pone.0267706

PLOS ONE
RESEARCH ARTICLE
The efficiency and safety of alendronate

versus teriparatide for treatment
glucocorticoid-induced osteoporosis: A meta-
analysis and systematic review of randomized
controlled trials
Zhi-Ming Liu1, Min Zhang2, Yuan Zong1, Ding Zhang1, Zhu-Bin Shen1, Xiao-Qing Guan1,
Fei Yin ID1*
a1111111111 1 Department of Spine Surgery, China-Japan Union Hospital of Jilin University, Changchun, 130033, China,
a1111111111 2 Department of Neonatology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou
a1111111111 Medical University, Wenzhou, 325027, China
a1111111111
* yinfei999@jlu.edu.cn
a1111111111
Abstract
OPEN ACCESS
Citation: Liu Z-M, Zhang M, Zong Y, Zhang D, Background

Shen Z-B, Guan X-Q, et al. (2022) The efficiency
Glucocorticoid-induced osteoporosis (GIOP) is the most common secondary osteoporosis,
and safety of alendronate versus teriparatide for
treatment glucocorticoid-induced osteoporosis: A alendronate (ALE) and teriparatide (TPTD) are widely used in the treatment of GIOP. How-
meta-analysis and systematic review of ever, which of these two drugs has a better curative effect needs the support of evidence-
randomized controlled trials. PLoS ONE 17(5): based medicine.
e0267706. https://doi.org/10.1371/journal.
pone.0267706
Editor: Wisit Cheungpasitporn, Mayo Clinic

Methods
Rochester: Mayo Clinic Minnesota, UNITED We searched PubMed, Embase, Cochrane Library, Web of Science, and Google Scholar
STATES
for randomized controlled trials of ALE and TPTD in the treatment of glucocorticoid-induced
Received: January 4, 2022 osteoporosis until February 2022. These patients included in the study took glucocorticoid
Accepted: April 13, 2022 doses greater than 7.5 mg/d for more than 3 months before treatment with ALE and TPTD.
Published: May 31, 2022
The risk ratio (RR) and its 95% confidence interval (CI) are used as the influence index of
discontinuous data, and the standardized mean difference (SMD) and its 95% CI are used
Peer Review History: PLOS recognizes the
benefits of transparency in the peer review
as the influence index of continuous data.
process; therefore, we enable the publication of
all of the content of peer review and author Results
responses alongside final, published articles. The
editorial history of this article is available here: A total of 4102 patients were enrolled in all 5 studies that met the admission criteria. We
https://doi.org/10.1371/journal.pone.0267706 found that compared with ALE, TPTD could reduce the rate of new vertebral fracture (RR =
Copyright: © 2022 Liu et al. This is an open access 0.13, 95% CI: 0.05–0.34, P<0.00001). TPTD increased LS bone mineral density (BMD)
article distributed under the terms of the Creative (0.53, 95% CI 0.42–0.64, P<0.00001), TH BMD (0.17, 95% CI 0.05–0.28, P = 0.004) and
Commons Attribution License, which permits
FN BMD (0.17, 95% CI 0.05–0.29, P = 0.006) compared to ALE. However, there was no sig-
unrestricted use, distribution, and reproduction in
any medium, provided the original author and nificant difference in the incidence of non-vertebral fracture and adverse events between
source are credited. the two groups.
PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 1 / 15

PLOS ONE The efficiency and safety of alendronate versus teriparatide for treatment glucocorticoid-induced osteoporosis
Data Availability Statement: All relevant data are Conclusions

within the paper and its Supporting Information
files. Compared with ALE, TPTD is an effective drug to reduce vertebral fracture risk in patients
with GIOP. Furthermore, long-term use of TPTD can increase the bone mineral density of
Funding: The authors received no specific funding
for this work. LS, FN, and TH.
Competing interests: The authors have declared

that no competing interests exist.
Introduction
Glucocorticoids are widely used in the treatment of rheumatic and autoimmune-related dis-
eases (rheumatoid arthritis, systemic lupus erythematosus, polymyositis, vasculitis), inflamma-
tory bowel disease, nephrotic syndrome, interstitial pneumonia, severe infection, shock, and
so on. However, glucocorticoids cause severe side effects on bones, which makes GIOP the
most common secondary osteoporosis [1]. In patients who receive long-term glucocorticoid
treatment, 30–50% may have fractures, especially the lumbar spine (LS) femoral neck (FN),
and total hip (TH) [2]. Taking 2.5 mg of oral prednisone daily increases the risk of fractures,
and when the dose is greater than 7.5 mg (dosage equivalent to daily endogenous glucocorti-
coid production), the risk increases 5 times [3]. In addition, the risk of fractures increases sig-
nificantly with the increasing dose of glucocorticoids and the prolongation of time [4].
The mechanism of GIOP can be summarized as follows: glucocorticoids reduce the number
of osteoblasts and inhibit their function, stimulate the production of osteoclasts and increase
their activity, thereby hindering bone growth and development. Glucocorticoid mainly inter-
feres with bone formation by up-regulating peroxisome proliferator-activated receptor γ
receptor 2 (PPARγ2) and affecting the Wnt/β-catenin signaling pathway. The former is benefi-
cial to the differentiation of pluripotent precursor cells into adipocytes, resulting in a reduction
in the number of osteoblasts. The latter is due to increased expression of sclerostin, inhibits
Wnt signaling, resulting in reduced differentiation of osteoclast precursors into mature osteo-
blasts and increases apoptosis of osteoblasts and osteocytes [5].
The pathogenesis of GIOP is multifactorial, with both glucocorticoids’ direct effects on
osteocytes and indirect effects on multiple neuroendocrine and metabolic pathways.
The latter is mainly manifested by hypogonadism, decreased physical activity, increased cal-
cium loss from the kidneys and intestines, and decreased production of growth hormone,
insulin-like growth factor 1 (IGF1), and IGF1 binding protein (IGF-BP) [6]. In addition,
excessive use of glucocorticoids can adversely affect bones and muscles, causing bone and
muscle atrophy and weakness, and increasing the risk of falls and fractures [7].
Bisphosphonate is a synthetic pyrophosphate analog, which can inhibit osteoclast activity,
inhibit bone resorption and increase bone mineral density in patients treated with glucocorti-
coid. It has been proved to be an effective method for the prevention and treatment of GIOP.
ALE is bisphosphate that can effectively increase the BMD of the LS, FN, and TH. It has been
widely used to prevent and treat GIOP [8]. TPTD, as a parathyroid hormone analog, can effec-
tively induce pre-osteoblasts to differentiate into osteoblasts, improve osteoblasts’ activity,
stimulate pre-existing osteoblasts to form new bone, and reduce osteoblasts apoptosis [9].
The meta-analysis previously published did not focus on the specific disease of glucocorti-
coid-induced osteoporosis, nor two specific drugs, nor did it discuss the spines that exert drug
effects at the micro-level such as bone metabolism indicators, nor did it pay more attention to
the main adverse reactions of drugs. The main purpose of this systematic review and meta-
analysis is to compare the safety and effectiveness of TPTD and ALE and to provide a new idea
for the clinical treatment of GIOP.

Methods
This study is reported by PRISMA (Preferred Reporting Items for Systematic Reviews and
Meta-Analyses). Please refer to S1 file for detailed table contents.
Search strategy and selection criteria

We searched PubMed, Embase, Cochrane Library, Web of Science, and Google databases for
randomized controlled trials of ALE and TPTD in the treatment of glucocorticoid-induced
osteoporosis until February 2022. In the retrieval process, we use keywords and Medical Sub-
ject Headings (MESH) terms to search the database. Search strategy is as follows: ("alendrona-
te"[MeSH Terms] AND "teriparatide"[MeSH Terms]) AND ((("glucocorticoid "[MeSH
Terms]) AND "osteoporosis"[MeSH Terms) OR "glucocorticoid-induced osteoporosis "[All
Fields] OR "GIOP "[All Fields]])). In this meta-analysis, all data are extracted from previously
published studies, so patient consent and ethical approval are not required. Specific literature
search strategies can refer to S2 File.
Study inclusion and exclusion criteria

The inclusion criteria are as follows: (1)Patients were at least 21 years old; (2) Patients had
taken prednisone or its equivalent at a dosage of �5 mg/day for�3 months before screening;
(3) Patients were required to have an LS or TH BMD T score of �−2.0 or �−1.0 plus at least
one fragility fracture while taking glucocorticoids; (4) Studies’ language was English; (5) Stud-
ies were RCTs.
The exclusion criteria are as follows:(1) Primary osteoporosis (including postmenopausal
osteoporosis, senile osteoporosis, and idiopathic osteoporosis) and other secondary osteoporo-
sis caused by non-glucocorticoid; (2) The type of articles was review, meta-analysis, and other
non-RCT; (3) The content and outcome are not the incidences of vertebral fracture and the
change of BMD.
Data extraction and quality assessment

ZML, YZ, DZ, XQG, and ZBS were responsible for the literature No. 11–14, including extrac-
tion of relevant content in this article, including major and minor outcomes. ZML was also
responsible for collecting and integrating the data extracted by the five authors.
The primary outcome of this study was the incidence of vertebral fracture and non-verte-
bral fracture, while the secondary outcome was the mean percent changes from baseline to
6,12,18 months in the ALE and TPTD groups in the lumbar spine(LS) bone mineral density
(BMD), the mean percent changes from baseline to 18 months in the two groups in the BMD
of the femoral neck (FN) and total hip (TH), the incidence of 5 adverse events with the highest
incidence, and changes in bone formation and resorption markers in both groups. In this
paper, two researchers independently conducted the literature search, screening, data extrac-
tion, and heterogeneity analysis. If there is any objection, we will reach an agreement after dis-
cussion, complete the preliminary search according to the established search strategy, and read
the abstract and full text to exclude studies that do not meet the inclusion criteria.
Data synthesis and analysis

All data are summarized using mean and standard deviation (SD). We use risk ratio (RR) with
a 95% confidence interval (CI) as the effective index of discontinuous data and standardized
mean difference (SMD) as the effective index of continuous data. We use I2 to evaluate hetero-
geneity between studies, and if I2 � 50% is considered to be high heterogeneity, a random

effect model is used, otherwise, a fixed-effect model is used. All of the above analysis was done
through Review Manager version 5.3. Egger linear regression test and funnel plot were per-
formed using Stata 16.0 to estimate publication bias. Specific data processing processes and
code can refer to S2 File.
Results
Search results and study characteristics
Of the 62 articles initially searched, 30were excluded because of content and outcome irrele-
vant, 15were excluded because of repetition, and17 were excluded because of non-RCTs. A
total of 4102patients were included in the 5 studies [10–14] that met the inclusion criteria of
this article (Fig 1).
We counted the baseline characteristics of these studies, including the studies’ first author
and year of publication, the number of patients in each study, the dose and duration of gluco-
corticoids taken, and gender, age, menopause (female), and BMD or T-score of the LS and FN
before taking the drug (Table 1).
Risk of bias in the included studies

All studies are randomized controlled trials but do not explain the random sequence genera-
tion process, and some of them have reporting biases (Fig 2).
The Egger linear regression test and funnel plot were used to measure the percent change in
LS BMD at 18 months. The funnel plot does have certain asymmetry, but each study is within
a 95% confidence interval, and the Egger linear regression test P = 0.07 > 0.05, which shows
that publication bias is not statistically significant, but the number of studies included in this
study is limited, and the interpretation of the results should be more cautious (Fig 3).
Incidence of vertebral and non-vertebral fractures

We found that compared with ALE, TPTD could significantly reduce the rate of new vertebral
fracture (RR = 0.13, 95% CI: 0.05–0.34, P<0.00001), but there was no significant difference
between the two in terms of non-vertebral fractures (RR = 1.28, 95% CI: 0.81–2.02, P = 0.29)
(Figs 4 and 5).
Mean percent change from baseline in the BMD at the LS, FN, TH
We first analyzed the percentage change of LS BMD at 6, 12, and 18 months. The results
showed that compared with ALE, TPTD could increase LS BMD from baseline to 6 months
(0.30, 95% CI 0.19–0.42, P<0.00001), 12 months (0.48, 95% CI 0.36–0.60, P<0.00001) and 18
months (0.53, 95% CI 0.42–0.64, P<0.00001) (Fig 6).
Compared with ALE, TPTD increased the BMD of FN from baseline to 18 months (0.17,
95% CI 0.05–0.29, P = 0.006); and increased the BMD of TH from baseline to 18 months (0.17,
95% CI 0.05–0.28, P = 0.004) (Figs 7 and 8).
We further analyzed that the longer the time of taking TPTD within a certain period, the
more obvious the increase of LS BMD, and the LS BMD at 18 months was significantly higher
than that at 6 months and 12 months. In addition, TPTD had different effects on different
parts bone tissue. After taking TPTD for 18 months, the increase of BMD of LS was higher
than that of FN and TH.

Fig 1. Flow diagram of literature search and study inclusion.

https://doi.org/10.1371/journal.pone.0267706.g001

Table 1. Baseline characteristicsa.

Comparison N GC dose(mg/ GC duration Age(y) Sex (M/ Postmenopause n(%) LS BMD(gm/cm2)/ T- PINP (ug/ CTX(pmol/
d)b (m) F) score l) l)
Benito R. Losada
2008d
alendronate 32 7.5±1.7 5.3±2.9 54.9±4.5 5/27 NM 0.8 ±0.05 NM NM
teriparatide 29 8.8±1.9 2.7±3.2 52.5 ±5.0 5/24 NM 0.8 ±0.05 NM NM
Alan L. Burshell
2009d
alendronate 77 8.0 16.8 60.6±2.5 17/60 50(64.9) −2.7±0.1 39.7±4.5 3570.8
±616.6
teriparatide 80 7.5 14.4 56.1±2.6 13/67 41(51.3) −2.5±0.1 44.5±4.8 3585.0
±643.2
Jean-Pierre 2009d
alendronate 192 10.1±0.7 5.1 ± 0.5 57.1±1.0 NM NM 0.85±0.01 NM NM
teriparatide 195 9.4±0.4 5.2 ± 0.6 55.8±1.0 NM NM 0.85±0.01 NM NM
B. L. Langdahl 2009d
alendronate
Postmenopausal 143 7.3 26.4 62.1±1.2 0/143 143(100) −2.7±0.1 39.0±4.7 3844.8
±580.5
Premenopausal 30 10.0 10.8 35.8±2.1 0/30 0 −2.6±0.2 43.0±3.6 2670.0
±217.6
Men 41 10.0 25.2 59.7±1.9 41/0 0 −2.3±0.2 36.5±9.6 4173.8
±977.4
teriparatide
Postmenopausal 134 7 31.2 61.9±1.2 0/134 134(100) −2.7±0.1 47.3±6.4 4030.8
±606.5
Premenopausal 37 8 21.6 40.0±1.9 0/37 0 −2.4±0.2 34.8±4.2 2331.0
±602.0
Men 42 10 27.6 55.5±1.9 42/0 0 −2.3±0.2 36.3±8.0 3236.0
±837.8
Kenneth G. Saag
2009d
alendronate 214 �5 24 57.3 41/173 143 (66.8) 0.864±0.014 39.5±4.0 3604.0
±14.0 ±540.1
teriparatide 214 �5 27.6 56.1 42/172 134 (62.6) 0.863±0.014 41.0±5.1 3384.5
±13.4 ±486.4
a
All patients received supplements of calcium (1000 mg/d) and vitamin D (800 IU/d).
b
prednisone or equivalent.
c
values are mean±SD.
d
values are mean±SE.
BMD = bone mineral density.
LS = lumbar spine.
PINP = N-terminal propeptide of type I collagen.
CTX = C-telopeptide of type I collagen.
GC = glucocorticoid.
M = male.
F = female.
NM = not mentioned.
https://doi.org/10.1371/journal.pone.0267706.t001

Fig 2. Risk of bias assessment of each included study. (A) Risk of bias graph. (B) Risk of bias summary.

Fig 3. Funnel plot of percent change in LS BMD at 18 months with alendronate and teriparatide.
Percent change in markers of bone formation and resorption

Two studies have reported bone metabolic markers, of which N-terminal propeptide of type I
collagen (PINP) is a marker of bone formation and C-telopeptide of type I collagen (CTX) is a
marker of bone resorption. In patients taking TPTD, both PINP and CTX increased compared
to the baseline, began to rise at 1 month, peaked at 6 months, and decreased slowly at 18
months. However, in patients taking ALE, both PINP and CTX decreased from the baseline,
began to decline at 1 month, reached the lowest level at 6 months, and increased slowly at 18
months (Figs 9 and 10).
Adverse events
A total of 3 studies reported the incidence of adverse reactions to the two drugs, we selected 5
high-incidence adverse events for research. The results showed that, overall, there was no sig-
nificant difference in the incidence of adverse reactions between the two groups (RR = 1.00,
Fig 4. Forest plots of incidence of vertebral fractures.


Fig 5. Forest plots of incidence non-vertebral fractures.

95% CI: 0.89–1.12, P = 0.58). Patients taking TPTD had a higher incidence of nausea than ALE
(RR = 1.68, 95% CI: 1.19–2.36, P = 0.003). In contrast, patients taking ALE had a higher inci-
dence of dyspepsia (RR = 0.51, 95% CI: 0.31–0.83, P = 0.007) and urinary tract infections
(RR = 0.69, 95% CI: 0.48–0.99, P = 0.04) than TPTD (Fig 11).
Discussion
Through meta-analysis and systematic review of 5 randomized controlled trials, we found that
compared with ALE, TPTD can effectively increase the BMD of LS, FN, and TH, and the
Fig 6. Forest plots of mean percent change from baseline to 6, 12, and 18 months in the LS BMD.

Fig 7. Forest plots of mean percent change from baseline to 18 months in the FN BMD.
incidence of vertebral fracture was lower. However, there was no significant difference in the
incidence of non-vertebral fracture and adverse reactions between the two groups.
Consistent with the results of this article, Ya-Kang Wang et al. [15] conducted a meta-anal-
ysis of ALE for GIOP and found that ALE can significantly increase the BMD of the LS and
FN. Similarly, Chun-Lin Liu et al. [9] conducted a meta-analysis of bisphosphonates and
TPTD for osteoporosis and found that TPTD can significantly increase the BMD of LS, TH,
and FN, especially GIOP; and compared with bisphosphonates, TPTD cannot reduce the inci-
dence of non-vertebral fractures.
Another meta-analysis showed that ALE, as a second-generation bisphosphonate, could sig-
nificantly increase the BMD of LS, TH, and FN, and the incidence of gastrointestinal adverse
reactions was very low, but could not reduce the incidence of vertebral and non-vertebral frac-
tures [16]. But our study shows that TPTD is more effective than ALE in reducing the inci-
dence of vertebral fractures, which reflects the unique advantages of TPTD.
Because of the high price and gastrointestinal adverse reactions, TPTD is used as a second-
line drug, but the results show that compared with ALE, it can effectively reduce the incidence
of vertebral fracture, and there is no significant difference in adverse reactions. In addition,
TPTD also has its unique advantages, as a synthetic metabolic agent, it is significantly better
than bisphosphonate in preventing glucocorticoid-induced bone loss and fracture, and can
reduce the adverse reactions of glucocorticoids, which is consistent with the results of this
study. However, the guidelines do not yet use TPTD as a first-line drug [2].
Through meta-analysis and systematic evaluation of five randomized controlled trials, the
main outcomes were as follows: Compared with ALE, patients taking TPTD had a lower inci-
dence of vertebral fracture; secondary outcomes: similarly, patients taking TPTD improved
the BMD of LS, FN, and TH compared to those taking ALE, and the BMD of LS, FN, and TH
gradually increased with the prolongation of dosing time. There was no statistical difference
between the two drugs in the incidence of non-vertebral fractures and adverse reactions.
Fig 8. Forest plots of mean percent change from baseline to 18 months in the TH BMD.

Fig 9. Forest plots of percentage changes of bone formation marker PINP.

Fig 10. Forest plots of percentage changes of bone resorption marker CTX.


Fig 11. Forest plots of five high incidence adverse events.

Ya-Kang Wang et al. [15] conducted a meta-analysis on the efficacy of ALE in the treatment
of GIOP and found that ALE could significantly improve the BMD of LS and FN. After 12
months of medication, the BMD of LS increased without significant gastrointestinal adverse
reactions. The results of these studies are consistent with this study. In addition, they also
found that the fracture risk of patients who took ALE for 12 months did not change signifi-
cantly, but our study found that ALE could reduce the incidence of vertebral fractures.
Chun-Lin Liu et al. [9] compared the efficacy of bisphosphonates and TPTD in the treat-
ment of osteoporosis and found that TPTD could significantly increase the BMD of LS, TH,
and FN in osteoporosis patients, especially GIOP. In addition, there was no difference in the
effect of TPTD on the incidence of non-vertebral fractures when compared to bisphospho-
nates. The results of this study are consistent with our study.
Shun-Li Kan et al. [16] performed a meta-analysis on the efficacy of ALE in preventing
GIOP in rheumatic patients and found that ALE could increase the BMD of LS, TH, and tro-
chanter, which were consistent with the results of our study. There were no significant differ-
ences in the incidence of gastrointestinal adverse reactions and vertebral and non-vertebral
fractures, in contrast, our study found that both TPTD and ALE were found to reduce the inci-
dence of vertebral fractures. Compared with the previously published meta-analysis, this study
differs in that it focuses mainly on glucocorticoid-induced osteoporosis rather than on osteo-
porosis in general. In our study, two of the two anti-osteoporosis drugs were selected to com-
pare the efficacy and safety of GIOP, so it was more targeted. The main outcome of this study
was the incidence of vertebral fracture, which was also more targeted. In addition, this study
also had unique features that previous studies did not have. In our study, bone metabolism
indexes were innovatively taken as evaluation indexes of drug efficacy, so that the mechanism
of drug action can be explored from a microscopic perspective. In this study, the main adverse
reactions of drugs were also used as evaluation indicators, instead of focusing on gastrointesti-
nal reactions as in the previous study.
Limitations
However, there are still some shortcomings in our study. First, whether the female subjects are
postmenopausal or not may have an impact on the efficacy of drug treatment, but the women
included in this study include both menopausal and non-menopausal women. Second, all the
patients included in this study were given long-term additional calcium and vitamin D supple-
mentation, which also had a certain impact on the efficacy of drug treatment. Third, the lon-
gest study included in this article is only 36 months, and the long-term efficacy of the drug
needs to be further explored.
Conclusion
In general, compared with ALE, TPTD can reduce the incidence of vertebral fracture, increase
the BMD of LS, FN, and TH, and increase the bone metabolic markers. However, there was no
significant difference in the incidence of non-vertebral fracture and main adverse reactions
between the two groups.
Supporting information
S1 File. PRISMA_2020_checklist.
(PDF)

S2 File. Specific literature search strategies, data processing procedures and codes.
(ZIP)
Acknowledgments
The author thanks Min Zhang for polishing the language of this article.
Author Contributions
Conceptualization: Zhi-Ming Liu, Ding Zhang, Zhu-Bin Shen.
Data curation: Zhi-Ming Liu, Yuan Zong.
Formal analysis: Zhi-Ming Liu, Min Zhang.
Investigation: Zhi-Ming Liu, Xiao-Qing Guan.
Methodology: Zhi-Ming Liu, Xiao-Qing Guan.
Project administration: Zhi-Ming Liu.
Resources: Min Zhang, Zhu-Bin Shen.
Software: Yuan Zong, Ding Zhang, Zhu-Bin Shen.
Supervision: Fei Yin.
Validation: Fei Yin.
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PLOS ONE

The efficiency and safety of alendronate

Citation: Liu Z-M, Zhang M, Zong Y, Zhang D, Background

Editor: Wisit Cheungpasitporn, Mayo Clinic

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 1 / 15

Data Availability Statement: All relevant data are Conclusions

Competing interests: The authors have declared

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 2 / 15

Search strategy and selection criteria

Study inclusion and exclusion criteria

Data extraction and quality assessment

Data synthesis and analysis

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 3 / 15

Risk of bias in the included studies

Incidence of vertebral and non-vertebral fractures

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 4 / 15

Fig 1. Flow diagram of literature search and study inclusion.

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 5 / 15

Table 1. Baseline characteristicsa.

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 6 / 15

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 7 / 15

Percent change in markers of bone formation and resorption

Fig 4. Forest plots of incidence of vertebral fractures.

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 8 / 15

Fig 5. Forest plots of incidence non-vertebral fractures.

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PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 10 / 15

Fig 9. Forest plots of percentage changes of bone formation marker PINP.

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 11 / 15

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 12 / 15

Fig 11. Forest plots of five high incidence adverse events.

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 13 / 15

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 14 / 15

PLOS ONE | https://doi.org/10.1371/journal.pone.0267706 May 31, 2022 15 / 15

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