BONE METABOLISM IN PATIENTS AFFECTED BY GLYCOGEN STORAGE DISEASE TYPE I

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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
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Glycogen storage disease type I (GSD I)

• Disorder of glucose homeostasis
  (glycogenolysis/gluconeogenesis)
• Incidence 1/100.000
• Autosomal recessive transmission
• Type Ia ? glucose-6-phosphatase deficiency
• Type Ib ? glucose-6-phosphatase translocase

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• 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.
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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)

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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

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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

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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) ?

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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)
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Why vitamin D?
background

• 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)

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Why vitamin D?
background

• 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)

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Vitamin D/skin production

• Sun exposure could be sufficient to cover
  requests (UVB exposure for 10-15 min generates
  10000-20000 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.

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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)
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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
• 800-1000 UI/day (20-25µg/day).

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Daily recommended amount of calcium and vitamin D
(L.A.R.N.)
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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 Crohns disease (Jahnsen
et al. 2002). Moreover, supplementation with
vitamin D or calcitriol significantly ameliorated
symptoms (Cantorna et al. 2000).
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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

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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

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RESULTS and DISCUSSION
Bone mineral density (BMD)
Reduced BMD in 69 of patients
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RESULTS and DISCUSSION
BMD in GSD Ia/Ib
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RESULTS and DISCUSSION
BMD and markers of bone turnover
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BMD and metabolic control
RESULTS and DISCUSSION
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Vitamin D status
RESULTS and DISCUSSION
Low 25(OH)D in 69 of patients
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Vitamin D and BMD
RESULTS and DISCUSSION
pz taking supplements
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CONCLUSIONS
Correlation between bone disease and metabolic
control
High prevalence of low 25(OH)D levels
Low 25(OH)D levels despite supplementation
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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

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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, 266-281 (2007).

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• Thanks for your attention!