Tereos – Structure of

presentation
 Introduction
 Bones and its ultrastructure
 Bone cells
 Bone Mineral Metabolism – Role of Ca, Vit D3, PTH & Calcitonin
 Bone Homeostasis
 Bone remodelling
 Metabolic bone disease – osteoporosis
 Agents to treat osteoporosis
 Tereos and its clinical experience
 Tereos v/s other agents
 summary
OSTEOPOROSIS
 BONES
 One of the largest organs- a dynamic connective
tissue
 Provides support; protects internal organs
 Produces blood cells
 Consistently remodelled throughout life
 Reservoir for Ca, P, Mg, Na, and other ions
 Helps in movement
 A store house of growth regulatory factors (CSF,
TNF, IL, etc)
 Highly vascular (10% of cardiac output)
Bone Shapes
 Long
 Ex. Upper and lower limbs
 Short
 Ex. Carpals and tarsals
 Flat
 Ex. Ribs, sternum, skull,
scapulae
 Irregular
 Ex. Vertebrae, facial
 COMPOSITION OF BONE
Osteoblasts - bone forming cells
Cells (2%) Osteocytes - mineralised osteoblasts
Osteoclasts - bone resorbing cells

Organic
30%
Type I collagen (90-95%)
Matrix (98%)
Non collagenous proteins (5%)

hydroxyapatite Ca10(PO4)6(OH)2 Examples :

Osteonectin
Mg Osteopontin
Mineral Na Osteocalcin
70% K Fibronectin
F Sialoproteins
Cl Thrombospondin
Proteoglycans
Bone Histology
 Recall that bone is a connective tissue that consists of a
matrix, cells, and fibers
 Bone matrix
 Resembles reinforced concrete. Rebar is collagen fibers,
cement is hydroxyapetite
 Organic components (35%)
 Composed of cells, fibers and organic substances (osteoid)
 Collagen is most abundant organic substance
 Inorganic mineral salts (65%):
 Primarily calcium phosphate (hydroxyapatites)
 Gives bone its hardness; resists compression
Bone Matrix

 If mineral removed, bone is too bendable

 If collagen removed, bone is too brittle
 Bone Cells

 Bone cells (see following slides for particulars)

 Osteoblasts
 Osteocytes
 Osteoclasts
 Stem cells or osteochondral progenitor cells
 Bone cells
 OSTEOBLASTS
 Bone forming cells
 Mesenchymal stem cells origin (CFU –F)
 Synthesize and secrete the organic matrix
 Have PTH, calcitriol, and oestrogen receptors
 OSTEOCYTES
 Relatively quiescent – permanent cells
 Developed from osteoblasts
 Role in mobilising bone minerals
 OSTEOCLASTS
 Bone resorbing multinucleated giant cells
 Originated from CFU – GM
 In acidic environment degrades the matrix by proteolytic enzymes
 Does not have PTH & Calcitriol receptors
 Activity stimulated by IL1, PGE2 and TNF alpha
 OSTEOID
 Unmineralised bone tissue
At any one time osteoclasts and osteoblasts occupy 10 – 15% of the bone
surface
 TYPES OF BONES

 Cortical or compact 80% (4 kg)

 Trabecular or spongy or cancellous 20% (1kg)

 Cortical bone predominates in the shaft of long

bones serves mechanical and protective
functions- Osteon - basic function unit of compact
bone
 Trabecular bone serves most of the metabolic
functions
Structure of a Long Bone

Figure 6.3a-c
Microscopic Structure of Compact
Bones

Figure 6.6
 CORTICAL & TRABECULAR BONE
 Diaphyses are made up of cortical bones whereas
metaphyses (extremities of the long bones & vertebral
bodies) are made up of trabecular bone
 Vertebrae - 50% trabecular & 50% cortical bone
 Femoral neck - 30% trabecular & 70% cortical bone
 Activation frequency is higher in trabecular bone
 3-4% of cortical bone & 25% of trabecular bone
undergoes renewal every year
 Number of remodelling units activated each hour for
cortical & trabecular bone 100 & 760 respectively
Flat, Short, Irregular Bones
 Flat Bones
 No diaphyses or epiphyses
 A sandwich of cancellous
(spongy) bone between
compact bone
 Cancellous bone (Spongy
bone)
 Composed of bony plates
known as trabeculae
Cancellous (Spongy) Bone

 Trabeculae: interconnecting rods or plates of bone. Like

scaffolding.
 Spaces filled with marrow.
 Covered with endosteum.
 Oriented along stress lines
 BIOMECHANICS OF BONE &
FRACTURE
 Loading is important for the maintenance of bone strength
during normal aging
 In young individuals the load bearing capacity of a lumbar
vertebral body is 1000 kg or more
 In an elderly it is reduced to 120-150 kg
 In osteoporosis it is 60-90 kg
 During immobilization, bone loss becomes 60-70% within
6 months
 In osteoporosis there may be upto 90% loss of “Peak Bone
Strength (Bone strength is determined by factors like cortical
thickness, trabecular bone density, architecture and bone size )
 OSTEOCLASTS
 Large polarised multinucleated cells with an average of 10-20 nuclei
 Produce bone matrix degrading enzyme acid phosphatease and
cathepsin-k to degrade collagen
 Bone modelling : New bone is formed at a location different from the
one destroyed, resulting in a change of theskeleton during growth
 Bone remodelling - (resorption & formation occur in same place
without change in shape of bone)
 Cycle lasts approximately 3 months in adult bone
 1 mio BRU are activated sequentially
 The remodelling rate is between 2-10% of the skeleton mass per year
 Bone remodelling
 Bone is never metabolically at rest
 Process of bone resorption followed by bone formation
(coupling)
 Accounts for >95% of skeletal turnover in normal adult for
creating mechanically more competent bone
 Femur replaced every 4 months
 About 10% of adult skeleton is remodeled each year
 Mechanical, systemic, hormonal, and local factors are
involved
 Approximately 20% of trabecular bone surface is remodeled
at any one time.
 Normally there is a balanced osteoclast mediated bone
resorption and osteoblast mediated bone formation
Remodeling, Spongy Bone
 The Bone Remodelling Cycle

Nuki G. et al, Davidson’s Principles & Practice of Medicine.,

18th edition ,1999; 805
 A diagram of bone structure to show
the relationship of different cell types

Osteoclast

Osteoblasts
Bone lining cell
Ruffled
border Osteoid

Howships Gap
resorption junctions Mineralized
lacuna bone

Canaculi
Osteocytes
The remodelling events on the surface of bone
Thin osteoid
Osteoblasts
layer
deposit
1 Mineralized osteoid on
bone 4 cement line

Multinucleated Newly formed

osteoclasts from osteoid is
precurosors minerlized
2 5

Mononuclear Cycle
cells: smooth complete in
resorption pit young adult no
and deposit change in
3 cement line 6 bone mass
 ENDOCRINE

PTH 1,25(OH)2D3 Oestrogen Cortisol

MECHANICAL NUTRITIONAL

Osteoblast Lining cells

Proteoblasts GENETIC
Osteocytes

Synthesis Mineralization of
Collagen Cell control
osteoclasts osteoid
Non-collagen
proteins
Proteoglycans

The central position of the osteoblast in bone physiology. Broad arrows show the
origin of osteoblasts from preosteoblasts, themselves derived from stromal cell (fibroblast
colony forming unit) lineage, and of the lining cells and osteocytes
 The likely relationship between Bone cells, their precursors and Cytokines

ENDOCRINE
ENDOCRINE

MECHANICAL
MECHANICAL PTH
PTH Calcitriol
Calcitriol Oestrogen
Oestrogen Cortisol
Cortisol NUTRITIONAL
NUTRITIONAL
+
+ – + +
–
Osteoblast
Osteoblast Lining
Stromal Liningcells
cells
CFU-F Preosteo- GENETIC
GENETIC
Stem Cell blast Osteocytes
Osteocytes
+ Oestrogen
Oestrogen
PTH,
PTH,Calcitriol +
Calcitriol –
IL
IL1,1,IL
IL66

+ +
Stromal CFU-GM Preosteoclast Osteoclast Apoptosis
Stem Cell –
Oestrogen
+
activity &
number
– Calcitonin-endorphin  analgesia
Oxford Text Book of Rheumatology, 1998
– Bisphosphonates
 BONE HOMEOSTASIS
Resorption Formation
NORMAL BONE

Greater resorption

Less formation

OSTEOPOROSIS
RESORPTION FORMATION
Systemic influences : Ca ?
Estrogen Vit D ?
Calcitonin Physical activity ?
PTH
Local influences :
Osteoclastic activity
IL1
 CALCIUM
250 mg/day Ca removed from bone (1000 gm).
Thus for the whole skeleton the average turnover time is
11 years or 9% p.a.
Ca - Tetany & convulsions
Ca - Delayed neuromuscular
transmission & paralysis
40%
50%

10%

Composition of total serum calcium

Anatomy and Feedback Inhibition
CALCIUM METABOLISM IN HEALTHY ADULT
Vit D + (e.g Calcitriol) Vit D +
1000 mg

ECF B
400 mg Ca net 200 mg
O
transport = 200 mg N
GUT 200 mg 200 mg
E
CT -
Vit D +
800 mg
PTH + PTH +
Vit D + 9800 mg
facilitates PTH 10000 mg

Total body calcium is 1 kg

99% is in bone & 1% I.e.
200 mg 10000 mg is in plasma
KIDNEY
Calcium Homeostasis
Correction for Hypercalcemia
Sequence of Adjustments to Hypocalcemia
PTH and Osteoblastogenesis
 VITAMIN D METABOLISM
Skin (U.V. irradiation)
Diet, Ergosterol
7 dehydrocholesterol

Cholecalciferol (Vit D3)

can be stored in liver for months

INHIBITION
Vit D3 in blood
liver by hydroxylation

25 (OH)D3 (2-5 days persists)

kidney by 1  hydroxylase
+ PTH

1,25(OH)2D3 in intestinal epithelium

Intestinal absorption of calcium

Plasma Ca+2  (negative feedback)

 VIT D3 METABOLISM
Skin
7-Dehydrocholesterol Diet
UV Vit D2 + D3

Vitamin D3 Plasma
Growth hormone Cholecalciferol
Prolactin
Insulin  Hepatic microsomes in liver
Placental 25(OH)D3
lactogen Renal 1(OH)lase The major circulating forms
Renal
mitochondria 24,25 (OH)2D3
 1,25 (OH)2D3
Ca
Ca in plasma
PO4 Bone
rapidly cleared
PTH
PTH
Intestine Kidney
Bone Parathyroid
striated muscle
Calcium & Phosphate
absorption Bone remodelling
The synthetic pathways and cellular effects of 1,25(OH) 2D
Skin Food
Provitamin D3 Vitamin D3
Vitamin D2
Previtamin D3 (irradiated ergosterol)

Vitamin D3 + Vitamin D2

Vitamin D
Liver Increased by
25 OHD Phosphate
Decreased by Ca Kidney 1-Hydroxylase Ca
Increased by 24 – hydroxylase PTH
1,25(OH)2D 1,25(OH)2D
Oestrogen
24, 25 (OH)2D combines with
widespread cell
receptor

Gene activation or repression

Effects on

Differentiation of Proliferation Calcium and phosphorus Development

cells and homeostatis
 The sources and metabolism of vitamin D
and causes of rickets and osteomalacia
Sunlight
Northern latitude Poor skin exposure
Atmospheric pollution Pigmentation
Precursors

Malabsorption Anticonvulsants

Vitamin D Food Vitamin D 25 OHD

Plasma Liver
Phytate
Chapatti
(increased utilization)
Renal failure
25 OHD
Nephrectomy
Low PTH Kidney
High phosphate
Vitamin D dependent 1,25(OH)2D
rickets (Type I)
Oncogenous rickets
 Endocrine regulations in Post - menopausal
Osteoporosis

In Post-menopausal Osteoporosis
Bone resorption (due to 2-3 fold increase of Osteoclasts)

Serum Ca - -ve
less Oestrogen
PTH less
due to 1-, (OH) lase
Calcitriol production &
Renal tubular reabsorption of Ca which offsets the effects of
Hypercalcemia challenge & is an imp. sparing mechansim.

Although estrogen is a stimulus for PTH production but there is

Sensitivity of the skeleton to PTH.
 Endocrine regulations in Age - related
Osteoporosis
In AGE - RELATED OSTEOPOROSIS

Aging 4-fold conc. Vit D 25(OH)D3

Calcitriol
Aging renal mass 1- (OH) lase

PTH Serum Ca

Osteoclastic activity

resorption Osteoporosis

Aging the responsiveness of 1-, (OH) lase

Oestrogen deficiency and inhibition of intestinal calcium
absorption
OESTROGEN
OESTROGEN
(IL-6,
(IL-6,IL-1,
IL-1,TNF-)
TNF-)
BONE
BONERESORPTION
RESORPTION 


CALCIUM
CALCIUM

PTH
PTHSECRETION
SECRETION


SYNTHESIS
SYNTHESISOF
OF1,25
1,25(OH)
(OH)22DD33


Intestinal
Intestinal1,25
1,25(OH)
(OH)22DD33receptors
receptors

(Vitamin
(VitaminDDresistance)
resistance) 

CALCIUM
CALCIUMABSORPTION
ABSORPTION

 PHYSIOLOGICAL BONE REMODELLING

 Bone resorption phase 14-30 days

 Switch over phase 10 days
(E2 is responsible for the apoptosis
of osteoclasts)
 Bone formation phase 90 days
 Resting phase 900 days
Total bone renewal : approx 4-10% per annum
 REGULATORS OF BONE
REMODELLING
 Systemic :
 Parathyroid hormone (PTH)
 Calcitriol
 Calcitonin
 Prostaglandins
 Local :
 Cytokines (concerted action)
 Mechanical stress
STEPS IN BONE REMODELLING
(4-7 months)

QUIESCENCE

ACTIVATION (preparation for resorption)

(by osteoclasts)
RESORPTION

REVERSAL

OSTEOID FORMATION

MINERALISATION
 BONE REMODELLING

 PTH & Calcitriol increase activation frequency

 IL1, IL6, IL11, TNF, GM-CSF, M-CSF,, PGs are stimulators of
osteoclast activity
 A team of osteoclasts can cut a depth of upto 20
microns/day
 Life span of osteoclasts is 4-12 days and excavates 40-60
microns during this time
 30-50% of osteoblasts buried within the osteoid matrix to
become osteocytes; rest become bone lining cells
 In osteoporosis, osteoclasts increase 2-3 fold; decreased
oestrogen stimulates osteoclast formation
Factors regulating bone formation &
resorption
 Calcium regulating hormones
 PTH
 Calcitriol
 Calcitonin
 Systemic hormones
 Glucocorticoids
 Growth hormone
 Somatomedins
 Thyroxine
 Sex hormones
 Factors regulating bone formation &
resorption - Contd
 Cytokines & local growth factors
 IL-1 : Resorption, hypercalcaemia
 IL-6 : Minimal resorption mild calcaemia
 TNF : Resorption hypercalcaemia
 LT : Resorption hypercalcaemia
 M-CSF : Osteoclast formation
 BMP : Osteoclast formation
 TGF-a : Osteoclast progenitor cell replication
 PGE2 : Bone resorption
 PDGF : Bone resorption
 Inspite of its dormant appearance when visualised on radiographs, bone is
an active tissue with a dynamic metabolism
 There is a balance between osteoclast mediated bone resorption and
osteoblast mediated formation of new bone
 CORTICOSTEROID-INDUCED OSTEOPOROSIS
GLUCOCORTICOIDS
GLUCOCORTICOIDS

Osteoblast
Testosterone
function 
(IGF I+II, TGF-
IGFBP’s)

Urinary Calcium absorption in

Calcium  GI tract 

PTH 

Bone resorption  Bone formation 

 CORTICOSTEROIDS -
THE BONE ROBBERS
Inadequate
Inadequate Heredity
peak Heredity
peakbone
bonemass
mass
Ageing
Ageing

Menopause
Menopause Increased
Increased Low
Low
Bone
Bone Bone
Bone
Local Loss Density
Local Factors
Factors Loss Density
Fractures
Fractures

Sporadic Trauma
Sporadic Factors
Factors Trauma

Pathogenesis of Fractures related to Osteoporosis

Ref. : Osteoporosis, Riggs L.B., Melton J.L., 2nd Edn, 1995 Lippincott Raven Publishers, p - 217
 EFFECT OF CORTICOSTEROIDS

 Corticosteroids inhibit vitamin D mediated intestinal

calcium absorption
 Corticosteroids inhibit bone mineral mobilization

 Patients receiving corticosteroids have depressed

circulating levels of calcitriol - (mechanism unknown)

Ref. : Harrison’s, Principle of Internal Medicine, 14 Edn., 1998, p-2221

Effects of Excess Corticosteroids on
Skeletal Metabolism
TARGET
TARGET TISSUE
TISSUE ACTION
ACTION EFFECT
EFFECT

Recruitment
Recruitment

Osteoblasts Osteocalcin
Osteocalcin
Osteoblasts (rapid)
(rapid)
Collagen
Collagen Formation
Formation
synthesis
synthesis
Adrenals
Adrenals &
& Gonadal
Gonadal
gonads
gonads hormones
hormones Bone
Bone
loss
loss
Parathyroid
Parathyroid ? Secretion
Secretion

Sensitivity
Sensitivity to
to
Gut
Gut Vitamin D
Vitamin D
Activation
Activation
Renal
Renal tubule
tubule Calcium
Calcium
reabsorption
reabsorption

Muscle
Muscle
Bone
Bone Skeletal
Skeletal load
load
immobilization
immobilization
Ref. : Osteoporosis, J.A. Kanis, Ed., 1994, p-92
 EFFECT OF CORTICOSTEROIDS
ON OSTEOBLASTS

 Direct effect on osteoblast function

 Acute administration of corticosteroids results

in the suppression of osteoblast markers such
as alkaline phosphatase and osteocalcin
 Over a longer period the wall thickness of newly
completed bone remodelling units is reduced by
25% indicating a decreased amount of bone
deposited within each erosion cavity
Ref.: Osteoporosis, J.A. Kanis, 1994, p-93
 EFFECT OF CORTICOSTEROIDS ON
PTH AND GONADAL STEROIDS

 A degree of hyperparathyroidism
complicates corticosteroid induced
osteoporosis

 Corticosteroids affect the secretion and

metabolism of gonadal steroids which
would increase bone resorption
 EFFECT OF CORTICOSTEROIDS ON
BONES

 Loss of bone occurs at femoral neck, trochanter,

ward’s triangle and lumbar spine
 Bone loss may occur preferentially at axial rather
than appendicular site. Hence, loss at
cancellous sites are expected to be greater than
at cortical sites
 Long-term exposure therefore decreases bone
mass at all sites, but vertebral fractures occur
sooner than hip fractures
Ref.: Osteoporosis, J.A. Kanis, 1994, p-93
 CLASSIFICATION OF OSTEOPOROSIS

PRIMARY

 Type I (Post menopausal)

Involutionary
Osteoporosis
 Type II (Senile)

 Idiopathic (at ages <50)

 OSTEOPOROSIS
Factors contributing to bone loss
 Advancing age
 Female sex
 Nulliparity
 Fair skin
 Short stature
 Slender body build
 Early menopause
 Intercurrent illness
 Cigarette smoking
 Sedentary lifestyle
 Possibly genetic factor
 Low calcium intake
 OSTEOPOROSIS
 WHO has estimated that 30% of all women aged
over 50 (post menopausal) has osteoporosis
 Hip fractures are the most serious and costly
potential results of osteoporosis.
 Two types
 Type I post menopausal 51-65 years; vertebral,
distal radius
 Type II men and women > 75 years; vertebral, hip,
pelvis, humerus, tibia

Ref. : B.M.J. 18.05.96

 POSTMENOPAUSAL OSTEOPOROSIS
Estrogen deficiency

Direct renal effects Skeletal effects Direct intestinal effects

Bone loss Other factors

PTH Secretion

1,25(OH)2D3
production

Renal calcium
Calcium absorption
excretion

PROPOSED MODEL FOR PATHOGENESIS OF TYPE I OSTEOPOROSIS

 Endocrine regulations in Post –
menopausal Osteoporosis
In post-menopausal Osteoporosis
Bone resorption (due to 2 –3 fold increase of Osteoclasts)

Serum Ca -ve
Less Oestrogen
PTH
Less
Due to 1 - , (OH)lase

Calcitriol production &

Renal tubular resorption of Ca which offsets the effects of Hypercalcemia
challenge and is an imp. Sparing mechanism

Although estrogen is a stimulus for PTH production but there is

sensitivity of the skeleton to PTH
 AGE RELATED OSTEOPOROSIS
AGING

Bone formation Intestinal resistance to 1alpha

(cellular level) 1,25(OH)2D3 hydroxylase activity

1,25(OH)2D3
production

Calcium absorption

Secondary hyperparathyroidism

Bone loss
PROPOSED MODEL FOR THE PATHOGENESIS OF TYPE II
OSTEOPOROSIS
 Drugs Enhancing Bone Loss Or
Increasing The Likelihood Of Falls
Glucocorticoids
Anticonvulsants
Long term heparin Sedatives
Excessive Thyroid Hypnotics
supplementation Anxiolytics
Certain Chemotherapy Antidepressants
Gonadotropin altering agents Antipsychotics
Ca Absorption altering agents Vasodilators
Tetracycline Diuretics
Loop diuretics
Phenothiazines
Al - containing Antacids
Ref: - Phamacotherapy VOL 19;No 1 Part 2,JAN 99
 OSTEOPOROSIS IN ELDERLY
 Due to age associated bone losses , all elderly
are prone to osteoporosis , which often leads
to fractures
 5% of falls in elderly result in to fractures
 Goal is to prevent bone loss ,falls and
fractures
 Currently no drugs exist to promote new bone
formation
 Vertebral fractures in pts.with
established OSTEOPOROSIS
 Diagnosed by symptoms ,or during screening & finally by X-
ray
 In women presence of a vertebral fracture creates a 5 fold
risk for a subsequent fracture
 2/3 rd of the fractures are asymptomatic
 1/3 rd draws attention because of fall, trauma
 Pain due to fracture resolve over 6-8 weeks
 Pts . With >1inch height loss should be evaluated for
vertebral fractures
Pharmacotherapy Vol 19 ; No 1 ,Part 2 J an 1999
 CAUSES OF
SECONDARY OSTEOPOROSIS - 1
Endocrine
 Male hypogonadism
 Hyperthyroidism
 Hyperparathyroidism
 Hypercortisolism
 Diabetes
Amenorrhea
 Amenorrheic athletes
 Anorexia nervosa
 Hyperprolactinemia
Drugs
 Steroids
 Anticonvulsants
 Heparin
 CAUSES OF
SECONDARY OSTEOPOROSIS - 2
Neoplastic disease
 Multiple myeloma
 Skeletal metastases

Other conditions
 Transplantation
 Gastric surgery
 Celiac disease
 Alcoholism
 Pregnancy
 Immobilisation
 Osteogenesis imperfecta
 Homocystinuria
 Systemic mastocytosis
INVESTIGATIONS FOR SECONDARY
OSTEOPOROSIS
 Full blood count
 Erythrocyte sedimentation rate
 Urea and electrolytes
 Liver function tests
 Calcium, Phosphate and alkaline phosphatase
 Thyroid function tests
 Serum and urine electrophoresis
 Prostrate specific antigen (in men)
 Testosterone, follicles-stimulating hormone, and
luteinizing hormone
 PREVALENCE OF SECONDARY
OSTEOPOROSIS IN WOMEN & MEN
Others 13% WOMEN
WOMEN Others 10%
MEN
MEN
Alcoholism 1%
Alcoholism 6%
Neoplasia 1%

Hyper- Neoplasia 9%
thyroidism 5%
Primary 46%
Primary 70%

Steroids 10% Hypo-

gonadism 16%

Steroids 13%

Ref : J.R. Soc. Med. 1994; 87: 200-202; Age Aging 1992; 21:139-141
 FACTORS THAT INFLUENCE RENAL
1, - HYDROXYLASE ACTIVITY
 Calcitriol is a critical differentiation factor in the
skeleton for both osteoblasts and osteoclasts. PTH
and calcitriol are important factors in the
differentiation of committed preosteoclasts
Calcitriol also regulates osteoblasts ontogeny,
leading to the differentiation of the osteoblasts, and
organises the regulation of matrix-protein production

Ref : NEJM July 20, 1995

 Impaired renal function ( 1-alpha hydroxylase)

conversion of 25 (OH)
cholecalciferol to 1,25(OH)2
PO4 excretion cholecalciferol

DISEASED KIDNEY

Plasma PO4
Ca absorption
Parathyroid
gland
PTH correction of

Stimulation
of parathyroid bone resorption in an
glands leading attempt to increase Plasma (Ca+2)
to hyperplasia Ca+2

PATHOGENESIS OF RENAL OSTEODYSTROPHY

 RELATIONSHIP WITH PARATHYROID
GLAND, CALCITRIOL AND BONE

KIDNEY
KIDNEY
+

PTH
PTH PTG
PTG – 1,25(OH)2D3

+ Ca +
– Ca
–
BONE GUT
The effects of renal glomerular failure
on the skeleton

GFR Urea P Ca  PTH

1,25(OH)2D Osteoclasts
(via osteoclasts)
Calcium absorption
defective 

Defective Bone
mineralization reabsorption
rickets/osteomalacia

Renal glomerular osteodystrophy

 DISORDERS OF VITAMIN D
METABOLISM
Senile osteoporosis (type II)
 Vitamin D substrate deficiency (diet, synthesis in the skin)

 1,25(OH)2D3 deficiency
(1-hydroxylase deficiency in the kidneys and bone)
 1,25(OH)2D3 receptor (VDR) deficiency
(GI tract, bone)

 Proliferation of parathyroid cells

 Disturbances of active calcium absorption (mechanisms

unknown)
 Pharmacology of vit. D and its analogues
Characteristic Calciferol D3 Calcifedol Calcitriol
25-OH-D3 Rocaltrol
1, 25-(OH)2D3 1-Hydroxy D3

Need for 25 – + - -
hydroxylation +

Need for 1- + + -

hydroxylation -

Time for 4-8 2-4 0.5-1.0

normocalcaemia 1-2
(weeks)

Persistence after 6-18 4-12 0.5-1 1-2

cessation (weeks)

Approx. Daily Dosage 1000-3000(40000- 75-225 0.5 mcg 1-3

(mcg) 120000 I.U.)