>> The primary endpoint of the study was the diagnosis of depression (ICD-10: F32, F33), which was recorded in the database for the first time between the index date and the end of the follow-up period. In addition, the proportion of women with osteoporosis and depression with and without a fracture diagnosis was estimated.

Differences in patient characteristics (osteoporosis patients vs. controls) were determined using Wilcoxon paired-samples tests or McNemar's tests. Depression-free survival analyses were performed using Kaplan-Meier curves and log-rank tests. Fracture diagnosis (ICD-10: M80, S02, S12, S22, S32, S42, S52, S62, S72, S82, S92, T02, T08, T10, T12) at baseline was used as a covariate. Other chronic conditions potentially associated with the risk of a depression diagnosis were identified based on primary care diagnoses and included the following: diabetes mellitus (E10-14), hypertension (I10), dementia (F01, F03, G30), stroke (F63, F64, G45), coronary heart disease (I24, I25), myocardial infarction (I21-23), heart failure (I50), and cancer (C). P values <0.05 were considered statistically significant. Analyses were conducted using SAS version 9.3.

Patient characteristics
Patient characteristics are listed in Table 1. A total of 70,966 individuals were included in the osteoporosis and control groups. The mean age was 71.8 years (SD 10.6 years), and 7.6% of the osteoporosis patients and controls were privately insured. The proportion of patients with a previous diagnosis of depression (>12 months before the index date) was 20.7% in both groups. Hypertension, coronary heart disease, stroke, cancer, dementia, and heart failure were slightly more common in the osteoporosis group than in the control group, as the diagnosis of diabetes was slightly more common in the control group.

Proportion of patients diagnosed with depression
The Kaplan-Meier curves for the time to depression diagnosis in the osteoporosis and control groups are shown in Figure 1. Overall, 11.7% of the osteoporosis patients and 8.2% of the controls developed depression within the first year of follow-up (p<0.001). A depression diagnosis was made within the five-year follow-up period in 33.0% of the patients in the osteoporosis group and 22.7% of the patients in the control group (p<0.001).

Risk factors for the diagnosis of depression
The results of the multivariate Cox regression model for depression diagnosis in osteoporosis patients and controls, adjusted for fractures, concomitant diagnoses of diabetes, hypertension, coronary heart disease, myocardial infarction, stroke, heart failure, cancer, and dementia, are shown in Table 2.
Osteoporosis was a major risk factor for the development of depression (HR: 1.51, p<0.0001). Logically, previous episodes of depression also increased the risk of a new diagnosis of depression (HR: 2.67, p<0.0001). Furthermore, dementia (HR: 1.18), cancer (HR: 1.13), heart failure (HR: 1.13), coronary heart disease (HR: 1.08), and diabetes (HR: 1.08) were associated with a higher risk of depression (p<0.001). In contrast, membership in private health insurance (HR=0.79) was associated with a lower risk of depression. Fractures had no significant effect on the risk of depression (Table 2).

The current study shows that osteoporosis is a major risk factor for the development of depression. There are several possible explanations for this observation. Osteoporosis may require patients to change their daily habits. These changes can increase the risk of depression. Furthermore, these changes serve to prevent falls, resulting in patients no longer being able to participate in certain activities they once performed regularly. Because of their weakened bones and existing or worsening pain, individual routines become more difficult to perform, and ultimately, patients may lose their independence, become irritable, and experience an overwhelming feeling that they are losing valuable personal attributes [12]. Surprisingly, fractures had no significant effect on the risk of depression.
When assessing depression, the interrelationship with other physical illnesses must be considered. Several surveys postulate that comorbid mental illnesses should also be considered, especially in multimorbid patients [13,14]. Furthermore, the risk of comorbid depression increases continuously with the number of comorbidities [13,14]. As already mentioned in this current study, illnesses such as dementia, cancer, heart failure, coronary artery disease, and diabetes were associated with a higher risk of depression [15-21].
Although women have an increased risk of developing depression, female gender does not appear to be a significant risk factor for recurrence [22].
Our results regarding the development of depression also show that previous episodes of depression increased the risk of a new diagnosis of depression. However, it is generally known that recurrent episodes usually occur within five years of the first depressive episode [23]. Taking this relationship into account, recurrence rates are higher than incidence rates [23].
Based on our results, we found that membership in private health insurance was associated with a lower risk of depression. When analyzing this result, it is important to consider that the German statutory health insurance system publishes a largely uniform list of benefits for its members. In contrast, private health insurance companies have a much broader range of benefits and minimal restrictions. As a result, privately insured patients generally benefit greatly from additional benefits [24]. Given our observation, it is not unlikely that it could have a protective effect on the development of other disorders, especially depression.
The current study on the diagnosis of depression in osteoporosis patients is based on primary care documentation. General practitioners are often confronted with complex chronic diseases and risk constellations in their daily medical practice. The aspect of comorbidity diagnoses is becoming increasingly important in healthcare and research, and within the somatomedical field, it can be observed that physicians primarily focus on the primary diagnosis. This could explain the small amount of meaningful data regarding significant co- and multimorbidities in primary care [14]. To improve the medical care of osteoporosis patients, the development of comorbidities must be considered based on the primary diagnosis. The German Association of Occupational Therapy (DVO) guidelines already recommend that physicians examine patients for psychotropic medications as an influencing factor in falls [2]. Furthermore, mental disorders can exacerbate somatic illnesses with increasingly severe pain syndromes [25].
In general, retrospective primary care database analyses are limited by the validity and completeness of the data on which they are based. The current study is subject to several limitations that should be mentioned here. The most significant limitation relates to the documentation of diagnoses conducted by primary care physicians. However, this documentation also includes diagnoses from psychiatrists and other specialists. Primary care physicians are notified of the psychiatrists' diagnoses by letter or email. These diagnoses are then included in the documentation. However, the database does not contain any information on how the depression diagnoses, including those made by psychiatrists, were made.
Several factors potentially affecting fracture risk were also missing (e.g., reduced bone density and muscle mass, nutritional problems, and physical inactivity). Data on socioeconomic status (such as education and income) and lifestyle risk factors (such as smoking, alcohol consumption, and physical activity) were also unavailable.
The strengths of the study lie in the use of the large nationwide database and the objective assessment of diagnoses and prescriptions.
In summary, the increased likelihood of depression in osteoporosis patients has been identified. The goal is to improve patient care in line with the national health mandate for the prevention and treatment of depression [26]. Therefore, primary care physicians, as the first point of contact, require support in implementing comprehensive and proactive measures of acute patient-centered healthcare [27, 28].