphosphonate when denosumab is discontinued, but the optimal drug, dose, and schedule remains undefined,” she said.
“We hypothesized that a single dose of zoledronic acid, 5 mg, would maintain the large and rapid increases in bone density induced by 15 months of overlapping teriparatide and denosumab in women at high risk of fracture,” she said.
High risk of fracture was defined at a BMD T-score ≤ -2.5 at any anatomic site; or a T-score ≤2 with one or more clinical risk factors; or a T-score ≤ -1 plus a history of fragility fracture.
At month 15 in DATA-HD, the average gain in BMD was 13.6% at the lumbar spine and 5.1% and 5.6% at the total hip and femoral neck, respectively. At month 27, 12 months after the single dose of zoledronic acid, these gains were maintained at all three sites, with changes since baseline of 13.8%, 5.1%, and 5.5%, respectively.
At month 42, which was 27 months after the single dose of zoledronic acid, bone density was only partially maintained at the lumbar spine, remaining 10.1% above baseline, but was maintained at the total hip and femoral neck, with changes of 4.8% and 6.4% from baseline.
She and her colleagues also looked at changes in serum biomarkers of bone turnover. At 15 months, osteocalcin, amino-terminal propeptide of type 1 collagen (P1NP), and C-telopeptide of type 1 collagen (CTx) all were suppressed, as expected with denosumab treatment. After the transition to zoledronic acid, a gradual return of the biomarkers toward baseline was observed. At 42 months, osteocalcin and P1NP concentrations were comparable to baseline, while CTx concentration remained suppressed at 32% below pretreatment baseline.
“It has also been hypothesized that administering a bisphosphonate while denosumab suppression of bone remodeling is still maximal may be less effective than if it was delayed until modeling has resumed,” Ramchand said.
They therefore analyzed responses according to when the zoledronic acid was given: early, less than 26 weeks after the last dose of denosumab; on time, at 26 to 30 weeks; or late, beyond 30 weeks.
At 27 months at the hip sites there appeared to be a beneficial effect on bond density of late, rather than early, administration of zoledronic acid, and at 42 months a similar pattern was observed but the results were no longer statistically significant.
“Our study was not designed to assess this endpoint, however, and was likely underpowered for this,” she cautioned.
While the findings indicate that the single dose of zoledronic acid was effective for maintaining the gains in spine and hip BMD for 12 months after administration, the subsequent return to baseline concentrations of bone turnover markers and the loss of some BMD at the spine “suggest that more frequent dosing of zoledronic acid is required,” she concluded.
The DATA-HD trial was funded by the NIH and the Dart Foundation.
Ramchand disclosed no relevant relationships with industry.