Risk Factors for Non-Response to 2 Years of Denosumab Administration in Patients with Osteoporosis: a retrospective cohort study

doi:10.21203/rs.3.rs-1755134/v1

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Risk Factors for Non-Response to 2 Years of Denosumab Administration in Patients with Osteoporosis: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-1755134/v1

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Background: To investigate the factors associated with changes in bone mineral density and the incidence of fractures in osteoporotic patients treated with denosumab.

Methods: This retrospectively registered study included 162 osteoporotic patients treated with denosumab for 24 months between 2013 and 2019. Patients were divided according to the changes in BMD as non-responders (NL group: <3% increase in lumbar spine BMD [LBMD], NH group: <0% increase in femoral neck BMD [HBMD]) or responders (RL group: ≥3% increase in LBMD, RH group: ≥0% increase in HBMD).

Results: The respective changes in the LBMD and HBMD after 24 months of denosumab treatment were 9.3% (95% confidence interval (CI): 8.1–10.6) and 3.3% (95% CI: 2.1–4.5). Twenty-eight (15.3%) patients were in the NL group, and 134 (82.7%) were in the RL group. A history of bisphosphonate treatment was a risk factor for being in the NL group (odds ratio [OR]: 3.84, 95% CI: 1.38–10.71, p=0.007; adjusted OR: 3.21, 95% CI: 1.01–10.19, p=0.048). Although the NH and RH groups had similar baseline characteristics, the NH group had a significantly higher baseline HBMD than the RH group (p=0.003). The change in HBMD was negatively associated with the HBMD at baseline (r=-0.34, p<0.001). No new osteoporotic fractures occurred in either group during follow-up.

Conclusion: In osteoporotic patients receiving denosumab treatment, a history of bisphosphonate treatment was a risk factor for a lack of increase in LBMD, and a higher HBMD at baseline was negatively associated with the change in HBMD.

Bone mineral density

Denosumab

Non-responder

Osteoporosis

Responder

As the older adult population in Japan grows, the number of osteoporotic patients is continuously increasing. Population-based epidemiologic studies estimate that there are approximately 13 million patients with osteoporosis in Japan, although only 20% are receiving treatment[1]. Osteoporosis is a well-known condition that results in low bone mineral density (BMD) and high risk of fracture[2, 3] and is influenced by diverse epidemiological factors including age, sex, lower body mass index (BMI), transition to menopause, lower calcium intake, vitamin D deficiency, less physical activity, and low thyroid function. Osteoporotic individuals commonly develop fractures of the vertebral body, forearm bone, and proximal femur, and the treatment strategies are an important social issue.

There are currently many available therapeutic agents that aim to prevent fractures associated with osteoporosis[4, 5]. The two main types of osteoporotic agents are bone anabolic agents and bone resorption inhibitors. Although bone resorption inhibitors are widely used worldwide and reportedly achieve good outcomes regarding increased bone density and prevention of fractures, the existence of non-responders have been reported[6, 7]. Denosumab is a bone resorption inhibitor that is a fully human monoclonal antibody against receptor activator of nuclear factor-κB ligand[8–10], which is a key activator of osteoclast formation, function, and survival. Denosumab was launched in Japan in June 2013 as a therapeutic option for osteoporosis. A domestic phase III clinical trial of patients with primary osteoporosis with vertebral fractures demonstrated that up to 2 years administration of denosumab decreases the incidence of vertebral fractures, increases bone density, and positively influences bone metabolism markers[11]. However, in clinical practice, the BMD of certain patients does not increase after denosumab administration. As few studies have reported non-responders to denosumab treatment, their background characteristics are unknown.

We conducted this retrospective cohort study to investigate the risk factors for a low BMD increase rate among osteoporotic patients treated with denosumab.

Subjects

This retrospective observational study was approved by the Institutional Review Board of Juntendo University (registration number: 18–037), which waived the requirement for informed patient consent because of the anonymous nature of the data. Patients with osteoporosis were recruited from the outpatient clinic of our university hospital between September 2013 and November 2019.

The sample size was determined based on the number of eligible patients enrolled during the study period. All enrolled patients were diagnosed with osteoporosis and had received denosumab for 24 months or longer. Subjects were excluded if they did not have available BMD data at either baseline or after 24 months of denosumab treatment. Patients who had either lumbar spine (L2-L4) BMD (LBMD) data or femoral neck BMD (HBMD) data were eligible for study inclusion.

All BMD measurements were carried out using DXA densitometry (Discovery A, Hologic, Inc.). The final study cohort comprised 162 men and women with osteoporosis who were aged 50 years or older and were administered denosumab (60 µg/6 months) for 24 months. Patients were categorized as non-responders or responders in accordance with the criteria used in previous studies^{[7, 12]}. We defined non-responders as those with a LBMD increase of < 3% in 2 years (N_L group) and a HBMD increase of < 0% in 2 years (N_H group). We defined responders as those with a LBMD increase of ≥ 3% in 2 years (R_L group) and those with a HBMD increase of ≥ 0% in 2 years (R_H group).

Variables

The following data were obtained from the medical records: age, sex, height, weight, BMI, presence or absence of pretreatment with bisphosphonates, supplementation with either native or active vitamin D₃ during the treatment period, history of fracture, baseline LBMD and HBMD, baseline serum calcium and tartrate-resistant acid phosphatase 5b (TRACP-5b) levels, and incidence of clinical vertebral fracture during the study period.

Statistical Analysis

The baseline patient characteristics and relevant bone turnover biomarkers were summarized. A pairwise comparison was performed to examine the differences in baseline characteristics among the groups. The distribution of the variables was examined using the Shapiro-Wilk test. Height, BMI, and baseline HBMD were compared between two groups using the two-sample t-test; age, weight, baseline LBMD, serum calcium level, and serum TRACP-5b level were compared between two groups using the Wilcoxon rank sum test. The chi-squared test was used for intergroup comparisons of the presence or absence of pretreatment with bisphosphonates. The supplementation with either native or active vitamin D3 was compared between groups using a test of difference in proportions. The differences between groups in sex and history of fracture were examined using Fisher's exact test. The association between the pretreatment BMD and the changes in the LBMD and HBMD after 2 years of denosumab treatment was examined using Spearman's rank correlation coefficient. The correlation between various variables and the changes in the LBMD and HBMD after 2 years of denosumab treatment was examined using partial correlation analysis. The odds ratio (OR) was obtained using logistic regression analysis after adjusting for age, sex, and BMI. A two-sided 5% α level was used to assess the statistical significance. All data were analyzed using statistical software for Windows, STATA version 16.1 (Stata Corp LLC, College Station, TX, USA).

The baseline characteristics of the osteoporotic patients treated with denosumab for 24 months are shown in Table 1. The percentage of women was 94% (152/162) and the average age was 73.1 ± 8.1 years. The administration of denosumab for 24 months increased the LBMD and HBMD by 9.3% (95% confidence interval (CI): 8.1–10.6) and 3.3% (95% CI: 2.1–4.5), respectively.

Table 1

Baseline characteristics of the patients with osteoporosis
A	N_L Group (n = 28)	R_L Group (n = 134)	p value
Change of LBMD, mean (95%CI), %	0.2 (-0.9 ~ 1.3)	11.2 (9.9 ~ 12.5)	< 0.001***
Age, mean (SD, range), years	73.6 (8.4, 53–84)	73.0 (8.1, 50–88)	0.66
Female, n (%)	28 (100)	124 (92)	0.21
Height, mean (range), cm	150.9 (130–166)	152.6 (139–175)	0.22
Body weight, mean (range), kg	45.3 (35–55)	48.5 (31–73)	0.07
BMI, mean (range), kg/m²	19.9 (14.5–23.8)	20.8 (14.3–29.4)	0.17
Prevalent fracture, n (%)
Thoracic vertebra, n (%)	2 (7)	21 (16)	0.37
Lumber vertebra, n (%)	10 (36)	36 (27)	0.36
Femoral neck, n (%)	0 (0)	3 (2)	1.0
Other, n (%)	1 (4)	9 (7)	1.0
BMD
Baseline LBMD, mean (95%CI), g/cm²	0.72 (0.65–0.80)	0.71 (0.68–0.73)	0.93
Baseline HBMD, mean (95%CI), g/cm²	0.49 (0.46–0.52)	0.49 (0.48–0.50)	0.78
Serum calcium levels, mean (95%CI), mg/dL	9.5 (9.3–9.7)	9.4 (9.3–9.4)	0.34
Serum TRACP-5b levels, mean (95%CI), mU/dL	292.1 (233.2–351.0)	320.4 (292.7-348.1)	0.43
Bisphosphonate, n (frequency, %)	22 (79%)	72 (54%)	0.007**
B	N_H Group (n = 48)	R_H Group (n = 108)	p-value
Change of HBMD, mean (95%CI), %	-3.8 (-5.0 ~ -2.6)	6.5 (5.2 ~ 7.7)	< 0.001***
Age, mean (SD, range), years	74.8 (7.5, 50–85)	72.9 (8.3, 50–88)	0.13
Female, n (%)	44 (92)	102 (94)	0.50
Height, mean (range), cm	153.0 (130–162)	151.9 (139-175.5)	0.35
Body weight, mean (range), kg	48.0 (35–63)	47.6 (31–73)	0.52
BMI, mean (range), kg/m²	20.4 (14.5–26.7)	20.7 (14.3–29.4)	0.64
Prevalent fracture, n (%)
Thoracic vertebra, n (%)	8 (17)	14 (13)	0.62
Lumber vertebra, n (%)	15 (31)	29 (27)	0.57
Femoral neck, n (%)	0 (0)	3 (3)	0.55
Other, n (%)	2 (4)	8 (7)	0.73
BMD
Baseline LBMD, mean (95%CI), g/cm²	0.73 (0.68–0.79)	0.70 (0.67–0.73)	0.40
Baseline HBMD, mean (95%CI), g/cm²	0.52 (0.50–0.53)	0.48 (0.47–0.49)	0.003**
Serum calcium, mean (95%CI), mg/dLa	9.4 (9.2–9.5)	9.4 (9.3–9.5)	0.89
TRACP5b, mean (95%CI), mU/dL	285.1, (249.0-321.1)	329.9, (296.9-362.9)	0.22
Bisphosphonate, n (frequency, %)	30 (63%)	61 (56%)	0.48
Patients were divided into two groups according to the changes in bone mineral density in the spine (A) and hip (B). N_L Group: non-responders regarding LBMD (< 3% increase), N_H group: responders regarding LBMD (≥ 3% increase), R_H group: responders regarding HBMD (≥ 0% increase).
SD: standard deviation, BMI: body mass index, BMD: bone mineral density, 95%CI: 95% confidence interval, LBMD: lumbar spine BMD, HBMD: femoral neck BMD, TRACP-5b: tartrate-resistant acid phosphatase 5b
P < 0.01, *P < 0.001

When the subjects were divided into two groups according to the changes in the LBMD after denosumab treatment, the R_L group contained 134 of 162 subjects (66.7%; 124 women, 10 men) and the N_L group contained 28 subjects (33.3%; 24 women, four men). The change in the LBMD was 11.2% (95% CI: 9.9–12.5) in the R_L group and 0.2% (95% CI: -0.9–1.3) in the N_L group (p < 0.001). There were no significant differences between the R_L and N_L groups in age, history of fracture, baseline LBMD and HBMD, calcium level, and TRACP-5b level. However, pretreatment with bisphosphonate before the initiation of denosumab treatment was significantly more common in the N_L group (79%; 22/28) than the R_L group (54%; 72/134) (p = 0.007) (Table 1A). Univariate analysis showed that pretreatment with bisphosphonate was a risk factor for a < 3% increase in the LBMD after 24 months of denosumab treatment (OR: 3.84, 95% CI: 1.38–10.71, p = 0.01); multivariate logistic analysis adjusted for age, sex, and BMI showed a similar result (OR: 3.21, 95% CI: 1.01–10.19, p = 0.048).

One-hundred-and-forty-four of 162 subjects (88.9%) received either native vitamin D₃ (n = 46) or active vitamin D₃ (n = 98) in addition to denosumab treatment for 24 months, while 14 subjects (8.6%) received both native and active vitamin D₃; the remaining four subjects (2.5%) did not receive either native or active vitamin D₃. Of the 144 subjects who received either native vitamin D₃ or active vitamin D, 121 (84.0%) were in the R_L group (40 (33.1%) received native vitamin D₃ and 81 (66.9%) received active vitamin D₃), while 23 (16.0%) were in the N_L group (six (26.1%) received native vitamin D₃ and 17 (74.0%) received active vitamin D₃). The distribution of the two types of vitamin D₃ did not significantly differ between the R_L and N_L subgroups (p = 0.056).

When the subjects were divided into two groups according to the changes in the HBMD after denosumab treatment, the R_H group contained 108 of 156 subjects (69.2%; 102 women, six men) and the N_H group contained 48 subjects (30.8%; 44 women, four men). Eleven subjects (7.1%) were included in both the N_L and N_H groups. The change in the HBMD was 6.5% (95% CI: 5.2–7.7) in the R_H group and − 3.8% (95% CI: -5.0 to -2.6) in the N_H group (p < 0.001). There were no significant differences between the R_H and N_H groups in the history of spine, hip, and other fractures. Although the LBMD at baseline did not significantly differ between the R_H and N_H groups, the HBMD at baseline was significantly lower in the R_H group than the N_H group (p = 0.003). There were no significant differences between the R_H and N_H groups in the serum levels of calcium and TRACP-5b. The frequency of pretreatment with bisphosphonate did not significantly differ between the N_H and R_H groups (63% (30/48) in the N_H group and 56% (61/108) in the R_H group) (Table 1B).

One-hundred-and-forty of 156 subjects (89.7%) received either native vitamin D₃ (n = 45) or active vitamin D₃ (n = 95) in addition to denosumab treatment for 24 months, while 14 subjects (9.0%) received both native and active vitamin D₃; the remaining two subjects (1.3%) did not receive either native or active vitamin D₃. Of the 140 subjects who received either native vitamin D₃ or active vitamin D, 42 (30.0%) were in the N_H group (15 (35.7% received native vitamin D₃ and 27 (64.3%) received active vitamin D₃), while 98 subjects (70.0%) were in the R_H group (30 (30.6%) received native vitamin D₃ and 68 (69.4%) received active vitamin D₃). The distribution of the two types of vitamin D₃ did not significantly differ between the R_H and N_H subgroups (p = 0.19).

The change in the LBMD was associated with the change in the HBMD in osteoporotic patients who received 24 months of denosumab treatment (Spearman's rho = 0.19, p = 0.02). The change in the LBMD was positively associated with the serum level of TRACP-5b at baseline (Spearman's rho = 0.34, p < 0.001) and negatively associated with the serum level of calcium at baseline (Spearman's rho=-0.18, p = 0.02) (Table 2). The HBMD at baseline was also negatively associated with the change in the HBMD in osteoporotic patients treated with denosumab for 24 months (r=-0.34, p < 0.001) (Fig. 1).

Table 2

Associations between the changes in LBMD and HBMD and various baseline variables
Variable	ΔLBMD		ΔHBMD
Variable	r	P-value	r	P-value
Age (years)	-0.09	0.26	-0.16	0.053
Height (cm)	0.06	0.40	-0.14	0.09
Body weight (kg)	0.07	0.36	-0.03	0.76
BMI (kg/m²)	0.04	0.63	0.05	0.54
Serum calcium level (mg/dLa)	-0.18	0.02*	0.02	0.81
TRACP-5b level (mU/dL)	0.34	< 0.001***	0.14	0.08
LBMD: lumbar spine bone mineral density, HBMD: femoral neck bone mineral density, BMI: body mass index, TRACP-5b: tartrate-resistant acid phosphatase 5b
**P < 0.001, P < 0.05
The HBMD increase rate was weakly negatively associated with the HBMD at baseline (r=-0.34, p < 0.001)
HBMD: femoral neck bone mineral density

During the 24 months of denosumab treatment, no patients developed new clinical vertebral body fractures.

Denosumab has been reported to reduce the incidence of vertebral and non-vertebral fractures and increase BMD in patients with osteoporosis[13, 14]. In the current study, new clinical vertebral fractures did not occur in patients who received denosumab for 2 years, and the mean increase rate was 109.3% for LBMD and 103.3% for HBMD. Denosumab was well tolerated in the present study and the mean BMD gains achieved were similar to those observed with the same denosumab regimen in other populations[11, 13]. However, the present cohort included non-responders with no or little increase in the BMD of the lumbar spine and femoral neck. We found that 15.4% of the total patient cohort did not achieve more than a 3% increase in LBMD, and 30.8% did not achieve more than a 0% increase in HBMD after 24 months of denosumab treatment, which is similar to the findings of a previous study[15].

The present study showed that a history of administration of bisphosphonates was associated with a non-response to denosumab regarding the LBMD after adjusting for age, sex, and BMI. In the process of suppressing bone resorption, denosumab does not have the same mechanism as bisphosphonates[16]. A previous phase 3 trial showed that denosumab has strong inhibitory effects on bone resorption despite prior bisphosphonate therapy and confirmed that denosumab produces more pronounced bone resorption inhibition; similar results were shown in other studies[17–20]. As the mean BMD increase rate in the present study was similar to these previous reports, our data were not inconsistent with previous reports. In the non-responder cases, we speculate that the removal of highly mineralized bone during the initial treatment phase may account for the higher non-response rate to denosumab. However, it remains unclear why patients with prior bisphosphonate administration only showed a smaller BMD increase in the lumbar spine region, but not the femoral neck.

We showed that the HBMD increase rate was negatively associated with the HBMD at baseline. Patients with lower baseline HBMD responded well to denosumab treatment, while those with high baseline HBMD did not. We also found a significant association between the change in LBMD and the change in HBMD from pretreatment to 2 years after denosumab initiation. These data suggest that denosumab works on the spine and femoral neck in patients with osteoporosis. It should be noted that 6% of patients in the present cohort were categorized as non-responders regarding both LBMD and HBMD.

To evaluate the effects of the denosumab treatment, many studies use TRACP-5b as a biomarker for bone resorption[21–24]. Previous research has shown that the concentration of TRACP-5b in blood increases with the increase in bone resorption and accurately reflects the state of bone resorption^[25]. Our study revealed a significant positive correlation between the change in LBMD and the TRACP-5b level at the time of denosumab initiation. This suggests that patients with a high TRACP-5b level at baseline are likely to respond to the denosumab treatment and their BMD is likely to increase. We consider this an understandable result because the main action of denosumab is as a bone resorption inhibitor and the effect may not be sufficient in patients whose bone resorption is already suppressed. In other words, our results suggest that the TRACP-5b level at denosumab initiation may be a predictable biomarker of BMD increase. However, the TRACP-5b level did not significantly differ between non-responders and responders in terms of both LBMD and HBMD. Future studies may be needed to interpret the results.

Vertebral fractures and hip fractures are considered to be strongly associated with reductions in spine BMD and hip BMD, respectively [26]. Previous research has shown that denosumab reduces the risk of new radiographic vertebral fractures [11, 13]. In the FREEDOM trial, 36 months of denosumab treatment significantly reduced the risk of vertebral fractures by 68%, nonvertebral fractures by 20%, and hip fractures by 40% compared with placebo[13]. In the present study, no patient developed a new clinical fracture. As there were no new fractures in either group, we could not conclude that the BMD increase rate was a predictor of the increased incidence of new clinical fractures within 24 months. However, denosumab might have a preventive effect on new fractures even for patients whose BMD does not increase. This notion is supported by a previous study that reported no major fractures after 2 years of denosumab treatment, regardless of the response to denosumab based on the spine BMD^[15]. We will monitor the cohort to determine whether the BMD level continues to stay stable or decreases in the future and whether the incidence of new fractures decreases over the longer term.

In Japan, both active vitamin D and native vitamin D supplementation with denosumab treatment are covered by national healthcare insurance. Patients receiving denosumab are recommended to take combination treatment with vitamin D to prevent hypocalcemia caused by the pharmacological action of denosumab[27–29]. We found no difference in the response to denosumab (in terms of the LBMD and HBMD increase rates) depending on the type of vitamin D used. A previous study reported that the denosumab plus active vitamin D group and the denosumab plus native vitamin D group showed similar increases in the BMD of the lumbar spine (6.5% vs. 6.4%) and total hip (3.4% vs. 3.3%) from baseline to 12 months after treatment, but showed different increases in the BMD of the femoral neck (1.0% vs. 4.9%)^[28]. Although we do not know how much vitamin D affects the rate of BMD increase, the administration of both types of vitamin D with denosumab had a similar effect on the BMD increase in our study.

The present study had some limitations. First, the choice of patients who received denosumab depended on each physician's preference. Although we adjusted the analysis to remove the effects of some key baseline characteristics (age, sex, and BMI), there were other potential confounders such as exercise, diet, smoking history, and prevalence of osteoarthritis. Second, in our study, although the BMD change did not influence the incidence of new clinical fractures, the observation period was relatively short. Therefore, a further long-term longitudinal study is needed.

In osteoporotic patients, a history of bisphosphonate treatment before denosumab treatment is a risk factor for a lack of increase in the LBMD. In addition, a higher HBMD at baseline was negatively associated with the change in HBMD caused by denosumab treatment in patients with osteoporosis. As no patients experienced new clinical vertebral body fractures in the 24 months after denosumab initiation, denosumab might have a preventive effect on new fractures even in patients whose BMD does not increase.

BMD

bone mineral density

LBMD

lumbar spine BMD

HBMD

femoral neck BMD

BMI

body mass index

TRACP-5b

tartrate-resistant acid phosphatase 5b.

Ethics approval and consent to participate

This retrospective observational study was approved by the Institutional Review Board of the Juntendo University (registration number: 18-037). The Institutional Review Board of the Juntendo University waived the requirement for patients’ informed consent because of the anonymous nature of the data. All methods were carried out in accordance with relevant guidelines and regulations

Consent for publication

Not applicable

Availability of data and materials

Data are available from the corresponding author upon reasonable request and with permission

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors' contributions

All authors contributed to the study conception and design as well as the material preparation, data collection and analysis. The first draft of the manuscript was written by Akiko Yamamoto and all authors commented on previous versions of the manuscript. All authors have read and agreed and approved to the published version of the manuscript.

Acknowledgements

We thank Mrs. Nahoko Shinada for managing the database of our orthopaedic osteoporosis group. We also thank Dr Kelly Zammit, BVSc, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Authors' information (optional)

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No competing interests reported.

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Risk Factors for Non-Response to 2 Years of Denosumab Administration in Patients with Osteoporosis: a retrospective cohort study

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