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. 2023 Oct 19;18(10):e0293143. doi: 10.1371/journal.pone.0293143

The prevalence of age-related macular degeneration and osteoporosis in the older Polish population: Is there a link?

Agnieszka Budnik 1, Marcin Palewski 1, Magdalena Michnowska-Kobylińska 1, Łukasz Lisowski 1, Magda Łapińska 2, Zofia Stachurska 3, Anna Szpakowicz 4, Jerzy Konstantynowicz 5, Karol Kamiński 2, Joanna Konopińska 1,*
Editor: Tatsuya Inoue6
PMCID: PMC10586687  PMID: 37856460

Abstract

Background

Age-related macular degeneration is the primary cause of irreversible blindness in developed countries, whereas the global prevalence of osteoporosis–a major public health problem–is 19.7%. Both diseases may coincide in populations aged >50 years, leading to serious health deterioration and decreased quality of life.

Objectives

This study aimed to analyze the relationship between age-related macular degeneration and osteopenia, defined as decreased bone mineral density, in the Polish population.

Methods

Participants were derived from the population-based Bialystok PLUS Study. Randomized individuals were stratified into two groups, those with age-related macular degeneration (AMD-1 group) or without age-related macular degeneration (AMD-0 group). Using a cutoff value of −1.0 to identify low bone mass, participants with femoral bone mineral density T-scores above −1.0 were assigned to the normal reference, and those with T-scores below −1.0 were assigned to the osteopenia category. Among 436 Caucasian participants aged 50–80 years (252 women, 184 men), the prevalence of age-related macular degeneration was 9.9% in women and 12.0% in men. Decreased bone mineral density based on T-scores was observed in 36.9% of women and in 18.9% of men. Significant differences in femoral bone mineral density between the AMD-0 and AMD-1 groups were detected only in men (mean difference [95% confidence interval] = 0.11 (0.02; 0.13); p = 0.012 for femoral bone mineral density, and 0.73 [0.015; 0.94]; p = 0.011 for the femoral T-score). No associations were observed between bone mineral density and age-related macular degeneration in women.

Conclusion

Decreased femoral bone mineral density may be associated with a higher risk of age-related macular degeneration in men, but a causal link remains unclear.

Introduction

Age-related macular degeneration (AMD) is the primary cause of irreversible blindness in developed countries [1]. The number of European patients with AMD is projected to increase as the population ages [2].

AMD primarily affects the macula, leading to vision loss in the central 15 to 20 degrees of the visual field, often in both eyes. Not surprisingly, patients with AMD frequently sustain injuries, including skeletal trauma and fragility fractures [3, 4]. These fractures may be at least partly associated with (or caused by) age-related bone loss and osteoporosis. An association between hip bone mineral density (BMD) and the risk of AMD was observed in female participants in the Study of Osteoporotic Fractures [5]. However, concomitant osteoporosis was not associated with other age-related ocular disorders, such as cataracts, open-angle glaucoma, or diabetic retinopathy in a Korean study [6].

In 2010, the prevalence of osteoporosis among 50- to 84-year-old women from the European Union was estimated at 21%, compared with only 6% among men [7]. However, a growing body of evidence suggests that the prevalence of male osteoporosis may be underestimated [8]. Clinically, osteoporosis manifests as a higher risk of skeletal fragility and frequently leads to premature mortality. Every third woman and every fifth man over the age of 50 years in developed countries are estimated to experience a bone fracture during their remaining lifetime [3, 9, 10]. Furthermore, a two-fold higher risk of falls was observed in older women with AMD than in those without AMD in a prospective cohort study [11].

We could identify only two published studies revealing an epidemiological link between osteoporosis and AMD [4, 6]. Given their importance to public health, assessments of the coincidence of osteoporosis and AMD and underlying mechanisms thereof are warranted. The objective of this study was to analyze the relationship between osteoporosis and AMD.

Materials and methods

Study design and participants

The study included participants of the Bialystok PLUS Study, who were 50–80 years of age. The Bialystok PLUS Study was a prospective, population-based, cohort study in which the determinants and occurrence of cardiovascular, neurological, ophthalmic, psychiatric, musculoskeletal, and endocrine diseases were analyzed among residents of the city of Bialystok (Northeastern Poland). It had a fully randomized design. The aims, methodology, and protocol of the study have been described in detail elsewhere [12]. The study data were collected from November 2018 to June 2021. The minimum age limit was set at 50 years, in line with the diagnostic criteria for AMD.

Bone mineral density measurement

The analyzed parameters included the areal BMD of the total hip, femoral neck, lumbar spine, and total body/whole skeleton. The BMD was measured using dual-energy X-ray absorptiometry (Lunar iDXA; GE Healthcare, Madison, WI, USA). Standard densitometric procedures and quality assurance were performed, and standard scanning conditions were used, according to official recommendations. The percent coefficient of variation of the dual-energy X-ray absorptiometry method was 2.8% for the total femur measurements. Individuals with femur T-scores of −1.0 and above were assigned to the normal T-score group, and those with T-scores below −1.0 to the low T-score group. An operational diagnosis of osteoporosis was made based on the International Society for Clinical Densitometry standard guidelines. However, the cutoff T-score of −1.0 was intentionally used for the stratification to prevent underestimation, and to identify participants at increased risk of low bone mass.

Diagnosis of AMD

Fundus photography was performed on all study participants without previous pharmacological mydriasis by using a 35° color digital fundus camera (Canon CR-2 PLUS AF; Canon U.S.A., Inc., New York, USA). Fundus images were graded according to the Wisconsin AMD grading system [13] and the modified International Classification System [14] by appropriately trained retinal specialists (ŁL, MMK). The eyes of each participant were separately graded and classified and the eye with the more severe grade was selected for further analyses. Similar to a previous population-based study [15], we distinguished between early and late AMD. We also analyzed the presence of AMD-specific lesions, such as retinal pigmentary alterations, large drusen (≥125 μm), and a large drusen area (≥331 820 μm2) [16], as a separate outcome variable. Patients were assigned to one of two groups based on the presence (AMD-1 group) or absence (AMD-0 group) of AMD.

Other characteristics and methods

Anthropometric measurements were performed in a standard manner using certified equipment. Body weight and height were measured with the participants barefoot and wearing lightweight indoor clothing. Body mass index was calculated as weight (kg)/(height [m])2. Fasting blood samples were collected from all participants to determine their serum concentration of 25-hydroxyvitamin D (25[OH]D) by using a gamma counter (1470 Wizard; Perkin-Elmer, Turku, Finland) and radioimmunoassay (DiaSorin, Stillwater, MN, USA).

Statistical analysis

Statistical analyses were performed using the R statistical package (version 4.1.3), with the α-value set to 0.05. Quantitative variables were compared between groups using the Mann–Whitney U-test or Student t-test for independent samples, as applicable. The normal distribution of the study variables was verified using the Shapiro–Wilk test, and the homogeneity of their variances was verified using Levene’s test. Mean differences (MDs) and odds ratios (ORs) were calculated, along with their 95% confidence intervals (CIs). The relationships between categorical variables were analyzed using the chi-square test. Univariate and multivariable logistic regression models were created using AMD as the outcome variable. The results were presented as ORs with 95% CIs. To verify the significance and goodness of fit of the models, the chi-square statistic and Nagelkerke pseudo-R2 were calculated. Nagelkerke pseudo-R2 may take values from 0 to 1, the higher the value, the better quality of the model. The significance of the relationship was verified with the chi-square test (OR 95% CI, odds ratio with a 95% confidence interval).

The study was conducted in accordance with the provisions of the Declaration of Helsinki, and all participants provided written informed consent prior to enrollment. The Bioethics Committee of the Medical University of Białystok approved the study protocol (approval number R-I-002/108/2016 of 31 March 2016).

Results

The study sample consisted of 436 patients aged 50–80 years (252 women). Detailed characteristics of the study participants are listed in Table 1. AMD was diagnosed in 47 patients (10.8%). The prevalence of AMD in women and men were 9.9% and 12.0%, respectively. Decreased BMD based on T-scores was observed in 36.9% of women and 18.9% of men. The group of women included seven patients (five in the AMD-0 group and two in the AMD-1 group) who received treatment for osteoporosis in the form of bisphosphonates (n = 6), calcium supplements (n = 3), and/or vitamin D (n = 5).

Table 1. Demographic, clinical, and densitometric characteristics of study participants.

Overall (n = 436) Women (n = 252) Men (n = 184)
AMD-0 (n = 389) AMD-1 (n = 47) p AMD-0 (n = 227) AMD-1 (n = 25) p AMD-0 (n = 162) AMD-1 (n = 22) p
Age, years 63.00 (58.00; 68.00) 66.00 (59.00; 69.00) 0.100 62.00 (58.00; 67.50) 67.00 (63.00; 72.00) 0.008 63.00 (56.00; 69.00) 64.50 (56.25; 66.00) 0.683
Body mass index, kg/m2 27.99 28.01 … 27.84 (24.34; 31.70) 28.33 (23.16; 31.47) 0.445 28.96 ± 4.59 27.86 ± 3.58 0.281*
Height, cm 165.40 (160.20; 72.60) 166.30 (158.20;175.10) 0.691 161.07 ± 5.49 159.29 ± 7.25 0.244* 174.25 ± 6.22 176.20 ± 7.46 0.178*
Weight, kg 78.70 (67.40; 89.90) 78.60 (66.30; 90.50) 0.628 72.70 (64.05; 80.95) 69.80 (59.30; 79.50) 0.222 87.70 (79.27; 97.20) 86.90 (78.70; 92.68) 0.674
Serum 25(OH)D, ng/ml 23.84 (17.31; 31.40) 24.90 (17.21; 33.35) 0.733 25.30 (19.41; 33.40) 32.87 (24.68; 37.85) 0.065 21.24 (16.48; 26.75) 18.59 (16.55; 25.12) 0.348
Whole-body BMD, g/cm2 1.10 ± 0.14 1.08 ± 0.13 0.266* 1.03 ± 0.12 1.00 ± 0.12 0.246* 1.20 ± 0.11 1.16 ± 0.10 0.113*
Whole-body T-score −0.28 ± 1.18 −0.60 ± 1.10 0.079* −0.47 ± 1.20 −0.77 ± 1.18 0.246* −0.02 ± 1.09 −0.42 ± 0.99 0.104*
Lumbar spine BMD, g/cm2 1.14 (0.99; 1.28) 1.12 (1.01; 1.26) 0.716 1.03 (0.94; 1.17) 1.07 (0.92; 1.14) 0.970 1.26 ± 0.17 1.21 ± 0.17 0.212*
Femoral neck BMD, g/cm2 0.91 (0.82; 0.99) 0.88 (0.79; 0.91) 0.031 0.87 (0.78; 0.96) 0.81 (0.77; 0.89) 0.058 0.96 (0.88; 1.03) 0.90 (0.84; 0.98) 0.084
Femoral neck T-score −1.08 (−1.66; −0.46) −1.45 (−1.92; −0.94) 0.015 −1.20 (−1.84; −0.53) −1.61 (−1.94; −1.04) 0.058 −0.88 (−1.46; −0.30) −1.28 (−1.73; −0.73) 0.082
Total femoral BMD, g/cm2 1.00 (0.90; 1.10) 0.95 (0.89; 1.02) 0.060 0.95 ± 0.14 0.92 ± 0.13 0.325 1.07 (0.99; 1.16) 0.96 (0.92; 1.09) 0.012 *
Total femur T-score −0.37 (−1.09; 0.33) −0.78 (−1.27; −0.24) 0.028 −0.44 ± 1.11 −0.67 ± 1.01 0.325 −0.23 (−0.75; 0.42) −0.96 (−1.27; −0.09) 0.011 *
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* Variables with normal distributions were compared using the Student t-test, and those with non-normal distributions were compared using Wilcoxon’s test for independent samples.

AMD-0: group without AMD; AMD-1: group with AMD.

AMD, age-related macular degeneration; BMD, bone mineral density.

Women in the AMD-0 group were younger than those in the AMD-1 group, and the two groups did not differ in terms of body mass index, height, body weight, or serum 25(OH)D concentration. Men were homogenous in terms of age and biometric parameters.

Significant differences in femoral BMD and femur T-scores between the AMD-0 and AMD-1 groups were observed only in men (MD = 0.11 [0.02; 0.13]; p = 0.012 for femoral BMD and MD = 0.73 [0.015; 0.94]; p = 0.011 for femur T-score). The parameters of femoral neck BMD were worse in the AMD-1 group than in the AMD-0 group, with the between-group difference nearing the statistical significance. No association was observed between BMD and AMD in women. 25(OH)D status was not associated with the prevalence of AMD or the risk of a low femoral BMD in men or women.

The proportions of men in the AMD-0 and AMD-1 groups who had decreased T-scores for femoral BMD were 15% and 46%, respectively, demonstrating a statistically significant difference (OR = 4.65 (1.81; 11.97); p = 0.001) The presence of AMD did not exert a significant effect on the occurrence of decreased T-score values among women (p = 0.633), (Table 2).

Table 2. The relationship between T-Score (Cutoff, −1.0) for femoral BMD and the occurrence of age-related macular degeneration in women and men.

Variable Women Men
AMD-0 (n = 223) AMD-1 (n = 23) Odds ratio (95% CI) p AMD-0 (n = 158) AMD-1 (n = 22) Odds ratio (95% CI) p
Total femur T-score” ≥ −1.0 144 (64.6) 16 (69.6) 0.80 (0.31; 2.02) 0.633 134 (84.8) 12 (54.5) 4.65 (1.81; 11.97) 0.001
Total femur T-score” < -1.0 79 (35.4) 7 (30.4) 24 (15.2) 10 (45.5)
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AMD-0: group without AMD; AMD-1: group with AMD.

AMD, age-related macular degeneration; CI, confidence interval.

Femoral BMD was a significant predictor of AMD in men based on univariate logistic regression models. A one-unit increase in femoral BMD was associated with a 98% decrease in the risk of being in the AMD-1 group (95% CI = <0.01; 0,80; p = 0.043), whereas a one-unit increase in the femur T-score was associated with a 42% risk reduction (95% CI = 0.34; 0.96; p = 0.041)). For women only age was a significant predictor of AMD, the odds for AMD were growing with age, one-year growth was increasing odds for AMD by 8% (95% CI = 1.02; 1.15; p = 0.012). Femoral BMD as well as femur T-score were not significantly associated with occurrence of AMD in women (p = 0.352 in both cases), (Table 3).

Table 3. Univariate logistic regression models with age-related macular degeneration as an outcome variable in women and men.

Variable Women Men
Odds ratio 95% Confidence interval p Odds ratio 95% Confidence interval p
Total femoral BMD 0.22 0.01; 5.03 0.352 0.02 <0.01; 0.80 0.043
Total femur T-score 0.82 0.54; 1.23 0.352 0.58 0.34; 0.96 0.041
Age 1.08 1.02; 1.15 0.012 0.98 0.92; 1.04 0.502
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BMD, bone mineral density.

Two multivariable logistic regression models were created for women and men, both with AMD as the outcome variable: the predictors were age and crude femoral BMD in one (Table 4), and age and femur T-score in the other (Table 5). For men femoral BMD and femur T-score were both significant predictors, whereas age was not significant in either model (p = 0.409 for the model with BMD and p = 0.406 for the model with the T-score). The Nagelkerke pseudo-R2 for both multivariable models and the univariate models, including crude values of BMDs and T-scores, was 0.05, indicating that the inclusion of age in the multivariable models did not improve their goodness of fit. However, the Nagelkerke pseudo-R2 was low, implying that the occurrence of AMD in men was influenced by variables not included in the models. Based on the chi-square statistics, none of the multivariable models that included age were statistically significant (p = 0.074 for the model with T-score and p = 0.080 for the model with BMD). For women none of variables was significant in both models (p > 0.05 in all cases) indicating that both multivariate models for women were not significant.

Table 4. Multivariable logistic regression model with age-related macular degeneration as an outcome variable and age and femoral BMD as independent variables in women and men.

Variable Women Men
Odds ratio 95% Confidence interval p Odds ratio 95% Confidence interval p
Total femoral BMD 0.40 0.01; 9.35 0.576 0.02 <0.01; 0.70 0.037
Age 1.06 0.98; 1.13 0.0504 0.98 0.92; 1.03 0.409
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BMD, bone mineral density.

Table 5. Multivariable logistic regression model with age-related macular degeneration as an outcome variable and age and femur T-score as independent variables in women and men.

Variable Women Men
Odds ratio 95% Confidence interval p Odds ratio 95% Confidence interval p
Femur T-score 0.89 0.58; 1.33 0.576 0.57 0.33; 0.94 0.035
Age 1.06 0.95; 1.13 0.051 0.98 0.92; 1.03 0.406
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Discussion

Our study revealed an association between a decrease in femoral BMD and the occurrence of AMD in men older than 50 years. In contrast, we did not observe any differences in the densitometric parameters of women in relation to AMD prevalence. The results of our study provide grounds for actively screening for AMD among patients with osteopenia. Routine screening diagnostics in the form of the Amsler grid eye test should be considered in patients with low bone density.

Published data on the coincidence of osteoporosis and AMD are scarce. The first such study included only Caucasian women aged >75 years from the USA [5], in which women with a high hip BMD presented with concomitant AMD less often than those with a lower BMD. In that study, the average patient age was 80 years; therefore, the results may not be generalizable to younger women. The authors suggested an inverse association between BMD and AMD, which may be caused by the protective effect of estrogen against AMD. In the second study, conducted in a Korean population [6], a linear relationship was discovered between the osteoporosis status of the femoral neck and AMD in female participants, but showed no significant relationship between the co-occurrence of osteoporosis with either early or late AMD in men. The authors of that report suggested that the lack of an association among men might have been due to the low prevalence of osteoporosis and AMD in the male population. They also suggested that calcium and phosphate deposited in the bloodstream during bone transformation in osteoporosis may initiate drusen formation and contribute to the development of early AMD. Moreover, they discovered a strong correlation between early AMD and osteoporosis, whereas this correlation did not occur in late stages of AMD [16]. In our study only men had significant association between AMD and osteoporosis. This may result from the fact that, in the Korean study, the cutoff point used for the T-score was −2.5, whereas, in our study, we included patients with osteoporosis and osteopenia in the low bone density group (T-score <−1.0). Although they didn’t reveal a relation between osteoporosis and AMD in men, they demonstrated a significantly lower hip and femoral neck BMD for men with AMD than for men without AMD. In the study from the USA the median age of women was several years older than that in our study, which may explain the differences in results.

The pathogenesis of AMD is multifactorial, and the molecular mechanisms underlying its development are still not understood. Its pathogenesis involves environmental and genetic factors, disorders of the complement system, lipid abnormalities, angiogenic and inflammatory pathways, and the extracellular matrix [16, 17]. A growing body of evidence suggests that oxidative stress and impaired protein degradation and clearance pathways in retinal pigment epithelial (RPE) cells may lead to their functional impairment and damage. Autophagy plays a key role in eliminating cellular waste materials, such as aggregated proteins and dysfunctional cell organelles, from RPE cells. RPE cells cultured from donors with AMD are reportedly more sensitive to oxidative stress and impairment of autophagy than RPE cells from donors without AMD [18]. Autophagy is vital for the survival of cells under stress, especially RPE cells, given their metabolic activity and paucity of physiological functions. Impairment of autophagy leads to lipofuscin accumulation in RPE cells and deposition of lipoproteins, in the form of drusen, in the extracellular spaces [18, 19].

One possible reason for the coexistence of AMD with bone loss or decreased BMD is the impairment of autophagy observed in both conditions. Both AMD and senile osteoporosis are associated with decreased autophagic activity. Impaired autophagy plays a pivotal role in the onset and progression of osteoporosis [18]. Although the underlying mechanisms remain unclear, another common feature of osteoporosis and AMD is the p62 protein encoded by the SQSTM1 gene (p62/SQSTM1). Intracellular p62 is associated with autophagy, bone remodeling, bone marrow integrity, cancer progression, and the maintenance of systemic homeostasis. P62/SQSTM1 acts as an effective suppressor of inflammation by reducing oxidative stress and proinflammatory signals. It is involved in the elimination of proteins from RPE cells via autophagy. Owing to impairment of autophagy, an accumulation of p62/SQSTM1-labeled waste material has been observed in patients with AMD, which leads to the activation of inflammasome signaling in conjunction with IL-1β secretion [20]. P62/SQSTM1 also contributes to an increase in the secretion of IL-8, the most potent chemotactic factor, via IL-1β stimulation in RPE cells. Patients with AMD have elevated p62/SQSTM1 levels in the retina. While the foveomacular area in such patients reportedly exhibit higher p62/SQSTM1 staining than the perimacular and peripheral areas, no regional differences were observed in persons without AMD [21]. Oxidative stress reportedly results in the increase of p62/SQSTM1 mRNA and protein levels, which activates autophagy and constitutes a protective mechanism against oxidative stress-induced cell death. In turn, the downregulation of p62/SQSTM1 reportedly decreases the sensitivity of RPE cells to oxidative stress, as it reduces autophagic degradation [22].

P62/SQSTM1 may also be involved in bone diseases, as a high frequency of SQSTM1 gene mutations were reportedly observed in patients with Paget’s disease [23, 24]. Impaired activity of the p62/SQSTM1 protein upregulates osteoclast functioning [25]. Moreover, a DNA plasmid encoding p62/SQSTM1 (p62 DNA) exhibited strong anti-osteoporotic activity in animal models [26]. Furthermore, the retinoprotective effect of p62 DNA in AMD warrants mention [27]. This plasmid decreases the severity of retinopathy, slows the progression of destructive alterations within RPE cells, and inhibits microglia/macrophage migration to the outer retina in senescence-accelerated OXYS rat models. Additionally, sharp downregulation of master proinflammatory cytokines and upregulation of endogenous p62 protein have been observed after administration of p62 DNA [26].

The prevalence of AMD in our study was 10.8%. Although the global prevalence of AMD is estimated at 8.7%, a meta-analysis has suggested that its prevalence is higher in European countries (12.3%–18.3%) [28].

Our study is not without limitations. First, it was limited by its observational nature, relatively small number of patients, and lack of detailed data on AMD status. Second, we did not analyze the effects of other factors involved in the coincident development of AMD and osteoporosis, e.g., smoking, alcohol consumption, and dietary calcium intake. We did not have access to fragility fracture data or a fall registry for the study population. Furthermore, the health data of the study participants were obtained at a single timepoint. As certain parameters, such as BMD, body mass index, calcium intake, and serum vitamin D level, change over time, this factor should be considered a potential confounder. Third, the group of women with AMD was older than that without AMD. As the risks of AMD and osteoporosis both increase with age, this factor may explain the lack of a significant relationship between AMD and low BMD in women in this study. Differences in BMD between men with and those without AMD were detected only in the femoral region and not in the lumbar spine. We could not further explore this association, as dual-energy X-ray absorptiometry does not provide insights into bone quality and structure. Despite these limitations, this is the first study in which the link between a low hip BMD and AMD was demonstrated in a Polish population.

In conclusion, further longitudinal research with a larger group of participants is required to confirm the link and potential pathogenic association between AMD and a low BMD in the Polish population.

Data Availability

All relevant data are available on Harvard Dataverse: https://dataverse.harvard.edu/dataset.xhtml?persistentId=doi:10.7910/DVN/TZVNHA.

Funding Statement

This study was supported by funds of the Ministry of Science and Higher education (Poland) within the project "The Excellence Initiative - Research University" (proteomic research), and from statutory funds of Medical University of Bialystok.

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Decision Letter 0

Tatsuya Inoue

24 Jul 2023

PONE-D-23-18141

The prevalence of age-related macular degeneration and osteoporosis in the older Polish population: is there a link?

PLOS ONE

Dear Dr. Konopińska,

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Reviewer #1: Partly

Reviewer #2: Yes

**********

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Reviewer #1: I Don't Know

Reviewer #2: Yes

**********

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Reviewer #2: No

**********

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Reviewer #2: Yes

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Reviewer #1: Please see the attachment-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

Reviewer #2: This is generally a well planned work. However, there are a few of observations which when addressed will greatly improved the quality of this research presentation.

Line 36-56 - kindly breakdown your abstract into ; Background, Objectives, Methods, Results and conclusion.

Line 71-72 - Did the cohort study from Australia find the predisposing factors for in ARM? Again, what if the poor vision which commonly predisposes to fall which can cause fractures.

Line 80-82 - please apart from Geography and ethnicity, is there any contributory factor to osteoporosis in the countries mentioned?

Line 84-85 - Please did your literature source state why prevalence of osteoporosis is underestimated in men?

Line 87-88 - why not say 'Estimates from developed countries suggest ...'

Line 91-93 - This point is the reason for the comment on line 71-72

Tables 4,5 & 6 has various variables of interest among men alone.

I suggest analysis for same variable among women should be done and reported. For each variable, results should be merged and clearly labeled 'men and women'

Table 2 - 6 it appears authors reported analysis of different variables for men and women.

Suggestion, authors should analyse the same variable for men and women and show results on same table.

Example

Table 2 shows relationship between T-score (cut off, --1.0) for femoral BMD and occurrence of AMD in men.

It is actually possible to report same in women and present in the same table.

The table can be labeled relationship between T-Score (cut off, -1.0) for femoral BMD and occurrence of AMD in men and women.

I suspect table 2 & 3 are the same for men and women. If they are the same, it's important to note that the labels are different. This ought not be so.

If they are the same, they should be merged.

There should be results with the same headings for tables 4, 5 & 6 among males and females. Also the tables should be merged with clear labels for men and women.

Suggested Analysis - Authors should consider running a correlation analysis for BMD/osteoporosis and occurrence of ARMD in both sexes.

Like I said before, if these are implemented the quality of your presentation will further improve.

**********

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Reviewer #2: No

**********

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Attachment

Submitted filename: Review_1st.docx

Click here for additional data file. (21.7KB, docx)
PLoS One. 2023 Oct 19;18(10):e0293143. doi: 10.1371/journal.pone.0293143.r002

Author response to Decision Letter 0

5 Sep 2023

23/AUG/2023

Emily Chenette

Editor-in-Chief

PLoS One

Dear Editor:

I wish to re-submit the manuscript titled “The prevalence of age-related macular degeneration and osteoporosis in the older Polish population: is there a link?” The manuscript ID is PONE-D-23-18141.

We thank you and the reviewers for your thoughtful suggestions and insights. The manuscript has benefited from these insightful suggestions. I look forward to working with you and the reviewers to move this manuscript closer to publication in PLoS One.

The manuscript has been rechecked and the necessary changes have been made in accordance with the reviewers’ suggestions. The responses to all comments have been prepared and attached herewith. All of the relevant changes in the revised manuscript have been indicated with red font.

We would like to add information regarding to the founding as follows: “This study was supported by funds of the Ministry of Science and Higher education (Poland) within the project "The Excellence Initiative - Research University" (proteomic research), and from statutory funds of Medical University of Bialystok.”

We have also publicated the data for our study in repositorium on the following link:

https://dataverse.harvard.edu/dataset.xhtml?persistentId=doi:10.7910/DVN/TZVNHA

Thank you for your consideration. I look forward to hearing from you.

Sincerely,

Joanna Konopińska

Medical University of Białystok

Kilinskiego 1 STR 15-201

Poland

joannakonopinska@o2.pl

Phone:

+48857468372

E-mail: joannakonopinska@o2.pl

Responses to the Reviewers’ comments

Dear Reviewers:

We would like to thank you for the detailed review of our manuscript and your valuable remarks. The manuscript has been rechecked and the necessary changes have been made in accordance with your suggestions. All changes were highlighted in red font. The responses to all comments are given below. We hope that you will find our explanations and manuscript modifications satisfactory for publication in PLoS One.

Reviewer 1

Comments to the Authors.

This handles an interesting theme regarding the association between the osteoporosis and AMD. There are several comments and questions.

Response:

Thank you for this comment, we appreciate it!

Major points:

1. Comment: How relevant the findings are for practitioners and patients? That is, what impact will the findings have on the current clinical practice? The authors should discuss about it.

Response: Thank you for pointing out this issue, you are right as we did not sufficiently emphasize the importance of the study results for practisioners. We have added a relevant paragraph about it in the Discussion, as follows: “The results of our study provide grounds for actively screening for AMD among patients with osteopenia. Routine screening diagnostics in the form of the Amsler eye grid test should be considered in patients with low bone density.” (lines 250-253)

2. Comment: Line 337: “As the risks of AMD and osteoporosis both increase with age, this factor may explain the lack of a significant relationship between AMD and low BMD in women in this study.”

This explains why there was no significant association between AMD and osteoporosis for women. What do the authors think about only men having significant association? The findings seem to be opposite to the previous reports from the USA and Korea the authors cited.

Response: : We agree. This is an important point. We have added the clarification as follows: “This may result from the fact that, in the Korean study, the cutoff point used for the T-score was −2.5, whereas, in our study, we included patients with osteoporosis and osteopenia in the low bone density group (T-score <−1.0). Although they didn't reveal a relation between osteoporosis and AMD in men, they demonstrated a significantly lower hip and femoral neck BMD for men with AMD than for men without AMD. In the study from the USA the median age of women was several years older than that in our study, which may explain the differences in results”. (lines 249-256)

3. Comment: Were there any data on cataract, glaucoma and diabetic retinopathy? The association between these disorders and osteoporosis would be valuable, which would clarify if the current findings are a disease-specific association, that is, if only AMD is associated with osteoporosis.

Response:

Thank you for your comment. Unfortunately, we did not collect any data regarding cataracts, glaucoma, or diabetic retinopathy in this study. Little data to this effect have been reported. Although cataracts and AMD are different conditions, they can coexist in the same individual owing to the shared risk factor of age. Interestingly, glaucoma and AMD share some risk factors. Both glaucoma and AMD are more common in older individuals. Moreover, family history and genetics play a role in the development of these diseases. Some studies suggest that cardiovascular factors, such as high blood pressure and atherosclerosis, may contribute to the development of these pathologies. In addition, smoking is a significant risk factor for AMD and has also been associated with an increased risk of glaucoma. Having diabetes can increase the risk of developing other eye conditions and complications, including cataracts, glaucoma, and possibly AMD. However, the development of AMD is not solely due to diabetic retinopathy. Despite these shared risk factors, the underlying mechanisms and pathophysiology of glaucoma, cataracts, and AMD have not yet been clearly identified.

Huang HK, Lin SM, Loh CH, Wang JH, Liang CC. Association Between Cataract and Risks of Osteoporosis and Fracture: A Nationwide Cohort Study. J Am Geriatr Soc. 2019 Feb;67(2):254-260. doi: 10.1111/jgs.15626. Epub 2018 Oct 3. PMID: 30281143.

Roberts SB, Silver RE, Das SK, Fielding RA, Gilhooly CH, Jacques PF, Kelly JM, Mason JB, McKeown NM, Reardon MA, Rowan S, Saltzman E, Shukitt-Hale B, Smith CE, Taylor AA, Wu D, Zhang FF, Panetta K, Booth S. Healthy Aging-Nutrition Matters: Start Early and Screen Often. Adv Nutr. 2021 Jul 30;12(4):1438-1448. doi: 10.1093/advances/nmab032. Erratum in: Adv Nutr. 2021 Jul 30;12(4):1597-1598. PMID: 33838032; PMCID: PMC8994693.

Minor point:

1. Comment: Introduction is too long. The authors might want to reduce it below 300 words. General explanation of the disease would be unnecessary like “Clinically, osteoporosis manifests as a higher risk of skeletal fragility and apparent major osteoporotic fractures that frequently lead to disability, mobility restriction, decreased quality of life, and premature mortality.”

Response:

Thank you for this comment. The introduction has been shortened, accordingly.

2. Comment: Line 223-233: “the predictors were age and crude femoral BMD in one (Table 5), and age and femur T-score in the other (Table 6).” This should be removed to the Method section.

Response:

Thank you for this suggestion. The paragraph has been moved to the Methods section.

3. Comment: The authors should describe why the threshold (T-score = -0.1) was selected (e.g. it’s clinically important, often used, etc.).

Response:

We are terribly sorry for this typographical error. The T-score has been set to −1.0. The mistake has been corrected throughout the manuscript.

4. Comment: What is the difference between the “Total femur T-score” in the bottom row of Table 1 and “T-score≥-0.1” or “T-score<-0.1” in Table 2? Is something just categorized “Total femur T-score” into used in Table 2? Why did the authors take the trouble to do so? This is related to the comment 3.

Response:

We apologize for being imprecise. “T-score” in Table 2 has been corrected to “Total femur T-score.”

5. Comment: I couldn’t understand the part of Nagelkerke pseudo-R2. The authors should explain how to interpret this statistic value for readers to be able to understand easily in the Methods section (not in the Results section).

Response:

For clarification purposes we have added the explanation as follows’ and we have moved this part to the Method section

6. Comment: I think the following paragraph is redundant and not necessary (lines 265-272): “The first manifestation of AMD is damage to the retinal pigment epithelium (RPE), a monolayer of cuboidal, pigmented epithelial cells located between the neurosensory retina and the choroid. It has a plethora of functions, including delivering blood-derived nutrients to photoreceptors; transporting ions, water, and metabolites from the subretinal space to the blood; absorbing light; phagocytizing photoreceptor outer segments; supporting recycling of all‐ trans retinal back to 11‐ cis retinal; secreting neurotrophic factors; and scavenging damaged reactive oxygen species [19]. Thus, functional abnormalities in the RPE lead to impaired function of the entire neural retina.”

Response:

Thank you for this significant comment. We agree and removed that paragraph from the revised manuscript.

7. Comment: I think the following paragraph is so long and should be made short (lines 273-294): “The pathogenesis of AMD is multifactorial, and the molecular mechanisms underlying its development are still not understood. Its pathogenesis involves environmental and genetic factors, disorders of the complement system, lipid abnormalities, angiogenic and inflammatory pathways, and the extracellular matrix [19,20]. A growing body of evidence suggests that oxidative stress and impaired protein degradation and clearance pathways in RPE cells may lead to their functional impairment and damage. Autophagy plays a key role in eliminating cellular waste materials, such as aggregated proteins and dysfunctional cell organelles, from RPE cells. RPE cells cultured from donors with AMD are reportedly more sensitive to oxidative stress and impairment of autophagy than RPE cells from donors without AMD [21]. Autophagy is vital for the survival of cells under stress, especially RPE cells, given their metabolic activity and paucity of physiological functions. Impairment of autophagy leads to lipofuscin accumulation in RPE cells and deposition of lipoproteins, in the form of drusen, in the extracellular spaces. Drusen formation is the first manifestation of one of the two forms of AMD, namely, dry AMD (dAMD). dAMD is also characterized by RPE dysfunction and photoreceptor loss. In approximately 10%–15% of cases, dAMD progresses to wet AMD (wAMD), characterized by choroidal neovascularization with intra- and subretinal shunting, hemorrhages, and RPE detachment. wAMD can be treated with intravitreal injections of antiVEGF agents. Although this form of AMD accounts for only 10%–15% of all AMD cases, it is the leading cause of substantial eyesight deterioration and the principal source of expenditures associated with treatment for AMD [21,22]. A conservative estimate of the cost of wAMD treatment in the USA was demonstrated to generate a cost of $1.1 billion for the entire population in year 1 and $5.1 billion in year 3 [22].”

The next paragraph refers to “autophagy”, which is only the element needed in this paragraph (lines 273-294).

Response: Thank you for the suggestion. We agree and shortened that paragraph, accordingly.

8. Comment: Line 342: “Nonetheless, even considering that the vertebral BMD in these individuals remained unaffected, a lower femoral BMD may increase the risk of osteoporosis and subsequent hip fractures in men”

I couldn’t understand this sentence. I thought the authors investigated the association between AMD and osteoporosis (T-score), not hip fractures. Did the authors look into hip fractures?

Response:

We apologize for the confusion. We indeed did not investigate hip fractures. We have removed this sentence.

Reviewer 2

1. Comment: This is generally a well-planned work. However, there are a few of observations which when addressed will greatly improve the quality of this research presentation.

Response:

Thank you very much for this comment. We appreciate it.

2. Comment: Line 36-56 - kindly breakdown your abstract into ; Background, Objectives, Methods, Results and conclusion.

Response:

Thank you for this comment. The abstract has been structured accordingly

3. Comment: Line 71-72 - Did the cohort study from Australia find the predisposing factors for in ARM? Again, what if the poor vision which commonly predisposes to fall which can cause fractures.

Response: Taking into account the higher risk of falls in patients with poor vision, we want to emphasize that those falls in the AMD group resulted in fractures characteristic of osteoporosis. The Australian study showed that, apart from ARM, cataracts and corneal diseases were associated with a high risk of spinal and humero-radio-ulnar fractures.

4. Comment: Line 80-82 - please apart from Geography and ethnicity, is there any contributory factor to osteoporosis in the countries mentioned?

Response:

Osteoporosis is a multifactorial disease, and its prevalence and risk factors can vary significantly between different countries and populations. While some factors may be universal, others may be more prevalent in specific regions owing to cultural, environmental, or genetic differences. First, ethnicity and genetic variations can influence bone mineral density and fracture risk, leading to differences in osteoporosis prevalence across populations. Moreover, dietary patterns can differ significantly between countries, and nutrition plays a crucial role in bone health. Countries with diets rich in calcium and vitamin D tend to have better bone health. In addition, levels of physical activity and exercise habits can vary by culture and lifestyle. Regular weight-bearing exercises are proven to be beneficial for bone health, and countries with more active populations may have lower osteoporosis rates. Interestingly, certain hormonal factors, such as early menopause or hormonal disorders, can increase the osteoporosis risk. These factors can be influenced by genetics and lifestyle and may differ between populations. Next, countries with higher rates of alcohol and tobacco consumption may have an increased prevalence of osteoporosis, as both these substances can negatively impact bone health. Moreover, populations with different obesity rates may experience varying impacts on bone health. Both very-low and very-high BMI levels can be associated with an increased risk of osteoporosis. Access to healthcare and awareness about osteoporosis and its prevention can affect its prevalence. Countries with better healthcare systems and osteoporosis education programs may have lower rates of the disease. Importantly, these factors can interact and have complex relationships with each other. The prevalence of osteoporosis in different countries can also be influenced by the aging population and changes in lifestyle and dietary habits over time.

Chotiyarnwong P, McCloskey EV, Harvey NC, Lorentzon M, Prieto-Alhambra D, Abrahamsen B, Adachi JD, Borgström F, Bruyere O, Carey JJ, Clark P, Cooper C, Curtis EM, Dennison E, Diaz-Curiel M, Dimai HP, Grigorie D, Hiligsmann M, Khashayar P, Lewiecki EM, Lips P, Lorenc RS, Ortolani S, Papaioannou A, Silverman S, Sosa M, Szulc P, Ward KA, Yoshimura N, Kanis JA. Is it time to consider population screening for fracture risk in postmenopausal women? A position paper from the International Osteoporosis Foundation Epidemiology/Quality of Life Working Group. Arch Osteoporos. 2022 Jun 28;17(1):87. doi: 10.1007/s11657-022-01117-6. PMID: 35763133; PMCID: PMC9239944.

5. Comment: Line 84-85 - Please did your literature source state why prevalence of osteoporosis is underestimated in men?

Response:

Yes, the literature states that: “Osteoporosis is commonly recognized as a disease in women following menopause, which is often overlooked in men mainly because there is no aging process in men analogous to menopause with a resultant rapid loss of bone mass. In men, secondary osteoporosis is more frequent; common causes include glucocorticoid excess, hypogonadism, and alcohol abuse.”A relevant high quality references have been now included in the revised version.

Vilaca T, Eastell R, Schini M. Osteoporosis in men. Lancet Diabetes Endocrinol. 2022 Apr;10(4):273-283. doi: 10.1016/S2213-8587(22)00012-2. Epub 2022 Mar 2. PMID: 35247315.

6. Comment: Line 87-88 - why not say 'Estimates from developed countries suggest ...'

Response:

The introduction was shortened to within 300 words, according to a suggestion of Reviewer 1. The related sentence now states: “Every third woman and every fifth man over the age of 50 years in developed countries are estimated to experience a bone fracture during their remaining lifetime” We hope that this is suitable.

7. Comment:

Line 91-93 - This point is the reason for the comment on line 71-72

Tables 4,5 & 6 has various variables of interest among men alone.

I suggest analysis for same variable among women should be done and reported. For each variable, results should be merged and clearly labeled 'men and women'

Response:

Data for women were added to tables 4,5,6 and labels were corrected accordingly.

8. Comment: Table 2 - 6 it appears authors reported analysis of different variables for men and women. Suggestion, authors should analyse the same variable for men and women and show results on same table.

Example

Table 2 shows relationship between T-score (cut off, --1.0) for femoral BMD and occurrence of AMD in men.

It is actually possible to report same in women and present in the same table.

The table can be labeled relationship between T-Score (cut off, -1.0) for femoral BMD and occurrence of AMD in men and women.

9. Comment: I suspect table 2 & 3 are the same for men and women. If they are the same, it's important to note that the labels are different. This ought not be so.

If they are the same, they should be merged.

Response:

This is correct. Tables 2 and 3 are the same with data for men in table 2 and data for women in table 3. Both tables were merged into one table (2) and original table 3 was removed.

10. Comment: There should be results with the same headings for tables 4, 5 & 6 among males and females. Also, the tables should be merged with clear labels for men and women.

Response:

Re. your comments and suggestions specified above. We agree, and we have made appropriate revisions accordingly. The data have been presented for both women and men when possible. And therefore, some data in the tables have been merged and modified.

11. Comment: Suggested Analysis - Authors should consider running a correlation analysis for BMD/osteoporosis and occurrence of ARMD in both sexes.

Response: Thank you for this suggestion. We are aware that there is, in fact, a strong connection between BMD (crude values, Z-scores and T-scores) and osteoporosis, given that the diagnoses of ‘osteopenia’ and ‘osteoporosis’ are based just on BMD T-score values. This analysis is included in tables 2 ad 3 of initial manuscript (table 2 of current version).

Like I said before, if these are implemented the quality of your presentation will further improve.

Attachment

Submitted filename: Responses_plos_one.docx

Click here for additional data file. (31KB, docx)

Decision Letter 1

Tatsuya Inoue

6 Oct 2023

The prevalence of age-related macular degeneration and osteoporosis in the older Polish population: is there a link?

PONE-D-23-18141R1

Dear Dr. Konopińska,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Tatsuya Inoue

Academic Editor

PLOS ONE

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Acceptance letter

Tatsuya Inoue

11 Oct 2023

PONE-D-23-18141R1

The prevalence of age-related macular degeneration and osteoporosis in the older Polish population: is there a link?

Dear Dr. Konopińska:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

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Kind regards,

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on behalf of

Dr. Tatsuya Inoue

Academic Editor

PLOS ONE

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    Attachment

    Submitted filename: Review_1st.docx

    Click here for additional data file. (21.7KB, docx)
    Attachment

    Submitted filename: Responses_plos_one.docx

    Click here for additional data file. (31KB, docx)

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    All relevant data are available on Harvard Dataverse: https://dataverse.harvard.edu/dataset.xhtml?persistentId=doi:10.7910/DVN/TZVNHA.

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