Metabolic bone disease

BONE METABOLISM ANDBONE METABOLISM AND
SOME METABOLIC BONESOME METABOLIC BONE
DISEASESDISEASES
BYBY
PROF. / MOUSTAFA RIZKPROF. / MOUSTAFA RIZK
CLINICAL PATHOLOGY DEPAR.
ALEX UNIVERSITY

Outline
Normal bone structure
Normal calcium/phosphate
metabolism
Presentation and investigation of
bone metabolism disorders
Common diseases of bone
metabolism

Normal Bone Structure
What are the normal types of bone in the
mature skeleton?
1-Lamellar
Cortical in long bones
Cancellous in vertebrae
2-Woven
Immature
Healing
Pathological

What is the composition of
the bone
A-The matrixA-The matrix
1-40% organic:1-40% organic:
type 1 collagen(tensil strength)type 1 collagen(tensil strength)
Proteoglycans(compressive stre.)Proteoglycans(compressive stre.)
osteocalcin,osteopontinosteocalcin,osteopontin
growth factors/cytokinesgrowth factors/cytokines
2-60% inorganic2-60% inorganic
calcium hydroxyapatitecalcium hydroxyapatite
Amorphous calcium phosphateAmorphous calcium phosphate

What is the composition ofWhat is the composition of
the bonethe bone
B- The cellsB- The cells
OsteoclastOsteoclast
OsteoblastOsteoblast
OsteocyteOsteocyte
Progenitor cellsProgenitor cells
Endothelial cellsEndothelial cells
Haematopoitic cellsHaematopoitic cells

Bone turnover
How does normal bone remodel ?
Old bone is first resorbed and new bone then deposited
through the effect of humoral circulating factors or by
Local factors derived from bone cells or bone matrix.
In cancellous bones the number of the basic multi-
-cellular unit(BMU) which is responciple for remodelling
are of higher number due to large surface area to
volume (this is responciple for the trabecular pattern)

Factors affecting bone turnoverFactors affecting bone turnover
 Other hormonesOther hormones
 OestrogenOestrogen
 gut - increased absorptiongut - increased absorption
 bone - decreased re-absorptionbone - decreased re-absorption
 GlucocorticoidsGlucocorticoids
 gut - decrease absorptiongut - decrease absorption
 bone - increased re-absorption/decreasedbone - increased re-absorption/decreased
formationformation
 ThyroxineThyroxine
 stimulates formation/resorptionstimulates formation/resorption
 net resorptionnet resorption

 Local factorsLocal factors
 I-LGF 1 (somatomedin C)I-LGF 1 (somatomedin C)
 increased osteoblast prolifnincreased osteoblast prolifn
 TGFTGF
 increased osteoblast activityincreased osteoblast activity
 IL-1/OAFIL-1/OAF
 increased osteoclast activity (myeloma)increased osteoclast activity (myeloma)
 PG’sPG’s
 increased bone turnover (#’s/inflammn)increased bone turnover (#’s/inflammn)
 BMPBMP
 bone formationbone formation

 Other factorsOther factors
 Local stressesLocal stresses
 Electrical stimulnElectrical stimuln
 EnvironmentalEnvironmental
 temptemp
 oxygen levelsoxygen levels
 acid/base balanceacid/base balance

Calcium BiologicalCalcium Biological
FunctionsFunctions About 99% of our body's calcium is deposited in theAbout 99% of our body's calcium is deposited in the
bones and teeth, the remaining 1% in body fluids.bones and teeth, the remaining 1% in body fluids.
 There are about 180 different known uses for calciumThere are about 180 different known uses for calcium
in the human body as:in the human body as:
11-Calcium controls muscle contraction and relaxation.-Calcium controls muscle contraction and relaxation.
22-Responsible for nerve impulse transmission.-Responsible for nerve impulse transmission.
33-Transfer of information between our brain cells.-Transfer of information between our brain cells.
44-Calcium controls osmosis and diffusion through the-Calcium controls osmosis and diffusion through the
cell membranes.cell membranes.
55-Passing of information within the cell.-Passing of information within the cell.

Calcium BiologicalCalcium Biological
FunctionsFunctions
 66-Calcium controls the rhythm of the heart.-Calcium controls the rhythm of the heart.
77-The formation of enzymes , hormones and-The formation of enzymes , hormones and
also the DNA formation in chromosomes.also the DNA formation in chromosomes. 88--
Calcium is used in blood clotting.Calcium is used in blood clotting.
99-And of course in the-And of course in the formation andformation and
maintenance of the bonesmaintenance of the bones and teeth.and teeth.
1010-And perhaps, Calcium is the main buffer-And perhaps, Calcium is the main buffer
used in the body to neutralize acids and toused in the body to neutralize acids and to
maintain the proper pH.maintain the proper pH.

CALCIUM HOMEOSTASISCALCIUM HOMEOSTASIS

CALCIUM HOMEOSTASISCALCIUM HOMEOSTASIS
Approximately 500 mg of calcium are removedApproximately 500 mg of calcium are removed
from the bones daily and replaced by an equalfrom the bones daily and replaced by an equal
amount.amount.
Normally, the amount of calcium absorbed byNormally, the amount of calcium absorbed by
the intestines is matched by urinary calciumthe intestines is matched by urinary calcium
excretion.excretion.
Despite these enormous fluxes of calcium, theDespite these enormous fluxes of calcium, the
levels of ionized calcium remainlevels of ionized calcium remain stablestable becausebecause
of the rigid control of parathyroid hormone (PTH)of the rigid control of parathyroid hormone (PTH)
and vitamin D levels.and vitamin D levels.

Metabolic systems thatMetabolic systems that
maintain calcium homeostasismaintain calcium homeostasis

Ionized Calcium(Active FormIonized Calcium(Active Form((
Ionic CalciumIonic Calcium is the only physiologically active form ofis the only physiologically active form of
Calcium.Calcium.
- Bone serves as a- Bone serves as a storagestorage deposit for ionic calcium ,thedeposit for ionic calcium ,the
protein-bound calcium of the blood is thought to serve asprotein-bound calcium of the blood is thought to serve as
aa secondarysecondary reservoir, becoming available locally onlyreservoir, becoming available locally only
during excessive loss or use of ionic calcium.during excessive loss or use of ionic calcium.
- Because ionic calcium is the only physiologically usable- Because ionic calcium is the only physiologically usable
form of calcium, calcium from all sources, whether fromform of calcium, calcium from all sources, whether from
diet or from the bones, organs, and tissues, must bediet or from the bones, organs, and tissues, must be
broken downbroken down into ionic form before it can be utilized byinto ionic form before it can be utilized by
the body for any of the 180 biological functions.the body for any of the 180 biological functions.

BONE AS A STORAGEBONE AS A STORAGE
DEPOSIT FOR IONICDEPOSIT FOR IONIC
CALCIUMCALCIUM

Calcium metabolismCalcium metabolism
 There are multiple entities involved in theThere are multiple entities involved in the
metabolism of calcium:metabolism of calcium:
11- Hormones as parathyroid (PTH), calcitonin ,- Hormones as parathyroid (PTH), calcitonin ,
1,25-dihydroxycholecalciferol ( a biologically1,25-dihydroxycholecalciferol ( a biologically
active form of vitamin D3).active form of vitamin D3).
22-The intestine, kidney, liver, thyroid gland,-The intestine, kidney, liver, thyroid gland,
parathyroid gland, and, of course, bone.parathyroid gland, and, of course, bone.
Each plays one or more roles in the metabolismEach plays one or more roles in the metabolism
and bone formation/resorption.and bone formation/resorption.

ROLE OF VITAMIN D ONROLE OF VITAMIN D ON
CALCIUM ABSORPTIONCALCIUM ABSORPTION
 Calcium needs someCalcium needs some assistance to crossassistance to cross
through cell membranes. While very smallthrough cell membranes. While very small
amounts of calcium can be absorbed throughamounts of calcium can be absorbed through
cellular membranes throughout the smallcellular membranes throughout the small
intestine,intestine, 1,25-DHCC1,25-DHCC enables the calciumenables the calcium
absorption across the membranes of theabsorption across the membranes of the
duodenum.duodenum.
Fusion absorption, that done without theFusion absorption, that done without the
assistance of 1,25-DHCC, is not nearly asassistance of 1,25-DHCC, is not nearly as
effective in maintaining proper calcium levels aseffective in maintaining proper calcium levels as
is calcium absorbed with that form of vitamin D.is calcium absorbed with that form of vitamin D.

 Normal metabolismNormal metabolism
Vit DVit D
25-HCC (Liver)25-HCC (Liver)
Ca/PTHCa/PTH
1,25-DHCC 24,25-DHCC1,25-DHCC 24,25-DHCC
(Kidney) (Kidney)(Kidney) (Kidney)

ROLE OF VITAMIN D ONROLE OF VITAMIN D ON
CALCIUM ABSORPTIONCALCIUM ABSORPTION

Calcium AbsorptionCalcium Absorption
 Calcium absorption is also affected by the degree to which it isCalcium absorption is also affected by the degree to which it is
soluble and thus usable.soluble and thus usable.
11-Acidic levels of the ingested food, and the presence of-Acidic levels of the ingested food, and the presence of
substances such assubstances such as oxalatesoxalates (found in spinach, and to a lesser(found in spinach, and to a lesser
extent in carrots) binds the calcium, rendering it unusable.extent in carrots) binds the calcium, rendering it unusable.
22-Diets high in-Diets high in fatfat relative to the levels consumed in the wild, canrelative to the levels consumed in the wild, can
impede calcium absorption; faulty fat metabolism can adverselyimpede calcium absorption; faulty fat metabolism can adversely
affect the metabolism ofaffect the metabolism of vitamin Dvitamin D..
Diets high in oxalates or fats, in other words, both lead toDiets high in oxalates or fats, in other words, both lead to
metabolic bone disease, coming by different routes.metabolic bone disease, coming by different routes.

DISORDERS OF CALCIUMDISORDERS OF CALCIUM
MATABOLISMMATABOLISM
1-HYPOCALCEMIA1-HYPOCALCEMIA
2-HYPERCALCEMIA2-HYPERCALCEMIA

HYPOCALCEMIAHYPOCALCEMIA
At a plasma pH of 7.4, each gram of albumin binds
0.8 mg of calcium. This bond is dependent on
the carboxyl groups of albumin and is highly
dependent on pH.
Acute acidemia decreases calcium binding to
albumin, whereas alkalemia increases binding,
which decreases ionized calcium.
Clinical signs and symptoms are observed only
with decreases in ionized calcium concentration
(normally 4.5-5.5 mg/dL )

Hypocalcemia causes neuromuscularHypocalcemia causes neuromuscular
irritability and tetany.irritability and tetany.
Alkalemia inducesAlkalemia induces tetanytetany due to adue to a
decrease in ionized calcium, whereasdecrease in ionized calcium, whereas
acidemia isacidemia is protectiveprotective..
This pathophysiology is important inThis pathophysiology is important in
patients with renal failure who havepatients with renal failure who have
hypocalcemia because of rapid correctionhypocalcemia because of rapid correction
of acidemia or development of alkalemiaof acidemia or development of alkalemia

Calcium sensing receptorsCalcium sensing receptors
Normocalcemia requires PTH and normal target-Normocalcemia requires PTH and normal target-
organ response to PTH.organ response to PTH.
--The parathyroid gland has a remarkableThe parathyroid gland has a remarkable
sensitivity to ionized serum calcium changes.sensitivity to ionized serum calcium changes.
--These changes are recognized by theThese changes are recognized by the calcium-calcium-
sensing receptor (CaSR),sensing receptor (CaSR), a 7-transmembranea 7-transmembrane
receptor linked to G-protein with a largereceptor linked to G-protein with a large
extracellular amino-terminal region.extracellular amino-terminal region.
--Binding of calcium to the CaSRBinding of calcium to the CaSR
inducesinduces inhibitioninhibition of PTH secretion.of PTH secretion.

Calcium sensing receptorsCalcium sensing receptors
On the other hand, a slight decrease inOn the other hand, a slight decrease in
calcium stimulates the chief cells of thecalcium stimulates the chief cells of the
parathyroid gland to secrete PTH.parathyroid gland to secrete PTH.
CaSR is crucial in PTH secretionCaSR is crucial in PTH secretion
A loss of CaSR function leads toA loss of CaSR function leads to
pathological states, such as familialpathological states, such as familial
hypocalciuric hypercalcemia and neonatalhypocalciuric hypercalcemia and neonatal
severe hyperparathyroidismsevere hyperparathyroidism

Patients with a decreased total serumPatients with a decreased total serum
calcium may not have "calcium may not have "truetrue" hypocalcemia" hypocalcemia
which is defined as a decrease in ionizedwhich is defined as a decrease in ionized
calcium.calcium.
A reduced total serum calcium can resultA reduced total serum calcium can result
from a decrease infrom a decrease in albuminalbumin secondary tosecondary to
liver disease, nephrotic syndrome, orliver disease, nephrotic syndrome, or
malnutrition.malnutrition.

Once laboratory resultsOnce laboratory results
demonstrate hypocalcemia, thedemonstrate hypocalcemia, the
first question is whether thefirst question is whether the
hypocalcemia is true, ie,hypocalcemia is true, ie,
representative ofrepresentative of a decrease ina decrease in
ionized calciumionized calcium

The presence of chronic diarrhea orThe presence of chronic diarrhea or
intestinal disease, such as is observedintestinal disease, such as is observed
with Crohn disease, sprue, or chronicwith Crohn disease, sprue, or chronic
pancreatitis, suggests the possibility ofpancreatitis, suggests the possibility of
hypocalcemia due tohypocalcemia due to malabsorptionmalabsorption ofof
calcium and/or vitamin D.calcium and/or vitamin D.

PreviousPrevious neck surgeryneck surgery suggestssuggests
hypoparathyroidism; a history of seizureshypoparathyroidism; a history of seizures
suggests hypocalcemia secondary tosuggests hypocalcemia secondary to
anticonvulsants.anticonvulsants.

TheThe length of timelength of time that a disorder is presentthat a disorder is present
is an important clue. Hypoparathyroidismis an important clue. Hypoparathyroidism
and pseudohypoparathyroidism areand pseudohypoparathyroidism are
lifelong disorders. Instead, acute transientlifelong disorders. Instead, acute transient
hypocalcemia may be associated withhypocalcemia may be associated with
acute gastrointestinal illness, nutritionalacute gastrointestinal illness, nutritional
deficiency, or acute or chronic renaldeficiency, or acute or chronic renal
failure.failure.

 Severe hypomagnesemiaSevere hypomagnesemia can lead tocan lead to
hypocalcemia, despite the presence of a positivehypocalcemia, despite the presence of a positive
calcium balance. The hypocalcemia is resistantcalcium balance. The hypocalcemia is resistant
to administration of calcium and vitamin D.to administration of calcium and vitamin D.
Restoration of the calcium levels can occurRestoration of the calcium levels can occur onlyonly
after the magnesium deficiency is corrected.after the magnesium deficiency is corrected.
These patients present withThese patients present with low orlow or
inappropriately normal PTHinappropriately normal PTH levels in thelevels in the
presence of hypocalcemia.presence of hypocalcemia.

 The mechanisms for hypocalcemia includeThe mechanisms for hypocalcemia include
resistance to PTH in bone and kidneys, asresistance to PTH in bone and kidneys, as
well as a decrease in PTH secretion.well as a decrease in PTH secretion.
Acute magnesium restoration rapidlyAcute magnesium restoration rapidly
corrects the PTH level, suggesting thatcorrects the PTH level, suggesting that
hypomagnesemia affects the releasehypomagnesemia affects the release ofof
PTH, rather than its synthesisPTH, rather than its synthesis

The causes of hypocalcemia can beThe causes of hypocalcemia can be
grouped intogrouped into 44 major categories:major categories:
1-PTH-related1-PTH-related
2-Vitamin D deficiency2-Vitamin D deficiency
3-Drugs3-Drugs
4-Miscellaneous disorders.4-Miscellaneous disorders.

PTH DEFIENCIESPTH DEFIENCIES
Decreased secretionDecreased secretion
(hypoparathyroidism) or(hypoparathyroidism) or
resistance to the effects of PTHresistance to the effects of PTH
can cause PTH deficiencies.can cause PTH deficiencies.

HypoparathyroidismHypoparathyroidism
This condition can be hereditary or acquired.This condition can be hereditary or acquired.
AcquiredAcquired hypoparathyroidism may result from :hypoparathyroidism may result from :
11-Surgical removal of parathyroid glands .-Surgical removal of parathyroid glands . 22--
Compromise of the blood supply to the glandsCompromise of the blood supply to the glands
from postsurgical fibrosis .from postsurgical fibrosis .
33-Treatment with radioiodine.-Treatment with radioiodine.
44-Metastatic malignant infiltration of the glands.-Metastatic malignant infiltration of the glands.
55-Overload of copper or iron.-Overload of copper or iron.
66-Amyloidosis, or granulomatous disease.-Amyloidosis, or granulomatous disease.

HypoparathyroidismHypoparathyroidism
HereditaryHereditary oror idiopathicidiopathic hypoparathyroidism may be familial orhypoparathyroidism may be familial or
sporadic, can occur as an isolated entity, or typically can besporadic, can occur as an isolated entity, or typically can be
associated with other endocrine manifestations.associated with other endocrine manifestations.
1-The1-The familialfamilial forms include autosomal dominant and autosomalforms include autosomal dominant and autosomal
recessive, as well as a sex-linked form of early onset, for which therecessive, as well as a sex-linked form of early onset, for which the
gene has been located on the long arm of the X chromosome.gene has been located on the long arm of the X chromosome.
2-2-SporadicSporadic hypoparathyroidism includes late-onsethypoparathyroidism includes late-onset
hypoparathyroidism associated withhypoparathyroidism associated with DiGeorgeDiGeorge syndrome, whichsyndrome, which
also is associated with congenital heart disease, cleft palate/lip, andalso is associated with congenital heart disease, cleft palate/lip, and
abnormal facies.abnormal facies.
Late-onset hypoparathyroidism can be observed in other congenitalLate-onset hypoparathyroidism can be observed in other congenital
abnormalities or as part of a complex autoimmune disorder involvingabnormalities or as part of a complex autoimmune disorder involving
ovarian failure, adrenal failure, and parathyroid failure which isovarian failure, adrenal failure, and parathyroid failure which is
termedtermed polyglandular autoimmune disease (PGA type I)polyglandular autoimmune disease (PGA type I)

PseudohypoparathyroidismPseudohypoparathyroidism
This condition is characterized by end-organThis condition is characterized by end-organ
resistance to the effects of PTH.resistance to the effects of PTH.
PTH binds to the PTH receptor, which, in turn,PTH binds to the PTH receptor, which, in turn,
activates cyclic adenosine monophosphateactivates cyclic adenosine monophosphate
(cAMP) through guanine nucleotide regulatory(cAMP) through guanine nucleotide regulatory
proteins (Gs). These proteins consist of alpha,proteins (Gs). These proteins consist of alpha,
beta, and gamma subunits.beta, and gamma subunits.
Pseudohypoparathyroidism is classified intoPseudohypoparathyroidism is classified into
typestypes II andand IIII. Type I is further subdivided into Ia,. Type I is further subdivided into Ia,
Ib, and Ic.Ib, and Ic.

Type Ia results from a decrease in theType Ia results from a decrease in the Gs-alpha proteinGs-alpha protein..
In 1942, Albright et al described a disorder, known asIn 1942, Albright et al described a disorder, known as
Albright hereditary osteodystrophy (AHO),Albright hereditary osteodystrophy (AHO), comprised ofcomprised of
short stature, mental retardation, obesity, round-shapedshort stature, mental retardation, obesity, round-shaped
face, brachymetacarpia, brachymetatarsia, andface, brachymetacarpia, brachymetatarsia, and
subcutaneous bone formation.subcutaneous bone formation.
These somatic features of Albright hereditaryThese somatic features of Albright hereditary
osteodystrophy and the presence of the biochemicalosteodystrophy and the presence of the biochemical
features of pseudohypoparathyroidism constitute type Ia.features of pseudohypoparathyroidism constitute type Ia.

Laboratory findings include :Laboratory findings include :
11-Hypocalcemia, hyperphosphatemia (with-Hypocalcemia, hyperphosphatemia (with
normal or high PTHnormal or high PTH levels).levels).
22-Low calcitriol, Vitamin D may be decreased-Low calcitriol, Vitamin D may be decreased
because of inhibition by elevated levels ofbecause of inhibition by elevated levels of
phosphorus and by decreased PTH stimulationphosphorus and by decreased PTH stimulation
of the 25-hydroxyvitamin D 1-alpha-hydroxylase.of the 25-hydroxyvitamin D 1-alpha-hydroxylase.
The low calcitriol levels, in turn, may cause theThe low calcitriol levels, in turn, may cause the
resistance to the hypercalcemic effects of PTHresistance to the hypercalcemic effects of PTH
in bone.in bone.

The defect of the Gs-alpha protein is not confinedThe defect of the Gs-alpha protein is not confined
to the effects of PTH but also affects otherto the effects of PTH but also affects other
hormonal systems (eg, resistance to glucagon,hormonal systems (eg, resistance to glucagon,
thyroid-stimulating hormone, gonadotropins).thyroid-stimulating hormone, gonadotropins).
The gene for the Gs-alpha protein is located onThe gene for the Gs-alpha protein is located on
chromosomechromosome 2020..
Some family members carry the mutation andSome family members carry the mutation and
display the AHO phenotype but do not havedisplay the AHO phenotype but do not have
pseudohypoparathyroidism. This is termedpseudohypoparathyroidism. This is termed
pseudo-pseudohypoparathyroidism.pseudo-pseudohypoparathyroidism.

TypeType IbIb::
These patients do not present with theThese patients do not present with the
somatic features of Albright hereditarysomatic features of Albright hereditary
osteodystrophy, have normal Gs-alphaosteodystrophy, have normal Gs-alpha
protein, with hormonal resistance to PTHprotein, with hormonal resistance to PTH
—an—an impaired cAMPimpaired cAMP response to PTH,response to PTH,
suggesting that the defect lies on thesuggesting that the defect lies on the
receptor.receptor.
At what level the receptor is affected is notAt what level the receptor is affected is not
yet clear.yet clear.

TypeType IcIc::
Patients with this type present withPatients with this type present with
resistance to multiple hormonal receptorsresistance to multiple hormonal receptors
but have normal Gs-alpha proteinbut have normal Gs-alpha protein
expression.expression.

TypeType IIII::
In patients with this type of pseudohypoparathyroidism,In patients with this type of pseudohypoparathyroidism,
PTH raises cAMP normally but fails to increase levels ofPTH raises cAMP normally but fails to increase levels of
serum calcium or urinary phosphate excretion,serum calcium or urinary phosphate excretion,
suggesting that the defect is located downstream of thesuggesting that the defect is located downstream of the
generation of cAMP.generation of cAMP.
If the patient presents withIf the patient presents with hypocalcemia,hypocalcemia,
hypophosphaturia, and elevated immunoreactivehypophosphaturia, and elevated immunoreactive
parathyroid hormone (iPTH) levelsparathyroid hormone (iPTH) levels, first rule out vitamin, first rule out vitamin
D deficiency, which has a similar presentation. InD deficiency, which has a similar presentation. In
patients with a vitamin D deficiency, all parameterspatients with a vitamin D deficiency, all parameters
return to normal after vitamin D administrationreturn to normal after vitamin D administration

HYPERCALCEMIAHYPERCALCEMIA
 Hypercalcemia is a disorder that most commonlyHypercalcemia is a disorder that most commonly
results fromresults from malignancy or primarymalignancy or primary
hyperparathyroidismhyperparathyroidism. Other causes of elevated. Other causes of elevated
calcium are less common and usually are notcalcium are less common and usually are not
considered until malignancy and parathyroidconsidered until malignancy and parathyroid
disease are ruled out.disease are ruled out.
 HypercalcemicHypercalcemic crisiscrisis does not have an exactdoes not have an exact
definition, although marked elevation of serumdefinition, although marked elevation of serum
calcium, usually more thancalcium, usually more than 14 mg/dL14 mg/dL, is, is
associated with acute signs and symptoms ofassociated with acute signs and symptoms of
hypercalcemia. Treatment of the elevatedhypercalcemia. Treatment of the elevated
calcium level may resolve the crisis.calcium level may resolve the crisis.

Measured versus correctedMeasured versus corrected
CaCa..
Hypercalcemia is defined as a serum calcium levelHypercalcemia is defined as a serum calcium level
greater thangreater than 10.510.5 mg/dL. Because calcium bindsmg/dL. Because calcium binds
to albumin and only the unbound (free) calciumto albumin and only the unbound (free) calcium
is biologically active, the serum level must beis biologically active, the serum level must be
adjusted for abnormal albumin levels. For everyadjusted for abnormal albumin levels. For every
1 g/dL drop in serum albumin below 4 g/dL,1 g/dL drop in serum albumin below 4 g/dL,
measured serum calcium decreases by 0.8measured serum calcium decreases by 0.8
mg/dL. Therefore, to correct for an albumin levelmg/dL. Therefore, to correct for an albumin level
of less than 4 g/dL, one should add 0.8 to theof less than 4 g/dL, one should add 0.8 to the
measured value of calcium for each 1-g/dLmeasured value of calcium for each 1-g/dL
decrease in albumindecrease in albumin

Measured versus correctedMeasured versus corrected
CaCa..
Without this correction, an abnormally highWithout this correction, an abnormally high
serum calcium level may appear to beserum calcium level may appear to be
normal.normal.
A patient with a serum calcium ofA patient with a serum calcium of 10.310.3
mg/dL but an albumin ofmg/dL but an albumin of 33 g/dL appears tog/dL appears to
have a normal serum calcium level.have a normal serum calcium level.
However, when corrected for the lowHowever, when corrected for the low
albumin, the real serum calcium value isalbumin, the real serum calcium value is
11.111.1 mg/dL (10.3 + 0.8), a more obviouslymg/dL (10.3 + 0.8), a more obviously
abnormal level.abnormal level.

PathophysiologyPathophysiology
Hypercalcemia affects nearly every organ systemHypercalcemia affects nearly every organ system
in the body, but it particularly affects thein the body, but it particularly affects the CNSCNS
andand kidneyskidneys..
11-Mild hypercalcemia may not produce any-Mild hypercalcemia may not produce any
symptoms.symptoms.
22-With modest hypercalcemia, most patients-With modest hypercalcemia, most patients
begin to feel fatigued.begin to feel fatigued.
33-With higher levels, patients may have anxiety,-With higher levels, patients may have anxiety,
depression, personality changes, and confusion.depression, personality changes, and confusion.
44-With very high levels, somnolence, coma, and-With very high levels, somnolence, coma, and
death may ensure. The CNS effects are thoughtdeath may ensure. The CNS effects are thought
to be due to the direct depressant effect ofto be due to the direct depressant effect of
hypercalcemia .hypercalcemia .

 Renal effects include nephrolithiasis from theRenal effects include nephrolithiasis from the
hypercalciuria. Distal renal tubular acidosis may behypercalciuria. Distal renal tubular acidosis may be
observed, and the increase in urine pH andobserved, and the increase in urine pH and
hypocitraturia also may contribute tohypocitraturia also may contribute to stone diseasestone disease..
Nephrogenic diabetes insipidus occurs from medullaryNephrogenic diabetes insipidus occurs from medullary
calcium deposition.calcium deposition.
 High calcium levels also affect the conducting system ofHigh calcium levels also affect the conducting system of
the heart and cause cardiac arrhythmias.the heart and cause cardiac arrhythmias.
 The GI manifestations of hypercalcemia includeThe GI manifestations of hypercalcemia include
anorexia, nausea, vomiting, and constipation.anorexia, nausea, vomiting, and constipation.
 Serum calcium levels greater thanSerum calcium levels greater than approximately 15approximately 15
mg/dL usually are considered to be a medicalmg/dL usually are considered to be a medical
emergency and must be treated aggressively.emergency and must be treated aggressively.

CausesCauses
 ApproximatelyApproximately 90%90% of cases of hypercalcemia are caused byof cases of hypercalcemia are caused by
malignancy or hyperparathyroidism. Of the cases due tomalignancy or hyperparathyroidism. Of the cases due to
malignancy, approximately 80% are due to bony metastases,malignancy, approximately 80% are due to bony metastases,
while the other 20% are due to PTHrP effects.while the other 20% are due to PTHrP effects.
 The remainingThe remaining 10%10% of cases of hypercalcemia are caused byof cases of hypercalcemia are caused by
many different conditions, including vitamin D–related problems,many different conditions, including vitamin D–related problems,
disorders associated with rapid bone turnover, thiazides or renaldisorders associated with rapid bone turnover, thiazides or renal
failure, and, in rare cases, familial causes.failure, and, in rare cases, familial causes.
 Those related toThose related to malignancymalignancy (lung, breast, and myeloma are the(lung, breast, and myeloma are the
most common tumors)most common tumors)
 Those related to theThose related to the parathyroidparathyroid include the following:include the following:
 Primary hyperparathyroidismPrimary hyperparathyroidism
 Familial cases of high PTHFamilial cases of high PTH
 Those related toThose related to vitamin Dvitamin D include the following:include the following:
 Vitamin D toxicityVitamin D toxicity
 Those related to high bone turnoveThose related to high bone turnove
 Renal failure (Renal failure (milk-alkali syndromemilk-alkali syndrome), triad of hypercalcaemia,), triad of hypercalcaemia,
metabolic alkalosis and renal insufficiencymetabolic alkalosis and renal insufficiency

Other causesOther causes
 Other causes related to particular mechanisms are as follows:Other causes related to particular mechanisms are as follows:
 Increased intestinal calcium absorptionIncreased intestinal calcium absorption
 Idiopathic infantile hypercalcemia (Williams syndrome)Idiopathic infantile hypercalcemia (Williams syndrome)
 Vitamin D intoxicationVitamin D intoxication
 Vitamin A intoxicationVitamin A intoxication
 Granulomatous disorders, eg, sarcoidosisGranulomatous disorders, eg, sarcoidosis
 Decreased renal calcium excretionDecreased renal calcium excretion
 HyperparathyroidismHyperparathyroidism
 Familial hypocalciuric hypercalcemiaFamilial hypocalciuric hypercalcemia
 Thiazide diureticsThiazide diuretics
 Increased bone resorptionIncreased bone resorption
 ImmobilizationImmobilization
 HyperparathyroidismHyperparathyroidism
 MalignancyMalignancy
 Mutations of the calcium-sensing receptorMutations of the calcium-sensing receptor
 Familial benign hypocalciuric hypercalcemiaFamilial benign hypocalciuric hypercalcemia
 Neonatal severe hyperparathyroidismNeonatal severe hyperparathyroidism
 Uncertain mechanismUncertain mechanism
 HypophosphatasiaHypophosphatasia
 Subcutaneous fat necrosisSubcutaneous fat necrosis
 Blue diaper syndromeBlue diaper syndrome
 Dietary phosphate deficiencyDietary phosphate deficiency

Routine Lab StudiesRoutine Lab Studies
 11-If calcium levels have been mildly elevated for-If calcium levels have been mildly elevated for
months or years, malignancy is anmonths or years, malignancy is an unlikelyunlikely
cause.cause.
22-Hypercalcemia from malignancy usually is-Hypercalcemia from malignancy usually is
rapidly progressiverapidly progressive; thus, rapidly rising calcium; thus, rapidly rising calcium
levels should increase suspicion of malignancy.levels should increase suspicion of malignancy.
Breast, lung, and kidney cancers should beBreast, lung, and kidney cancers should be
considered, as should multiple myeloma,considered, as should multiple myeloma,
lymphoma, and leukemia.lymphoma, and leukemia.

 33-Immunoreactive PTH and ionized calcium-Immunoreactive PTH and ionized calcium
should be simultaneously measured.should be simultaneously measured.
PTH levels should bePTH levels should be suppressedsuppressed inin
hypercalcemia; thus, the presence of normalhypercalcemia; thus, the presence of normal
PTH levels with elevated calcium levelsPTH levels with elevated calcium levels
suggests mild hyperparathyroidism.suggests mild hyperparathyroidism.
Hyperparathyroidism may be part of multipleHyperparathyroidism may be part of multiple
endocrine neoplasia type 1, ie, Wermerendocrine neoplasia type 1, ie, Wermer
syndromesyndrome

 44-Measurement of serum phosphate, alkaline-Measurement of serum phosphate, alkaline
phosphatase, serum chloride, serumphosphatase, serum chloride, serum
bicarbonate, and urinary calcium may be usefulbicarbonate, and urinary calcium may be useful
in some cases.in some cases.
55-Renal function should be evaluated and-Renal function should be evaluated and
thyroid-stimulating hormone should be checkedthyroid-stimulating hormone should be checked
to help rule out hyperthyroidism.to help rule out hyperthyroidism.
66-In rare cases, measurement of vitamin D and-In rare cases, measurement of vitamin D and
its metabolites and measurement of PTHrP mayits metabolites and measurement of PTHrP may
be necessary.be necessary.

APPROCH TOAPPROCH TO
HYPERCALCEMIAHYPERCALCEMIA

MARKERS OF BONEMARKERS OF BONE
METABOLISMMETABOLISM
AA- MARKERS OF- MARKERS OF BONE FORMATIONBONE FORMATION
1-OSTEOCALCIN1-OSTEOCALCIN
2-ALKALINE PHOSPHATASE2-ALKALINE PHOSPHATASE
3-PROCOLLAGEN PEPTIDES3-PROCOLLAGEN PEPTIDES
BB- MARKERS OF- MARKERS OF BONE RESORPTIONBONE RESORPTION
1-COLLAGEN CROSS LINKS1-COLLAGEN CROSS LINKS
2-TARTARATE RESISTENT ACID P2-TARTARATE RESISTENT ACID P

3-URINARY GALACTOSYL3-URINARY GALACTOSYL
HYDROXYLYSINHYDROXYLYSIN
4-URINARY HYDROXYPROLINE4-URINARY HYDROXYPROLINE

BONE METABOLICBONE METABOLIC
DISORDERSDISORDERS
22-OSTEOPOROSIS-OSTEOPOROSIS
33-OSTEOMALACIA-OSTEOMALACIA
44-PAGETS DISEASE-PAGETS DISEASE
11--RENAL OSTEODYSTROPHYRENAL OSTEODYSTROPHY

Renal osteodystrophyRenal osteodystrophy
Combination ofCombination of
 osteomalaciaosteomalacia
 secondary PTH incrsecondary PTH incr
 osteoporosis/sclerosisosteoporosis/sclerosis

CALCIUM METABOLISM INCALCIUM METABOLISM IN
KIDNEY FAILUREKIDNEY FAILURE

. In renal failure,. In renal failure, CaSR agonistsCaSR agonists suppress thesuppress the
progression of hyperparathyroidism andprogression of hyperparathyroidism and
parathyroid gland growth.parathyroid gland growth.

OSTEOPOROSISOSTEOPOROSIS
 Osteoporosis is a bone diseaseOsteoporosis is a bone disease
best described as "porous bones".best described as "porous bones".
Bones are living tissue, constantlyBones are living tissue, constantly
being rebuilt.being rebuilt.
With osteoporosis, the rate of boneWith osteoporosis, the rate of bone
loss is greater than that of boneloss is greater than that of bone
rebuilding, causing thin, porousrebuilding, causing thin, porous
bones that break easily.bones that break easily.

OsteoporosisOsteoporosis
 Definition?Definition?
 Decrease in bone mass per unit volumeDecrease in bone mass per unit volume
 Fragility (perfn of trabecular plates)Fragility (perfn of trabecular plates)
 Primary (post-menopausal/senile)Primary (post-menopausal/senile)
SecondarySecondary

Primary osteoporosisPrimary osteoporosis
Post-menopausalPost-menopausal
Aetiology?Aetiology?
 Menopausal loss 3% vs 0.3% previouslyMenopausal loss 3% vs 0.3% previously
 Loss of oestrogen - incr osteoclastic activityLoss of oestrogen - incr osteoclastic activity
Risk factors?Risk factors?
 RaceRace
 HeredityHeredity
 BuildBuild
 Early menopause/hysterectomyEarly menopause/hysterectomy
 Smoking/alcohol/drug abuseSmoking/alcohol/drug abuse
 Calcium intakeCalcium intake

Primary osteoporosisPrimary osteoporosis
SenileSenile
 7-8th decade steady loss of 0.5%7-8th decade steady loss of 0.5%
 physiological manifestation of agingphysiological manifestation of aging
Risk factors?Risk factors?
 Prolonged uncorrected post-menopausal lossProlonged uncorrected post-menopausal loss
 chronic illnesschronic illness
 urinary insuffurinary insuff
 muscle atrophymuscle atrophy
 diet def/lack of exposure to sun/mild osteomalaciadiet def/lack of exposure to sun/mild osteomalacia

Secondary OsteoporosisSecondary Osteoporosis
 Nutrition - scurvy, malnutr,malabsNutrition - scurvy, malnutr,malabs
 Endocrine - Hyper PTH, Cush, Gonad, ThyroidEndocrine - Hyper PTH, Cush, Gonad, Thyroid
 Drug induced - steroid, alcohol, smoking, phenytoinDrug induced - steroid, alcohol, smoking, phenytoin
 Malignancy , myeloma , leukaemiaMalignancy , myeloma , leukaemia
 Chronic disease - RA, TB, CRFChronic disease - RA, TB, CRF
 Idiopathic - juvenileIdiopathic - juvenile
 GeneticGenetic

OsteomalaciaOsteomalacia
 A softening of the bones in adults causedA softening of the bones in adults caused
by a failure of the normal calcificationby a failure of the normal calcification
-In children, the condition is called rickets and is usually caused
by a deficiency of vitamin D.
-Conditions that may result in osteomalacia include inadequate
dietary intake of vitamin D, inadequate exposure to sunlight , and
malabsorption of vitamin D by the intestine.
-Other conditions include hereditary or acquired disorders of
vitamin D metabolism, kidney failure , and side effects of
medications used to treat seizures.
-In the elderly, there is an increased risk for those who tend to
remain indoors and who avoid milk because of lactose
intolerance.

Osteomalacia vs osteoporosisOsteomalacia vs osteoporosis
OsteomalOsteomal OsteoporOsteopor
Ageing fem decreased bone densAgeing fem decreased bone dens
IllIll Not illNot ill
General acheGeneral ache Asympt till #Asympt till #
Weak musclesWeak muscles normalnormal
Alk ph incrAlk ph incr normalnormal
PO4 decrPO4 decr normalnormal
Ca x PO4 <2.4Ca x PO4 <2.4 Ca x PO4 >2.4Ca x PO4 >2.4

Paget’s diseasePaget’s disease
 Throughout a person’s life bone is constantly breaking
down and growing back. With Paget’s disease the
normal process of bone growth is changed. The bone
breaks down more quickly, and when it grows again it is
softer than normal bone.
 Soft bones can bend or break more easily. The area
affected by Paget’s disease can become shorter
because the bone bends.
 With Paget’s disease the bone can also grow larger than
before.
 Paget’s disease can affect any bone, but usually affects
the skull, the hip and pelvis bones and bones in the legs
and back.

What causes Paget’s
disease?
 The exact cause of Paget’s disease isThe exact cause of Paget’s disease is
not known.not known.
 Some people with Paget’s disease haveSome people with Paget’s disease have
other family members with it.other family members with it.

What causes Paget’s
disease?
 Some studies have shown that up toSome studies have shown that up to 30%30% ofof
people with Paget’s disease have other familypeople with Paget’s disease have other family
members with it. members with it.
The disease is also more prevalent in areasThe disease is also more prevalent in areas
where much of the population is of Anglo-Saxonwhere much of the population is of Anglo-Saxon
descent This has led some researchers todescent This has led some researchers to
believe there may bebelieve there may be a genetic factora genetic factor in thein the
development of Paget’s disease. development of Paget’s disease.
A slow acting virus may also be involved, thoughA slow acting virus may also be involved, though
the virus has not yet been identified.the virus has not yet been identified.

Lab Studies
 Biochemical indices reveal elevated alkalineBiochemical indices reveal elevated alkaline
phosphatase levels of bone origin, due to increasedphosphatase levels of bone origin, due to increased
osteoblasticosteoblastic activity and bone formation.activity and bone formation.
 Analysis ofAnalysis of alkaline phosphatase isoenzymesalkaline phosphatase isoenzymes isis
important.important.
 Procollagen I N-terminal peptideProcollagen I N-terminal peptide (PINP) recently has(PINP) recently has
emerged as a sensitive serum marker for boneemerged as a sensitive serum marker for bone
formation.formation.
 Many patients with elevated alkaline phosphatase levelsMany patients with elevated alkaline phosphatase levels
have been found to havehave been found to have osteocalcinosteocalcin measurementsmeasurements
within the reference range.within the reference range.

Lab Studies
 In Paget disease, urinary hydroxyproline levels are
elevated as they reflect increased osteoclastic activity
and bone resorption. Hydroxyproline is a product of
collagen breakdown.
 Approximately 20-30% of total hydroxyproline levels
are from bone resorption.
 Dietary sources of collagen may increase
hydroxyproline excretion in 24-hour urine collections;
therefore, an overnight fast often is necessary before
testing.
 Patients with skin disease also may have elevated
hydroxyproline levels since the skin is a major site of
collagen synthesis.

Lab Studies
 More recently, measurement of the urinary excretion of
bone-specific pyridinium collagen cross-links has been
found to be a sensitive and specific index of bone
resorption. Additionally, levels of excreted bone-specific
pyridinium collagen cross-links may be better indicators
of bone resorption and response to treatment than the
hydroxyproline assay.
 Urinary N-telopeptide (NTX) and alpha-C telopeptide
(CTX) have emerged recently as sensitive
biochemical markers for bone resorption.
 An abnormally high alpha-CTX:beta-CTX ratio is
present with active Paget disease.
 This ratio returns to the reference range following
treatment with bisphosphonates.

Lab Studies
 SerumSerum total acid phosphatasetotal acid phosphatase is an osteoclasticis an osteoclastic
enzyme, which may be elevated in active Pagetenzyme, which may be elevated in active Paget
disease, but it is of little clinical value, as it alsodisease, but it is of little clinical value, as it also
may be elevated in the present of metastaticmay be elevated in the present of metastatic
prostate carcinoma.prostate carcinoma.
 SerumSerum calcium and phosphatecalcium and phosphate levels should belevels should be
within the reference range in patients with Pagetwithin the reference range in patients with Paget
disease.disease.
 Urinary excretion of calcium also should beUrinary excretion of calcium also should be
normal.normal.
 Hypercalcemia or hypercalciuria may developHypercalcemia or hypercalciuria may develop
with immobilization or coincident primarywith immobilization or coincident primary
hyperparathyroidism.hyperparathyroidism.

THANK YOUTHANK YOU
PROF./MOSTAFA RIZKPROF./MOSTAFA RIZK

Family history of hypocalcemiaFamily history of hypocalcemia
Low-calcium dietLow-calcium diet
Lack of sun exposureLack of sun exposure

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