1. Department of Pediatrics San Paolo Hospital University of Milan
International meeting
glycogen storage diseases associations
2-3 October, Milan
BONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE I
Ilaria Giulini Neri
Department of Pediatrics
San Paolo Hospital University of Milan

2. Glycogen storage disease type I (GSD I)
Disorder of glucose homeostasis (glycogenolysis/gluconeogenesis)
Incidence: 1/
Autosomal recessive transmission
Type Ia  glucose-6-phosphatase deficiency
Type Ib  glucose-6-phosphatase translocase

3. Clinical and biochemical features of GSD I
Accumulation of glycogen in liver, kidney, and intestine
Metabolic derangements: fasting hypoglycaemia, lactic acidosis, hyperuricaemia, hyperlipidaemia
Type Ib: neutropenia and neutrophil dysfunction
Several long term complications: short stature, liver adenoma, renal damage, osteoporosis, polycistic ovaries.

4. Bone matrix loss in GSD/literature data
Histopathological study: osteoporosis, no osteomalacia (Soejima et al., Pediatr Pathol, 1985)
Radiographic study: osteopenia, retarded bone maturation, fractures, nonspecific skeletal abnormalities (Miller et al., AM J Roentgenol, 1979)
BMC in prepubertal patients (Lee et al., Eur J Pediatr 1995)
Association with reduced muscle force and metabolic control (Schwan et al., J Pediatr 2002)
BMD in adolescence/adult patients: diminished bone mass accretion during childhood or historical differences in treatment? (Rake et al., J Inherit Met Dis, 2003)
No correlation between BMD and markers of bone turnover (Cabrera-Abreu et al., J Inherit Met Dis, 2004)

5. Bone matrix loss in GSD/pathophysiology
Restrictive diet (dairy products, other sources of sucrose, fructose, galactose need to be avoided)
Hypoglycaemia and low insulin values lead to a low non-enzymatic glycosilation of bone matrix proteins  impaired bone resistance
Chronic lactic acidosis:
increase of mobilization and release of bone alkaline salts (calcium phosphate and carbonate) in response to a acid load to mantain acid-base balance
loss of calcium and phosphate with urine  hypercalciuria and reduced tubular reabsorption of phosphate
high activity of osteoclasts, reduced of osteoblasts

6. Bone matrix loss in GSD/pathophysiology
Endogenous glucocorticoid excess, altered levels of GH and IGF-1 seems to reduce collagen content in bone and matrix synthesis
Abnormal pubertal growth spurt with sex hormone secretory dysfunction (important role in bone formation and adequate peack bone mass, especially during puberty)
Decreased calcium absorption

7. Bone matrix loss in GSD/pathophysiology
Hypotrophic muscles and decreased muscle function (result of reduced whole-body protein synthesis and of increased proteinolysis due to increased gluconeogenesis, especially in poor metabolic control)
Decreased physical activity (chronic disease) ?

8. BONE METABOLISM AND VITAMIN D ROLE
AIM OF THE STUDY
BONE METABOLISM AND VITAMIN D ROLE
IN PATIENTS WITH GSD I
To study prevalence of osteopenia and osteoporosis
To evaluate correlation between metabolic balance and bone markers
To determine plasmatic levels of 25(OH)D and to research a correlation with bone mineral density (BMD)

9. background Why vitamin D?
Important role in calcium homeostasis and bone metabolism
Vitamin D insufficiency  osteoporosis (not rickets or osteomalacia) as a result of calcium malabsorption
Vitamin D deficiency  proximal muscle weakness (receptor for vitamin D (VDR) is expressed in human muscle tissue, and VDR activation may promote de novo protein synthesis in muscle)

10. background
Why vitamin D?
Serum 25(OH)D is the correct functional indicator of vitamin D status; reference values according to Holick, M. F. Vitamin D deficiency. N Engl J Med (2007).
The increment in serum 25(OH)D produced by an oral dose of vitamin D is greater at low basal levels than at higher values.
Safe upper limit: 2000UI(=50 ug)/day (Food and Nutrition Board)

11. Vitamin D/skin production
Sun exposure could be sufficient to cover requests (UVB exposure for min generates UI vit D3/24 h).
Problems: winter months, sunscreen, sun- protective clothing, low outdoor activities, northern latitudes, dark skin pigmentation, reduced skin synthesis in older people.

12. Vitamin D/food content
1UI = 0,025 µg/die
Modified by Zittermann, Vitamin D in preventive medicine: are we ignoring the evidence?British Journal of Nutrition (2003)

13. Vitamin D/recommended adequate intake
American Academy of Pediatrics (2008):
400 IU per day to prevent ricket and vitamin D deficiency in children and adolescents
Institute of Medicine (1997):
200 IU per day for adults up to 50 years of age
400 IU per day for adults between age 51 and 70
600 IU per day for those aged 70 years and over.
In absence of adequate sun exposure:
UI/day (20-25μg/day).

14. Daily recommended amount of calcium and vitamin D (L.A.R.N.)

15. Vitamin D/inflammatory bowel disease
Serum concentrations of 25(OH)D levels are low in patients with inflammatory bowel diseases such as ulcerative colitis and Crohn’s disease (Jahnsen et al. 2002).
Moreover, supplementation with vitamin D or calcitriol significantly ameliorated symptoms (Cantorna et al. 2000).

16. In GSD type I: Dietary restrictions Metabolic derangements
Intestinal malabsorption
The current guidelines for GSD I do not recommend evaluation of vitamin D as part of routine follow up
Banugaria et al., Mol Genet Met, 2009: “Hypovitaminosis D in glycogen storage disease type I”

17. Nutritional evaluation Laboratory analysis DXA scans
PATIENTS and METHODS
PATIENTS:
n = 13
Ia/Ib = 6/7
M/F = 8/5
Median age: 22 y, 7 mo
Range = 8 – 30 y
METHODS:
Every 4 – 6 months:
Clinical evaluation
Nutritional evaluation
Laboratory analysis
DXA scans

18. Bone mineral density (BMD)
RESULTS and DISCUSSION
Bone mineral density (BMD)
Reduced BMD in 69% of patients

19. RESULTS and DISCUSSION
BMD in GSD Ia/Ib

20. BMD and markers of bone turnover
RESULTS and DISCUSSION
BMD and markers of bone turnover

21. BMD and metabolic control
RESULTS and DISCUSSION
BMD and metabolic control

22. RESULTS and DISCUSSION
Vitamin D status
Low 25(OH)D in 69% of patients

23. RESULTS and DISCUSSION
Vitamin D and BMD
pz^ : taking supplements

24. Correlation between bone disease and metabolic control
CONCLUSIONS
Correlation between bone disease and metabolic control
High prevalence of low 25(OH)D levels
Low 25(OH)D levels despite supplementation

25. Correction of low 25(OH)D concentration - 1
Some or all of the following:
encouragement of safe, moderate exposure of skin to ultraviolet light
appropriate increases in food fortification with vitamin D
provision of higher doses of vitamin D in supplements
Banugaria et al., Hypovitaminosis D in glycogen storage disease type I. Mol Genet Met, 2009

26. Correction of low 25(OH)D concentration - 2
50,000 IU for adult patients (4,000 IU daily for children) of vitamin D2 once weekly for 8 weeks.
Maintenance dose = 1000 IU vitamin D daily or, alternatively, 50,000 IU vitamin D every other week
Holick et al., Vitamin D deficiency. N Engl J Med 357, (2007).

28. Thanks for your attention!