
==== Front
CNS Drugs
CNS Drugs
CNS Drugs
1172-7047
1179-1934
Springer International Publishing Cham

39174745
1104
10.1007/s40263-024-01104-0
Original Research Article
Assessment of Bone Mineral Density Over 1 Year in a Cross-Sectional Cohort of Migraine Patients Receiving Anti-CGRP Monoclonal Antibodies
Para Davide 1
http://orcid.org/0000-0002-0678-3240
Camponovo Chiara 2
http://orcid.org/0000-0002-1202-5534
Riccitelli Gianna Carla 13
http://orcid.org/0000-0002-0031-9594
Mallucci Giulia 1
http://orcid.org/0000-0002-5898-145X
Maino Paolo 4
http://orcid.org/0000-0001-8586-9925
Mondini Trissino da Lodi Camilla 1
Saudina Demurtas 1
http://orcid.org/0000-0002-2125-4937
Trimboli Pierpaolo 2
http://orcid.org/0000-0002-7554-0664
Gobbi Claudio 13
http://orcid.org/0000-0002-9990-3431
Zecca Chiara chiara.zecca@eoc.ch

13
1 https://ror.org/00sh19a92 grid.469433.f 0000 0004 0514 7845 Ente Ospedaliero Cantonale, Regional Hospital of Lugano, Department of Neurology, Neurocenter of Southern Switzerland, 6900 Lugano, Switzerland
2 https://ror.org/00sh19a92 grid.469433.f 0000 0004 0514 7845 Ente Ospedaliero Cantonale, Regional Hospital of Lugano, Clinic for Endocrinology and Diabetology, Lugano, Switzerland
3 https://ror.org/03c4atk17 grid.29078.34 0000 0001 2203 2861 Faculty of Biomedical Sciences, Università della Svizzera Italiana, Lugano, Switzerland
4 https://ror.org/00sh19a92 grid.469433.f 0000 0004 0514 7845 Ente Ospedaliero Cantonale, Regional Hospital of Lugano, Department of Anesthesiology, Neurocenter of Southern Switzerland, Lugano, Switzerland
22 8 2024
22 8 2024
2024
38 10 819825
18 6 2024
© The Author(s) 2024
2024
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Background

Calcitonin gene-related peptide (CGRP), implicated in migraine pain, also possesses bone anabolic properties, which leads to the possibility that monoclonal antibodies targeting CGRP (anti-CGRPs) might increase the risk of bone density abnormalities.

Objective

The objective of this study was to explore bone mineral density abnormalities in a cohort of migraine patients treated with anti-CGRPs.

Methods

This was a single-center, cross-sectional, cohort study including migraine patients who underwent a densitometry assessment during anti-CGRP treatment. We assessed the frequency of osteopenia or osteoporosis (OSTEO+ status), defined as a bone mineral density T-score of −1 to −2.5, and <−2.5 standard deviations from the young female adult mean, respectively. Additionally, the association of OSTEO+ status with anti-CGRP treatment duration and primary osteoporosis’ risk factors was investigated using logistic regression models.

Results

Data from 51 patients (43 female, mean age 46 ± 13.9 years) were evaluated. The mean duration of anti-CGRP treatment was 15.7 (±11.8) months. Twenty-seven patients (53%) were OSTEO+ (n = 22 osteopenia; n = 5 osteoporosis). In the final model, menopause [odds ratio 11.641 (95% confidence interval 1.486–91.197), p = 0.019] and anti-seizure drug use [odds ratio 12.825 (95% confidence interval 1.162–141.569), p = 0.037] were associated with OSTEO+ status.

Conclusions

In our cohort of migraine patients, no evidence of an association between anti-CGRP treatment duration and an increasing risk of bone mineral density abnormalities was found. However, these findings are preliminary and necessitate further longitudinal research with larger cohorts and extended follow-up to be validated.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40263-024-01104-0.

Università della Svizzera italianaOpen access funding provided by Università della Svizzera italiana

issue-copyright-statement© Springer Nature Switzerland AG 2024
==== Body
pmcKey Points

Calcitonin gene-related peptide is a migraine pain mediator but also a bone anabolic factor.	
In our small cohort of migraine patients, there was no evidence of a time-dependent risk of bone mineral density abnormalities associated with anti-calcitonin gene-related peptide treatment over 12 months.	
Because of the small sample size and the study design, further studies are required to confirm our results.	

Background

Migraine is one of the most frequent chronic neurological disorders affecting 1 billion people worldwide. It leads to a substantial impairment in patients’ quality of life and incurs significant healthcare costs [1].

To improve migraine management, various prevention strategies are employed. These strategies encompass both pharmacological and non-pharmacological interventions, aimed at reducing the frequency, severity, and duration of migraine episodes [2].

Pharmacological migraine prevention strategies have relied on the use of beta-blockers, anti-seizure medications, and antidepressants. However, these treatments are often discontinued because of their frequent and sometimes severe side effects. [3].

More recently, monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) such as galcanezumab, fremanezumab, and eptinezumab or its receptor such as erenumab (anti-CGRPs) have been introduced to the market for migraine prevention. These drugs are not only very effective but also well tolerated compared to other migraine preventive therapies. Their most common side effects seen in clinical practice are constipation and pain at the injection site [4, 5].

Calcitonin gene-related peptide is a potent microvascular vasodilator implicated in migraine pathogenesis [6–8]. Calcitonin gene-related peptide and its metabolic pathways are also involved in other physiological processes, such as cardiovascular, renal, immunologic, and metabolic, and especially in bone homeostasis. Calcitonin gene-related peptide has anabolic properties and stimulates the proliferation of osteoblastic cells as well as new bone formation and increases levels of insulin-like growth factor-1, thus contributing to bone growth as well as fracture repair [9]. Blocking the CGRP system might therefore impair bone metabolism resulting in osteoporosis or osteopenia, increased fracture risk, and reduced fracture repair. In addition, migraine, osteopenia, and osteoporosis affect more frequently female individuals, implying that many migraine sufferers might develop bone complications under anti-CGRPs, particularly over the long term. Despite the potentially relevant clinical implications, research into the relationship between anti-CGRP treatments and their potential adverse effects on bone metabolism remains scant [10]. Against this background, the aim of this study is to investigate potential changes in bone density among migraine patients treated with anti-CGRP therapies.

Methods

This was a single-center cross-sectional cohort study. From May 2021, consecutive adult patients (aged ≥18 years) affected with migraine with or without aura [11] under anti-CGRP treatment (erenumab, galcanezumab, fremanezumab) seen at the Headache Centre of the Neurocenter of Southern Switzerland are offered to undergo bone densitometry according to a local clinical standard of care because of concerns of a possibly increased risk of bone density abnormalities. We prospectively collected demographic, clinical, and densitometry data of patients who underwent bone densitometry between May 2021 and March 2022. All participants consented for the reuse of their clinical data for research purposes. Data of patients previously known diagnosis of and/or treatment for osteoporosis or osteopenia were excluded from the analysis.

Demographic and clinical data such as age, sex, age at bone densitometry, migraine type and duration, previous and/or current migraine preventive therapies, type of anti-CGRP, and duration of anti-CGRP treatment up to the date of bone densitometry were obtained from medical records available at our hospital. We also documented the presence/absence of osteo-metabolic disease’s risk factors including smoking, history of cancer, endocrinopathies (especially thyroid diseases and sexual hormone dysfunctions), autoimmune and rheumatic diseases, previous use of medications at risk of osteoporosis/osteopenia (yes/no) [such as corticosteroids, anti-seizure drugs, heparin, serotonin and norepinephrine reuptake inhibitors, selective serotonin reuptake inhibitors, progestins, and antineoplastic drugs], previous non-traumatic fractures (yes/no), menopause (yes/no), and malabsorption syndromes (yes/no). These variables were collected as dichotomous in order to ensure reliability and consistency across the study cohort, as additional details were not available for all patients. Body mass index was also recorded.

Reference Standard for Diagnosis of Osteoporosis and Osteopenia

Lumbar spine (L1–L4) and femoral neck bone mineral density (BMD) were obtained by dual energy X-ray absorptiometry (GE Lunar iDXA; GE Healthcare). Lumbar spine (L1–L4) trabecular bone score (TBS) was calculated using the TBS iNsight® software version 3.0.2.0 (Medimaps, Pessac, France). The diagnosis of osteoporosis/osteopenia was based on the dual energy X-ray absorptiometry assessment using the lowest among the lumbar spine (L1–L4) and femoral neck T-scores. Osteoporosis was defined by a BMD T-score value of 2.5 standard deviations (SDs) or more below the young female adult mean (T-score ≤ −2.5) or by the occurrence of a low trauma fracture during treatment with anti-CGRP [12]. Osteopenia was defined as a BMD T-score between −1 SD and −2.5 SDs being lower than the young female adult mean (T-score < −1 and > −2.5) [13]. Patients exhibiting osteoporosis or osteopenia were categorized as OSTEO+, while those with normal BMD were designated as OSTEO−.

Statistical Analysis

Continuous variables were described by using mean (±SD) and median (interquartile range) while frequency was used for categorical variables. Normal distribution assumption was checked with Kolmogorov–Smirnov and Shapiro–Wilk tests as well as graphical inspection of Q-Q plots. Demographic, clinical, and densitometry characteristics of patients with and without osteoporosis/osteopenia were compared with Mann–Whitney U test and Chi-square test.

To investigate demographic and clinical features associated with the diagnosis of osteoporosis/osteopenia, we used univariate and multivariable logistic regression models. We included anti-CGRP treatment duration as a surrogate treatment effect (we hypothesized that in case anti-CGRPs have an impact on osteopenia/osteoporosis risk, a positive association between this adverse effect and increasing treatment duration would be found).

A post-hoc power analysis was conducted after the study was completed to evaluate whether the study had sufficient statistical power to detect an effect of a given size. Thus, considering a 40% risk of osteoporosis in the general population, a sample size of 51 individuals allows 80% power to detect a significant association (with alpha = 0.05) between the outcome of interest and a continuous risk factor with an expected odds ratio of 2.2 for an increase of 1 SD above the mean [14]. Finally, a bivariate Pearson correlation analysis was performed between anti-CGRP treatment duration and densitometry measures. All analyses were performed using the statistical software SPSS (Statistical Package for Social Science, version 23; SPSS Inc., Chicago, IL, USA).

Results

Between May 2021 and March 2022, out of the 253 migraine patients ever treated with anti-CGRPs at our Center, 52 were consecutively seen and underwent bone densitometry. Data of one patient were excluded from the analysis as the patient was already diagnosed with osteoporosis before the start of anti-CGRP treatment. Therefore, owing to the data availability, a convenient sample of 51 patients was included in the present study.

Forty-three (84.3%) patients were women, mean age was 46 (±13.9) years. Twenty-four (47.1%) patients had episodic migraine, 27 (52.9%) had chronic migraine, and 13 (25.5%) had migraine with aura. Thirty-one (60.8%) were treated with erenumab, 11 (21.5%) with galcanezumab, and 9 (17.7%) with fremanezumab; mean treatment duration was 15.7 (±11.8) months. Mean body mass index was 23.2 (±4.6). Overall, 42 (82.4%) patients had at least one and 19 (37.2%) patients had two or more osteo-metabolic disease risk factors, the most frequently reported being the use of one or more at-risk drugs (n = 40, 78.4%) and menopause (n = 18, 35.3%). The anti-seizure drug exposure was similar between patients treated with anti-CGRP for ≥1 year (22 patients exposed out of 28) and those treated for <1 year (15 patients exposed out of 23), χ2 = 1.1307 (p = 0.28). Additional risk factors are displayed in Table 1.Table 1 Demographic and clinical characteristics

Characteristics	Overall
n = 51 (100%)	OSTEO+
n = 27 (53%)	OSTEO−
n = 24 (47%)	
Age at scan, years; mean (SD)	46 (±13.9)	48.1 (±13.5)	43.6 (±14.3)	
Sex, F (%)	43 (84.3)	24 (47)	19 (37.2)	
Episodic migraine, n (%)	24 (47.1)	9 (17.6)	15 (29.4)	
Chronic migraine, n (%)	27 (52.9)	18 (35.3)	9 (17.6)	
Migraine with aura, n (%)	13 (25.5)	3 (5.8)	10 (19.6)	
Treatment, n (%)				
 Erenumab	31 (60.8)	19 (37.2)	12 (23.5)	
 Galcanezumab	11 (21.5)	3 (5.8)	8 (15.6)	
 Fremanezumab	9 (17.7)	5 (9.8)	4 (7.8)	
Anti GGRP treatment duration, months; mean (SD)	15.7 (±11.8)	17.5 (±12.1)	13.7 (±11.4)	
BMI, kg/m2; mean (SD)	23.2 (±4.6)	23.3 (±5.8)	23.1 (±2.8)	
Number of patients with osteo-metabolic disease’s risk factors, n (%)				
 No risk factors	9 (17.6)	1 (1.9)	8 (15.7)	
 ≥1	42 (82.4)	26 (50.9)	16 (31.4)	
 ≥2	19 (37.2)	16 (31.4)	3 (1.5)	
Drugs	40 (78.4)	27 (52.9)	13 (25.4)	
 Anti-seizure medications	37 (68.6)	24 (47)	13 (25.4)	
 SNRIs/SSRIs	10 (19.6)	5 (9.8)	5 (9.8)	
 Corticosteroids	3 (5.8)	2 (3.9)	1 (1.9)	
Menopause	18 (35.3)	15 (29.4)	3 (5.8)	
History of cancer	3 (5.8)	2 (3.9)	1 (1.9)	
 Breast cancer	2 (3.9)	1(1.9)	1(1.9)	
 Hodgkin lymphoma	1 (1.9)	0	0	
BMI >30 or BMI <18	5 (9.8)	4 (19.2)	1 (1.9)	
Smoking	3 (5.8)	2 (3.9)	1 (1.9)	
Previous low-impact fractures	2 (3.9)	2 (3.9)	0	
Endocrinopathies	0	0	0	
Autoimmunity	0	0	0	
Malabsorption	0	0	0	
BMI body mass index, CGRP calcitonin-gene related peptide, F female, OSTEO+/OSTEO− patients with/without a diagnosis of osteopenia/osteoporosis, SD standard deviation, SNRIs serotonin and norepinephrine reuptake inhibitors, SSRIs selective serotonin reuptake inhibitors

Based on densitometry findings, 27 (53%) of 51 patients were diagnosed with osteoporosis (n = 5, 9.8%) or osteopenia (n = 22, 43%) [OSTEO+], while 24 (47%) were not (OSTEO−) [Table 1]. All bone densitometry measures were different between OSTEO+ and OSTEO− groups (lumbar T-score: p < 0.001; femoral T-score: p < 0.001; TBS: p = 0.004, lumbar BMD and femoral BMD p < 0.001; Table 2).Table 2 Median and interquartile range of bone densitometry measures

Measures	Overall
n = 51	OSTEO+
n = 27	OSTEO−
n = 24	P-value	
Lumbar T-score	−0.70

(−1.50 to −0.10)

	−1.20

(-2.30 to -0.80)

	−0.10

(−0.60 to 1.10)

	<0.001	
Femoral T-score	−1.20

(−1.6 to −0.50)

	−1.50

(−1.70 to −1.30)

	−0.30

(−0.80 to −0.30)

	<0.001	
TBS	1.37

(1.33–1.44)

	1.35

(1.32–1.39)

	1.41

(1.36–1.47)

	0.004	
Lumbar BMD	1.11

(0.99–1.25)

	1.04

(0.95–1.11)

	1.20

(1.12–1.29)

	<0.001	
Total femoral BMD	0.93

(0.86–1.04)

	0.89

(0.85–0.93)

	1.03

(0.97–1.10)

	<0.001	
Values OSTEO+ vs OSTEO were compared with the Mann–Whitney U test. T-score: number of standard deviations by which the BMD in an individual differs from the mean value expected in young healthy individuals. Osteoporosis is defined by a T-score ≤ −2.5. Osteopenia is defined by a T-score < −1 and > −2.5

BMD bone mineral density, TBS trabecular bone score, a measure of bone texture correlating to bone microarchitecture

According to the power analysis and our sample size of 51 individuals, the osteo-metabolic risk factors occurring at a frequency of at least 30% were included in our logistic regression model. At the univariate analysis, OSTEO+ status was associated with the presence of aura [odds ratio (95% confidence interval): 5.71 (1.34–24.33), p = 0.018], migraine type [episodic vs chronic: 0.30 (0.10–0.95), p = 0.040], anti-seizure drug exposure [6.76 (1.60–28.69), p = 0.009], and menopause [8.89 (2.06–39.22), p = 0.004] (Table 3). In the multivariate analysis, only anti-seizure drug exposure [12.82 (1.16–141.56), p = 0.037] and menopause [11.64, (1.48–91.19), p = 0.019] remained associated with OSTEO+ (Table 3). The multiple regression analysis was statistically significant, X2 = 24.775, p < 0.001. The model explained 56% (Nagelkerke R2) of variance of OSTEO+ status and classified correctly 86% of cases. The correlation analysis did not show any significant relationship between the duration of anti-CGRP treatments and the lumbar BMD T-score or the femoral BMD T-score (r = −0.69, p = 0.63; and r = −0.78, p = 0.58, respectively). Additionally, there was no correlation between the duration of anti-CGRP treatments and the TBS; r = −0.47, p = 0.74 (Fig. 1 of the Electronic Supplementary Material).Table 3 Logistic regression models

Parameters	Univariate analysis		Multivariate analysis	
OR (95% CI)	P-value		OR (95% CI)	P-value	
Age (per year of age)	1.02 (0.98–1.06)	0.25				
Sex (female vs male)	2.10 (0.44–9.94)	0.347				
Aura (presence vs absence)	5.71 (1.34–24.33)	0.018		0.27 (0.03–2.17)	0.22	
Type of migraine (episodic vs chronic)	0.3 (0.09–0.94)	0.04		0.17 (0.02–1.17)	0.073	
Disease duration	1.02 (0.98–1.08)	0.244				
Anti-CGRP treatment duration	0.73 (0.35–1.50)	0.396				
BMI	1.00 (0.89–1.13)	0.89				
Anti-seizure treatment	6.76 (1.59–28.68)	0.009		12.82 (1.16–141.56)	0.037	
Menopause	0.11 (0.25–0.49)	0.004		11.64 (1.48–91.19)	0.019	
The multiple regression analysis was statistically significant, X2 = 24.775, p < 0.001.The multivariate model explains 56% (Nagelkerke R2) of variance of osteopenia/arthritis disease and classifies correctly 86% of cases

BMI body mass index, CGRP calcitonin gene-related peptide, OR odds ratio

Discussion

Calcitonin gene-related peptide mediates migraine pain and exerts bone anabolic effects [15]. Therefore, targeting the CGRP pathway with anti-CGRPs might potentially induce osteo-catabolic effects. We reported findings of consecutively collected densitometry assessments to explore bone abnormalities in a cohort of migraine patients treated with anti-CGRPs. In our multivariate analysis, we evaluated the association between OSTEO+ status and anti-GCRP treatment duration, finding an OR of 1.02 (95% confidence interval 0.98–1.08) with a p > 0.05 suggesting a lack of an association between the two variables. In contrast, anti-seizure drug exposure and menopause increased the risk of osteopenia or an osteoporosis condition by approximately 12 and 11 times, respectively.

Of note, the prevalence of bone density abnormalities in our population is in line with those of the general European and US populations [13, 16]. Similarly, the association between menopause and osteoporosis/osteopenia is well established and related to the key role played by estrogens in maintaining bone health [15, 17, 18].

While the risk of osteoporosis in individuals with migraine has not yet been extensively evaluated, some drug classes in use for migraine prevention are known to modify osteoporosis risk. An increased risk of fractures is well established for selective serotonin reuptake inhibitors, tricyclic antidepressants, and anti-seizure treatments such as topiramate, while scientific evidence of an effect of calcium channel blockers, angiotensin-converting enzyme inhibitors, and beta-blockers on BMD is conflicting [18]. Concurring with the literature, our analysis highlighted a strong association between anti-seizure drug exposure and the presence of osteopenia/osteoporosis. We unfortunately could not dissect the effects of the various anti-seizure treatments as well as that of other classes of migraine preventive treatments because of their scarce frequency.

Our main finding, that the risk of osteopenia/osteoporosis in our migraine population treated with anti-CGRP was similar to that of the general European and US populations and did not increase with anti-CGRP treatment duration, argues in favor of the good tolerability and safety profile of anti-GCRPs as has emerged in registration clinical trials [19–28] and post-marketing observational studies [5, 29]. Considering the proven detrimental effect on bone metabolism of several other migraine preventive therapies and in line with the recent European Headache Federation guidelines [30], our finding contributes to further weaken objection to early use of anti-CGRPs as migraine preventive therapy.

We acknowledge several limitations in our study that may impact the interpretation and generalizability of our findings. These include the absence of a control group, the small sample size, and the relatively short mean follow-up, which limit the statistical power and robustness of our conclusions. Particularly, bone metabolism is a slow process, and the short duration of follow-up might not be sufficient to observe changes that would emerge over a longer period. The lack of a pre-treatment densitometry assessment to establish baseline bone health status in our study subjects before initiating anti-CGRP prevents any analysis for assessing the degree of change attributable to the treatment. Additionally, the heterogeneous timing of bone densitometry assessments during therapy could have further biased study results. Moreover, eating habits, physical activity, and calcium, magnesium, and vitamin D intake were not evaluated.

The collection of categorical variables, such as menopause status and anti-seizure exposure, was conducted to ensure consistency across the study cohort. However, this approach also limited the depth of information available for these variables and their potential impact on the study outcomes.

Finally, patients on long-term anti-CGRP therapy might have been more likely to discontinue anti-seizure medications, which might in turn affect BMD findings. Therefore, to mitigate this bias, we evaluated the frequency of anti-seizure medication exposure between patients on anti-CGRP treatment for less than 1 years versus more than 1 year, and we did not find any differences.

Our statistical approach partially mitigated these limitations, as the treatment duration was included as a covariate in our logistic regression model as a surrogate of treatment effect. We cannot exclude, however, immediate onset, minor size, as well as and the longer term effects of anti-CGRPs on the risk of osteopenia/osteoporosis. Replicating the finding that anti-seizure drugs and menopause are significant risk factors for osteopenia/osteoporosis [16, 18, 31-34] reinforces the representativeness of this migraine population. Our sample reported a higher number of female individuals, in line with migraine epidemiology.

Conclusions

In this cross-sectional cohort study, our findings do not suggest a time-dependent risk of BMD abnormalities associated with anti-CGRP treatment in a cohort of migraine patients over an average duration of approximately 1 year. It is crucial to interpret these results within the context of the study’s limitations, including its cross-sectional nature, relatively short average treatment duration, and the absence of a control group. Controlled larger sample studies with a longer follow-up are needed to confirm our results.

Supplementary Information

Below is the link to the electronic supplementary material.Supplementary file1 (PDF 201 KB)

The authors thank Liliane Petrini for her help with manuscript editing and submission.

Declarations

Funding

Open access funding provided by Università della Svizzera italiana.

Conflicts of Interest

Davide Para, Chiara Camponovo, Gianna Carla Riccitelli, Giulia Mallucci, Paolo Maino, Camilla Mondini Trissino da Lodi, Demurtas Saudina, Pierpaolo Trimboli, Claudio Gobbi, and Chiara Zecca have no relevant financial or non-financial interests that are directly relevant to the content of this article. Claudio Gobbi: Ente Ospedaliero Cantonale (employer) received compensation for C.G.’s speaking activities, consulting fees, or research grants from Almirall, Biogen Idec, Bristol Meyer Squibb, Lundbeck, Merck, Novartis, Sanofi, Teva Pharma, and Roche. Chiara Zecca: Ente Ospedaliero Cantonale (employer) received compensation for C.Z.’s speaking activities, consulting fees, or research grants from Almirall, Biogen Idec, Bristol Meyer Squibb, Lundbeck, Merck, Novartis, Sanofi, Teva Pharma, and Roche. Chiara Zecca is a recipient of a grant for senior researchers provided by AFRI (Area Formazione Accademica, Ricerca e Innovazione), Ente Ospedaliero Cantonale.

Ethics Approval

Approval by an ethics committee was not necessary.

Consent to Participate

All participants consented for the reuse of their clinical data for research purposes.

Consent for Publication

Not applicable.

Availability of Data and Material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Code Availability

Not applicable.

Authors’ Contributions

DP collected the clinical data, interpreted the results, and drafted the manuscript. CC performed the BMD measurements and revised the manuscript for intellectual content. GCR performed the statistical analysis. GM performed the statistical analysis, interpreted the results, and managed manuscript revision. PM interpreted the results and revised the manuscript. CMTdL collected the clinical data. DS collected the clinical data. PT performed the BMD measurements. CG conceptualized the work and interpreted the results. CZ conceptualized, planned, and supervised the work and interpreted the results.
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