Metabolic bone diseases

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Metabolic bone diseases

• K. Bernášková

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Bone functions

• Body shape and movement
• Protection of cavities
• Acid base ballance
• Erythropoesis, immunity
• Calcium homeostasis
• Regulation of glucose metabolism

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Mature bone consists of

• 1. Mineral component
• hydroxyapatite (Ca10(PO4)6)OH)2
• (calcium and phosphate)

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Regulation of calcium homeostasis
PTH Calcitriol Calcitonin Cortizol
Calcemia ? ?? ? ??
Bone resorption ? ?? ? ?
Ca2 reabsorption in the kidneys ? ? ( phosphates) _ _
Ca2 resorption in the gut Indirectly ? ? ( phosphates) _ ?
Mutual influences Activates the conversion of vitamin D in the kidneys ? level ? decreases PTH concentration (directly and indirectly) ? PTH effect on the bone ? PTH secretion, ? calcitriol effect in the gut
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Mature bone consists of

• 1. Mineral component

• 2. Organic matrix (osteoid)
• collagen fibers (type 1)
• osteocalcin
• protein S
• proteoglycans, glycoproteins

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Regulation of glucose metabolism
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On the contrary Body metabolism regulates bone
metabolism
? secretion of insulin
Increased metabolism of nutrients
Pancreatic beta cells
Osteocalcin production
Adipocytes
? secretion of adiponectin
Leptin
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Leptin regulates bone mass
LEPTIN
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Mature bone consists of

• 1. Mineral component

• 2. Organic matrix (osteoid)

• 3. Bone cells
• osteoblasts
• osteocytes
• osteoclasts

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Osteoblasts

• Derived from mesenchymal stem cells of the bone
  marrow stroma

• Rich in alkaline phosphatase

• Have receptors for PTH, vitamin D, growth
  factors, estrogen
• mechanoreceptors

• Function bone matrix production, bone
  mineralisation, control of osteoclasts
  maturation and function

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Osteocytes

• Derived from osteoblasts

• Trapped in formed bone

• Function Calcium homeostasis, bone nutrition
  (?), help in bone remodelation process (sensor
  of bone load)

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Osteoclasts

• Derived from hemopoetic
• stem cells  
• (monocyto-makrofage series)

• Maturation and function is controlled by
  osteoblasts

• Receptors for calcitonin

• Function bone resorption, changes of blood
  calcium concentration

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Osteoclast
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Structure of a long bone
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Bone remodeling

• Continuous process
• 2 types targeted (started by microingury,
  cycle lasts for 4 months)
• stochastic (whole skeleton)
• Resorption and formation should be in ballance

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Bone remodeling cycle
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Importance of bone remodeling

• Maintenance of calcium and phosphate homeostasis

• Maintenance of structural integrity of the bone -
  reparation of small injuries (microtrauma)

• Adaptation of shape and bone organisation to
  changes in biomechanical forces

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Regulation of the remodeling process
by

• calcaemia and phosphataemia
• mechanical forces
• body metabolism
• hormones
• local factors

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Bone remodeling regulation 1

• Systemic regulation

Resorption Formation
PTH ? ? (?)
calcitriol ? ? (?)
calcitonin ? 0
cortizol ? ?
STH (?) (?)
T3, T4 ? (?)
estrogen androgen ? (?) (?) ?
insulin 0 ?
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Bone remodeling regulation 2

• Local factors

Resorption Formation
Cytokines ? ?
PRG E2 ?
Factors from osteoblasts ?, (?) ?
Growth factors (?) ?
?
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Metabolic bone diseases

• due to imbalance between bone resorption and
  formation

characterized by abnormal structure of the
entire bony skeleton, increased fragility and
pain

• may reflect disturbances in the mineral phase,
  organic matrix, the cellular processes of
  remodeling and the endocrine, nutritional and
  other factors

• may be hereditary or acquired

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Types of metabolic bone diseases

• Osteoporosis
• Osteomalacia
• Osteitis fibrosa cystica
• Pagets disease
• Renal osteopathy
• Osteopetrosis

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1. Osteoporosis

• is a systemic bone disease characterized by
  decreased bone density, resulting in thinning and
  increased porosity of the bone

• bone resorption predominates (of both organic
  and mineral components)

• the trabecular (spongiform) bone is affected
  more

• fragility of the bones increases (increases
  propensity to fractures)

• epidemiologically significant occurrence !

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Osteoporotic changes in vertebrae
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The development of osteoporosis depends on

• Colour of skin
• Sex
• Basal bone density (peak bone mass)
• Activity (sports)
• Nutrition, body weight (smoking)
• Calcium and phosphate intake
• Vitamin D presence
• Estrogen and androgen level
• Family history

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Types of osteoporosis

• primary
• juvenile
• postmenopausal
• (? estrogen ? ? bone resorption ? ? plasmatic
  Ca2 ? ? PTH ? ? activation of vit D to
  kalcitriol ? ? Ca2 resorption from the gut)
• senile
• (? kalcitriol - ? Ca2 resorption from GIT ? ?
  PTH ? ? bone resorption)
• secondary (many causes)

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Causes of secondary osteoporosis
Endocrine Hypogonadism Thyreotoxikosis Hype
rparathyreosis Cushings syndrome
Connective tissue diseases Osteogenesis
imperfecta Marfans syndrome
Ehlers-Danloss syndrome
Other causes Gastrointestinal
disorders Chronic kidney disease
Immobilization Diet
Malignancies Myeloma Leukemia Lymfoma Oste
olytic metastases
Drugs glucocorticoids, alcohol, warfarine,
(antiepileptics)
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Signs and symptoms of osteoporosis

• Osteopenia on RTG
• Compressing fractures and wedging of the
  vertebrae
• Kyphotic deformity of the spine
• Pain
• Fractures of the femoral neck and distal
  radius (Colles)

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Osteoporosis
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Osteoporosis
26- year-old man Substituted by cortisol for a
long time (hypopituitarism)
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Therapy of osteoporosis

• Prevention!
• Estrogen selective modulators of estrogen
  receptors in bones (tamoxifen) (androgen)
• Calcium
• Vitamin D
• Bisfosfonates (fosamax)
• Sodium fluorid
• PTH, calcitonin, (leptin)
• Vitamin K

Resorption Formation
PTH ? ? (?)
calcitriol ? ? (?)
calcitonin ? 0
cortizol ? ?
STH (?) (?)
T3, T4 ? (?)
estrogen androgen ? (?) (?) ?
insulin 0 ?
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2. Osteomalatia/rickets

• Due to invalide mineralisation of bone (late or
  missing)
• in children called ricketts (seraph disease)
• not so rare as affirmed

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Pathophysiology of osteomalatia

• ? vitamin D ? hypocalcaemia ? ? PTH ? ? calcaemia
  , but ?? phosphataemia
• calcium phosphate disproportion doesnt allow
• normal mineralisation
• ? wide osteoid border, decreased bone formation
• changes in both spongiform and compact bone

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Causes of osteomalatia

• vitamin D deficit
• (diet malabsorption disorders of vitamin D
  metabolism in skin, liver or kidneys receptor
  disease)

• phosphate deficit
• disorder of phosphate reuptake in kidneys
  (phosphate diabetes, Fanconis sy)

• deficit of alcalic phosphatase in osteoblasts

• toxic substances
• (fluorid, aluminium, antacids binding phospate)

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Signs and symptoms of osteomalatia

• diffuse bone pain (predominantly hip region)
• muscle weakness
• fractures due to minimal forces
• biochemistry
• hypocalcaemia, hypophosphataemia, slightly ? PTH
• in children growth retardation, bone
  deformities

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Signs of ricketts
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Ricketts
Enlarged epiphysis at wrist
Deformation of long bones
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Ricketts
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Rickets

• tetany, convulsions
• failure to thrive
• apathy

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3. Osteitis fibrosa cystica

• complication of advanced hyperparathyreosis
  (very rare recently)
• extensive activity of osteoclasts ?
• ? bone resorption and fibrous replacement,
  fibrous degeneration of bone marrow, cystic or
  tumor-like lesions (brown tumours)
• Softened bones of the entire skeleton ?
  deformations

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Osteitis fibrosa cystica
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Osteitis fibrosa cystica
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4. Pagets disease
osteitis deformans

• the second most common metabolic bone disease
• bone cells increase their volume, number and
  activity
• local damage
• metabolic turnover of bone increases up to 40x

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4. Pagets disease (osteitis deformans)

• Abnormal activity of osteoclasts ? bizarre and
  irregular pattern of resorption
• Increased osteoblastic response ? irregular
  bone formation
• So called Woven bone

• Cause unknown (viruses?)

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Signs, symptoms and complications of Pagets
disease
Signs and symptoms often asymptomatic pain,
fracture, warmth feeling

• Complications
• Bone deformation (bowing long bones,
  deformation of hip, growing of the head)
• Nerve compression ? palsies (? deafness, ?
  weakness and paresthesias in lower extremities)
• Fractures
• Left heart failure (rare)
• Neoplastic transformation of affected bone

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Pagetsdisease- bowing long bones
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Pagets disease
Massy (1513) Portrait of an
old woman
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5. Renal osteopathy

• Bone damage due to chronic renal failure
• Multifactorial
• Combination of osteoporosis, osteosclerosis,
  osteomalatia, osteitis fibrosa

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Renal osteopathy
Drugs
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6. Osteopetrosis

• Rare hereditary disease
• Heterogenous pathophysiology
• (? quantity or activity of osteoclasts)
• Bone resorption failure ? thickening of bones ? x
  incresed fragility
• Dg RTG skull changes
• Alien

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Thank you for your attention
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Literature

• http//depts.washington.edu/bonebio/ASBMRed/diseas
  es.html

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Calcium phosphate relationships

? phosphate ? calcium primary hyperparathyreosis PTHrp
? phosphate N calcium Phosphaturia Secondary hyperparathyreosis in vitamin D deficiency
? phosphate ? calcium D hypovitaminosis Vitamin D receptor insensitivity
? phosphate ? calcium Terciary or quartery hyperparathyreosis in failing kidneys Vitamin D excess Sarcoidosis Increased bone resorption (myeloma, lymphoma, bone metastases, bone tumours)
? phosphate N calcium Increased phosphate intake (laxatives) Transiently in secondary hyperparathyreosis due to kidney failure
? phosphate ? calcium Decreased PTH Phosphate retention in chronic kidney failure metastatic calcification