(2024) 22:366
Wang et al. BMC Medicine
https://doi.org/10.1186/s12916-024-03586-7

BMC Medicine

RESEARCH ARTICLE

Open Access

Effect of salt substitution on fracture—asecondary analysis of the Salt Substituteand Stroke Study (SSaSS)
Faxuan Wang1,2, Yangyang Pi1, Yi Zhao1,2* , Yuhong Zhang1, Bo Zhou3, Zhifang Li4, Jixin Sun5, Yan Yu6,
Maoyi Tian7, Minghui Yang8, Liping Huang9, Hongyi Song10, Bruce Neal9,11 and Katrina R. Kissock9

Abstract
Background Associations of dietary sodium and potassium intake with fracture risk are inconsistent and the effectsof salt substitute on fracture incidence are unknown. We assessed the effect of salt substitute compared to regular salt
intake on fracture incidence using data from the Salt Substitute and Stroke Study (SSaSS).
Methods SSaSS was a cluster-randomized controlled trial conducted in 600 villages in northern China. Villages wererandomly allocated into intervention and control groups in a 1:1 ratio. Salt substitute was provided to intervention
villages and control villages continued regular salt use for 5 years. The primary outcome for this secondary analysis
was the incidence of all fractures. Secondary outcomes included incidence of vertebral fracture, non-vertebral fracture, and fracture of unknown or non-specific location.
Results 20,995 participants were included in this study, and 821 fractures occurred during follow-up. Intention-totreat analyses showed no differences between the salt substitute and regular salt groups in the incidence of all fractures (rate ratio (RR) 0.96; 95% CI 0.81 to 1.14), vertebral fracture (RR 0.82; 95% CI 0.53 to 1.26), non-vertebral fracture(RR 1.05; 95% CI 0.86 to 1.29), or fracture of unknown or non-specific location (RR 0.80; 95% CI 0.54 to 1.18).
Conclusions Use of salt substitute compared to regular salt had no detectable effect on the incidence of fracture
in a population at high risk of cardiovascular disease and fracture.
Trial registration ClinicalTrials.gov, NCT02092090. Registered on March 12, 2014.
Keywords Low-sodium salt, Salt substitute, Fracture, Osteoporosis, Randomized-controlled trial*Correspondence:
Yi Zhaozhaoyi751114@hotmail.com
1
School of Public Health, Ningxia Medical University, Yinchuan, Ningxia,
China
2
NHC Key Laboratory of Metabolic Cardiovascular Diseases Research,
Ningxia Medical University, Yinchuan, Ningxia, China
3
Department of Evidencebased Medicine, First Hospital of China Medical
University, Shenyang, China
4
School of Public Health, Changzhi Medical College, Changzhi, China
5
Department of Noncommunicable Disease Prevention and Control,
Center for Disease Control of Hebei Province, Shijiazhuang, China
6
School of Public Health, Xi’an Jiaotong University School of Medicine,
Xi’an, China
7
School of Public Health, Harbin Medical University, Harbin, China

8

Department of Orthopaedics and Traumatology, Beijing Jishuitan
Hospital, Capital Medical University, Beijing, China
9
The George Institute for Global Health, University of New South Wales,
Sydney, NSW, Australia
10
The George Institute for Global Health China, Beijing, China
11
School of Public Health, Imperial College London, London, UK© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0
International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as longas you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if
you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article orparts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicatedotherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not
permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To
view a copy of this licence, visit http://​creat​iveco​mmons.​org/​licen​ses/​by-​nc-​nd/4.​0/.

Wang et al. BMC Medicine(2024) 22:366

BackgroundThe global population is aging with an increase in thenumber and proportion of older adults [1], and this has
led to a rise in fractures associated with fragility due toreduced bone mineral density (BMD) and microstructural degeneration of bone tissue [2]. In 2019, there were
178 million new fractures globally, an increase of 33.4%
from 1990 [3]. Fractures in older adults pose a serious
economic and disease burden [3–6], causing increased
risks of disability and mortality and an increased need for
outpatient and inpatient medical services [7].
Reduced BMD is a leading cause of fracture, due toincreases in bone fragility that compounds the increased
fracture risk attributed to falls. BMD is associated withnutritional, hormonal, lifestyle, genetic, and environmental factors [8]. In regard to nutrition, increased dietarycalcium intake is associated with reduced age-relatedbone loss and reduced risks of fragility fractures [9]. Highsodium chloride (regular salt) intake may be associatedwith reduced BMD because sodium competes with calcium for reabsorption by the kidneys [10]. Several crosssectional [11] and animal [12] studies show an inverse
relationship between sodium intake and BMD, thoughlongitudinal studies show no association of sodium intake
with BMD [8]. On the other hand, studies have found thatbones release sodium during prolonged hyponatremia
leading to bone loss at the cellular level and osteoporosis
due to increased bone turnover [13–15]. Higher levels of
potassium intake appear to improve calcium homeostasis and reduce bone catabolism and are associated withhigher BMD levels [16–18].
It is also possible that reducing sodium intake andincreasing potassium intake could cause fractures
through excessive blood pressure lowering in susceptible individuals that leads to falls [19]. This is aconsideration that has also been raised for blood pressure-lowering drugs more broadly, though adverse
effects of blood pressure-lowering drugs on fracture risk
are inconsistent [20, 21].
Given the very positive results of the Salt Substituteand Stroke Study (SSaSS) for cardiovascular protection,and subsequent likely wider use of potassium-enrichedsalt over coming years, it is important to understand thebalance of risks and benefits for fracture risk and how
positive effects on cardiovascular disease (CVD) mighttrade off against possible harms through increased risks
of fractures [12, 22]. To the knowledge of the authors,
there is no research exploring the effect of salt substitute on fracture risk. While SSaSS was designed primarily to determine the effect of salt substitute on the risk ofstroke, it also collected data on all other serious adverse
events including fracture. Accordingly, the aim of thecurrent study was to assess the effect of salt substitutePage 2 of 10

versus regular salt intake on fracture incidence over a
5-year period in a population at high risk for CVD.

Methods
Study design

This is an ad hoc analysis using data from SSaSS. SSaSS
was an open-label, cluster-randomized trial conducted in
20,995 participants from 600 villages across five northern
provinces in China, including Hebei, Liaoning, Ningxia,
Shanxi, and Shaanxi. Each village recruited about 35 individuals at elevated risk of stroke. The trial commenced in2013 and concluded in 2021. The detailed design of thestudy has been described previously [23, 24].
Written informed consent was obtained from all participants and the trial was registered with ClinicalTrials.
gov (NCT02092090) and approved by ethics committees
at the Peking University Health Science Center in China
and the University of Sydney in Australia. The George
Institute for Global Health sponsored the trial and completed the data analysis.
Participants

Individuals were eligible to participate if they had a previous history of stroke or were aged 60 years or older
and had uncontrolled high blood pressure (SBP ≥ 140
mmHg if receiving blood pressure lowering medication;
SBP ≥ 160 mmHg if not). Participants were required to
be able to be contacted by phone or through nominatedrelatives or friends.
Individuals were excluded if they or someone livingin the household was using potassium-sparing diuretics
or potassium supplements, had a severe renal impairment, or had other reasons to be concerned about theuse of salt substitute. Participants whose life expectancy
was expected to be < 6 months or who ate the majorityof meals outside the home were also excluded. Only one
family member from a household was included.
Randomization

After completion of the baseline survey for all participants, villages were randomly assigned in a 1:1 ratio
through a central computerized process to either theintervention group, in which the participants used a salt
substitute, or the control group, in which the participants continued to use regular salt. Participants were notblinded to the intervention.
Procedures

Participants in the intervention group were provided with
sufficient quantities of salt substitute to cover all salt use
at home for the entire household free of charge. The salt
substitute was produced according to Chinese national
standards comprising 75% ± 10% sodium chloride andWang et al. BMC Medicine(2024) 22:366

25% ± 10% potassium chloride. Use of salt substitute isconsidered generally safe but can lead to hyperkalemia if
consumed in very large amounts (e.g., more than 50 g/day) or in the presence of serious kidney disease [23].
Recommendations to reduce salt intake were provided toall villages at the start of the trial.
Participants were followed up every 6 months throughout the trial to collect data about all events leading tohospitalization (including fracture) or death as well asother serious adverse events. Follow-up visits during
the first 24 months and the final 5-year follow-up wereconducted face-to-face. Follow-up after 24 months andup to the final 5-year follow-up were conducted throughlinkage to the administrative databases of the New Rural
Cooperative Medical Scheme (NCMS) and the National
Mortality Surveillance System which together covers
hospital admissions for 98% of the rural population in
China. Data linkage was also completed retrospectively
for the first 24 months of the trial and at the final visit
to collect all hospitalization and death events since trial
commencement. All events were coded using the Medical Dictionary for Regulatory Activities (MedDRA) tothe lowest level term. Where possible, MedDRA coding
was done automatically; however, manual coding was
employed by a clinician familiar with MedDRA where
there were no matching terms. Once a term was coded,
all future diagnoses of the same nature were coded withthe same MedDRA terms for consistency. Investigators and outcome assessors were blinded to participant
allocation.
Outcomes

The primary outcome of interest in this paper was theincidence of all fractures. The key secondary outcomes
were the incidence of vertebral fracture, non-vertebral fracture, and fracture of unknown or non-specificlocation.
All fracture events were identified using hospitalization
data searched for relevant MedDRA codes. Within thehierarchy of MedDRA coding, any preferred term including “fracture” was included. Preferred terms including“fracture” were found under the “Injury, poisoning andprocedural complications” and the “Musculoskeletal andconnective tissue disorders” system organ classes. All
fractures were classified into fracture types and mappedto vertebral fracture, non-vertebral fracture and fractureof unknown or non-specific location classification. Vertebral fractures were defined as fracture events where
the MedDRA preferred term included the words “vertebral” or “spinal.” Non-vertebral fractures were definedas all fracture events excluding vertebral fractures andfractures of unknown or non-specific location. Fracturesof unknown or non-specific location were defined asPage 3 of 10

fracture events where the MedDRA preferred term was“fracture,” “compression fracture,” “multiple fractures,”or “osteoporotic fracture.” More detail around relevant
MedDRA codes for fracture is provided in the Additional
file.
Statistical analysis

All statistical analyses applied the same statistical methodology as used for the main trial analyses [24] and were
performed using an intention-to-treat approach. Baselinecharacteristics were summarized as mean (SD) for continuous variables and counts and proportions (%) for categorical variables by randomized group and overall.
The effect of the intervention on the total incidenceof the primary and secondary outcomes were analyzed
using a hierarchical Poisson regression model withadjustment for clustering at the village level as a random
intercept and follow-up time as an offset. Rate ratios
and 95% CIs were calculated. All events of fracture were
included in this analysis, which was based on rates, nottime to the first event. Cumulative time-to-event curves
by randomized group for the primary and secondary outcomes were generated with the use of the Kaplan–Meiermethod, with censoring at time of death or end of last
follow-up. All time-to-event curves were based on thefirst recorded fracture event for an individual during thetrial period that was relevant to each analysis. Specifically, participants with more than one fracture recorded
throughout the trial period contributed only once to theanalysis of all fractures but might have contributed tomultiple analyses of different fracture types. Subgroup
analyses to explore differences in intervention effects
between participant populations were based on characteristics pre-defined in the main trial statistical analysis
plan, including age, sex, education, history of diabetes,
history of hypertension, use of antihypertensive medication, systolic blood pressure, diastolic blood pressure,and body mass index. Statistical tests were two-tailed,and a p-value < 0.05 was considered statistically significant. All statistical analyses were conducted with R and
RStudio (version 4.2.2).

Results
Participant characteristics

Between April 2014 and January 2015, there were
20,995 participants enrolled from 600 villages and randomly assigned at the village level to the salt substitutegroup (n = 10,504) or the control (regular salt) group(n = 10,491). The overall mean and median durations offollow-up were 4.74 years and 5.12 years, respectively.
Vital status at trial conclusion was verified for all participants; there were 8,535 and 8,288 people alive at the

Wang et al. BMC Medicine(2024) 22:366

end of the study in the intervention and control groups,
respectively (Fig. 1).
The demographic and clinical characteristics of theparticipants at baseline were similar between the randomized groups (Table 1). Among participants, 72.6%
had a history of stroke, and 59.3% were > 60 years old andhad hypertension. The mean age was 65.4 ± 8.5 years, and49.5% were female. Mean systolic blood pressure was
154.0 ± 23.5 mmHg, and diastolic blood pressure was89.2 ± 14.0 mmHg. The mean BMI was 24.8 ± 3.6; 33.5%
of participants smoked in the past, and 18.8% were current smokers. Most participants had an education levelof primary school or below (72.5%). A high proportionof participants had a history of hypertension (88.4%), followed by ischemic heart disease (16.0%) and transientischemic attack (14.1%). Overall, 79.3% of participants
were taking antihypertensive medication, while 12.3%
were taking lipid-lowering medication and 39.7% weretaking aspirin or other antiplatelet agents.
Outcome events

A total of 821 fractures occurred over the duration of
the trial, of which 132 were vertebral fractures, 540
were non-vertebral fractures, and 149 were fractures of
unknown or non-specific location. Six hundred sixty-six
participants had one fracture event, and 72 participants
had two or more fracture events (Table 2).
There was no detectable effect of salt substitute compared to regular salt on the risk of all fractures (RR 0.96,
95% CI 0.81 to 1.14), vertebral fracture (RR 0.82, 95%
CI 0.53 to 1.26), non-vertebral fracture (RR 1.05, 95%
CI 0.86 to 1.29), or fracture of unknown or non-specificlocation (RR 0.80, 95% CI 0.54 to 1.18) (Figs. 2 and 3).

Page 4 of 10

Subgroup analysis

There was no detectable modification of age, sex, education, history of diabetes, history of hypertension,use of antihypertensive medication, blood pressure, orbody mass index on the association between salt substitute and all fracture risk (all p for heterogeneity ≥ 0.05)(Table 3).

Discussion
In this large-scale cluster randomized controlled trial,consumption of salt substitute compared with regularsalt had no detectable effect on the incidence of fracture in participants at high risk of cardiovascular disease during the 5-year trial period. This was true forvertebral fractures which often have a fragility cause as
well as non-vertebral fractures which are often causedby trauma. These observations and their related likely
cause of fracture suggest that the null overall effectwas not a consequence of balanced effects of protection against fragility fractures through enhanced bonemetabolism or traumatic fractures due to hypotensionrelated falls or other trauma; rather, it appears that
there was no detectable effect for either mechanism.
While the absence of a beneficial effect on fracture may
be viewed as disappointing, the absence of any adverse
effect on fracture is a key observation. The very positive finding for cardiovascular protection observed in
the main report from SSaSS will likely result in largely
expanded use of salt substitute for cardiovascular protection among elderly and frail patients. As such, it
is important for clinicians and policymakers to knowthat advocating the use of salt substitute for cardiovascular prevention will not be achieved at the expense ofincreased fracture risk [24, 25].

Fig. 1 Flow of participants during the trial including enrolment, randomization, and follow-up

Wang et al. BMC Medicine(2024) 22:366

Page 5 of 10

Table 1 Baseline characteristics of participants by randomized group
Intervention(n = 10,504)
Inclusion criteria (%)

Sex (%)

Control(n = 10,491)

Overall(n = 20,995)

History of prior stroke with diagnosis made in hospital

73.3

71.9

72.6

Age > 60 years and two measures of SBP ≥ 140 mmHg and using BP lowering treatment or two measures of SBP ≥ 160 mmHg and not using BP
lowering treatment

59.4

59.2

59.3

Female

49.7

49.2

49.5

Male

50.3

50.8

50.5

Age
mean (SD)65.2 (8.5)

65.5 (8.5)

65.4 (8.5)

BMI
mean (SD)24.8 (3.6)

24.9 (3.7)

24.8 (3.6)

SBP
mean (SD)

153.8 (23.37)

154.2 (23.6)

154.0 (23.5)

DBP
mean (SD)89.1 (14.0)

89.4 (14.0)

89.2 (14.0)

Smoking (%)
Level of education (%)

Disease history (%)

Medication (%)

Past smoker

32.8

34.2

33.5

Current smoker

18.7

18.9

18.8

Primary school or lower

72.3

72.6

72.5

Junior high school

23.2

22.4

22.8

Senior high school or above

4.5

5.0

4.7

Transient ischemic attack

13.2

14.9

14.1

Ischemic heart disease

16.4

15.7

16.0

Congestive heart failure

2.5

2.5

2.5

Peripheral arterial disease

5.1

3.6

4.4

Hypertension

88.6

88.3

88.4

Diabetes mellitus

10.6

10.5

10.6

Diuretic

11.5

11.2

11.3

ACE inhibitor or ARB

23.0

23.0

23.0

α-blocker

0.7

1.1

0.9

β-blocker

5.0

6.3

5.6

Calcium antagonist

43.3

40.0

42.0

Any of the above medications

59.1

58.7

58.9

Other antihypertensive agents

38.2

37.5

37.8

Any antihypertensive medication

79.9

78.7

79.3

Statin or other lipid-lowering agents

12.6

12.0

12.3

Aspirin or other antiplatelet agents

40.0

39.4

39.7

Abbreviations: BMI body mass index, BP blood pressure, DBP diastolic blood pressure, SBP systolic blood pressure

In regard to possible metabolic impacts of salt substitute on fracture, multiple studies have shown that higher
urinary sodium excretion (a proxy for dietary sodium(salt) intake) is associated with reduced BMD in pre- andpost-menopausal women, reduced bone mineral content,
and positively associated with an increased risk of osteoporosis [11, 22, 26]. Another smaller study found that
increased urinary sodium excretion was strongly associated with increased markers of bone resorption providing
a plausible mechanism for protective effects of dietarysodium reduction on fracture risk [27]. However, BMD,
bone mineral content, and osteoporosis are intermediatemarkers for fracture risk, and all are affected by multiple
different factors. Observational studies are also prone toconfounding and the absence of an association between
dietary sodium intake and fracture risk in another large
study may reflect the methodological limitations of thistype of research [28]. There is similar uncertainty about
the effects of dietary potassium intake on bone metabolism and fracture risk. There are some limited data suggesting supplementary potassium intake may increase
BMD and bone mineral content [16, 29, 30], but no studies show clear associations with fracture risk [29]. On
balance, the findings of no detectable change in fractureWang et al. BMC Medicine(2024) 22:366

Page 6 of 10

Table 2 Number of fracture events during the intervention
periodn
All fractures

821

Vertebral fracture132

  Cervical vertebral fracture1

  Lumbar vertebral fracture78

  Thoracic vertebral fracture41

  Spinal fracture of unknown or non-specific ­locationa

12

Non-vertebral fracture540

  Ankle fracture37  Clavicle fracture25  Femoral neck fracture

41

  Femur fracture

166

  Fibula fracture

4

  Foot fracture

15

  Forearm fracture3

  Fractured Ischium1  Hand fracture11  Hip fracture9  Humerus fracture39  Ilium fracture

1

  Jaw fracture1

  Lower limb fracture

21

  Patella fracture25

  Pelvic fracture5  Pubis fracture

14

  Radius fracture

38

  Rib fracture

43

  Scapula fracture2  Skull fractured base1

  Sternal fracture2  Tibia fracture24  Ulna fracture5  Upper limb fracture6

  Wrist fracture

1

Fracture of unknown or non-specific location

149

  Compression fracture2

  Fracture

130  Multiple fractures5

  Osteoporotic fracture

12n for all participantsSome participants had more than one fracture event throughout theintervention periodaCombined “spinal fracture” and “spinal compression fracture” MedDRA terms

risk with salt substitute in the current study are consistent with the prior data which have shown inconsistentassociations of sodium and potassium with markers offracture risk and no clear associations with fracture itself[31, 32].

Observational data have also identified associationsof high blood pressure with increased fracture risk that
may be attributed to reductions in BMD [33], whileother studies show an association independent of BMD[34]. It has also been noted that blood pressure lowering following initiation of antihypertensive therapy
is a risk for fracture which is believed to be mediatedby dizziness, fainting, and alterations in postural balance, leading to an increased risk of falls [20]. On thisbasis, salt substitute could have increased the risk offalls and fracture through its blood pressure-lowering
effect [25]. However, the associations of blood pressure
lowering and fracture risk are all derived from observational analyses, while secondary investigations ofmultiple randomized trials of blood pressure lowering
therapies compared to control have not identified any
increased risk of fracture.
The present study was done among a study populationconsisting mostly of older people, about half of whichwere post-menopausal women and many with cerebrovascular disease who would be susceptible to both falls
and fragility fractures. It is among these populations thatany adverse effect of salt substitute on fracture would be
expected to be identified. However, the null result for
fracture is highly reassuring in regard to the use of salt
substitute for cardiovascular protection within thesesame populations.
There was no detectable difference in the effects of salt
substitute on fracture risk across the participant subgroups studied, including for groups defined by sex andbody mass index. Post-menopausal women are at particularly high risk of low BMD and fracture, but while
there was an anticipated higher incidence of fracture
among females compared to males [35], there was no evidence that the effects of salt substitute on fracture risk
varied by sex. Malnutrition, which may be indicated bybody mass index, is another key risk factor for falls andfractures among older adults [36, 37], mediated by muscle wastage, bone fragility, and gait instability [38, 39].
There was, however, no evidence of differences in fracture incidence or the effects of salt substitute on fracturerisk between participant subgroups defined on the basisof body mass index.
This analysis benefits from being based upon data froma large-scale randomized trial such that it is likely to have
had adequate power to detect plausible effects of salt
substitute on total fracture risk; however, power would
have been reduced for subgroup analyses of fracture
type. The study population included key subsets of interest including females and the elderly. The randomized
design means that the results are unlikely to be importantly biased, and the large number of all fractures available for analysis means that while small effects might have

Wang et al. BMC Medicine(2024) 22:366

Page 7 of 10

Fig. 2 Effects of salt substitute on all fractures and fracture sub-types

Fig. 3 Cumulative incidence of fracture classifications over the 5-year intervention period. Cumulative incidence curves using the Kaplan–Meiermethod of all fractures (A), vertebral fracture (B), non-vertebral fracture (C), and fracture of unknown or non-specific location (D)been missed, moderate to large effects have been reliably
excluded.
The study also has several limitations. The study population is not representative of the global population,
so direct generalizability of the results to other populations and nations cannot be guaranteed. The constancyof the findings across participant subgroups does, however, provide some reassurance about the likely applicability of the findings beyond the trial population. This

was a secondary analysis of data therefore these investigations need to be interpreted in light of their post hoc
nature and how they fit within the broader evidence
base. Fracture was a secondary outcome, and event
data were obtained mostly through hospitalization
records, excluding emergency and outpatient data, sosome cases of fracture that were mild in nature may be
missed. There is likely to be misclassifications of somefracture events, though in general, fractures are more

Wang et al. BMC Medicine(2024) 22:366

Page 8 of 10

Table 3 Subgroup analysis of the effects of salt substitute on all fractures
Regular salt
(N = 10,491)

Salt substitute(N = 10,504)

Rate ratio (95% CI)ap value forheterogeneity

0.96

No. of events per 1000 person-years
Subgroups
Age≤ 65 years

6.95

6.65

0.97

0.76 to 1.23

> 65 years

10.12

9.72

0.96

0.77 to 1.20

Sex
Female

11.24

10.64

0.96

0.79 to 1.17

Male

5.62

5.41

0.98

0.74 to 1.30

0.93

Education
Primary school or lower

9.30

9.33

1.01

0.84 to 1.21

Junior high school or higher

6.21

4.78

0.77

0.52 to 1.15

0.17

History of diabetes
Yes

9.04

8.39

0.90

0.55 to 1.48

No

8.38

8.02

0.96

0.80 to 1.15

Yes

8.50

8.23

0.97

0.81 to 1.16

No

8.00

6.68

0.92

0.50 to 1.72

0.92

History of hypertension
0.54

Antihypertensive use
Yes

8.68

8.69

1.00

0.83 to 1.20

No

7.54

5.48

0.79

0.51 to 1.23

0.11

Systolic blood pressure≤ 153 mm Hg

7.60

7.12

0.94

0.74 to 1.20

> 153 mm Hg

9.33

9.05

0.97

0.78 to 1.22

0.75

Diastolic blood pressure≤ 89 mm Hg

8.08

8.61

1.07

0.86 to 1.33

> 89 mm Hg

8.81

7.49

0.86

0.67 to 1.10

0.12

Body-mass indexa≤ 24.6

8.83

7.93

0.89

0.70 to 1.13

> 24.6

8.08

8.18

1.02

0.82 to 1.27

0.28

All non-significant (p ≥ 0.05)

likely to be missed from a hospital record than classified as another form of event. Misclassification of typesof fractures is more likely and any conclusions based on
fracture causation are more uncertain. Both misclassification and omission may reduce power to detect aneffect and create bias towards the null hypothesis. Current analyses were unable to account for whether thefracture was due to high-energy trauma or force froma chance accident or hypotensive fall or due to a fallsecondary to low BMD and/or osteoporosis in which
consumption of sodium through regular salt may be
a contributing factor. However, in the present study,
analyses of vertebral fractures which are likely causedby fragility and non-vertebral fractures which most arelikely caused by trauma indicate that salt substitute has
no detectable effect on fracture or contributes to any
cause of fracture.

Conclusions
These analyses identify no detectable effect of salt substitute on fracture risk and provide further reassurance about
the safety of salt substitute use for cardiovascular prevention among individuals at high risk of fracture. While thedata cannot exclude any harmful effect or any protective
effect of salt substitute on the incidence of fracture, thefindings indicate that any real effect is likely to be small.
Concerns about fracture risk should not be a clinical or
public health contraindication to the use of salt substitute.
Abbreviations
SSaSS	Salt Substitute and Stroke Study
BMD	Bone mineral density
CVD	Cardiovascular diseaseHR	Hazard ratio
BMI 	Body mass index
DBP	Diastolic blood pressure
SBP	Systolic blood pressure

Wang et al. BMC Medicine(2024) 22:366

Supplementary Information
The online version contains supplementary material available at https://​doi.​
org/​10.​1186/​s12916-​024-​03586-7.

Page 9 of 10

4.
5.

Additional file 1: Identification of all fractures.
6.
Acknowledgements
The authors would like to thank Jiangsu Sinokone Technology Co Ltd forproviding salt substitutes free of charge in years 3 and 4 of the study. Thanks
are also extended to all participants and local collaborators.

7.

Authors’ contributions
FW, YZ1, MT, and BN contributed to the concept and design of the study. FW,
YZ1, YZ2, BZ, ZL, JS, YY, MT, MY, LH, HS, and KRK contributed to the acquisition,
analysis, and interpretation of data. LH, HS, and KRK had full access to all thedata and take responsibility for the integrity of the data and the accuracy ofthe data analysis. FW, YP, LH, BN, and KRK drafted the manuscript. All authors
contributed to the final version of the manuscript and accept responsibility forsubmitting for publication. All authors read and approved the final manuscript. YZ1, MT, and BN obtained funding to support this study.

8.

Funding
This study was funded by grants APP1049417 and APP1164206 from the Australian National Health and Medical Research Council and funded by grants
2021BEG02026 from the Key Research and Development Program of Ningxia
Hui Autonomous Region. The funders of the study had no role in design, datacollection, data analysis, data interpretation, or writing of the report.

12.

Availability of data and materials
Complete deidentified patient data set collected for the study can berequested from professor Bruce Neal, email: bneal@georgeinstitute.org.au.
Once the data access is granted, data can be accessed via a secured environment hosted by The George Institute for Global Health, China, in line with
China’s Cyber Security Law. The SSASS protocol and statistical analysis plan areavailable from https://​osf.​io/​2u9jm/.

Declarations

9.
10.
11.

13.
14.
15.
16.

17.

Ethics approval and consent to participate
The ethics committees of Peking University Health Science Center in China(IRB00001052-13069) and the University of Sydney in Australia (2013/888)
reviewed and approved the study, and all participants willingly provided written informed consent.

18.

Consent for publication
All authors critically revised drafts of the manuscript and approved the final
version.

20.

Competing interests
The authors declare no competing interests.

21.

Received: 2 December 2023 Accepted: 27 August 2024

22.

19.

23.
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