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Effect of salt substitution on fracture—a secondary analysis of the Salt Substitute and Stroke Study (SSaSS)

BMC Medicine volume 22, Article number: 366 (2024) Cite this article

Abstract

Background

Associations of dietary sodium and potassium intake with fracture risk are inconsistent and the effects of 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 were randomly 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-to-treat 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.

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Background

The global population is aging with an increase in the number and proportion of older adults [1], and this has led to a rise in fractures associated with fragility due to reduced 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 [3,4,5,6], 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 to increases in bone fragility that compounds the increased fracture risk attributed to falls. BMD is associated with nutritional, hormonal, lifestyle, genetic, and environmental factors [8]. In regard to nutrition, increased dietary calcium intake is associated with reduced age-related bone loss and reduced risks of fragility fractures [9]. High sodium chloride (regular salt) intake may be associated with reduced BMD because sodium competes with calcium for reabsorption by the kidneys [10]. Several cross-sectional [11] and animal [12] studies show an inverse relationship between sodium intake and BMD, though longitudinal studies show no association of sodium intake with BMD [8]. On the other hand, studies have found that bones release sodium during prolonged hyponatremia leading to bone loss at the cellular level and osteoporosis due to increased bone turnover [13,14,15]. Higher levels of potassium intake appear to improve calcium homeostasis and reduce bone catabolism and are associated with higher BMD levels [16,17,18].

It is also possible that reducing sodium intake and increasing potassium intake could cause fractures through excessive blood pressure lowering in susceptible individuals that leads to falls [19]. This is a consideration 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 Substitute and Stroke Study (SSaSS) for cardiovascular protection, and subsequent likely wider use of potassium-enriched salt over coming years, it is important to understand the balance of risks and benefits for fracture risk and how positive effects on cardiovascular disease (CVD) might trade 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 of stroke, it also collected data on all other serious adverse events including fracture. Accordingly, the aim of the current study was to assess the effect of salt substitute 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 in 2013 and concluded in 2021. The detailed design of the study 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 nominated relatives or friends.

Individuals were excluded if they or someone living in the household was using potassium-sparing diuretics or potassium supplements, had a severe renal impairment, or had other reasons to be concerned about the use of salt substitute. Participants whose life expectancy was expected to be < 6 months or who ate the majority of 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 the intervention group, in which the participants used a salt substitute, or the control group, in which the participants continued to use regular salt. Participants were not blinded 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 25% ± 10% potassium chloride. Use of salt substitute is considered 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 to all villages at the start of the trial.

Participants were followed up every 6 months throughout the trial to collect data about all events leading to hospitalization (including fracture) or death as well as other serious adverse events. Follow-up visits during the first 24 months and the final 5-year follow-up were conducted face-to-face. Follow-up after 24 months and up to the final 5-year follow-up were conducted through linkage 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) to the 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 with the same MedDRA terms for consistency. Investigators and outcome assessors were blinded to participant allocation.

Outcomes

The primary outcome of interest in this paper was the incidence of all fractures. The key secondary outcomes were the incidence of vertebral fracture, non-vertebral fracture, and fracture of unknown or non-specific location.

All fracture events were identified using hospitalization data searched for relevant MedDRA codes. Within the hierarchy of MedDRA coding, any preferred term including “fracture” was included. Preferred terms including “fracture” were found under the “Injury, poisoning and procedural complications” and the “Musculoskeletal and connective tissue disorders” system organ classes. All fractures were classified into fracture types and mapped to vertebral fracture, non-vertebral fracture and fracture of 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 defined as all fracture events excluding vertebral fractures and fractures of unknown or non-specific location. Fractures of unknown or non-specific location were defined as 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. Baseline characteristics 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 incidence of the primary and secondary outcomes were analyzed using a hierarchical Poisson regression model with adjustment 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, not time 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–Meier method, with censoring at time of death or end of last follow-up. All time-to-event curves were based on the first recorded fracture event for an individual during the trial period that was relevant to each analysis. Specifically, participants with more than one fracture recorded throughout the trial period contributed only once to the analysis of all fractures but might have contributed to multiple 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 substitute group (n = 10,504) or the control (regular salt) group (n = 10,491). The overall mean and median durations of follow-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 end of the study in the intervention and control groups, respectively (Fig. 1).

Fig. 1
figure 1

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

Full size image

The demographic and clinical characteristics of the participants 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 and had hypertension. The mean age was 65.4 ± 8.5 years, and 49.5% were female. Mean systolic blood pressure was 154.0 ± 23.5 mmHg, and diastolic blood pressure was 89.2 ± 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 level of primary school or below (72.5%). A high proportion of participants had a history of hypertension (88.4%), followed by ischemic heart disease (16.0%) and transient ischemic attack (14.1%). Overall, 79.3% of participants were taking antihypertensive medication, while 12.3% were taking lipid-lowering medication and 39.7% were taking aspirin or other antiplatelet agents.

Table 1 Baseline characteristics of participants by randomized group
Full size table

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).

Table 2 Number of fracture events during the intervention period
Full size table

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-specific location (RR 0.80, 95% CI 0.54 to 1.18) (Figs. 2 and 3).

Fig. 2
figure 2

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

Full size image
Fig. 3
figure 3

Cumulative incidence of fracture classifications over the 5-year intervention period. Cumulative incidence curves using the Kaplan–Meier method of all fractures (A), vertebral fracture (B), non-vertebral fracture (C), and fracture of unknown or non-specific location (D)

Full size image

Subgroup analysis

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

Table 3 Subgroup analysis of the effects of salt substitute on all fractures
Full size table

Discussion

In this large-scale cluster randomized controlled trial, consumption of salt substitute compared with regular salt 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 for vertebral fractures which often have a fragility cause as well as non-vertebral fractures which are often caused by trauma. These observations and their related likely cause of fracture suggest that the null overall effect was not a consequence of balanced effects of protection against fragility fractures through enhanced bone metabolism or traumatic fractures due to hypotension-related 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 know that advocating the use of salt substitute for cardiovascular prevention will not be achieved at the expense of increased fracture risk [24, 25].

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- and post-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 dietary sodium reduction on fracture risk [27]. However, BMD, bone mineral content, and osteoporosis are intermediate markers for fracture risk, and all are affected by multiple different factors. Observational studies are also prone to confounding and the absence of an association between dietary sodium intake and fracture risk in another large study may reflect the methodological limitations of this type 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 risk with salt substitute in the current study are consistent with the prior data which have shown inconsistent associations of sodium and potassium with markers of fracture risk and no clear associations with fracture itself [31, 32].

Observational data have also identified associations of high blood pressure with increased fracture risk that may be attributed to reductions in BMD [33], while other 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 mediated by dizziness, fainting, and alterations in postural balance, leading to an increased risk of falls [20]. On this basis, salt substitute could have increased the risk of falls 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 of multiple 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 population consisting mostly of older people, about half of which were post-menopausal women and many with cerebrovascular disease who would be susceptible to both falls and fragility fractures. It is among these populations that any 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 these same 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 and body 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 by body mass index, is another key risk factor for falls and fractures 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 fracture risk between participant subgroups defined on the basis of body mass index.

This analysis benefits from being based upon data from a 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 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 constancy of 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, so some cases of fracture that were mild in nature may be missed. There is likely to be misclassifications of some fracture events, though in general, fractures are more likely to be missed from a hospital record than classified as another form of event. Misclassification of types of fractures is more likely and any conclusions based on fracture causation are more uncertain. Both misclassification and omission may reduce power to detect an effect and create bias towards the null hypothesis. Current analyses were unable to account for whether the fracture was due to high-energy trauma or force from a chance accident or hypotensive fall or due to a fall secondary 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 caused by fragility and non-vertebral fractures which most are likely 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 the data cannot exclude any harmful effect or any protective effect of salt substitute on the incidence of fracture, the findings 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.

Availability of data and materials

Complete deidentified patient data set collected for the study can be requested 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 are available from https://osf.io/2u9jm/.

Abbreviations

SSaSS:

Salt Substitute and Stroke Study

BMD:

Bone mineral density 

CVD:

Cardiovascular disease

HR:

Hazard ratio

BMI :

Body mass index

DBP:

Diastolic blood pressure

SBP:

Systolic blood pressure

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Acknowledgements

The authors would like to thank Jiangsu Sinokone Technology Co Ltd for providing salt substitutes free of charge in years 3 and 4 of the study. Thanks are also extended to all participants and local collaborators.

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, data collection, data analysis, data interpretation, or writing of the report.

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Authors and Affiliations

  1. School of Public Health, Ningxia Medical University, Yinchuan, Ningxia, China

    Faxuan Wang, Yangyang Pi, Yi Zhao & Yuhong Zhang

  2. NHC Key Laboratory of Metabolic Cardiovascular Diseases Research, Ningxia Medical University, Yinchuan, Ningxia, China

    Faxuan Wang & Yi Zhao

  3. Department of Evidencebased Medicine, First Hospital of China Medical University, Shenyang, China

    Bo Zhou

  4. School of Public Health, Changzhi Medical College, Changzhi, China

    Zhifang Li

  5. Department of Noncommunicable Disease Prevention and Control, Center for Disease Control of Hebei Province, Shijiazhuang, China

    Jixin Sun

  6. School of Public Health, Xi’an Jiaotong University School of Medicine, Xi’an, China

    Yan Yu

  7. School of Public Health, Harbin Medical University, Harbin, China

    Maoyi Tian

  8. Department of Orthopaedics and Traumatology, Beijing Jishuitan Hospital, Capital Medical University, Beijing, China

    Minghui Yang

  9. The George Institute for Global Health, University of New South Wales, Sydney, NSW, Australia

    Liping Huang, Bruce Neal & Katrina R. Kissock

  10. The George Institute for Global Health China, Beijing, China

    Hongyi Song

  11. School of Public Health, Imperial College London, London, UK

    Bruce Neal

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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 the data and take responsibility for the integrity of the data and the accuracy of the data analysis. FW, YP, LH, BN, and KRK drafted the manuscript. All authors contributed to the final version of the manuscript and accept responsibility for submitting for publication. All authors read and approved the final manuscript. YZ1, MT, and BN obtained funding to support this study.

Corresponding author

Correspondence to Yi Zhao.

Ethics declarations

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.

Consent for publication

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

Competing interests

The authors declare no competing interests.

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Wang, F., Pi, Y., Zhao, Y. et al. Effect of salt substitution on fracture—a secondary analysis of the Salt Substitute and Stroke Study (SSaSS). BMC Med 22, 366 (2024). https://doi.org/10.1186/s12916-024-03586-7

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Keywords

BMC Medicine

ISSN: 1741-7015

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