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. 2020 Sep 2;9(9):2839. doi: 10.3390/jcm9092839

Metformin Attenuates Osteoporosis in Diabetic Patients with Carcinoma in Situ: A Nationwide, Retrospective, Matched-Cohort Study in Taiwan

Chieh-Hua Lu 1,2, Chi-Hsiang Chung 3,4, Feng-Chih Kuo 1, Kuan-Chan Chen 1, Chia-Hao Chang 1, Chih-Chun Kuo 1, Chien-Hsing Lee 1, Sheng-Chiang Su 1, Jhih-Syuan Liu 1, Fu-Huang Lin 3, Chang-Huei Tsao 5,6, Po-Shiuan Hsieh 2,7,8, Yi-Jen Hung 1, Chang-Hsun Hsieh 1,*, Wu-Chien Chien 2,3,*
PMCID: PMC7565460  PMID: 32887312

Abstract

Patients with diabetes are at increased risk of cancer development and osteoporosis. Metformin is an effective agent for diabetes management. Epidemiological studies have identified an association between metformin use and cancer prevention. This article outlines the potential for metformin to attenuate the rate of osteoporosis in diabetic patients with carcinoma in situ (CIS). From the National Health Insurance Research Database of Taiwan, 7827 patients with diabetes with CIS who were receiving metformin therapy were selected, along with 23,481 patients as 1:3 sex-, age- and index year-matched controls, who were not receiving metformin therapy. A Cox proportional hazard analysis was used to compare the rate of osteoporosis during an average of 15-year follow-up. Of the subjects who were enrolled, 801 (2.56%) had osteoporosis, including 168 from the metformin group (2.15%) and 633 from the without metformin group (2.70%). The metformin group presented a lower rate of osteoporosis at the end of follow-up (p = 0.009). The Cox proportional hazard regression analysis revealed a lower rate of osteoporosis for the metformin group (adjusted hazard ratio of 0.820; 95% confidence interval = 0.691–0.972, p = 0.022). Diabetic patients with CIS under metformin therapy presented lower osteoporosis rate than those who were not receiving metformin therapy.

Keywords: osteoporosis, diabetes, metformin, carcinoma in situ, National Health Insurance Research Database

1. Introduction

Patients with diabetes are at increased risk of cancer development [1] and associated with an increased risk of fragility fractures compared to the general population [2]. Type 2 diabetes mellitus (T2DM) and cancer share many risk factors, such as age, obesity, diet and physical inactivity [3]. The possible mechanisms for a direct link between T2DM and cancer include hyperinsulinemia [4], hyperglycemia [5] and inflammation [6,7].

Diabetes and cancer are clinical risk factors used for fragility fracture probability assessments across the general population [8,9]. Osteoporosis is a skeletal disorder that is characterized by low bone mass and compromised bone strength [10]. T2DM may affect bone metabolism and leads to osteoporosis [11] and cancer may affect both, through the direct effects of cancer cells on the skeleton and the deleterious effects of cancer-specific therapies on bone cells [9].

Metformin is an effective agent for T2DM management [12]. Furthermore, epidemiological studies have identified an association between metformin use and cancer prevention [13]. Fractures are a clinically important consequence of osteoporosis and result not only in disabilities, but also in excess mortality; however, the pathogenic mechanisms that underlie the relationship between osteoporosis, diabetes and cancer remain incompletely understood. The aim of this study was to determine the potential for metformin to attenuate the rate of osteoporosis in diabetic patients with carcinoma in situ using data from the Taiwan National Health Insurance Research Database (NHIRD), which is a nationwide health insurance database.

2. Materials and Methods

2.1. Data Sources

Our study used data from the NHIRD to investigate whether metformin therapy in diabetic patients with carcinoma in situ could lower osteoporosis rates, compared to a group of individuals who were not receiving metformin, over a 15-year period, from the outpatient Longitudinal Health Insurance Database (LHID) in Taiwan (2000–2015). The National Health Insurance (NHI) Program was launched in Taiwan in 1995, and as of June 2009, it included contracts with 97% of the medical providers in Taiwan, with approximately 23 million beneficiaries or more than 99% of the entire Taiwan population [14]. The NHIRD uses International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to record diagnoses [15]. All diagnoses of T2DM, carcinoma in situ, and osteoporosis were made by a board-certified medical specialist. The Bureau of NHI randomly reviews the records of 1 in 100 ambulatory care visits and 1 in 20 in-patient claims, to verify the accuracy of the diagnoses [16]. Several studies have demonstrated the accuracy and validity of the diagnoses in the NHIRD [17,18].

2.2. Study Design and Sampled Participants

Our study was a retrospective matched-cohort design. Patients with diagnosed T2DM, carcinoma in situ, and osteoporosis were selected from 1 January 2000 to 31 December 2015, according to ICD-9-CM 230.XX-234.XX (carcinoma in situ), ICD-9-CM 733.XX (osteoporosis) and ICD-9-CM 250.XX (T2DM). Furthermore, each enrolled patient was required to have made at least three outpatient visits within the study period, according to these ICD-9-CM codes whether or not they were receiving metformin therapy. Patients with osteoporosis diagnoses before 2000 and those less than 18 years of age were excluded. Furthermore, patients with diabetes who received thiazolidinedione or canagliflozin therapy were also excluded.

The covariates included Charlson comorbidity index (CCI), T2DM, sex, age, geographical area of residence (north, center, south and east of Taiwan) and urbanization level of residence (level 1 to 4). The urbanization level of residence was defined according to the population and various indicators of the level of development. Level 1 was defined as a population >1,250,000 and a specific economic, cultural, metropolitan and political development designation. Level 2 was defined as a population between 500,000 and 1,249,999 that played an important role in the political system, culture and economy. Urbanization levels 3 and 4 were defined as either populations between 149,999 and 499,999 or <149,999, respectively [19].

2.3. Outcome Measures

All of the study participants were followed from the index date until the onset of osteoporosis, from the NHI program, before the end of 2015.

2.4. Statistical Analysis

All statistical analyses were performed using SPSS software version 22 for Windows (SPSS, Inc., Chicago, IL, USA). chi-squared and t-tests were used to evaluate the distributions of categorical and continuous variables, respectively. A regression analysis of multivariate Cox proportional hazards was used to determine the risk of osteoporosis under metformin therapy in patients with diabetes and carcinoma in situ. The statistical analyses were presented as hazard ratio (HR) with ninety-five percent confidence interval (CI). The difference in the risk of osteoporosis for patients with diabetes and carcinoma in situ, with or without metformin therapy, was estimated using the log rank test—Kaplan-Meier method. A two-tailed test p-value less than 0.05 was considered to indicate statistical significance.

2.5. Ethics

Our study was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki). The Institutional Review Board of Tri-Service General Hospital (TSGH) approved our study and waived the need for individual written informed consent (TSGH IRB No.2-105-05-082).

3. Results

Of the 61,307 enrolled patients, 11,151 were excluded and 50,156 patients with cancer and T2DM were included. Furthermore, 9030 of the included patients were receiving metformin therapy, of which 1203 patients had used metformin for less than 90 days and were excluded and 7827 were enrolled (case group). For the control group, we enrolled 41,126 individuals who were not receiving metformin therapy to represent the 1:3 sex-, age- and index year-matched control group and excluded 17,645 patients used metformin less than 90 days, for a final count of 23,481 subjects (control group) (Figure 1). Overall, the diabetic patients with carcinoma in situ under metformin therapy presented a lower rate of osteoporosis than those who were not receiving metformin (adjusted HR 0.820 (95% CI = 0.691–0.972, p = 0.022). Figure 2 shows the Kaplan-Meier analysis for the cumulative risk of osteoporosis in patient and control groups and the difference is statistically significant (log rank, p = 0.017).

Figure 1.

Figure 1

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Flowchart of study patient selection from the National Health Insurance Research Database in Taiwan. DM—Diabetes mellitus: ICD-9-CM 250; Carcinoma in situ: ICD-9-CM 230–234; Osteoporosis: ICD-9-CM 733.0; Metformin: ≥90 days.

Figure 2.

Figure 2

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Kaplan-Meier analysis of cumulative risk of osteoporosis among patients with diabetes mellitus with carcinoma in situ aged 18 and over, stratified by metformin use and analyzed using a log-rank test.

The baseline sex, age, comorbidities, location, urbanization, level of care and income of the study subjects and controls is presented in Table 1. Of the 31,308 adult diabetic patients with carcinoma in situ, 13,284 (42.43%) were male, 12,928 (41.29%) were ≥60 year of age and the mean age was 55.95 ± 14.28 years (Table 1). There were no significant differences between the metformin and control groups in age distribution, sex, comorbidities and covariates, after propensity-score matching.

Table 1.

Characteristics of study in the baseline.

Metformin Total With Without p
Variables n % n % n %
Total 31,308 - 7827 25.00 23,481 75.00 -
Gender - - - - - - 0.999
Male 13,284 42.43 3321 42.43 9963 42.43 -
Female 18,024 57.57 4506 57.57 13,518 57.57 -
Age (years) 55.95 ± 14.28 55.91 ± 14.36 55.96 ± 14.25 0.759
Age groups (years) - - - - - - 0.999
18–49 11,960 38.20 2990 38.20 8970 38.20 -
50–59 6420 20.51 1605 20.51 4815 20.51 -
≥60 12,928 41.29 3232 41.29 9696 41.29 -
Low-income - - - - - - 0.952
Without 30,998 99.01 7749 99.00 23,249 99.01 -
With 310 0.99 78 1.00 232 0.99 -
Catastrophic Illness - - - - - - 0.206
Without 25,374 81.05 6382 81.54 18,992 80.88 -
With 5934 18.95 1445 18.46 4489 19.12 -
Marital status - - - - - - 0.073
Without 12,841 41.02 3278 41.88 9563 40.73 -
With 18,467 58.98 4549 58.12 13,918 59.27 -
Education (years) - - - - - - 0.683
<12 13,692 43.73 3407 43.53 10,285 43.80 -
≥12 17,616 56.27 4420 56.47 13,196 56.20 -
CCI_R 0.61 ± 1.75 0.60 ± 1.70 0.61 ± 1.77 0.641
Season - - - - - - 0.866
Spring (Mar–May) 8070 25.78 2037 26.03 6033 25.69 -
Summer (Jun–Aug) 8425 26.91 2101 26.84 6324 26.93 -
Autumn (Sep–Nov) 7896 25.22 1982 25.32 5914 25.19 -
Winter (Dec–Feb) 6917 22.09 1707 21.81 5210 22.19 -
Location - - - - - - 0.659
Northern Taiwan 13,289 42.45 3335 42.61 9954 42.39 -
Middle Taiwan 8492 27.12 2150 27.47 6342 27.01 -
Southern Taiwan 8227 26.28 2017 25.77 6210 26.45 -
Eastern Taiwan 1253 4.00 315 4.02 938 3.99 -
Outlets islands 47 0.15 10 0.13 37 0.16 -
Urbanization level - - - - - - 0.877
1 (Highest) 12,423 39.68 3115 39.80 9308 39.64 -
2 14,419 46.06 3603 46.03 10,816 46.06 -
3 1346 4.30 324 4.14 1022 4.35 -
4 (Lowest) 3120 9.97 785 10.03 2335 9.94 -
Level of care - - - - - - 0.083
Hospital center 16,949 54.14 4319 55.18 12,630 53.79 -
Regional hospital 10,975 35.05 2668 34.09 8307 35.38 -
Local hospital 3384 10.81 840 10.73 2544 10.83 -
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P—chi-squared/Fisher’s exact test on category variables and t-test on continue variables.

At the end of the follow-up period, 801 enrolled subjects (2.56%) had osteoporosis, including 168 from the metformin group (2.15%) and 633 from the without metformin group (2.70%), as shown in Table 2. The metformin group was associated with a lower rate of osteoporosis at the end of the follow-up (p = 0.009). There were no significant differences between the metformin and control groups in age distribution, sex, comorbidities and covariates at the end of the follow-up period.

Table 2.

Characteristics of study in the endpoint.

Metformin Total With Without p
Variables n % n % n %
Total 31,308 - 7827 25.00 23,481 75.00 -
Osteoporosis - - - - - - 0.009
Without 30,507 97.44 7659 97.85 22,848 97.30 -
With 801 2.56 168 2.15 633 2.70 -
Gender - - - - - - 0.999
Male 13,284 42.43 3321 42.43 9963 42.43 -
Female 18,024 57.57 4506 57.57 13,518 57.57 -
Age (yrs) 61.37 ± 15.55 61.32 ± 15.60 61.39 ± 15.54 0.707
Age groups (yrs) - - - - - -- 0.393
18–49 8106 25.89 2061 26.33 6045 25.74 -
50–59 6647 21.23 1625 20.76 5022 21.39 -
≥60 16,555 52.88 4141 52.91 12,414 52.87 -
Low-income - - - - - - 0.336
Without 30,936 98.81 7726 98.71 23,210 98.85 -
With 372 1.19 101 1.29 271 1.15 -
Catastrophic Illness - - - - - - 0.652
Without 22,517 71.92 5647 72.15 16,870 71.85 -
With 8791 28.08 2180 27.85 6611 28.15 -
Marital status - - - - - - 0.058
Without 12,846 41.03 3283 41.94 9563 40.73 -
With 18,462 58.97 4544 58.06 13,918 59.27 -
Education (years) - - - - - - 0.659
<12 13,687 43.72 3405 43.50 10,282 43.79 -
≥12 17,621 56.28 4422 56.50 13,199 56.21 -
CCI_R 1.96 ± 3.70 1.99 ± 3.76 1.95 ± 3.68 0.320
Season - - - - - - 0.486
Spring 7236 23.11 1782 22.77 5454 23.23 -
Summer 7995 25.54 2017 25.77 5978 25.46 -
Autumn 8780 28.04 2232 28.52 6548 27.89 -
Winter 7297 23.31 1796 22.95 5501 23.43 -
Location - - - - - - 0.499
Northern Taiwan 12,321 39.35 3067 39.18 9254 39.41 -
Middle Taiwan 9222 29.46 2340 29.90 6882 29.31 -
Southern Taiwan 8108 25.90 1993 25.46 6115 26.04 -
Eastern Taiwan 1548 4.94 399 5.10 1149 4.89 -
Outer islands 109 0.35 28 0.36 81 0.34 -
Urbanization level - - - - - - 0.727
1 (Highest) 10,135 32.37 2522 32.22 7613 32.42 -
2 14,118 45.09 3502 44.74 10,616 45.21 -
3 2131 6.81 537 6.86 1594 6.79 -
4 (Lowest) 4924 15.73 1266 16.17 3658 15.58 -
Level of care - - - - - - 0.590
Hospital center 12,771 40.79 3156 40.32 9615 40.95 -
Regional hospital 13,322 42.55 3340 42.67 9982 42.51 -
Local hospital 5215 16.66 1331 17.01 3884 16.54 -
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P—chi-squared/Fisher’s exact test on category variables and t-test on continue variables.

The results of the Cox regression analysis of the factors associated with osteoporosis are shown in Table 3. The Cox proportional hazard regression analysis showed a lower rate of osteoporosis for patients receiving metformin therapy (adjusted hazard ratio of 0.820; 95% confidence interval = 0.691–0.972, p = 0.022).

Table 3.

Factors of osteoporosis by using Cox regression.

Variables Crude HR 95% CI 95% CI p Adjusted HR 95% CI 95% CI p
Metformin - - - - - - - -
Without 1 - - - 1 - - -
With 0.813 0.686 0.964 0.017 0.820 0.691 0.972 0.022
Gender - - - - - - - -
Male 0.662 0.497 0.883 0.005 0.576 0.431 0.770 <0.001
Female 1 - - - 1 - - -
Age groups (yrs) - - - - - - - -
18–49 1 - - - 1 - - -
50–59 2.827 1.648 4.851 <0.001 3.113 1.813 5.345 <0.001
≥60 13.133 8.114 21.257 <0.001 15.456 9.533 25.059 <0.001
Low-income - - - - - - - -
Without 1 - - - 1 - - -
With 1.083 0.490 1.973 0.961 1.505 0.747 3.030 0.253
Catastrophic Illness - - - - - - -
Without 1 - - - 1 - - -
With 0.521 0.426 0.638 <0.001 1.030 0.883 1.214 0.166
Marital status - - - - - - - -
Without 1 - - - 1 - - -
With 1.234 0.724 2.013 0.306 1.305 0.896 2.284 0.299
Education (years) - - - - - - - -
<12 1 - - - 1 - - -
≥12 0.903 0.512 1.894 0.376 0.865 0.483 1.881 0.425
CCI_R 0.892 0.860 0.925 <0.001 0.880 0.840 0.921 <0.001
Season - - -- - - - - -
Spring 1 - - - 1 - - -
Summer 0.946 0.778 1.150 0.576 0.993 0.817 1.208 0.946
Autumn 0.785 0.644 0.957 0.017 0.769 0.653 0.971 0.024
Winter 1.008 0.827 1.229 0.938 1.013 0.831 1.235 0.898
Location - - - - - - - -
Northern Taiwan 1 - - - Multicollinearity with urbanization level
Middle Taiwan 1.318 1.111 1.563 0.002
Southern Taiwan 1.151 0.958 1.383 0.113
Eastern Taiwan 1.675 1.274 2.204 <0.001
Islands outer of Taiwan 1.584 0.590 4.253 0.362
Urbanization level - - - - - - - -
1 (Highest) 0.525 0.374 0.736 <0.001 0.560 0.420 0.827 0.002
2 0.707 0.591 0.846 <0.001 0.856 0.706 1.038 0.113
3 0.725 0.598 0.878 0.001 0.912 0.733 1.135 0.410
4 (Lowest) 1 - - - 1 - - -
Level of care - - - - - - - -
Hospital center 0.646 0.536 0.778 <0.001 0.712 0.594 0.853 <0.001
Regional hospital 0.670 0.560 0.800 <0.001 0.761 0.615 0.942 0.012
Local hospital 1 - - - 1 - - -
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HR—hazard ratio; CI—confidence interval; Adjusted HR—adjusted variables listed in table.

For the subgroups in which osteoporosis factors were stratified by the variables listed in Table 4, the Cox regression analysis showed that the male, age < 60 years, better income, without catastrophic illness, unmarried, longer education, live in the higher urbanization level and care in hospital center were associated with a much lower osteoporosis rate.

Table 4.

Factors of osteoporosis stratified by variables listed in table by using Cox regression.

Metformin With Without Ratio With vs. Without (Reference)
Stratified Events PYs Rate (per 105 PYs) Events PYs Rate (per 105 PYs) Adjusted HR 95% CI 95% CI p
Total 168 83,045.71 202.30 633 254,028.18 249.18 0.812 0.820 0.691 0.972 0.022
Gender - - - - - - - - - - -
Male 8 24,313.43 32.90 42 72,902.21 57.61 0.571 0.572 0.483 0.689 0.007
Female 160 58,732.28 272.42 591 181,125.97 326.29 0.835 0.843 0.710 1.006 0.054
Age groups (yrs) - - - - - - - - - - -
18–49 1 16,823.43 5.94 16 48,608.18 32.92 0.181 0.180 0.150 0.218 <0.001
50–59 7 18,252.93 38.35 52 56,989.26 91.25 0.420 0.422 0.352 0.513 <0.001
≥60 160 47,969.35 333.55 565 148,430.74 380.65 0.876 0.886 0.746 1.072 0.241
Low-income - - - - - - - - - - -
Without 166 82,125.32 202.13 626 251,334.43 249.07 0.812 0.818 0.682 0.954 0.019
With 2 920.40 217.30 7 2693.75 259.86 0.836 0.845 0.703 0.998 0.047
Catastrophic Illness - - - - - - - - - - -
Without 148 63,571.83 232.81 562 192,669.45 291.69 0.798 0.806 0.672 0.958 0.020
With 20 19,473.89 102.70 71 61,358.72 115.71 0.888 0.899 0.758 1.094 0.182
Marital status - - -- - - - - - - - -
Without 70 38,033.11 184.05 295 120,005.45 245.82 0.749 0.754 0.632 0.891 <0.001
With 98 45,012.60 217.72 338 134,022.73 252.20 0.863 0.870 0.731 0.984 0.022
Education (years) - - - - - - - - - - -
<12 88 38,948.45 225.94 320 122,940.53 260.29 0.868 0.867 0.721 0.979 0.023
≥12 80 44,097.26 181.42 313 131,087.65 238.77 0.760 0.765 0.634 0.910 <0.001
Season - - - - - - - - - - -
Spring 38 18,725.29 202.93 155 57,375.11 270.15 0.751 0.759 0.632 0.902 0.001
Summer 39 20,940.50 186.24 165 65,150.71 253.26 0.735 0.743 0.621 0.880 <0.001
Autumn 40 25,007.28 159.95 162 72,600.25 223.14 0.717 0.724 0.608 0.863 <0.001
Winter 51 18,372.65 277.59 151 58,902.11 256.36 1.083 1.094 0.924 1.286 0.388
Urbanization level - - - - - - - - - - -
1 (Highest) 42 24,936.20 168.43 182 79,857.63 227.91 0.739 0.742 0.611 0.897 <0.001
2 66 37,254.28 177.16 269 112,534.77 239.04 0.741 0.749 0.620 0.903 0.002
3 11 5966.48 184.36 36 18,479.15 194.81 0.946 0.953 0.798 1.138 0.265
4 (Lowest) 49 14,888.76 329.11 146 43,156.63 338.30 0.973 0.981 0.824 1.206 0.402
Level of care - - - - - - - - - - -
Hospital center 54 31,037.93 173.98 214 97,437.34 219.63 0.792 0.799 0.635 0.950 0.009
Regional hospital 71 37,481.36 189.43 270 114,617.84 235.57 0.804 0.812 0.682 0.964 0.018
Local hospital 43 14,526.42 296.01 149 41,973.00 354.99 0.834 0.843 0.710 0.997 0.047
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PYs—person-years; Adjusted HR—adjusted hazard ratio, adjusted for the variables listed in Table 3; CI—confidence interval.

4. Discussion

We found that diabetic patients with carcinoma in situ under metformin therapy presented lower osteoporosis rates than those who were not receiving metformin. The overall adjusted HR was 0.820 (p = 0.022), even after adjusting for comorbidities and other covariates. The Kaplan-Meier analysis revealed that the study subjects had a significantly lower 15-year risk of osteoporosis than the controls. This study is the first to indicate that diabetic patients with carcinoma in situ under metformin therapy have a lower osteoporosis risk in a nationwide, population-based study.

Prior research that has found that patients with diabetes have a relatively high risk of fracture [20], and one systematic review that showed that patients with diabetes have up to a three-fold greater fracture risk than the average person, with hip fracture being the largest [21]. Cancer is a major risk factor for osteoporosis, which is a common bone disease characterized by reduced bone mass and increased risk of fracture. Furthermore, these factors are associated both with the direct effects of cancer cells on the skeleton and the deleterious effects of cancer-specific therapies on bone cells [9]. One review article showed that certain key factors, osteoprotegerin (OPG)/ receptor activator of NF-κB ligand (RANKL)/receptor activator of NF-κB (RANK), underlie the molecular mechanism of osteoclastogenesis [22], and the anti-human RANKL monoclonal antibody has been successfully applied to the treatment of osteoporosis and cancer-related bone disorders [23,24].

Metformin is the preferred initial pharmacologic medicine for T2DM treatment, unless there are contraindications [25]. First-line metformin therapy has beneficial effects on HbA1C and weight [26] and may reduce the risk of cardiovascular events and death [27]. Patients with diabetes who received thiazolidinedione or canagliflozin therapy were excluded, due to the potential risk of osteoporosis [28]. Some studies have reported that older age, diabetes, and cancer under chemotherapy were associated with increased fracture risk, which was associated with elevated bone resorption [29,30].

Will metformin treatment reduce the incidence of osteoporosis in diabetic patients with carcinoma in situ? No study has investigated this in the past, and therefore, we used a cohort investigation to evaluate this issue. We found that the diabetic patients with carcinoma in situ under metformin therapy presented lower osteoporosis rates than those who were not receiving metformin. Evans and other scholars first proposed that metformin could reduce the cancer risk of patients with diabetes through epidemiological studies [31], in accordance with our results.

The impact of metformin on osteoporosis has been studied in the past. In vitro data on metformin suggest a protective effect on bones [32] and that metformin improves bone quality and decreases the risk of fracturs in patients with diabetes, in addition to improving glycemic control and insulin sensitivity [33]. Recent studies have shown that metformin can be osteogenic in vitro through the activation of AMP-activated protein kinase (AMPK), which results in osteoblastic cells differentiation, bone matrix synthesis and osteoblasts proliferation [34,35]. An in vivo study in mice showed that metformin enhances osteoblast proliferation and inhibits osteoclast differentiation to attenuate cancellous bone loss [36]. Furthermore, molecular research has found that metformin reduces RANKL and stimulates OPG expression in osteoblasts, which further inhibits osteoclast differentiation and prevents bone loss in ovariectomized rats [37]. Furthermore, metformin has been found to promote the proliferation of murine preosteoblasts by regulating the AMPK-mechanistic target of rapamycin 2 (mTOR2) and the AKT-mTORC1 signaling axis [38]. Additionally, metformin promotes the proliferation and differentiation of murine preosteoblasts by regulating the expression of sirtuin 6 (sirt6) and oct4 [39].

We therefore hypothesized that diabetic patients with carcinoma in situ who are on metformin therapy may present attenuated cancellous bone loss through metformin regulation of AMPK signaling in preosteoblasts, which reduces RANKL and stimulates OPG expression. Hence, metformin could be associated with reduced osteoporosis. Our findings are similar to many studies that have shown that females and older patients have a greater risk of osteoporosis. Clinical factors could be associated with those projected by demographic changes, with regards to age- and sex-specific risks [40]. Otherwise, the reasons why the subgroups that lived in higher urbanized areas and received therapy in hospital centers showed lower rates of osteoporosis are unknown and warrant further studies.

The present study has a few limitations. First, our study lacks analyses of disease duration, disease severity and patient parameters, such as body weight, BMI and waistline. Hip fracture risk is increased in patients with diabetes, whereas BMD is increased in patients with T2DM [41]. While the pathophysiological mechanism is only partially understood, a common complication may explain the increased fracture risk, whereas BMI may ameliorate the increased fracture risk in patients with T2DM [42]. Finally, a longer follow-up period may be necessary to clarify the osteoporosis risk for diabetic patients with carcinoma in situ.

In conclusion, diabetic patients with carcinoma in situ under metformin therapy presented a lower osteoporosis rate than those who were not receiving metformin therapy, and this effect may be attributed to the decreased levels of proinflammatory factors and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism.

Author Contributions

C.-H.L. (Chieh-Hua Lu), F.-C.K., K.-C.C., C.-H.C. (Chia-Hao Chang), C.-C.K., C.-H.L. (Chien-Hsing Lee), S.-C.S., J.-S.L., F.-H.L., C.-H.T., P.-S.H. and Y.-J.H. participated in the conceptualization of the manuscript. C.-H.C. (Chi-Hsiang Chung) participated in data curation and the formal analysis of this study. C.-H.L. (Chieh-Hua Lu) wrote the original draft of the manuscript. C.-H.H. and W.-C.C. participated in manuscript review and editing. All authors have read and approved the final version of the manuscript.

Funding

This study was funded by the Tri-Service General Hospital Research Foundation (TSGH-C108-003, TSGH-C108-142, TSGH-C108-143, TSGH-C108-144) and the National Defense Medical Center, Ministry of National Defense-Medical Affairs Bureau (MAB-109–062) and the Teh-Tzer Study Group for Human Medical Research Foundation.

Conflicts of Interest

The authors declare no conflict of interest.

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