Building Strong Foundations: Bone Health in Pediatric Patients with Diabetes

Abstract

Purpose of Review

Skeletal development begins in childhood with all bone accrual complete by early adulthood, making bone health an important topic in pediatric medicine. This is especially true for patients with diabetes as these and other chronic conditions are associated with increased lifelong risk of fracture. The purpose of this review is to give a broad overview of bone health in diabetes including etiology, pathogenesis, and current recommendations for management.

Recent Findings

Studies continue to demonstrate lifelong increased risk of osteoporotic fractures in patients with diabetes. Like all diabetes complications, tight glycemic control, nutrition, and exercise play crucial roles in the prevention of this diabetes complication. Bisphosphonate therapy for osteoporosis in pediatrics is limited to those with a history of fragility fractures.

Opinion Statement

Pediatricians should promote lifestyle modifications to optimize bone health for all patients with diabetes, including ensuring adequate nutrition (vitamin D and calcium intake), exercise, and glycemic control. Dual-energy x-ray absorptiometry (DXA) scan should be considered for any patient with diabetes and a history of clinically significant fracture (vertebral fracture, low impact long-bone fracture, or multiple fractures). Referral to an endocrinologist with experience in osteoporosis treatment is appropriate for any patient with diabetes and a history of pathologic fracture.

Introduction

Childhood and adolescence represent critical times of bone growth and development, with peak bone mass occurring by early adulthood¹. Chronic disease during childhood, such as diabetes, increases the lifelong risk of osteoporosis and fractures. Adult osteoporosis (low bone mineral density) is a significant risk factor for fractures and affects approximately 12.6% of all Americans ≥ 50 years. Osteoporosis and pathologic fractures account for significant health and financial burden throughout the world^2,3. While osteoporosis typically occurs in later life, protection against this condition begins in childhood with optimal bone accrual. As such, bone health has become an increasingly important topic for pediatricians and those who care for children with chronic diseases.

Type 1 diabetes is a chronic autoimmune condition that often begins during childhood or adolescence. Type 2 diabetes is characterized by insulin resistance and failure of the beta cells to compensate, resulting in hyperglycemia. While type 1 diabetes is still the most common cause of diabetes in pediatric patients, type 2 diabetes is increasing in prevalence in this patient population⁴.

Robust adult data on bone health in diabetes show clear association with the increased rate of fractures in adults with both type 1 and type 2 diabetes^5,6 While the pediatric data are limited, there are several studies that demonstrate the risk of bone disease begins in childhood for those living with diabetes.

In this review, we explore the relationship of bone health to diabetes and management techniques to optimize bone health in pediatric patients with diabetes.

Pediatric Bone Health: normal bone development

The skeleton is an ever-changing structure critical to an individual’s health throughout their life. Bones are not only utilized for their structural characteristics, but also as a storage source of calcium and phosphorus, which are critical for homeostasis.

Skeletal growth begins prenatally, with the majority of calcium and phosphorus deposition occurring during the third trimester of pregnancy. Throughout infancy and early childhood, bone growth continues relatively steadily until puberty, at which time bone accrual and growth is mediated primarily by puberty hormones. Peak bone mass accrual typically occurs with 2 years of peak growth velocity, though may occur as late as 21 years in females and 25 years in males^1,7.

After young adulthood, bone mass gradually declines. Osteoporosis can result from either impaired bone density development in childhood or increased bone loss in adulthood. Interventions to optimize bone density must occur early in life, while interventions in adulthood aim to slow bone loss.

Factors impacting bone health

There are both modifiable and non-modifiable factors impacting peak bone mass. The most impactful determination of an individual’s bone health is genetic makeup and sex. Males have a higher peak bone mineral density than females, and approximately 60–85% of one’s bone mineral density is determined by genetics⁸. As the name implies, non-modifiable factors are static and therefore not currently targets for intervention. As a result, much of pediatric bone health is focused on modifiable factors.

Important modifiable factors include appropriate nutrition, exercise, lean body mass, smoking/tobacco use, and inflammation; we will discuss these factors and their relation to diabetes throughout this review⁹.

Bone Health and Diabetes

Individuals with diabetes, both type 1 and type 2, are at an increased lifelong risk of fractures. In adult patients, studies have consistently shown that bone mineral density (BMD) is lower in those with type 1 diabetes. Despite this difference in BMD being only slightly lower than unaffected peers, there are significantly increased rates of fracture among adults with type 1 diabetes¹⁰. Therefore, bone fragility in diabetes is multifactorial and includes several proposed mechanisms including alterations of bone development/remodeling, inflammatory effects, vascular alterations, increased reactive oxygen species, and advanced glycation end-products (AGEs).

Research related to bone disease in children and adolescents with diabetes is not as robust as adult data. However, several studies have demonstrated altered bone development in those with diabetes in childhood, which in turn can impact lifelong fracture risk. Meta-analyses have shown that when compared to their unaffected peers, pediatric patients with diabetes have lower bone mineral density¹² and altered bone formation/remodeling.¹³ These alterations at a critical period of bone development, therefore, impact lifelong fracture risk and partially account for the increased fracture rates seen in adults with diabetes.

A recent study comparing youth with type 2 diabetes to controls with obesity (without diabetes) demonstrated age-related differences in bone density between the two groups: children with type 2 diabetes had a higher bone mineral density than their peers with obesity alone. However, during the time of adolescence and early adulthood, this relationship reversed; those with diabetes had lower bone mineral density compared to their unaffected peers¹⁴. Peak bone mass accrual occurs in adolescence and young adulthood. Thus, this data suggests that diabetes negatively impacts bone accrual during this critical period, resulting in bone mineral density of subjects without diabetes surpassing their peers with diabetes by early adulthood.

Patients with diabetes at highest risk for lifelong fractures include those with longer disease duration, poor glycemic control, or other contributing lifestyle or medical conditions causing bone fragility^12,15,16,17. Patients who developed diabetes at age < 20 years are at increased risk of fracture, suggesting that alterations of bone structure during the critical accrual period of adolescence may contribute to lifelong fracture risk. Other factors associated with increased risk of fracture in diabetes include poor glycemic control (A1c ≥8%), microvascular complications, concurrent celiac disease, smoking history, and history of severe hypoglycemia/hypoglycemic coma^12,15,16,17.

Alterations in bone development

A major contributing factor to poor bone health in adulthood are alterations in bone development and formation, leading to microarchitectural weakening in those with diabetes compared to unaffected peers. While studies have shown that those with diabetes have lower bone density when measured via DXA, the rate of fractures is out of proportion to the degree of lower BMD. Importantly, when measured by peripheral quantitative computed tomography: (pQCT, a three-dimensional imaging modality allowing for evaluation of bone volume and strength), type 1 diabetes is consistently associated with lower bone trabecular scores^18,19.

Inflammation

Hyperglycemia and diabetes is associated with increased inflammatory cytokines and decreased ability to downregulate inflammation, which can predispose individuals to micro and macrovascular complications²⁰. Inflammation is itself a risk factor for fracture, as has been demonstrated by increased rates of fracture in those with inflammatory conditions such as rheumatoid arthritis. Inflammatory mediators including tumor necrosis factor – alpha (TNF-alpha), cortisol, histamine, bradykinin, and interleukins lead to alterations in receptor activator of nuclear factor kappa- B (RANK)and RANK ligand (RANKL), leading to increased bone resorption²¹.

Low insulin-like growth factor- 1 (IGF-1)

In those with type 1 diabetes, lack of pancreatic beta cells leads to decreased circulating IGF-1 levels. IGF-1 has direct effects on bone growth and development stimulation of osteoblasts. Therefore, insulin deficiency (in either type 1 or type 2 diabetes) may lead to decreased bone formation through this mechanism¹⁰.

Advanced glycation end products (AGEs)

AGEs increase with hyperglycemia and are associated with long-term micro and macrovascular diabetic complications^{10, 22}. One proposed mechanism of poor bone health is activation of AGEs in bone cells, leading to increased inflammation, reactive oxygen species, and bone resorption. This theory is supported by studies that have shown increased risk of bone disease with poor glycemic control.

RANK/RANKL/osteoprotegerin (OPG) system

In healthy individuals, bone remodeling is balanced through the RANK/RANKL/OPG system). RANK/RANKL stimulates differentiation of osteoclasts, leading to bone resorption/breakdown. OPG, secreted by osteoblasts, inhibits RANK/RANKL. Therefore, the body is constantly balancing the opposing parts of this system to ensure appropriate breakdown and rebuilding of bone²³.

When evaluating the RANK/RANKL/OPG system, researchers found that children with type 1 diabetes had altered expression within this system, with upregulated OPG messenger RNA expression (favoring bone formation and reducing bone breakdown)¹³. This defective bone remodeling balance is one proposed mechanism for findings of bone fragility out of proportion to the relative decrease in bone mineral density²⁴. Upregulated OPG leads to more bone formation, but without appropriate remodeling and removal of the old bone (bone breakdown), bone fragility occurs.

Diagnostic Evaluation

Bone Health Screening

All children should have evaluation and counseling regarding factors contributing to bone health. In children with diabetes, screening should include evaluation of glucose control, assessing concurrent conditions that can impact bone health (such as celiac disease, eating disorders, or nutritional deficiencies), and taking a fracture history for any evidence of fragility fractures. Some patients with diabetes may benefit from imaging to assess their bone health. Further discussion on patients’ historical screening is provided in the management section of this paper below.

Who to image

There are no consensus guidelines on when or whether to begin routine bone density evaluation in pediatric patients with type 1 or type 2 diabetes who are otherwise healthy. The International Society for Clinical Densitometry (ISCD) published official position statements regarding skeletal health assessment in pediatric patients. These position statements include appropriate imaging modalities and alternatives for all pediatric patients, with special focus on patients with primary or secondary osteoporosis²⁵.

In this statement, the task force noted that there is inadequate data to support routine DXA evaluation for patients with diabetes. However, the positions do note that for any pediatric patient at risk for a secondary bone disease (such as those with diabetes), DXA “should be performed when the patient may benefit from interventions to decrease their elevated risk of clinically significant fracture, and the DXA results will influence that management.”²⁵ Therefore, it is the authors’ opinion that patients with diabetes should be evaluated on an individual basis to determine whether bone density evaluation may be indicated. Those who may benefit would be those with other evidence of osteoporosis or low bone mineral density, such as those with fragility fracture. In this case, consultation with a pediatric endocrinologist with experience in bone density measurement, interpretation, and osteoporosis treatment is indicated.

How to Image

Dual- energy X-Ray Absorptiometry (DXA)

DXA is the preferred method for measuring bone density in children and adolescents due to several benefits including ready access, minimal radiation exposure, non-invasive imaging, and wealth of normative data in pediatric patients^25,26,27. In adults, reduced bone density on DXA is predictive of future fracture risk, but data for children and adolescents is not as robust. For pediatric patients, current data is also lacking on the fracture risk for pediatric patients with chronic medical conditions based on DXA results alone. As such, unlike adults, it is important to note that low bone density on DXA alone does not indicate osteoporosis in a pediatric patient; low bone density in addition to evidence of fragility fracture is required for the diagnosis of osteoporosis (see “ISCD criteria for diagnosis” below)²⁵.

DXA reports include bone mineral content (BMC) and areal BMD, which are then interpreted using the patient’s age, gender, height, and ethnicity to produce a height-adjusted Z-score ^27,28. For all cases of DXA measurement in children, pediatric software and use of valid reference data are essential for accurate interpretation²⁵.

Preferred sites for evaluation include the total body less head and posterior-anterior (PA) spine, though alternative sites may be needed depending on the individual patient. Distal 1/3 radius measurement may be an alternative for those in whom a whole body or spine score is not possible (such as those with surgical hardware that will impact measurement). In non-ambulatory children, proximal or lateral distal femur may be used²⁵.

Peripheral quantitative computed tomography (pQCT)

There are no formal guidelines for the use of pQCT in pediatric patients at this time. However, this imaging technique allows for more robust measurement of bone strength that accounts for aspects aside from density alone. For this reason, pQCT is mostly utilized in research settings rather than for clinical management^{25, 29}. In the future, pQCT may allow for more individualized assessment of bone architecture in patients with diabetes.

ISCD Criteria for diagnosis of Osteoporosis in children and adolescents

The ISCD criteria for diagnosis of osteoporosis in children and adolescents are recommended for use for all children, including those with risk factors such as diabetes. The same criteria are used regardless of other medical conditions. However, those with osteoporosis due to an underlying risk are said to have “secondary osteoporosis,” while those with a bone fragility syndrome (such as osteogenesis imperfecta) have “primary osteoporosis.” These criteria include any of the following²⁵:

• One or more vertebral compression (crush) fractures (in the absence of high-energy trauma or local disease) regardless of DXA results

• Clinically significant fracture history and BMD Z-score ≤ −2.0

  • Clinically significant fractures include:

    • Two or more long bone fractures by age 10 years
    • Three or more long bone fractures by age 19 years

Management

Guidelines for Optimizing Bone Health in Pediatric Patients

For all pediatric patients, the pediatrician plays a crucial role and primary prevention of bone disease through nutritional and lifestyle guidance. The American Academy of Pediatrics (AAP) published a clinical report on optimizing bone health in children and adolescents, which are important for all patients regardless of presence of chronic diseases²⁶. These guidelines should be used when counseling pediatric patients with diabetes on the importance of lifestyle factors in their long-term bone health. In addition, physical activity, Vitamin D status, and glycemic control are critical for this population. At each well visit and with each diabetes management visit, evaluation of the patient’s lifestyle and counseling regarding ways to build healthy bones should be incorporated to address the aspects in this section. Figure 1 includes a quick reference for bone health management.

Figure 1:

Bone Health Management Quick Reference For Pediatric and Adolescent Patients

Nutrition

Important nutritional influences of bone health include adequate calcium and vitamin D intake. Vitamin D insufficiency is common among children with diabetes and in those with conditions associated with type 1 diabetes (such as celiac disease) and type 2 diabetes (such as obesity)^30,31,33

The current recommended daily allowance (RDA) of calcium and vitamin D based on the Centers for Disease Control and Prevention (CDC) are included in Table 1. Infants should receive 400 IU per day of vitamin D while ages 1–18 years should have 600 IU daily^33,34. Elemental calcium RDA ranges 200mg-1300 mg daily based on age (see table). The role of vitamin D is crucial in periods of rapid skeletal growth, and as such the endocrine society recommends routine supplementation of vitamin D in all children and adolescents for the prevention of rickets, which can be achieved via fortified foods or nutritional supplements such as tablets or drops³⁵.

Table 1:

Recommended daily allowance and replacement doses for calcium and Vitamin D by age

RDA and Replacement Dosing
Age	Elemental Calcium RDA in mg	Vitamin D RDA in IU*	Replacement for Vitamin D Deficiency in daily IU*
0–6 months	200	400	600–2000
7–12 months	260	400	600–2000
1–3 years	700	600	1000–2000
4–8 years	1,000	600	1000–5000 or 50,000 every 7–14 days
9–18 years	1,300	600	2000–5000 or 50,000 every 7 days

RDA- recommended daily allowance; IU- international units;

^*400IU = 1mcg

There remains debate about whether to screen all patients with diabetes for vitamin D deficiency. However, the Endocrine Society does recommend screening patients considered “at risk” for vitamin D deficiency. Therefore, given the known risk for vitamin D deficiency on bone health, the prevalence of vitamin D deficiency, and the independent risk of diabetes on bone health, we recommend screening all children with a serum 25-hydroxy-vitamin D (25OHVitamin D) level with their routine diabetes monitoring labs (yearly or every 1–2 years). Supplementation with additional vitamin D above RDA should be started on patients with serum 25OHVitamin D less than 30 ng/mL. Vitamin D supplementation depends on age and range from 600 IU – 2000 IU daily or can be given weekly with higher doses (see table 1). Note that some patients with diabetes may require higher doses of vitamin D to achieve a normal serum 25OHVitamin D level.

Physical activity

Exercise and mechanical forces on the bone are crucial for bone mineral accrual in children and adolescents²⁶. Studies have shown that even small amounts of weight-bearing exercise (10 minutes 3 times per week) can improve bone mineral density in children and adolescents.

As seen with all children and adults, physical activity including weight-bearing exercise has beneficial effects on bone mineral density in children with type 1 diabetes. A small study evaluating the improvement of bone mineral density in youth with type 1 compared to controls after completing a nine-month physical activity intervention demonstrated that both groups had improvement in their BMD without significant difference between those with or without diabetes. This suggests that although bone development is altered in diabetes, lifestyle interventions such as exercise are still an effective management tool in this population³⁶. All patients should aim to include at least 60 minutes of vigorous exercise daily and strength training at least 3 times per week.

Body weight

Both low body mass index (BMI) and increased adiposity pose risks to lifelong bone health. Those with low BMI are at increased risk for low BMD, while increased adiposity is associated with increased fracture risk regardless of BMD. Lean muscle mass is beneficial for bone mineral density and decreases fracture risk³⁷. Therefore, counseling should be provided for all patients with diabetes regarding strengthening exercises to build lean body mass and the importance of appropriate nutrition to avoid over or underweight status.

Other lifestyle factors: salt, smoking, alcohol, caffeine, and carbonated beverages

Other lifestyle factors that have been associated with decreased bone mineral density include smoking, consumption of carbonated beverages, alcohol, and caffeine, and increased salt intake^26,37. Like their unaffected peers, teens and adolescents with diabetes should be encouraged to avoid tobacco use, alcohol intake, and excessive intake of carbonated beverages and salt.

Glycemic control

Glycemic control is an important determining factor of risk of fractures during childhood or adolescence for patients with diabetes^{12,13,15,17,18}.

Children with type 1 diabetes and higher A1c have increased rates of fractures compared to their well-controlled peers with type 1 diabetes. This risk is further increased in those with a history of severe hypoglycemia (with or without coma), celiac disease, or history of smoking¹⁵.

Children with poor glycemic control also have increased expression of OPG messenger RNA, suggesting that poor glycemic control is a risk factor for disruption in normal bone remodeling¹³.

Therefore, optimizing glucose control is a crucial component of preventing diabetes-related bone disease as well as microvascular complications, which can further increase fracture risk. It is important to note that hypoglycemia is a risk for fracture as well, and therefore management of diabetes should focus on prevention of both excessive hyperglycemia and hypoglycemia.

Management of co-morbidities

As mentioned previously, type 1 and type 2 diabetes can be associated with other conditions that pose additional risk to bone health. Table 2 lists conditions that have independent impacts on bone health and are often associated with type 1 or type 2 diabetes. If present, these conditions may put a patient at additional risk for lifelong fractures. For example, patients with type 1 diabetes have increased rates of celiac disease³⁸, which itself is associated with poor bone health. Patients with type 1 diabetes and celiac disease have increased fracture risk compared to their peers with only one of these conditions¹⁵. Eating disorders are another condition that is seen more often in patients with diabetes^39. Eating disorders are a significant risk for low bone mineral density and fracture, and this risk develops after a relatively short duration⁴⁰. Hormonal deficiencies, such as hypogonadism, are more prevalent in poorly controlled diabetes⁴¹; pubertal hormones are required for normal bone accrual and hypogonadism is a major risk factor for poor bone health²⁶. Management of these conditions should therefore be of equal importance to promote bone health in pediatric patients. Treatment for these conditions may require referral to subspecialists when available (for example, referral to a pediatric gastroenterologist and a registered dietician for those with celiac disease).

Table 2:

comorbid conditions and their impact on bone health in children with diabetes

Co-morbid condition	Prevalence in diabetes patients	Impact on bone health
Celiac disease	1.4–21.2% in T1DM38, <1% in T2DM	Autoimmune enteropathy → malabsorption of Ca & vit D → secondary hyperparathyroidism; pro-inflammatory cytokines; low BMI → decreased BMD15
Autoimmune Thyroid disease	14–28% Hashimoto’s hypothyroidism in T1DM 0.5–7% Graves Disease in T1DM50	Thyroid dysfunction alters bone remodeling: hypo → reduced turnover; hyper → increased resorption → decreased BMD50
Rheumatologic disease (JIA, SLE, other inflammatory arthritis)	<1%-5% in T1DM, <1% in T2DM51	Chronic inflammation & corticosteroid use → increased osteoclast activity and inhibited osteoblasts → bone loss
Obesity	72–77% of T2DM, ~35% of T1DM52	Sequestration of vit D in fat tissue → lower bioavailability; inflammation → impaired bone mineralization; mechanical load may paradoxically increase BMD but quality suffers52
Vitamin D deficiency	~20–50% in general pediatric; 29–49% in overweight/obese; ~34% linked with obesity52	Impaired Ca absorption & mineralization → rickets/osteomalacia; reduced bone mass, increased fracture risk
PCOS	~20–30% in adolescent girls with T2DM/T1DM54	Hyperandrogenism + insulin resistance → altered bone turnover; obesity component; potential for vitamin D deficiency
Eating disorders	AN ~0.3–0.8%, BN ~0.9%, BED ~1.6–4% in children with T1DM55	Nutritional deficiency & low BMI/hormone levels → impaired bone accrual and BMD; amenorrhea → estrogen deficiency
Hypogonadism	rare in children	Low sex hormones → decreased bone formation, reduced peak bone mass → low BMD

Medications

There are no medications currently indicated for primary prevention of fractures in pediatric patients with diabetes and low bone mineral density without evidence of fracture. Bisphosphonate therapy (alendronate, pamidronate, zoledronic acid) has been used in pediatric patients with primary or secondary osteoporosis and has been shown to improve DXA scores⁴². Therefore, these medications may be considered in patients with diabetes who have fragility fractures. Administration of these medications should be managed by a pediatric endocrinologist with experience in osteoporosis treatment.

Bisphosphonates have been used for pediatric patients with primary osteoporosis (osteogenesis imperfecta) since the late 1990s and have been shown to improve bone density, though long term data on their prevention of adult osteoporosis is still lacking^{42, 43}. These medications have a high affinity for bone, especially in areas of bone remodeling and work primarily by inhibiting osteoclasts (thus slowing bone resorption)^42,43. While slowing bone resorption is the primary mechanism of action, bisphosphonates also prevent osteoblast and osteocyte apoptosis, though the clinical benefits of this remain unclear⁴³.

Due to the benefits in primary osteoporosis and their relatively safe profile, bisphosphonates have been used for children with secondary osteoporosis due to other chronic conditions. A recent meta-analysis demonstrated that children with secondary osteoporosis had increased lumbar spine bone density without significant increase of adverse events, supporting bisphosphonate use in pediatric secondary osteoporosis⁴⁴. Of note, none of the studies in this meta-analysis evaluated pediatric patients with secondary osteoporosis due to diabetes.

There are no Food and Drug Administration (FDA) approved indications for use of bisphosphonates in children. However, two bisphosphonates have been used most often in research trials on children and therefore are more commonly utilized: zoledronic acid and pamidronate^42,45,47. In 2018, the Australasian Paediatric Endocrine Group published consensus guidelines for the use of bisphosphonate therapy in children⁴⁶. These guidelines recommend using zoledronic acid or pamidronate with periodic post treatment reassessment to determine length and frequency of treatment in patients with secondary osteoporosis. Reassessment of ongoing risk factors, including management of underlying conditions leading to secondary osteoporosis, is recommended following the initial 12 months of treatment.

Both pamidronate and zoledronic are IV medications. Zoledronic acid is utilized more often, likely due to adult data supporting its benefits to prevent fractures in osteoporosis⁴⁸. Zoledronic acid is dosed over a single infusion (while pamidronate is dosed over several days of IV infusion), which is an additional benefit in pediatric patients and may be a driver for its use. There does not appear to be a significant difference between the two drugs in relation to bone mineral density benefits in children, but data comparing the two is limited⁴⁹.

Specific treatment regimens vary by country and institution. In general, these regimens should be developed on an individual basis by an experienced pediatric endocrinologist.

Conclusion

As is the case with many conditions, the prevention of osteoporosis begins in childhood and adolescence. Pediatric patients with diabetes have lifelong complications for which they must be managed long before their presence is evident. Osteoporosis remains the most significant risk factor for fractures in adulthood, and those with diabetes are at significantly increased risk. Modifiable risk factors should be addressed beginning in childhood to prevent low bone mineral density. Most importantly, all patients both with and without diabetes should develop healthy lifestyles during childhood to promote bone health including adequate nutrition, exercise, development of healthy lean body mass, and avoidance of detrimental habits such as smoking, excess caffeine intake, and soda consumption.

Those with diabetes can additionally benefit from achieving adequate glycemic control, which decreases the risk of fracture and protects against other microvascular and microvascular diabetes complications.

Data are still lacking on further interventions such as medication management for primary prevention of fractures in pediatric patients with diabetes and low bone mineral density. At this time, medication management is limited to those meeting diagnostic criteria for osteoporosis and should be managed by a pediatric endocrinologist.