Metabolic Bone Diseases
Consultant orthopaedic surgeon
Choithram Hospital & Research Centre
Indore , India
• Structural integrity + strength to body
• Protect vital organs
• Blood cell formation
• Storage of essential minerals, calcium,
phosphate, magnesium, and sodium.
• Largest organ systems in the body.
• 10% cardiac out-put.
• Frequent site for deposition of abnormal
1 – 2 kg calcium, 1 kg phosphates
• Maximum strength with minimal minerals
• Metabolically very active organ.
• Trabecular bone is > cortical.
• Remodelling increases with age.
• 25% cancellous & 3% cortical bone / annum
• 50% of trabecular & 30% of cortical bone in
lifetime in female
• 18% of total skeleton deposited or removed/year.
• Osteocytes - terminally differentiated bone-forming long
lived most abundant cells in bone.
• Stimulated by calcitonin; inhibited by PTH
• Osteocytes- actively involved in bone turnover;
• Osteocyte network is through its large cell-matrix contact
surface involved in ion exchange;
• Osteocytes are the mechanosensory cells of bone, play a
pivotal role in functional adaptation of bone.
• Periosteocytic space filled with Extracellular fluid.
• Sensation of mechanical load is perceived as fluid shear
stress on bone surface.
• apoptosis of osteocytes may generate signals that activate
•Periosteocytic space filled with Extracellular fluid.
•Sensation of mechanical load is perceived as fluid
shear stress on bone surface.
•Apoptosis of osteocytes may generate signals that
activate osteoclast resorption
Osteocyte with Cytoplasmic Extensions
• Synthesize organic components of matrix
(collagen type I, proteoglycans,
• Collagen forms osteoids: strands of spiral
fibers that form matrix
• Influence deposit of Ca++, PO4.
• Active vs inactive osteoblasts
• Estrogen, PTH stimulate activity
• Mesenchymal linage
• Derived from monocytes; engulf bony material
• Active osteoblasts stimulate osteoclast
• Large, branched, motile cells
• Secrete enzymes that digest matrix
• Heamopiotic linage.
• Past : Deficiency disease
• Present : Disabling disease
• Future : Space age disease
Metabolic Bone Diseases
• Mineralization; osteomalacia/rickets
• Low bone mineral content; osteoporoses; OI
• High bone mineral content; osteopetrosis;
bisphosphonate; benign high bone mass
• High bone turnover; pagets; hyperparathyroidism
• Low bone turnover; adynamic disease
Bone Metabolic Unit
Bone multi-cellular Unit
• Bone turn-over is tightly coupled with
osteoclast mediated bone resorption
followed by osteoblast stimulated bone
• This delicate balance in bone remodelling
results in no net change in skeletal mass.
• Basic Six steps are responsible for
• Activation: Osteoclasts
• Resorption: Bone matrix
• Reversal: pre-osteoblasts
• Formation: osteoid
Blue – the lining resting cell layer,
Red – newly deposited osteoid,
Green- mineralized bone,
Dark green – old mature bone.
One BMU lasts about 11 seconds and represents about 6
months of real time. A micro-crack starts the process, the
osteocytes sense damage and send signals into the marrow
space. Preosteoclasts turn into multi-nucleated osteoclasts and
start resorption, meanwhile preosteoblasts turn into osteoblasts
and start forming osteoid (orange) which then mineralizes
One remodeling cycle takes between about 3 and 6 months,
and approximately 10% to 20% of the cancellous bone surface
at any one time will be undergoing some stage of bone
• Human body is very sensitive to “Calcium”
• Cardiovascular and Nervous
systems need calcium for –
• 99% stored in bones
• The irritability and conductivity of nerve and the
irritability and contractility of smooth and skeletal
muscle are inversely proportional to the concentration of
• The irritability and contractility of cardiac muscle are
directly proportional to the concentration of Ca.
• When the serum calcium concentration is low, the
patient becomes hypertonic and hyper-reflexic,
convulses, and dies in diastole.
• When the serum Ca is elevated, the reverse is seen -
that is, there is hypotonicity, hyporeflexia, obtundation,
and coma, and death occurs in systole.
Calcium cannot cross a cell barrier without a transport system.
The first and principal of these components is 1,25-
dihydroxyvitamin D, which acts to enhance the mRNA to
increase synthesis of one or several calcium-binding proteins
(calbindin or cholecalcin), which transport the calcium across
the cell barrier to the extracellular space.
A second component is the cytosolic concentration of phosphate,
which, if above a critical level, may “turn off” transport.
A third, less important, component is parathyroid hormone,
which enhances the production of 1,25-dihydroxyvitamin D in
the kidneys. The parathyroid hormone molecule binds to a
receptor on the cell membrane and, through the action of adenyl
cyclase and cyclic adenosine monophosphate, the hormone
enhances the entry of calcium into the cell and may also activate
the release of calcium by the mitochondria.
• Calcium stored – Hydroxyapatite
• A small proportion is in circulation
• To maintain the critical level of
calcium in blood --
Hormones like – Parathyroid, Vit.-D
Calcitonin, Sex steroids, Thyroid &
• Disorders of key-players will cause a
metabolic bone disease.
• PTH and calcitonin
• Vitamin D
• Calcium absorption defects:
– ↓ Dietary intake
– ↑ Renal excretion
– Calcium substitution by fluorine.
of bone matrix
due to calcium
Osteomalacia results when the osteoid does not have mineral.
The active hormone is
responsible for the
absorption of calcium
from gut. Probably it
acts indirectly by
calcium level thus
reducing the effect of
PTH on bone.
Synthesized in Skin
+ Liver + Kidney
Vitamin D- calcitriol
Physiologic and Pharmaco-dynamic Effects
• Bone -- will increase bone resorption, thus increasing
the loss of bone calcium and phosphorus to the serum.
• Kidney -- increases calcium and phosphorus
reabsorption passively, by decreasing their secretion.
• Intestine -- will increase the intestinal absorption of
dietary calcium and phosphorus.
• The net effect of the calcitriol form of vitamin D is to
increase serum levels of both calcium and phosphorus.
• Involved with PTH release, insulin secretion, cytokine
production, and cell proliferation.
The actions of 1,25-dihydroxyvitamin D are
somewhat broader than simply stimulation of
calcium-binding proteins; they include activities that
have an effect on osteocalcin production,
osteoclastic resorption, monocytic maturation,
myelocytic differentiation, skin growth, and insulin
Vitamin D analog
• 25-dihydrovitamin D (calcifediol)
• Secalcifediol – 24,25-dihydroxyvitamin D
• Dihydrotachysterol (DHT)
• Calcipotriene (calcipotriol)
• Calcitriol -- the 1,25 dihydroxyvitamin D
• Vitamin D Deficiency
• Impaired 25 OH Vitamin D production
• Impaired 1,25 OH2 Vitamin D production
• Defective Vitamin D receptor
Vitamin D Deficiency
housebound; frail elderly; immigrant from low
to high latitude; gastrectomy; malabsorption
dark skin pigmentation
D low; 25D low; 1,25D low to normal ; Ca
low; PTH high; Alk Ph high; P low
Impaired 25D production
hepatic failure; drugs affecting CYP liver
mutations in 25Dhydroxylase: not described
D normal; 25D low; 1,25 D low to normal;
Ca low; PTH high; Alk ph high; P low
Impaired 1,25 D production
chronic renal failure
mutations in 25D 1 alpha hydroxylase (D
dependent rickets type 1)
D normal; 25D normal; 1,25D low; Ca low;
PTH high; Alk Ph high; P high in CRF and
low in D dependent rickets
Defective D receptor (VDR)
• Environmental non described
mutations in VDR ( D dependent rickets
D normal; 25D normal; 1,25D high; Ca low;
PTH high; Alk Ph high; P low
Deficiency of Vit. D
• Dietary lack of the vitamin
• Insufficient ultraviolet skin exposure
• Malabsorption of fats and fat-soluble
vitamins- A, D, E, & K.
• Abnormal metabolism of vitamin D
chronic renal failure.
Disease of Affluent class
Vitamin D Resistant
• In the renal tubular disorders, rickets and
osteomalacia develop in the presence of
normal intestinal function and are not cured
by normal doses of vitamin D.
• Resistant or refractory rickets.
Defective final conversion of Vit. D in to active form.
Effect at growth end plate
• Inadequate growth plate mineralization.
• Defective calcification in the interstitial regions of
the hypertrophic zone.
• The growth plate increases in thickness.
• The columns of cartilage cells are disorganized.
• Cupping of the epiphyses.
• Bones incapable of withstanding mechanical
stresses and lead to bowing deformities.
• Eventual length of the long bones is diminished.
( short stature)
Genu valgus Tri radiate pelvis Wrist widening
Wrist cupping Looser’s zones Wide metaphysis
dietary phosphate depletion;
prematurity in neonates; mesenchymal
tumors; renal tubule disease
mutations in PHEX; mutations in FGF
The principal control mechanism for phosphate is renal, in that there is
not only a tubular maximum (and hence a so-called spill) and tubular
secretion but a very finely tuned tubular reabsorption mechanism for
phosphate. This mechanism is affected by a number of factors but is
principally under the control of parathyroid hormones.
Thus, conditions such as rickets, osteomalacia, or renal osteodystrophy,
which cause an increase in parathyroid hormone release (principally
in response to a lowered Caı concentration), cause a simultaneous
decline in the percentage of tubular resorption of phosphate and a
resultant hyperphosphatunia and hypophosphatemia’.
Such a mechanism is clearly protective since, if both the ionic calcium
and the phosphate concentrations rise, we are dangerously close to
turning to stone!
Phosphate: Fanconi Syndrome
• Disease of the renal tubule
can be genetic or acquired
P low; TmP low; aminoaciduria;
glycosuria; Ca normal; PTH normal; Alk
Ph normal; D normal; 25D normal; 1,25D
• Kidney - homeostasis of Ca, PO4 and metabolism of
• CKD disturbances in this homeostasis
abnormalities of PTH and vitamin D systems
• A spectrum of bone disorders:
– Osteitis Fibrosa
– Mixed Osteodystrophy
– Adynamic Bone Disease
– Cystic Disease (occurs in DRA)
Renal bone disease
• Osteitis fibrosa cystica
• ↓ GRF.
• ↑ Phosphate excretion
• serum phosphate - ↓ serum Ca.
• turn over of bone
→ Secondary Hyper Parathyroidism
• Demineralized bone ( osteoid)
• Aluminum deposition
• ↓ Vitamin D active metabolites
Adynamic Bone Disease
• Profound in number of active remodelling sites
in number of osteoblasts and osteoclasts
bone formation and mineralization
• Bone structure predominantly lamellar
• Reduced trabecular bone formation and resorption
• Unlike osteomalacia – no increase in osteoid formation or
• The relationship between osteoid seam thickness and
adjusted apposition rate is normal - osteoid seam thickness
Adynamic Bone Disease
• Low PTH levels (state of relative hypoparathyroidism)
• More common in older patients
• Patients with DM
• Patients on PD
• Overtreatment with vit D, aluminum intoxication, steroids,
low sexual and thyroid hormone levels
• ?cytokines and other related factors
• Originally associated with excess aluminum
• Emergence of idiopathic of ABD unrelated to aluminum in
• Adynamic Bone disease:
– → Peritoneal + Hemodialysis patients.
– ↓ Bone turn over.
– ↑ Osteoid formation.
– ↑ Aluminum deposition.
– ↓ PTH activity due to use of Vit.D + calcium.
– ↓ Vit. K – carboxylation of matrix.
• Normal mineral to
The resorption cavities go a little deeper and resorption lasts a
little longer, and the bone formation increases but doesn't quite match the
higher resorption rate.
• Estrogen receptors (ERs) in both
osteoclasts and osteoblasts.
• Two iso-forms of ERs
– ER-alpha and ER-beta.
– Synthetic estrogens and selective estrogen
receptor modulators (SERMs) act on these
iso-forms differently and produce different
Reloxiphen selectively on bone & not on breast
• In bone cells to regulate the process of
programmed cell death, called apoptosis.
• Accelerates the death of osteoclasts, while
prolonging the life of osteoblasts.
• ↑ intestinal absorption of calcium
• ↑ reabsorption of calcium from the renal
positive calcium balance.
Estrogen effects may be mediated in part by growth factors
and interleukins. For example, interleukin 6 is a potent
stimulator of bone resorption, and estrogen blocks the
osteoblast's synthesis of interleukin 6. Estrogen may also
antagonize the interleukin 6 receptors.
Estrogen has multiple other effects that relate to the
skeleton. For example, enhanced intestinal calcium
absorption can be beneficial to bones. Estrogen protects
the bone from the resorptive effects of PTH. Estrogens
may interact with mechanical forces to build bone. There
are different effects on the endocortical surfaces and the
periosteal surfaces that result in different shapes of bones
in men compared to women.
This movie shows the effect of Raloxifene in women with osteoporosis.
• Interfere with osteoclast cytoskeleton.
• Inhibit mevalonate pathway enzymes.
• Decrease protein-tyrosine phosphatases.
• Stimulate apoptosis of osteoclasts.
• Inhibit osteoclast attachment to bone.
• Inhibit proton pump of osteoclasts.
Anti osteoclast → Anti resorptive
• Negative charges on the two phosphate groups of the
bisphosphonate nucleus gave these compounds a high
affinity for the surface of bone. After binding to
mineralized bone surface, they are taken up by
osteoclasts during bone resorption. Within these cells,
they inhibit the enzyme farnesyl pyrophosphate
synthase. This is a key enzyme in the mevalonate
pathway, which leads to the synthesis of cholesterol.
This ultimately leads to the death of Osteoclast.
After the estrogen deficiency in the first 6 months show high turnover;
then the little blue diamonds representing a bisphosphonate start to
attach to the bone; resorption stops suddenly and formation stops after a
few months. The bone continues to become more mineralized (darker),
and only a few BMU's are still active.
• Increase rates of
woven bone. Plicamycin (Mithramycin),
• uncontrolled Biphosphonates,
Steroid induced bone disease
• Osteoblastic activity
• ↑ Rate of bone resorption
• ↓ BMU
• ↑ Hypercalciuria
• ↓ Collagen synthesis
• ? Secondary hyper parathyroidism
Steroid Induced osteoporosis
Corticosteroids increase the bone resorption rate and depth,
similar to menopause. The steroids block action of
osteoblasts, so the bone formation does not increase.
• Failure of osteoclastic
• Failure of remodelling
• Defiency of carbonic anhydrase in osteoclasts.
• Defective hydrogen ion pumping by osteoclasts and
this in turn causes defective bone resorption by
• acidic environment is needed for dissociation of
calcium hydroxyapatite from bone matrix and its
release into blood circulation.
• Hence, bone resorption fails while its formation
persists. Excessive bone is formed
• Abnormal matrix
• Crystals of
Endemic in India
• Mechanism of Action -- In the prevention of dental
caries, fluoride stabilises hydroxyapatite crystals.
The cellular mechanism of action of fluoride in
increasing bone density is not known. However, it is
known that fluoride induces osteoblastic
mitogenesis. Moreover, it is ineffective unless the
patient also takes calcium supplements.
• Pharmacodynamic Effect -- Fluoride with calcium
supplementation will increase bone mineral density
• Change of shape of osteoblast
• ↑ secretion of neutral collagenase by osteoblast cells.
• Collagenase digests the protective layer of matrix
exposing the bone surface for osteoclastic
PTH is to increase
serum calcium and receptors
decrease serum only on
phosphate levels Osteoblasts
PTH on Bone
• Bone -- High doses of PTH will increase the number
and activity of osteoclasts, resulting in bone
resorption (breakdown). This effect may be
secondary to PTH-induced stimulation of osteoblasts
(bone forming cells) which then stimulates
osteoclastic activity. Osteoblast activity resulting
from PTH action has been linked with intracellular
increases in both cAMP and calcium. Despite the
activity of osteoblasts, the net effect of high dose
PTH is bone resorption and loss of calcium to the
serum. At low doses, PTH may stimulate bone
formation (osteoblast action alone) and no calcium is
PTH on Kidney
• Kidney -- PTH increases calcium and magnesium
reabsorption and decreases the reabsorption of
phosphate, amino acids, bicarbonate, sodium,
chloride, and sulphate. PTH will also cause the
formation of the calcitriol form of vitamin D.
• Intestine -- PTH increases the absorption of dietary
calcium and phosphate. This action is secondary to
vitamin D formation and activity.
• The net effect of PTH on these systems is to increase
serum calcium and decrease serum phosphate levels.
PTH in response -> hypocalcemia
• mobilize calcium from bone – blood
• ↓ renal clearance of calcium
• ↑ calcium absorption - intestine
Diagram showing the mechanism of the development of the biochemical
and osseous findings of primary hyperparathyroidism. PTH =
parathyroid hormone. GI gastrointestinal. and TR tubular resorption.
Disease of Stone & Bone
• Hyper calcemia
• Hypo phoshphatemia
• Hyper calciuria
• High alk.phosphatase level
• PTH immune assay
• Ultrasosnography of neck.
• Secreted by Thyroid C cells in response to
elevations in circulating calcium
concentrations, thus provides a fine tuning of
the calcium homeostasis and retain the dietary
calcium in skeleton.
• Potent inhibitor of osteoclastic activity, &
• Osteoclast have calcitonin receptors 300,000/
Anti – PTH, Anti – Vit D3
• Bone --↓ osteoclastic activity in bone to
decrease calcium and phosphate loss into
• Kidney -- ↑ renal loss of calcium and
phosphorus by inhibiting their reabsorption.
• Other effects -- ↓ gastric acid and gastrin
secretion and increases the secretion of
sodium, potassium, chloride, and water into
• To diagnose a metabolic bone disease
• To assess the effect of anti-resorptive
agents at earliest.
• Can be used within 3 – 6 months
• BMD assessments takes more than a
To assess bone formation:
• Serum immunoassays for osteocalcin.
• Alkaline phosphatase – both types
• N-terminal extension peptide (PINP) of
type I collagen.
To assess bone resorption:
• Immunoassays for the type I collagen
pyridinoline crosslink and related
FORMATION- Osteoblast RESORPTION- Osteoclast
(Bone GlaProtein) Free pyridinoline and
Total and bone specific alkaline deoxypyridinoline
phosphatase Type I collagen N and C-
Procollagen I carboxy (PICP) telopeptide breakdown products
and N-terminal (PINP)
extension peptides Urine
Pyridinoline and deoxpyridinoline
Bone Markers Type I collagen N and C-
telopeptide breakdown products
Fasting calcium and
• Three vitamin-K dependent proteins have been isolated in
bone: osteocalcin, matrix Gla protein (MGP), and protein S.
• The synthesis of osteocalcin by osteoblasts is regulated by the
active form of vitamin D - 1,25(OH)2D3 .
• The mineral-binding capacity of osteocalcin requires vitamin
K-dependent gamma-carboxylation of three glutamic acid
• MGP prevents the calcification of soft tissue and cartilage,
while facilitating normal bone growth and development.
• The vitamin K-dependent anticoagulant protein S is
synthesized by osteoblasts,
• Protein S deficiency suffer complications related to increased
blood clotting as well as decreased bone density .
• antineoplastic antibiotic that decreases protein
• Its mechanism of action that accounts for efficacy in
bone loss is not known, but is presumed to be
mediated by decreased protein synthesis.
• Pharmacodynamic Effect -- Plicamycin reduces bone
resorption, thus increasing bone density.
• Therapeutic Uses -- Paget's disease and
Calcium and Bone Modulators
• Plicamycin (Mithramycin)
Selected Clinical Aspects of Bone Homeostasis
gallium nitrate, plicamycin,
• Hypocalcæmia calcium supplementation with vitamin D
• Hyperphosphotæmia aluminium hydroxide antacids
• Rickets & Osteomalasia vitamin D + Calcium supplementation
• Chronic Renal Failure
• Paget's Disease
↓ calcium absorption,
uncontrolled osteoclastic bone resorption.
Space age bone disease
• Cosmonauts and astronauts who spent many
months on space station Mir revealed that
space travelers can lose (on average) 1 to 2
percent of bone mass each month.
• 5 – 20% ↓ in bone mineral mass in 6 months.
• Journey to Mars is 2 years.
• The gravity on the Red Planet is about one half
of that found on Earth.
Space age bone disease
• Weightlessness in “Zero G”.
• Minimal mechanical stress on bone.
• ↓ numbers of osteoblasts.
• Osteoclast number – normal.
• NASA projects
– hPTH(1-31) as potent osteoblastic agent
under extensive study.
– Effect of exercises in “Zero G”.
• Recent advancement on
– Co-relation with Coronary disease
– Molecular manipulation for osteogenesis
– Co-relation with Obesity
– Fracture prevention
– Space age osteoporosis
• paracrine communication, where the products of
cells diffuses in the ECF to affect neighboring cells
that may be some distance away.
• Paracrine system is essential to bone metabolism
• Mediators are
1. molecules RANK = receptor activator for nuclear
factor kb ,RANK ligand (RANKL)
2. Osteoprotegrin ( OPG)
RANK =Receptor activator for
nuclear factor kb
• RANK is a member of TNF family of receptors
expressed mainly on cells of macrophages /
monocytes lineage such as preosteoclasts
• When this receptor binds its specific ligand
(RANKL) through cell- cell contact ,
osteoclastogenesis is initiated
• RANKL is produced by and expressed on the cell
membranes of osteoblast & marrow stromal cells
• Its major role is stimulation of osteoclast formation ,
fusion, differentiation, activation , survival
–In chemistry, a ligand is either an atom, ion, or
molecule (functional group) that binds to a central
metal to produce a coordination complex.
– The bonding between the metal and ligand
generally involves formal donation of one or more
of the ligand's electrons.
– The metal-ligand bonding ranges from covalent to
more ionic. Furthermore, the metal-ligand bond
order can range from one to three. Ligands are
viewed as Lewis bases, although rare cases are
known involving Lewis acidic "ligands."
• Osteoprotegrin is a soluble protein member of TNF
• Produced by bone , hematopoetic marrow , immune
• OPG blocks action of RANKL , inhibits
osteoclastogenesis by acting as a decoy receptor that
binds to RANKL , thus preventing interaction
between RANK & RANKL
• Therefore interplay between bone cells & these
molecules permits osteoblasts and stromal cells to
control osteoclasts development
• OPG an important role in vascular biology. In
fact, OPG could represent the long sought-after
molecular link between arterial calcification and
bone resorption, which underlies the clinical
coincidence of vascular disease and
osteoporosis, which are most prevalent in
postmenopausal women and elderly people.
• Sclerostin produced by the osteocytes blocks the
mineralization at the later stages.
• osteocytes main source of sclerostin.
• osteocytes play a major role in regulating bone
• Defects in the SOST gene -absence or reduced
production of sclerostin, causes Sclerosteosis and
van Buchem diseases, hypertrophic bones which are
• sclerostin binds to LRP5 and antagonizes the Wnt
Osteoclast : target organ
• Blocked of RANK ligend by human antibody to
RANK ligand, Denosumab
• Cathepsin K- deficiency: Picnodisostosis
• Corbonic anhydrase deficiency: – Osteopetrosis
• RANKL decoy by Osteoprotegrin: ↓ Osteoclastosis.
• Over production of RANKL by parathyroid
harmones: ↑ osteoclastosis – brown lesions.
• Sclerostatin by osteocytes : prevents extra new bone
RANK Ligand and Osteoprotegerin.
Paracrine Regulators of Bone Metabolism
and Vascular Function
• Receptor activator of nuclear factor (NF-kappaB)
ligand (RANKL), its cellular receptor, receptor
activator of NF-kappaB (RANK), and the decoy
receptor osteoprotegerin (OPG) constitute a novel
cytokine system. RANKL produced by osteoblastic
lineage cells and activated T lymphocytes is the
essential factor for osteoclast formation, fusion,
activation, and survival, thus resulting in bone
resorption and bone loss. RANKL activates its
specific receptor, RANK located on osteoclasts and
dendritic cells, and its signaling cascade involves
stimulation of the c-jun, NF-kappaB, and
serine/threonine kinase PKB/Akt pathways..
• The effects of RANKL are counteracted by OPG which acts
as a soluble neutralizing receptor. RANKL and OPG are
regulated by various hormones (glucocorticoids, vitamin D,
estrogen), cytokines (tumor necrosis factor alpha,
interleukins 1, 4, 6, 11, and 17), and various mesenchymal
transcription factors (such as cbfa-1, peroxisome
proliferator-activated receptor gamma, and Indian
hedgehog). Transgenic and knock-out mice with excessive
or defective production of RANKL, RANK, and OPG
display the extremes of skeletal phenotypes, osteoporosis
Abnormalities of the RANKL/OPG system have been
implicated in the pathogenesis of postmenopausal
osteoporosis, rheumatoid arthritis, Paget's disease,
periodontal disease, benign and malignant bone
tumors, bone metastases, and hypercalcemia of
malignancy, while administration of OPG has been
demonstrated to prevent or mitigate these disorders in
RANKL and OPG are also important
regulators of vascular biology and
calcification and of the development of a
lactating mammary gland during pregnancy,
indicating a crucial role for this system in
extraskeletal calcium handling. The discovery
and characterization of RANKL, RANK, and
OPG and subsequent studies have changed the
concepts of bone and calcium metabolism,
have led to a detailed understanding of the
pathogenesis of metabolic bone diseases, and
may form the basis of innovative therapeutic
The molecular triad OPG/RANK/RANKL:
involvement in the orchestration of
pathophysiological bone remodeling.
– The recent identification of the receptor activator of
nuclear factor kappaB ligand (RANKL), its cognate
receptor RANK, and its decoy receptor osteoprotegerin
(OPG) has led to a new molecular perspective on
osteoclast biology and bone homeostasis. Specifically,
the interaction between RANKL and RANK has been
shown to be required for osteoclast differentiation. The
third protagonist, OPG, acts as a soluble receptor
antagonist for RANKL that prevents it from binding to
and activating RANK. Any dysregulation of their
respective expression leads to pathological conditions
such as bone tumor-associated osteolysis, immune
disease, or cardiovascular pathology. In this context, the
OPG/RANK/RANKL triad opens novel therapeutic areas
in diseases characterized by excessive bone resorption.
Role of osteoprotegerin and its ligands and
competing receptors in atherosclerotic
Vascular calcification significantly impairs cardiovascular
physiology, and its mechanism is under investigation.
Many of the same factors that modulate bone
osteogenesis, including cytokines, hormones, and lipids,
also modulate vascular calcification, acting through
many of the same transcription factors. In some cases,
such as for lipids and cytokines, the net effect on
calcification is positive in the artery wall and negative in
bone. The mechanism for this reciprocal relation is not
• A recent series of reports points to the possibility that two
bone regulatory factors, receptor activator of NF-kappaB
ligand (RANKL) and its soluble decoy receptor,
osteoprotegerin (OPG), govern vascular calcification and
may explain the phenomenon. Both RANKL and OPG are
widely accepted as the final common pathway for most
factors and processes affecting bone resorption. Binding of
RANKL to its cognate receptor RANK induces NF-kappaB
signaling, which stimulates osteoclastic differentiation in
preosteoclasts and induces bone morphogenetic protein
(BMP-2) expression in chondrocytes.
• A role for RANKL and its receptors in vascular
calcification is spported by several findings: a
vascular calcification phenotype in mice genetically
deficient in OPG; an increase in expression of
RANKL, and a decrease in expression of OPG, in
calcified arteries; clinical associations between
coronary disease and serum OPG and RANKL levels;
and RANKL induction of calcification and
osteoblastic differentiation in valvular
Associations between coronary disease
and serum OPG and RANKL levels
Obesity and Osteoporosis
• It has been proposed that increases in adipose tissue, with
increasing BMI in postmenopausal women, results in
increased estrogen production, osteoclast suppression, and a
resultant increase in bone mass.
• Obesity has been associated with insulin resistance,
characterized by high plasma levels of insulin. High plasma
insulin levels may contribute to a variety of abnormalities,
including androgen and estrogen overproduction in the
ovary, and reduced production of sex hormone-binding
globulin by the liver. These changes may result in elevated
sex hormone levels, leading to increased bone mass due to
reduced osteoclast activity and possibly increased osteoblast
• M/F ratio of Coronary artery disease 4/1
• F/M average age F 3 years > M
• Obesity increases Bone mineral mass
• Extra production of Estrogen by adipose tissues
• Perimenopausal Hypothyroidism ↑ body
Fat cell targets for skeletal health
• Adipocytes are derived from a mesenchymal
precursor stem cell that also gives rise to
osteoblasts, chondroblasts, myoblasts, and
fibroblasts. An osteoblast can be transformed
to an adipocyte if Pparγ2 (peroxisome
proliferator-activated receptor γ2) is
expressed, while an adipocyte can be
converted to an osteoblast if Runx2 is
• Emerging evidence points to a critical role for the
skeleton in several homeostatic processes, including
energy balance. The connection between fuel
utilization and skeletal remodeling begins in the
bone marrow with lineage allocation of
mesenchymal stem cells to adipocytes or
• Mature bone cells secrete factors that influence
insulin sensitivity, and fat cells synthesize cytokines
that regulate osteoblast differentiation; thus, these
two pathways are closely linked. The emerging
importance of the bone–fat interaction suggests that
novel molecules could be used as targets to enhance
bone formation and possibly prevent fractures.
Three pathways that could be pharmacologically targeted for
the ultimate goal of enhancing bone mass and reducing
osteoporotic fracture risk: the leptin, peroxisome proliferator-
activated receptor gamma and osteocalcin pathways. Not
surprisingly, because of the complex interactions across
homeostatic networks, other pathways will probably be
activated by this targeting, which could prove to be beneficial
or detrimental for the organism. Hence, a more complete
picture of energy utilization and skeletal remodeling will be
required to bring any potential agents into the future clinical
How is the close pairing of the osteoclast and osteoblast
• Osteoblasts regulate osteoclast formation via the RANKL–
RANK and the M-CSF–OPG mechanism, but there is no
known direct feedback of osteoclasts on osteoblasts.
• Instead, the whole bone remodeling process is primarily
under endocrine control.
• Parathyroid hormone accelerates bone resorption and
estrogens slow bone resorption by inhibiting the production of
• An interesting new observation is that intracerebroventricular
but not intravenous leptin decreases bone formation. This
finding is consistent with the observations that obesity protects
against bone loss and that most obese humans are resistant to
the effects of leptin on appetite). Thus, there may be
neuroendocrine regulation of bone mass via leptin.
Bone Remodeling. The remodeling process of bone comprises
the coupled activity of bone resorbing osteoclasts and bone
forming osteoblasts. This system is tightly controlled by a
number of soluble regulatory factors and through cellular
interactions within the bone microenvironment.
Resorbed bone is nearly precisely replaced in location and
amount by new bone.
Bone loss through osteoclast-mediated bone resorption and
bone replacement through osteoblast-mediated bone formation
are tightly coupled processes.
Osteoblasts direct osteoclast differentiation.
Key questions remain, however, as to how osteoblasts are
recruited to the resorption site and how the amount of bone
produced is so precisely controlled.
Osteoclasts play a crucial role in the promotion of bone
Osteoclast conditioned medium stimulates human
mesenchymal stem (hMS) cell migration and differentiation
toward the osteoblast lineage as measured by mineralized
nodule formation in vitro.
Induction of sphingosine kinase 1 (SPHK1), which catalyzes
the phosphorylation of sphingosine to form sphingosine 1-
phosphate (S1P), in mature multinucleated osteoclasts as
compared with preosteoclasts.
S1P induces osteoblast precursor recruitment and promotes
mature cell survival. Wnt10b and BMP6 also were
significantly increased in mature osteoclasts, whereas
sclerostin levels decreased during differentiation.
Stimulation of hMS cell nodule formation by osteoclast
conditioned media was attenuated by the Wnt antagonist
Dkk1, a BMP6-neutralizing antibody, and by a S1P
antagonist. BMP6 antibodies and the S1P antagonist, but not
Dkk1, reduced osteoclast conditioned media-induced hMS
Obesity and Osteoporosis
• Extensive epidemiological data show that high body
weight or BMI is correlated with high bone mass, and
that reductions in body weight may cause bone loss .
The basic mechanisms underlying this observed
obesity: bone mass correlation remain unclear,
though several explanations have been proposed. It is
generally accepted that a larger body mass imposes a
greater mechanical loading on bone, and that bone
mass increases to accommodate the greater load.
Further, adipocytes are important sources of estrogen
production in postmenopausal women, and estrogen
is known to inhibit bone resorption by osteoclasts.
• Information contained and transmitted by this presentation is based on
personal experience and collection of cases at Choithram Hospital &
Research centre, Indore, India, during past 30 years.
• It is intended for use only by the students of orthopaedic surgery.
•Many GIF files are taken from Internet.
• Views and opinion expressed in this presentation are personal opinion.
• Depending upon the x-rays and clinical presentations viewers can make
their own opinion.
• For any confusion please contact the sole author for clarification.
• Every body is allowed to copy or download and use the material best
suited to him. I am not responsible for any controversies arise out of this
• For any correction or suggestion please contact email@example.com
All animation slides are taken from , Osteoporosis and Bone Physiology”
web site, 1999 - 2006 http://courses.washington.edu/bonephys
of Dr. Susan Marie Ott, MD. Medical staff of University of Washington