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 Table of Contents  
ORIGINAL ARTICLE
Year : 2021  |  Volume : 16  |  Issue : 3  |  Page : 276-283

Effect of type 2 diabetes mellitus on bone mineral density in patients with rheumatoid arthritis


1 Department of Rheumatology, Omkar Rheumatology Clinic, Nashik, Maharashtra, India
2 Research Officer, Hirabai Cowasji Jehangir Medical Research Institute, Pune, Maharashtra, India

Date of Submission19-Oct-2020
Date of Acceptance10-Mar-2021
Date of Web Publication21-Sep-2021

Correspondence Address:
Dr. Praveen Pratap Jadhav
Department of Rheumatology, Omkar Rheumatology Clinic, Nashik Road, MH 422101
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_293_20

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  Abstract 


Background: RA affection of bone manifests as low bone mineral density (BMD), generalised osteoporosis and increased risk of fragility fractures. Whereas, Type 2 Diabetes Mellitus (T2DM) produces many micro and macro vascular complications, its effects on bone and bone density is not very clear. The effect of coexistent RA and T2DM on BMD has not been well studied.
Objective: The aim of this study was to investigate the effect of T2DM on BMD in patients with newly diagnosed RA.
Methods: Patients diagnosed as RA were assigned to undergo BMD testing. Patients with T2DM were gathered from this population and formed a separate group. Healthy controls were drawn from subjects who came for a check-up. BMD was done with the GE Lunar DPX machine. Mean T Scores at spine, femur neck and total femur were recorded. Multivariate analysis was performed to compare T scores at various sites in the 3 groups. Age, gender, and steroid use were checked as confounding factors.
Results: A total of 449 patients were diagnosed as RA during the period of 48 months. Of these, 337 (M-56, F-321) diagnosed as RA who had their BMD examined were enrolled in the study. Five hundred and one (M-248, F-253) healthy controls were enrolled. The mean T score values at femur neck, femur total and spine were -1.2+0.9, -0.8+1, -1.2+1.3 for controls, -2.4+0.8, -2.2+0.9, -2.9+0.9 for patients with RA and -1.7+1, -1.3+1, -1.7+1.2 for patients with RA+T2DM. The T scores at all sites in patients with additional T2DM were significantly better than those with only RA but significantly less than compared to controls. Similar results were obtained when separate analyses were done for males and females.
Conclusion: Coexisting T2DM partly negates the low BMD measures and present with significantly higher values as compared to RA alone. In patients with this co morbidity, the BMD measures should be read with caution. With increasing evidence of diabetics having higher fragility fracture risk, measures other than the standard BMD need to be investigated which can quantify the exact fracture risk in patients with RA and T2DM.

Keywords: Bone mineral density, rheumatoid arthritis, type 2 diabetes mellitus


How to cite this article:
Jadhav PP, Patwardhan VG. Effect of type 2 diabetes mellitus on bone mineral density in patients with rheumatoid arthritis. Indian J Rheumatol 2021;16:276-83

How to cite this URL:
Jadhav PP, Patwardhan VG. Effect of type 2 diabetes mellitus on bone mineral density in patients with rheumatoid arthritis. Indian J Rheumatol [serial online] 2021 [cited 2021 Dec 5];16:276-83. Available from: https://www.indianjrheumatol.com/text.asp?2021/16/3/276/324121




  Introduction Top


Rheumatoid Arthritis (RA) is a chronic inflammatory disease which affects multiple organs. The involvement of bone in RA manifests as low bone mineral density (BMD),[1],[2] generalized osteoporosis,[3],[4] and increased risk of fragility fractures.[5],[6] In fact, this has led to inclusion of RA as one of the key factors determining the risk of fractures in the assessment of fracture risk assessment score (FRAX).[7]

Type 2 diabetes mellitus (T2DM) is also a chronic disease with multisystem involvement. Although the micro- and macrovascular complications are well known, the knowledge about its effects on bone and bone density is not very clear. Many studies have shown that T2DM has a positive effect on BMD,[8],[9],[10],[11] some have shown none,[12],[13] while a few others have shown a variable effect at different sites.[14],[15] In spite of reports of variable effect of T2DM on BMD, most studies have shown an increased risk of fragility fractures in patients with T2DM,[8],[16],[17] and a few show no raised risk for fragility fractures.[9]

However, the effect of coexistent RA and T2DM on BMD has not been well studied. The primary aim of this study was to investigate the effect of T2DM on BMD in patients with newly diagnosed RA. Since RA and osteoporosis mainly affect women, we also wanted to check if gender had a differential effect on BMD in diabetics with RA. Another secondary aim was to study the effect of confounders such as age, body mass index (BMI), and steroid use on BMD parameters in patients with RA and T2DM.


  Methods Top


This was a single-center observational study. Patients with the diagnosis of RA were enrolled in the study and were assigned to undergo BMD testing. The diagnosis of RA was based on the American College of Rheumatology Criteria 2010.

Patients with T2DM were gathered from this population to form a separate group. These patients were diagnosed as diabetics prior to their diagnosis of RA by their primary physicians based on their fasting blood sugar levels (>126 mg %) and post lunch blood sugar levels (>200 mg %). All these patients were on medications.

A total of 449 patients were diagnosed as RA during the period of 48 months from January 2016 to December 2019. Apart from their anthropological data, information about their comorbidities and history of steroid consumption was obtained. Of these, 72 patients refused to giving consent to undergo BMD testing. A total of 377 patients (male – 56, female – 321) diagnosed as RA who had their BMD examined were enrolled in the study. Of these, 75 (male – 17, female – 56) patients had T2DM. The average duration of T2DM was 3.5 years.

Five hundred and one (male – 248, female – 253) healthy controls were drawn from subjects who came for a health check-up during the same period. As a group, the controls were age matched with patients in the study. Unlike the study population of RA which had female preponderance, the controls had an almost equal number of males and females. Hence, after their initial comparison with the above two patient groups, the controls were divided based on their genders. Male and female patient groups were analyzed separately with gender-matched controls.

Ethical committee clearance was obtained from the institutional ethics committee vide letter number ECM1/03/15 dated November 15, 2015.

BMD was analyzed using the GE Lunar DPX machine. The mean T-scores at the spine, femur neck, and total femur were recorded.

Data were analyzed using the SPSS software for Windows (version 26.0, IBM Corporation, USA). Normality of the variables was tested using skewness, kurtosis, one-sample Kolmogorov–Smirnov test, and Shapiro–Wilk test before performing statistical analysis. Levene's test was used to test homogeneity of variance. Continuous variables were presented as mean with standard deviation. In the entire study, P < 0.05 was considered to be statistically significant. All the hypotheses were formulated using two-tailed alternatives against each null hypothesis (hypothesis of no difference). One-way ANOVA was used to examine differences in mean of variables between groups. Kruskal–Wallis test was used for nonnormal data. Welsh correction was used for nonhomogeneous data.


  Results Top


The results indicated that as compared to controls, patients with only RA had significantly lower T-scores at the spine, total femur, and femur neck. Compared to patients with only RA, patients with additional T2DM had higher T-scores at all three sites. The controls had significantly superior T-scores at all three sites as compared to the other two groups. The patients with coexisting RA and T2DM had intermediate T-score values at all three sites, with values lying between those of controls and patients with only RA [Table 1].
Table 1: Comparison of mean age, body mass index, and T-scores at various sites in different groups

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A separate analysis was done for men and women with age- and gender-matched controls. Subset analysis based on gender showed only minor differences as compared to the whole group. The behavior of T-scores in the female group was similar to behavior of T-scores of the total population. This was expected since women formed 83% of the population. The results indicated that in females, the overall significant difference was seen in mean age (P < 0.05), BMI (P < 0.05), T-score femur neck (P < 0.05), T-score femur total (P < 0.05), and T-score spine (P < 0.05) between controls, patients with RA, and patients with RA and coexisting T2DM. In males, the overall significant difference was seen in mean BMI (P < 0.05), T-score femur neck (P < 0.05), T-score femur total (P < 0.05), and T-score spine (P < 0.05) between controls, patients with RA, and patients with RA and coexisting T2DM. In males with T2DM and RA, the T-scores at the spine and total femur were significantly better than males with RA alone but were not significantly different than in controls. The T-scores at the femur neck in diabetic males had a trend toward superiority over that of RA alone but did not reach significance [Figure 1], [Figure 2], [Figure 3].
Figure 1: Box plot showing T-scores at the femur neck in different groups

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Figure 2: Box plot showing T-scores for the total femur in different groups

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Figure 3: Box plot showing T-score at the spine in different groups

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Analysis indicated that in female patients, age was significantly higher (P < 0.01) in patients with additional T2DM than in patients with RA alone, while there was no statistically significant difference between all three groups in males [Figure 4]. In females, BMI was significantly different in all three groups (P < 0.05), being highest in controls and lowest in RA group. In males, BMI was significantly (P < 0.01) lower in RA patients compared to patients with coexisting T2DM and also with controls, while no statistically significant difference was seen in patients with RA + T2DM patients and controls [Figure 5].
Figure 4: Box plot showing T-scores by age

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Figure 5: Box plot showing T-scores by body mass index. RA: Rheumatoid arthritis, T2DM: Type 2 Diabetes mellitus, BMI: Body mass index

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Linear regression analysis suggested that the age had inverse and BMI had direct correlation with BMD in all groups. The results from multiple regression analysis suggested that BMI alone did not explain the higher T-score values in RA + T2DM patients.


  Discussion Top


T2DM is a chronic disease, whose incidence is increasing at alarming proportions. Like in the general population, the incidence of T2DM in rheumatologic diseases is also expected to rise proportionately. In patients with RA, BMD is checked by DEXA scan, which is commonly used to evaluate the bone health. Decisions to treat osteopenia and osteoporosis and prevent fragility fractures depend on the results of BMD measures and FRAX scores. Hence, rheumatologists should be aware of how the coexisting T2DM can affect the bone density as examined by DEXA scan.

RA causes bone loss and negatively affects the BMD which is further confirmed by this study.[1],[2],[3],[4],[18] The group of patients with only RA had the significantly low BMD parameters as compared to the controls. Various mechanisms have been postulated for the same. Probable causes of bone loss in RA include active systemic inflammation, immobilization, and the use of glucocorticoids.[19] Evidence indicates that bone loss in RA is related to reduced bone formation and increased bone resorption.[20] The systemic and synovial inflammation is mediated by bone-resorbing cytokines such as interleukin (IL)-1α and IL-1 β, tumor necrosis factor (TNF)-α, macrophage colony-stimulating factor, IL-6, IL-11, parathormone-related peptide, and the T-cell-derived cytokine IL-17.[20] These cytokines upregulate RANKL, which, in turn, increases the differentiation, proliferation, and survival of osteoclasts, ultimately leading to bone loss.[21] TNF, as a potent inducer of dickkopf-related protein 1, inhibits the wingless (Wnt) signaling pathway causing limitation of bone formation.[22] TNF-α also acts by inducing production of other pro-inflammatory cytokines such as IL-1, IL-6, and IL-8 in RA.[22] In fact, biologic drugs blocking these cytokines, especially TNF α blockers, have shown to steady or reverse the osteoporotic effect of RA on bones.[23]

More importantly, this study suggests that the additional comorbidity of T2DM partially negates the effect of RA on BMD. The results suggest that diabetic patients with RA have significantly higher BMD parameters as compared to patients with RA alone but significantly lower than the controls.

In contrast to RA, the association between T2DM (without RA) and BMD measures is inconsistent. While a few studies have shown no association,[13],[14] most other studies have shown a positive effect of T2DM on BMD.[9],[10],[12],[24] Morever, meta-analysis of 15 studies by Ma et al concluded that T2DM has a positive effect on BMD in both sexes.[15] We did not find any study examining the effects of T2DM on BMD in RA patients. To the best of our knowledge, this is the first study to suggest that T2DM negates the effect of RA on BMD.

Different mechanisms have been put forth to explain the higher BMD in diabetics. Similar mechanisms can be extrapolated to explain higher BMD in our patients with RA and coexisting T2DM. These mechanisms could be so strong that they probably override the negative effect of RA on BMD. The association of various confounders such as age, BMI, and steroid use could possibly account for this effect. We studied the effect of these confounders on BMD in our population.

In our study population, women with additional T2DM were significantly older than those with only RA. No age difference was found in men between different groups [Figure 2]. In general, RA is supposed to affect the patients at a younger age, while T2DM strikes at maturity (older age). Increasing age has shown to be negatively associated with BMD values.[25] However, in spite of the significantly higher age, BMD values were significantly higher in diabetic women with RA than in women with RA alone. Hence, it can be concluded that age may not have a role in determining the BMD measures in diabetic patients with RA.

The diabetic patients in our group had a significantly higher BMI as compared to patients with RA alone [Figure 2]. This may be an important mechanism which may help to explain the higher BMD measures in diabetics. Higher BMI has shown to be associated with higher BMDs in earlier studies too. A meta-analysis has shown that BMD is higher in overweight and obese diabetics.[15] Several mechanisms can cause higher BMD in obese people. Higher plasma leptin in diabetics,[26] known to stimulate osteoblasts and bone formation in vitro,[27] can help to increase both BMI and BMD. Evidence indicates that circulating adiponectin[28] is reduced in T2DM. Recent reports demonstrate that patients with higher adiponectin levels have lower BMD.[29] Although these hormonal mechanisms may help to explain the effect of high BMI on BMD, multiple regression analysis of our data indicates that BMI alone may not be responsible for a higher BMD measures in patients with RA and T2DM.

In our group, 49% of RA patients and 32% from the RA + T2DM group had a history of steroid consumption at the time of performing BMD. An analysis of BMD parameters of steroid users and nonusers of both the groups was performed [Table 2]. There was no statistically significant difference in BMD parameters of steroid users and nonusers in either group. Thus, in our population, steroid use did not affect the BMD values. The probable reason for this was that steroids were used for short term prior to the diagnosis of RA. In larger population and in real-world scenario, it can be anticipated that steroid use would further reduce the BMD values in patients with RA.[19] Moreover, in patients with additional diabetes, the use of steroids would be restricted to bare minimum, thus contributing to a wider gap in BMD values between the two groups.
Table 2: The effect of steroids on various bone mineral density parameters in patients with rheumatoid arthritis and rheumatoid arthritis + type 2 diabetes mellitus

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Estimation of insulin levels was beyond the scope of our study. This could be another mechanism which could partly explain a higher BMD in diabetics, with or without RA. Type 2 diabetics are known to have higher insulin levels. Structurally, insulin has a lot of similarity with insulin-like growth factor 1 (IGF-1). IGF-1 has been shown to contribute to inhibition of bone resorption and in maintaining the bone mass of the proximal femur in men aged <60 years.[30] A review of 14 studies checking the effect of IGF-1 therapy for low bone density showed some bone resorption, but a significant bone formation leads to an anabolic bone effect.[31]

Some drugs used in T2DM could also be responsible for an improved BMD in diabetics. Metformin[32] and statins[33] have been suggested to favorably affect the BMD. The usage of these medications is expected to be more in the diabetic group than the nondiabetic group of RA patients. Due to the fewer number of diabetic patients and meager data of their drug consumption, it was difficult to decipher the effect of these drugs on BMD from our data.

Thus, BMI seems to be the main, but not the only, factor which may be responsible for elevated BMD parameter in diabetics with RA. Higher insulin levels in T2DM could be another factor responsible for the same.

Does higher BMD translate into protection against fragility fractures?

Whether the higher bone density in patients with RA and T2DM translates into protection against fragility fractures is not known. We are not aware of a subgroup analysis of the incidence of fragility fractures in patients with RA and coexisting T2DM. Longitudinal studies in this population will be immensely helpful but are lacking. While some studies have not shown an increased risk of fragility fractures in diabetics (without RA),[9] most others have shown an elevated risk.[8],[16],[17] Researchers argue that in spite of a higher BMD, the quality of the bones in diabetics is not up to the mark. Poor glycemic control is shown to be associated with thicker femoral cortices in narrower bones, high BMD, and a high fracture risk.[8] This fragility in apparently “strong” bones in poorly controlled diabetics could result from microcrack accumulation and/or cortical porosity, reflecting impaired bone repair.[8] The BMD is a measure of both cortical and medullary bone densities. However, in diabetics, it is the cortical bone, rather than the medullary bone which has been shown to be affected. Indeed, studies using high-resolution peripheral quantitative computed tomography reported up to twice the cortical porosity in type 2 diabetics as compared to controls.[34]

Presuming that the risk of fragility fractures in diabetics is elevated, this study suggests the inability of the standard BMD to explain this risk. Hence, till the time we have a definitive answer on the probability of fragility fractures in diabetic patients with RA, the readings of BMD measures in these patients should be viewed with caution. The usual way of determining the bone quality by DEXA scan may not be valid in diabetic patients.

This study raises several questions. A few of the postulated mechanisms like hyperinsulinemia used to explain the improved BMD in diabetics should have made an explanation for “good” quality of bone. However, it seems absurd that a chronic inflammatory disease like diabetes, especially if poorly controlled, can cause improvement in bone quality. Indeed, the exact nature of the quality of bone, histopathologically and biochemically, in diabetics has not been fully characterized. There is a huge gap in understanding the nature of bone in diabetics. This study underscores the need of research in bone health of diabetics. Second, whatever the mechanism, it appears that the effect of T2DM on bone density seems to be quite profound. The phenomenon of overriding the negative effects of RA on bone density is remarkable and needs further research.

There could be a few drawbacks to this study. Ideally, the incidence of fractures should have been determined in the study population. This could be an important topic for further research. Second, not all diabetic patients had their HbA1C levels done at the time of their BMD as their diabetes was being managed by their primary physicians. Hence, the level of control of their diabetes at the time of their study was not known. Therefore, we could not ascertain the effect of diabetes control on BMD. Finally, estimation of insulin levels in diabetics could have helped to elucidate the mechanism of the observed phenomenon.


  Conclusion Top


This study suggests that RA patients with coexisting T2DM have significantly higher BMD measures as compared to patients with RA alone. Hence, in these patients, the BMD measures should be read with caution. With increasing evidence of diabetics having higher fragility fracture risk, measures other than the standard BMD need to be investigated which can quantify the exact risk in these patients. More importantly, longitudinal studies need to be conducted the check the incidence of fragility fractures in patients with RA and T2DM.

Acknowledgment

We thank Dr. Vinod Ravindran for his help in preparation of this manuscript.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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