Metabolic bone diseases
K. Bernášková
Bone functions
•
•
•
•
Body shape and movement
Protection of cavities
Acid – base ballance
Erythropoesis, immunity
• Calcium homeostasis
• Regulation of glucose metabolism
2
Mature bone consists of:
1. Mineral component
– hydroxyapatite (Ca10(PO4)6)OH)2
(calcium and phosphate)
3
Regulation of calcium homeostasis
PTH
Calcitriol
Calcitonin
Cortizol




Bone
resorption




Ca2+
reabsorption
in the
kidneys

 (+
phosphates)
_
_
Ca2+
resorption in
the gut
Indirectly

 (+
phosphates)
_

Activates the
conversion of
vitamin D in
the kidneys
 level 
decreases
PTH
concentration
(directly and
indirectly)
Calcemia
Mutual
influences
 PTH effect
on the bone
 PTH
secretion, 
calcitriol
effect in the
gut
4
Mature bone consists of:
1. Mineral component
2. Organic matrix (osteoid)
–
–
–
–
collagen fibers (type 1)
osteocalcin
protein S
proteoglycans, glycoproteins
5
Mature bone consists of:
1. Mineral component
2. Organic matrix (osteoid)
3. Bone cells
– osteoblasts
– osteocytes
– osteoclasts
9
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
10
Osteocytes
• Derived from osteoblasts
• Trapped in formed
bone
• Function: Calcium
homeostasis, bone
nutrition (?), help in bone
remodelation process
(sensor of bone load)
11
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
12
Osteoclast
13
Structure of a long bone
14
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
15
Bone remodeling cycle
16
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
17
Regulation of the remodeling process
by





calcaemia and phosphataemia
mechanical forces
body metabolism
hormones
local factors
18
Bone remodeling regulation 1
• Systemic regulation
Resorption Formation
PTH

 ()
calcitriol

 ()
calcitonin

0
cortizol


STH
()
()
T3, T4

()
estrogen
androgen

()
()

insulin
0

19
Bone remodeling regulation 2
• Local factors
Resorption Formation
Cytokines


PRG E2


Factors
from
osteoblasts
, ()

Growth
factors
()

20
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
21
Types of metabolic bone diseases
1. Osteoporosis
2. Osteomalacia
3. Osteitis fibrosa cystica
4. Paget‘s disease
5. Renal osteopathy
6. Osteopetrosis
22
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 !
23
Osteoporotic changes in
vertebrae
24
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
25
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)
26
Causes of secondary osteoporosis
Endocrine
Connective tissue diseases
Hypogonadism
Osteogenesis imperfecta
Thyreotoxikosis
Marfan‘s syndrome
Hyperparathyreosis
Ehlers-Danlos‘s syndrome
Cushing‘s syndrome
Malignancies
Myeloma
Leukemia
Lymfoma
Osteolytic metastases
Other causes
Gastrointestinal disorders
Chronic kidney disease
Immobilization
Diet
Drugs
glucocorticoids, alcohol, warfarine, (antiepileptics)
27
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‘)
28
Osteoporosis
29
Osteoporosis
26- year-old man
Substituted by
cortisol for a long
time
(hypopituitarism)
30
Therapy of osteoporosis
• Prevention!
Resorption
• Estrogen; selective
modulators of estrogen
receptors in bones
(tamoxifen); (androgen)
• Calcium
• Vitamin D
• Bisfosfonates (fosamax)
• Sodium fluorid
• PTH, calcitonin, (leptin)
• Vitamin K
Formation
PTH

 ()
calcitriol

 ()
calcitonin

0
cortizol


STH
()
()
T3, T4

()
estrogen 
androgen ()
()

insulin

0
31
2. Osteomalatia/rickets
• Due to invalide
mineralisation of bone
(late or missing)
• in children called
ricketts (seraph
disease)
• not so rare as
affirmed
32
Pathophysiology of osteomalatia
•  vitamin D 
hypocalcaemia   PTH
calcaemia , but  phosphataemia

calcium – phosphate disproportion doesn‘t allow
normal mineralisation

wide osteoid border, decreased bone formation
• changes in both spongiform and compact bone
33
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, Fanconi‘s sy)
• deficit of alcalic phosphatase in osteoblasts
•
toxic substances
(fluorid, aluminium, antacid‘s binding phospate)
34
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
35
Signs of
ricketts
36
Ricketts
Enlarged epiphysis at wrist
Deformation of long bones
37
Ricketts
38
Rickets
• tetany, convulsions
• failure to thrive
• apathy
39
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
40
Osteitis fibrosa cystica
41
Osteitis fibrosa cystica
42
4. Paget‘s 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
43
4. Paget‘s 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?)
44
Sign‘s, symptoms and complications
of Paget‘s 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
45
Paget‘s
disease
- bowing long bones
46
Paget‘s disease
Massy (1513): Portrait of an
old woman
47
5. Renal osteopathy
• Bone damage due to chronic renal failure
• Multifactorial
• Combination of osteoporosis,
osteosclerosis, osteomalatia, osteitis
fibrosa
48
Renal osteopathy

amount of nephrons
 kidney excretory functions
 biosyntethic activity
 calcitriol formation
Proteincaloric
malnutritio
n
 Ca and P
resorption
in GIT
Aluminium
toxicity
Growth
disturbanc
e in
children
Retention of toxic
metabolits

phosphataemia
 calcaemia
 bone
senzitivity
to
calcitriol
Osteomalatia
Metabolic
acidosis
(bone -buffer)

Osteoporosis
Drugs
Calcium –
phosphate
disbalance
 PTH secretion
Remodeling of
bone 
Osteosclero
sis
Osteitis
fibrosa
Metastatic
calcification
s
49
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“
50
Thank you for your attention
51
Literature:
• http://depts.washington.edu/bonebio
/ASBMRed/diseases.html
52
Calcium – phosphate relationships
 phosphate
 phosphate
+  calcium


+ N calcium


+  calcium


+  calcium

+ N calcium


+  calcium


primary hyperparathyreosis
PTHrp
Phosphaturia
Secondary hyperparathyreosis in vitamin D
deficiency
D hypovitaminosis
Vitamin D receptor insensitivity
Terciary or quartery hyperparathyreosis in
failing kidneys
 Vitamin D excess
 Sarcoidosis
 Increased bone resorption (myeloma,
lymphoma, bone metastases, bone tumours)
Increased phosphate intake (laxatives)
Transiently in secondary hyperparathyreosis
due to kidney failure
Decreased PTH
Phosphate retention in chronic kidney
failure + metastatic calcification
53