Review Explores Relationship Between Bone Health, Pediatric T1D

In a review published in World Journal of Diabetes, researchers outlined the current knowledge of mechanisms underlying altered bone remodeling among children with type 1 diabetes (T1D).

“Bone fragility is a well-known complication related to [T1D], and it can manifest from the disease onset, already in childhood,” authors explained, noting the exact role of metabolic control in preventing bone impairment is not yet fully understood.

In the last 10 years, incidence of T1D has been rising while age of onset has been steadily declining. In addition, “reduced bone mass may be present at an early stage after diagnosis, but it is unclear whether it is the duration of diabetes or degree of glycemic control that may induce a lifelong increased risk of fractures.”

To prevent osteoporosis, improving bone mineral gains during an individual’s growing years (ie, childhood and adolescence) is key. As peak T1D onset ranges between the ages 9 and 14, it coincides with puberty, during which main gender differences in bone growth emerge.

According to researchers, “impaired bone mass accrual (density and quality) in T1D children has been attributed to multiple local factors in the bone marrow, as well as to systemic factors, which affect osteoblast (OB) differentiation and function.”

Hyperglycemia may also impair the biology and function of bone marrow-derived mesenchymal stem cells (BMSCs), by reducing the proliferation and increasing the senescence of these cells in vitro.

Animal models have revealed bone marrow adipose tissue was significantly augmented in those with T1D, while bone formation was inversely associated with adipocytes in bone marrow.

However, bone morphogenetic protein-6 (BMP6) supplementation in diabetic mice has been demonstrated to directly restore bone mineral density (BMD) without influencing glucose levels, suggesting hyperglycemia may not be the main cause of bone loss in patients with T1D. “Other factors, like insulin and the growth hormone/ insulin-like growth factor 1 (GH/IGF-1) axis, could modulate BMSCs osteogenesis via BMP6 or other pathways,” authors wrote.

Insulin stimulates osteoclast (OC) formation and OB proliferation, while insulin signaling is “essential for normal bone acquisition.” According to authors “bone health depends on the balance between OCs, the bone-reabsorbing cells, and OBs, the bone-forming cells.”

Abnormalities in the GH/IGF-1 axis have also been reported in patients with T1D especially during puberty due to increased insulin requirements experienced at this stage of development. Studies have established a relationship between low BMD, low IFG-1, and glycemic control in youths with T1D

Although OC activity and bone resorption in patients with T1D are still debated, investigations have revealed low serum levels of OB markers in those with T1D.

When it comes to the relationship between muscles and bones in these patients, elevated irisin levels have been found to be closely related to both better metabolic control and improved bone mass, researchers wrote. “These findings are in agreement with the recent data showing that irisin can promote insulin synthesis as well as glucose-stimulated insulin secretion,” they said.

As patients with T1D exhibit a low bone turnover, this constitutes another mechanism underlying bone fragility in these individuals. Results of one study showed markers of bone formation and resorption “were significantly decreased in both sexes, and [glycated hemoglobin] levels were negatively correlated to the resorption marker C-terminal cross-link of collagen but not to any of the bone formation markers.”

However, results also indicated impairment of bone health in patients with T1D begins early in childhood, independent of age or puberty state. Low bone turnover resulting from insulin deficiency could also occur over time and may not be detected in studies based on acute changes in insulin levels, investigators noted.

Use of diabetes technology, including insulin pumps and continuous glucose monitors seem to be correlated with improved bone health in this population, although more studies are needed to confirm this finding. Prospective studies are also warranted to better understand the causal relationships among metabolic control, bone turnover markers, and bone mineralization in patients with T1D.

“To date, no specific biomarkers are available to predict accurately fracture outcomes in T1DM patients. Additional large-scale prospective studies are needed to identify high-risk patients,” authors wrote. Data is also not available regarding early interventions to avoid the risk of osteoporosis in patients with T1D.

Few studies exist looking into the effects of vitamin D, calcium intake, or physical activity on bone health in this cohort.

“Further studies are warranted to clarify better the factors responsible for bone damage in diabetic subjects and to identify efficacious strategies to prevent osteopenia/osteoporosis and the risk of fractures in these subjects,” researchers concluded.

Reference

Brunetti G, D’Amato G, De Santis S, Grano M, and Faienza MF. Mechanisms of altered bone remodeling in children with type 1 diabetes. World J Diabetes. Published online July 15, 2021. doi:10.4239/wjd.v12.i7.997