Background
Diabetes mellitus is a chronic whole-body disease leading to a wide range of complications, such as cardiovascular disease, retinopathy, nephropathy, neuropathy and also “sweet bone” disease [
1]. Although the underlying pathophysiological background is very different, type 1 (T1D) and type 2 diabetes (T2D) are both associated with an increased fracture risk - which is multifactorial and only partially explained by falls and bone mineral density (BMD) [
2]. The most consistent effect is upon the hip fracture risk, ranging between 2.4- and 7-fold increase in T1D [
3] and being two to three times higher in T2D compared to the general population [
1].
Diabetic osteopathy in T1D and T2D is characterized by low serum vitamin D, negative calcium balance, low bone turnover and high sclerostin levels [
4]. However, bone mass may differ to some extent in T1D when compared to T2D [
5], but not in all studies [
6]. Low BMD occurs early after disease onset due to the deleterious effects of insulinopenia upon bone turnover and bone mass accrual in T1D, remaining rather stable afterwards [
7]. Reported BMD in T2D varies from unaltered bone density [
8,
9] to a paradoxically higher BMD [
5] compared to controls. Low bone mass was also found in the later stages of T2D, possibly linked to microvascular disease [
10].
Skeletal fragility is nevertheless described in both T1D and T2D, independently of BMD [
2]. Advanced glycation end products (AGEs) alter the structure of the collagen, promote oxidative stress and inflammation, and also contribute to low bone turnover [
1,
3]. The effect of glycemic control - reflected by HbA1c levels - upon bone is inconsistent, with some studies reporting an elevated fracture risk with increasing HbA1c [
11,
12], while bone density evolution appears rather independent of HbA1c levels [
5,
6]. In T2D, the protective effect of an increased body weight and hyperinsulinemia upon bone are counterbalanced by the negative impact of increased visceral adiposity and insulin resistance, an inadequate adaptation of bone strength to increased mechanical load, the long duration of disease evolution and various anti-diabetic drugs (e.g., thiazolidinediones or sodium-glucose cotransporter type 2 inhibitors – SGLT-2) [
1].
We aimed at investigating independent predictors of BMD in T1D and T2D patients compared to controls with regard to general and diabetes - specific parameters.
Discussion
T1D and T2D patients had similar BMD compared to controls, respectively. Diabetes duration, but not HbA1c, was found to negatively predict femoral neck BMD in T1D, but not T2D patients. In the T2D group, BMI was an independent predictor of bone density, while female gender was negatively associated with low BMD in both T1D and T2D, independently of other factors. Unlike patients with diabetes, age was the other major independent predictor of bone mass in controls, in addition to gender.
Albeit BMD underestimates fracture risk in patients with diabetes, it still remains the cornerstone in bone evaluation in this particular group due to high accessibility and low costs [
16]. Data reporting BMD values in T1D and T2D patients are very heterogenous and rather inconsistent with regard to BMD predictive factors.
An older meta-analysis [
5] reported negative Z-scores for T1D patients and positive Z-scores for T2D subjects, thus concluding that T1D is associated with lower bone mass, while T2D patients generally have higher BMD. More recent studies reported, however, similar BMD values both between patients with diabetes and controls and between T1D and T2D patients, respectively [
6,
17]. Another recent study performed investigating bone mass in long-standing (longer than 50 years) T1D patients with good glycemic control and low rates of vascular complications reported similar or even better BMD expressed as Z-score compared to age-, gender- and race-matched population [
18]. We found lower bone mass scores at the femoral neck in T1D women compared to T2D women and controls; nevertheless, the differences did not reach statistical significance, probably due to the limited number of patients. Also, more women in the T2D group were postmenopausal compared to the T1D group, and this may account for the lack of a statistical difference regarding BMD between types of diabetes. More so, the different stages of evolution and disease management captured in various studies, the potentially erroneous diabetes classification and also the adjustment for various confounding variables may account for the variability of reported data. The early and rather acute insulinopenia associated with diabetes onset impairs bone mass accrual and negatively impacts peak bone mass. Thus, bone mass acquisition is hampered in the early stages of T1D [
3]. Nonetheless, bone density was demonstrated to stabilize or even increase after exogenous insulin treatment is well installed, with studies reporting age – and gender - expected bone density measurements [
19]. More so, T1D patients with low bone mass are reported to follow lower insulin dose regimens compared to those with normal bone mass [
20].
Disease duration - and not age – proved to be one of the main independent predictors of low femoral neck BMD in T1D patients in our study, suggesting that diabetes-related factors, such as diabetes duration, may be more important for bone. Indeed, T1D patients experiencing diabetes-specific complications had a longer disease history and also the tendency towards lower femoral neck BMD. Low rates of vascular complications have been linked to preserved BMD in long-lasting T1D [
18]. According to recent consensus in the field, diabetes-specific risk factors for fracture include age, low BMD, the presence of complications of diabetes, disease duration, previous fractures and glycemic control (particularly in T1D with HbA1c > 8–9 %) [
21]. Our results are in agreement with other studies reporting long-lasting disease as a risk factor for fragility fractures [
11,
22]. The presence of micro- and macrovascular complications is associated with low BMD [
5,
6] and was also reported to increase fracture risk [
22,
23]. Microvascular complications as a result of collagen glycation and impaired bone turnover due to AGEs are thought to compromise bone quality and material properties, thereby significantly increasing fracture risk [
2,
24,
25]. Although we and others [
26] failed to find any significant BMD variation according to the presence of complications, microvascular damage is demonstrated to alter bone microarchitecture, possibly via VEGF linking diabetic complications and skeletal health. This explains the disproportionate fracture risk in T1D versus T2D, compared to differences in BMD [
27]. Complications are also associated with longer disease history, an independent factor for low BMD, once again supporting the link between bone mass and microarchitecture changes and the long exposure to diabetic milieu. Similar to other studies [
6,
20], we failed to find a significant effect of HbA1c (which shows only the severity of recent diabetes dysregulation) upon BMD. However, we did not assess fracture risk, as long standing poor glycemic control is known to be associated with increased fracture risk, independently of bone mass [
20].
T2D patients in the current study had similar BMD compared to matched controls, although fewer patients in the diabetes group exhibited low bone mass. T2D patients are generally reported to have increased BMD compared to reference populations, although not in all studies [
5,
28]. Potential disease misclassification, lack of a matched control group and inability to adjust for covariates are important sources of bias and heterogeneity [
28]. Diabetes duration is an important confounder: the osteoanabolic effects of the hyperinsulinemia secondary to insulin resistance may explain the apparently higher bone density in early T2D, while insulinopenia in T1D and late T2D is accompanied by sarcopenia and low bone mass [
1]. Despite using metformin which is known to positively impact bone mass and reduce fracture risk [
29,
30], the T2D patients in the current study had a rather long disease history of approximately 10 years, with one quarter also experiencing complications. A diabetes duration longer than 5 years is a risk factor for low bone mass [
31] and the presence of microvascular complications in T2D is associated with lower cortical volumetric BMD and altered bone microarchitecture, namely increased cortical porosity and diminished cortical thickness at the radius [
32]. BMD did not differ in patients with complicated T2D compared to T2D patients without complications in the current study. At the same time, our T2D patients had a good glycemic control, while an increased HbA1c is associated with increased BMD according to the meta-analysis of Ma et al.[
28]. Other meta-analyses failed to find a significant correlation of HbA1c with BMD in T2D [
5]. Also, BMD progressively increases with clinical cutoffs for fasting glucose (normal, impaired and overt T2D) [
33]. However, this increased BMD may be explained by the diminished bone mineral area of these patients, which also exhibit low bone turnover as assessed by serum markers, such as osteocalcin or cross-laps [
33].
An increased BMI is a protective factor against osteoporosis in all populations [
34] (including patients with diabetes [
34]), via the increased mechanical loading. Obesity is a risk factor for insulin resistance and diabetes [
35], being at the same time associated with higher areal and volumetric BMD and improved cortical bone structure [
1,
35]. It also contributes to higher BMD in T2D patients, as demonstrated by the current study and also by many others [
28]. At the same time, diabetes and obesity are associated with systemic inflammation and adipokine dysregulation, all contributing to impaired bone metabolism [
36]. Despite variable BMD, alterations in cortical bone microarchitecture are reported in T2D patients, explaining the higher fracture risk compared to the reference population [
37].
None of the patients in our study were under anti-diabetic therapy known to negatively impact bone mass, such as thiazolidinediones or SGLT-2 inhibitors. While all T2D patients were using the “bone-friendly” metformin, the subgroup also using a sulfonylurea drug tended to have a rather lower BMD, without reaching statistical significance. This is still to be clarified as the mechanisms of action of the sulfonylurea class of medication upon bone remain unelucidated up to present [
38].
Age and gender (female sex was associated with a lower BMD compared to men, independently of other factors) were the main independent BMD predictors in the reference populations in our study. Interestingly, the effect of age, unanimously recognized as a risk factor for low bone mass, was not detected in the T1D and T2D patients in our study. It is possible that other factors surpass the effect of aging upon BMD in diabetes, particularly in young or obese patients.
Our study is limited by the relatively small number of patients, lack of assessment of bone microarchitecture, bone turnover markers or fracture risk. The effect of vitamin D levels, known to be altered in individuals with diabetes [
4], was also not assessed. Nonetheless, the presence of matched control groups for T1D and T2D subjects, respectively, together with the evaluation of BMD predictors in patients with diabetes versus matched healthy individuals are important study strengths.
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