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L-shaped association of bone mineral density with all-cause mortality in individuals with osteoarthritis

BMC Musculoskeletal Disorders volume 26, Article number: 397 (2025) Cite this article

Abstract

Background

Osteoarthritis (OA) is a common joint disease that poses a significant public health burden, particularly in older adults. Despite research on its impact, the role of bone mineral density (BMD) in OA prognosis remains underexplored. This study investigates the association between BMD, measured using dual-energy X-ray absorptiometry (DXA), and all-cause mortality in individuals with OA using data from the National Health and Nutrition Examination Survey (NHANES).

Methods

This retrospective cohort study utilized NHANES data from 1999 to 2018, including participants aged 20 years and older (n = 55,081). After excluding individuals with missing BMD or mortality data, 1,573 participants diagnosed with OA were analyzed.

Results

The multivariate-adjusted hazard ratio (HR) for BMD and all-cause mortality was 0.344 (0.153, 0.774), indicating a protective effect of higher BMD. We observed an L-shaped relationship between BMD and mortality: a 1-unit decrease in BMD was associated with a 97.3% increased HR for mortality when BMD was below 1.216 g/cm² (HR 0.027, 95% CI 0.010–0.069). No significant association was found for higher BMD levels (HR 4.490, 95% CI 0.431–46.754). In age-stratified analysis, a significant association was found in both those under and over 50 years old.

Conclusions

This study reveals an L-shaped association between BMD and all-cause mortality in individuals aged 20 and older with OA, underscoring the importance of maintaining bone health in this population. These findings highlight BMD as a prognostic marker and suggest that monitoring BMD could improve clinical outcomes for OA patients.

Clinical trial number

Not applicable.

Peer Review reports

Introduction

Osteoarthritis (OA) is a prevalent degenerative joint disease characterized by the progressive breakdown of articular cartilage, subchondral bone alterations, and synovial inflammation, leading to pain, stiffness, and functional impairment [1, 2]. Due to its high prevalence, OA is a significant public health concern, especially among older adults, and its association with substantial disability and reduced quality of life [3, 4]. Despite extensive research on the pathophysiology and management of OA, the potential impact of bone mineral density (BMD) on the prognosis of OA patients remains underexplored.

BMD, a critical determinant of bone strength, has been widely studied in the context of osteoporosis and fracture risk [5]. However, its role in the prognosis of OA patients is not well established. Several studies have suggested that OA and osteoporosis, though seemingly distinct, may share common pathophysiological pathways and risk factors, such as aging and systemic inflammation [6,7,8,9]. BMD can be assessed using various techniques, including dual-energy quantitative computed tomography (DEQCT), single-energy quantitative computed tomography (QCT), dual-energy X-ray absorptiometry (DXA), and others. Each method generates distinct data and could potentially lead to discrepancies in the results of BMD-OA research. In this study, we used DXA to measure BMD, which is widely accepted and commonly employed in large-scale epidemiological studies. Moreover, higher BMD has been paradoxically associated with an increased risk of knee and hip joints OA, suggesting a complex interplay between bone density and joint health [10]. Body composition variables, such as fat mass, lean mass, and body fat percentage, have been demonstrate to be associated with the development and progression of osteoarthritis. These variables can influence joint loading, inflammation, and overall musculoskeletal health, which may, in turn, affect OA outcomes. While body composition is not the primary focus of this study, its potential influence on OA outcomes warrants consideration [11].

Previous research has primarily focused on the association between BMD and incident OA, with conflicting results. While some studies have reported an inverse relationship between BMD and OA severity [12], others have found no significant association [13]. Given that OA is a chronic condition that often coexists with other health problems, understanding the impact of BMD on the risk of mortality could provide valuable insights into the clinical management of OA patients. Therefore, this study aims to explore the relationship between BMD and all-cause mortality in individuals with OA.

In this study, data from the National Health and Nutrition Examination Survey (NHANES), a large, nationally representative cohort was used. We analyzed the data of OA patients employing Cox regression models to examine the relationship between BMD and mortality. Additionally, we utilized Cox proportional hazards models and generalized additive models to explore potential nonlinear associations between BMD and mortality. By elucidating the relationship between BMD and mortality in OA patients, our study seeks to provide new insights into the prognostic significance of bone health in this population, thereby informing future research and clinical practice.

Methods

Study design and population

This retrospective cohort study utilized data from NHANES collected between 1999 and 2018. NHANES is a nationally representative survey conducted by the National Center for Health Statistics (NCHS) that assesses the health and nutritional status of the civilian, non-institutionalized U.S. population through interviews, physical examinations, and laboratory tests [14.15].

The initial sample included 101,316 participants. For this study, we included participants aged 20 years and older (n = 55,081) and excluded individuals younger than 20 years (n = 46,235). Among those aged 20 and older, we further selected participants diagnosed with OA based on self-reported doctor diagnosis (n = 3,768). Participants missing BMD data (n = 2,191) or mortality data (n = 4) were excluded from the final analysis, resulting in a study population of 1,573 individuals (Fig. 1).

Fig. 1
figure 1

Flow chat of sample selection from the NHANES

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Bone mineral density measurement

BMD was measured using dual-energy X-ray absorptiometry (DXA) scans. The BMD values were recorded in grams per square centimeter (g/cm²) and included measurements of the total body, lumbar spine, and femoral neck. For this analysis, the total body BMD was used as the primary exposure variable. The DXA scans were performed using standardized protocols and calibrated equipment to ensure accuracy and reliability of the measurements.

Mortality ascertainment

Mortality data were obtained by linking NHANES participants to the National Death Index (NDI) through December 31, 2018. The primary outcome was all-cause mortality. Follow-up time was calculated from the date of the NHANES survey to the date of death or the end of the study period, whichever came first.

Covariates

Covariates were selected based on their potential confounding effects on the relationship between BMD and mortality. These included age, sex, race/ethnicity (Hispanic, non-Hispanic White, non-Hispanic Black, and others), body mass index (BMI), family poverty income ratio (PIR), hypertension (having received the diagnosis of hypertension from a doctor), diabetes (having received the diagnosis of diabetes mellitus from a doctor), vigorous work activity (yes/no), smoking status (smoked at least 100 cigarettes in life), and heavy alcohol consumption (ever have 4/5 drinks every day). Age was further categorized into two groups: <50 years and ≥ 50 years [16, 17]. Serum specimens were collected as part of the NHANES laboratory examination component, and rigorous procedures were used throughout the blood collection and analysis process [18]. At baseline, creatinine (µmol/L), blood urea nitrogen (mmol/L), glucose serum (mmol/L), glycohemoglobin (%), C-reactive protein (CRP) (mg/dL), serum uric acid (µmol/L) levels were measured.

Statistical analysis

Baseline characteristics of the study population were compared between age groups (< 50 years and ≥ 50 years) using linear regression for continuous variables and chi-square tests for categorical variables. Three Cox regression models were developed to investigate the association between BMD and all-cause mortality: Model 1 was unadjusted. Model 2 was adjusted for age, sex, and race. Model 3 was fully adjusted for age, sex, race, BMI, hypertension, diabetes, vigorous work activity, smoking status, and heavy alcohol consumption.

To assess the potential nonlinear relationship between BMD and all-cause mortality, we used generalized additive models and smoothed curve fitting (penalized spline method). We further applied a two-piecewise Cox proportional hazards model to identify inflection points. To assess the validity of the proportional hazards assumption for the Cox regression models, we performed the phtest in Stata. The results indicated that the proportional hazards assumption was met (p > 0.05), meaning that the proportional hazards assumption holds for all covariates in the model. The log-likelihood ratio test was used to compare the fit of the two-piecewise model with the standard Cox model. Stratified analyses were conducted to examine the consistency of the association between BMD and all-cause mortality across different subgroups defined by age, sex, race, BMI, hypertension, vigorous work activity, smoking status, and heavy alcohol consumption. Interaction terms were included in the Cox models to test for statistical interaction. All analyses were carried out with R 3.4.3 and EmpowerStats 2.0, and a two-tailed P < 0.05 was considered statistically significant.

Results

Baseline characteristics of study participants

The baseline characteristics of the research population according to age were displayed in Table 1. BMD was significantly higher in the younger group (1.15 ± 0.12 g/cm²) compared to the older group (1.07 ± 0.14 g/cm², P < 0.001). The poverty-income ratio (PIR) was lower in the younger group (2.51 ± 1.67) than in the older group (2.77 ± 1.58, P = 0.013). In terms of lipid profiles, total cholesterol (5.10 ± 1.03 mmol/L vs. 5.39 ± 1.07 mmol/L, P < 0.001) and HDL cholesterol (1.32 ± 0.39 mmol/L vs. 1.43 ± 0.44 mmol/L, P < 0.001) were significantly lower in the younger group, although LDL cholesterol did not show a significant difference (3.04 ± 0.88 mmol/L vs. 3.19 ± 0.93 mmol/L, P = 0.100). The younger group had a higher BMI (31.21 ± 7.84 kg/m² vs. 29.95 ± 6.58 kg/m², P = 0.003), and lower levels of creatinine (75.71 ± 49.82 µmol/L vs. 81.10 ± 33.72 µmol/L, P = 0.025), blood urea nitrogen (4.35 ± 1.90 mmol/L vs. 5.83 ± 2.44 mmol/L, P < 0.001), serum glucose (5.43 ± 2.05 mmol/L vs. 5.82 ± 2.08 mmol/L, P = 0.003), and glycohemoglobin (5.51 ± 0.83% vs. 5.84 ± 1.01%, P < 0.001). CRP levels were higher in the younger group (1.19 ± 3.31 mg/dL vs. 0.67 ± 1.58 mg/dL, P < 0.001), while serum uric acid was lower (319.59 ± 100.70 µmol/L vs. 335.44 ± 90.40 µmol/L, P = 0.007). Regarding categorical variables, there were no significant differences in sex distribution (P = 0.631), but significant differences were observed in race (P < 0.001), hypertension (P < 0.001), diabetes (P < 0.001), vigorous work activity (P < 0.001), and heavy alcohol consumption (P = 0.022).

Table 1 Baseline characteristics of participants with OA according to age
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Relationships of BMD with all-cause mortality

To investigate the independent role of BMD levels in mortality, we designed three Cox regression models. After adjusting for age, sex, race, BMI, hypertension, diabetes, vigorous work activity, smoking status, and heavy alcohol (Model 3), the multivariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) for BMD was 0.344 (0.153, 0.774), indicating a significant protective effect of higher BMD on all-cause mortality. Further subgroup analyses were performed by stratifying participants into two age groups (< 50 years and ≥ 50 years). In the fully adjusted model, the HR (95% CI) for the < 50 years group was 0.003 (0.000, 0.152), and for the ≥ 50 years group, it was 0.069 (0.030, 0.158), both showing significant associations between higher BMD and reduced mortality risk. For females, BMD was found to be protective across all three models. The significance remained high in each case, particularly in Model 3 (HR = 0.253, 95% CI: 0.075, 0.853, p = 0.027), suggesting that higher BMD is associated with a reduced risk of mortality. For males, BMD showed a significant protective effect only in Model 1 (HR = 0.121, 95% CI: 0.045, 0.325, p < 0.001). In Models 2 and 3, however, the effect was no longer statistically significant, indicating that the protective effect of BMD on mortality in males may be influenced by other factors such as age, sex, race, and lifestyle adjustments (Table 2).

Table 2 HRs (95% CIs) for mortality according to BMD among participants with OA
Full size table

The detection of nonlinear relationships

Using generalized additive models and smoothed curve fitting (penalized spline method), we discovered L-shaped associations between BMD and all-cause mortality (Fig. 2A). A Cox proportional hazards model combined with a two-piecewise Cox proportional hazards model was used to investigate the nonlinear relationship between BMD levels and all-cause mortality in patients with OA (P for log-likelihood ratio < 0.001) (Table 3). The inflection point for all-cause mortality was determined to be 1.216 g/cm². When BMD was less than 1.216 g/cm², a 1-unit decrease in BMD was associated with a 97.3% greater adjusted HR of all-cause mortality (HR 0.027; 95% CI 0.010, 0.069). When BMD exceeded 1.216 g/cm², there was no significant association with all-cause mortality (HR 4.490; 95% CI 0.431, 46.754).

Table 3 Threshold effect analysis of BMD on all-cause and mortality in OA patients (fitting by the two-piecewise linear model)
Full size table

To validate the relationship across different age groups, stratified analyses were conducted (Fig. 2B). The results indicated a negative correlation in the < 50 years group and an L-shaped relationship in the ≥ 50 years group. Table 3 also showed the calculated inflection points, confirming these findings.

Fig. 2
figure 2

Association between BMD and all-cause mortality in total OA patients (A), and stratified by age (B). Adjusted for age, sex, race, BMI, hypertension, diabetes, vigorous work activity, smoking status and heavy alcohol; age was not adjusted in the analysis stratified by age

Full size image

Stratified analyses

The survival advantage of higher BMD (≥ 1.216 g/cm²) versus lower BMD (< 1.216 g/cm²) in OA patients was consistent across various subgroups stratified by age, sex, race, BMI, history of hypertension, vigorous work activity, smoking status, and heavy alcohol consumption (Fig. 3). No significant interactions were observed between BMD and the stratified variables, indicating that the protective effect of higher BMD on all-cause mortality was robust across different demographic and clinical characteristics.

Fig. 3
figure 3

Forest plots of stratified analyses of BMD and all-cause mortality. Age, sex, race, BMI, hypertension, vigorous work activity, smoking status and heavy alcohol were all adjusted except the variable itself

Full size image

Discussion

To our knowledge, this is the first retrospective study with a relatively large sample size to examine the link between BMD levels and all-cause mortality in OA patients. We discovered L-shaped relationship between BMD and mortality, with lower BMD associated with a higher risk of mortality. Specifically, a 1-unit decrease in BMD was associated with a 97.3% greater adjusted HR of all-cause mortality when BMD was below the inflection point of 1.216 g/cm². These results underscore the complex interplay between bone health and survival outcomes in OA patients, aligning with previous studies that have identified a link between lower BMD and increased mortality risk in the general population [19, 20].

The observed L-shaped relationship suggests that while higher BMD may initially provide a protective effect against mortality, this benefit plateaus and does not confer additional survival advantages beyond a certain threshold. This non-linear association is particularly pronounced in older adults, reflecting the intricate balance between bone density and overall health. Our results are consistent with some prior studies that have reported an inverse relationship between BMD and mortality. Ensrud et al. found that low BMD in older women is associated with an increased risk of all-cause mortality [21], a finding echoed by Johnell and Kanis, who highlighted the global impact of osteoporotic fractures on mortality, particularly hip fractures among the elderly [22]. Similarly, Cummings and Melton and Curtis et al. emphasized that low BMD, as a predictor of fractures, is closely linked to higher mortality in older adults [23, 24]. These studies collectively underscore the critical role of maintaining bone health to reduce mortality risk in the elderly. However, to date, similar studies investigating the relationship between BMD and mortality in patients with OA remain scarce.

The underlying mechanisms linking low BMD to increased mortality in OA patients are likely multifaceted. One possible explanation is that low BMD may reflect poor overall bone quality and strength, predisposing individuals to a higher risk of fractures. Fractures, particularly hip fractures, are associated with significant morbidity and mortality, particularly in older adults [22]. Additionally, low BMD may reflect poor overall health and nutritional status. Malnutrition and deficiencies in essential nutrients such as calcium and vitamin D are common in individuals with low BMD and may contribute to increased mortality risk [25]. These nutritional deficiencies can impair immune function, increase susceptibility to infections, and exacerbate chronic conditions [26]. Moreover, systemic inflammation, a common feature in both OA and osteoporosis, may play a critical role in the observed association. Chronic inflammation can contribute to bone resorption and decreased BMD, as well as increase the risk of cardiovascular diseases and other comorbidities that elevate mortality risk [27, 28]. Elevated levels of inflammatory markers such as CRP have been associated with both lower BMD and higher mortality [29]. What’s more, hormonal factors, particularly in postmenopausal women, may influence the relationship between BMD and mortality. Estrogen deficiency after menopause accelerates bone loss and increases the risk of osteoporosis and fractures [30]. Hormone replacement therapy has been shown to improve BMD and reduce fracture risk, potentially lowering mortality. However, its use is also associated with an increased risk of certain cancers and cardiovascular events, highlighting the need for a balanced approach [31].

Moreover, the observed L-shaped relationship suggests that while extremely low BMD is detrimental, higher BMD beyond a certain threshold does not confer additional survival benefits. This could be due to the fact that excessively high BMD, particularly in the context of OA, may indicate increased subchondral bone sclerosis and joint damage, potentially leading to greater disability and impaired mobility [32]. The complex interplay between BMD, bone quality, and joint health highlights the need for a balanced approach in managing bone health in OA patients.

There are some benefits in this study. First, we used a nationally representative sample of adults with OA in the United States, which had a relatively large sample size and helped generalize our results. Furthermore, the number of deaths in long-term follow-ups provided sufficient strength for the analysis in the present study. Second, by adjusting for socioeconomic status, comorbidity, and other potential confounding factors, we could improve the effectiveness of the conclusion. Finally, the BMD in the NHANES database were measured using a standard method, ensuring the data analysis reliability.

However, since this was an observational study, cause and impact could not be determined. BMD measurements were only taken at one time point, limiting our ability to assess changes in BMD over time. Further, with a national database it was likely a different DXA machine and that introduces error. While we found that higher BMD was associated with a reduced risk of all-cause mortality, the potential for reverse causality cannot be ignored. OA could lead to the formation of bone spurs, which might in turn result in higher BMD readings in certain areas. Further research using advanced imaging techniques, such as quantitative computed tomography (QCT) or magnetic resonance imaging (MRI), could help clarify whether higher BMD is a result of OA-related bone changes or an independent risk factor for mortality in OA patients. Finally, our study, like other observational studies, could not rule out residual or unknown confounding or accidental confounding effects due to measurement errors and unmeasured variables (i.e., psychosocial stress or genetic susceptibility). While total body BMD provides a broad measure of bone density, it is important to note its limitations compared to more specific measurements such as lumbar spine or femoral neck BMD. These site-specific measurements are often considered more reflective of bone strength and the risk of fractures. Future studies incorporating these specific BMD measurements would likely provide more detailed insights into the relationship between bone health and OA.

Our findings suggesting that routine BMD screening in OA patients, particularly those with low BMD, may help identify individuals at higher risk for mortality and allow for earlier interventions to improve long-term survival outcomes. Additionally, addressing systemic inflammation and managing comorbidities are critical components of comprehensive care for OA patients with low BMD. Future research should focus on elucidating the precise mechanisms linking BMD, OA, and mortality, and investigating the potential benefits of interventions aimed at improving bone health and reducing inflammation in this population. Longitudinal studies with larger sample sizes and diverse populations are needed to confirm our findings and further explore the impact of BMD on mortality in OA patients.

Conclusion

In conclusion, our study demonstrates a significant L-shaped association between BMD and all-cause mortality in individuals with OA. Lower BMD is associated with a higher risk of mortality, highlighting the importance of bone health in this population. These findings provide new insights into the prognostic significance of BMD in OA patients and underscore the need for integrated approaches to improve clinical outcomes in this vulnerable population.

Data availability

The datasets generated and/or analysed during the current study are available in the NHANES website (www.cdc.gov/nchs/nhanes, accessed on 21 October 2024).

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Funding

This study was funded by the National High Level Hospital Clinical Research Funding (2022-PUMCH-B-039) and Peking Union Medical College Hospital Young Reserve Talent Development Program (UHB12125).

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Authors and Affiliations

  1. Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Yixuan He, Juan Sun, Lu Gao & Bo Pan

  2. Department of Anesthesiology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Yixuan He

  3. Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

    Jie Li

  4. Department of Breast Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, No. 1 Shuaifuyuan, Dongcheng District, Beijing, 100730, China

    Lu Gao & Bo Pan

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Contributions

Yixuan He and Juan Sun contributed to data collection, statistical analysis, and writing of the manuscript, were co-first authors of this manuscript. Jie Li contributed to data collection and statistical analysis. Lu Gao and Bo Pan supervised the study and contributed to polishing and reviewing of the manuscript, were co-corresponding authors. All authors contributed to the article and approved the submitted version.

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Correspondence to Lu Gao or Bo Pan.

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Ethics approval and consent to participate

The NHANES was reviewed and approved by the National Centre for Health Statistics Research Ethics Review Board. The study was conducted in accordance with the principles of the Declaration of Helsinki (1964) and its later amendments. Informed consents were obtained from all participants in each year’s survey.

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The authors declare no competing interests.

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He, Y., Sun, J., Li, J. et al. L-shaped association of bone mineral density with all-cause mortality in individuals with osteoarthritis. BMC Musculoskelet Disord 26, 397 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12891-025-08416-2

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  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12891-025-08416-2

Keywords

BMC Musculoskeletal Disorders

ISSN: 1471-2474

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