Romosozumab and antiresorptive treatment: the importance of treatment sequence

Over the past two decades, studies comparing bone-forming with antiresorptive agents in head-to-head trials have shown significantly lower incidence of fractures with bone-forming agents [1‐5]. These findings have led to recommendations to consider treatment with bone-forming agents as initial therapy in patients at very high risk for fracture, particularly those who require rapid fracture risk reduction [6, 7]. Most participants in these trials have been treatment naïve or have had minimal recent exposure to osteoporosis treatment. Fracture outcomes are not available from smaller studies designed to evaluate the BMD effects of teriparatide or romosozumab following treatment with bisphosphonates [8‐13] or denosumab [13, 14].

In a large meta-regression analysis of 38 randomized clinical trials involving 19 different therapeutic agents for osteoporosis, the magnitude of total hip BMD gain has emerged as a relevant surrogate endpoint for estimating fracture risk reduction [15]. In that analysis, treatments producing a total hip BMD gain of 2% would be expected to reduce hip fracture occurrence by 16%, whereas treatments producing a total hip BMD gain of 6% would be expected to reduce hip fracture incidence by 40% [15]. Furthermore, in individual patients, the total hip BMD level attained during or after treatment with alendronate, zoledronic acid, denosumab, or romosozumab is a major predictor of subsequent absolute risk of fracture and accordingly could serve as a treatment target for osteoporosis therapy [16‐20].

Past treatment sequence studies indicate that starting with teriparatide and then transitioning to an antiresorptive agent increases BMD more than the reverse sequence, with the most prominent differences seen in the hip region [14, 21]. In fact, total hip BMD declines and remains below baseline for at least 12 months in patients who transition from bisphosphonates to teriparatide and declines prominently and remains below baseline for up to 24 months in patients who switch from denosumab to teriparatide [14, 21]. Data evaluating the sequence of a bisphosphonate or denosumab followed by abaloparatide are not available, although the sequence of abaloparatide first, followed by alendronate, produces substantial benefits to hip BMD [22, 23].

Romosozumab (EVENITY^® [romosozumab-aqqg in the USA]) [24] is a bone-forming agent with the dual effect of increasing bone formation and decreasing bone resorption [25, 26]. When romosozumab is given as the initial therapy, marked increases in BMD have been observed, with further BMD increases upon transition to an antiresorptive agent as reported in the FRAME and ARCH randomized controlled trials (RCTs) [5, 27]. Two additional RCTs provide data for evaluation of bone turnover markers and BMD effects when antiresorptive agents are given first, followed by romosozumab [12, 28].

In this analysis, we reviewed data from the four RCTs that evaluated treatment sequences of romosozumab administered before or following an antiresorptive agent, either alendronate or denosumab [5, 12, 27‐29]. We evaluated changes in total hip and lumbar spine BMD, the proportions of patients who achieved BMD gains ≥ 3% and ≥ 6% at the total hip and lumbar spine, and the profile of changes in levels of the bone formation marker procollagen type I N-terminal propeptide (PINP) and the bone resorption marker β-isomer of the C-terminal telopeptide of type I collagen (β-CTX) after 12 and 24 months of treatment with the different treatment sequences.

When used as initial therapy, 1 year of romosozumab produced large BMD gains at the total hip and lumbar spine, which appear greater than those seen with any other single therapy [32‐34]. In women pretreated with alendronate, BMD gains with 1 year of romosozumab were lower than those in treatment-naïve women; approximately 50% and 75% of the BMD increments achieved in treatment-naïve patients at the total hip and lumbar spine, respectively. These gains in total hip and lumbar spine BMD remain significant and were higher than those achieved upon transition from alendronate to teriparatide, as shown directly in STRUCTURE [12]. In women pretreated with denosumab, net BMD gains with 1 year of romosozumab were substantially lower than those in treatment-naïve women or those observed following transition from alendronate. However, stability of total hip BMD with romosozumab after denosumab compares favorably with transition to teriparatide in the DATA-Switch study (though not head-to-head data) [14], where hip BMD remained below the transition baseline, even after 2 years of teriparatide treatment. For the 2-year treatment sequences, large BMD gains at both the total hip and lumbar spine were observed when romosozumab was followed by denosumab or alendronate. BMD gains with the 2-year sequence of denosumab followed by romosozumab were comparably lower, with a more substantial differential effect on hip BMD. The 2-year responder analyses also indicate that a very high proportion of women will attain ≥ 6% BMD gain at the lumbar spine, regardless of treatment sequence. However, the sequence of romosozumab and denosumab had a greater differential impact on BMD response at the total hip.

Our results from the four RCTs reviewed are consistent with results observed in a prospective real-world study of patients treated with romosozumab for 12 months as first therapy or after receiving antiresorptive agents [13, 35]. In that study, BMD gains differed significantly in previously untreated patients, patients previously treated with bisphosphonates, or patients previously treated with denosumab; at the total hip, mean BMD gains were 5.6%, 3.3%, and 0.6%, respectively, and at the lumbar spine, mean BMD gains were 18.2%, 10.2%, and 6.4%, respectively. Similar BMD gains at the total hip and lumbar spine were also reported in another prospective real-world study in which previously untreated patients and patients previously treated with bisphosphonates or denosumab were treated with romosozumab for 12 months [36] and in a retrospective real-world study in which previously untreated patients and patients previously treated with bisphosphonates were treated with romosozumab for 12 months [37].

We have limited data on the morphological basis of bone strength gains following antiresorptive or anabolic therapy. In the primary Phase 2 study, with romosozumab as initial therapy, quantitative computed tomography (QCT) assessments indicated that volumetric BMD and bone strength at the total hip increased 4.1% and 3.6%, respectively, and these changes were a reflection of increments in both cortical and cancellous compartments; similarly, volumetric BMD and bone strength at the lumbar spine increased 17.7% and 27.3%, respectively, with romosozumab, again with demonstrable increments in both cortical and cancellous compartments [38, 39]. In a subset of women from ARCH, QCT assessments of the lumbar spine also demonstrated increments in volumetric BMD and bone strength of both cortical and cancellous bone compartments [40]; however, there is no information about the cortical and cancellous bone compartments at the total hip since QCT assessments were not performed in the hip region in ARCH. In STRUCTURE, with romosozumab after alendronate, volumetric BMD and bone strength at the total hip increased 3.4% and 2.5%, respectively, with improvements in both cortical and cancellous bone compartments; however, gains in both compartments were diminished with the alendronate-to-romosozumab sequence, compared with the romosozumab first sequence [12].

Despite the known limitations of interpreting bone turnover marker levels, absolute changes in serum levels of PINP and β-CTX across the studies reviewed here can help explain some of the BMD effects observed. In the four studies, serum PINP increments peaked at 34–48 µg/L above baseline with romosozumab and were similar across the studies; however, the kinetics of the PINP increase were different when romosozumab was administered after denosumab, where we observed a slower, progressive elevation and delayed peak. Moreover, the effects on β-CTX varied significantly based on whether patients were previously untreated, pretreated with alendronate, or pretreated with denosumab. Since most of the bone formation with romosozumab is modeling-based, and thus independent from baseline bone remodeling rate [41], we would expect minimal influence of previous antiresorptive treatment on PINP kinetics and BMD gain achieved with romosozumab as compared with teriparatide, where the majority of the bone formation is remodeling-based. Our findings are consistent with this thesis; however, some of the initial BMD gain might be related to overfilling of the remodeling cavities open at the time romosozumab is administered. The magnitude of bone remodeling surface is lower in patients who received prior antiresorptive agents compared with that in previously untreated patients [42‐44], particularly with prior denosumab.

Consistent with the known dual effect of romosozumab, in previously untreated women, serum PINP levels increased and β-CTX levels declined in ARCH and FRAME. Serum β-CTX level decreased further upon transition to alendronate, again indicating that the antiresorptive potency of alendronate is greater than that of romosozumab. This has been demonstrated previously with direct comparisons of romosozumab and alendronate in the first year of the Phase 2 study [25] and in the first year of ARCH [5]. β-CTX levels declined to an even greater degree after transition from romosozumab to denosumab, consistent with the known greater antiresorptive potency of denosumab compared with alendronate [45‐48]. The bigger differential effect between alendronate and denosumab (after romosozumab) on BMD gain at the hip, compared with the spine, might be related to differences in alendronate activity at these two skeletal sites. The effect of alendronate on remodeling suppression is near complete in cancellous bone of the spine, but much less prominent in cortical bone [48], leading to greater ultimate BMD gain at the total hip, with the sequence of romosozumab followed by denosumab in FRAME [27] versus romosozumab followed by alendronate in ARCH [5].

Following alendronate treatment [12], serum PINP increased on transition to romosozumab, while there was no significant change in β-CTX. This lack of change in β-CTX suggests that the antiresorptive effect of romosozumab is sufficiently potent to replace the partial loss of antiresorptive activity, superimposed on the residual alendronate action seen after alendronate withdrawal [49]. No further antiresorptive action is observed when romosozumab is substituted for alendronate. The most unusual profile of bone turnover marker changes with romosozumab was observed when administered after denosumab. The delayed increase in serum PINP suggests that ambient bone remodeling activity at the time of romosozumab initiation might contribute to romosozumab’s early bone-forming effects. The progressive increase in β-CTX implies that the antiresorptive potency of romosozumab is insufficient to completely prevent the bone turnover rebound that normally occurs after denosumab cessation, suggesting that there is more bone resorbed over the year, certainly compared with that observed after transition from alendronate to romosozumab. Regardless, even after denosumab discontinuation, there is still a positive net balance between resorption and formation, as shown by the bone mass increase, albeit smaller than observed in treatment-naïve patients or when transitioning from alendronate. Our bone turnover marker results are also consistent with those observed in a prospective real-world study where the PINP response in previously untreated patients and in patients previously treated with bisphosphonates peaked at 1 month after transition to romosozumab, whereas the PINP response was delayed (peaked at 6 months) and prolonged in patients previously treated with denosumab after transition to romosozumab [13, 35].

For patients on bisphosphonates who still appear to be at high risk for fracture, switching to romosozumab leads to superior increases in BMD and bone strength than switching to teriparatide [12]. For patients on denosumab who have had a suboptimal response or who must discontinue treatment for other reasons [50], switching to romosozumab improves spine BMD and maintains or produces a small increment in hip BMD. In contrast, in the DATA-Switch study [14], women who switched from denosumab to teriparatide had a rapid decline in hip BMD, which persisted during 2 years of teriparatide treatment, and a large increase in serum β-CTX levels associated with both the effect of denosumab discontinuation and the pro-remodeling action of teriparatide [32, 51, 52]. In contrast to the transition from denosumab to teriparatide, the moderate intrinsic antiresorptive activity of romosozumab may contribute to a more favorable net balance between bone formation and resorption upon transition from denosumab. This might be of particular importance for patients sustaining a vertebral fracture despite denosumab therapy and for whom transition to romosozumab might be a preferred option. However, further research is needed to confirm the BMD effects with romosozumab after longer denosumab therapy and to confirm that this treatment sequence will be protective against occurrence of multiple vertebral fractures associated with denosumab withdrawal [53]. Although the transition from denosumab to romosozumab appears to be superior to the transition to teriparatide, this inference results from two separate studies with a limited number of participants and with no fracture endpoints; currently, there are no RCTs directly comparing these two regimens.

There are no fracture data from STRUCTURE and the Phase 2 extension where antiresorptives were given as the first treatment followed by romosozumab. We have drawn conclusions about the effectiveness of romosozumab treatment as first therapy based on mean BMD changes; BMD changes have been shown to relate to fracture resistance in multiple [15] but not all studies [54]. However, even in Reid et al. [54], where BMD gain was not associated with fracture risk, absolute BMD level attained after treatment was associated with fracture risk. The relationship between BMD attained on treatment and subsequent fracture rates has also been demonstrated in prior studies with zoledronic acid [18], alendronate [17, 20], denosumab [19], and romosozumab [20]. In this analysis, we are not comparing different treatments; our focus is on the effect of treatment sequence with romosozumab as the first therapy, compared with romosozumab as the second therapy. Our data show that greater improvement is likely when romosozumab is used first.

There are several limitations to the findings in our analysis. We summarized BMD data across four studies that had different populations with varying age, fracture prevalence, and baseline BMD; however, baseline BMD was adjusted within each trial to calculate BMD change (except in the Phase 2 extension due to small sample size). In contrast to the large sample sizes in ARCH, FRAME, and STRUCTURE, for the Phase 2 extension, only 16 patients were evaluated. Interestingly, the findings discussed here are very similar to those observed in another small arm of the Phase 2 extension when patients received a second course of romosozumab after an intervening year of denosumab [28]. A very important caveat is that the effects of switching from denosumab to romosozumab were investigated after only 1 year of denosumab. In contrast, in STRUCTURE [12], women had been on bisphosphonates for more than 6 years (median treatment) before transition to romosozumab. Clearly, more research is needed to evaluate the safety and efficacy of longer pretreatment with denosumab prior to romosozumab [55]. Data are not available for the first year of the alendronate-to-romosozumab sequence because BMD increments on alendronate in STRUCTURE [12] were not determined (as the study was not designed to answer this question). We also acknowledge that the changes in bone turnover markers may not necessarily reflect what is occurring at the bone surface level in different skeletal sites and that the BMD changes are influenced by both change in mass and mineralization. The results here are entirely descriptive without formal statistical analyses conducted. Finally, we recognize that in some regions, financial considerations require initial antiresorptive therapy rather than the more expensive bone anabolic therapy. It is imperative that clinicians understand the differential bone effects of bisphosphonates versus denosumab as initial therapy before transitioning to romosozumab in the clinical management of their patients. The strengths of this analysis include the robustness of the studies conducted [5, 12, 27‐29], with frequent quality measurements of both bone turnover markers and BMD and the power to detect significant changes in the endpoints considered. Our findings are consistent with those from similar groups of patients in real-world observational studies [13, 35‐37].

In conclusion, results from our study show that initial treatment with 1 year of romosozumab produces substantial BMD gains at the total hip and lumbar spine, and subsequent transition from romosozumab to a potent antiresorptive augments those gains. Romosozumab also effectively increases both hip and spine BMD after alendronate and may improve or at least maintain BMD in patients after short-term denosumab (1 year). Since BMD on treatment is a strong surrogate for fracture reduction [17‐20], these findings support the concept that untreated patients at high risk of fracture should be considered for initial treatment with romosozumab. Our results are concordant with recent estimates that a sequence of bone-forming agents followed by antiresorptive agents would prevent more fractures than the reverse sequence [56]. Since osteoporosis is a chronic condition requiring long-term therapy, for those patients at very high risk for fracture who will likely need both bone-forming and antiresorptive agents, improved clinical efficacy will be seen if the bone-forming agent is used as initial therapy.