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Dipeptidyl peptidase-4 inhibitors attenuates osteoporosis in patients with diabetes: A nationwide, retrospective, matched-cohort study in Taiwan

Chang, Chia-Haoa; Lu, Chieh Huab,c; Chung, Chi-Hsiangd,e; Su, Sheng-Chiangb; Kuo, Feng-Chihb; Liu, Jhih-Syuanb; Li, Peng-Feib,f; Huang, Chia-Luenb; Chen, Kuan-Chanb; Ho, Li-Jub; Kuo, Chih-Chunb; Chang, Chun-Yungb; Lin, Ming-Shiunb; Liu, Yi-Chenb; Chu, Nain-Fengb; Lee, Chien-Hsingb,c; Hung, Yi-Jenb,g; Hsieh, Po-Shiuang,h; Lin, Fu-Huangd; Hsieh, Chang-Hsunb; Chien, Wu-Chienc,d,e,*

Author Information
Journal of the Chinese Medical Association: July 2022 - Volume 85 - Issue 7 - p 747-753
doi: 10.1097/JCMA.0000000000000743
  • Open

Abstract

1. INTRODUCTION

As the world gradually enters an era of an increasingly aging society and modern lifestyle changes, the number of patients with diabetes and osteoporosis is observed to be increasing,1 especially in the older population and postmenopausal women.2 Osteoporosis pertains to bone loss caused by aging. More than 8.9 million people suffer from bone fractures each year worldwide, with hip fractures being the most common.2 From 1996 to 2000, other treasury cabinets in Taiwan reported the annual incidence rate of fractures to be 225 and 505 per 100 000 in men and women over 65 years of age, respectively.3

Previous studies have explored the association between diabetes and osteoporosis.4 According to these studies, patients with diabetes have a relatively high risk of fracture.5–7 The pathophysiological mechanism behind this association is partially understood, yet inconclusive. Patients with type 2 diabetes mellitus (T2DM) have reduced bone mass density (BMD) and an increased risk of fracture. T2DM is considered to be one of the risk factors for reducing BMD, osteoporosis, and fractures.8 Few previous clinical studies and experimental data have shown that some hypoglycemic drugs, such as metformin or sulfonylurea, can increase or reduce the risk of fractures,9 whereas insulin treatment has no significant effect on bone mineral density.10 Conversely, in the Canagliflozin Cardiovascular Assessment Study, canagliflozin increased the risk of fracture11 and thiazolidinediones increased bone loss as well as fracture risk.12

Metformin is an effective drug for the treatment of T2DM, and additive treatment is recommended.13 Dipeptidyl peptidase-4 inhibitors (DPP-4i) should be neutral to the risk of cardiovascular disease in all patients with T2DM, and should not increase or decrease the same.14,15 In a large comprehensive analysis study, it was found that the use of DPP-4i can relatively reduce the patient’s risk of fracture.16 However, in another retrospective generational study, the database UK Clinical Practice Research Datalink was used to analyze data from 2007 to 2012, and it was found that DPP-4i was not associated with fracture risk.17

Based on the current evidence, the effect of DPP-4i on osteoporosis is inconclusive. In addition, whether the association between DPP-4i and osteoporosis is a class effect or affected by other factors (such as treatment duration) remains to be clarified. The purpose of this study was to use data from the National Health Insurance Research Database (NHIRD) of Taiwan, a national health insurance database, to determine the potential of DPP-4i in reducing the incidences of osteoporosis in patients with diabetes.

2. METHODS

2.1. Data sources

In this study, we used 7 years of data from the NHIRD, based on two million (2008–2015) in Taiwan’s Longitudinal Health Insurance Database (LHID). The National Health Insurance (NHI) program was launched in Taiwan in 1995. As of June 2009, it had signed contracts with 97% of medical providers and approximately 23 million beneficiaries, accounting for more than 99% of the total population.18 The NHIRD uses International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes to record diagnoses. All diagnoses of T2DM and osteoporosis were made by physicians, endocrinologists, or other experts certified by the committee. The NHI management department periodically reviewed the records of outpatient visits and hospitalization claims to verify the accuracy of the diagnosis. Therefore, the NHIRD was considered suitable for this study on the association between osteoporosis and DPP-4i use.

2.2. Research design and sampling participants

Sitagliptin was the first DDP-4i approved by the United States Food and Drug Administration. Approved on October 16, 2006, it has been marketed in Taiwan since 2008. This study had a retrospective matched-cohort design and was conducted between January 1, 2008 and December 31, 2015. Using the LHID, we identified and selected 57 054 patients with diabetes (ICD-9-CM 250.XX), who were consecutively administered oral hypoglycemic drugs for more than 90 days. Each enrolled patient was required to have made at least three outpatient visits during the study period. Diabetic patients younger than 20 years, those with previously diagnosed osteoporosis, and those who were on DPP-4i before the index date were excluded. In addition, patients who received glucagon-like peptide 1 receptor agonist (GLP-1 RA), thiazolidinedione, or canagliflozin before tracking were excluded.

Data on the use of DPP-4i, including sitagliptin, linagliptin, saxagliptin, vildagliptin, and alogliptin were collected. This study recruited 6339 patients on DPP-4i use (DPP-4i group), and 25 356 patients without DPP-4i use (non-DPP-4i group), who were then matched by 1:4 propensity score matching using confounding variables, including sex, age, comorbidities, medication, and index year (Fig. 1).

F1
Fig. 1:
Flow chart of the sample selection process. DM = diabetes mellitus; DPP-4i = dipeptidyl peptidase-4 inhibitor; GLP-1 receptor agonist = glucagon-like peptide 1 receptor agonist; OHA = oral hypoglycemic agents.

2.3. Comorbidity

Comorbidities included hyperthyroidism, hyperparathyroidism, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA), Cushing’s syndrome, hypogonadism, acromegaly, vitamin D deficiency, hypercalciuria, alcoholism, and multiple myeloma. The Charlson comorbidity index was used to categorize comorbidities based on the ICD-9-CM codes, and the scores for each comorbidity-category were combined into a single comorbidity score. A score of zero indicated that no comorbidities were found, and a higher score indicated a higher burden of comorbidities.

2.4. Outcome measurements

All study participants were followed up, from the index date until the diagnosis of osteoporosis (ICD-9-CM codes: 733.00), until withdrawal from the NHI program, or until the end of 2015.

2.5. Statistical analysis

All analyses were performed using the SPSS software version 22 (SPSS Inc., Chicago, IL, USA). The χ2 and Student’s t-tests were used to evaluate the distribution of categorical and continuous variables, respectively. Fisher’s exact test was used to analyze the differences in categorical variables between the two cohorts. Multivariate Cox proportional hazards regression analysis was used to determine the risk of osteoporosis, and the results are presented as hazard ratios (HRs) with 95% confidence intervals (CIs). The difference in the risk of osteoporosis between the DPP-4i and non-DPP-4i groups was estimated using the Kaplan–Meier method with the log-rank test. Statistical significance was defined as a two-tailed p-value < 0.05.

2.6. Ethics approval

This study was conducted in accordance with the code of ethics of the World Medical Association (Declaration of Helsinki). The Institutional Review Board of the Tri-Service General Hospital approved this study (TSGH IRB No.2-105-05-082).

3. RESULTS

Table 1 presents the demographic data of the study participants. There were 6339 patients in the DPP-4i group and 47 989 in the non-DPP-4i group. After propensity score matching at a ratio of 1:4, 25 356 pairs remained. Both groups had a mean age of 66 years, mild male preponderance (51.79%), and were followed up for a mean duration of 7 years. Fig. 2 shows the Kaplan–Meier analysis for the cumulative risk of osteoporosis in the case and control groups, with a statistically significant difference (log-rank, p = 0.039).

Table 1 - Characteristics of study in the baseline
WithDPP-4i use WithoutDPP-4i use p
Variables n % n %
Total 6339 25,356
Number of men (percentage) 3283 (51.79%) 13132 (51.79) 0.999
Age (years) 66.02 ± 11.96 66.04 ± 11.82 0.923
Age groups (years) 0.999
 18-49 731 (11.53%) 2924 (11.53%)
 50-64 1746 (27.54%) 6984 (27.54%)
 ≧65 3862 (60.92%) 15448 (60.92%)
Hyperthyroidism 13 (0.21%) 64 (0.25%) 0.563
Hyperparathyroidism 0 (0%) 4 (0.02%) 0.59
Cushing’s syndrome 52 (0.82%) 181 (0.71%) 0.368
Hypogonadism 0 (0%) 1 (0%) 0.817
Acromegaly 6 (0.09%) 26 (0.10%) 0.86
Vitamin D deficiency 0 (0%) 1 (0%) 0.817
Hypercalciuria 10 (0.16%) 38 (0.15%) 0.857
Rheumatoid arthritis 16 (0.25%) 38 (0.15%) 0.088
Chronic obstructive pulmonary disease 617 (9.73%) 2315 (9.13%) 0.126
Alcoholism 20 (0.32%) 73 (0.29%) 0.707
Multiple myeloma 5 (0.08%) 13 (0.05%) 0.383
CCI_R 0.80 ± 1.73 0.78 ± 1.77 0.411
P: Chi-square/Fisher exact test on category variables and t-test on continue variables

F2
Fig. 2:
Kaplan–Meier curve for the cumulative risk of osteoporosis in patients with DM on OHA (≥20) stratified by DPP-4i with log-rank test. DM + diabetes mellitus; DPP-4i = dipeptidyl peptidase-4 inhibitor; OHA = oral hypoglycemic agents.

Table 2 shows that at the end of the follow-up, 113 (0.36%) of all enrolled subjects had osteoporosis, including 15 (0.24%) in the case group and 98 (0.39%) in the control group. The results of the Cox regression analysis of factors related to the incidence of osteoporosis. Cox proportional hazards regression analysis showed that patients receiving DPP-4i treatment were associated with a lower incidence of osteoporosis (adjusted HR, 0.616 [95% CI, 0.358-0.961, p = 0.011]) than those not receiving the treatment. The study subjects with female, increasing age, and comorbidity free of diseases such as hyperthyroidism, hyperparathyroidism, Cushing’s syndrome, hypogonadism, acromegaly, vitamin D deficiency, hypercalciuria, RA, COPD, alcoholism, and multiple myeloma were associated with a higher rate of osteoporosis in those without DPP4i therapy groups. The reduction in the risk of osteoporosis in the DPP-4i group was independent of sex or age.

Table 2 - Factors of osteoporosis stratified by variables listed in the table using Cox regression
DPP-4i With Without With vs Without
Group Events Rate (%) Events Rate (%) Adjusted HR p
Total 15 0.24 98 0.39 0.616
(0.358-0.961)
0.011
Sex
 Male 4 0.10 29 0.22 0.562
(0.322-0.878)
0.001
 Female 11 0.36 69 0.56 0.638
(0.364-0.980)
0.029
Age gourps (years)
 18-49 0 0.00 4 0.18 0.000 0.785
 50-64 2 0.13 15 0.25 0.521
(0.298-0.816)
<0.001
 ≧65 13 0.30 79 0.46 0.674
(0.391-1.043)
0.126
Disease free of
 Hyperthyroidism 15 0.24 97 0.38 0.622
(0.357-0.973)
0.018
 Hyperparathyroidism 15 0.24 98 0.39 0.616
(0.358-0.961)
0.011
 Cushing’s syndrome 14 0.22 97 0.38 0.597
(0.362-0.909)
<0.001
 Hypogonadism 15 0.24 98 0.39 0.616
(0.358-0.961)
0.011
 Acromegaly 15 0.24 98 0.39 0.616
(0.358-0.961)
0.011
 Vitamin D deficiency 15 0.24 98 0.39 0.616
(0.358-0.961)
0.011
 Hypercalciuria 15 0.24 98 0.39 0.616
(0.358-0.961)
0.011
 Rheumatoid arthritis 15 0.24 97 0.38 0.623
(0.362-0.968)
0.01
 Chronic obstructive pulmonary disease 13 0.21 86 0.34 0.603
(0.299-0.943)
0.005
 Alcoholism 15 0.24 98 0.39 0.616
(0.358-0.961)
0.011
 Multiple myeloma 15 0.24 98 0.39 0.616
(0.358-0.961)
0.011
CI = confidence interval; adjusted HR = adjusted hazard ratio: adjusted for the variables listed in Table 2; PYs = person-years.

Table 3 shows a comparison of the risk of osteoporosis among the different combinations of DDP-4i. Various DPP-4i are observed to significantly protect against the development of osteoporosis. Cumulative protective effects of all types of DPP-4i were observed, especially when the treatment duration was greater than 6 months and persisted for more than 1 year. In patients treated with alogliptin, saxagliptin, and vildagliptin, it was observed that the use of these DPP-4 for more than 1 year reduced the risk of osteoporosis.

Table 3 - Factors of osteoporosis among different DDP4 subgroups using Cox regression
Events PYs Rate
(per 105 PYs)
Adjusted
HR
Lower
CI
Higher
CI
p
All DDP-4i 15 31 223.90 48.04 0.616 0.358 0.961 0.011
All DDP-4i
(90-180 days)
8 8657.38 92.41 1.186 0.690 1.847 0.283
 Alogliptin 2 1820.22 109.88 1.410 0.823 2.195 0.394
 Linagliptin 2 1836.12 108.93 1.394 0.808 2.173 0.373
 Saxagliptin 1 1025.67 97.50 1.233 0.714 1.918 0.290
 Sitagliptin 2 2425.11 82.47 1.017 0.613 1.622 0.275
 Vildagliptin 1 1550.26 64.51 0.815 0.482 1.280 0.211
All DDP-4i
(181-364 days)
4 10170.86 39.33 0.505 0.293 0.786 <0.001
 Alogliptin 1 2091.9 47.80 0.613 0.355 0.957 0.018
 Linagliptin 1 2108.95 47.42 0.609 0.352 0.949 0.009
 Saxagliptin 1 1900.81 52.61 0.677 0.392 1.059 0.186
 Sitagliptin 1 2571.41 38.89 0.498 0.290 0.777 <0.001
 Vildagliptin 0 1497.79 0.00 0.000 - - 0.989
All DDP-4i
(≧365 days)
3 12 395.66 24.20 0.311 0.181 0.484 <0.001
 Alogliptin 1 2118.14 47.21 0.605 0.351 0.943 0.007
 Linagliptin 0 2538.07 0.00 0.000 - - 0.986
 Saxagliptin 1 2009.42 49.77 0.624 0.364 0.913 <0.001
 Sitagliptin 0 2590.42 0.00 0.000 - - 0.994
 Vildagliptin 1 3139.61 31.85 0.408 0.234 0.633 <0.001
CI = confidence interval; adjusted HR = adjusted hazard ratio: adjusted for the variables listed in Table 3; PYs = person-years.

4. DISCUSSION

Our study demonstrated that compared with no DPP-4i use, the use of DPP-4i was associated with a 38.4% lower risk of developing osteoporosis in patients with T2DM. As the duration of treatment increased from 181 to 364 days and to more than 365 days, we found that DPP4i therapy such as alogliptin, saxagliptin, and vildagliptin decreased the risk of osteoporosis. This information may be important for physicians when choosing optimal antidiabetic medications to prevent osteoporosis development in patients with T2DM without osteoporosis. We also observed that the effect was seen in both sexes but only among subjects 50–64 years old.

DPP-4i is a type of incretin-based therapy that can increase the concentration of circulating GLP-1, has a relatively low risk of causing hypoglycemia, and is often used to treat T2DM.19 A recent meta-analysis found that there was no difference in fracture risk among DPP-4i users compared to placebo or active comparator.20 Similarly, observational data examining the association between DPP-4 inhibitors and fragility fractures do not support an increase or decrease in the fracture risk.21 These results were inconsistent with those of the previous human studies.17,22 The differences between the studies may be attributed to the population and number of study participants, study design, duration of follow-up, efficacy, and analysis of previous observational studies.

Several previous human studies reported that DPP-4i is beneficial for bone metabolism, which is consistent with our findings.23–25 DPP-4i is associated with fewer fracture events than placebo or control treatments, the basis of which could be explained by the protective effect of DPP-4i on bones.16 DPP-4i may promote bone formation and reduce bone resorption through a variety of mechanisms that inhibit DPP-4, while possibly promoting bone metabolism by lowering glucose levels. Also, the energy metabolism associated with DPP-4 substrate and DPP-4 may affect bone metabolism. The DPP-4i may increase the serum concentration of 25-hydroxy vitamin D3, which affects the risk of bone fracture, BMD, and bone quality through vitamin D-related and other related signaling pathways.26

Systemic osteoporosis has several different causes and pathogenesis.27 When assessing the underlying causes of osteoporosis, it was found that up to 30% of postmenopausal women and 50%-80% of men have factors that lead to osteoporosis, with glucocorticoid-induced osteoporosis being the most common form of secondary osteoporosis.28,29 The term secondary applies to all patients with osteoporosis whose identifiable causes are not aging or menopause.30 Our study also demonstrated that the incidence of osteoporosis development diminished among patients with co-existence of T2DM and underlying diseases that caused secondary osteoporosis, such as endocrine diseases, RA, COPD, and multiple myeloma. This was to analyze whether the use of DPP4i reduces the risk of osteoporosis. One should be cautious while interpreting the results. Owing to the limited number of cases, it is impossible to draw any firm conclusions. However, in patients with diabetes without these diseases, the use of DPP4i reduces the risk of osteoporosis compared to patients who do not use DPP4i.

One study showed that the use of DPP-4i significantly reduced the risk of lower extremity fractures in men and women aged 46-55 years and reduced the risk of all fractures only in women aged 45-54 years with diabetes.25 Similarly, in our subgroup analysis, there was an association between the use of DPP-4i in patients with diabetes aged >50 years with a lower risk of osteoporosis; however, we found that the benefits of DPP-4i are weaker in people over 65 years of age. We are currently unable to explain the reasons for the differences between relevant age groups based on the results of previous literature studies and our study.

One study showed no association with increased fracture risk when stratified by the duration of current DPP-4i use >4.0-8.5 years.31 Moreover, a previous meta-analysis of 28 randomized clinical trials concluded that DPP-4i treatment reduced fracture risk compared with placebo or other treatments (HR = 0.60, 95% CI, 0.37-0.99, p = 0.045).16 These studies have shown that, as compared to linagliptin and saxagliptin, alogliptin and sitagliptin have beneficial effects on fractures.24 Furthermore, in another study elucidating the effect of different classes of DPP-4i on bone metabolism, alogliptin may be associated with a lower risk of fracture compared to placebo, linagliptin, or saxagliptin, whereas other antidiabetic medications appear to be associated with fracture risk.23 In our subgroup analysis, we found some kinds of DPP-4i in which alogliptin, saxagliptin, and vildagliptin were used, the treatment time was longer (more than 6 months and persisted for more than 1 year), and the risk of osteoporosis was reduced. Some possible reasons include different sample sizes and usage doses of DPP-4i in studies, making some of the results lack statistical power. Further large-scale RCT trials should be designed to clarify this issue.

There were several limitations to our study, including the lack of an analysis of the course of the disease, severity of the disease, and patient parameters. The pathophysiological mechanisms are partially understood, whereas common factors, such as sex and aging, can explain the increased risk of osteoporosis.32 Furthermore, our study lacked laboratory data such as adjustment for renal function, as it was not available in the NHIRD. However, we compared the number of DPP-4i and non-DPP-4i users before and after propensity score matching and observed no significant differences. Other residual confounding factors, such as HbA1c or vitamin D levels, dietary factors, and BMI, were also not included in the NHIRD. This was a population-based study, and it was impossible to elucidate the actual mechanism of the association between DPP-4i use and osteoporosis in patients with T2DM.

In conclusion, compared with no DPP-4i use, DPP-4i use was associated with a lower risk of osteoporosis in patients with T2DM in Taiwan. Based on a longer follow-up period, further research on the effects of DPP-4i on bone remodeling, vitamin D level, and other mechanisms may be needed to verify the risk of osteoporosis using DPP-4i.

ACKNOWLEDGMENTS

This study was funded by the Tri-Service General Hospital Research Foundation (TSGH-C108-142, TSGH-B-110012, TSGH-D-110058, and TSGH-B-111246) and the Teh-Tzer Study Group for Human Medical Research Foundation. We also appreciate the Health and Welfare Data Science Center, Ministry of Health and Welfare (HWDC, MOHW), Taiwan, for providing the National Health Insurance Research Database (NHIRD).

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Keywords:

Bone mass density; Diabetes mellitus; DPP-4 inhibitor; National Health Insurance Research Database; Osteoporosis

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