Type 1 diabetes (T1D) is autoimmune disease with chronic hyperglycaemic state. Besides diabetic retinopathy, nephropathy, and neuropathy, T1D is characterized by poor bone health. The reduced bone mineralization and quality/strength, due to hyperglycemia, hypoinsulinemia, autoimmune inflammation, low levels of insulin growth factor-1 (IGF-1), and vitamin D, lead to vertebral/hip fractures. Young age of T1D manifestation, chronic poor glycemic control, high daily insulin dose, low BMI, reduced renal function, and the presence of complications can be helpful in identifying T1D patients at risk of reduced bone mineral density. Although risk factors for fracture risk are still unknown, chronic poor glycemic control and presence of diabetic complications might raise the suspicion of elevated fracture risk in T1D. In the presence of the risk factors, the assessment of bone mineral density by dual-energy X-ray absorptiometry and the search of asymptomatic vertebral fracture by lateral X-ray radiography of thorax-lumbar spine should be recommended. The improvement of glycemic control may have a beneficial effect on bone in T1D. Several experiments showed promising results on using anabolic pharmacological agents (recombinant IGF-1 and parathyroid hormone) in diabetic rodents with bone disorder. Randomized clinical trials are needed in order to test the possible use of bone anabolic therapies in humans with T1D.
Type 1 diabetes (T1D) is an autoimmune disease that precipitates in genetically susceptible individuals by environmental factors. The body’s own immune system attacks the beta-cells in the islets of Langerhans of the pancreas, destroying or damaging them sufficiently to reduce and eliminate insulin production, leading to the hypoinsulinemia and chronic hyperglycaemia [
Chronic hyperglycaemia in T1D leads, in course of time, to chronic complications. Besides acute diabetic complications, nowadays, health providers give more attention to the prevention of disabling chronic complications, such as diabetic retinopathy, nephropathy, neuropathy, and precocious atherosclerosis with early cardiovascular disease. Recently, a major interest has been focused on poor bone metabolism in T1D that can represent an overlooked complication of diabetes.
An association between diabetes and reduced bone mass was firstly described by Albright and Reifenstein in 1948 [
It should be admitted that it is rather difficult to study bone metabolism in such population as children/adolescents whose skeleton is still in the way of growing. Moreover, the majority of studies included the children/adolescents at different stages of puberty and, therefore, at different stages of acquisition of bone mass. This probably, has been one of the main reasons of the lack of concordant results about the impact of diabetes on growing bones. Some authors [
Indeed, the majority of studies, performed on the T1D adults, consistently showed a reduction of BMD either at lumbar spine and/or at femur [
Frequency of reduced BMD in T1D varies largely from 3 to 40% [
Another important observation about bone parameters in T1D, besides low bone mineralization, is the reduced bone size. Indeed, both studies on T1D animals [
Bone strength and bone quality play an important role in the bone health and contribute in the relevant manner to a fracture event.
Biomechanical parameters (maximum load, displacement, energy absorption capacity, stiffness, ultimate stress, toughness, and elastic modulus), measured with tensile test and nanoindentation, reflect how the bone is able to resist the applied load. In the studies [
Few studies addressed the issue of bone quality in T1D. At one hand, STZ-induced diabetic animal models [
In T1D patients the frequency of lifetime fractures at any site has been reported to be increased as compared to counterparts without diabetes [
In conclusion, there is strong evidence that bones in T1D patients are characterized by poor mineralization and smaller and thinner size with reduced bone strength and quality, which can lead to a higher fracture incidence at any site, predominantly at femoral neck.
Bone remodeling consists of bone formation and resorption, which are performed by osteoblasts and osteoclasts, respectively. Remodeling causes renewals to bone by removing old material with microcracks and consequently by constructing a new one. The coupling of these two processes represents a crucial moment in the maintenance of bone health. When the function of osteoblasts and/or osteoclasts is impaired, the bone apposition and resorption are altered, rendering bone remodeling inefficient to repair old material.
Remodeling is regulated by several hormones and cytokines, among which insulin, insulin-like growth factor-1 (IGF-1), parathyroid hormone (PTH), thyroid hormones, cortisol, estrogen, vitamin D, and other cytokines of inflammation such as interleukin-1 and 6 (IL-1,6), tumor necrosis factor-
Osteocalcin is the most abundant noncollagenous protein of the bone matrix. It is a product of differentiated osteoblasts, and it promotes the recruitment and differentiation of circulating monocytes and osteoclasts precursors, suggesting its role on osteoblast-osteoclast interaction and bone resorption [
Several studies demonstrated that bone metabolism in T1D is characterized by low bone turnover and, in particular, by reduced bone formation [
At the molecular level, it is thought that inhibition of the Wnt/
It is possible that hyperglycemia, hypoinsulinemia, and autoimmune inflammation, well known characteristics of T1D, play a crucial role in impairing osteoblast differentiation and function. Moreover, the low levels of IGF-1 [
Pathophysiological aspects of bone disorder in type 1 diabetes.
Hyperglycemia itself, regardless of its etiology, is detrimental for bone. Hyperglycemia may have a direct toxicity for osteoblasts, affecting the osteoblast signaling pathways [
Research over several decades has supported a primary role for insulin and IGF-1 in anabolic bone formation. Expression of insulin and IGF-1 receptors has been detected at different steps of osteoblast differentiation, from preosteoblast to mature ones [
As it has been already mentioned before, T1D is characterized by hypoinsulinemia and also by an IGF-1 decrease [
Beside the insulin and IGF-1 levels reduction, recent studies on diabetic rodents [
Therefore, the presence of hypoinsulinemia, IGF-1 reduction, and of an altered signaling of these molecules can impair both osteoblastic function and the osteogenic potential of BMSCs, leading to reduced bone formation.
Autoimmune inflammatory state is one of pathogenic characteristics of T1D. In humans, some studies indicate no inflammation while others indicate higher intracellular TNF-
However, this is only animal models, and there are no human studies so far. Therefore, this topic about the link between autoimmune inflammation and bone damage in T1D still remains less explored.
Vitamin D plays an important role in the bone health. Its active form 1,25(OH)2D interacts with its vitamin D nuclear receptor, which is present in the small intestine, kidneys, and other tissues. It stimulates intestinal calcium absorption and calcium reabsorption from the glomerular filtrate. 1,25(OH)2D interacts with its vitamin D receptor in the osteoblast, stimulating the expression of receptor activator of nuclear factor B ligand (RANKL). This, in turn, interacts with receptor activator of nuclear factor B (RANK) to induce immature monocytes to become mature osteoclasts, which dissolve the matrix and mobilize calcium and other minerals from the skeleton [
Vitamin D insufficiency/deficiency in T1D is a common finding in most [
when evaluating T1D patients in clinical practice, it is very important to give the answers to the following questions: who is at the risk of bone disorder and who should be evaluated for it? In order to respond correctly to these questions, adequate algorithms, including clinical factors able to reflect poor bone health in T1D, should be developed.
Clinical factors associated with poor bone health in T1D can be divided into two groups (Table
Clinical risk factors associated with poor bone health in T1D.
Clinical risk factors for low bone mineralization | Clinical risk factors for fracture risk |
---|---|
(1) Young age of T1D manifestation |
(1) Low lumbar spine BMD (only for moderate and severe vertebral fractures) |
T1D: type 1 diabetes; BMD: bone mineral density; BMI: body mass index.
The age of diabetes manifestation, disease duration, glycosylated hemoglobin (HbA1c), diabetic complications, daily insulin dose, BMI, and renal function can give information about the possible presence of low BMD in T1D.
The age of T1D manifestation may be crucial for the acquisition of bone mass. Although data about bone mineralization in children/adolescents are inconsistent, some authors [
On the other hand, the majority of studies have found no association between low BMD and duration of T1D [
On the basis of the data regarding the effect of hyperglycemia on osteoblast, one could expect to find an association between BMD and glycometabolic control as reflected by HbA1c. However, only few studies have found the link between poor glycemic control and low BMD [
Semantic connectivity map of studied variables. The figures on the connections represent the strength of the link on a 0-1 scale. Low BMD femur, presence of low F-BMD; low BMD spine, presence of low LS-BMD. Males and females are both connected to neuropathy but with a different conditional probability. The link for females is stronger (0.95) than it is for males (0.93). BMD: bone mineral density; F: femur; LS: lumbar spine; BMI: body mass index; ClCr: clearance creatinine; HbA1c: glycosylated hemoglobin. (Diabetes care by American Diabetes Association Reproduced with permission of American Diabetes Association in the format Journal/magazine via Copyright Clearance Center. Order Detail ID: 64182026).
The chronic diabetes complications
Insulin is considered an anabolic agent for bone [
Beside all the factors described above, some studies [
Finally, kidney function seems to be important for femoral BMD not only in general population [
Interestingly, Eller-Vainicher and coauthors [
Besides BMD, the other BMD-independent clinical factors associated with fractures have not been well studied. However, one can hypothesize that HbA1c and diabetic complications, being the result of high blood glucose levels, may be associated with fractures in T1D.
Although low bone mass is a common finding in T1D, it seems that low BMD is of poor fracture prediction in this kind of patients [
Since the elevated fracture risk in T1D seems to be related to reduced bone quality and strength rather than to reduced bone mass and AGEs (the effect of the chronic hyperglycemia) are the main responsible of low bone quality, the association between fractures and HbA1c should be logical. Nevertheless, only in one study [
The diabetic complications
In our study we tried to define an algorithm for individuating the T1D patients to be screened for bone damage. In summary, in T1D patients with the diabetic complications (retinopathy, nephropathy, and neuropathy) and/or with daily insulin dose > 0.67 U/kg, BMI < 23.5 kg/m2, and renal function < 88.8 mL/min, the screening for the bone disorder (low bone mineralization + high fracture risk) should be recommended.
There is still no consensus on the correct evaluation and management of T1D patients at risk of bone disorder. However, we propose the following measures which are necessary to be done in these patients (Figure
Flow-chat for evaluation, management, and treatment of T1D patients at risk of bone disorder.
In order to exclude other possible causes of secondary osteoporosis some laboratory tests should be performed including [
In order to assess bone mineralization and the presence of vertebral fractures, a DXA evaluation at lumbar spine and at femoral neck and lateral X-ray radiography of thorax-lumbar spine or DXA combined with vertebral fracture assessment (VFA) should be performed [
The best approach to treat patients with T1D related bone disorder is still not clear. On the basis of the pathogenesis of the bone disorder in T1D, the following strategies may lead to the improvement of poor bone health: (1) restoration of hypoinsulinemia and glycometabolic control; (2) reduction of autoimmune inflammation; (3) restoration of low levels of IGF-1; and (4) restoration of low levels of vitamin D.
Since hypoinsulinemia and hyperglycemia play an important role in damaging bone, insulin treatment accompanied by reduction of glycaemia seems to be the pivotal point in treatment and prevention of bone disorder in T1D. In the prospective study of Campos Pastor et al. [
Recently several experiments on animal models have been focused on the reduction of autoimmune inflammation and on the treatment with recombinant IGF-1 (rhIGF-1), in order to improve bone mineralization and quality in T1D. Treatment with TNF-
The efficacy of vitamin D on T1D related bone damage has been examined only minimally in animal models. In the STZ-induced rat model of T1D, low femoral BMD has improved significantly after treatment with 1
As T1D related osteoporosis is characterized by a reduced bone apposition and osteoblast differentiation and function, the anabolic therapy with PTH seems to be an interesting option. Motyl et al. [
Finally, weight-bearing physical activity has been recently demonstrated to have a positive effect on bone mineral acquisition in children with T1D, similarly to what happen in children without T1D [
Due to the lack of data on the possible therapeutic options on humans, most recommendations that can be given nowadays to the T1D patients at risk and with manifested bone disorder are derived from the good clinical practice and from the experience of the physician rather than from evidence-based guidelines.
Intensive insulin treatment, being a standard treatment of T1D, with improvement of glycemic control should be taken in consideration in all patients. Insulin with reduction of hyperglycemia would be beneficial not only for bone but also for prevention of chronic diabetic complications. Annual screening for microalbuminuria, annual ophthalmologic exam, and annual testing for pressure and vibration sensation should be performed in order to reach early diagnosis of diabetic nephropathy, retinopathy, and neuropathy, respectively.
Supplementation with calcium and vitamin D should be advised to the T1D patients with bone disorder. A daily uptake of 1200 mg calcium is generally required, ideally through the diet, but supplementation can be used if dietary uptake is inadequate. According to the guidelines regarding prevention and treatment of vitamin D deficiency [
Weight-bearing sports, including ball games, jumping activities, or gymnastics should be encouraged in T1D children to optimize bone mineral acquisition during growth and potentially prevent the development of osteoporosis later in life [
At the end of this chapter we propose a flow-chat (Figure
In summary, T1D is characterized by poor bone health, which should be recognized as a diabetic complication among the other well-known complications such as retinopathy, nephropathy, and neuropathy. Slow bone turnover is the main characteristic of T1D-associated bone disorder, which leads to reduced mineralization and reduced quality and strength with consequent fracture event as the most important clinical manifestation. Although during last decade many studies both on animals and humans have been focused on the pathogenesis of T1D related bone damage and on the risk factors for the identification of T1D patients at risk of bone disorder, several questions still remain to be answered.
Firstly, since BMD represents a poor clinical tool for fracture prediction, as it often happens in case of secondary osteoporosis [
Secondly, it is possible that good glycemic control may exert a beneficial effect on bone, but it is not clear how strict we should maintain glycemic control and below which level we should lower HbA1c in order to prevent or improve bone disorder in T1D. Therefore, we need prospective studies focused on the changes of bone metabolism/mineralization/fracture risk after intensification of insulin treatment (e.g., through insulin pump), which is known to lead to a notable improvement of glycemic control.
Finally, it is not clear yet what kind of drugs should be used in T1D patients with manifested bone disorder, who do not improve with only good glycemic control and supplementation of calcium/vitamin D and who, probably, need pharmacological intervention. Some promising results seem to come from the use of anabolic pharmacological agents (rhIGF-1 and PTH) in diabetic rodents with bone disorder. Therefore, randomized clinical trials are needed in order to understand whether it could be the case in humans.
The authors declare that there is no conflict of interests regarding the publication of this paper.