Osteoporosis, osteodystrophy and
osteomalacia. Bone state in
patients with chronic renal failure
TZKM 7. 4. 2017
Bone remodeling
 Osteoclast activation
 Resorbtion phase- due to osteoclast
activation- short period
 Reverse phase- bone surface is covered by
mononuclear cell
 Formation phase- osteoblast production in
bone matrix - long.
Bone remodelling - final evaluation as
physiological state of the bone
 Equilibrium between osteoclastic and
osteoblastic activities chronically
 Adequate time remodelling in
dependence on mechanic powers
necessities
Bone properties
 Bones must be stiff so that they do not bend when loaded.
 Bones must also be flexible so they can absorb the energy imposed
by loading as potential energy by elastic then plastic deformation.
Structural failure may occur if bones deform too little or too much.
 Age- and menopause-related abnormalities in bone remodeling
produce loss of material and structural properties.
 High remodeling reduces the mineral content of bone, resulting in loss
of stiffness.
 Sex hormone deficiency increases the volume of bone resorbed and
reduces the volume of bone formed in each BMU. The contributions
made by differences
 in material composition, tissue mineral content, collagen type and
cross-linking)
 structure (bone size, cortical thickness and porosity, trabecular
number, thickness, connectivity), and
 other factors (microdamage burden, osteocyte density) to sex and
racial differences in bone fragility remain poorly defined.
Skeletal fragility
Skeletal fragility can result from:
 1. failure to produce a skeleton of optimal mass and strength
during growth
 2. excessive bone resorption resulting in decreased bone mass
and microarchitectural deterioration of the skeleton; and an
inadequate formation response to increased resorption during
bone remodeling.
 In addition, the incidence of fragility fractures, particularly of
the hip and wrist, is further determined by the frequency and
direction of falls.
a) Several endogenic factors support
osteoblastogenesis against
adipogenesis.
b) High levels of cortisol prefer
adipogenesis to osteoblastogenesis
Low [GC] low (physiological)
concentrations of glucocorticoids, GHgrowth
hormone, IGF-1 insulin-like
growth factor-1, FGF-2 fibroblast growth
factor-2, IL-11 interleukin-
11, CT-1 cardiotrophin-1, OSM
oncostatin M, OB osteoblast, AD-
adipocyte
Equilibrium between osteoblastogenesis (OB) and adipogenesis
(AD)
Alterations of bone remodelling
 Metabolic bone diseases:
 Osteoporosis (chronic predominance
of osteoclastic above osteblastic
activities)
 Osteodystrophy (increased bone
remodelling rate)
 Rickets/osteomalacia (decreased
bone remodelling rate)
RANK
RANKL
Osteoprotegerin
OPG/RANK/RANKL as a common effector in bone immune
system and a vascular system ( to the previous figure)
 OPG, RANK and RANKL are selectively produced by
many cell types in diferent tissue: lymphocytes,
osteoblasts and endothelial cells.
 RANKL is functioning as a survival factor for dendritic
cells and as a osteoclastogenic factor after RANK
ligation.
 OPG inhibits osteolysis and blocks RANKL/RANK
interaction.
 OPG/RANKL/RANK triad is considered a
osteoimmunomodulating complex.
RANK-RANKL signální cesta, inhibice vazby RANK-RANKL
osteoprotegerinem (OPG)
TNF receptor-associated
factor
Metabolic bone diseases
Osteoporosis
Osteodystrophy
Osteomalacia (rickets in
childhood)
Osteoporosis
 Osteoporosis remains the most common
metabolic abnormality of bone. It has been
described as “a silent epidemic” affecting
one in two women and one in five men, older
than 50 years of age, during their lifetime.
 It is now defined as a systemic skeletal
disease characterized by low bone mass and
micro-architectural deterioration of bone
resulting in fractures with little or no trauma.
Osteoporosis
Osteoporosis
 is a skeletal disease characterised by
low bone mass and
microarchitectural deterioration with
a resulting increase in bone fragility
and hence susceptibility to fracture.
 It is an important public health issue
because of the potentially
devastating results and high
cumulative rate of fractures.
Osteoporosis - causes
 Insufficiency of estrogenes
 Age (both men and women)
 Immobilisation
 Increased levels of glucocorticoids
 Decreased levels of vitamin K2
Osteoporosis
 Oestrogen has a central role in normal physiological
remodelling, and oestrogen deficiency after the menopause
results in a remodelling imbalance with a substantial increase
in bone turnover.
 This imbalance leads to a progressive loss of trabecular bone,
partly because of increased osteoclastogenesis.
 Enhanced formation of functional osteoclasts seems to be the
result of increased elaboration of osteoclastogenic
proinflammatory cytokines such as interleukin-1 and tumour
necrosis factor, which are negatively regulated by oestrogen.
 A direct effect of oestrogen in accelerating osteoclast
apoptosis has also been attributed to increased production of
transforming growth factor β.
Etiopathogenesis of osteoporosis
 Osteoporosis is likely to be caused by complex interactions
among local and systemic regulators of bone cell function.
 The heterogeneity of osteoporosis may be due not only to
differences in the production of systemic and local
regulators, but also to changes in receptors, signal
transduction mechanisms, nuclear transcription factors, and
enzymes that produce or inactivate local regulators.
 Since the first human osteoporosis study indicated an
association among bone mass, fragility, and polymorphisms
in the vitamin D receptor (VDR) gene, more than 30
candidate genes have been reported that might influence
skeletal mass and fragility.
 Since osteoporosis is a complex, polygenic disorder, the
contributions of specific gene polymorphisms are likely to be
relatively small, but may still be clinically important.
Estrogen deficiency
 Fracture risk is inversely related to estrogen levels in
postmenopausal women.
 Recent studies in humans have shown that the level of
estrogen required to maintain relatively normal bone
remodeling in older postmenopausal women is lower
than that required to stimulate classic target tissues
such as the breast and uterus.
 As little as one-quarter of the dose of estrogen that
stimulates the breast and uterus is sufficient to
decrease bone resorption and increase bone mass in
older women. This greater sensitivity of the skeleton
may be age related.
Estrogen influence on bone state
 Estrogen is critical for epiphyseal closure in puberty in
both sexes and regulates bone turnover in men as well
as women.
 In fact, estrogen has a greater effect than androgen in
inhibiting bone resorption in men, although androgen
may still play a role.
 Estrogen may also be important in the acquisition of
peak bone mass in men.
 Osteoporosis in older men is more closely associated
with low estrogen than with low androgen levels.
Central role of estrogen deficiency
 The concept that estrogen deficiency is critical to the
pathogenesis of osteoporosis was based initially on the fact that
postmenopausal women, whose estrogen levels naturally
decline, are at the highest risk for developing the disease.
Morphologic studies and measurements of certain biochemical
markers have indicated that bone remodeling is accelerated at
the menopause, as both markers of resorption and formation are
increased.
 Now, an increase in bone resorption, and not impaired bone
formation, appears to be the driving force for bone loss in the
setting of estrogen deficiency. But the rapid and continuous
bone loss that occurs for several years after the menopause must
indicate an impaired bone formation response, since in younger
individuals going through the pubertal growth spurt, even faster
rates of bone resorption can be associated with an increase in
bone mass. However, the increased bone formation that
normally occurs in response to mechanical loading is diminished
in estrogen deficiency, suggesting estrogen is both anti-catabolic
and anabolic.
A: Oestrogen replete state. Osteoclasts are formed by interaction between macrophagic,
monocytic precursor cells and cells of the osteoblast lineage, but might also be initiated by
inflammatory cells, especially T cells. Osteoclasts express receptor activator of NFκB (RANK). The
RANK ligand (RANKL) enhances each of these steps whereas osteoprotegerin, a decoy
receptor, blocks this interaction.
B: Oestrogen deficient state. Important bone sparing effects of oestrogen take place via
modulation of bone cell lifespan and reduced cytokine-driven osteoclastogenesis. In the
absence of oestrogen, the pool of T cells secreting tumour necrosis factor is expanded through
a mechanism involving reduced transforming growth factor β. Additionally, monocytes secrete
increased amounts of interleukin-1. Tumour necrosis factor stimulates M-CSF (macrophage
colony-stimulating factor) and RANKL production and acts on osteoclast progenitors primed by
RANKL, to heighten osteoclast generation. RANKL and interleukin-1 also act to increase
osteoclast survival by preventing apoptosis. As a result, in oestrogen deficiency, the number of
functional basic multicellular units in bone is substantially increased. This model is based
predominantly on studies in ovariectomised animals.
Osteoporosis
 Osteoporotic fractures result from a combination of
reduced bone strength and increased rate of falls.
Although bone mineral density remains the best
available non-invasive assessment of bone strength in
routine clinical practice, many other skeletal
characteristics also contribute to bone strength.
 These include bone macroarchitecture (shape and
geometry), bone microarchitecture (both trabecular
and cortical), matrix and mineral composition, as well as
the degree of mineralisation, microdamage
accumulation, and the rate of bone turnover, which
can affect the structural and material properties of
bone.
Common adverse effects of glucocorticoid therapyglucocorticoid-induced
osteoporosis
 Glucocorticoid-induced osteoporosis is the most
common type of iatrogenic osteoporosis and a frequent
cause of secondary osteoporosis.
 An estimated 50% of patients taking glucocorticoids for
longer than 6 months will develop secondary
osteoporosis .
 The absolute risk for glucocorticoid-induced osteoporosis
is higher in patients aged 65 years or older given their
baseline age-related fracture risk, although the relative
risk of fracture related to glucocorticoid use may be
even higher in patients under 65 .
Common adverse effects of glucocorticoid therapy
 There is substantial and accelerated decreases in bone mineral density
(BMD) with oral glucocorticoid therapy, most pronounced in the first year,
with trabecular bone more quickly affected than cortical bone.
 Even after only 2 months of high-dose glucocorticoids, studies show markedly
decreased BMD at the lumbar spine, femoral neck and whole body, with the
greatest loss in the trabecular lumbar vertebrae.
 In light of the high incidence of glucocorticoid-induced osteoporosis and
associated fractures, screening and treatment rates for glucocorticoidinduced
osteoporosis has come under substantial scrutiny.
 Less than 50% of patients receiving long-term glucocorticoids have been
evaluated for osteoporosis, and less than 25% have been treated. There is
great variability among clinicians in both the awareness of glucocorticoidinduced
osteoporosis and the importance of prevention and treatment as
the standard of care.
 The use of antiosteoporotic medication was observed to be most common
among postmenopausal women, where it approached 50%.
Osteoporosis induced by cortisol
 Cortisol modifies proliferative and
mewtabolic activities of bone cells
 Cortisol inhibits osteoblastogenesis
 Reduces half-life time of osteoblasts
which is leading to decreased bone
formation
Age-specific and sexspecific
incidence of
radiographic vertebral,
hip, and distal forearm
fractures
Data derived from
European Prospective
Osteoporosis Study and
General Practice
Research Database.
o Vitamin K2 is substantial cofactor for γ-carboxylase, enzyme which
catalyses conversion of specific residuals of glutamic acid to Gla
residuals
o Vitamin K2 is necessary for γ-carboxylation of proteins of bone matrix
which contain Gla as MGP (= matrix Gla protein) a osteokalcin.
o Uncompleted γ-carboxylation of osteocalcin and MGP during
vitamin K decrease lead to osteoporosis and high risk of fractures.
Vitamin K2 stimulates synthesis of osteoblastic markers and bone
deposition.
o Vitamin K2 decreases bone reabsorbtion by inhibition of osteclasts
formation and by decrease of their resorbtion activity.
o Vitamin K2 treatment induces osteoclast apoptosis, but inhibits
osteoblasts apoptosis which is leading to increased bone formation.
o Vitamin K2 supports osteocalcin expression ( increases its mRNA)
which can be further modulated by 1, 25-(OH)2 vitamin D3.
Vitamin K and bones
Cortisol
generally
antagonizes
insulin …
Vitamin K2 is transcription
regulator od specific bone
genes, functioning using SXR
which will lead to increase of
osteoblastic markers
expression.
SXR originally identifies as
xenobiotic sensor…
Recommended therapy of
osteporosis
99m-Technetium-
hydroxymethylene
diphosphonate bone
scintigraphy. The scan is
typical for a bone
metabolic disease, even
though, in theory, any foci
could correspond to a
primary bone tumor. The
FDG PET/CT study ruled
out the hypothesis.
Calcium deficiency in blood
Calcium overload in blood
Calcium, vitamin D, and parathyroid
hormone
 The active 1,25 dihydroxy vitamin D (calcitriol), is not
only necessary for optimal intestinal absorption of
calcium and phosphorus, but also exerts a tonic
inhibitory effect on parathyroid hormone (PTH)
synthesis, so that there are dual pathways that can
lead to secondary hyperparathyroidism.
 Vitamin D deficiency and secondary
hyperparathyroidism can contribute not only to
accelerated bone loss and increasing fragility, but
also to neuromuscular impairment that can increase
the risk of falls.
Calcium Deprivation Calcium Loading
Parathyroid hormone Secretion stimulated Secretion inhibited
Vitamin D
Production stimulated by increased
parathyroid hormone secretion
Synthesis suppressed due to low parathyroid hormone
secretion
Calcitonin Very low level secretion Secretion stimulated by high blood calcium
Intestinal absorption of calcium
Enhanced due to activity of vitamin D on
intestinal epithelial cells
Low basal uptake
Release of calcium and phosphate
from bone
Stimulated by increased parathyroid hormone
and vitamin D
Decreased due to low parathyroid hormone and
vitamin D
Renal excretion of calcium
Decreased due to enhanced tubular
reabsorption stimulated by elevated
parathyroid hormone and vitamin D;
hypocalcemia also activates calcium sensors
in loop of Henle to directly facilitate calcium
reabsorption
Elevated due to decreased parathyroid hormonestimulated
reabsorption.
Renal excretion of phosphate
Strongly stimulated by parathyroid hormone;
this phosphaturic activity prevents adverse
effects of elevated phosphate from bone
resorption
Decreased due to hypoparathyroidism
General Response
Typically see near normal serum
concentrations of calcium and phosphate due
to compensatory mechanisms. Long term
Low intestinal absorption and enhanced renal excretion
Hormonal calcium control systems
 Maintaining normal blood calcium and phosphorus
concentrations is managed through the concerted action
of three hormones that control fluxes of calcium in and out
of blood and extracellular fluid:
 Parathyroid hormone serves to increase blood
concentrations of calcium.
 Mechanistically, parathyroid hormone preserves blood
calcium by several major effects:
 Stimulates production of the biologically-active form of vitamin D
within the kidney.
 Facilitates mobilization of calcium and phosphate from bone. To
prevent detrimental increases in phosphate, parathyroid hormone
also has a potent effect on the kidney to eliminate phosphate
(phosphaturic effect).
 Maximizes tubular reabsorption of calcium within the kidney. This
activity results in minimal losses of calcium in urine.
Parathyroid hormone is released in response to low
extracellular concentrations of free calcium.
Changes in blood phosphate concentration can be
associated with changes in parathyroid hormone secretion,
but this appears to be an indirect effect and phosphate per se
is not a significant regulator of this hormone.
When calcium concentrations fall below the normal range,
there is a steep increase in secretion of parathyroid hormone.
Low levels of the hormone are secreted even when blood
calcium levels are high. The figure to the right depicts
parathyroid hormone release from cells cultured in vitro in
differing concentrations of calcium.
The parathyroid cell monitors extracellular free calcium
concentration via an integral membrane protein that functions
as a calcium-sensing receptor.
Control of parathyroid hormone secretion
Disease states due to hyperathyroidism-
osteodystrophies
 (Both increased and decreased secretion of
parathyroid hormone are recognized as causes of
serious disease in man).
 Excessive secretion of parathyroid hormone is seen
in two forms:
 Primary hyperparathyroidism is the result of
parathyroid gland disease, most commonly due to
a parathyroid tumor (adenoma) which secretes the
hormone without proper regulation. Common
manifestations of this disorder are chronic
elevations of blood calcium concentration
(hypercalcemia), kidney stones and remodelation
of bone.
Disease states due to hyperathyroidism- renal
osteodystrophy
 Secondary hyperparathyroidism is the situation
where disease outside of the parathyroid gland
leads to excessive secretion of parathyroid
hormone. A common cause of this disorder is
kidney disease - if the kidneys are unable to
reabsorb calcium, blood calcium levels will fall,
stimulating continual secretion of parathyroid
hormone to maintain normal calcium levels in
blood. Secondary hyperparathyroidism can also
result from inadequate nutrition - for example, diets
that are deficient in calcium or vitamin D, or which
contain excessive phosphorus (e.g. all meat diets
for carnivores). A prominent effect of secondary
hyperparathyroidism is remodelation of bone,
leading to pathologic fractures or "rubber bones".
Disease states due to hypoparathyroidism
 Inadequate production of parathyroid hormone hypoparathyroidism
- typically results in decreased
concentrations of calcium and increased
concentrations of phosphorus in blood.
 Common causes of this disorder include surgical
removal of the parathyroid glands and disease
processes that lead to destruction of parathyroid
glands. The resulting hypocalcemia often leads to
tetany and convulsions, and can be acutely lifethreatening.
Treatment focuses on restoring normal
blood calcium concentrations by calcium infusions,
oral calcium supplements and vitamin D therapy.
Vitamin D (Calcitriol)
 Bioactive vitamin D or calcitriol is a steroid
hormone that has long been known for its
important role in regulating body levels of
calcium and phosphorus, and in
mineralization of bone.
 This hormone has biologic effects which
extend far beyond control of mineral
metabolism.
Vitamin D- synthesis
Non-enzymatic reaction in the skin
Transport to liver
UV radiation 270 – 300 nm
Fotolýza
(trvá asi 12 dní)
Liver Kidneys
Inactive form
Copyright ©2006 American Society for Clinical Investigation
Holick, M. F. J. Clin. Invest. 2006;116:2062-2072
Vitamin D Receptor Binding and Interactions with
DNA
 Being lipids, steroid hormones enter the cell
by simple diffusion across the plasma
membrane. The receptors exist either in the
cytoplasm or nucleus, which is where they
meet the hormone. When hormone binds to
receptor, a characteristic series of events
occurs:
 Receptor activation is the term used to
describe conformational changes in the
receptor induced by binding hormone. The
major consequence of activation is that the
receptor becomes competent to bind DNA.
Vitamin D at the level of DNA
Vitamin D Receptor Binding and
Interactions with DNA
 Activated receptors bind to "hormone
response elements", which are short
specific sequences of DNA which are
located in promoters of hormoneresponsive
genes. In most cases, hormonereceptor
complexes bind DNA in pairs, as
shown in the figure below.
 Transcription from those genes to which
the receptor is bound is affected. Most
commonly, receptor binding stimulates tor
inhibits transcription of different genes. The
hormone-receptor complex thus functions
as a transcription factor.
Nuclear receptor function
Regulation of gene expression by VDR
The vitamin D receptor and mechanism of action
 The vitamin D receptor forms a complex with
another intracellular receptor, the retinoid-X
receptor, and that heterodimer is what binds to
DNA. In most cases studied, the effect is to
activate transcription, but situations are also
known in which vitamin D suppresses
transcription.
 The vitamin D receptor binds several forms of
cholecalciferol. Its affinity for 1,25dihydroxycholecalciferol
is roughly 1000 times
that for 25-hydroxycholecalciferol, which explains
their relative biological potencies.
Vitamin D deficiency
 The classical manifestations of vitamin D deficiency are rickets,
which are seen in children and results in bony deformabilitieas
including bowed long bones.
 Deficiency in adults leads to the osteomalacia. Both rickets
and osteomalacia reflect impaired formation of newly
synthesized bone matrix, and usually result from a combination
of inadequate exposure to sunlight and decreased dietary
intake of vitamin D.
 Vitamin D deficiency or insufficiency occurs in several other
situations, which you might predict based on the synthetic
pathway described above:
 Genetic defects in the vitamin D receptor: a number of
different mutations have been identified in humans that lead
to hereditary vitamin D resistance.
 Severe skin, liver or kidney disease: this can interfere with
generation of the biologically active form of vitamin D.
 Insufficient exposure to sunlight: Elderly people that stay inside
and have poor diets often have at least subclinical deficiency.
Osteomalacia and rickets
 Classically, the deficiency of vitamin D,
essential for the absorption of calcium,
has been the major cause of rickets in
the child and osteomalacia in the adult
resulting in absence or delay in the
mineralization of growth cartilage or
newly formed bone collagen.
Osteomalacia and rickets
 As a consequence of a low serum phosphate
and normal serum calcium.
 Two such conditions are x-linked
hypophosphatemic rickets/osteomalacia
and oncogenic osteomalacia.
 When present, the signs of rickets and
osteomalacia in the low serum phosphate
states are indistinguishable from the classic
hypocalcemic states.
Differential diagnosis of hypophosphatemic
rickets in children
VDRR Proximal RTA Dent's disease
Gender Both Both Male
Ser. phosphate Low Low Low
Ser. calcium Normal Low Normal
Calcitriol levels Normal/low Low Normal/Mild high
Hypercalciuria No No Yes
Nephrocalcinosis No No Yes
Ser. PTH Normal/mild high High Normal
VDRR = Vitamin-D resistant rickets; RTA = Renal tubular acidosis;
PTH = Parathormone
Vitamin D deficiency
 Sunscreens, especially those with SPF
ratings greater than 8, effectively block
synthesis of vitamin D in the skin.
 Vitamin D toxicity:
 Excessive exposure to sunlight does not
lead to overproduction of vitamin D.
 Vitamin D toxicity is inevitably the result
of overdosing on vitamin D
supplements. Ingestion of milligram
quantities of vitamin D over periods of
weeks of months can be severely toxic
to humans and animals.
Heritability of vitamin D insufficiency
 2 GWASy – 3 polymorphic areas
 4p12- GC gene(rs2282679)
 11q12- DHCR7/NADSYN1 (rs2211q12)-7dehydrocholesterol
reduktase/NAD
synthetase 1
 11p15-CYP2R1 (rs10741657)-cytochrom
P450, subfamily IIR
 1-4% of the whole variance of serum
25(OH)D3 levels
Vitamin D and health
Deficit and insufficincy of vitamin D = global healthy problem.
High risk for acute and chronic disease, as
 Infection diseases
 Autoimmune diseases
 DM type I and II
 High risk of atherosclerosis
 Some tumor types (colorectal carcinoma, breast and prostate
cancer, ovarial cancer)
 Cognitive dysfunction
 Infertility
 Gravidity and around delivery complications
Pludowski P et al. Vitamin D effects on musculoskeletal health, immunity,
autoimmunity, cardiovascular disease, cancer, fertility, pregnancy,
dementia and mortality—A review of recent evidence, Autoimmunity
Reviews, Volume 12, Issue 10, August 2013, Pages 976-989
Insufficiency of vitamin D
 Can be recognised in a half of „healthy“
adults in developped countries.
 Vitamin D levels in the winter seems to be
too low in latitude more than 35° without
supplementation by sunshine and diet
 High heritability - to 53% - important
influence of gene polymorphisms
(SUNLIGHT consortium – Study of
Underlying Genetic Determinants of
Vitamin D and Highly Related Traits, based
2008)
Calcitonin
 Calcitonin is a hormone known to participate in calcium
and phosphorus metabolism. It main role is to increase
calcium deposition in bones.
 In mammals, the major source of calcitonin is from the
parafollicular or C cells in the thyroid gland, but it is also
synthesized in a wide variety of other tissues, including
the lung and intestinal tract.
 Calcitonin is a 32 amino acid peptide cleaved from a
larger prohormone. It contains a single disulfide bond,
which causes the amino terminus to assume the shape of
a ring.
 Alternative splicing of the calcitonin pre-mRNA can yield
a mRNA encoding calcitonin gene-related peptide; that
peptide appears to function in the nervous and vascular
systems. The calcitonin receptor has been cloned and
shown to be a member of the seven-transmembrane, G
protein-coupled receptor family.
Control of calcitonin secretion
 The most prominent factor controlling
calcitonin secretion is the extracellular
concentration of ionized calcium.
 Elevated blood calcium levels strongly
stimulate calcitonin secretion, and
secretion is suppressed when calcium
concentration falls below normal.
 A number of other hormones have been
shown to stimulate calcitonin release in
certain situations, and nervous controls
also have been demonstrated.
Cytokines, prostaglandins, NO, and leukotrienes
 There is evidence that polymorphisms of IL-1, IL-6, TNF- , and
their receptors can influence bone mass in humans.
 Prostaglandins have both stimulatory and inhibitory actions;
the predominant effect of PGE2, which is the major
prostaglandin produced by bone cells, is to stimulate both
resorption and formation.
 Prostaglandins, particularly PGE2, are produced by bone cells
largely through the action of inducible cyclooxygenase 2
(COX2). COX2 is induced by most of the factors that stimulate
bone resorption and thus may enhance the response to these
agents. Treatment with COX inhibitors blunts the response to
impact loading and fluid shear stress, indicating that
prostaglandins play an important role in the response on
mechanical forces, and this may be enhanced by estrogen. In
epidemiologic studies, small increases in BMD and decreases
in fracture risk have been reported in individuals using NSAIDS.
Cytokines, prostaglandins, NO, and
leukotrienes
 NO is produced by bone cells and is a
cofactor for the anabolic response to
mechanical loading. However, unlike
prostaglandins, NO may inhibit bone
resorption, perhaps by increasing OPG
production.
 Leukotrienes, the products of lipoxygenase,
can affect bone by stimulating resorption
and inhibiting formation.
Collagen abnormalities
 A polymorphism of the first intron of the gene
coding for the type I collagen 1 chain and
increased levels of homocysteine can
influence fracture risk independent of BMD
(bone mass density). This may be due to
differences in helix formation or cross-linking
of collagen, challenging the concept that
mineral and matrix composition are normal in
osteoporosis and that only structural
abnormalities account for skeletal fragility.
Gene Mutation Disease
RANK
18 bp duplication Familial expansile osteolysis
27 bp duplication Early onset Paget’s disease
15 bp duplication
Expansile skeletal
hyperphosphatasia
RANKL
Deletion of amino acids 145-177
Autosomal recessive
osteopetrosis
A single nucleotide change (596T-A) in exon 8 of
both alleles
Autosomal recessive
osteopetrosis
Deletion of two nucleotides (828_829delCG)
Autosomal recessive
osteopetrosis
OPG Deletion making OPG inactive Juvenile Paget’s disease
20 bp deletion resulting in premature termination of
OPG translation
Juvenile Paget’s disease
X-linked hypophosphatemic osteomalacia
 The condition is characterized by low
tubular reabsorption of phosphate in
the absence of secondary
hyperparathyroidism.
 X-linked hypophosphatemia occurs in
about 1 in 25,000 and is considered the
most common form of genetically
induced rickets.
Oncogenic osteomalacia
 Oncogenic osteomalacia is a
paraneoplastic syndrome in which a
bone or soft tissue tumor or tumor-like
lesion induces hypophosphatemia and
low vitamin D levels that reverse when
the inciting lesion is resected.
Oncogenic osteomalacia
 In the past 15 or so years, a humoral factor,
phosphotonin, has been identified in clinical and
experimental studies as being responsible for the serum
biochemical changes.
 Phosphotonin causes hyperphosphaturia by inhibiting
the reabsorption of phosphate by the proximal renal
tubules.
 Fibroblast growth factor 23, phosphate-regulating
gene with homologies to endopeptides located on
the ‘x’ chromosome (PHEX) and matrix extracellular
phosphoglycoprotein (MEPE) are candidates
proposed for the production of phosphatonin and the
altered pathophysiology in oncogenic osteomalacia.
Oncogenic osteomalacia or tumor-induced
osteomalacia (TIO)
 To date, more than 160 cases have
been reported. Due to this relative
rarity, its diagnosis is usually delayed by
months or years.
 TIO combines severe
hypophosphatemia,
hyperphosphaturia, very low plasma
1,25-(OH)2 vitamin D levels and severe
osteomalacia.
Parathyroid Hormone Relation Peptide (PTHrP)
 PTHrP was discoverded as mediator of syndrome "humoral
hypercalcemia of malignancy" (HHM).
 During the syndrome inn different type of cancer (in
absebce of metastases) similar compounds to PTH are
produceds which is related to:
 Hypercalcemia
 Hypophosphatemia
 Increased cAMP exctretion by urine
 The effects are similar to those caused by PTH; no PTH
levels are detected.
Genetic families of PTH and PTHrP: PTHrP, PTH and TIP39
are probably members of the same fgenetic family.
Their receptors PTH1R and PTH2R are 7 transmembrane
G protein-coupled receptors.
Production of PTHrP regulated by growth factor (GF) in tumor states. Tumor cells
are able to be stimulated at a distance (outside the bone) by autocrine
growth factors to an increased production of PTHrP. It reaches via circulation
the bone tissue and supports bone resorption. Metastatic tumor cells in the
bone are able to secrete PTHrP supporting bone resorption and paracrine
growth factors which further support PTHrP production.
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