Low fracture incidence, continued BMD increase with 10-year denosumab treatment
Postmenopausal women with osteoporosis had a low incidence of fracture and a continuous increase in bone mineral density (BMD) after 7–10 years of denosumab treatment, according to results of the open-label, 7-year extension of the phase III FREEDOM* trial.
“These findings suggest a continued favourable balance between benefit and risk through 10 years of treatment with denosumab,” said the researchers. “Fracture rates remained consistently low throughout the study, similar to rates observed in the active treatment group during FREEDOM and lower than in a virtual long-term placebo cohort. Our results support the skeletal safety of long-term treatment with denosumab,” they said. [Lancet Diabetes Endocrinol 2017;doi:10.1016/S2213-8587(17)30138-9]
Participants in the 3-year FREEDOM trial were 7,808 postmenopausal women aged 60–90 years with osteoporosis who were randomized to receive subcutaneous denosumab (60 mg) or placebo every 6 months for 3 years.
Women who completed the trial without treatment discontinuation or missing more than one dose of investigational drug were enrolled in the extension trial where all participants were given subcutaneous denosumab (60 mg) every 6 months and asked to take calcium (≥1.0 g) and vitamin D (≥400 IU) daily.
A total of 2,626 women completed the extension study (1,343 and 1,283 were given denosumab [long-term group] and placebo [crossover group] in the initial FREEDOM study, respectively, mean age 80.8 years at extension end).
Over the extension period, five and four subtrochanteric or diaphyseal femoral fractures occurred in the long-term and crossover groups, respectively, with one in each group determined as atypical.
The annual incidence of new vertebral and nonvertebral fractures in the long-term group was low (0.90–1.86 percent and 0.84–2.55 percent, respectively) during the extension period and comparable to that of the initial FREEDOM trial, while in the crossover group, incidence of new fractures was comparable to that in the first 7 years of denosumab treatment in the long-term group.
BMD increased over time in both the long-term and crossover groups (increase of 21.7 and 16.5 percent at the lumbar spine, 9.2 and 7.4 percent at total hip, 9.0 and 7.1 percent at femoral neck, and 2.7 and 2.3 percent at the one-third radius; p<0.05 for all, based on FREEDOM and extension baseline, respectively).
“Closing of the remodelling space and increases in secondary mineralization of bone matrix”, “modelling-based bone formation”, and “reductions in cortical porosity” were among the potential mechanisms behind the improvement in BMD, said the researchers.
Over the 10-year treatment period, yearly incidence of adverse events reduced from 165.3 to 95.9 per 100 participant-years among all individuals on denosumab, while the incidence of serious adverse events ranged from 11.5 to 14.4 per 100 participant-years.
Incidence of osteonecrosis of the jaw was comparable between groups (seven and six in the long-term and crossover groups, respectively). Aside from one patient who discontinued the study (long-term group) and one who withdrew consent (crossover group), all other cases were resolved. None of the participants developed neutralizing antibodies to denosumab.
However, the prescribing information for denosumab was revised to suggest a possible increase in incidence of osteonecrosis of the jaw with longer exposure, said the researchers.
“Given the need for long-term treatment in many people with osteoporosis, this evidence that the safety profile of denosumab remains stable over many years in an ageing population is important,” said Professor Juliet Compston from the University of Cambridge, UK, in a commentary. [Lancet Diabetes Endocrinol 2017;doi:10.1016/S2213-8587(17)30178-X]
“The results of our study support the use of denosumab as primary long-term therapy in patients with postmenopausal osteoporosis similar to our study population. [However], routine interruption of treatment is not recommended,” said the researchers.
“[Cessation] of denosumab is followed by rapid bone loss and an increase in the rate of vertebral fractures; therefore, if treatment is discontinued, patients should be switched to an alternative therapy,” cautioned Compston.