Incidence and risk factors for osteoporosis in people with type 2 diabetes mellitus in Thailand

doi:10.21203/rs.3.rs-4985177/v1

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Incidence and risk factors for osteoporosis in people with type 2 diabetes mellitus in Thailand

https://doi.org/10.21203/rs.3.rs-4985177/v1

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Background: Type 2 diabetes mellitus (T2DM) is documented to alter bone structure and increase fracture risk. This study aimed to determine the risk factors and incidence rate of osteoporosis in Thai adults with T2DM.

Methods:A retrospective cohort study was conducted at Ramathibodi Hospital. People aged 18 or above whom were diagnosed with T2DM between January 2010 and December 2019 and started diabetic medication were included. Participants with a history of osteoporosis were excluded. Osteoporosis was diagnosed by BMD T-score ≤ -2.5, ICD10 for osteoporosis, ICD9 for fragility fracture, or prescription of osteoporosis medication. The participants that did not meet the criteria would be categorized as non-osteoporosis. Univariate and multivariate Cox regression analyses were used to determine risk factors for osteoporosis.

Results:25,635 participants were recruited. 772 participants were diagnosed with osteoporosis during the study period. The incidence rate was 57/10,000 person-year. Older age and female sex were associated with a greater risk for osteoporosis with hazard ratios (HR) of 1.07 (1.06-1.08) and 4.30 (3.48-5.30) respectively, while higher BMI was associated with a reduction in osteoporosis [HR 0.95 (0.94-0.97)]. For Diabetes-related risk factors, dipeptidyl peptidase-4 inhibitors (DPP4-inhibitors), insulin, sulfonylureas, and thiazolidinediones were related with an increased risk of osteoporosis, HR were 1.41 (1.09-1.81), 1.34 (1.07-1.69), 1.22 (1.01-1.48) and 1.45 (1.05-1.99)respectively. Dyslipidemia is also associated with osteoporosis [HR 1.36 (1.12-1.66)].

Conclusion:Older women with T2DM and dyslipidemia had a significantly higher risk of osteoporosis. Furthermore, insulin, sulfonylureas, thiazolidinediones, and DPP4-inhibitors are associated with increased fracture risk when compared to metformin.

osteoporosis

type 2 diabetes mellitus

risk factors

diabetes-related risk factors

Type 2 diabetes mellitus (T2DM) is a major health concern worldwide, with increasing prevalence each year [1]. T2DM affects multiple organs, and there is substantial evidence supporting the impact of T2DM on bone health and fracture risk [2–4]. Data from 2014 demonstrated that the prevalence of osteoporosis in people with T2DM is higher than in those without T2DM [5]. A study from China in 2019 showed that the pooled prevalence rate of osteoporosis in T2DM patients was 37.8% [6].

Several mechanisms related to fragility fractures in people with T2DM have been documented, including impaired bone matrix plasticity, low bone turnover rate, increased fall risk due to hypoglycemia, and the effects of diabetic medications [2–4]. Multiple studies have also identified T2DM-specific factors, such as hypo- or hyperglycemic events and albuminuria, as potential risk factors for osteoporosis and fragility fractures [7, 8]. Diabetic medications themselves can also be risk factors for osteoporosis. Insulin and sulfonylureas increase the risk of fractures due to falls from hypoglycemic episodes, and thiazolidinediones reduce bone density by promoting adipogenesis, which suppresses osteoblast differentiation [2–4].

Despite the increased fracture risk indicated in several studies, the identification of osteoporosis in people with T2DM remains underrecognized. People with T2DM face challenges in diagnosing osteoporosis since their BMD is typically higher than that of the general population and the FRAX tool has been shown to underestimate fracture risk in people with T2DM [9]. The ADA 2024 guideline for diabetes mellitus addresses the fact that T2DM increases the risk of fragility fractures and lists diabetes-specific risk factors for fractures [10]. However, there are limited data on these determinants in the Thai population. Our study aimed to identify risk factors for osteoporosis and fragility fractures in people with T2DM. We also assessed the incidence rate of osteoporosis in our cohort.

Study design

We retrospectively reviewed data from all individuals diagnosed with T2DM at Ramathibodi Hospital in Bangkok, Thailand, from January 2010 to December 2019. T2DM was identified using the International Statistical Classification of Diseases, Ninth and Tenth Revisions (ICD-9 and ICD-10). All participants were required to be 18 years or older and to have received any of the following antihyperglycemic drugs: metformin, sulfonylureas, thiazolidinediones, or dipeptidyl peptidase-4 inhibitors (DPP-4 inhibitors). Participants were excluded if they had osteoporosis or a fragility fracture before being diagnosed with T2DM or if they had any of the following diseases that could affect bone health: prostate cancer, bone malignancy, hematologic malignancy, a history of bilateral orchidectomy or oophorectomy, hyperparathyroidism, or a calcium disorder. We also excluded participants who were administered SGLT2 inhibitors or GLP-1RAs due to the minimal usage in our cohort (Fig 1). The study was approved by the Institutional Review Board of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (COA. MURA2023/414).

Osteoporosis

The diagnosis of osteoporosis was determined by one of the following criteria: first, a BMD T-score less than or equal to -2.5 in the lumbar spine, femoral neck, or total hip. BMD was assessed using either Hologic’s Horizon® DXA scan (Hologic, Inc., USA) or the Lunar Prodigy densitometer (GE Healthcare, Madison, WI, USA). T-scores were analysed using reference databases for the Asian population supplied by the manufacturer. In participants with a prior hip fracture, the BMD T-score was evaluated from the contralateral, non-fractured hip. In participants with a history of previous vertebral fractures, lumbar spine BMD was evaluated from two or more vertebrae, excluding the fractured vertebrae.

Second, if the participant had never been tested for BMD, the diagnosis of osteoporosis was made if at least two of the following conditions were met: ICD-10 code for osteoporosis (M80.X-M82.X), ICD-9 code for fragility fracture (781X, 784X-786X, 790X-793X), or prescription of osteoporosis medication. Third, if the participant had only one of the ICD-10 or ICD-9 codes or osteoporosis medication, the investigators reviewed their electronic medical record (EMR) to determine the diagnosis of osteoporosis. Participants who did not meet any of these criteria were categorized as non-osteoporosis.

Covariates

The risk factors for osteoporosis in people with T2DM were examined. The variables were divided into two groups: diabetes-related risk factors and traditional risk factors. All data were retrieved at the time of T2DM diagnosis from the Ramathibodi Hospital database.

For diabetes-related risk factors, fasting plasma glucose (FPG) and haemoglobin A1c (HbA1c) were used to indicate diabetic control. Diabetic retinopathy (DR) was identified based on information in the EMR. Chronic kidney disease (CKD) was defined as a glomerular filtration rate (GFR) below 60 ml/min/1.73 m² for more than three months, calculated using the CKD-EPI creatinine formula. Participants were categorized based on their first non-metformin diabetic medication. Those who were solely administered metformin were identified as members of the metformin group. Since it is well established that metformin does not affect bone, we used it as a comparison to other diabetic medications.

For traditional risk factors for osteoporosis, we collected demographic information such as age, sex, and body mass index (BMI). ICD-10 codes were used to identify comorbidities of interest, including hypertension, dyslipidemia, and coronary heart disease. Additionally, ICD-10 codes were used to collect data on conditions known to be risk factors for osteoporosis, such as rheumatoid arthritis, hyperthyroidism, hypogonadism, malnutrition, chronic liver disease, and human immunodeficiency virus (HIV) infection. Medications that can affect bone health, such as statins, proton pump inhibitors (PPIs), anticoagulants, glucocorticoids, aromatase inhibitors, gonadotropin-releasing hormone (GnRH) agonists and antagonists, diuretics, antiepileptic drugs, antiretroviral drugs, vitamin D, and calcium supplements, were also collected from the hospital databases. Hemoglobin levels were obtained from the hospital databases.

Statistical Analysis

Demographic data were calculated and presented as numbers and percentages for categorical data, and as mean with standard deviation or median with range for continuous data, as appropriate. The incidence rate of osteoporosis, along with a 95% confidence interval (CI), was estimated. Factors associated with osteoporosis were assessed in the following steps: first, a univariate Cox regression was performed by fitting each factor individually. Second, factors with a p-value of less than 0.2 in the previous step were simultaneously considered in a multivariable Cox model. The likelihood ratio test was applied to select only significant factors for the final model. Hazard ratios (HR) along with 95% CI were estimated accordingly. All data were analyzed using STATA version 18.0 (StataCorp®, TX). A p-value of less than 0.05 was considered statistically significant.

A total of 25,635 participants were enrolled, and their demographic data at the time of T2DM diagnosis are presented in Table 1. The mean age of the participants was 55.9 ± 14.4 years, with more women than men (61.4%), and a mean BMI of 28.3 ± 5.5 kg/m². The majority of the participants did not develop diabetic complications; DR and CKD were found in 1.1% and 2.5%, respectively. Metformin was administered to most participants (65.1%). DPP-4 inhibitors, insulin, sulfonylureas, and thiazolidinediones were given alone or with metformin in 6.9%, 9.5%, 14.3%, and 4.2% of participants, respectively. The mean FPG and HbA1c were 137 mg/dL and 7.7%, respectively.

Table 1

Characteristic of patients
Characteristics	N = 25,635
Age, years, mean (SD)	55.9 (14.4)
Sex, n (%)
Female	15,741 (61.4)
Male	9,894 (38.6)
BMI, kg/m², mean (SD)	28.3 (5.5)
Diabetes-related risk factors for osteoporosis
Diabetic retinopathy, n (%)
Yes	276 (1.1)
No	25,359 (98.9)
Chronic kidney disease, n (%)
Yes	629 (2.5)
No	25,006 (97.5)
Treatment
Metformin	16,700 (65.1)
Insulin	2,426 (9.5)
Sulfonylureas	3,660 (14.3)
Thiazolidinediones	1,076 (4.2)
DPP4-inhibitors	1,773 (6.9)
FPG, mg/dL, median (IQR)	137.0 (114.0, 174.0)
HbA1c, %, mean (SD)	7.7 (1.8)
Traditional risk factors for osteoporosis
Hypertension, n (%)
Yes	17,677 (69.0)
No	7,958 (31.0)
Dyslipidemias, n (%)
Yes	18,691 (72.9)
No	6,944 (27.1)
Rheumatic disease, n (%)
Yes	100 (0.4)
No	25,535 (99.6)
Hyperthyroidism, n (%)
Yes	213 (0.8)
No	25,422 (99.2)
Hypogonadism, n (%)
Yes	64 (0.2)
No	25,571 (99.8)
Malnutrition/Intestinal malabsorption, n (%)
Yes	227 (0.9)
No	25,408 (99.1)
Chronic liver disease, n (%)
Yes	507 (2.0)
No	25,128 (98.0)
Coronary heart disease, n (%)
Yes	388 (1.5)
No	25,247 (98.5)
HIV infection, n (%)
Yes	158 (0.6)
No	25,477 (99.4)
Medications
Statins, n (%)
Yes	7,034 (27.4)
No	18,601 (72.6)
Proton pump inhibitors, n (%)
Yes	3,962 (15.5)
No	21,673 (84.5)
Anticoagulants, n (%)
Yes	554 (2.2)
No	25,081 (97.8)
Glucocorticoid, n (%)
Yes	4,374 (17.1)
No	21,261 (82.9)
Antiepileptic drug, n (%)
Yes	2,867 (11.2)
No	22,768 (88.8)
Aromatase inhibitors/GnRH agonists/GnRH antagonists, n (%)
Yes	127 (0.5)
No	25,508 (99.5)
Diuretic, n (%)
Yes	957 (3.7)
No	24,678 (96.3)
Antiretroviral drug, n (%)
Yes	205 (0.8)
No	25,430 (99.2)
Vitamin D supplement, n (%)
Yes	2,585 (10.1)
No	23,050 (89.9)
Calcium carbonate, n (%)
Yes	3,659 (14.3)
No	21,976 (85.7)
Hemoglobin, mg/dL, mean (SD)	13.3 (1.7)

Abbreviation: BMI, Body Mass Index; DPP4-inhibitors, dipeptidyl peptidase-4 inhibitors; FPG, fasting plasma glucose; HbA1c, hemoglobin A1C; HIV, human immunodeficiency virus; GnRH, gonadotropin releasing hormone

Hypertension and dyslipidemia were diagnosed in 69% and 72.9% of the participants, respectively. Participants were diagnosed with rheumatoid arthritis, hyperthyroidism, hypogonadism, malnutrition, chronic liver disease, coronary heart disease, and HIV infection at rates of 0.4%, 0.8%, 0.2%, 0.9%, 2.0%, 1.5%, and 0.6%, respectively. Regarding medications, 27.4% of the participants were prescribed statins, and 15.5% were prescribed PPIs. Anticoagulants, glucocorticoids, antiepileptic drugs, aromatase inhibitors, GnRH suppression treatment, diuretics, and antiretroviral drugs were used by 2.2%, 17.1%, 11.2%, 0.5%, 3.7%, and 0.8% of participants, respectively. Additionally, 10.1% of the participants received vitamin D supplements, and 14.3% were prescribed calcium supplements. The mean hemoglobin level was 13.3 ± 1.7 g/dL.

Of the 25,635 participants, 772 were diagnosed with osteoporosis. BMD was performed in 1,833 participants, with 271 diagnosed with osteoporosis based on a BMD T-score of less than or equal to -2.5, 194 diagnosed by combining at least two of the ICD-9, ICD-10, or medication for osteoporosis criteria, and 307 diagnosed by reviewing their EMR. The incidence rate of osteoporosis was 57 per 10,000 person-years [95% CI 53/10,000 to 61/10,000].

Table 2 shows the hazard ratios for each factor by univariate analysis. Older age was associated with osteoporosis, with an HR of 1.08 (95% CI 1.07–1.09). Females were more likely to develop osteoporosis [HR 4.20 (95% CI 3.41–5.17)] compared to males, while higher BMI decreased the risk of osteoporosis [HR 0.90 (95% CI 0.89–0.92)].

Table 2

Factors association with Osteoporosis: A univariate analysis
Factors	Osteoporosis	Time at risk	Rate/Year	HR (95% CI)	P − value
Factors	N = 772	(Year)	Rate/Year	HR (95% CI)	P − value
Age, years, mean (SD)	68.7 (10.8)	−	−	1.08 (1.07, 1.09)	< 0.001
Sex
Female	669	82,120.9	0.009	4.20 (3.41, 5.17)	< 0.001
Male	103	53,220.2	0.002	1
BMI, kg/m², mean (SD)	26.1 (4.7)	−	−	0.90 (0.89, 0.92)	< 0.001
Diabetes-related risk factors for osteoporosis
Diabetic retinopathy
Yes	9	1,488.5	0.007	1.07 (0.56, 2.06)	0.848
No	763	133,852.6	0.006	1
Chronic kidney disease
Yes	19	3,693.5	0.006	0.91 (0.58, 1.44)	0.684
No	753	131,647.6	0.006	1
Treatments
Insulin	103	11,696.3	0.009	1.84 (1.48, 2.28)	< 0.001
Sulfonylureas	137	21,774.6	0.007	1.34 (1.11, 1.62)	0.003
Thiazolidinediones	41	5,647.1	0.008	1.53 (1.11, 2.10)	0.010
DPP4-inhibitors	71	8,030.3	0.009	1.84 (1.43, 2.36)	< 0.001
Metformin	420	88,192.9	0.005	1
FPG, mg/dL, median (IQR)	142.1 (122.0, 182.2)	−	−	1.001 (1.000, 1.002)	0.054
HbA1c, %, mean (SD)	7.6 (1.6)	−	−	0.98 (0.94, 1.02)	0.276
Traditional risk factors for osteoporosis
Hypertension
Yes	648	93,485.2	0.007	2.34 (1.93, 2.84)	< 0.001
No	124	41,855.9	0.003	1
Dyslipidemia
Yes	651	100,238.0	0.007	1.90 (1.56, 2.30)	< 0.001
No	121	35,103.0	0.004	1
Rheumatic disease
Yes	7	508.3	0.014	2.42 (1.15, 5.10)	0.020
No	765	134,832.8	0.006	1
Hyperthyroidism
Yes	5	1,175.9	0.005	0.75 (0.31, 1.80)	0.515
No	767	134,165.2	0.006	1
Hypogonadism
Yes	4	385.3	0.011	1.85 (0.70, 4.94)	0.220
No	768	134,955.8	0.006	1
Malnutrition/Intestinal malabsorption
Yes	4	689.7	0.006	0.95 (0.36, 2.54)	0.916
No	768	134,651.3	0.006	1
Chronic liver disease
Yes	10	2,961.4	0.004	0.60 (0.32, 1.11)	0.100
No	762	132,379.7	0.006	1
Coronary heart disease
Yes	15	2,382.0	0.007	1.13 (0.68, 1.87)	0.661
No	757	132,959.0	0.006	1
HIV infection
Yes	1	869.7	0.002	0.21 (0.03, 1.44)	0.109
No	771	134,471.4	0.006	1
Medications
Statins
Yes	272	39,953.1	0.007	1.32 (1.14, 1.53)	< 0.001
No	500	95,388.0	0.006	1
Proton pump inhibitors
Yes	205	20,739.4	0.010	2.00 (1.71, 2.35)	< 0.001
No	567	114,601.7	0.005	1
Anticoagulants
Yes	27	2,967.7	0.010	1.62 (1.11, 2.38)	0.014
No	745	132,373.3	0.006	1
Glucocorticoid
Yes	164	23,061.7	0.008	1.32 (1.11, 1.56)	0.002
No	608	112,279.4	0.006	1
Antiepileptic drugs
Yes	101	12,747.7	0.008	1.43 (1.16, 1.76)	0.001
No	671	122,593.4	0.006	1
Aromatase inhibitors/GnRH agonists/GnRH antagonists
Yes	3	553.9	0.006	0.93 (0.30, 2.89)	0.900
No	769	134,787.2	0.006	1
Diuretics
Yes	37	5,333.1	0.007	1.24 (0.89, 1.72)	0.213
No	735	130,008.0	0.006	1
Antiretroviral drugs
Yes	2	1,010.6	0.002	0.35 (0.09, 1.38)	0.131
No	770	134,330.5	0.006	1
Vitamin D supplement
Yes	154	12,873.0	0.012	2.36 (1.98, 2.81)	< 0.001
No	618	122,468.0	0.006	1
Calcium carbonate
Yes	236	20,527.9	0.012	2.49 (2.13, 2.90)	< 0.001
No	536	114,813.2	0.005	1
Hemoglobin, mg/dL, mean (SD)	12.6 (1.5)	−	−	0.78 (0.74, 0.82)	< 0.001

For diabetes-related factors, DR and CKD were not associated with osteoporosis. However, DPP-4 inhibitors, insulin, sulfonylureas, and thiazolidinediones were associated with osteoporosis compared to metformin, with hazard ratios of 1.84 (95% CI 1.43–2.36), 1.84 (95% CI 1.48–2.28), 1.34 (95% CI 1.11–1.62), and 1.53 (95% CI 1.11–2.10), respectively. Glycemic control, as measured by FPG and HbA1c levels, did not correlate with osteoporosis.

Regarding comorbidities, hypertension, dyslipidemia, and rheumatoid arthritis were associated with an increased risk of osteoporosis, with hazard ratios of 2.34 (95% CI 1.93–2.84), 1.90 (95% CI 1.56–2.30), and 2.42 (95% CI 1.15–5.10), respectively. Other comorbidities were not significantly associated with osteoporosis. Among medications, statins were related to an increased risk of osteoporosis [HR 1.32 (95% CI 1.14–1.53)]. PPIs, anticoagulants, glucocorticoids, and antiepileptic drugs were also shown to increase the incidence of osteoporosis, with hazard ratios of 2.00 (95% CI 1.71–2.35), 1.62 (95% CI 1.11–2.38), 1.32 (95% CI 1.11–1.56), and 1.43 (95% CI 1.16–1.76), respectively. Vitamin D and calcium supplements were associated with osteoporosis, with hazard ratios of 2.36 (95% CI 1.98–2.81) and 2.49 (95% CI 2.13–2.90), respectively. Aromatase inhibitors, GnRH agonists/antagonists, diuretics, and antiretroviral drugs did not show an association with osteoporosis. Haemoglobin levels appeared to be related to a decreased incidence of osteoporosis, with a hazard ratio of 0.78 (95% CI 0.74–0.82).

Table 3 shows the multivariate analysis used to identify independent risk factors for osteoporosis. Older age and female sex were associated with a greater risk for osteoporosis, with hazard ratios of 1.07 (95% CI 1.06–1.08) and 4.30 (95% CI 3.48–5.30), respectively. Higher BMI was associated with a reduced risk of osteoporosis, with an HR of 0.95 (95% CI 0.94–0.97). Among diabetic medications, DPP-4 inhibitors, insulin, sulfonylureas, and thiazolidinediones were associated with an increased risk of osteoporosis compared to metformin, with hazard ratios of 1.41 (95% CI 1.09–1.81), 1.34 (95% CI 1.07–1.69), 1.22 (95% CI 1.01–1.48), and 1.45 (95% CI 1.05–1.99), respectively.

Table 3

Factors association with Osteoporosis: A multivariable Cox regression analysis
Factors	HR (95% CI)	P − value
Age, years	1.07 (1.06, 1.08)	< 0.001
Female	4.30 (3.48, 5.30)	< 0.001
BMI, kg/m²	0.95 (0.94, 0.97)	< 0.001
Diabetic medication
Insulin	1.34 (1.07, 1.69)	0.012
Sulfonylureas	1.22 (1.01, 1.48)	0.048
Thiazolidinediones	1.45 (1.05, 1.99)	0.026
DPP4-inhibitors	1.41 (1.09, 1.81)	0.009
Metformin	1
Traditional risk factors for osteoporosis
Dyslipidemia	1.36 (1.12, 1.66)	0.002
Medications
Proton pump inhibitors	1.36 (1.15, 1.60)	< 0.001
Antiepileptic drugs	1.34 (1.08, 1.65)	0.008
Vitamin D supplement	1.46 (1.13, 1.88)	0.004
Calcium carbonate	1.66 (1.37, 2.02)	< 0.001

Abbreviation: BMI, Body Mass Index; DPP4-inhibitors, dipeptidyl peptidase-4 inhibitors

Regarding comorbidities, dyslipidemia was associated with an increased risk of osteoporosis, with an HR of 1.36 (95% CI 1.12–1.66). Among medications, PPIs and antiepileptic drugs were associated with an increased risk of osteoporosis, with hazard ratios of 1.36 (95% CI 1.15–1.60) and 1.34 (95% CI 1.08–1.65), respectively. In the multivariate analysis, vitamin D and calcium supplements were also associated with osteoporosis, with hazard ratios of 1.46 (95% CI 1.13–1.88) and 1.66 (95% CI 1.37–2.02), respectively.

Our study examined potential risk factors for osteoporosis in individuals with T2DM. We found that fractures were more common among older individuals, women, and those with a low BMI. Among diabetes-related factors, only specific antidiabetic drugs—DPP-4 inhibitors, insulin, sulfonylureas, and thiazolidinediones—were associated with osteoporosis when compared to metformin. Additionally, participants with dyslipidemia and those using PPIs or antiepileptic drugs were more likely to have osteoporosis. Surprisingly, vitamin D and calcium supplements were linked to an increased risk of osteoporosis.

In our cohort, well-established risk factors such as older age, female sex, and low BMI had a substantial impact on bone health. However, other traditional risk factors for osteoporosis, such as hypogonadism, hyperthyroidism, malnutrition, chronic liver disease, HIV, glucocorticoids, aromatase inhibitors, GnRH agonists/antagonists, diuretics, and antiretroviral drugs, were not significantly associated with osteoporosis. This may be due to the small number of participants with these conditions, suggesting that the study may have been underpowered to detect significant associations.

Diabetes-related risk factors such as high HbA1c and microvascular complications (indicated by DR and CKD) were not associated with osteoporosis in our study. Our participants had low rates of DR and CKD, and since the study included individuals diagnosed with T2DM within 10 10-year study period, and osteoporosis was diagnosed after T2DM, the relatively short duration of diabetes before osteoporosis might have limited the impact of diabetic-associated risk factors on bone health. Studies with longer durations of T2DM have shown significant correlations between specific diabetic risk factors and osteoporosis or fragility fractures. For example, a study of T2DM participants with a mean duration of 11.5 years found a significant association between albuminuria and increased osteoporosis prevalence [8]. Similarly, individuals with T2DM for 15-20 years who experienced severe hypoglycemic episodes and poorly controlled diabetes (HbA1c ≥ 9%) had increased fracture risks, with hazard ratios of 2.24 and 1.42, respectively [7].

Our findings on diabetic medications are consistent with previous research showing that insulin and sulfonylureas are significantly associated with osteoporosis compared to metformin, primarily due to an increased risk of falls [11, 12]. The association with pioglitazone is notable. Pioglitazone has been shown to increase osteoporosis risk by promoting adipogenesis over osteoblastogenesis from mesenchymal stem cells [4]. Unexpectedly, we found an association between DPP-4 inhibitors and osteoporosis, though the underlying mechanism remains unclear. An animal study suggested that saxagliptin, a DPP-4 inhibitor, may reduce osteoblastogenesis transcription factors [13]. In contrast, some studies have reported positive or neutral effects of DPP-4 inhibitors on bone health [14, 15]. Further research is needed, particularly to investigate the impact of switching diabetes medications and the use of multiple antidiabetic drugs, which were not explored in our study.

Our study also found that dyslipidemia itself affects bone health and is associated with osteoporosis, while statin use does not. A 2023 meta-analysis indicated that high levels of low-density lipoprotein (LDL) may lead to inflammation, reducing bone mass and increasing fracture risk [16]. Given the established link between inflammation and osteoporosis [17], dyslipidemia’s effects on bone health might be influenced by obesity, which typically results in higher BMD [18].

Our study identified associations between vitamin D and calcium supplements and osteoporosis. Despite the known roles of vitamin D and calcium in bone health, the evidence supporting their use for improving BMD or reducing fracture risk remains unclear. Multiple meta-analyses have failed to demonstrate a clear benefit of vitamin D and/or calcium supplements in preventing osteoporosis or reducing fracture risk [19, 20]. In our study, vitamin D and calcium were prescribed to only 10.1% and 14.3% of participants, respectively. These participants were older and predominantly female, potentially indicating a higher baseline risk of osteoporosis, which could bias the analysis. Additionally, since Cox regression analysis assumes a linear association, the complex relationship between these supplements and osteoporosis might interfere with the analysis. Further research is needed to clarify the effects of vitamin D and calcium supplements on bone health.

The incidence rate of osteoporosis in our study was 57/10,000 person-years, which is lower compared to previous studies. A 2021 study in Taiwan reported an incidence rate of 34.20 per 1,000 person-years for osteoporosis in T2DM patients [21]. In Thailand, where BMD testing is limited and osteoporosis diagnosis relies on physician-coded EMR data, our study’s incidence rate might be underestimated due to low BMD testing rates and incomplete EMR. Moreover, previous studies have shown that postmenopausal women and men with T2DM diagnosed for more than 5-10 years have higher fracture rates [22, 23]. Individuals with T2DM for over 10 years also have significantly higher FRAX Major Osteoporotic Fracture (MOF) scores compared to those without T2DM [24]. Most of our participants were newly diagnosed with T2DM, which may explain the lower incidence rate of osteoporosis in our cohort.

Our study has several strengths, including being the first to explore risk factors for osteoporosis in people with recently diagnosed T2DM using comprehensive data from a large hospital database. However, there are limitations to consider. BMD testing is still limited in Thailand, and osteoporosis diagnosis is not widely recognized. Only 1,833 participants were tested for BMD, while 7,627 participants met the age criteria (female aged over 65 years and male aged over 70 years) for BMD testing. This could lead to false categorization of some participants as non-osteoporosis, potentially resulting in an underestimated incidence rate. Additionally, our study is cross-sectional, which limits our ability to establish causality. We also could not determine the onset of T2DM, and the study period might not align with the disease onset. Furthermore, our data only included Thai patients from a single hospital, and we lacked information on other risk factors such as history of falls, hypoglycemia, smoking, and alcohol use.

In conclusion, our study found that older women with newly diagnosed T2DM and dyslipidemia have a significantly higher risk of osteoporosis. Additionally, antidiabetic medications associated with hypoglycemia and impaired osteoblastogenesis increase fracture risk. Other diabetes-related factors may not significantly contribute to fracture risk in individuals diagnosed with T2DM for less than 10 years. In resource-limited settings like Thailand, BMD testing should be guided by traditional risk factors and antidiabetic medications. Clinicians must be aware of osteoporosis as a major complication of T2DM, and timely fracture risk assessment and diagnosis are crucial for improving quality of life and reducing healthcare costs.

BMD bone mineral density

BMI body mass index

CI confidence interval

CKD chronic kidney disease

DPP4-inhibitors dipeptidyl peptidase-4 inhibitors

DR diabetic retinopathy

EMR electronic medical record

FPG fasting plasma glucose

GFR glomerular filtration rate

GnRH gonadotropin-releasing hormone

HIV human immunodeficiency virus

HbA1c haemoglobin A1c

HR hazard ratio

ICD9 and 10 International Statistical Classification of Diseases, Ninth and Tenth Revisions

PPIs proton pump inhibitors

T2DM Type 2 diabetes mellitus

Acknowledgements

Not applicable.

Author contributions

Dueanchonnee Sribenjalak and Hataikarn Nimitphongconducted the study and prepared the manuscript. Chanika Sritaraand Sasithorn Amnuaywattakorn provided the BMD data, Panu Looareesuwan, Sukanya Siriyotha and Ammarin Thakkinstian provided the statistic calculation, Boonsong Ongphiphadhanakul revised the manuscript.

Funding

The cohort on which this study data was based was funded by the National Research Council of Thailand (NRCT) N42A640323. The sponsor had no role in the design or conduct of the study.

Data availability

Upon request, the corresponding author will provide the data supporting the conclusions of this study.

Ethical approval

Ethics approval was obtained from the Institutional Review Board of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University (COA. MURA2023/414).

Consent to participate

Informed written consent was obtained from all participants.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

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No competing interests reported.

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Incidence and risk factors for osteoporosis in people with type 2 diabetes mellitus in Thailand

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