Study Summary: STAND

Background

Osteoporosis is a chronic progressive condition that increases bone fragility and risk of fracture. In 2000, an estimated 75 million people in the United States, Europe, and Japan were affected by osteoporosis. Given the numerous osteoporosis therapies and common therapy changes that may occur, the impact and effects of transitioning from one therapy to another are important clinical considerations. Bisphosphonates, such as alendronate, are one of the most common classes of agents used in osteoporosis; thus, it is important to consider the prolonged skeletal retention of bisphosphonates and other safety concerns when transitioning to another therapy.¹

Denosumab is a human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa-B ligand (RANKL). Its therapeutic effects are achieved through reducing bone resorption and increasing bone mineral density (BMD). Although bisphosphonates and denosumab both reduce bone resorption by impeding osteoclast activity and survival, RANKL inhibition disrupts osteoclasts at a more immature stage, before they adhere to the bone matrix, unlike bisphosphonates. Study findings show that denosumab, for up to 4 years, significantly increased BMD of the lumbar spine, hip, one-third radius, and total body compared with placebo. In postmenopausal women with osteoporosis, denosumab was shown to significantly reduce the risk of vertebral, nonvertebral, and hip fractures over 3 years. Compared with alendronate in treatment-naïve patients, denosumab showed greater increases in BMD of the hip, lumbar spine, and other sites.¹

Methods

In the phase 3 Study of Transitioning from Alendronate to Denosumab (STAND), investigators sought to evaluate the efficacy and safety of transitioning from alendronate to denosumab in postmenopausal women 55 years or older who had been receiving alendronate 70 mg/week for at least 6 months. A baseline lumbar spine or total hip BMD T-score of —2.0 or less and –4.0 or greater was required for enrollment. Patients were randomized to receive subcutaneous denosumab 60 mg injections every 6 months or to continue weekly alendronate 70 mg. Monitoring included BMD at 4 sites (lumbar spine, total hip, femoral neck, and one-third radius) via dual-energy x-ray absorptiometry scans and serum levels of type 1 C-telopeptide (CTX-1) and intact N-terminal propeptide of type 1 procollagen (P1NP), which have previously been established as biomarkers of bone turnover. The primary efficacy end point was the change in total hip BMD from baseline to month 12. Secondary end points included change in serum CTX-1 at month 3 and changes in BMD of the lumbar spine at month 12. Other endpoints included BMD changes at month 12 at the femoral and one-third radius sites. Safety end points included adverse events (AEs), changes in safety laboratory analytes, serum calcium levels, and vital signs.¹

Results

Of the 504 women enrolled, 481 completed the 12 months of follow-up. At baseline, the average BMD T-scores at the total hip and lumbar spine were —1.80 and –2.63, respectively, and 50% of patients previously had an osteoporosis-related fracture. The median baseline serum CTX-1 and P1NP levels (0.204 ng/ml and 22.1 µg/L, respectively) reflected prior bisphosphonate therapy.¹

With regard to BMD changes, a greater increase in total hip BMD from baseline was seen in the denosumab group than in the alendronate group (1.90% vs 1.05%). The between-group difference of 0.85% (95% CI, 0.44%-1.25%) demonstrated that denosumab was statistically superior to alendronate in increasing BMD at the total hip site and the lumbar spine (P <.0001 for both)(Table).¹ Statistically significant BMD increases with denosumab compared with alendronate were seen as early as month 6 at the lumbar spine and femoral neck (P <.01). The investigators conducted subgroup analyses to evaluate factors that may influence BMD when transitioning to denosumab, such as duration of prior alendronate therapy and baseline CTX-1. Subgroup analysis of BMD changes based on time-on-prior alendronate (6 to <12 months vs 12 to 24 months vs >24 months) showed that denosumab had greater increases in BMD than alendronate across all subgroups at all 4 sites. Although there was a pattern of larger BMD increases of denosumab in patients who had a shorter duration of alendronate therapy, the patterns at the other 3 sites differed and were not uniform. Subgroup analysis based on baseline CTX-1 level quartiles showed that the largest BMD increases with denosumab were in the 2 highest quartiles, whereas BMD changes with alendronate were similar across all quartiles.¹

Median baseline serum CTX-1 levels for the alendronate and denosumab groups (0.207 ng/ml and 0.187 ng/ml, respectively) were near the lower limit of the premenopausal reference range (0.2 ng/ml), which is expected in patients treated with bisphosphonates. CTX-1 levels remained relatively stable around baseline levels throughout the trial in the alendronate group. In the denosumab group, a significant decrease in CTX-1 levels was seen by day 5 after the first dose of denosumab, and reduced levels remained stable through month 3, evidencing a decrease in bone turnover. CTX-1 levels returned to near baseline by month 6, when the second dose of denosumab was to be administered. A similar trend was seen with the second dose of denosumab. With P1NP levels, a pattern similar to CTX-1 level changes with denosumab was seen; however, the decrease was slower. A more modest decrease in P1NP levels was seen in the alendronate group from months 3 to 9, with levels returning near baseline by month 12.¹

Percentage of patients who reported AEs was similar between the 2 groups (79% alendronate, 78% denosumab). The most common AEs reported by both groups were nasopharyngitis, back pain, bronchitis, arthralgia, constipation, and pain in an extremity. The percentage of patients reporting serious AEs (eg, infections and neoplasms) was also similar between groups (6.4% alendronate, 5.9% denosumab).¹

Discussion

Based on these results, the investigators found that denosumab had a similar safety profile to alendronate but was significantly more effective in increasing BMD and reducing bone turnover, as evidenced by the initial rapid reduction in serum CTX-1, than continued alendronate therapy in postmenopausal women with low BMD. The investigators deduced that the significantly greater increases in BMD and decrease in bone turnover with denosumab were attributed to its differing mechanism of action from alendronate. The investigators concluded that transitioning from alendronate to denosumab in postmenopausal women with low BMD may provide incremental increases in bone mass without increasing risk of AEs.¹

Reference

1. Kendler, DL, Roux C, Benhamou CL, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res. 2010;25(1):72-81. doi: 10.1359/jbmr.090716