This study addresses whether metabolic control has an effect on bone health in patients with T1D who have not yet achieved peak bone mass. Adolescents with T1D in consistently poor metabolic control appear to have lower iPTH levels than a group of adolescents with T1D in favorable metabolic control, although this association was attenuated when adjusted for age, gender and race. After adjustment, urine calcium is associated with metabolic control, consistent with lower iPTH levels. We also explored the prevalence of 25-hydroxyvitamin D abnormalities in adolescents with T1D, as vitamin D abnormalities have been increasingly recognized as a significant health problem both for healthy patients and those with chronic illnesses [26
]. Adolescents with T1D have significant 25-hydroxyvitamin D abnormalities, but these abnormalities are not more prevalent than in the general adolescent population.
Poor bone health is a significant problem for many adults with T1D, as is demonstrated by a two-fold increase in fracture risk in the lumbar spine, femoral neck, and distal radius [1
]. Women with T1D have more than a 10-fold increase in risk of hip fractures compared with age-matched controls [2
]. Almost 20% of patients with T1D ages 20-56 years meet criteria for osteoporosis [27
], which is a debilitating illness that impairs functionality and quality of life [28
]. However, the etiologies of decreased BMD in adults with T1D have been unclear [29
]. The mechanisms of osteoporosis associated with T1D differ from the development of osteoporosis associated with aging [31
], and several potential mechanisms have been proposed, including effects of advanced glycation end products in bone collagen [32
], increased urinary excretion of calcium, phosphate and magnesium [33
], inflammatory cytokines [34
], low levels of iPTH [12
], diabetic microangiopathy with reduced blood flow to bone [35
], decreased bone resorption [16
], decreased bone formation [36
], and vitamin D deficiency [37
]. We sought to evaluate whether poor metabolic control during adolescence is associated with abnormal bone health.
Previous studies investigating the role of metabolic control and BMD in patients with T1D have been limited by older BMD measurement methods which may be inaccurate, limited knowledge in the consistency of patients' actual metabolic control (many studies use only a single HbA1c measurement as the index of metabolic control), and confounding factors affecting BMD such as the use of oral contraceptives. In this study, we controlled confounding factors and found no correlations between metabolic control and BMD, similar to others [3
], but differing from some [4
]. Although subjects had stable diabetes control for two years prior to the study, two years of poor diabetes control may not be long enough to lead to changes in BMD demonstrated by DEXA scans in adolescents.
The role of IGF-I as a critical anabolic regulator of BMD is clearly demonstrated in animal studies in which genetic manipulation of the IGF system led to osteopenia [7
]. In humans, cross-sectional and cohort studies in various populations, including subjects from the Framingham Heart Study, have demonstrated a strong correlation between serum levels of IGF-I and BMD [6
]. Dysregulation of the IGF-I/IGFBP system has been reported in patients with T1D [9
]. We found no associations between metabolic control and components of the IGFI system, although other studies have reported that IGF-I levels correlate with metabolic control [11
]. As we did not have a control group of healthy subjects, IGFI levels may be too low within a population of T1D patients to detect significant differences.
Only 35% of healthy non-Hispanic white adolescents are sufficient in 25-hydroxyvitamin D [23
], which plays an important role in the maintenance of bone health. Similar to recent studies, we found a significant prevalence of 25-hydroxyvitamin D abnormalities in adolescents with T1D [37
], but we did not find a difference in 25-hydroxyvitamin D status between adolescents with T1D and the normal adolescent population [23
]. However, the proportions of vitamin D sufficiency status by gender were limited by small numbers which resulted in proportions with wide confidence intervals. There is not enough evidence to support that metabolic control plays a role in vitamin D status, and other risk factors need to be evaluated.
Only one subject reported consuming the current RDA for vitamin D, with 16% consuming the RDA for calcium. This is not different from the healthy adolescent population, as previous data from NHANES III (1988-1994) demonstrated that only 53-63% of all US children consume at least 200 IU of vitamin D per day from diet and/or supplementation. (200 IU was reported in this paper because it was considered Adequate Intake for vitamin D at that time) [42
]. This is of particular concern for adolescent patients with T1D, as vitamin D and calcium intake are modifiable factors that have a significant impact on BMD.
Our study had several limitations. We stratified by design the subjects into poor and favorable metabolic control groups, and we could have missed relationships between HbA1c and study variables due to a lack of a full continuous spectrum of HbA1c values. We did not have a control group of non-diabetic patients. Also, we did not obtain information regarding exercise and specifics regarding pubertal development, which clearly have an effect on BMD and bone turnover. However, we attempted to address this issue by excluding patients with obesity as well as known pubertal delay, amenorrhea, or polycystic ovarian syndrome.
In summary, metabolic control is not associated with BMD as evaluated by DEXA in this adolescent population with T1D, and bone anabolic and turnover markers are not affected by metabolic control, once age, gender, and race are taken into account. Adolescents with T1D are frequently vitamin D insufficient, which is likely also playing an important role in bone metabolism.