In severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab is unclear. We utilised a novel overlapping strategy in three patients with very-high fracture risk despite long-term denosumab which led to greater bone density improvements than previously reported with standard approaches. Larger confirmatory prospective studies are needed.
Purpose/introduction
In patients with severe osteoporosis, the optimal approach for sequential treatment between denosumab and romosozumab has not been established. The ideal strategy would maximise gains in bone mineral density (BMD) with romosozumab and effectively mitigate the risk of rebound increased bone turnover when sequencing from denosumab. Limited studies exploring the sequence from denosumab to romosozumab report only modest-to-no improvement in BMD and inadequate suppression of rebound bone turnover.
Methods
We describe three patients with severe osteoporosis and multiple fragility fractures despite long-term denosumab. A novel overlapping sequential treatment approach was utilised to maximise therapeutic benefit given these patients had a very high fracture risk. Romosozumab was commenced 3 months after the last denosumab dose. Instead of waiting until completion of romosozumab, denosumab was recommenced 6 months after commencing romosozumab in response to rising bone turnover markers.
Results
Patients experienced a ~ 5–22% increase in lumbar spine BMD, and one patient had an 8% increase in total hip BMD after 12 months romosozumab. Serum bone turnover markers demonstrated an anabolic effect of romosozumab occurred despite overlapping treatment with denosumab. Recommencement of denosumab suppressed an increase in bone resorption in all cases. No new vertebral fractures occurred during this treatment.
Conclusions
A novel overlapping sequential treatment approach between denosumab and romosozumab produced greater improvements in lumbar spine and hip BMD than previously reported with standard approaches. Larger prospective controlled studies are needed to confirm these findings and establish the optimal use of romosozumab in patients pre-treated with denosumab to maximise BMD gains and minimise fracture risk.
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Introduction
Denosumab is a monoclonal antibody against receptor activator nuclear factor-kappa B ligand (RANKL) that exerts potent antiresorptive activity by diminishing osteoclast recruitment and proliferation [1]. Continuous denosumab for 10 years is associated with durable robust bone mineral density (BMD) gains and fracture risk reduction [2]. Denosumab discontinuation triggers a rebound increase in bone turnover peaking at 12 months after the last dose, which is detected by an overshoot in serum C-terminal telopeptide of type 1 collagen (CTx) and procollagen type 1 N-propeptide (P1NP). This leads to rapid loss of bone density gains by 18 months after the last dose and, in some cases, precipitates spontaneous vertebral fractures [3‐5]. The degree of rebound bone loss is associated with duration of denosumab treatment and magnitude of BMD gains during denosumab [4, 5], whilst prior vertebral fractures are a risk factor for rebound-associated vertebral fractures.
Romosozumab is an anti-sclerostin antibody with dual osteoanabolic and antiresorptive effects and has demonstrated greater fracture risk reduction and dramatic improvements in lumbar spine and hip BMD vs placebo and alendronate [6, 7]. Romosozumab effects on BMD are greatest when used first-line and blunted with prior antiresorptive use [8]. Several guidelines recommend osteoanabolic agents, such as romosozumab, be considered as initial therapy in patients at very high fracture risk [9, 10]. In clinical practice however, due to high drug cost, romosozumab is often used second-line in patients with severe osteoporosis with persistently low T-scores or those who fracture despite prior antiresorptives (e.g. denosumab). In patients with osteoporosis sequencing between denosumab and a 12-month romosozumab course, two major challenges arise: (1) the potential attenuation of BMD gains with prior denosumab treatment and (2) the risk of post-denosumab rebound increase in bone turnover upon sequencing to romosozumab. Novel effective strategies to optimise this therapeutic sequence are needed.
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Few studies have explored the skeletal effects of sequencing patients between denosumab and romosozumab [11‐14]. These studies utilised a standard approach of commencing romosozumab 6 months after the last denosumab dose and resuming denosumab after completion of 12 months of romosozumab. However, this approach leads to significantly attenuated gains in BMD which may be comparable to remaining on denosumab in patients on prolonged denosumab therapy [2]. Initiating romosozumab at an earlier timepoint (i.e. at 3 months from the last denosumab dose) may ensure that its peak anabolic effect precedes a rebound in osteoclast activity. Second, rebound increase in bone resorption may be insufficiently suppressed by romosozumab in patients on long-term denosumab. Hence, monitoring for rebound increases in bone turnover and considering earlier resumption of denosumab may be warranted. We describe three patients with severe osteoporosis and multiple fragility fractures on prolonged denosumab treatment whose condition improved significantly through a novel overlapping sequential regimen between denosumab and romosozumab.
Case records
Case 1
An 82-year-old woman with history of severe osteoporosis and chronic vertebral compression fractures presented with two acute painful vertebral fractures (Supplementary Fig. 1). This occurred despite seven injections of 6 monthly subcutaneous 60 mg denosumab. A dual-energy X-ray absorptiometry (DXA) BMD scan demonstrated osteoporotic T-scores in the lumbar spine (L2-L4) (BMD 0.787 g/cm2, T-score − 3.3 SD) and left total hip (BMD 0.676 g/cm2, T-score − 2.8 SD). The acutely fractured L1 vertebra was excluded from total lumbar spine BMD analyses. Biochemical screen was negative for secondary osteoporosis including myeloma. She had normal renal function (eGFR 67 mL/min/1.73m2) and replete vitamin D (68 nmol/L, NR 51–200 nmol/L). Two months after her last denosumab injection, she commenced a 12-month course of romosozumab (monthly subcutaneous 210 mg injections). Overlapping denosumab treatment was recommenced 7 months after commencing romosozumab (i.e. 9 months since the last denosumab dose) in response to rising serum CTx concentration within the last 3 months from 235 to 439 ng/L (NR 50–800 ng/L) (Table 1). At completion of 12 months romosozumab, lumbar spine (L2-L4) BMD dramatically improved by 22.3% (BMD 0.963 g/cm2, T-score − 2.0 SD), whilst left total hip (BMD 0.661 g/cm2, T-score − 2.9 SD) remained stable. Her back pain improved, and there was no clinical suspicion of further vertebral fractures.
Table 1
Case characteristics and bone mineral density response with sequential overlapping romosozumab and denosumab treatment
Case
1
2
3
Age at romosozumab commencement
82 years
59 years
50 years
Sex
Female
Female
Male
Fracture history
Multiple vertebrae (T11-L3, L5)
Multiple vertebrae (T8, L5)
Right neck of femur
Prior denosumab doses (n)
7
5
10
Timing of romosozumab commencement (after last denosumab dose)
2 months
3 months
3 months
Timing of denosumab recommencement (after commencing romosozumab)
7 months
6 months
7 months
Pre-romosozumab (lumbar spine)
- BMD (g/cm2)
0.787
0.785
1.109
- T-score (SD)
− 3.3
− 3.5
− 0.9
Post-romosozumab (lumbar spine)
- BMD (g/cm2)
0.963
0.804
1.284
- T-score (SD)
− 2.0
− 3.0
+ 0.5
Pre-romosozumab (left total hip)
BMD (g/cm2)
0.676
0.791
0.701
- T-score (SD)
− 2.8
− 1.9
− 3.0
Post-romosozumab (left hip)
- BMD (g/cm2)
0.661
0.810
0.759
- T-score (SD)
− 2.9
− 1.8
− 2.5
Post-romosozumab BMD change
- Lumbar spine
+ 22.3%
+ 5.1%
+ 15.8%
- Left hip
− 2.2%
+ 2.4%
+ 8.3%
CTx during romosozumab (normal-range 100–600 ng/L)
- Baseline
NR
73
< 70
- 3 months
235
100
130
- 6 months
439
430
420
- 9 months
NR
< 70
< 70
- 12 months
95
< 70
< 70
P1NP during romosozumab (normal-range 15–80 ug/L)
- Baseline
NR
15
NR
- 3 months
68
24
66
- 6 months
71
58
99
- 9 months
NR
28
32
- 12 months
34
13
35
SD, standard deviation; BMD, bone mineral density; CTx, C-terminal telopeptide of type 1 collagen; P1NP, procollagen type 1 N-propeptide; NR, not reported
L1 vertebra was excluded for case 1 given recent fracture. For each individual patient, pre- and post-romosozumab DXA BMD scans were performed using the same scanner. Serum CTx and P1NP concentrations were measured using commercially available automated chemiluminescent assays (Roche Cobas). BMD data are presented at the commencement and completion of 12 months romosozumab, whilst bone turnover data are presented 3-monthly during a 12-month course of romosozumab
Case 2
A 59-year-old woman with history of severe osteoporosis and chronic vertebral compression fractures had received five doses of denosumab. Despite this, a BMD scan demonstrated persistently severe osteoporotic values in the lumbar spine (L2–L4) of 0.758 g/cm2 (T-score − 3.5 SD) and osteopenic values in the left total hip of 0.791 g/cm2 (T-score − 1.9 SD). Prior to developing vertebral fractures, she received 6 months of glucocorticoids for a systemic immune-mediated inflammatory condition. Biochemical screen was negative for secondary osteoporosis, and she had normal renal function (eGFR 84 mL/min/1.73 m2) and replete vitamin D (94 nmol/L). She commenced romosozumab 3 months after her last denosumab dose. Serum CTx increased by 489% to 430 ng/L in the first 6 months after commencing romosozumab, prompting earlier recommencement of denosumab rather than waiting until completion of her romosozumab course. Prior to restarting denosumab, serum P1NP also increased by 286% to 58 ug/L (NR 15–90 ug/L). After 12 months of romosozumab, lumbar spine (L2–L4) BMD improved by 5.1% (BMD 0.804 g/cm2, T-score − 3.0 SD) and left total hip BMD by 2.4% (BMD 0.810 g/cm2, T-score − 1.8 SD). These improvements were considered substantive given recent history of high-dose glucocorticoid exposure and lack of improvement on denosumab alone.
Case 3
A 50-year-old man with severe osteoporosis relating to history of anorexia nervosa experienced a fragility neck of femur fracture despite 5 years of alendronate followed by 5 years of denosumab 60 mg 6-monthly. On referral to our service, he had a persistently osteoporotic BMD in the contralateral total hip of 0.701 g/cm2 (T-score − 3.0 SD) with normal-range lumbar spine (L1–L4) BMD of 1.109 g/cm2 (T-score − 0.9 SD) with mild degenerative changes. His weight had remained stable for the last 10 years (BMI 19.5 kg/m2), and anorexia nervosa was no longer an active clinical concern. A secondary osteoporosis screen was negative (including for testosterone deficiency), and he had normal renal function (eGFR > 90 mL/min/1.73 m2) and replete vitamin D (96 nmol/L). He commenced romosozumab 3 months after his last denosumab dose. Prompted by a rise in serum CTx from 130 to 420 ng/L over 3 months, denosumab was recommenced 7 months after commencing romosozumab. After completion of 12 months romosozumab, lumbar spine and left total hip BMD increased by 15.8% (BMD 1.284 g/cm2, T-score + 0.5 SD) and 8.3% (BMD 0.759 g/cm2, T-score − 2.5 SD), respectively. BMD continued to increase with ongoing denosumab 12 months after completing romosozumab, by a further 9.4% in the lumbar spine (BMD 1.405 g/cm2, T-score + 1.5 SD) and 2.5% in the left total hip (BMD 0.778 g/cm2, T-score − 2.4 SD), resulting in a remarkable 11% increase in total hip BMD over 24 months.
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Rising serum CTx concentrations were suppressed in all patients 3 months after recommencing denosumab (Table 1). Although vertebral fracture analyses were not performed during this treatment sequence, patients were routinely examined for change in height and presence of vertebral tenderness or deformity and no new clinical fractures occurred. There were no reports of osteonecrosis of the jaw, atypical femur fracture or hypocalcaemia (serum calcium was measured for 3 months during romosozumab treatment). Both denosumab and romosozumab were well-tolerated during periods of overlapping treatment. For each individual patient, pre- and post-romosozumab DXA BMD scans were performed using the same machine (GE Lunar software). Serum CTx and P1NP concentrations were measured using commercially available automated chemiluminescent assays (Roche Cobas).
Literature review
A literature review was performed to identify studies evaluating the sequence between denosumab and romosozumab in patients with osteoporosis and effects on fracture risk, bone turnover markers and BMD. PubMed/MEDLINE databases were searched using the following terms: ‘Romosozumab AND Denosumab AND Osteoporosis/fracture/sequence/switch/rebound’. Four articles were identified (including a total of 206 patients) with most patients having over two prior denosumab doses although two smaller studies included patients with ≤ 1-year prior exposure [11‐14] (Supplementary Table 1). All studies commenced romosozumab 6 months after the last denosumab dose with no reports of an overlapping treatment approach. BMD outcomes after recommencing denosumab were reported in one study [13].
There are no reports of new vertebral fractures occurring in patients commencing romosozumab 6 months after their last denosumab dose [11‐14]. One patient with severe osteoporosis was reported to develop new spontaneous vertebral fractures shortly after transitioning to romosozumab; however, romosozumab had been commenced 9 months after their last denosumab dose [15].
Studies indicated a counterproductive rise in bone resorption markers when patients are sequenced from denosumab to romosozumab despite commencing romosozumab 6 months after the last denosumab dose [11‐13]. McClung et al. found that serum CTx and P1NP concentrations gradually increased to pre-denosumab levels despite 12 months romosozumab, consistent with increased bone turnover during romosozumab despite only brief (12 months) denosumab pre-treatment [11]. Tominaga et al. demonstrated that TRAcP-5b (a marker of osteoclast number) slowly increased above baseline after 9 months of sequential romosozumab [12]. Ebina et al. showed that mean P1NP and TRAcP-5b concentrations increased in the first month and continued to rise during 12 months of romosozumab [13]. These results suggest 12 months of romosozumab is unable to prevent a rise in bone turnover as seen during post-denosumab rebound.
Two studies investigated BMD outcomes with sequential denosumab and romosozumab treatment in patients with short-term (≤ 1 year) prior denosumab exposure, whereby romosozumab led to mean gains of 5.3% and 10.2% in lumbar spine BMD, respectively [11, 12]. Total hip BMD was maintained in one study and increased by 5.9% in another study [9, 12]. However, the BMD response to romosozumab in patients with longer denosumab pre-treatment (mean 2–3 years) has been less substantial. One potential explanation is the higher risk of post-denosumab rebound bone loss with longer duration of denosumab exposure [4, 5]. In Tominaga et al.’s cohort, multiple regression analysis showed the change in lumbar spine BMD was influenced by duration of prior denosumab treatment (p = 0.0086) [12]. Two other studies showed similar ~ 6–7% improvements in lumbar spine BMD [13, 14], whilst studies consistently showed no change in total hip and femoral neck BMD after sequencing from longer-term denosumab to romosozumab [12‐14]. Only one study reported BMD outcomes after recommencing denosumab, which increased by a mean of 9.7% at the lumbar spine and 2.2% at the total hip, with no change in the femoral neck in the 24 months since commencing romosozumab [13].
Discussion
Romosozumab is amongst the most potent therapies available for osteoporosis and is indicated for patients at high imminent fracture risk [16, 17]. Although particularly effective first-line, real-world use in patients receiving prior prolonged denosumab has been associated with relatively disappointing improvements in BMD (~ 0–7%) [12‐14]. Two potential explanations include (1) commencing romosozumab 6 months after denosumab risks attenuation of its early anabolic effect during the rebound increase in osteoclast activity and (2) the antiresorptive effect of romosozumab may be insufficient to suppress increased osteoclast activity following temporary denosumab withdrawal. Consistent with this, a rise in serum CTx in patients sequencing from long-term denosumab to romosozumab has been demonstrated [11‐13].
In our patients, a high imminent fracture risk in the context of very low BMD (T-scores < − 3.0 in all cases), recent vertebral (cases 1 and 2) and hip fractures (case 3) and substantial decline in BMD on glucocorticoids (case 2) led us to consider osteoanabolic therapy before recommencing long-term denosumab. Modest BMD responses reported using the standard sequential approach between denosumab and romosozumab raised concerns including that of increased bone turnover on sequencing from denosumab. No studies have explored the efficacy of adding teriparatide, an alternative osteoanabolic agent, to existing denosumab treatment and given concerning published results of exaggerated bone turnover and early BMD decline with this sequence; this approach was not employed in our patients [18]. Hence, we devised a novel off-label overlapping treatment schedule with the goal of maximising bone density gains by harnessing the early osteoanabolic effect of romosozumab and mitigating effects of rebound bone turnover by resuming denosumab at an earlier time-point when bone turnover began to increase (Fig. 1). A 12-month course of romosozumab was commenced within 3 months after the last denosumab dose. The timing of romosozumab commencement was designed to avoid blunting of the early peak osteoanabolic effect of romosozumab during the profound early suppression of bone turnover with denosumab (2, 6, 7). Patients were closely monitored with 3-monthly bone turnover markers. A DXA scan was performed prior to commencing romosozumab and at 12 months. We observed a rise in CTx approximately 6 months after commencing romosozumab (9 months after the last denosumab dose) prompting intervention with earlier recommencement of denosumab, rather than at completion of 12 months of romosozumab. This successfully suppressed rising CTx in all cases. Using this approach, all patients experienced significant increases in lumbar spine BMD (22%, 5% and 16%, respectively), whilst one patient had an 8% improvement in total hip BMD (Supplementary Fig. 2).
Fig. 1
Overlapping sequential treatment approach with denosumab and romosozumab
×
We utilised a novel overlapping sequential treatment approach between denosumab and romosozumab to minimise denosumab cessation rebound and maximise bone mineral density gains in three patients with severe osteoporosis. The x-axis designates months since last denosumab dose. Timing of romosozumab doses (orange diamonds) and denosumab doses (green triangles) are represented. Horizontal arrows designate active periods of both medications whereby overlapping of the arrows represents the periods of overlapping treatment. Romosozumab 210 mg monthly subcutaneous injections were commenced approximately 3 months after the last denosumab 60 mg dose. Baseline serum bone turnover markers (CTx, P1NP) and DXA bone mineral density scan were performed pre-romosozumab. Bone turnover markers were then repeated every 3 months. Approximately, 6 months after commencing romosozumab (9 months since the last denosumab dose), denosumab was recommenced at an earlier time-point in response to rising bone turnover markers. Bone turnover markers were then repeated 3 months later to confirm suppression of bone turnover. DXA bone mineral density scan was then repeated at completion of the 12-month course of romosozumab to assess percentage change at lumbar spine and hip. Denosumab was then continued at 6-month intervals for maintenance of bone mineral density gains.
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There was no control group of patients in our cohort receiving standard non-overlapping sequential denosumab and romosozumab to facilitate direct comparisons in our retrospective case series. However, the ~ 5–22% improvement at 12 months in lumbar spine BMD in our small cohort and 8% improvement in total hip BMD in one of our patients are far greater than would be expected with standard sequential treatment in patients with severe osteoporosis [11‐14]. These positive BMD outcomes were achieved despite all patients having long-term denosumab for at least 2 years (and one patient for 5 years). There is minimal data on BMD outcomes after recommencing denosumab in this treatment sequence [13]. This was examined in one of our patients, who experienced a 26.7% and 11% improvement in lumbar spine and total hip BMD, respectively, in 24 months since commencing romosozumab which is far greater than expected based on published data. There were no concerning safety signals with periods of overlapping denosumab and romosozumab treatment; however, our cohort was small (n = 3) and patients were not systematically investigated for such risks.
Putative biological mechanisms in denosumab withdrawal include an increase in osseous RANKL with concurrent deficit of osteocyte osteoprotegerin (OPG), triggering an increase in number of active osteoclasts [19, 20]. Sclerostin inhibits osteoblastic OPG expression, giving plausibility to an anti-resorptive effect of romosozumab during post-denosumab rebound. However, in our cohort, we demonstrated that serum CTx increased by a mean of 213% from 6 to 9 months after the last denosumab dose. Despite our patients receiving overlapping treatment with romosozumab, this CTx trend is similar to previous reports using a standard non-overlapping treatment approach. Hence, we hypothesise the anti-resorptive effect of romosozumab is insufficient to combat increases in bone turnover seen after denosumab withdrawal. Recommencing denosumab at this stage effectively re-introduced a potent antiresorptive effect in our patients earlier than would have occurred with resuming denosumab at completion of romosozumab. The dramatic improvements in BMD in our cohort which occurred despite rising CTx concentrations also suggest there was no meaningful impairment of the anabolic effect of romosozumab during overlapping treatment with denosumab. Although our data was limited by missing baseline P1NP values in two patients, P1NP consistently increased during the first 6 months of commencing romosozumab, further indicating an anabolic effect in all patients. Whether this was attenuated by prior denosumab is difficult to ascertain without a treatment-naïve comparator group.
Conclusions
We have described a novel overlapping sequential treatment approach between denosumab and romosozumab in patients with severe osteoporosis which achieved greater BMD gains at both the lumbar spine and hip compared to prior reports utilising a standard non-overlapping approach. Re-commencement of long-term denosumab at an earlier time-point when bone turnover markers increased was able to suppress the increased bone turnover seen when sequencing from denosumab to romosozumab. Larger prospective controlled studies are needed in patients with severe osteoporosis sequencing from longer-term denosumab to romosozumab, comparing the standard treatment approach with an overlapping strategy as described. Relevant outcomes may include interval changes in BMD, serum concentrations of bone turnover markers (e.g. CTx, P1NP and TRAcP-5b), fracture rates and trans-iliac bone biopsy to evaluate histomorphometric markers of bone turnover. Such data will provide further insights into the efficacy and safety of this novel approach to mitigate rebound bone turnover and maximise bone density gains when sequencing between denosumab and romosozumab in patients with severe osteoporosis.
Declarations
Statement of human rights
Ethics approval for retrospective review of data on patients presenting to osteoporosis and fracture prevention clinics at Westmead Hospital, Sydney, was obtained from the Western Sydney Local Health District (WSLHD) Human Research Ethics Committee (Protocol ID: 2101–12).
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Informed consent
Informed consent was obtained from all individual participants included in the study.
Conflict of interest
The authors declare no competing interests.
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