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. 2025 Nov 29;11(4):137–144. doi: 10.1016/j.afos.2025.11.002

Preliminary analysis of combined romosozumab and denosumab versus teriparatide and denosumab on bone mineral density

Ming-Hung Chiang a, Tian-Sin Fan b, Chia-Che Lee c,d, Tzu-Hao Tseng c, Hung-Kuan Yen a,c, Chih-Chien Hung e, Yi-Chien Lu f, Ning-Huei Sie f,g, Chen-Yu Wang f,h,⁎, Shau-Huai Fu c,e,⁎⁎
PMCID: PMC12766607  PMID: 41498097

Abstract

Objectives

The effectiveness of combining romosozumab (ROMO) with denosumab (Dmab) remains uncertain. We compare the six-month effects of Dmab plus monthly ROMO versus Dmab plus daily teriparatide (TPTD) on bone mineral density (BMD) in treatment-naïve postmenopausal women with osteoporosis.

Methods

This retrospective cohort study analyzed 26 treatment-naïve postmenopausal women with primary osteoporosis. Participants received either a monthly regimen of ROMO and Dmab (N = 14) or a daily regimen of TPTD plus Dmab (N = 12). BMD at the lumbar spine, total hip, and femoral neck was measured at baseline, 3 months, and 6 months by dual-energy X-ray absorptiometry. Serum levels of C-terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (P1NP) were assessed at the same intervals.

Results

Both regimens significantly improved lumbar spine BMD at 6 months (ROMO + Dmab: +9.75%; TPTD + Dmab: +7.42%). Improvements in total hip and femoral neck BMD were modest and similar between groups (∼2%). Serum CTX and P1NP were significantly suppressed in both groups at 3 months, but P1NP suppression waned in the TPTD + Dmab group by 6 months. No statistically significant differences in BMD or marker changes were detected between the two regimens.

Conclusions

Both combination therapies effectively improve lumbar spine BMD over 6 months. The ROMO + Dmab regimen yielded numerically greater increases with fewer injections.

Keywords: Osteoporosis, Denosumab, Romosozumab, Teriparatide, Combination therapy

1. Introduction

Osteoporosis-related fractures represent significant health burdens globally. Conventional anti-resorptive monotherapy effectively reduces fracture risk but typically demonstrates limited incremental bone mineral density (BMD) gains [[1], [2], [3], [4], [5]].

To better address the needs of individuals at very high fracture risk, current evidence and international guidelines recommend initiating treatment with an anabolic agent, such as teriparatide, abaloparatide, or romosozumab, followed by transitioning to an antiresorptive agent (eg, bisphosphonates or denosumab) [[6], [7], [8], [9], [10], [11], [12], [13], [14], [15]]. This sequential strategy is intended to achieve a rapid reduction in fracture risk through prompt BMD improvement, while maintaining long-term skeletal benefits. To accelerate gains in bone mineral density, combination therapy with an anabolic and an antiresorptive agent—most commonly teriparatide plus denosumab—can produce rapid and substantial improvements in BMD, particularly at the lumbar spine. However, due to higher costs and limited long-term safety data, such intensive therapy is typically reserved for selected patients with extremely high fracture [[16], [17], [18], [19], [20], [21]].

Romosozumab, a humanized monoclonal antibody that neutralizes sclerostin, exemplifies the newer anabolic therapies in osteoporosis. By simultaneously stimulating osteoblast-mediated bone formation and inhibiting osteoclast-mediated bone resorption via Wnt signaling, romosozumab produces a robust net increase in bone mass. Clinical trials have demonstrated promising gains in bone mineral density and significant reductions in fracture risk [11,14,15,[22], [23], [24], [25], [26]]. Although adding romosozumab to ongoing denosumab produced an increase of BMD at 6 months [27], the combined effect in treatment-naïve patients remains unclear, and head-to-head data comparing romosozumab–denosumab with other dual-agent strategies are unavailable, underscoring the need for direct comparative trials.

In this context, the present study was undertaken to evaluate the real-world effectiveness of romosozumab plus denosumab versus teriparatide plus denosumab over a 6-month period. By comparing these two combination strategies in a retrospective cohort, we aimed to address the above knowledge gaps and provide insights to guide personalized osteoporosis therapy for patients at very high risk of fracture.

2. Methods

2.1. Study design

We carried out this observational, retrospective study in at two branches of National Taiwan University Hospital—Hsinchu Branch and Yunlin Branch—from June 2015 to June 2025. This study was approved by the Institutional Review Board (IRB No. 202506039RINA).

2.2. Patients

Eligible patients were postmenopausal women aged 50–80 years with T-scores ≤ −2.5 at the lumbar spine, total hip, or femoral neck, and no prior exposure to osteoporosis therapies before initiating the combination treatment. Patients were identified as having received either Romosozumab 210 mg once monthly (Evenity®, Amgen Inc.) plus Denosumab 60 mg every 6 months (Prolia®, Amgen Inc.) (Group A) or Teriparatide 20 μg once daily (Alvosteo®, Lotus Pharmaceutical Co., Ltd) combined with denosumab 60 mg (Group B).

Patients were excluded if they were receiving long-term systemic corticosteroids or had secondary osteoporosis, any other metabolic bone disorder, active malignancy, or hypocalcemia; if they were on hormone replacement therapy or any medication known to affect bone metabolism.

2.3. Study procedures

We used the electronic health record to identify all variables, including past history of anti-osteoporosis treatment, adverse events, and fragility fractures. BMD and bone turnover markers (BTMs), including C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (P1NP) measured according to hospital standards, were obtained. BMD was assessed using dual-energy X-ray absorptiometry (DXA) with a Discovery Wi scanner (Hologic, USA). Scans performed within 3 months prior to therapy initiation were defined as baseline measurements, with follow-up assessments conducted at 3 and 6 months post-initiation. CTX and P1NP measurements were obtained at these same time points, and baseline BTM values were defined as those collected within one week prior to the start of therapy. All tests were analyzed at Union Clinical Laboratory using electrochemiluminescence immunoassays on a Cobas 411 analyzer (Roche Diagnostics) [28]. Patients who did not complete the 6-month course of treatment for any reason and therefore lacked follow-up BMD measurements were omitted from the effectiveness analyses.

2.4. Primary and secondary endpoints

The primary endpoint was the percentage change in lumbar-spine BMD from baseline to 6 months. Secondary endpoints included changes in total hip and femoral neck BMD and changes in serum BTMs.

2.5. Statistical analysis

For baseline demographics, continuous variables that met normality (Shapiro–Wilk test) and homogeneity of variance (Levene's test) were compared between groups using independent-samples t-tests; skewed continuous variables were analyzed with the Mann–Whitney U test and are presented as median [interquartile range]. Categorical variables, including the prevalence of prior fracture history, were compared between groups using Fisher's exact test. Two-tailed P-values < 0.05 were considered statistically significant. Data are presented as mean ± SD, median [IQR], or LS-mean ± SE depending on the statistical method used.

Changes in repeated measures of BMD and bone turnover markers over time were analyzed using linear mixed-effects models with a random intercept for each subject. This approach accounts for inter-individual variability in baseline values while evaluating the fixed effects of time and treatment group. Given the relatively small sample size and the limited number of follow-up timepoints, a random slope was not included to avoid overfitting and unstable parameter estimation. A subgroup analysis was conducted to compare the proportion of participants with meaningful spine BMD improvement, defined as an increase greater than 5% [29,30]. All statistical analyses were performed in Python (version 3.11.2).

3. Results

Forty-one post-menopausal women met the inclusion criteria. Four participants discontinued therapy within the first 6 months (dental extraction = 1, gastrointestinal discomfort = 1, intracranial malignancy = 1, personal preference = 1) and 11 had not yet reached the 6-month DXA time-point at data cut-off; these 15 women were excluded from the longitudinal efficacy set (Fig. 1). The per-protocol population therefore comprised 14 women who received romosozumab plus denosumab (Group A) and 12 women who received teriparatide plus denosumab (Group B).

Fig. 1.

Fig. 1

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Study flow diagram.

Baseline characteristics were broadly comparable between the two treatment groups (Table 1). Participants in Group A had a mean age of 64.6 ± 8.2 years, whereas those in Group B had a mean age of 68.9 ± 6.3 years (P = 0.149). BMI, prior history of fragile fractures, serum calcium, 25-hydroxy-vitamin D, and baseline bone-turnover markers (CTX, P1NP) showed no significant differences. In Group A, two patients had a history of hip fracture, and one patient had no prior fracture. All other patients, including those in Group B, had vertebral compression fractures. The lumbar spine BMD did not differ significantly between groups (Group A, 0.68 ± 0.08 g/cm2; Group B, 0.74 ± 0.17 g/cm2, P = 0.169; T-score = −3.10 [−3.40, −2.52] vs −2.70 [−3.08, −1.88], P = 0.225). Group A had higher baseline total hip BMD (0.70 ± 0.06 g/cm2 vs 0.62 ± 0.06 g/cm2, P = 0.002; T-score = −1.32 ± 0.48 vs −2.00 ± 0.51, P = 0.002) and femoral neck BMD (0.56 ± 0.06 g/cm2 vs 0.49 ± 0.04 g/cm2, P = 0.003; T-score = −2.26 ± 0.59 vs −2.93 ± 0.41, P = 0.003).

Table 1.

Baseline demographic and clinical characteristics of study participants.

Group A (N = 14) Group B (N = 12) P-value
Age, yrs 64.6 (8.2) 68.9 (6.3) 0.149
Body Height, cm 152.1 (3.6) 153.8 (8.2) 0.501
Body Weight, kg 52.6 (5.1) 55.3 (8.9) 0.355
Body-mass index, kg/m2 23.0 [20.9,24.4] 22.0 [20.1,24.9] 0.777
BMD, g/cm2
 Lumbar spine 0.68 (0.08) 0.74 (0.17) 0.169
 Total hip 0.70 (0.06) 0.62 (0.06) 0.002∗
 Femoral neck 0.56 (0.06) 0.49 (0.04) 0.003∗
T score
 Lumbar spine −3.10 [-3.40,-2.52] −2.70 [-3.08,-1.88] 0.225
 Total hip −1.32 (0.48) −2.00 (0.51) 0.002∗
 Femoral neck −2.26 (0.59) −2.93 (0.41) 0.003∗
Serum 25(OH)D, ng/mL 27.94 (10.97) 24.55 (10.35) 0.429
Calcium, mmol/L 2.32 (0.15) 2.30 (0.12) 0.647
CTX, ng/mL 0.45 (0.23) 0.43 (0.20) 0.900
P1NP, μg/L 64.15 [42.58,70.00] 51.90 [36.20,67.35] 0.341
History of fractures 13 (0.93) 12 (1.00) 1.000
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BMD, bone-mineral density; P1NP, procollagen type I N‐terminal propeptide; CTX, C‐terminal telopeptide of type I collagen; 25(OH)D, 25-hydroxyvitamin D.

Group A (romosozumab + denosumab) and Group B (teriparatide + denosumab).

Continuous variables are presented as mean (SD) or median [IQR], and categorical variables as number (%).

∗P < 0.05.

No evidence of new fractures was observed in 6-month period in both groups.

3.1. Bone mineral density

At the lumbar spine, Group A exhibited significant increases at 3 months (+5.79 ± 1.43%, P = 0.001), which further improved at 6 months (+9.75 ± 1.21%, P < 0.001). Similarly, significant increases were observed in Group B at both 3 months (+5.44 ± 0.85%, P < 0.001) and 6 months (+7.42 ± 1.36%, P < 0.001). No statistically significant differences between groups were identified at either time point (P > 0.05) (see Table 2, Fig. 2). Subgroup analysis showed a higher proportion of participants in Group A showing meaningful spine BMD improvement (> 5%) than Group B (78.6% vs. 58.3%, Supplementary Table 1).

Table 2.

Percentage change in bone mineral density from baseline to 3 and 6 months.

Group A
 Group B
 Group A vs Group B
Mean % Change P-value Mean % Change P-value Mean % Change P-value
LS
3 months 5.79 (1.43) 0.001∗ 5.44 (0.85) <0.001∗ 0.34 (1.66) 0.836
6 months 9.75 (1.21) <0.001∗ 7.42 (1.36) <0.001∗ 2.33 (1.82) 0.213
FN
3 months 0.68 (1.13) 0.555 3.00 (1.09) 0.019∗ 2.31 (1.57) 0.153
6 months 2.36 (1.18) 0.068 1.64 (1.32) 0.240 0.72 (1.77) 0.689
TH
3 months 2.12 (0.34) <0.001∗ 1.67 (1.16) 0.178 0.45 (1.21) 0.715
6 months 2.43 (0.78) 0.008∗ 2.07 (1.21) 0.115 0.36 (1.44) 0.806
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FN, femoral neck; TH, total hip; LS, lumbar spine.

Group A: romosozumab plus denosumab; Group B: teriparatide plus denosumab.

Results are derived from linear mixed‐effects models with a random intercept for each subject. Values are expressed in least-squares means (standard error) as the percent change from baseline.

∗P < 0.05.

Fig. 2.

Fig. 2

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Percent changes in femoral neck, total hip, and lumbar spine bone mineral density (BMD) from baseline to 3 and 6 months are shown for Group A (romosozumab + denosumab, blue lines) and Group B (teriparatide + denosumab, orange lines). Data are presented as estimate ± 95% confidence interval, derived from linear mixed-effects models (random intercept only). ∗P < 0.05. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

In the total hip region, Group A demonstrated significant improvements at 3 months (+2.12 ± 0.34%, P < 0.001) and sustained these improvements through 6 months (+2.43 ± 0.78%, P = 0.008). Group B showed a trend towards improvement at 3 months (+1.67 ± 1.16%, P = 0.178) and at 6 months (+2.07 ± 1.21%, P = 0.115), although these changes did not reach statistical significance. There were no significant between-group differences at either time point (P > 0.05).

At the femoral neck, Group A demonstrated positive but non-significant changes at 3 months (0.68 ± 1.13%, P = 0.555) and at 6 months (2.36 ± 1.18%, P = 0.068). Group B had a significant increase at 3 months (+3.00 ± 1.09%, P = 0.019), though this improvement was not statistically significant at 6 months (+1.64 ± 1.32%, P = 0.240). Between-group comparisons revealed no significant differences (P > 0.05).

3.2. Bone turnover markers

Serum CTX levels in Group A decreased significantly by 81.09 ± 3.35% at 3 months and by 63.18 ± 6.41% at 6 months (both P < 0.001). In Group B, CTX fell by 82.67 ± 3.12% at 3 months (P < 0.001) and by 43.26 ± 19.45% at 6 months (P = 0.048). No significant between-group differences in CTX were observed at any time point (P > 0.05) (see Table 3, Fig. 3).

Table 3.

Percentage change in bone turnover markers from baseline to 3 and 6 months.

Group A
 Group B
 Group A vs Group B
Mean % Change P-value Mean % Change P-value Mean % Change P-value
CTX
3 months −81.09 (3.35) < 0.001∗ −82.67 (3.12) < 0.001∗ 1.58 (4.58) 0.733
6 months −63.18 (6.41) < 0.001∗ −43.26 (19.45) 0.048∗ −19.91 (20.48) 0.348
P1NP
3 months −40.98 (7.21) < 0.001∗ −33.91 (12.45) 0.020∗ −7.06 (14.39) 0.630
6 months −58.04 (5.75) < 0.001∗ −20.30 (23.50) 0.406 −37.74 (24.20) 0.144
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P1NP, procollagen type I N‐terminal propeptide; CTX, C‐terminal telopeptide of type I collagen.

Group A: romosozumab plus denosumab; Group B: teriparatide plus denosumab.

Results are derived from linear mixed‐effects models with a random intercept for each subject. Values are expressed in least-squares means (standard error) as the percent change from baseline.

∗P < 0.05.

Fig. 3.

Fig. 3

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Percent changes in serum C-terminal telopeptide of type I collagen (CTX) and procollagen type I N-terminal propeptide (P1NP) from baseline to 3 and 6 months are shown for Group A (romosozumab + denosumab, blue lines) and Group B (teriparatide + denosumab, orange lines). Data are presented as estimate ±95% confidence interval, calculated from linear mixed-effects models (random intercept only). ∗P < 0.05. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

For P1NP, Group A demonstrated significant reductions at 3 months (−40.98 ± 7.21%, P < 0.001) and 6 months (−58.04 ± 5.75%, P < 0.001). In contrast, Group B exhibited significant reductions at 3 months (−33.91 ± 12.45%, P = 0.020) and non-significant reductions at 6 months (−20.30 ± 23.50%, P = 0.812). Between-group comparisons revealed no significant differences in P1NP at any time point (P > 0.05).

Together, these findings indicate that both combination strategies effectively improved BMD, particularly at the lumbar spine, and suppressed the bone resorption marker CTX over 6 months. The romosozumab-based regimen yielded a higher percentage of lumbar spine BMD gains than the teriparatide-based regimen, although the difference did not reach statistical significance.

4. Discussion

This study demonstrates that combining romosozumab or teriparatide with denosumab induces substantial 6-month BMD gains in postmenopausal women with osteoporosis, particularly at the lumbar spine. The 6-month effect in teriparatide combination group is comparable to the results in DATA study [19]. The romosozumab-based regimen yielded a 9.8% increase in spinal BMD, whereas the teriparatide combination showed numerically lower gains (7.4%), although this difference was not statistically significant. Clinically, the more than 20% higher rate of meaningful improvement suggests that romosozumab–denosumab could be preferable for patients needing rapid vertebral protection. In cortical-rich regions, including the femoral neck and total hip, both groups exhibited relatively modest BMD gains (approximately 2% at six months). Cortical bone adaptations, such as increased thickness or reduced porosity, occur more slowly and may require longer treatment durations before yielding detectable changes [15,26,[31], [32], [33]]. Despite the lack of statistically significant BMD change, monthly administration of romosozumab is far more convenient than daily injections of teriparatide. In clinical practice, this substantial difference may improve treatment adherence, particularly among elderly patients or those with an aversion to frequent injections [31].

Compared with monotherapy, bisphosphonates such as alendronate, risedronate, and zoledronate typically produce 5–6% lumbar spine BMD gains over 24–36 months before plateauing [1,5,8,34,35]. In FREEDOM trial, denosumab alone increases spine BMD by approximately 3% at six months and 9.2% at 36 months [2]. In contrast, our romosozumab–denosumab combination achieved similar, or greater, gains in just six months. Previous trials of romosozumab monotherapy have reported increases in BMD of 8.2–9.7% over the same interval [23,26], and our dual regimen produced comparable improvements. However, because this study did not include a direct comparison with romosozumab monotherapy, we cannot conclude that adding denosumab provides a superior response.

The efficacy of adding an anabolic agent to ongoing bisphosphonate or denosumab therapy is well documented [27,36,37]. In a real-world six-month study of postmenopausal women with persistent fracture risk, the addition of romosozumab to denosumab resulted in a 7.2% increase in lumbar spine BMD [27]. These findings further support the dual-agent treatment strategy, and, to our knowledge, this is the first study to report the use of romosozumab plus denosumab in treatment-naïve patient. Although combination therapy is more expensive and may carry a higher risk of adverse events, its potential to reduce fracture risk may outweigh these drawbacks.

CTX levels fell by over 80% in both groups at 3 months and remained significantly reduced at 6 months. The suppression observed in the teriparatide-denosumab combination is consistent with the DATA study, which demonstrated a similar effect with denosumab monotherapy [19]. The lack of between-group differences in our study may reflect the potent antiresorptive action of denosumab itself and a limited additive effect when combined with romosozumab during this period.

The patterns of P1NP suggested fundamentally different mechanisms of anabolic action. Romosozumab monotherapy induces a two-fold increase in bone formation markers within the first month, but return to baseline from months 3, as observed in other study [26]. In contrast, teriparatide alone typically produces a sustained increase in P1NP at 6 months [16,19,38,39]. These disparities may explain the divergent trends observed between the two groups at 6 months in our study. In our treatment-naïve patients, the romosozumab-denosumab combination produced P1NP changes opposite to those observed in the add-on study [27]. This phenomenon likely reflects denosumab's potent early suppressive action, which masks the bone-formation action of anabolic agents [19,40,41].

Several limitations must be acknowledged. First, the small sample size may have contributed to the baseline differences in femoral neck and total hip BMD and limited the study's power to detect significant differences in several parameters. The results should be interpreted with caution due to the small, non-randomized sample. Second, the six-month duration is too short to inform long-term clinical practice, particularly with respect to fracture risk. The incremental benefit of adding denosumab to romosozumab monotherapy remains unclear.

Future investigations should include prospective randomized trials with extended follow-up beyond six months to comprehensively characterize BMD trajectories following combination therapy and subsequent antiresorptive treatment. Incorporating fracture endpoints would clarify whether early lumbar spine differences translate into reduced vertebral fracture incidence. A direct comparison of combination therapy with romosozumab monotherapy is also warranted. Additionally, integrating microarchitectural assessments would provide mechanistic insights into bone quality changes not reflected by areal BMD alone. Cost‐effectiveness and adverse‐event profiles should also be assessed, balancing treatment costs against the morbidity and healthcare burden of fragility fractures.

5. Conclusions

To our knowledge, this is the first study to directly compare, in a head-to-head fashion, the effectiveness of romosozumab + denosumab versus teriparatide + denosumab combination regimens. Both approaches significantly improved BMD in the lumbar spine, but the romosozumab + denosumab regimen achieved comparable gains with fewer injections. These results suggest that, for patients needing a rapid anabolic response, the romosozumab-based combination may offer a clinically meaningful advantage.

CRediT author statement

Ming-Hung Chiang: Conceptualization, Formal analysis, Writing original draft. Tian-Sin Fan: Review and Editing. Chia-Che Lee: Review and Editing. Tzu-Hao Tseng: Review and Editing. Hung-Kuan Yen: Review and Editing. Chih-Chien Hung: Resources, Review and Editing. Yi-Chien Lu: Data curation. Ning-Huei Sie: Data curation. Chen-Yu Wang: Conceptualization, Resources, Data collection, Review and Editing. Shau-Huai Fu: Conceptualization, Resources, Data collection, Review and Editing.

Declaration of generative AI in scientific writing

The authors did not use generative AI or AI-assisted technologies in the preparation of this manuscript.

Conflicts of interest

The authors declare no competing interests.

Acknowledgments

This study was supported by the Grants 113-2314-B-400-005 (Dr. C.-Y. Wang) and 113-2314-B-002-196 (Dr. S.-H. Fu) from the National Science and Technology Council; The Grant NTUHYL114-X008 from the National Taiwan University Hospital Yunlin Branch (Dr. S.-H. Fu); and the Grants CG-113-GP-20 and CG-113-GP-05 (to Dr. C.-Y. Wang) from the National Health Research Institutes.

We sincerely acknowledge the contributions of the following individuals and departments to this research project: Syun-Ping Fu, BS; Wen-Yen Hsu, BS; and Nai-Fen Chuang, BS, staff members of National Taiwan University Hospital Yunlin Branch. We also extend our gratitude to the Departments of Medical Imaging, Laboratory Medicine, Pharmacy, and the Outpatient Department of NTUH Yunlin Branch for their support. No financial compensation was provided for these contributions.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.afos.2025.11.002.

Contributor Information

Chen-Yu Wang, Email: valinawang0220@nhri.edu.tw.

Shau-Huai Fu, Email: Y03900@ms1.ylh.gov.tw.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.docx (65.3KB, docx)

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