Next Article in Journal
Heat Shock Protein 27 Affects Myeloid Cell Activation and Interaction with Prostate Cancer Cells
Next Article in Special Issue
Clinical Usefulness of Non-Invasive Metabolic-Associated Fatty Liver Disease Risk Assessment Methods in Patients with Full-Blown Polycystic Ovary Syndrome in Relation to the MRI Examination with the Ideal IQ Sequence
Previous Article in Journal
Comparative Analysis of Co-Cultured Amniotic Cell-Conditioned Media with Cell-Free Amniotic Fluid Reveals Differential Effects on Epithelial–Mesenchymal Transition and Myofibroblast Activation
Previous Article in Special Issue
Cortisol as an Independent Predictor of Unfavorable Outcomes in Hospitalized COVID-19 Patients
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 10
Issue 9
10.3390/biomedicines10092191
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Treatment of Diabetes and Osteoporosis—A Reciprocal Risk?

by
Agnieszka Zawada
1,*,
Alicja Ewa Ratajczak
1,2,*,
Anna Maria Rychter
1,2,
Aleksandra Szymczak-Tomczak
1,
Agnieszka Dobrowolska
1 and
Iwona Krela-Kaźmierczak
1
1
Department of Gastroenterology, Dietetics and Internal Diseases, Poznan University of Medical Sciences, 61-701 Poznn, Poland
2
Doctoral School, Poznan University of Medical Sciences, 61-701 Poznan, Poland
*
Authors to whom correspondence should be addressed.
Biomedicines 2022, 10(9), 2191; https://doi.org/10.3390/biomedicines10092191
Submission received: 5 August 2022 / Revised: 29 August 2022 / Accepted: 30 August 2022 / Published: 5 September 2022
(This article belongs to the Special Issue State-of-the-Art Endocrinology and Metabolism Research in Poland)
Browse Figure
Versions Notes

Abstract

:
Diabetes mellitus is a metabolic and systematic disorder that requires individualized therapy. The disease leads to various consequences, resulting in the destruction of tissues and organs. The aforementioned outcomes also include bone mineral disorders, caused by medications as well as diet therapy and physical activity. Some drugs may have a beneficial effect on both bone mineral density and the risk of fractures. Nevertheless, the impact of other medications remains unknown. Focusing on pharmacotherapy in diabetes may prevent bone mineral disorders and influence both the treatment and quality of life in patients suffering from diabetes mellitus. On the other hand, anti-osteoporosis drugs, such as antiresorptive or anabolic drugs, as well as drugs with a mixed mechanism of action, may affect carbohydrate metabolism, particularly in patients with diabetes. Therefore, the treatment of diabetes as well as osteoporosis prevention are vital for this group of patients.

1. Introduction

According to the definition, diabetes mellitus (DM) represents a group of metabolic disorders characterized by chronic hyperglycemia, which stems from impaired production or action of insulin. The incidence of osteoporosis in patients with diabetes is influenced by a number of factors, such as the co-occurrence of obesity, the type and duration of diabetes, the presence of chronic complications, as well as the type of therapy applied. In type 2 diabetes, increased body fat inhibits the expression of genes involved in osteoblastogenesis. Furthermore, it also directly increases the expression of peroxisome proliferator activated receptor gamma (PPARγ receptors) and stimulates the Wnt/protein kinase C pathway [1,2]. Additionally, hyperglycemia occurring in diabetes induces oxidative stress and the formation of reactive oxygen species and advanced glycation end products-AGE (protein glycation) [3]. This, in turn, leads to the inhibition of osteoblasts, stimulation of osteoclasts, and increased bone turnover [4]. In type 1 diabetes, increased expression of growth factors IGF-1 and TGF-B1 results in a decreased bone mineral density. Conversely, in type 2 diabetes, excessive hyperinsulinemia leads to the stimulation of the IGF-1 receptor present on osteoblasts, resulting in an increased BMD. Nevertheless patients with this type of diabetes are also prone to fractures. Moreover, as experimental studies demonstrate, chronic hyperglycemia also affects every stage of bone formation, e.g., changes in bone microcirculation are observed in patients with a long history of hyperglycemia. In fact, since chronic hyperglycemia impairs osteoblastic function, it also possibly increases bone resorption [5].
Chronic hyperglycemia constitutes a strain on the body and affects various organs and systems [6]. Nevertheless, effective treatment maintains normal glycemia and may prevent the development of chronic consequences of DM [7]. A conceptual breakthrough in diabetes treatment has been visible in recent years. New medications and clinical trials taking into account evidence-based medicine, such as LIDER and EMPAREG OUTCAME, have changed the goal of diabetes treatment to achieve a reduction in glycemia and a decrease in mortality [8,9]. However, the treatment applying new anti-hyperglycemic agents should be supported by behavioral treatment on every step of diabetes therapy, because proper diet and physical activity may also prevent the consequences of diabetes [10]. Bone mineral disorder has been known for a number of years, although it has been underestimated as a complication of DM [11]. Therefore, it is interesting to observe how new, although known for a number of years, drugs together with behavioral treatment affect bone mineral balance. Additionally, diet and supplementation remain underestimated in preventing the abovementioned consequences in patients with DM. Hence, developing guidelines, early diagnosis, and proper supplementation in the early stages of bone mineral disorders may be effective in therapy of this complication among patients suffering from DM.

2. Dietary Management of Diabetes and Bone Metabolism: Do They Carry the Risk of Developing Osteoporosis?

2.1. Calcium

Calcium intake may protect against overweight and obesity, which are one of the risk factors associated with type 2 diabetes mellitus. Varenna et al. demonstrated an inverse relationship between BMI and increasing the dairy intake [12]. Their study suggests that calcium intake may protect against overweight and obesity as well as osteoporosis. Moreover, dairy calcium intake increases weight loss among patients suffering from T2DM [13], and the consumption of dairy products may help to maintain weight loss [14]. Nevertheless, 25-week long supplementation of calcium did not increase body weight and fat mass loss when compared with placebo [15].
Energy restriction reduces calcium absorption in comparison with a group with normal energy intake. Therefore, calcium intake should be greater during a weight loss diet since normal intake may disturb calcium balance [16]. It is worth bearing in mind that there was a difference in calcium intake in overweight patients who were on the intermittent fasting, Paleolithic, or Mediterranean diets, and the intake was found to be highest among patients on the Mediterranean diet. Additionally, energy intake was the highest in patients on the Mediterranean diet [17].

2.2. Vitamin D

Hemoglobin A1c was found to be inversely correlated to vitamin D level among patients suffering from T2DM [18]. According to Nam et al., children with T1DM presented lower concentrations of serum 25OHD and 1,25(OH)2 D when compared with the healthy population [19].
Due to the high affinity of adipose tissue for vitamin D, the incidence of obesity promotes the sequestration of vitamin D in adipose tissue. This results in a significant reduction in its serum levels compared to individuals presenting with normal weight [20].
In turn, the excess adipose tissue found in obesity and diabetes promotes the formation of reactive oxygen species, which significantly reduces the bioavailability of vitamin D. In fact, vitamin D decreases the expression of L-type Ca2+ channels, which reduces intracellular Ca2+ concentration. This, in turn, directly impacts intracellular calcium signaling, affecting insulin secretion by the pancreatic beta cells [21].
By means of affecting the passage of calcium across cell membranes, vitamin D also affects tissue sensitivity to insulin [22]. In addition, it also affects the expression of insulin receptors in the peripheral cells. Modulating the expression and the activity of cytokines reduces the overall pool of inflammatory response in the body, which is particularly important in patients with obesity and diabetes [23,24].
Vitamin D synthesis and metabolism may also be impaired in hepatic steatosis coexisting with obesity and overweight [25]. In addition, high levels of leptin and IL-6 impair the synthesis of this vitamin.
Additionally, the study demonstrated that the risk of abdominal obesity decreased by 8% when serum vitamin D levels increased by 25 nmol/L [26]. Moreover, low levels of vitamin D were also associated with an increase in adiposity and a higher fat infiltration in the muscle tissue [27]. In fact, vitamin D levels were lower among adolescents with obesity when compared with non-obese individuals [28]. It is important to note that low vitamin D levels in children have been linked to obesity but not to other cardiovascular risk factors such as hyperglycemia [29]. Additionally, vitamin D was negatively associated with BMI [30], although no association was found between vitamin D intake and low muscle mass [31]. As the mentioned studies indicate, vitamin D metabolism is significantly related to adipose tissue content. Thus, maintaining its normal levels in metabolic diseases may be crucial for reducing overall inflammation, improving, and compensating for carbohydrate disorders.

2.3. Low-Calorie Diet and Bodyweight Reduction

Undoubtedly, type 2 diabetes is strongly associated with obesity. However, patients with type 1 diabetes are more frequently diagnosed with excessive body weight, which is surprising, since clinical features of T1DM have been generally associated with weight-loss [32,33]. Regardless of diabetes type, a low-calorie diet (LCD) must be implemented in every patient with excessive body weight, not only for improving the glycemic control but also for the prevention of exacerbating comorbidities, which are already likely to be at an increased risk due to long-term hyperglycemia. Moreover, LCD should be introduced by a professional dietitian who should guide the patient through every stage of the weight-loss process. It is especially important because a poorly balanced LCD may lead to nutritional deficiencies, which in turn may deteriorate the course of the disease and the resulting comorbidities, including osteoporosis [34,35,36]. However, it should be noted that only a few studies investigated micronutrient deficiencies and LCD, especially in the context of diabetes and osteoporosis, and several individual factors may affect the real-life pattern. Damms-Machado et al. discovered that individuals with obesity undergoing LCD, the lowest micronutrients intake (compared to the dietary reference intake) was observed for retinol, vitamin C, vitamin E, vitamin D, folate, iodine, iron, calcium, and β-carotene—thus, nutrients vital for proper bone health were deficient in the majority of the study group [37]. Gardner et al. assessed micronutrient intake in four weight-loss diets (Atkins, LEARN, Zone, and Ornish) and found that each of them was characterized by inadequate intake of several micronutrients, among them vitamin C, vitamin E, and folate, which could negatively impact bone mineral density in the future [38]. Moreover, alternative weight loss strategies (e.g., very poor ketogenic diet) are becoming increasingly popular among patients and, as with any highly restrictive diet, may increase the risk of deficiencies to an even greater extent (if introduced improperly and without professional care) [39].

3. Antidiabetic Drugs and Bone Tissue Metabolism

Antidiabetic drugs may affect bone metabolism in a neutral, positive, or negative way. However, many clinical studies do not correspond to experimental studies.

3.1. Metformin

Metformin presents a pleiotropic mechanism, although it may also affect bone metabolism. The main action of metformin includes the activation of AMP-activated protein kinase (AMPK). AMPK may directly influence bone turnover by increasing osteoblastogenesis and decreasing osteoclastogenesis. Metformin increases osteogenesis by activating the AMPK and fructose 1,6-biphosphate pathways [40]. According to the experimental studies, metformin activates the differentiation of mesenchymal stem cells towards osteoblasts and inhibits osteoclasts differentiation [41]. In fact, clinical studies confirm experimental studies. According to Hidayat et al., fractures in patients treated with metformin were reduced, and Salari-Moghaddam et al. also supported the beneficial effects of metformin on bone metabolism [42,43]. Additionally, metformin inhibits adipocyte genesis in the marrow through decreased endothelial nitric oxide synthase (eNOS) [44].
Furthermore, metformin-mediated glucose utilization occurs via protein kinase-dependent on calcium [45]. One of the most common side effects is diarrhea, which may disturb the proper absorption of minerals essential for bone mineralization. However, diarrhea is usually short-term, subsides after a few days following the introduction of treatment, and does not eliminate the long-term positive effect of metformin on bone metabolism. In addition, metformin decreases the negative effects of rosiglitazone on the bone [46].

3.2. Sulfonylureas

According to the studies, glimepiride, belonging to sulfonylureas, presents a beneficial effect on the stimulation of bone formation [47]. In fact, glimepiride also inhibits bone loss linked to the menopause [48], although, generally, sulfonylureas are considered neutral for bone metabolism. However, it is vital to notice that sulfonylureas often cause hypoglycemia, particularly among the elderly, leading to an increased risk of fracture [49], which has been confirmed in a study conducted by Starup-Linde et al. They reported that treatment with sulfonylureas in the last 90 days among 5244 patients with DM2 was associated with a higher risk of femoral neck fractures [50].

3.3. Insulin Therapy

Similar to sulfonylureas, the clinical impact of insulin on bone stems mainly from the occurrence of hypoglycemia and is related to its risk of falls and bone fractures [51]. The last study, involving 58 853 newly-diagnosed diabetes patients, showed that patients treated with insulin presented a higher risk of osteoporotic fracture amounting to 38% [52]. Other clinical trials presented a higher risk of fractures among patients with DM2, particularly in postmenopausal women [53,54]. Nevertheless, it is currently difficult to account for due to the anabolic impact of insulin.

3.4. Thiazolidinoidiones

Thiazolidinoidiones decrease BMD and increase the risk of fractures by eliminating the inhibitory impact of PPAR-γ on the differentiation of osteoclasts, increasing sclerostin production in osteocytes, and increasing adipocyte infiltration in the marrow [55], which was considered for rosiglitazone and pioglitazone [56,57]. Rosiglitazone decreased bone regeneration, influenced trabecular bone in the metaphysis of the femur and decreased the density of osteoblasts and osteoclasts [46]. Additionally, it also affected TRAP-linked epiphyseal growth plate, leading to a decreased bone mass and an increased risk of fractures. The ex vivo study demonstrated that osteogenic involvement had been reduced during treatment with rosiglitazone, leading to an increased expression of PPARγ and decreased Runx2/Cbfa1, inhibiting phosphorylation AMP kinase, and inhibiting osteoblast mineralization and differentiation [46].

3.5. GLP-1 Antagonists

It is vital to note the impact of GLP-1 antagonists on bone metabolism and the risk of fractures. Treatment with GLP-1 antagonist decreases bone resorption by affecting osteoclast and osteoblast balance. In vivo studies showed that agonists of the GLP-1 receptor may affect the fat-bone axis through the promotion of osteogenic differentiation and inhibition of adipogenic mesenchymal precursor cells in the bone. Additionally, signaling of Wnt/β-catenin also takes part in this process. Mature osteocytes with GLP-1 receptor produce sclerostin, which inhibits Wnt/β-catenin signaling through binding with the low-density lipoprotein receptor-related protein 5 and preventing Wnt binding. GLP-1 analogues decrease the expression and concentration of sclerostin. The GLP-1 receptors are expressed in C cells in the thyroid, leading to the release of calcitonin, causing inhibition of bone resorption [58]. The anabolic effect of liraglutide and exenatide on GLP-1 receptors in preosteoblasts and osteocytes prevents bone mass loss linked to weight loss, and causes many fractures [59,60,61]. Additionally, GLP-1 may control bone resorption through interaction with GLP-2 and glucose-dependent insulinotropic polypeptide (GIP) and affects the pathway depending on calcitonin [62].

3.6. Dipeptidyl Peptidase-4 Inhibitors (DPP-4 Inhibitors)

In the conducted studies, sitagliptin, a dipeptidyl peptidase-4 inhibitor, caused inhibition of bone resorption among postmenopausal women; however, this result was not confirmed in the meta-analysis [63,64]. Additionally, a Korean study did not reveal the influence of DPP4 inhibitors on bone fracture frequency [65]. According to Qiu et al., increased serum DPP4 levels were associated with a higher risk of fractures among newly diagnosed patients with diabetes mellitus type 2 [66]. The cohort study, involving 340 participants and lasting five years, reported that using a DPP-4 inhibitor was linked with a decreased risk of fractures due to any cause and fracture of the upper limbs in patients suffering from type 2 diabetes mellitus [67].

3.7. Sodium-Glucose-2 Cotransporter Inhibitors-2

It was speculated that sodium-glucose cotransporter inhibitors, which were regarded by all specialists with a great deal of uncertainty, could affect bone. A hypoglycemic mechanism was associated with increased urinary calcium excretion, which resulted in an imbalance in calcium and phosphate homeostasis (associated with increased PTH secretion, which increases bone resorption) [68]. Similar results were obtained in the CANVAS study, in which a 4% higher incidence of fractures was observed when using canagliflozin [69]. However, these reports were not confirmed in the subsequent studies, such as CANVAS-R and CREDENCE [70,71]. In fact, the association between empagliflozin and bone fractures was also excluded [72]. SGLT2 may also lead to decreased BMD [73], although other studies did not support the effect of these drugs on calcium and phosphorus, vitamin D, or parathyroid hormone (PTH) levels [74]. Therefore, this group of drugs still requires detailed studies regarding their effects on bone. Finally, a meta-analysis by Chai et al. evaluated a total of 177 randomized trials and showed that modern antidiabetic drugs, such as DPP-4i, GLP-1 RA, and SGLT-2, did not increase the overall risk of fractures compared to insulin, metformin or sulfonylureas [75]. Therefore, it would imply that the use of modern and mortality-reducing drugs has no adverse effects on bone metabolism. The mechanism of action of the drugs used in diabetes on bone mineral metabolism has been shown in Figure 1. A summary of the effects of antihyperglycemic drugs on fracture risk has been provided in Table 1.

4. Anti-Osteoporosis Drugs and Glucose Metabolism

In the pharmacological treatment of osteoporosis, three groups of drugs are employed—antiresorptive drugs (bisphosphonates, denosumab, and selective estrogen receptor modulators), anabolic drugs (teriparatide), and drugs with a mixed mechanism of action (strontium ranelate).

4.1. Antiresorptive Drugs

In terms of antiresorptive drugs, their mechanism of action is mainly based on inhibiting the activity of osteoclasts, whereas anabolic drugs stimulate the action of bone-forming cells [76,77,78]. Bisphosphonates are a basic group of antiresorptive drugs used to treat osteoporosis. Chemically, they are stable inorganic pyrophosphate (PPi) derivatives where two phosphate groups are combined by esterification. Bisphosphonates bind to hydroxyapatite crystals and act through two mechanisms: on the one hand, they inhibit the activity of osteoclasts and stimulate their apoptosis, and on the other they act on osteoclasts [79]. Consequently, bisphosphonates lead to a reduced risk of vertebral fractures and non-vertebral fractures, including the proximal end of the femoral neck [80]. Researchers are also interested in the pleiotropic effects of bisphosphonates—, e.g., anti-cancer effects, modification of lipid concentrations—emphasizing the impact on carbohydrate metabolism. The population study of Toulis et al. showed a 50% reduction in the risk of type 2 diabetes in patients using bisphosphonates [81]. The observations of Karimi Fard et al. also seem to be promising as they showed that the use of oral alendronate at a dose of 70 mg/week for 12 weeks might significantly improve fasting glucose levels. Additionally, it may have a beneficial effect on glycated hemoglobin (HbA1C) in pre-diabetic and postmenopausal women and thus may slow down the rate of progression to diabetes [82]. Bone tissue is a rich source of cytokines, i.e., osteokines, which may affect glucose metabolism. Therefore, it is postulated that antiresorptive drugs modulate bone turnover and act on carbohydrate metabolism. Maugeri D et al. demonstrated a reduction in the daily insulin requirement in patients with type 1 diabetes and osteoporosis who are being treated with alendronate. The authors suggest that the results can be attributed not only to the increase in BMD and slowing down of bone turnover, but above all to the reduction of clinical symptoms of osteoporosis, such as pain and movement limitations, which led to a better physical performance of patients and, therefore, to the improvement of glucose metabolism [83]. Another essential issue in patients with diabetes is renal failure. Hence, it is worth mentioning that special care should be taken in terms of the use of bisphosphonates in this patient group, particularly in individuals with a creatinine clearance of less than 30 mL/min (GFR < 30 mL/min). In fact, it has been shown that intravenous preparations of bisphosphonates can lead to a severe deterioration of GFR, which may be due to the local accumulation of these drugs in the kidneys [84,85]. Nevertheless, no renal complications were observed when oral forms of bisphosphonates were used in patients with mild renal impairment [86]. Denosumab is a fully human monoclonal antibody against the nuclear factor ligand-receptor activator kappaB (RANKL), which blocks its binding to RANK, inhibiting the development and activity of osteoclasts and reducing bone resorption, which in turn leads to an increase in bone mineral density [87]. Denosumab reduces the risk of spinal fractures and non-vertebral fractures, including fractures of the proximal end of the femur [88]. In patients with different stages of renal failure, denosumab has a high efficacy and safety profile, which is clinically relevant [89]. Furthermore, Bonnet et al. showed that RANKL could affect insulin sensitivity and glucose uptake; hence, there have been suggestions that an antibody acting on the RANK/RANKL/OPG system may have an effect on carbohydrate metabolism [90]. However, the Napoli et al. study demonstrated no significant changes in fasting plasma glucose in osteoporotic postmenopausal women with prediabetes or type 2 diabetes following denosumab use [91]. According to the study, no effect was also observed on carbohydrate metabolism parameters in subjects with bone mineral density disorders but without diabetes mellitus [92]. The Passeri et al. study, conducted on patients with severe osteoporosis but without diabetes, also seems promising. The researchers reported that a single dose of 60 mg denosumab did not result in changes in fasting glucose, insulin, or HOMA-IR levels at both 4 and 12 weeks, although it did lead to a significant reduction in liver insulin resistance at 4 weeks and a decrease in HbA1c levels at 12 weeks [93].
Selective estrogen receptor modulators (SERMs) bind to estrogen receptors (ER) α and β and have an agonistic or antagonistic effect depending on the compound itself as well as the target tissue [94]. SERMs reduce the risk of vertebral fractures; however, they do not affect the risk of non-vertebral fractures, including the proximal end of the femoral neck [95]. Tamoxifen has been shown to contribute to numerous metabolic side effects, such as type 2 diabetes, lipid disorders, and fatty liver disease [96]. Hejazi et al. and Sun et al. showed an increased risk of diabetes in patients with breast cancer treated with tamoxifen [97,98]. Furthermore, it is possible that tamoxifen may have adverse effects on the β-cells in the pancreas and impair the survival of pancreatic islets [99]. In fact, treatment with tamoxifen may contribute to decreased insulin sensitivity, although the mechanism has not yet been fully understood [100]. Additionally, the effect of raloxifene on carbohydrate metabolism when used in the treatment of osteoporosis appears to be controversial and may depend on the duration of treatment. In postmenopausal women without diabetes, short-term treatment with raloxifene did not alter fasting blood glucose or insulin levels; however, long-term administration of this medication may contribute to a decreased insulin sensitivity [101,102].
The study by Campos et al. compared the effects of risedronate and conventional osteoporosis treatment based on calcium and vitamin D supplementation in patients with type 1 diabetes mellitus. The study demonstrated an increase in bone formation markers and a significant increase in BMD at the spine and hip [103], and a group of patients with type 1 and type 2 diabetes also showed a beneficial effect of alendronate [104]. In the Fracture Intervention Trial (FIT), alendronate reduced markers of bone turnover (C-terminal telopeptide and bone-specific alkaline phosphatase levels) and improved BMD in women with T2DM) [105]. However, as it has been established, BMD is an insufficient marker of fracture risk, and the vital question is whether an increase in BMD correlates with a reduction in fracture risk. In fact, low bone turnover found in patients with diabetes may be exacerbated via antiresorptive therapy, which may in turn have a detrimental effect on bones.

4.2. Anabolic Drugs

Teriparatide is a fragment of 1–34 molecules of human recombinant parathyroid hormone (PTH) and leads to increased bone mineral density by activating bone formation. Teriparatide reduces the risk of cervical fractures and non-vertebral fractures [106]. Conclusions from clinical trials regarding the action of teriparatide on carbohydrate management parameters are often contradictory, and the effect on glucose homeostasis remains unknown, although the role of calcium and its effect on glucose transport to the cell and the regulation of insulin receptors are postulated [107]. Celer et al. showed that the use of teriparatide in patients with postmenopausal osteoporosis increased glucose concentrations, whereas Anastasilakis et al. showed that this trend decreases when teriparatide treatment is continued [108,109]. In summary, there are no randomized trials using these therapies in patients with type 1 diabetes in terms of anabolic osteoporosis therapies. However, as far as type 2 diabetes is concerned, similar increases in BMD and reductions in fracture risk have been shown in T2DM patients as in non-diabetic individuals, and even the increase in BMD of the femoral neck was significantly greater in diabetic patients compared to controls [110].
All in all, anabolic drugs which stimulate both bone resorption and bone formation contribute to bone mass gain through high bone turnover and activation of the Wnt signaling pathway [111,112,113]. This may be particularly effective in diabetic patients with impaired osteoblast differentiation and maturation along with reduced bone formation.

4.3. Drugs with a Mixed Mechanism of Action

Drugs with a mixed anabolic-antiresorptive mechanism of action include strontium ranelate. The effect of this substance depends on various mechanisms, e.g., activation of calcium receptors located on osteoblasts and osteoclasts, and a positive effect on the OPG/RANKL ratio. Moreover, it has a proven anti-fracture effect on both the vertebrae and the femoral neck, both in women and in men. Nevertheless, due to possible thromboembolic complications and an increased risk of cardiovascular disease, the European Medicines Agency (EMA) has introduced significant restrictions with regard to its use. However, the study by Atteritano et al., including 40 women with postmenopausal osteoporosis, showed no statistically significant changes in fasting glucose concentrations following one year of strontium ranelate therapy [114].

5. Summary and Conclusions

As a systemic disease, diabetes requires a multifactorial approach concerning the proposed therapy and dietary treatment. It is crucial to keep in mind the impact of drugs on bone management and consider dietary recommendations in the prevention and treatment of bone disorders in individuals with diabetes. Although it is currently not recommended to screen for osteoporosis, and there are no particular recommendations for the prevention of osteoporosis in people with type diabetes, it is worth paying attention to the amount of calcium and vitamin D consumed and the frequency of physical activity as well as avoiding potential risk factors for osteoporosis such as smoking. In addition, drug selection for a patient with osteoporosis and diabetes is significant not only in view of osteoporosis therapy but also with regard to the impact on the already disturbed carbohydrate metabolism. Bisphosphonates appear to be a recommended first-line drug for osteoporosis therapy in patients with diabetes. In the elderly and patients with impaired renal function, denosumab is the preferred medication. In contrast, anabolic agents should be considered in patients with severe osteoporosis. Consequently, it can be concluded that dietary management constitutes an essential element of treating and preventing bone mineralization disorders in people with diabetes. Scientific studies confirm the beneficial effect of metformin on bone mineral density in individuals with diabetes. Conversely, drugs from the sulfonylurea group (due to the risk of hypoglycemia) and thiazolidinediones (due to the mechanism of action) are not recommended in people with bone mineral disorders and diabetes. The data regarding the effects of new antidiabetic drugs, such as SGLT2 inhibitors and DPP4 inhibitors, are inconclusive. However, GLP1 analogues show a positive effect on bone mineralization disorders. In fact, in terms of the drugs used to treat osteoporosis in patients with diabetes, the effects of bisphosphonates and denosumab remain best understood.

Author Contributions

Conceptualization, I.K.-K. and A.Z.; methodology, A.Z.; writing—original draft preparation, A.Z., A.E.R., A.M.R. and A.S.-T.; writing—review and editing, A.Z., A.S.-T.; A.M.R., A.E.R., A.D. and I.K.-K. visualization, A.M.R. and A.E.R.; supervision, I.K.-K.; project administration, I.K.-K. and A.D.; funding acquisition, A.D. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

Anna Maria Rychter and Alicja Ewa Ratajczak are participants of STER Internationalization of Doctoral Schools Program from NAWA Polish National Agency for Academic Exchange No. PPI/STE/2020/1/00014/DEC/02.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Li, Y.; Wang, L.; Zhang, M.; Huang, K.; Yao, Z.; Rao, P.; Cai, X.; Xiao, J. Advanced Glycation End Products Inhibit the Osteogenic Differentiation Potential of Adipose-Derived Stem Cells by Modulating Wnt/Β-Catenin Signalling Pathway via DNA Methylation. Cell Prolif. 2020, 53, e12834. [Google Scholar] [CrossRef] [PubMed]
  2. Volpe, C.M.O.; Villar-Delfino, P.H.; dos Anjos, P.M.F.; Nogueira-Machado, J.A. Cellular Death, Reactive Oxygen Species (ROS) and Diabetic Complications. Cell Death Dis. 2018, 9, 119. [Google Scholar] [CrossRef] [PubMed]
  3. Ipseiz, N.; Scholtysek, C.; Culemann, S.; Krönke, G. Adopted Orphans as Regulators of Inflammation, Immunity and Skeletal Homeostasis. Swiss Med. Wkly. 2014, 144, w14055. [Google Scholar] [CrossRef]
  4. Mizokami, A.; Kawakubo-Yasukochi, T.; Hirata, M. Osteocalcin and Its Endocrine Functions. Biochem. Pharmacol. 2017, 132, 1–8. [Google Scholar] [CrossRef] [PubMed]
  5. Poiana, C.; Capatina, C. Fracture Risk Assessment in Patients with Diabetes Mellitus. J. Clin. Densitom. 2017, 20, 432–443. [Google Scholar] [CrossRef] [PubMed]
  6. Škrha, J.; Šoupal, J.; Škrha, J.; Prázný, M. Glucose Variability, HbA1c and Microvascular Complications. Rev. Endocr. Metab. Disord. 2016, 17, 103–110. [Google Scholar] [CrossRef]
  7. Nordwall, M.; Arnqvist, H.J.; Bojestig, M.; Ludvigsson, J. Good Glycemic Control Remains Crucial in Prevention of Late Diabetic Complications—The Linköping Diabetes Complications Study. Pediatr. Diabetes 2009, 10, 168–176. [Google Scholar] [CrossRef]
  8. Marso, S.P.; Daniels, G.H.; Brown-Frandsen, K.; Kristensen, P.; Mann, J.F.E.; Nauck, M.A.; Nissen, S.E.; Pocock, S.; Poulter, N.R.; Ravn, L.S.; et al. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes. N. Engl. J. Med. 2016, 375, 311–322. [Google Scholar] [CrossRef]
  9. Zinman, B.; Wanner, C.; Lachin, J.M.; Fitchett, D.; Bluhmki, E.; Hantel, S.; Mattheus, M.; Devins, T.; Johansen, O.E.; Woerle, H.J.; et al. Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes. N. Engl. J. Med. 2015, 373, 2117–2128. [Google Scholar] [CrossRef]
  10. Hemmingsen, B.; Gimenez-Perez, G.; Mauricio, D.; Roqué, I.; Figuls, M.; Metzendorf, M.-I.; Richter, B. Diet, Physical Activity or Both for Prevention or Delay of Type 2 Diabetes Mellitus and Its Associated Complications in People at Increased Risk of Developing Type 2 Diabetes Mellitus. Cochrane Database Syst. Rev. 2017, 12, CD003054. [Google Scholar] [CrossRef] [Green Version]
  11. Ferrari, S.L.; Abrahamsen, B.; Napoli, N.; Akesson, K.; Chandran, M.; Eastell, R.; El-Hajj Fuleihan, G.; Josse, R.; Kendler, D.L.; Kraenzlin, M.; et al. Diagnosis and Management of Bone Fragility in Diabetes: An Emerging Challenge. Osteoporos. Int. J. Establ. Result Coop. Eur. Found. Osteoporos. Natl. Osteoporos. Found. USA 2018, 29, 2585–2596. [Google Scholar] [CrossRef] [PubMed]
  12. Varenna, M.; Binelli, L.; Casari, S.; Zucchi, F.; Sinigaglia, L. Effects of Dietary Calcium Intake on Body Weight and Prevalence of Osteoporosis in Early Postmenopausal Women. Am. J. Clin. Nutr. 2007, 86, 639–644. [Google Scholar] [CrossRef]
  13. Shahar, D.R.; Abel, R.; Elhayany, A.; Vardi, H.; Fraser, D. Does Dairy Calcium Intake Enhance Weight Loss among Overweight Diabetic Patients? Diabetes Care 2007, 30, 485–489. [Google Scholar] [CrossRef] [PubMed]
  14. Champagne, C.M.; Broyles, S.T.; Moran, L.D.; Cash, K.C.; Levy, E.J.; Lin, P.-H.; Batch, B.C.; Lien, L.F.; Funk, K.L.; Dalcin, A.; et al. Dietary Intakes Associated with Successful Weight Loss and Maintenance during the Weight Loss Maintenance Trial. J. Am. Diet. Assoc. 2011, 111, 1826–1835. [Google Scholar] [CrossRef] [PubMed]
  15. Shapses, S.A.; Heshka, S.; Heymsfield, S.B. Effect of Calcium Supplementation on Weight and Fat Loss in Women. J. Clin. Endocrinol. Metab. 2004, 89, 632–637. [Google Scholar] [CrossRef] [PubMed]
  16. Cifuentes, M.; Riedt, C.S.; Brolin, R.E.; Field, M.P.; Sherrell, R.M.; Shapses, S.A. Weight Loss and Calcium Intake Influence Calcium Absorption in Overweight Postmenopausal Women. Am. J. Clin. Nutr. 2004, 80, 123–130. [Google Scholar] [CrossRef]
  17. Jospe, M.R.; Roy, M.; Brown, R.C.; Haszard, J.J.; Meredith-Jones, K.; Fangupo, L.J.; Osborne, H.; Fleming, E.A.; Taylor, R.W. Intermittent Fasting, Paleolithic, or Mediterranean Diets in the Real World: Exploratory Secondary Analyses of a Weight-Loss Trial That Included Choice of Diet and Exercise. Am. J. Clin. Nutr. 2020, 111, 503–514. [Google Scholar] [CrossRef]
  18. Al-Hazmi, A.S. Association of Vitamin D Deficiency and Vitamin D Receptor Gene Polymorphisms with Type 2 Diabetes Mellitus Saudi Patients. Afr. Health Sci. 2019, 19, 2812–2818. [Google Scholar] [CrossRef]
  19. Nam, H.-K.; Rhie, Y.-J.; Lee, K.-H. Vitamin D Level and Gene Polymorphisms in Korean Children with Type 1 Diabetes. Pediatr. Diabetes 2019, 20, 750–758. [Google Scholar] [CrossRef]
  20. Wortsman, J.; Matsuoka, L.Y.; Chen, T.C.; Lu, Z.; Holick, M.F. Decreased Bioavailability of Vitamin D in Obesity. Am. J. Clin. Nutr. 2000, 72, 690–693. [Google Scholar] [CrossRef] [Green Version]
  21. Altieri, B.; Grant, W.B.; Della Casa, S.; Orio, F.; Pontecorvi, A.; Colao, A.; Sarno, G.; Muscogiuri, G. Vitamin D and Pancreas: The Role of Sunshine Vitamin in the Pathogenesis of Diabetes Mellitus and Pancreatic Cancer. Crit. Rev. Food Sci. Nutr. 2017, 57, 3472–3488. [Google Scholar] [CrossRef] [PubMed]
  22. Zakharova, I.; Klimov, L.; Kuryaninova, V.; Nikitina, I.; Malyavskaya, S.; Dolbnya, S.; Kasyanova, A.; Atanesyan, R.; Stoyan, M.; Todieva, A.; et al. Vitamin D Insufficiency in Overweight and Obese Children and Adolescents. Front. Endocrinol. 2019, 10, 103. [Google Scholar] [CrossRef] [PubMed]
  23. Rajakumar, K.; Fernstrom, J.D.; Holick, M.F.; Janosky, J.E.; Greenspan, S.L. Vitamin D Status and Response to Vitamin D3 in Obese vs. Non-Obese African American Children. Obesity 2008, 16, 90–95. [Google Scholar] [CrossRef]
  24. Elizondo-Montemayor, L.; Ugalde-Casas, P.A.; Serrano-González, M.; Cuello-García, C.A.; Borbolla-Escoboza, J.R. Serum 25-Hydroxyvitamin D Concentration, Life Factors and Obesity in Mexican Children. Obesity 2010, 18, 1805–1811. [Google Scholar] [CrossRef] [PubMed]
  25. Olson, M.L.; Maalouf, N.M.; Oden, J.D.; White, P.C.; Hutchison, M.R. Vitamin D Deficiency in Obese Children and Its Relationship to Glucose Homeostasis. J. Clin. Endocrinol. Metab. 2012, 97, 279–285. [Google Scholar] [CrossRef]
  26. Hajhashemy, Z.; Shahdadian, F.; Ziaei, R.; Saneei, P. Serum Vitamin D Levels in Relation to Abdominal Obesity: A Systematic Review and Dose-Response Meta-Analysis of Epidemiologic Studies. Obes. Rev. Off. J. Int. Assoc. Study Obes. 2021, 22, e13134. [Google Scholar] [CrossRef]
  27. Yakout, S.M.; Al-Daghri, N.M.; Bukhari, I.; Khattak, M.N.K.; Sabico, S.; Alokail, M.S.; Al-Attas, O.S. Vitamin D Level and Its Relation to Muscle and Fat Mass in Adult Male Arabs. Saudi J. Biol. Sci. 2020, 27, 2452–2456. [Google Scholar] [CrossRef]
  28. Doaei, S.; Jarrahi, S.; Torki, S.; Haghshenas, R.; Jamshidi, Z.; Rezaei, S.; Moslem, A.; Ghorat, F.; Khodabakhshi, A.; Gholamalizadeh, M. Serum Vitamin D Level May Be Associated with Body Weight and Body Composition in Male Adolescents; a Longitudinal Study. Pediatr. Endocrinol. Diabetes Metab. 2020, 26, 125–131. [Google Scholar] [CrossRef]
  29. Tang, Z.; Huang, S.; Ma, R.; Zheng, H.; Zhu, Y. Low Vitamin D Status Is Associated with Obesity but No Other Cardiovascular Risk Factors in Chinese Children and Adolescents. Nutr. Metab. Cardiovasc. Dis. NMCD 2020, 30, 1573–1581. [Google Scholar] [CrossRef]
  30. Kamycheva, E.; Joakimsen, R.M.; Jorde, R. Intakes of Calcium and Vitamin d Predict Body Mass Index in the Population of Northern Norway. J. Nutr. 2003, 133, 102–106. [Google Scholar] [CrossRef]
  31. Dupuy, C.; Lauwers-Cances, V.; van Kan, G.A.; Gillette, S.; Schott, A.-M.; Beauchet, O.; Annweiler, C.; Vellas, B.; Rolland, Y. Dietary Vitamin D Intake and Muscle Mass in Older Women. Results from a Cross-Sectional Analysis of the EPIDOS Study. J. Nutr. Health Aging 2013, 17, 119–124. [Google Scholar] [CrossRef] [PubMed]
  32. Conway, B.; Miller, R.G.; Costacou, T.; Fried, L.; Kelsey, S.; Evans, R.W.; Orchard, T.J. Temporal Patterns in Overweight and Obesity in Type 1 Diabetes. Diabet. Med. J. Br. Diabet. Assoc. 2010, 27, 398–404. [Google Scholar] [CrossRef] [PubMed]
  33. Rychter, A.; Zawada, A.; Kanikowska, A.; Grzymisławski, M.; Dobrowolska, A. Postępowanie dietetyczne i behawioralne chorych na cukrzycę typu 1 ze współistniejącą nadwagą. Forum Zaburzeń Metab. 2018, 9, 16–22. [Google Scholar]
  34. Villareal, D.T.; Fontana, L.; Das, S.K.; Redman, L.; Smith, S.R.; Saltzman, E.; Bales, C.; Rochon, J.; Pieper, C.; Huang, M.; et al. Effect of Two-Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non-Obese Younger Adults: A Randomized Clinical Trial: CALORIC RESTRICTION AND BONE HEALTH. J. Bone Miner. Res. 2016, 31, 40–51. [Google Scholar] [CrossRef]
  35. Via, M. The Malnutrition of Obesity: Micronutrient Deficiencies That Promote Diabetes. ISRN Endocrinol. 2012, 2012, 1–8. [Google Scholar] [CrossRef]
  36. Walker, A.F. Potential Micronutrient Deficiency Lacks Recognition in Diabetes. Br. J. Gen. Pract. J. R. Coll. Gen. Pract. 2007, 57, 3–4. [Google Scholar]
  37. Damms-Machado, A.; Weser, G.; Bischoff, S.C. Micronutrient Deficiency in Obese Subjects Undergoing Low Calorie Diet. Nutr. J. 2012, 11, 34. [Google Scholar] [CrossRef] [PubMed]
  38. Gardner, C.D.; Kim, S.; Bersamin, A.; Dopler-Nelson, M.; Otten, J.; Oelrich, B.; Cherin, R. Micronutrient Quality of Weight-Loss Diets That Focus on Macronutrients: Results from the A to Z Study. Am. J. Clin. Nutr. 2010, 92, 304–312. [Google Scholar] [CrossRef]
  39. Goday, A.; Bellido, D.; Sajoux, I.; Crujeiras, A.B.; Burguera, B.; García-Luna, P.P.; Oleaga, A.; Moreno, B.; Casanueva, F.F. Short-Term Safety, Tolerability and Efficacy of a Very Low-Calorie-Ketogenic Diet Interventional Weight Loss Program versus Hypocaloric Diet in Patients with Type 2 Diabetes Mellitus. Nutr. Diabetes 2016, 6, e230. [Google Scholar] [CrossRef]
  40. Aung, M.; Amin, S.; Gulraiz, A.; Gandhi, F.R.; Pena Escobar, J.A.; Malik, B.H. The Future of Metformin in the Prevention of Diabetes-Related Osteoporosis. Cureus 2020, 12, e10412. [Google Scholar] [CrossRef]
  41. Kheniser, K.G.; Polanco Santos, C.M.; Kashyap, S.R. The Effects of Diabetes Therapy on Bone: A Clinical Perspective. J. Diabetes Complications 2018, 32, 713–719. [Google Scholar] [CrossRef]
  42. Hidayat, K.; Du, X.; Wu, M.-J.; Shi, B.-M. The Use of Metformin, Insulin, Sulphonylureas, and Thiazolidinediones and the Risk of Fracture: Systematic Review and Meta-Analysis of Observational Studies. Obes. Rev. 2019, 20, 1494–1503. [Google Scholar] [CrossRef] [PubMed]
  43. Salari-Moghaddam, A.; Sadeghi, O.; Keshteli, A.H.; Larijani, B.; Esmaillzadeh, A. Metformin Use and Risk of Fracture: A Systematic Review and Meta-Analysis of Observational Studies. Osteoporos. Int. 2019, 30, 1167–1173. [Google Scholar] [CrossRef] [PubMed]
  44. Gu, Q.; Gu, Y.; Yang, H.; Shi, Q. Metformin Enhances Osteogenesis and Suppresses Adipogenesis of Human Chorionic Villous Mesenchymal Stem Cells. Tohoku J. Exp. Med. 2017, 241, 13–19. [Google Scholar] [CrossRef] [PubMed]
  45. Piccinin, M.A.; Khan, Z.A. Pathophysiological Role of Enhanced Bone Marrow Adipogenesis in Diabetic Complications. Adipocyte 2014, 3, 263–272. [Google Scholar] [CrossRef]
  46. Sedlinsky, C.; Molinuevo, M.S.; Cortizo, A.M.; Tolosa, M.J.; Felice, J.I.; Sbaraglini, M.L.; Schurman, L.; McCarthy, A.D. Metformin Prevents Anti-Osteogenic in Vivo and Ex Vivo Effects of Rosiglitazone in Rats. Eur. J. Pharmacol. 2011, 668, 477–485. [Google Scholar] [CrossRef]
  47. Lecka-Czernik, B. Diabetes, Bone and Glucose-Lowering Agents: Basic Biology. Diabetologia 2017, 60, 1163–1169. [Google Scholar] [CrossRef]
  48. Fronczek-Sokół, J.; Pytlik, M. Effect of Glimepiride on the Skeletal System of Ovariectomized and Non-Ovariectomized Rats. Pharmacol. Rep. 2014, 66, 412–417. [Google Scholar] [CrossRef]
  49. Lapane, K.L.; Yang, S.; Brown, M.J.; Jawahar, R.; Pagliasotti, C.; Rajpathak, S. Sulfonylureas and Risk of Falls and Fractures: A Systematic Review. Drugs Aging 2013, 30, 527–547. [Google Scholar] [CrossRef]
  50. Starup-Linde, J.; Gregersen, S.; Frost, M.; Vestergaard, P. Use of Glucose-Lowering Drugs and Risk of Fracture in Patients with Type 2 Diabetes. Bone 2017, 95, 136–142. [Google Scholar] [CrossRef]
  51. Conte, C.; Epstein, S.; Napoli, N. Insulin Resistance and Bone: A Biological Partnership. Acta Diabetol. 2018, 55, 305–314. [Google Scholar] [CrossRef] [PubMed]
  52. Losada-Grande, E.; Hawley, S.; Soldevila, B.; Martinez-Laguna, D.; Nogues, X.; Diez-Perez, A.; Puig-Domingo, M.; Mauricio, D.; Prieto-Alhambra, D. Insulin Use and Excess Fracture Risk in Patients with Type 2 Diabetes: A Propensity-Matched Cohort Analysis. Sci. Rep. 2017, 7, 3781. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  53. Nicodemus, K.K.; Folsom, A.R. Type 1 and Type 2 Diabetes and Incident Hip Fractures in Postmenopausal Women. Diabetes Care 2001, 24, 1192–1197. [Google Scholar] [CrossRef] [PubMed]
  54. Ivers, R.Q.; Cumming, R.G.; Mitchell, P.; Peduto, A.J. Diabetes and Risk of Fracture: The Blue Mountains Eye Study. Diabetes Care 2001, 24, 1198–1203. [Google Scholar] [CrossRef] [PubMed]
  55. Zhu, Z.-N.; Jiang, Y.-F.; Ding, T. Risk of Fracture with Thiazolidinediones: An Updated Meta-Analysis of Randomized Clinical Trials. Bone 2014, 68, 115–123. [Google Scholar] [CrossRef] [PubMed]
  56. Bilezikian, J.P.; Josse, R.G.; Eastell, R.; Lewiecki, E.M.; Miller, C.G.; Wooddell, M.; Northcutt, A.R.; Kravitz, B.G.; Paul, G.; Cobitz, A.R.; et al. Rosiglitazone Decreases Bone Mineral Density and Increases Bone Turnover in Postmenopausal Women with Type 2 Diabetes Mellitus. J. Clin. Endocrinol. Metab. 2013, 98, 1519–1528. [Google Scholar] [CrossRef]
  57. Portillo-Sanchez, P.; Bril, F.; Lomonaco, R.; Barb, D.; Orsak, B.; Bruder, J.M.; Cusi, K. Effect of Pioglitazone on Bone Mineral Density in Patients with Nonalcoholic Steatohepatitis: A 36-Month Clinical Trial. J. Diabetes 2019, 11, 223–231. [Google Scholar] [CrossRef] [PubMed]
  58. Luo, G.; Liu, H.; Lu, H. Glucagon-like Peptide-1(GLP-1) Receptor Agonists: Potential to Reduce Fracture Risk in Diabetic Patients?: GLP-1 RA: Potential to Reduce Fracture Risk in Diabetic Patients? Br. J. Clin. Pharmacol. 2016, 81, 78–88. [Google Scholar] [CrossRef] [PubMed]
  59. Pereira, M.; Jeyabalan, J.; Jørgensen, C.S.; Hopkinson, M.; Al-Jazzar, A.; Roux, J.P.; Chavassieux, P.; Orriss, I.R.; Cleasby, M.E.; Chenu, C. Chronic Administration of Glucagon-like Peptide-1 Receptor Agonists Improves Trabecular Bone Mass and Architecture in Ovariectomised Mice. Epigenetic Mech. Regul. Bone Biol. Pathol. 2015, 81, 459–467. [Google Scholar] [CrossRef]
  60. Wu, X.; Li, S.; Xue, P.; Li, Y. Liraglutide, a Glucagon-like Peptide-1 Receptor Agonist, Facilitates Osteogenic Proliferation and Differentiation in MC3T3-E1 Cells through Phosphoinositide 3-Kinase (PI3K)/Protein Kinase B (AKT), Extracellular Signal-Related Kinase (ERK)1/2, and CAMP/Protein Kinase A (PKA) Signaling Pathways Involving β-Catenin. Exp. Cell Res. 2017, 360, 281–291. [Google Scholar] [CrossRef]
  61. Cheng, L.; Hu, Y.; Li, Y.-Y.; Cao, X.; Bai, N.; Lu, T.-T.; Li, G.-Q.; Li, N.; Wang, A.-N.; Mao, X.-M. Glucagon-like Peptide-1 Receptor Agonists and Risk of Bone Fracture in Patients with Type 2 Diabetes: A Meta-Analysis of Randomized Controlled Trials. Diabetes Metab. Res. Rev. 2019, 35, e3168. [Google Scholar] [CrossRef]
  62. Yamada, C.; Yamada, Y.; Tsukiyama, K.; Yamada, K.; Udagawa, N.; Takahashi, N.; Tanaka, K.; Drucker, D.J.; Seino, Y.; Inagaki, N. The Murine Glucagon-Like Peptide-1 Receptor Is Essential for Control of Bone Resorption. Endocrinology 2008, 149, 574–579. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Hegazy, S.K. Evaluation of the Anti-Osteoporotic Effects of Metformin and Sitagliptin in Postmenopausal Diabetic Women. J. Bone Miner. Metab. 2015, 33, 207–212. [Google Scholar] [CrossRef] [PubMed]
  64. Chen, Q.; Liu, T.; Zhou, H.; Peng, H.; Yan, C. Risk of Fractures Associated with Dipeptidyl Peptidase-4 Inhibitor Treatment: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Diabetes Ther. 2019, 10, 1879–1892. [Google Scholar] [CrossRef] [PubMed]
  65. Ustulin, M.; Park, S.Y.; Choi, H.; Chon, S.; Woo, J.T.; Rhee, S.Y. Effect of Dipeptidyl Peptidase-4 Inhibitors on the Risk of Bone Fractures in a Korean Population. J. Korean Med. Sci. 2019, 34, e224. [Google Scholar] [CrossRef]
  66. Qiu, M.; Zhai, S.; Liu, D. DPP4 Activities Are Associated with Osteopenia/Osteoporosis and Fracture Risk in Newly Diagnosed Type 2 Diabetes. Int. J. Endocrinol. 2020, 2020, 8874272. [Google Scholar] [CrossRef]
  67. Hou, W.-H.; Chang, K.-C.; Li, C.-Y.; Ou, H.-T. Dipeptidyl Peptidase-4 Inhibitor Use Is Associated with Decreased Risk of Fracture in Patients with Type 2 Diabetes: A Population-Based Cohort Study. Br. J. Clin. Pharmacol. 2018, 84, 2029–2039. [Google Scholar] [CrossRef]
  68. Ye, Y.; Zhao, C.; Liang, J.; Yang, Y.; Yu, M.; Qu, X. Effect of Sodium-Glucose Co-Transporter 2 Inhibitors on Bone Metabolism and Fracture Risk. Front. Pharmacol. 2019, 9, 1517. [Google Scholar] [CrossRef]
  69. Watts, N.B.; Bilezikian, J.P.; Usiskin, K.; Edwards, R.; Desai, M.; Law, G.; Meininger, G. Effects of Canagliflozin on Fracture Risk in Patients with Type 2 Diabetes Mellitus. J. Clin. Endocrinol. Metab. 2016, 101, 157–166. [Google Scholar] [CrossRef]
  70. Perkovic, V.; Jardine, M.J.; Neal, B.; Bompoint, S.; Heerspink, H.J.L.; Charytan, D.M.; Edwards, R.; Agarwal, R.; Bakris, G.; Bull, S.; et al. Canagliflozin and Renal Outcomes in Type 2 Diabetes and Nephropathy. N. Engl. J. Med. 2019, 380, 2295–2306. [Google Scholar] [CrossRef]
  71. Neal, B.; Perkovic, V.; Mahaffey, K.W.; de Zeeuw, D.; Fulcher, G.; Erondu, N.; Shaw, W.; Law, G.; Desai, M.; Matthews, D.R. Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes. N. Engl. J. Med. 2017, 377, 644–657. [Google Scholar] [CrossRef]
  72. Kohler, S.; Kaspers, S.; Salsali, A.; Zeller, C.; Woerle, H.J. Analysis of Fractures in Patients with Type 2 Diabetes Treated with Empagliflozin in Pooled Data From Placebo-Controlled Trials and a Head-to-Head Study Versus Glimepiride. Diabetes Care 2018, 41, 1809–1816. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Bilezikian, J.P.; Watts, N.B.; Usiskin, K.; Polidori, D.; Fung, A.; Sullivan, D.; Rosenthal, N. Evaluation of Bone Mineral Density and Bone Biomarkers in Patients with Type 2 Diabetes Treated with Canagliflozin. J. Clin. Endocrinol. Metab. 2016, 101, 44–51. [Google Scholar] [CrossRef] [PubMed]
  74. Bays, H.E.; Weinstein, R.; Law, G.; Canovatchel, W. Canagliflozin: Effects in Overweight and Obese Subjects without Diabetes Mellitus. Obesity 2014, 22, 1042–1049. [Google Scholar] [CrossRef] [PubMed]
  75. Chai, S.; Liu, F.; Yang, Z.; Yu, S.; Liu, Z.; Yang, Q.; Sun, F. Risk of Fracture with Dipeptidyl Peptidase-4 Inhibitors, Glucagon-like Peptide-1 Receptor Agonists, or Sodium-Glucose Cotransporter-2 Inhibitors in Patients with Type 2 Diabetes Mellitus: A Systematic Review and Network Meta-Analysis Combining 177 Randomized Controlled Trials with a Median Follow-Up of 26 Weeks. Front. Pharmacol. 2022, 13, 825417. [Google Scholar] [CrossRef]
  76. Compston, J.E.; Watts, N.B.; Chapurlat, R.; Cooper, C.; Boonen, S.; Greenspan, S.; Pfeilschifter, J.; Silverman, S.; Díez-Pérez, A.; Lindsay, R.; et al. Obesity Is Not Protective against Fracture in Postmenopausal Women: GLOW. Am. J. Med. 2011, 124, 1043–1050. [Google Scholar] [CrossRef]
  77. Reginster, J.-Y. Antifracture Efficacy of Currently Available Therapies for Postmenopausal Osteoporosis. Drugs 2011, 71, 65–78. [Google Scholar] [CrossRef]
  78. Kanis, J.A.; Cooper, C.; Rizzoli, R.; Reginster, J.-Y. Review of the Guideline of the American College of Physicians on the Treatment of Osteoporosis. Osteoporos. Int. 2018, 29, 1505–1510. [Google Scholar] [CrossRef]
  79. Fleisch, H. Bisphosphonates: Mechanisms of Action. Endocr. Rev. 1998, 19, 80–100. [Google Scholar] [CrossRef]
  80. Drake, M.T.; Clarke, B.L.; Khosla, S. Bisphosphonates: Mechanism of Action and Role in Clinical Practice. Mayo Clin. Proc. 2008, 83, 1032–1045. [Google Scholar] [CrossRef]
  81. Toulis, K.A.; Nirantharakumar, K.; Ryan, R.; Marshall, T.; Hemming, K. Bisphosphonates and Glucose Homeostasis: A Population-Based, Retrospective Cohort Study. J. Clin. Endocrinol. Metab. 2015, 100, 1933–1940. [Google Scholar] [CrossRef]
  82. Karimi Fard, M.; Aminorroaya, A.; Kachuei, A.; Salamat, M.R.; Hadi Alijanvand, M.; Aminorroaya Yamini, S.; Karimifar, M.; Feizi, A.; Amini, M. Alendronate Improves Fasting Plasma Glucose and Insulin Sensitivity, and Decreases Insulin Resistance in Prediabetic Osteopenic Postmenopausal Women: A Randomized Triple-Blind Clinical Trial. J. Diabetes Investig. 2019, 10, 731–737. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Maugeri, D.; Panebianco, P.; Rosso, D.; Calanna, A.; Speciale, S.; Santangelo, A.; Rizza, I.; Motta, M.; Lentini, A.; Malaguarnera, M. Alendronate Reduces the Daily Consumption of Insulin (DCI) in Patients with Senile Type I Diabetes and Osteoporosis. Arch. Gerontol. Geriatr. 2002, 34, 117–122. [Google Scholar] [CrossRef]
  84. Chang, J.T.; Green, L.; Beitz, J. Renal Failure with the Use of Zoledronic Acid. N. Engl. J. Med. 2003, 349, 1676–1679. [Google Scholar] [CrossRef] [PubMed]
  85. Smetana, S.; Michlin, A.; Rosenman, E.; Biro, A.; Boaz, M.; Katzir, Z. Pamidronate-Induced Nephrotoxic Tubular Necrosis—A Case Report. Clin. Nephrol. 2004, 61, 63–67. [Google Scholar] [CrossRef] [PubMed]
  86. Miller, P.D. Treatment of Metabolic Bone Disease in Patients with Chronic Renal Disease: A Perspective for Rheumatologists. Curr. Rheumatol. Rep. 2005, 7, 53–60. [Google Scholar] [CrossRef]
  87. Delmas, P.D. Clinical Potential of RANKL Inhibition for the Management of Postmenopausal Osteoporosis and Other Metabolic Bone Diseases. J. Clin. Densitom. 2008, 11, 325–338. [Google Scholar] [CrossRef]
  88. Cummings, S.R.; Martin, J.S.; McClung, M.R.; Siris, E.S.; Eastell, R.; Reid, I.R.; Delmas, P.; Zoog, H.B.; Austin, M.; Wang, A.; et al. Denosumab for Prevention of Fractures in Postmenopausal Women with Osteoporosis. N. Engl. J. Med. 2009, 361, 756–765. [Google Scholar] [CrossRef]
  89. Block, G.A.; Bone, H.G.; Fang, L.; Lee, E.; Padhi, D. A Single-Dose Study of Denosumab in Patients with Various Degrees of Renal Impairment. J. Bone Miner. Res. 2012, 27, 1471–1479. [Google Scholar] [CrossRef]
  90. Bonnet, N.; Bourgoin, L.; Biver, E.; Douni, E.; Ferrari, S. RANKL Inhibition Improves Muscle Strength and Insulin Sensitivity and Restores Bone Mass. J. Clin. Investig. 2019, 129, 3214–3223. [Google Scholar] [CrossRef]
  91. Napoli, N.; Pannacciulli, N.; Vittinghoff, E.; Crittenden, D.; Yun, J.; Wang, A.; Wagman, R.; Schwartz, A.V. Effect of Denosumab on Fasting Glucose in Women with Diabetes or Prediabetes from the FREEDOM Trial. Diabetes Metab. Res. Rev. 2018, 34, e2991. [Google Scholar] [CrossRef] [PubMed]
  92. Lasco, A.; Morabito, N.; Basile, G.; Atteritano, M.; Gaudio, A.; Giorgianni, G.M.; Morini, E.; Faraci, B.; Bellone, F.; Catalano, A. Denosumab Inhibition of RANKL and Insulin Resistance in Postmenopausal Women with Osteoporosis. Calcif. Tissue Int. 2016, 98, 123–128. [Google Scholar] [CrossRef]
  93. Passeri, E.; Benedini, S.; Costa, E.; Corbetta, S. A Single 60 Mg Dose of Denosumab Might Improve Hepatic Insulin Sensitivity in Postmenopausal Nondiabetic Severe Osteoporotic Women. Int. J. Endocrinol. 2015, 2015, 352858. [Google Scholar] [CrossRef] [PubMed]
  94. Hadji, P. The Evolution of Selective Estrogen Receptor Modulators in Osteoporosis Therapy. Climacteric J. Int. Menopause Soc. 2012, 15, 513–523. [Google Scholar] [CrossRef] [PubMed]
  95. McClung, M.R. New Management Options for Osteoporosis with Emphasis on SERMs. Climacteric 2015, 18, 56–61. [Google Scholar] [CrossRef] [PubMed]
  96. Xu, B.; Lovre, D.; Mauvais-Jarvis, F. The Effect of Selective Estrogen Receptor Modulators on Type 2 Diabetes Onset in Women: Basic and Clinical Insights. J. Diabetes Complicat. 2017, 31, 773–779. [Google Scholar] [CrossRef]
  97. Hejazi, J.; Rastmanesh, R. Association between Tamoxifen Treatment and Diabetes: A Population-Based Study. Cancer 2012, 118, 6012. [Google Scholar] [CrossRef] [PubMed]
  98. Sun, L.-M.; Chen, H.-J.; Liang, J.-A.; Li, T.-C.; Kao, C.-H. Association of Tamoxifen Use and Increased Diabetes among Asian Women Diagnosed with Breast Cancer. Br. J. Cancer 2014, 111, 1836–1842. [Google Scholar] [CrossRef] [PubMed]
  99. Le May, C.; Chu, K.; Hu, M.; Ortega, C.S.; Simpson, E.R.; Korach, K.S.; Tsai, M.-J.; Mauvais-Jarvis, F. Estrogens Protect Pancreatic Beta-Cells from Apoptosis and Prevent Insulin-Deficient Diabetes Mellitus in Mice. Proc. Natl. Acad. Sci. USA 2006, 103, 9232–9237. [Google Scholar] [CrossRef]
  100. Johansson, H.; Gandini, S.; Guerrieri-Gonzaga, A.; Iodice, S.; Ruscica, M.; Bonanni, B.; Gulisano, M.; Magni, P.; Formelli, F.; Decensi, A. Effect of Fenretinide and Low-Dose Tamoxifen on Insulin Sensitivity in Premenopausal Women at High Risk for Breast Cancer. Cancer Res. 2008, 68, 9512–9518. [Google Scholar] [CrossRef]
  101. Cucinelli, F.; Soranna, L.; Romualdi, D.; Muzj, G.; Mancuso, S.; Lanzone, A. The Effect of Raloxifene on Glyco-Insulinemic Homeostasis in Healthy Postmenopausal Women: A Randomized Placebo-Controlled Study. J. Clin. Endocrinol. Metab. 2002, 87, 4186–4192. [Google Scholar] [CrossRef] [PubMed]
  102. Lasco, A.; Gaudio, A.; Morabito, N.; Previti, M.; Mileto, A.; Frisina, N.; Cucinotta, D. Effects of a Long-Term Treatment with Raloxifene on Insulin Sensitivity in Postmenopausal Women. Diabetologia 2004, 47, 571–574. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Campos Pastor, M.M.; Luna, J.D.; Escobar-Jiménez, F.; Gómez Jiménez, F.J.; Serrano Pardo, M.D.; López-Ibarra, P. Effects of Risedronate on Metabolic Bone Disease in Patients with Type 1 Diabetes and Osteoporosis. Rev. Esp. Enferm. Metabólicas Óseas 2008, 17, 66–70. [Google Scholar] [CrossRef]
  104. Vestergaard, P.; Rejnmark, L.; Mosekilde, L. Are Antiresorptive Drugs Effective Against Fractures in Patients with Diabetes? Calcif. Tissue Int. 2011, 88, 209–214. [Google Scholar] [CrossRef] [PubMed]
  105. Schwartz, A.V.; Ewing, S.K.; Porzig, A.M.; McCulloch, C.E.; Resnick, H.E.; Hillier, T.A.; Ensrud, K.E.; Black, D.M.; Nevitt, M.C.; Cummings, S.R.; et al. Diabetes and Change in Bone Mineral Density at the Hip, Calcaneus, Spine, and Radius in Older Women. Front. Endocrinol. 2013, 4, 62. [Google Scholar] [CrossRef]
  106. Neer, R.M.; Arnaud, C.D.; Zanchetta, J.R.; Prince, R.; Gaich, G.A.; Reginster, J.-Y.; Hodsman, A.B.; Eriksen, E.F.; Ish-Shalom, S.; Genant, H.K.; et al. Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis. N. Engl. J. Med. 2001, 344, 1434–1441. [Google Scholar] [CrossRef] [PubMed]
  107. Anastasilakis, A.D.; Tsourdi, E.; Tabacco, G.; Naciu, A.M.; Napoli, N.; Vescini, F.; Palermo, A. The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News? J. Clin. Med. 2021, 10, 996. [Google Scholar] [CrossRef]
  108. Celer, O.; Akalın, A.; Oztunali, C. Effect of Teriparatide Treatment on Endothelial Function, Glucose Metabolism and Inflammation Markers in Patients with Postmenopausal Osteoporosis. Clin. Endocrinol. 2016, 85, 556–560. [Google Scholar] [CrossRef]
  109. Anastasilakis, A.; Goulis, D.G.; Koukoulis, G.; Kita, M.; Slavakis, A.; Avramidis, A. Acute and Chronic Effect of Teriparatide on Glucose Metabolism in Women with Established Osteoporosis. Exp. Clin. Endocrinol. Diabetes 2007, 115, 108–111. [Google Scholar] [CrossRef]
  110. Schwartz, A.V.; Pavo, I.; Alam, J.; Disch, D.P.; Schuster, D.; Harris, J.M.; Krege, J.H. Teriparatide in Patients with Osteoporosis and Type 2 Diabetes. Bone 2016, 91, 152–158. [Google Scholar] [CrossRef]
  111. Russow, G.; Jahn, D.; Appelt, J.; Märdian, S.; Tsitsilonis, S.; Keller, J. Anabolic Therapies in Osteoporosis and Bone Regeneration. Int. J. Mol. Sci. 2019, 20, 83. [Google Scholar] [CrossRef] [PubMed]
  112. Baron, R.; Hesse, E. Update on Bone Anabolics in Osteoporosis Treatment: Rationale, Current Status, and Perspectives. J. Clin. Endocrinol. Metab. 2012, 97, 311–325. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Dempster, D.W.; Zhou, H.; Rao, S.D.; Recknor, C.; Miller, P.D.; Leder, B.Z.; Annett, M.; Ominsky, M.S.; Mitlak, B.H. Early Effects of Abaloparatide on Bone Formation and Resorption Indices in Postmenopausal Women with Osteoporosis. J. Bone Miner. Res. Off. J. Am. Soc. Bone Miner. Res. 2021, 36, 644–653. [Google Scholar] [CrossRef] [PubMed]
  114. Atteritano, M.; Catalano, A.; Santoro, D.; Lasco, A.; Benvenga, S. Effects of Strontium Ranelate on Markers of Cardiovascular Risk in Postmenopausal Osteoporotic Women. Endocrine 2016, 53, 305–312. [Google Scholar] [CrossRef] [PubMed]
Biomedicines 10 02191 g001 550
Figure 1. The mechanism of action of drugs used in diabetes on bone mineral metabolism. *—data come from observational studies; **—data come from in vivo studies; Ca-calcium; PPARγ-peroxisome proliferator-activated receptor gamma.
Figure 1. The mechanism of action of drugs used in diabetes on bone mineral metabolism. *—data come from observational studies; **—data come from in vivo studies; Ca-calcium; PPARγ-peroxisome proliferator-activated receptor gamma.
Biomedicines 10 02191 g001
Table
Table 1. Effects of antihyperglycemic drugs on the risk of fractures.
Table 1. Effects of antihyperglycemic drugs on the risk of fractures.
AuthorsType of PaperResults
Hidayat et al. [42]Meta-analysis of observational studyMetformin was associated with a reduced risk of fracture
Salari-Moghaddam et al. [43]Meta-analysisMetformin was inversely associated with the risk of fracture
Starup-Linde et al. [50]Original paperSulfonylureas were associated with hip fracture in DM2 patients
Losada-Grande et al. [52]A population-based matched cohort studyInsulin was probably associated with a 38% excess fracture risk among patients with DM2
Zhong-Ning et al. [55]Meta-analysis of randomized clinical trialsThiazolidinediones were associated with an increased risk of hip fracture among women
Bilezikian et al. [56]Randomized controlled trial52-week therapy of rosiglitazone in postmenopausal women with DM2 was associated with a small reduction in BMD of the total hip, femoral neck, and lumbar spine and increased markers of bone turnover
Cheng et al. [61]Meta-analysis of randomized clinical trialsGLP-1 agonist (liraglutide and lixisenatide) therapy were associated with a reduced risk of bone fractures
Chen et al. [64]Meta-analysis of randomized clinical trialsDDP-4 inhibitors did not affect the risk of fractures among DM2 women as compared with other antidiabetic drugs or placebo
Wen-Hsuan et al. [67]Population-based cohort studyDPP-4 inhibitors were associated with a reduced risk of upper limb fractures among DM2 patients
Watts et al. [69]Clinical trial Canaglifozin (Inhibitors of the sodium-glucose-2 cotransporter) increased the risk of fractures
Bilezikian et al. [73]Randomized controlled trialCanaglifozin (Inhibitors of the sodium-glucose-2 cotransporter) treatment over 104 weeks (dose 100–300 mg) was associated with a decrease in BMD of the total hip, but not of the femoral neck, lumbar spine, and distal forearm)
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Zawada, A.; Ratajczak, A.E.; Rychter, A.M.; Szymczak-Tomczak, A.; Dobrowolska, A.; Krela-Kaźmierczak, I. Treatment of Diabetes and Osteoporosis—A Reciprocal Risk? Biomedicines 2022, 10, 2191. https://doi.org/10.3390/biomedicines10092191

AMA Style

Zawada A, Ratajczak AE, Rychter AM, Szymczak-Tomczak A, Dobrowolska A, Krela-Kaźmierczak I. Treatment of Diabetes and Osteoporosis—A Reciprocal Risk? Biomedicines. 2022; 10(9):2191. https://doi.org/10.3390/biomedicines10092191

Chicago/Turabian Style

Zawada, Agnieszka, Alicja Ewa Ratajczak, Anna Maria Rychter, Aleksandra Szymczak-Tomczak, Agnieszka Dobrowolska, and Iwona Krela-Kaźmierczak. 2022. "Treatment of Diabetes and Osteoporosis—A Reciprocal Risk?" Biomedicines 10, no. 9: 2191. https://doi.org/10.3390/biomedicines10092191

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop