Glycemic Control and Fracture Risk in Patients With Type 2 Diabetes Mellitus

Abstract

Type 2 diabetes mellitus (T2DM) is a long-term metabolic disorder marked by persistent hyperglycemia, mainly due to insulin resistance and impaired insulin production. Rising rates of obesity and sedentary behavior have fueled a global increase in T2DM. While complications such as cardiovascular disease, nephropathy, neuropathy, and retinopathy are well known, recent research highlights a notable link between T2DM and bone health. Patients with T2DM face a higher risk of fractures, even with normal or increased bone mineral density (BMD), primarily due to compromised bone quality and a greater likelihood of falls.

In a study conducted in Finland using rat bone marrow, short-term hyperglycemia (lasting 1 or 3 days) was found to stimulate osteoblast activity. However, when hyperglycemia persisted for a longer duration (10 days), it led to increased production of reactive oxygen species (ROS), which ultimately impaired osteoblast function [1], highlights the dual effects of hyperglycemia on bone health, with transient elevations possibly supporting bone formation, while prolonged exposure contributes to oxidative stress and compromised osteoblast performance.

In a longitudinal study conducted in the United States, Ballato et al. examined 169 T2DM male patients and found that poor glycemic control over 1 year was linked to reduced bone turnover and impaired bone microarchitecture [2]. Further analysis of 51 male T2DM patients indicated that poorly managed long-term blood sugar levels were associated with an increase in circulating osteogenic progenitor (COP) cells, potentially hindering the maturation of these cells into osteoblasts [3]. This disruption in cellular development may contribute to weakened bone formation and structure, underscoring the impact of glycemic control on bone health in T2DM patients.

Chronic hyperglycemia leads to the accumulation of advanced glycation end products (AGEs), which impair bone formation by promoting osteoblast apoptosis [4]. A systematic review of 66 studies found that hyperglycemia decreases osteoblast and osteoclast activity, also resulting in reduced bone turnover and increased fracture risk in T2DM [5]. However, the BMD of patients with T2DM is generally normal to higher compared to non-diabetics [4]. The elevated risk of fractures may not directly correlate with BMD in T2DM.

Older patients had a higher osteoporosis fracture risk. This finding suggests that factors beyond BMD may contribute to the heightened fracture risk in patients with T2DM. Here, we explore some of these potential reasons.

Reduced physical activity causes sarcopenia through loss of type II fast-twitch muscle, which impairs glucose uptake by skeletal muscle, and T2DM is associated with sarcopenia [6]. A UK study found reduced proximal leg muscle strength in 20 T2DM patients with diabetic polyneuropathy compared to 20 healthy individuals, creating a vicious cycle [7]. With aging, sarcopenia leads to functional impairment and disability, increasing the risk of falls in elderly individuals with diabetes. This elevated fall risk raises the likelihood of fractures, including major osteoporotic fractures [6, 7].

A Canadian retrospective population-based cohort study involving 82,094 individuals (both type 1 and type 2 DM) demonstrated that those with a long disease duration had a higher risk of osteoporotic fractures [8]. Insulin therapy is associated with an increased risk of hypoglycemic episodes, which can manifest with neurological symptoms such as dizziness, confusion, or altered consciousness. A population-based study conducted in Sweden, involving 79 159 patients with T2DM with a mean age of 80.8 years, compared to 343 603 non-diabetic individuals, demonstrated that insulin use was significantly associated with an elevated risk of hip fractures [9]. Following a fracture, higher serum glucose levels, increased AGEs, and the generation of reactive oxygen species can hinder fracture healing. This often results in patients being unable to engage in weight-bearing physical activity, leading to prolonged bed rest and perpetuating a vicious cycle.

About the novel glucose-lowering agent including dipeptidyl peptidase-4 inhibitors (DPP-4i), glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium glucose cotransporter 2 (SGLT2) inhibitors, a meta-analysis combining 177 randomized controlled trials (RCTs) suggested that the use of DPP-4i, GLP-1 RAs, or SGLT2 inhibitors is unlikely to increase the risk of fractures in T2DM patients compared to treatments such as insulin, metformin, or sulfonylureas [10, 11].

Studies of T2DM patients have shown that hyperglycemia (HbA1c > 9) is associated with peripheral neuropathy [12, 13]. For instance, research involving 20 025 T2DM patients aged 65 and older in Taiwan and another study of 10 572 diabetic patients in Tennessee, USA, using ICD-9 electronic medical records, revealed this connection. Similarly, a patient-based cohort study in Sweden involving 429 313 individuals, including 79 159 with T2DM [8], reported comparable findings. T2DM patients often experienced sensory impairment, motor function deficits, reduced muscle mass, loss of pressure sensitivity, and poor balance [9, 13], all of which increase the risk of falls [13].

Managing bone health in diabetes requires a multifactorial approach; older patients also had higher osteoporosis fracture rates. Currently, osteoporosis medications fall into three categories: antiresorptive, anabolic, and drugs with a mixed mechanism of action. Research has shown that these medications either improve blood glucose control or have no change in glucose metabolism [14-19]. Table 1 highlights the effects of various osteoporosis medications on blood glucose levels from multiple studies. Bisphosphonates are the recommended first-line treatment for osteoporosis in patients with T2DM, despite the characteristic low bone turnover often observed in this population. This reduced bone turnover may be further suppressed by antiresorptive therapies, potentially impacting bone health. In elderly patients or those with renal impairment, denosumab is favored due to its safety profile and efficacy. For severe osteoporosis, anabolic agents are considered appropriate to address significant bone loss [14-19].

A population-based study in Canada from 1995 to 2005 indicated that successful treatment of diabetes reduces mortality rates. However, inadequate lifestyle-changing programs have contributed to rising obesity and a higher incidence of diabetes. A US study that recruited 77 206 postmenopausal women found that increased sedentary behavior was associated with a higher risk of total fractures and mortality [20]. Prolonged sedentary behavior diminishes physical function, reduces leg blood flow, and, with age, leads to a reduction in type II fast fibers [6], contributing to sarcopenia and an elevated risk of falls and fractures.

Elderly individuals often have multiple comorbidities and are frequently prescribed medications such as antihypertensives, statins, anticoagulants, and sedatives. As we move towards an aging society, future research should include RCTs to better understand the risk of fractures associated with polypharmacy.

The risk of fractures in patients with T2DM arises from a complex interplay of factors. To reduce this risk, it is essential to promote regular physical activity, optimize antidiabetic treatments, and consider early intervention with osteoporosis therapies. In elderly patients, the risk is heightened by the potential for drug interactions, especially in those managing multiple chronic conditions. Careful monitoring and adjustments to medication regimens can help minimize adverse effects. A coordinated approach to care, involving specialists in rheumatology, endocrinology, orthopedics, and nutrition, is necessary. This multidisciplinary strategy ensures comprehensive management, addressing both diabetes and fracture risk to improve patient outcomes.

S.-T.S.: wrote and revised manuscript. Y.-H.L.: assist with revising the manuscript. Y.-C.T and P.-C.S.: supervise and revised the manuscript. All the authors are responsible for the manuscript.

The authors declare no conflicts of interest.