Introduction
Osteoporosis is a chronic condition that requires long-term treatment. Increasing evidence supports treatment strategies designed to improve bone mineral density (BMD) until desired goals have been achieved and maintained in order to reduce the risk of fracture [
1,
2]. Therapies that stimulate bone formation can quickly increase BMD and improve bone microstructure. Such therapies increase bone strength [
3], resulting in a rapid reduction in fracture risk [
4,
5].
In the lifetime management of a patient with osteoporosis, more than one course of a therapy that stimulates bone formation may be clinically warranted. Currently available agents that stimulate bone formation, such as the parathyroid hormone (PTH) analogue teriparatide and the PTH receptor agonist abaloparatide, are limited to a combined 2 years of treatment in a patient’s lifetime due to lack of longer-term clinical data and carcinogenicity observed in animal models [
6,
7], thus generally limiting treatment to a single course of PTH agonist therapy.
Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin. This therapy for osteoporosis has a dual effect of increasing bone formation and decreasing bone resorption [
8,
9]. The first 12 months of this dose-finding, phase 2 study in postmenopausal women with low bone mass (
ClinicalTrials.gov, NCT00896532) evaluated the efficacy and safety of different romosozumab doses (70 mg, 140 mg, and 210 mg) administered by subcutaneous (SC) injection at 1- or 3-month intervals to identify the optimal romosozumab regimen [
8]. The 210 mg dose of romosozumab administered monthly (QM) for 12 months produced greater increases in BMD [
8], and was subsequently selected for further clinical development. This dose regimen was shown to reduce the risk of new vertebral, clinical, nonvertebral, and hip fractures in phase 3 pivotal fracture trials with 12 months of treatment [
4,
5], including in an alendronate-controlled active-comparator study [
5]. In an extension of the phase 2 study, we investigated the effects of switching from romosozumab to placebo or denosumab from month 24 to month 36 and observed that participants receiving denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels when romosozumab was switched to placebo without follow-on therapy [
10]. At month 36 of this phase 2 study, all participants were switched from placebo or denosumab to a second course of romosozumab 210 mg QM for another 12 months. Here, we report the efficacy and safety results of this second course of romosozumab treatment.
Discussion
The management of osteoporosis requires long-term therapy, which may include treatment with different agents, in sequence, over a patient’s lifetime [
12]. This study is the first to describe the efficacy and safety of a second course of romosozumab and provides further insight into potential treatment sequencing with this therapeutic agent.
In participants who received a second course of romosozumab following placebo, large BMD gains resulted at the lumbar spine, total hip, and femoral neck. These increases were similar in magnitude and rapidity to those observed during the initial 12 months of romosozumab treatment. The changes in bone turnover markers during the second course of romosozumab following placebo were also similar to those seen in the first romosozumab treatment course. The consistency and magnitude of the results of the second course of romosozumab compared with the first course of romosozumab therapy after 1 year without active therapy indicates that the responsiveness of the skeleton to sclerostin inhibition had fully reset within that time period, including the positive effect of romosozumab administration on modeling bone formation.
As bone mass and structure are major determinants of bone strength and thus fracture risk, it is reasonable to expect treatments that result in rapid and large gains in BMD to also result in faster and greater fracture risk reductions. Preclinical studies support maintenance of the relationship between bone mass and strength during romosozumab administration [
13,
14] and our study showed that a second course of romosozumab following placebo produced large and rapid gains in BMD, which were similar to those observed during the first romosozumab administration. In randomized controlled studies, large and rapid BMD gains with initial romosozumab treatment were demonstrated to result in significant reductions in fracture risk in postmenopausal women with osteoporosis, in comparison with not only placebo in the pivotal FRActure study in postmenopausal woMen with ostEoporosis (FRAME) [
4] but also with alendronate in the Active-controlled fRaCture study in postmenopausal women with osteoporosis at High risk (ARCH) [
5]. In FRAME, the large BMD increases with an initial 1 year of romosozumab treatment were associated with a rapid reduction in fracture risk. This benefit extended during year 2 [
4] and year 3 [
15], when all participants received denosumab. During the 24-month period after 12 months of romosozumab or placebo treatment, with all participants on denosumab in the second year, fewer fractures occurred in participants who first received romosozumab versus placebo in year 1. This suggests a persistent benefit from rapid bone mass accrual, conveying a stronger foundation on which to transition to denosumab treatment.
In our study, we also assessed switching from denosumab to romosozumab. BMD was either further increased (lumbar spine) or maintained (total hip) with romosozumab following denosumab. This stands in contrast to the declines in BMD after denosumab treatment that have been documented in studies evaluating the switching from denosumab to teriparatide, an agent that stimulates bone formation but also increases bone resorption. In the DATA-Switch study [
16], switching from denosumab to teriparatide showed transient losses in BMD at the spine and more pronounced losses at the hip in postmenopausal women with osteoporosis, demonstrating that the net effect of increased resorption from discontinuing denosumab cannot be fully compensated by teriparatide’s effect of stimulation of bone formation. This is not surprising given that teriparatide therapy also has a pro-remodeling effect, which may negatively affect BMD at cortical sites [
3,
17]. In contrast, in our study, continued BMD increases were observed at the lumbar spine, although these increases were of smaller magnitude than those observed in treatment-naïve patients. Hip BMD did not increase during the second course of romosozumab treatment following denosumab, but the bone-forming effects were sufficient to maintain BMD following denosumab discontinuation. This is explained by romosozumab’s stimulation of bone formation together with its antiresorptive effect, fully offsetting the expected loss of bone mass associated with the increased bone resorption known to occur following denosumab discontinuation. While histomorphometric confirmatory data are not available, the observed profile of the bone turnover markers is consistent with this interpretation. Overall, data from our study suggest that patients on denosumab could be transitioned to romosozumab. However, this sequence provides a lower increase in BMD compared to transitioning from no treatment to romosozumab; further, continuing on denosumab would be expected to offer similar BMD gains at the spine and greater BMD gains at the hip relative to romosozumab following denosumab [
18]. Additionally, the results from this study illustrate the resetting of skeletal responsiveness to romosozumab after a year off therapy, with a second course of romosozumab matching the increases in bone formation and decreases in bone resorption, as well as the BMD gains observed with the first administration of romosozumab. Additional studies would be needed to determine whether such skeletal responsiveness can be achieved at an earlier time point.
Pharmacokinetic and pharmacodynamic studies [
11] have demonstrated treatment efficacy with a 12-month course of treatment with romosozumab, wherein there were no further sustained increases in markers of bone formation when treatment was continued for a second year. Because osteoporosis is a chronic disease and the effects of romosozumab are reversible, transitioning to another therapy after 1 year of romosozumab treatment is required in order to maintain or augment the BMD gains and fracture risk reduction achieved. The phase 3 studies confirm the efficacy of antiresorptive therapy (denosumab or alendronate) following romosozumab in both maintaining BMD increases and reducing fracture risk [
4,
5]. In FRAME [
4,
15], after 12 months of romosozumab, participants who received 24 months of denosumab continued to exhibit a lower fracture risk and continued to demonstrate BMD increases at the lumbar spine and total hip versus participants who initially received placebo in the first 12 months. In this phase 2 study, decreases in BMD were observed on discontinuation of romosozumab, while switching to denosumab resulted in further gains in BMD [
10]. In ARCH [
5], after 12 months of romosozumab versus alendronate, switching to alendronate for up to 24 months maintained lower fracture risk and BMD gains at the lumbar spine, total hip, and femoral neck compared with alendronate alone, supporting the long-term benefit of early treatment with romosozumab and sequencing romosozumab before an antiresorptive agent.
Studies have also compared switching from bisphosphonate therapy to either romosozumab or teriparatide. In the STudy evaluating effect of RomosozUmab Compared with Teriparatide in postmenopaUsal women with osteoporosis at high risk for fracture pReviously treated with bisphosphonatE therapy (STRUCTURE) [
3], 12 months of romosozumab treatment resulted in BMD increases from month 0 at both the spine (9.8%) and the hip (2.9%), and significantly greater gains than with teriparatide (5.4% and − 0.5%, respectively). Larger increases in BMD were observed in participants switching from alendronate to romosozumab in the STRUCTURE study [
3] compared with those switching from denosumab to romosozumab in the present study. This is likely the result of offsetting the rapid increases in bone resorption on discontinuing denosumab, which is not observed following discontinuation of bisphosphonates due to their skeletal incorporation.
A second course of romosozumab in this small group of participants did not show new safety findings, with an observed adverse event profile comparable to that of the first course of romosozumab treatment during month 0 to month 12, and a low rate of neutralizing antibody development. As previously reported, no additional safety findings were observed with romosozumab treatment during month 12 to month 24 [
10]. Overall, our data suggest that a second course of romosozumab was well tolerated in participants off osteoporosis treatment for a year or transitioning from denosumab. Consistent with other studies in women with postmenopausal osteoporosis comparing romosozumab with placebo (FRAME) [
4] or teriparatide (STRUCTURE) [
3], we did not observe an imbalance in cardiovascular adverse events with romosozumab administration in this study. Results from the ARCH study [
5] indicated a higher incidence of positively adjudicated cardiovascular serious adverse events in postmenopausal women treated with romosozumab for 1 year (2.5%) versus those treated with alendronate (1.9%).
The main limitation of this study is the small sample size, adequate for the assessment of BMD but too small to evaluate fracture risk and low frequency safety signals. However, the BMD gains observed in participants receiving a second course of romosozumab after placebo were significant and similar to the gains observed in the initial romosozumab 210 mg QM treatment group [
8].
As would be expected with a reversible agent, in the absence of follow-on therapy, increases in BMD after initial romosozumab treatment reverse within a year off therapy; a second course of romosozumab again led to rapid and large BMD gains with similar rapidity and magnitude through its dual effect of increasing bone formation and decreasing bone resorption. The BMD effect of romosozumab after denosumab was less pronounced compared with the effect observed in treatment-naïve patients, but romosozumab compensated for the BMD declines associated with denosumab discontinuation, implying a significant bone-forming activity in these subjects as well. The data suggest that romosozumab is well tolerated and provide insight into osteoporosis treatment sequencing options for the long-term management of patients with osteoporosis. The effect of romosozumab on BMD is reversible upon discontinuation, and therefore should be followed by an antiresorptive agent to preserve BMD gains with the goal of maintaining fracture risk reduction over the long term. Since all currently available osteoporosis therapies are reversible over variable time frames, off-treatment patient response must be understood to properly sequence treatments to manage osteoporosis as a chronic disease. The effect of a second course of romosozumab provides needed data to inform possible long-term therapeutic decisions in those patients who remain at high risk for fracture.
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