La mineralizzazione ossea: cos, perch e come si misura

1
La mineralizzazione ossea cosè, perché e come
si misura

• Stefano Mora
• Laboratorio di Endocrinologia Infantile
• Istituto Scientifico San Raffaele
• Milano

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Osteoporosis

• Metabolic bone disease characterized by low bone
  mass and microarchitectural deterioration of bone
  tissue, leading to enhanced bone fragility and a
  consequent increase in fracture risk.

Consensus development conference Diagnosis,
prophylaxis, and treatment of osteoporosis. Am J
Med 94(6) 646-650 1993
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Requirements for the ideal bone densitometer

• Assessment of true volumetric bone mineral
  density
• Assessment of bone size
• Separate assessment of trabecular and cortical
  bone
• Fast and precise scans
• Little or no exposure to ionizing radiation
• Availability of large sets of normative values
• Predictivity of low trauma fracture
• Low cost

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Techniques for the evaluation of bone mass

• Standard radiography (RX)

• Radiogrammetry

• Dual-energy X-ray absorptiometry (DXA)

• Quantitative computed tomography (QCT)

• Quantitative ultrasound (QUS)

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QCTSites of measurement
Lumbar Spine
Femur Midshaft
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QCT Measurement characteristics

• True volumetric measurements of bone density.

• Separate measurements of trabecular and cortical
  bone.

• Measurements of bone dimensions.

• Measurements of the tissues surrounding bone.

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pQCTSites of measurement
Forearm
Tibia
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DXASites of measurement
Lumbar Spine
Femur Head
Whole body
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DXA
Detector
High-energy X-ray
Low-energy X-ray
X-ray source
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DXA
Pencil beam
Fan beam
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DXA Measurement characteristics

• Direct measurement of bone mineral content (BMC)
  and bone area (BA).

• Calculation of areal bone mineral density (BMD)
  by dividing BMC by BA

BMC
BMD
expressed in g/cm2
BA

• Integral measurement of bone.

• Measurements of different bone sites.

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QUSSites of measurement
Forearm
Phalanges
Tibia
Calcaneous
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Quantitative ultrasound
Speed of sound SOS
Transmitter
Receiver
Receiver
Transmitter
Speed of sound SOS
Broadband ultrasound attenuation BUA
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QUS Measurement characteristics

• Measurements related to the density of bone, and
  to its geometry.

• Measurements of different bone sites.

• No ionizing radiation involved

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Ionizing radiation
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From Mora S, Bachrach L, Gilsanz V.
Noninvasive techniques for bone mass
measurement. In Pediatric Bone. Physiology and
diseases. Academic Press, 2003.
17
From Blake GM, et al. Bone 2005 Dec 20 Epub
ahead of print
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Methods limitations
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DXA
2
BMC 1
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DXA size adjustment methods

• Carter et al. J Bone Miner Res 1992 BMAD
  BMC/BA1.5
• Prentice et al. Am J Clin Nutr 1995 Multivariate
  analysis including BA
• Nevill et al. J Bone Miner Res 2002 Multilevel
  regression analysis
• including lean mass.
• Fewtrell et al. Bone 2005 BMCh BMC/height3
• BMCa adjustment for BA
• BMCt adjustment for BA and height

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DXA measurement interpretation
From Mølgaard C, et al. Arch Dis Child 769-15,
1997
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DXA
BMC 1
?
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DXA
W1
W2
Detector array
X-ray source
Modified from Cole JH et al. J Clin Densitom
857-64, 2005
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DXA

• Artefatti da movimento

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QUS

• The position of the transducers affects heavily
  the measurements
• Presence of soft tissue around the skeletal
  segment alter the measurements

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Clinical evaluation
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Bone risk factors
Inactivity
Poor nutrition
Genetics
Endocrine Disorders
Chronic Illness
Medications
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Conditions associated with low bone mass or
osteoporotic fractures in childhood and
adolescence.
SECONDARY OSTEOPOROSIS 1. Chronic
diseases Malignancy Rheumatologic
disorders Anorexia nervosa Celiac
disease Inflammatory bowel disease Cystic
fibrosis Thalassemia Sickle-cell anemia Renal
failure HIV-infection 2. Endocrine
disorders Sex steroid deficiency or
resistance Turner syndrome Athletic
amenorrhea Growth hormone deficiency Glucocortic
oid excess Hyperthyroidism
PRIMARY OSTEOPOROSIS 1. Disorders of connective
tissue Osteogenesis imperfecta Homocystinuria
Ehlers-Danlos Syndrome Marfan syndrome Fibrous
dysplasia 2. Idiopathic juvenile osteoporosis
3. Neuromuscular disorders Cerebral
palsy Muscular dystrophy Prolonged
immobilization 4. Treatments Glucocorticoids Me
totrexate Heparin GnRH agonists L-thyroxine
suppressive ther. Cyclosporine Antiretrovirals
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Fracture risk
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Bone mineral density and fracture risk
From Faulkner KG. J Bone Miner Res 15(2)183-7,
2000
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Bone density and fractures in children
From Clark EM, et al. Pediatrics 117(2)e291-7,
2006.
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Bone density and fractures in children
Ten case-control studies, with a total of 730
fractures and 1328 control children, met the
criteria for this review. After combination of 8
case-control studies, our results show evidence
of an association between low bone mass, and
fractures in children, with a SMD of -0.32 (95
CI -0.43 to -0.21 P lt 0.001).
From Clark EM, et al. Pediatrics 117(2)e291-7,
2006.
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Diagnosis difficulties
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Osteoporosis - WHO Criteria

• Adults
• BMD T score within -1 and -2.5 OSTEOPENIA
• BMD T score lt -2.5 OSTEOPOROSIS
• BMD T score lt -2.5 one or more fractures
  SEVERE OSTEOPOROSIS
• Children
• OSTEOPENIA and OSTEOPOROSIS have not yet been
  defined.

World Health Organ Tech Rep Ser 8431-129 1994
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Modified from Gafni RI Baron J.. J Pediatr
144253-7, 2004
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DXA Software differences for pediatric studies
From Simpson DE, et al. Nucl Med Commun
26483-7, 2005
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Position of the International Society for
Clinical Densitometry (ISCD) on the use of DXA in
diagnosis in children (boys and girls less than
20 years of age)

• The WHO classification for defining osteopenia
  and osteoporosis should not be used.
• Z-scores should be used instead of T-scores in
  children.
• T-scores should not appear in reports or on DXA
  printouts for children.
• The diagnosis of osteoporosis in children should
  not be made on the basis of densitometric
  criteria alone.
• Terminology such as low bone density for
  chronological age may be used if the Z-score is
  below 2.0.
• Z-scores must be interpreted in light of the best
  available pediatric databases of age-matched
  controls. The reference database should be cited
  in the report.
• Preferred skeletal sites for measurement are
  spine and total body.
• The value of BMD to predict fractures in children
  is not clearly demonstrated.
• Standards for adjusting BMD or bone mineral
  content (BMC) for factors such as bone size,
  pubertal stage, skeletal maturity, or body
  composition have not agreed upon. Clearly state
  any adjustment on the report.
• Successive BMD studies should be done using the
  same machine, scanning mode, software, and
  analysis when appropriate. Changes may be
  required with growth of the child.
• Deviations from standard adult acquisition
  protocols, for example low-density software or
  any adjustment of ROI (region of interest)
  should be stated in the report.

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Quali possibilità di terapia?
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Therapy

• Environment
• Diet (calcium, vitamin D)
• Physical exercise
• Hormones
• Sex hormones
• GH
• Specific
• Bisphosphonates
• PTH (?)

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Vitamin D 25 OH
Vitamin D 1,25 (OH)2
Intestinal Ca absorption
Osteoblasts
Increased bone formation
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GH
Sex Hormones
Osteoclasts
Osteoblasts
Increased bone formation Decreased bone resorption
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BISPHOSPHONATES
Osteoblasts
Osteoclasts
Decreased bone formation Decreased bone resorption
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Bisfosfonati in Italia
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PTH
Osteoblasts
Increased bone formation Decreased bone resorption
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PTH in Italia
Indicazioni Osteoporosi post-menopausale. Nota
AIFA 79bis solo in pazienti che subiscono una
ulteriore frattura vertebrale o di femore non
dovuta a traumi efficienti in corso di
trattamento consolidato, da almeno 1 anno con
alendronato, risedronato e raloxifene.
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Monitoring therapy

• Bone resorption markers
• NTx
• CTx
• Pyr, Dpyr
• ICTP
• TRAP
• Bone density measurements