Introduction

Age-related macular degeneration (AMD) is counted among the leading causes of blindness in the elderly population and stands as the most common retinal disorder resulting in visual impairment in developed countries1. Normally, AMD predominantly affects individuals aged 55 years and older2, with age being the principal risk factor3. The manifestations of AMD include the presence of drusen and blurred vision4. The core features of early AMD are drusen and changes in the retinal pigment epithelium. These manifestations are characterized by light yellow patches caused by depigmentation and clumps formed as a result of pigment hyperplasia. Simultaneously, there is a mild reduction in contrast sensitivity and subtle metamorphopsia. As the disease advances, advanced AMD manifests in two distinct pathological forms: exudative and atrophic. Exudative (wet) AMD leads to acute vision loss as a result of choroidal neovascularization. It is characterized by the presence of central scotoma, progressive worsening of metamorphopsia, and abnormal color vision. In atrophic (dry) AMD, the gradual atrophy of the retinal pigment epithelium-choriocapillar complex gives rise to chronic visual impairment. This encompasses central visual field loss, impaired night vision, and challenges in facial recognition. Both of these late-stage manifestations have a substantial impact on the quality of life. The pathogenesis of AMD encompasses multiple factors, such as oxidative stress, chronic inflammation, immune system dysregulation, and genetic susceptibility5. Some investigations have demonstrated that low BMD is associated with AMD in middle-aged and elderly women6,7. A study of the Polish population8 demonstrated that a reduction in femoral BMD could be linked to an increased risk of AMD in men, especially in the wet AMD subtype. Simultaneously, the results of a Korean study9 suggested that osteoporosis might contribute to the progression of AMD in postmenopausal women. These investigations indicate that there could be a tight connection between AMD and osteoporosis.

Osteoporosis is a bone disease characterized by reduced bone mineral density and alterations in the microarchitecture of bone tissue10. This condition is more prevalent among elderly postmenopausal women11, and its management has emerged as a significant public health challenge on a global scale12. It has been documented that individuals with osteoporosis frequently experience hip and vertebral fractures13. Additionally, visual impairment due to age-related ocular diseases can increase the risk of falls and fractures in older adults. Some studies have proposed that enhancing vision may serve as an effective strategy to prevent such incidents14. Early investigations have indicated potential shared etiological factors between AMD and osteoporosis, such as systemic inflammation and metabolic syndrome15,16.

However, the relationship between osteoporosis and most age-related eye diseases remains poorly understood. Based on this knowledge gap, we hypothesized that AMD is associated with low BMD. It is of scientific interest to explore the underlying mechanisms linking osteoporosis and AMD. Therefore, we conducted this study using data from the National Health and Nutrition Examination Survey (NHANES) database to investigate the association between AMD and BMD, as well as to evaluate the relationship between osteoporosis and AMD across different anatomical sites.

Materials and methods

Study population and data source

This cross-sectional study included eligible participants from the NHANES survey. The NHANES is a comprehensive survey that includes demographics, socioeconomic status, dietary habits, and health-related questions. To ensure a diverse sample, NHANES used a stratified, multistage probability sampling method to select nationally representative participants. The study protocol was approved by the NCHS Institutional Review Board at the Centers for Disease Control and Prevention (CDC), and all participants provided written informed consent. Visit the official NHANES website (https://www.cdc.gov/nchs/nhanes/about_nhanes.htm17 to learn more. All statistical analyses were carried out using the NHANES complex survey design, which included weights, stratification, and clustering to ensure that our results reflected the larger US population. This technique increases the generalizability of our findings and strengthens their validity in the context of population-based health research. The study was approved by the Ethics Review Board of the National Center for Health Statistics, and all participants supplied signed informed consent.

A total of 4,550 participants were included in this study. Both female and male participants were included. We used publicly available NHANES survey data from 2005 to 2008. In NHANES 2005–2008, there were a total of 20,497 individuals. Among them, the individuals without a complete AMD diagnosis (N = 14,893), those who did not undergo the dual-energy X-ray absorptiometry (DXA) test (N = 795), and those with missing data of age, alcohol use, diabetes, hypertension, and BMI (n = 259) were excluded. Figure 1 reveals the flow chart of sample screening in this current study. We included the worse eye of each patient in our analysis.

Fig. 1
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Flowchart of participant inclusion from NHANES 2005–2008.

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Definition of AMD severity

The primary details of our study was the presence of AMD, as determined by NHANES using fundus photography. Forty-five-degree non-mydriatic digital images of the retina were captured from survey participants aged 40 years and older using the Canon Non-Mydriatic Retinal Camera CR6-45NM with a Canon 10D camera back (6.3 megapixels per image). Technicians conducting the exams received training in the use of the digital imaging system. By making the participants remain in a dark room for a specific duration, their pupils dilated physiologically without the use of any pharmacological agents. Two digital images were taken, the first of which was centered around the macula, and the other of which was centered around the optic nerve18. In the NHANES, a grader from the University of Wisconsin evaluated the diagnosis and grading of AMD on digital images. For this assessment, the grader utilized a modified version of the Wisconsin Age-related Macular Disease Grading and Classification System. Early AMD was defined as (1) soft drusen present with a grid area of greater than a 500 μm circle and a pigmentary abnormality present (increased pigment or depigmentation in the grid) or (2) soft drusen present in the center circle and a pigmentary abnormality present (increased pigment or depigmentation in the grid)19; late AMD was defined as the presence of any late lesions, including geographic atrophy, pigment epithelial or retinal detachments, subretinal hemorrhage, subretinal fibrous scar, subretinal new vessels, or laser treatment and/or photodynamic therapy for AMD20. The grading team included nine experienced graders. All images were further graded by at least two graders (a preliminary grader and a detail grader). Upon systematic grading, if the first two graders did not agree on pathology, a third grader graded the eye. If two of the three graders disagreed, the image was evaluated by an adjudicator to make a final decision. In this analysis, in cases where the retinal photographs of both eyes were eligible for grading, we selected the eye presenting more advanced levels of AMD.

Determination of BMD and the diagnosis of osteoporosis

Osteoporosis status was defined according to a self-reported health questionnaire. In any case, the answer of “yes” to the question “Ever told had osteoporosis/brittle bones” was included in the osteoporosis group; otherwise, it was included in the non-osteoporosis group. The bone mineral density (BMD) of the spine and femur was assessed by dual-energy X-ray absorptiometry (DXA). Osteoporosis was diagnosed in accordance with the classification criteria established by the World Health Organization. When the BMD T-score in any region of the femur is ≤ − 2.5, a value greater than 2.5 standard deviations below the reference mean is indicated for a young adult population21,22. In cases where there is a discrepancy between the patient’s self-reported information and the data obtained from DXA scans, the diagnosis of osteoporosis should be based on the DXA scan data.

Covariates

Demographic data covered age, gender, race, education level, and poverty income ratio (PIR)23. PIR was calculated as the ratio of total household income to the corresponding poverty line for the household size, multiplied by the square root of the number of household members, and categorized into four intervals: less than 1.0, between 1.0 and 3.0, more than 3.0, and missing information. In addition, in conjunction with the questionnaire, this study assessed smoking, drinking habits, diabetes and hypertension status as covariates. Smoking habits were categorized into three strata: never smoking (less than 100 total lifetime cigarettes), previous smoking (having smoked ≥ 100 cigarettes and having quit), and current smoking (having smoked ≥ 100 total lifetime cigarettes and still smoking). Alcohol consumption behavior was then subdivided into five categories: never drinking (lifetime alcohol intake of less than 12 drinks), past drinking (annual intake of ≥ 12 drinks, but not in the last year), heavy drinking (≥ 4 drinks/day for men or ≥ 3 drinks/day for women, or more than 4 days of heavy drinking per month), moderate drinking (≥ 3 drinks/day for men or ≥ 2 drinks/day for women, or 1–4 days of heavy drinking per month), and light drinking (below the moderation standard). The diagnosis of hypertension was based on (1) self-reported physician-confirmed diagnosis; (2) use of antihypertensive medications; and (3) systolic blood pressure ≥ 140 mmHg or diastolic blood pressure ≥ 90 mmHg. Diabetes mellitus was confirmed by one or more of the following: (1) fasting blood glucose ≥ 7.0 mmol/L; (2) randomized or 2-hour oral glucose tolerance test (OGTT) blood glucose ≥ 11.1 mmol/L; (3) glycosylated hemoglobin > 6.5%; (4) use of glucose-lowering medications; and (5) self-reported physician diagnosis24. Body mass index (BMI) was calculated from the body measurements taken during the physical examination, specifically weight in kilograms divided by the square of height in meters. All of the above covariates were carefully selected and accounted for in order to evaluate our targeted associations.

Statistical analysis

Statistical analyses were done with the help of the R software (version 4.4.2), and following the NHANES guidelines, we introduced sampling weights aimed at alleviating the problem of over-sampling for specific demographic categories. For continuous data, such as age, BMI, total femoral BMD, femoral neck BMD, trochanter BMD, and waist circumference, we described them in the form of means ± standard deviations (SD) and profiled them in depth with the help of weighted linear regression models. Categorical variables, including gender, race, education level, marital status, PIR (Poverty Income Ratio), smoking habits, drinking behavior, hypertension and diabetes status, we presented them through weighted percentages, and also applied a weighted chi-square test for analysis of variance.

To assess the potential association between BMD and AMD, we implemented a multivariate logistic regression analysis. In greater details, three models were evaluated for the adjusted odd ratios (OR) and their 95% confidence intervals (CIs) using multivariable logistic regression.

Results

Baseline characteristics

The characteristics of the study participants are shown in Table 1. The prevalence of all types of AMD (early and late AMD), early AMD, and late AMD were 5.60% (N = 125), 5.10% (N = 114), and 0.4% (N = 11) among women and 6.80% (N = 159), 6.50% (N = 151), and 0.3% (N = 8) among men, respectively. Compared with the control group participants (no AMD), women with AMD were older and exhibited a higher rate of hypertension. They also tended to exhibit a low BMD in the femoral trochanter, lumbar spine, and femoral neck, which resulted in a higher rate of osteoporosis (P < 0.001). Compared with the control group participants, men with AMD were older and exhibited a higher rate of hypertension and diabetes (P < 0.05). For females, the prevalence of osteoporosis was 11.365% for the control group (no AMD), 21.053% the early AMD group, and 36.364% for the late AMD group.

Table 1 Characteristics of the participants: a cross-sectional study using data from NHANES 2005–2008 (N = 4,550).
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Association of TN, FN, TR, L1, L2, L3, L4 and osteoporosis with AMD

The relationship between the AMD and the bone mineral density was assessed using multivariate logistic regression. Based on the data presented in Table 2, osteoporosis were significantly associated with all AMD (OR, 2.25; P < 0.001), early AMD (OR, 2.05; P = 0.003) and late AMD (OR, 4.25; P = 0.022). According to multivariate analyses, after adjusting for all covariates (age, gender, race, education, PIR, smoking habits, alcohol consumption behavior, hypertension, diabetes), the severity of total femoral, femoral neck, femoral trochanter, Spine, L1, L2, L3, L4 osteoporosis showed a negative correlation with all AMD (P < 0.004) and early AMD (P < 0.005) in women. Specifically, for each additional unit increase in Total Femoral BMD, the incidence of total AMD decreased by 0.08 (95% CI: 0.02, 0.30), and the incidence of early AMD decreased by 0.12 (95% CI: 0.03, 0.44). For each additional unit increase in Femoral neck BMD, the incidence of total AMD decreased by 0.06 (95% CI: 0.01, 0.22), and the incidence of early AMD decreased by 0.09 (95% CI: 0.02, 0.36). Furthermore, for each additional unit increase in Trochanter BMD, the incidence of total AMD decreased by 0.07 (95% CI: 0.02, 0.33), and the incidence of early AMD decreased by 0.10 (95% CI: 0.02, 0.50). Moreover, trend analysis showed no relationship between the bone mineral density and OR for late AMD in women. For men, multivariate analysis showed no association between osteoporosis and all AMD types (OR, 1.68; P = 0.281), early AMD (OR, 1.78; P = 0.231), and late AMD (OR, 0.00; P = 0.993).

Table 2 Odds ratios for AMD according to demographic factors for participants.
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Subgroup analysis

The subgroup analyses were conducted to examine the robustness of the association between the AMD and osteoporosis across different demographic and clinical subgroups. We first stratified the study by sex, race, education level, PIR, hypertension, smoking status, alcohol consumption and diabetes to investigate the overall subject’s interaction across distinct subgroups. As seen in Fig. 2, gender (p for interaction < 0.05) emerged as a significant factor impacting the outcomes. Specifically, this connection was stronger in women (P < 0.001, OR: 2.25 95%, CI: 1.45–3.50) than in males (P > 0.05). Since the previous analyses failed to reveal a significant association between AMD and osteoporosis in men (P > 0.05), our focus was shifted to different interactions in women (Fig. 3). Among racial groups, Mexican Americans exhibited the strongest positive association, with OR values of 3.52 (95% CI: 1.37, 9.04). Non-Hispanic Whites showed a more moderate association, with OR values of 1.86 (95% CI: 1.07, 3.24). Among smoking and alcohol intake groups, individuals who have never smoked or drunk alcohol demonstrate lower odds ratio values, indicating that adhering to healthy lifestyle habits may contribute to reducing the risk of AMD.

Fig. 2
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Forest plots for subgroup analysis among all subjects.

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Fig. 3
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Forest plots depicting the subgroup analysis of female participants.

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Non-linear relationships

To explore the overall association between BMD and AMD, we used generalized additive models with cubic spline regression. RCS curves indicated that the OR for all types of AMD decreased as BMD increased in the overall pattern among all participants. Early AMD presented a similar pattern; however, no significant association was obvious for advanced AMD. The RCS results (Fig. 4) indicated a U-shaped relationship between total femoral BMD and AMD (All participants -All AMD: p for nonlinear = 0.049; All participants - Early AMD: p for nonlinear = 0.037). However, among women, the p-value for nonlinearity was greater than 0.05, whereas the p-value for the overall association was less than 0.005. These findings indicate a statistically significant association between total femoral bone density and AMD. In contrast, there is insufficient evidence to substantiate a U-shaped, J-shaped, or other forms of nonlinear relationships between these two variables. In men, no significant association was observed between bone mineral density and AMD.

Fig. 4
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Restricted cubic spline analysis of Total Femoral BMD.

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The correlation between femoral neck density and AMD is illustrated in Fig. 5. As depicted in the figure, a significant negative correlation was observed in both the total population (All participants - All AMD: p for nonlinear = 0.001; All participants - Early AMD: p for nonlinear = 0.003) and among women (Female -Total AMD: p for nonlinear = 0.015; Female - Early AMD: p for nonlinear = 0.023). The curves shown were U-shaped, and we analyzed them for threshold effects. Table 3 shows that there was a threshold effect for the association between femoral neck BMD and AMD (P for likelihood test < 0.05). In female participants, when FN BMD was below 0.88, each unit increase in FN BMD was associated with a 0.01 decrease in the incidence of AMD and a 0.02 decrease in the incidence of early AMD; however, there was no significant correlation between AMD and FN BMD when FN BMD was above 0.88 (P > 0.05). In all participants, when FN BMD was lower than 0.84, each unit increase in FN BMD decreased the incidence of AMD by 0.02 and early AMD by 0.04; however, there was no significant correlation between AMD and FN BMD when FN BMD was higher than 0.84 (P > 0.05). Overall, femoral neck BMD and AMD were negatively associated, and when femoral neck BMD was higher than the inflection point, no association between Femoral neck BMD and AMD was found.

Fig. 5
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Restricted cubic spline analysis of Femoral neck BMD.

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Table 3 Threshold effect analysis of femoral neck BMD.
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The correlation between femoral trochanter density and AMD was comparable to that of the total femur BMD (Fig. 6). In the overall population, a significant nonlinear relationship was observed between these variables (All participants - All AMD: p for nonlinear = 0.011; All participants - Early AMD: p for nonlinear = 0.007). However, in women, this nonlinear trend was less pronounced (Female -Total AMD: p for nonlinear = 0.093; Female - Early AMD: p for nonlinear = 0.135).

Fig. 6
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Restricted cubic spline analysis of Trochanter BMD.

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The RCS curves of the spine (Fig. 7) and lumbar vertebrae (Fig. 8) with AMD reveal a U-shaped connection between BMD and AMD.

Fig. 7
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Restricted cubic spline analysis of spine BMD.

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Fig. 8
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Restricted cubic spline analysis of lumbar spine bone mineral density, including (1) L1BMD, (2) L2BMD, (3) L3BMD and (4) L4BMD.

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A thorough examination of the aforementioned RCS curves demonstrates that the lower the BMD, the greater the risk of AMD. In other words, BMD is negatively connected with the risk of AMD, and the relationship is stronger in women.

Discussion

To the best of our knowledge, although Seitzman et al.6 reported an association between BMD and AMD in an elderly female population, our study is the first to comprehensively verify this association and explore its nonlinear characteristics in a large and diverse US population. Prior to this, some researchers had conducted analyses on Asian populations7,9; consequently, this study utilized the NHANES database to examine other ethnic groups. This study conducted a comprehensive analysis of NHANES data spanning from 2005 to 2008. A comprehensive analysis of cross-sectional data from 4,550 participants revealed a complex correlation between BMD, osteoporosis, and AMD. Our study demonstrated that AMD was negatively associated with BMD in the TF, FN, TR, Spine, L1, L2, L3 and L4 regions, indicating that lower BMD is associated with higher AMD incidence rate (Table 2). In contrast, osteoporosis is positively correlated with the incidence of AMD; that is, as osteoporosis worsens, the incidence of AMD increases, and this correlation is more pronounced in women.

Previous research has demonstrated that osteoporosis is linked to systemic inflammation25, vitamin D insufficiency26, inadequate calcium intake27, metabolic disorders28 and oxidative stress29. Elevated levels of inflammatory markers in serum have been associated with the development of osteoporosis. For instance, IL-6 has been shown to enhance the activity of osteoclasts30, while TNF-α not only promotes the differentiation of osteoclast precursors but also stimulates the maturation of osteoclasts, thereby accelerating bone resorption. Meanwhile, systemic inflammation is also associated with the occurrence and progression of AMD. The study conducted by Huirong Long et al.31 demonstrates that interleukin-6 (IL-6) indirectly destabilizes the mRNA of DNA repair genes, thereby exacerbating oxidative damage to retinal pigment epithelium (RPE) cells and accelerating the progression of both AMD and diabetic retinopathy (DR). Furthermore, the research by Ochoa et al.32 indicates that oxidative stress and inflammatory responses form a feedback loop, amplifying retinal damage and contributing to the advancement of AMD. Specifically, the abnormal activation of the alternative pathway of the complement system acts as the critical link that connects genetic susceptibility to chronic inflammatory responses33. Polymorphisms in genes such as CFH, CFI, and CFB directly initiate chronic inflammatory responses and retinal degeneration by disrupting the complement regulatory network. These findings suggest that osteoporosis and AMD share common pathogenic mechanisms, specifically systemic inflammation and oxidative stress, which may underlie the association between osteoporosis and AMD.

Furthermore, clinical studies have demonstrated that a low serum concentration of 25-hydroxyvitamin D (25OHD) is associated with AMD, particularly in its advanced stages34. Additionally, research by Dong XX et al.35 has established a causal relationship between calcium intake and the risk of AMD and its subtypes. The calcium pathway is closely linked to aging and drusen accumulation36, and higher levels of dietary calcium and calcium supplementation have been shown to reduce the risk of AMD20. Consequently, vitamin D deficiency may also contribute to explaining the elevated risk of AMD in these patients.

In summary, AMD and osteoporosis share several common pathogenic factors, such as systemic inflammation, oxidative stress, insufficient calcium intake, and vitamin D deficiency. Most prior studies have primarily investigated the relationship between trace elements and AMD. For instance, Millen et al.37 suggested that calcium supplements used for osteoporosis prevention might be associated with the development of AMD in elderly populations. As a critical component of bone health, calcium deficiency not only reduces BMD but also contributes to the onset of osteoporosis38. Consequently, our study aimed to explore the risk correlation between BMD and AMD, thereby elucidating the association between osteoporosis and AMD at this level.

The study demonstrated that the correlation was more pronounced in women than in men, with no significant findings observed in the male population. It is hypothesized that this disparity may be attributed to estrogen levels in women. In females, estrogen plays a pivotal role in bone remodeling. The influence of estrogen significantly enhances calcium absorption in the duodenum, which may explain the significant correlation between the decline in estrogen levels in postmenopausal women and the increased prevalence of osteoporosis39. Additionally, estrogen is intricately linked to the pathogenesis of AMD. It modulates several signaling pathways associated with AMD development40 and exerts protective effects against the progression of AMD. Kaarniranta et al.41 conducted a systematic review and found that estrogen could retard the aging process of retinal pigment epithelial cells through its receptor-mediated antioxidant stress pathway (e.g., by updating the expression of SIRT1). As a result, this effect decreases drusen deposition, which is heavily associated with AMD. With advancing age, the reduction in estrogen levels following menopause diminishes anti-inflammatory and antioxidant capacities41, thereby influencing the onset and progression of both osteoporosis and AMD. In males, testosterone, the principal male hormone, has multiple effects on bone health. Additionally, different from estrogen in women, testosterone decreases at a relatively slower rate. It can directly promote the proliferation and differentiation of bone cells by binding to androgen receptors on osteoblasts42. As a result, this speeds up bone formation and makes significant contributions to bone growth, repair, and bone mass accumulation. Moreover, smoking and alcohol consumption rates were typically higher in men than in women. Smoking hinders calcium absorption and osteocyte production, thus accelerating the progression of osteoporosis43. Excessive alcohol intake disturbs bone metabolism and decreases bone mineral density44. As a result, these harmful habits may mask the true association between osteoporosis and AMD.

Our study revealed a more significant correlation between early-stage AMD and BMD. In contrast, late-stage AMD exhibited almost no correlation with BMD at specific sites. Furthermore, the correlation between femoral osteoporosis and AMD was found to be stronger compared to that of spinal and lumbar osteoporosis. Several studies have indicated that senile osteoporosis is primarily attributed to diminished calcium absorption due to reduced calcitriol formation, with the proximal femur being predominantly affected45, a finding that aligns with the results of our study. Similarly, for postmenopausal women, the alteration in the external diameter of the femoral neck parallels the continuous decline in BMD during the menopausal transition46. The weak association observed in this study regarding advanced AMD may be attributable to the limited number of patients with advanced AMD and insufficient data, which hindered the ability to derive more precise conclusions.

Notably, one result diverged from the findings of previous studies. Prior investigations have demonstrated that smoking serves as a widespread risk factor for both osteoporosis47 and AMD48. In our research, no significant correlation was identified between smoking and AMD. This result deviates from the conclusions of some previous studies. A reasonable explanation is that the sample size of smokers in this study is relatively small, which impacts the statistical power.

The primary strength of this study is its use of a large-scale, nationally representative database, which allows for an examination of the relationship between osteoporosis and AMD. However, several limitations should be acknowledged. First, because of the cross-sectional design of the study, which involved screening and analyzing pre-existing data in the database, we were unable to infer causal relationships between AMD and osteoporosis. Second, due to limitations in the available data, we could not adjust for all potential covariates that might have influenced both osteoporosis and AMD. For example, future research could incorporate various dietary patterns, lifestyle behaviors, the ingestion of vitamins and other nutrients, and the utilization of medications that might impact the progression of osteoporosis or AMD. Third, within the database, there exist no additional refined metrics for osteoporosis. Furthermore, relying exclusively on BMD may not comprehensively mirror the conditions of every patient. Consequently, we cannot rule out the possibility that unmeasured confounding variables may have impacted our results.

In conclusion, our findings reveal a significant association between osteoporosis in women and an elevated risk of AMD. However, further investigations are necessary to elucidate the precise mechanisms underlying this relationship. Studying the relationship between AMD and BMD, as well as osteoporosis, can enhance our understanding of the pathogenesis of AMD. These conditions may share common genetic factors, environmental influences, or metabolic abnormalities. Investigating their associations could lead to the identification of novel pathogenic genes, signaling pathways, or biomarkers, thereby providing new insights and directions for elucidating the mechanisms underlying AMD. For patients with both AMD and osteoporosis, the influence of osteoporosis should be taken into account during the treatment of AMD. For instance, the administration of anti-VEGF drugs, including ranibizumab and aflibercept, is taken into consideration. These drugs are regarded as the first-line treatment for wet AMD. Although its main target is the retina, the safety during long-term use still needs to be taken seriously. Existing studies have shown that anti-VEGF treatment may be associated with a decrease in bone density in patients with osteoporosis, but the specific mechanism remains unclear49. Therefore, during clinical medication, the changes in bone density and the progression of AMD in patients should be monitored regularly. Additionally, assessing bone mineral density and screening for osteoporosis can serve as predictive tools for AMD risk, enabling early detection of AMD signs and timely implementation of intervention strategies.