Tuesday, April 29, 2014

Understanding healthy bone growth in childhood to improve long-term quality of life

Deborah Mitchell, MD, Instructor in Pediatrics, Harvard Medical School, Assistant in Pediatrics, Division of Pediatric Endocrinology, Massachusetts General Hospital for Children.

Osteoporosis and associated fragility fractures including hip and spine fractures among the elderly are associated with enormous morbidity and mortality. Interventions in the pediatric time period thus have the potential to drastically improve quality of life during adulthood as well as to lead to significant cost savings to our health care system.

During my fellowship, under the mentorship of Dr. Sherri-Ann Burnett-Bowie, I investigated the regulation of the recently discovered hormone fibroblast growth factor 23 (FGF23) during childhood. FGF23 signaling in the distal tubule of the kidney leads to increased phosphate loss in the urine, and it is thought to be the primary hormone regulating phosphate homeostasis. Over the past 10 years, elevations in FGF23 have been reported to be the cause of several rare disorders associated with hypophosphatemia and rickets including X-linked hypophosphatemic rickets (XLH) and tumor-induced ostemalacia (TIO). Circulating levels of FGF23 are also extremely elevated in renal failure and are strongly associated with risk of mortality in this disorder. However, the role of FGF23 in the normal physiologic state as well as the factors which stimulate and/or suppress its secretion remain poorly understood. Interestingly, phosphate levels in childhood are higher than in adulthood, with a slow and steady decrease over the first two decades of life. The mechanism by which this is regulated is unknown. We hypothesized therefore that this decrease in serum phosphate would be mediated by increases in serum FGF23 levels. In a study of 90 healthy girls ages 9-18, we found the expected decrease in serum phosphate levels (Figure 1A) but no changes in either total FGF23 levels (Figure 1B) or intact

Deborah M. Mitchell, MD: Figure 1

FGF23 levels (Figure 1C). Surprisingly, we found an association of intact FGF23 with serum calcium levels (Figure 2A) and an inverse association of intact FGF23 with urinary calcium excretion (Figure 2B). Over the past year, accumulating data from animal models of altered FGF23 levels have suggested that FGF23 may play a role in calcium metabolism as well as phosphate metabolism. Our data is the first to suggest that this may be true in humans as well. Current research is underway to better define the complex interactions of calcium, phosphate, FGF23, and other hormones critical to bone mineral metabolism including parathyroid hormone and vitamin D metabolites.

My current research project is an examination of bone quality in patients with type 1 diabetes (T1DM). While long-term complications of diabetes are known to include nephropathy and vascular disease, diabetic osteopathy is increasingly recognized to be a serious outcome. Epidemiological data indicates that adults with T1DM have a rate of hip fracture six-fold higher than the general population. Bone mineral density is decreased approximately 10-20% in patients with T1DM and thus likely explains some of this risk. However, bone strength is impaired much more severely than this moderate decrease in BMD would predict. This suggests that other factors, including bone microarchitecture and bone matrix material properties, may also be altered in T1DM. We are therefore following a cohort of girls with T1DM to investigate predictors of poor bone mineral accrual as well as differences in bone microarchitecture and estimates of strength. Preliminary data suggests that microarchitectural changes are significant, with decreased thickness of individual bone trabeculae causing an overall decreased density of the trabecular compartment. Our hope is that a better understanding of the nature and causes of bone fragility in this patient population will help us design targeted interventional strategies to optimize bone health.

Deborah M. Mitchell, MD: Figure 2

In addition, in collaboration with Dr. Michael Mannstadt, I have an ongoing natural history project following a cohort of 120 patients, both pediatric and adult, with

hypoparathyroidism. This is a relatively rare but serious disorder in which parathyroid hormone levels are low leading to low serum calcium levels. Unlike most endocrine disorders which are treated with replacement of the missing hormone, hypoparathyroidism is typically treated by oral supplementation with calcium and calcitriol, the activated form of vitamin D. Because the absence of parathyroid hormone leads to impaired urinary resorption of calcium, this treatment is associated with a high risk of hypercalciuria and therefore of kidney stones and nephrocalcinosis. We have demonstrated a high rate of complications of this disorder and of its treatment. For example, 33% of our cohort had at some point required an emergency department visit or hospital admission due to their disease, and 8% had suffered at least one hypocalcemic seizure. Rates of renal disease were high, with the prevalence of chronic kidney disease stages 3-5 substantially higher than age-appropriate background levels (Figure 3). These data provide motivation for the development of improved therapies, including parathyroid hormone repletion treatment and small-molecule calcilytics, to decrease the morbidity of this disease.

Deborah M. Mitchell, MD: Figure 3


Mitchell DM, Jüppner H, and Burnett-Bowie SM. Fibroblast growth factor 23 is not associated with age-related changes in phosphate handling in children. Endocrine Reviews (in press)

Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, Burnett-Bowie SA, Mannstadt M. Long-term follow-up of patients with hypoparathyroidism. J Clin Endocrinol Metab. 2012 Dec;97(12):4507-14.

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