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Pakistan Society Of Chemical Pathologists
Distance Learning Programme In Chemical Pathology
(DLP-2)
Lesson No 16
Metabolic Bone Disease
By
Dr Lena Jafri
, FCPS
MBBS
Consultant Chemical Pathologist
Aga Khan University Hospital
Part I
MCQs (One Best Type)
Q.1: A 30 year old female complains of backache and generalized
weakness. Her biochemical profile was as following :
• Calcium:
7.5 mg/dl
• Phosphorous:
2.2 mg/dl
• Alkaline phosphatase :
107 U/l
She is most likely suffering from:
a.
Hypomagnesaemia
b.
Hypoparathyroidism
c.
Osteitis fibrosa cystica
d.
Paget’s Disease
e.
Vitamin D deficiency
e. Vitamin D deficiency
Introduction: Vitamin D
• Fat soluble hormone
• Major forms are Vitamin D2 (ergocalciferol) and D3
(cholecalciferol)
• Receptors have been identified for >30 tissues
• Function of the immune, reproductive, muscular, skeletal
and integumentary system
• VDR best characterized on intestine, kidney and bone
• Critical for maintenance of bone health
Role of Calcitriol
• Stimulates GI absorption of both calcium and
phosphate
• Stimulates renal reabsorption of both calcium and
phosphate
• Stimulates bone resorption
Net effect of calcitriol 
↑ serum calcium
↑ serum phosphate
Sources and Metabolism
of Vitamin D
Daily need of Vitamin D
• Exposure of arms & legs for
5-30 min (depending on time,
season, latitude & skin
pigmentation) between 10am3pm twice/week
• With longer exposure to UVB
rays, an equilibrium is
achieved in the skin, and it
degrades as fast as it is
generated
Serum Levels of
25 hydroxy vitamin D
“deficiency”
ng/ml
10
“Insufficiency”
20
“ Normal”
30
40
50
Hollick MF. NEJM. 2007; 266-280.
Boonen S et al. Osteoporosis Int. 2004;15:511-519.
Lips P. Endocr Rev. 2001;22:477-501.
Heaney RP. Osteoporosi Int. 2000;11:553-555.
Heaney RP. Am J Clin Nutr. 2004; 80 (suppl):1706S-1709S.
Thomas MK. NEJM. 1998;388:777-781.
Rickets and Osteomalacia
Slides courtesy of Dr Mariam Rafiq, QAMC, Bwp
Difference between Rickets and Osteomalacia
Rickets : deficient mineralization at the growth plate
• Disease of growing bone.
• Refer to changes at the growth plate caused by
deficient mineralization of bone.
• Occurs before the growth plates fuse.
Osteomalacia: impaired mineralization of the bone
matrix
• Rickets and osteomalacia usually occur together when
growth plates are open only osteomalacia occurs after
the growth plates have fused.
Classification of Rickets
Calcipenic Rickets
Vitamin D deficient ( Nutritional) Rickets
Vitamin D dependent Rickets
• Type I
• Type II
Phosphopenic Rickets
Hereditary
•
•
•
•
X-linked Hypophosphatemia(vitamin D-Resistant Rickets)
Autosomal Dominant
Autosomal Recessive
Hypophosphatemic rickets with hypercalciuria
Acquired disorder
• Tumor-induced (or oncogenic) osteomalacia
Clinical Features
Skeletal findings
•
•
•
•
•
•
•
Delayed closure of fontanelles
Parietal and frontal bossing
Craniotabes (soft skull bones)
Rachitic rosary
Harrison Grove
Widening of epiphyseal plate
Progressive lateral bowing of the femur and tibia
Radiological
• Disorganization of the growth plate with
cupping, splaying, cortical spurs, stippling.
• Cupping of metaphysis
• Looser zones/pseudofractures
• Osteopenia
Lab Findings
Calcipenic rickets
Phosphopenic rickets
Serum Phosphate
Decreased
Decreased
Serum Calcium
Decreased Or Normal
Normal
ALP
Raised
Raised
PTH
Increased
Normal
Vitamin D
Low Or Normal
Normal
TRP
Reduced
Reduced
TmP/GFR
Reduced
Reduced
FGF23
Increased
Q 2. Following is the bone profile of a technologist working in your
laboratory who fractured her ankle because of a minor trauma in the
laboratory.
• Calcium:
7.2 mg/dl
• Albumin :
4
g/dl
• Phosphorous: 5.47 mg/dl
• PTH:
5 pg/ml
The lab investigation you would like to request next would be:
a. 25-hydroxy vitamin D
b. Alkaline phosphatase
c. Creatinine
d. Magnesium
e. N-Telopeptide
d. Magnesium
Regulation of PTH Secretion
• Secretion of PTH is controlled chiefly by serum [Ca2+] through
negative feedback
• Calcium-sensing receptors located on parathyroid cells are
activated when [Ca2+] is elevated
• The G-protein coupled calcium receptors bind extracellular
calcium
• High concentrations of extracellular calcium result in activation
of the Gq G-protein coupled cascade through the action of
phospholipase C
• This hydrolyzes phosphatidylinositol 4,5-bisphosphate (PIP2)
to liberate intracellular messengers IP3 and diacylglycerol
(DAG)
Regulation of PTH Secretion
• These two messengers result in a release of calcium from
intracellular stores and a subsequent flux of extracellular
calcium into the cytoplasmic space
• This results in an intracellular Ca concentration that inhibits the
secretion of preformed PTH from storage granules in the gland
• In contrast to the mechanism that most secretory cells use,
calcium inhibits vesicle fusion and release of PTH. In the
parathyroids, magnesium serves this role in stimulus-secretion
coupling
• Hypomagnesemia inhibits PTH secretion and also causes
resistance to PTH, leading to a form of hypoparathyroidism
that is reversible
• Hypermagnesemia also results in inhibition of PTH secretion
Parathyroid Stimulators
• Decreased serum [Ca2+]
• Mild decreases in serum
[Mg2+]
• An increase in serum
phosphate (increased
phosphate causes it to
complex with serum
calcium, forming calcium
phosphate, which reduces
stimulation of Ca-sensitive
receptors (CaSr) that do not
sense calcium phosphate,
triggering an increase in
PTH)
Parathyroid Inhibitors
• Increased serum [Ca2+].
• Severe decreases in
serum [Mg2+], which
also produces symptoms
of hypoparathyroidism
(such as hypocalcemia)
• Calcitriol
Regulation of PTH
•
•
•
•
•
•
•
Ca binds to CaSR extracellular domain
Conformational changes
Interaction with G protein
Gqa activates phospholipase C
Intracellular Ca altered
Hydrolysis of phospatidyl inositol 4 5 bisphosphate
Inositol 3 phosphate inhibits PTH release
Q. 3: A 52-year-old woman with menopause at 42 years of age was being
evaluated by a physician for fracture risk. She fractured her ankle while getting
off a rickshaw 8 months previously. DXA scan showed her T score at the hip
was -2.3. Her mother had fractured her hip at the age of 63. She dislikes dairy
products and smokes occasionally.
The most significant risk factor for her fracture risk, independent of her bone
mineral density reading is:
a. Early menopause
b. Low calcium intake
c. Osteoporosis in mother
d. Previous fracture
e. Smoking
d. Previous Fracture
Osteoporosis
A disease characterized by:
• low bone mass
• microarchitectural deterioration of the bone
tissue
Leading to:
• enhanced bone fragility
• increase in fracture risk
Fractures
• Fractures are the most dangerous aspect of
osteoporosis
• Debilitating acute and chronic pain in the elderly
is often attributed to fractures from osteoporosis
and can lead to further disability and early
mortality
• These fractures may also be asymptomatic
• The most common osteoporotic fractures are of
the wrist, spine, shoulder and hip
Fragility fracture
• Type of pathologic fracture that occurs as result of normal
activities, such as a fall from standing height or less.
• There are 3 fracture sites said to be typical of fragility
fractures: vertebral fractures, fractures of the neck of the femur,
and Colles fracture of the wrist.
• This definition arises because a normal human being ought to
be able to fall from standing height without breaking any
bones, and a fracture therefore suggests weakness of the
skeleton.
Clinical risk categories for osteoporosis
and osteoporotic fractures
Extremely high risk
• Prior osteoporotic fracture
(without significant trauma)
• Glucocorticosteroid use
(prednisone ≥7.5 mg/d or
equivalent for ≥6 months)
• Solid organ transplant (pre
or post, especially in first 2-3
years)
High risk
• Glucocorticosteroid use
(prednisone ≥5 mg/day or
equivalent, for ≥3 months)
• Woman age >65 yrs /man age >70
yrs
• Postmenopausal woman or older
man with one or more of:
 Personal history of low impact fracture
 Family history of fracture hip, wrist, or
spine (first degree relative age ≥50 yrs)
 Currently smoking
 Rheumatoid arthritis
 BMI <20
 Recent weight loss <10%
 Multiple risk factors for falling
Clinical risk categories for osteoporosis
and osteoporotic fractures
Moderate risk
• Hormonal conditions
• Hypogonadism
• Late menarche (age >15
yrs)
• Early menopause (age <45
yrs)
• Cushing's syndrome
• Hyperparathyroidism
(primary or secondary)
• Thyrotoxicosis
• Gastrointestinal and
nutritional factors
• Gastrectomy
• Low gastric acid
•
•
•
•
Celiac disease
Bariatric surgery
Inflammatory bowel disease
Pancreatic insufficiency
• Heavy alcohol use
• Family history of
osteoporosis
Q.4: A 47-year-old female is noted to have a serum calcium level of 11.1
mg/dL (2.75 mmol/L) with normal creatinine at the time of a routine annual
visit. Investigations on follow-up after 1 month shows:
• Calcium:
• 25 hydroxy vitamin D 63 ng/ml
• Parathyroid hormone 125 pg/ml
11 mg/dL
(Ref Value for normal >30 ng/ml)
(16-87 pg/ml)
The most likely cause of hypercalcemia is:
a.
b.
c.
d.
e.
Humoral hypercalcemia of malignancy
Primary hyperparathyroidism
Secondary hyperparathyroidism
Tertiary hyperparathyroidism
Vitamin D toxicity
b. Primary hyperparathyroidism
Hyperparathyroidism
Primary
Secondary
Overproduction of PTH
secondary to a chronic
abnormal stimulus for its
production
Tertiary
Definition
Unregulated
overproduction of PTH
resulting in abnormal
calcium homeostasis
Cause
Adenoma
CKD 5
Familial (MEN 1/ MEN2) Vit D deficiency
Malabsorption
Prolonged secondary
hyperparathyroidism
Long standing CKD
LABS
Raised Ca
Raised PTH
Low P
Mild-to-mod increase in
24-hour urinary Ca
excretion
Raised Ca
Raised PTH
P often raised
Vitamin D normal
Low-normal Ca
Raised PTH
P levels depend on aetiology
(eg, high in CKD, low in
VDD)
Excessive secretion
of PTH after
longstanding
secondary
hyperparathyroidism
(low vitamin D or
CKD)
Effects of high PTH
• Increases the release of calcium from bone
matrix
• Increases calcium reabsorption by the kidney
• Increases phosphate excretion
• Increases renal production of 1,25dihydroxyvitamin D3 (calcitriol), which
increases intestinal absorption of calcium
Q. 5: Blood sample of parathyroid hormone
(PTH) is transported in ice because its half-life
is:
a.
b.
c.
d.
e.
20 seconds
30 seconds
2-4 min
8-10 min
15 min
c. 2-4 min
PTH molecule
• Linear peptide consisting of 84 amino acids
• PTH present in circulation is very heterogeneous
• Heterogeneity is the consequence of a complex metabolism that
starts in the parathyroid cells and continues in other tissues, mainly
in the kidneys and liver
• A circulation pool of “PTH peptides,” not only in pathological
conditions, but also in normal individuals
PTH assays: Evolution
• In the first gen, noncompetitive, “sandwich” type assay, a
single polyclonal antibody competes for labeled PTH and the
serum forms
• In the 2nd-gen assays, immunometric, 2 distinct antibodies
(usually monoclonal), directed against different epitopes, bind
the PTH forms present in the sample. One of the antibodies is
bound to a solid phase, and the other is labeled
• In the third gen assays, the recognition is based on other
principles (mass spectrometry) in serum samples previously
purified
Immunometric assays a
breakthrough
• Recognition of PTH by two different antibodies, one carboxyl terminal and
the other amino terminal
• Widely available
• Adapted to most of the automation platforms
• Specificity of the amino terminal antibody defines if the assay measures
only the bioactive PTH circulating form (including the first amino terminal
amino acids) or the “intact” PTH, which includes, besides bioactive PTH,
other “long” carboxyl-terminal forms, for example, 7–84-PTH
• Assays for “intact” PTH are the most commonly available and the potential
advantage of the bioactive PTH assays is still debatable
PTH Half Life
• The native or intact (1-84) PTH has a short half-life,
2-4 minutes
• Whereas the carboxy and midmolecule fragments,
which are biologically inactive, have half-lives 10- to
20-fold higher.
• The high concentrations of biologically inactive
fragments have interfered with use of C-terminal or
midmolecule assays for evaluation of parathyroid
function in patients with impaired renal function.
PTH Half Life (Cont)
• Intact PTH assays provide a more accurate
assessment of parathyroid patients including
those with various renal diseases.
• ESRD: predominance of the carboxyl terminal
ones, are present in great quantities in
comparison to the intact 1–84 form
Q. 6: A 65-year-old female, complains of nausea, lethargy and bone pains for
last 8-10 months. The investigations on admission showed:
• Serum Calcium 7.2 mg/dl
• Serum Albumin 2.9 g/dL
The corrected calcium (mg/dl) is:
a.
b.
c.
d.
e.
7.56
7.81
8.08
8.29
8.37
c. 8.08
Corrected Calcium
• One can derive a corrected Ca (adjusted Ca) level, to
allow for the change in total calcium due to the change in
albumin-bound calcium
• Gives an estimate of what the total calcium level would
be if the albumin were a specified normal value
• Each 1 g/dL decrease of albumin will decrease 0.8 mg/dL
in measured serum Ca and thus 0.8 must be added to the
measured Ca to get a corrected Ca value
Formula for Corrected Calcium
• Corrected calcium (mg/dL) = measured total Ca
(mg/dL) + 0.8 (4.0 - serum albumin [g/dL]),
where 4.0 represents the average albumin level in
g/dL.
• Corrected calcium (mmol/L) = measured total Ca
(mmol/L) + 0.02 (40 - serum albumin [g/L]),
where 40 represents the average albumin level in
g/L
Q. 7: A 55-year-old man with recurrent bone pains was evaluated in a bone clinic.
Following laboratory investigations were done:
• Serum creatinine: 0.5 mg/dl
• Serum phosphate: 1.2 mg/dl
• Serum calcium: 8.6 mg/dl
• Urinary phosphate: 340 mg/dl
• Urinary creatinine: 55 mg/dl
The TMP- GFR (mg/dl) of this man is:
a. 0.25
b. 0.06
c. 0.05
d. -0.25
e. -1.88
e. -1.88
Formula for TMP/GFR
• Tubular reabsorption of phosphate (TRP)
• Tubular maximal reabsorption rate of phosphate to GFR
(TmP/GFR)
Q. 8: Following is the biochemical bone profile of a 55-year-old man during routine annual checkup.
Bone X-ray was normal. He also gave history of recurrent kidney stones since last 3 years. His
biochemical results showed:
• Serum Na:
141 mmol/L
• Serum K:
3.8 mmol/L
• Serum Chloride:
111 mmol/L
• Blood Ionized Ca: 3.2 mmol/L
• Serum P:
0.86 mmol/L
• Serum ALP:
80 U/L
• Creatinine:
0.9 mg/dl
Investigation which would help in confirming your diagnosis in blood is:
a. 25-hydroxyvitamin D
b. FGF-23
c. Magnesium
d. N-telopeptide of type I collagen
e. Parathyroid hormone
e. Parathyroid Hormone
Q. 9: If the Parathyroid hormone is undetectable which
panel of laboratory investigations will help you make
the diagnosis?
a.
b.
c.
d.
e.
25OHD, PTH-rp , ACE
25OHD, PTH-rp, NTX
Ca, ACE, ALP
Ca, P, 25OHD
P, PTH-rp, ALP
e. Ca, P, 25OHD
Identify the mystery molecules!
Match the picture to the correct option:
10.1.c NTX
10.2. d. Parathyroid hormone
10.3.b. Bisphosphonate
10.4.e. Telopeptide cross links
10.5.a.1, 25 dihydroxy-vitamin D3
Part II
Short Answer Questions:
Q.11: A 5 year old girl is brought to a paediatrician for not being able to walk
properly since one and a half year. Mother explained that her marriage was
consanguineous and two of her boys (10 years and 8 years old) had deformed
bones and were unable to walk. On examination, there are skeletal deformities
of both upper and lower limbs, frontal bossing and pallor. Her extremities have
widened wrists and ankles.
The laboratory evaluation included:
Serum
• Creatinine
0.5 mg/dl
• Calcium
8.4 mg/dl
• Phosphorus
1.8 mg/dl
• Alkaline phosphatase
1917 U/l
• 25OHD 28 ng/ml (Ref Value for normal >30 ng/ml)
• PTH
90 pg/ml
Urine
• Urinary phosphate
740 mg/day
X-ray of wrist and legs was requested:
The paediatrician wanted to confirm his suspicion and ordered
TMP-GFR in this patient.
a. Which disease is the paediatrician
suspecting and why did he order
TmP-GFR?
• Hypophosphatemic rickets or vitamin D resistant
or X linked Hypophosphatemic rickets
• XLH usually presents with typical signs of
rickets in young children, accompanied by
hypophosphatemia and low TmP/GFR hence
TmP/GFR will confirm his suspicion
b. How TmP-GFR is calculated?
• This calculation is used to estimate the ratio of
phosphorus tubule maximum (TmP) to glomerular
filtration rate (GFR).
Fraction Excretion of P (FEPO4)= UPO4 /PPO4 / Ucreat /Pcreat
1 - FEPO4 = TRP
Assuming PPO4 = [PO4]GFR
TmPO4/GFR = TRP X PPO4
TmP/GFR
The ratio of renal tubular maximum reabsorption rate of phosphate to the
glomerular filtration rate
TmP/GFR is used to
1.
Diagnose:
•
•
•
2.
XLH
Hereditary hypophosphataemic rickets with hypercalciuria
Oncogenic osteomalacia
Indicate the need for phosphate replacement and extent of
its intracellular repletion.
3. Monitor recovery of renal tubular function after
Damage
Calculation of TmP/GFR
TRP=1-{(UP/Pp)×(Pcr/Ucr)}
If TRP =/< 0.86 then
TMP/GFR = TRP × Pp
If TRP > 0.86 then
TMP/GFR= 0.3×TRP/{1-(0.8×TRP)}× Pp
Where
TRP= fractional tubular reabsorption of phosphate
UP =Urinary Phosphate
Pp =Serum Phophate
Pcr = Serum Creatnine
Ucr= Urinary Creatnine
Interpretation of TmP/GFR
Interpretation:
Dependent upon clinical situation.
Interpreted in conjunction with the serum phosphorous
TMP/GFR is reduced in:
XLH
• primary hyperparathyroidism
• renal tubular disorder
• osteomalacia.
•
Increased in:
• Children
• Hypoparathyroidism.
c. How will you interpret the result of
TMP/GFR in diagnosing this child?
• TMP/GFR if low: confirms
Hypophosphatemic rickets and vice versa
d. Enlist possible findings in the bones
(physical examination and radiological) you
may find in such patients.
•
•
•
•
•
•
•
•
•
Disproportionate short stature
Delayed dentition
Dental absecces
Extrasekeltal calcification of tendons, ligaments, capsules
Craniosyntostosis
Rachitic rosary ribs
Cupping of ribs
Fraying and flaying of radius
Genu varum (bowed legs)
Enumerate tests/assays which are
essential for the diagnosis of this disease.
e.
•
•
•
•
•
•
•
•
•
Serum P
Serum Ca
Serum ALP
Serum PTH
Serum 25 OHD
Serum FGF23
TmP-GFR
Urinary Calcium
PHEX gene analysis (if there)
Q.12: A five and a half month old boy was brought to a pediatric
clinic by his mother. His mother told the doctor that she noticed
that her boy had difficulty in breathing since few months. On
examination he was not in acute distress, the boy’s chest had
prominent nodules on the costochondral junction and closed
anterior and posterior fontanelles.
Upon follow-up, laboratory tests showed:
• Ionised calcium: 7.5 mg/dl
• Serum phosphate: 2.4 mg/dl
• Alkaline phosphatase : 22 U/L
• X-ray wrist: widened metaphysis with osteopenia
a. What is the diagnosis?
• Hypophosphatasia
Hypophosphatasia
• Variable inheritance
• Mutation in liver/bone/kidney alkaline phosphatase gene
encoding the tissue non specific alkaline phosphatase
• Diagnosis is done by biochemical analysis and
sequencing of ALP gene
• Serum ALP markedly reduced
• Elevated urinary phosphoethanolamine
• Elevated pyridoxal 5 phosphate
Signs and Symptoms
•
•
•
•
•
•
•
•
•
•
•
•
Vary widely
Can appear anywhere from before birth to adulthood
The most severe forms of the disorder tend to occur before birth and in early infancy
Weakens/softens the bones
Skeletal abnormalities similar to rickets
Short limbs
Abnormally shaped chest
Soft skull bones
Poor feeding
Failure to gain weight
Respiratory problems
High levels of calcium in the blood
How common is
hypophosphatasia?
• Severe forms of hypophosphatasia affect an estimated 1 in
100,000 newborns
• Milder cases, such as those that appear in childhood or
adulthood, probably occur more frequently
• This condition appears to be most common in Caucasian
(white) populations
• It is particularly frequent in a Mennonite population in
Manitoba, Canada, where about 1 in 2,500 infants is born with
severe features of the condition
b. Name the pathognomic finding
present in this patient which supports
your diagnosis in this patient.
• Low Alkaline Phosphatase
c. What is the type of inheritance of
this disease?
• Variable
• AD
• AR
d. What are the different forms of this
disease that are recognized?
•
•
•
•
•
•
Perinatal lethal
Prenatal benign
Infantile
Childhood
Adult
Odonto hypophosphatasia
e. The boy’s mother is pregnant and would like her
baby in the womb to be tested for the disease. Which
investigation will you suggest?
• Mutation analysis of chorionic villous
DNAs
Q. 13: A 65 years male known hypertensive and diabetic since
last 20 years has extreme bone pains. On examination he has
puffiness under his eyes and pedal edema. He has the following
biochemical profile:
•
Serum Calcium:
8.2 mg/dl
•
Serum Urea:
191 mg/dl
•
Serum Phosphorus:
5.3 mg/dl
•
PTH:
211 pg/ml
•
Serum albumin
3.0 g/dl
a. What is the most probable cause of the
biochemical findings?
• Chronic kidney disease (+Metabolic Bone Disease)
b. What further laboratory investigations
would you like to request and why?
• Serum creatinine to calculate eGFR
• 25 hydroxy Vitamin D levels: the only barometer to know
VD status. It is imp to measure it as PTH is high. Plan is
to replace it if less than 30 ng/m,
• 1, 25 dihydroxy Vitamin D if available in your lab
• Baseline alkaline phosphatase has a prognostic
implication towards bone involvement, marker for bone
osteodystrophy in CKD
c. He was referred for dietary counseling because of the
serum phosphorous levels noted. How would the
nutritionist assist him?
• Low intake of P in diet
• Limit dietary P
• Understand high P content food (milk and cheese, dried
beans, peas, colas, canned iced teas, lemonade, nuts, and
peanut butter, chapati)
• Low P alternatives :Liquid non-dairy creamer,Cooked
rice, cereals,Popcorn,Peas
Lemon-lime soda, Powdered iced tea and lemonade
mixes
• Add phosphate binders
d. What could be the role of
FGF-23 in such patients?
• FGF23 correlates with decline in GFR
• FGF23 correlates with elevated phosphate
FGF-23
• Recently, role of phosphatanin has evolved in phosphate and
vitamin D homeostasis
• Many phosphotanins have been described; however role of
Fibroblast Growth Factor 23 (FGF23), which is an osteocytederived hormone, has been studied recently in regulation of
phosphate and vitamin D homeostasis
• FGF23 reduces serum 1,25(OH)2D level by suppressing the
expression of 25OHD-1α hydroxylase and also enhancing the
expression of 25OHD-24-hydroxylase
CKD and FGF-23
• It has become increasingly clear that P metabolism plays a
critical role in the pathophysiology in CKD
• Hyperphosphataemia should be aggressively treated to improve
life expectancy of CKD patients
• In addition to traditional cardiovascular risk factors,
disturbances in calcium-phosphate metabolism are regarded as
strong contributing factors of higher cardiovascular mortality in
CKD patients
e. What will be the therapeutic
goals and challenges in this patient?
Many challenges but 4 imp ones are:
• Normalize calcium and keep it in the range
• Reducing P levels and keep it in the range
• Evaluate Vit D deficiency and replace it
• Lower PTH by treating with calcitriol or vitamin D
analogs
• Reference: KDIGO
Q. 14: A 49-year-old woman, presents to metabolic bone physician with
complaints of severe knee pain. She is married with 3 children. She
does try to go on walks with her family and neighbors on and off. She
was diagnosed as having rheumatoid arthritis 7 years ago and since then
is on steroids. She does not smoke or drink. She completed her
transition to post menopause about 10 years ago and has never used any
hormones for menopause. Her father fractured his hip in a minor fall at
the age of 70 years. Her general physical examination showed:
• Height: 5'4",
• Weight: 203 lb,
• BP: 119/78 mmHg,
• Pulse: 70 beats/min,
• Respiratory rate: 12 breaths/min
a. Name the risk factors for osteoporosis and fracture present in this
patient which indicate osteoporosis screening by DXA scan?
•
•
•
•
•
Rheumatoid arthritis
Steroids
Premature menopause
Family history of low impact fracture
Weight
Bone Mass by Age and Sex
Pathogenesis of Estrogen
Deficiency and Bone Loss
Estrogen loss triggers increases in IL-1, IL-6, and TNF
due to:
• Reduced suppression of gene transcription of IL-6 and TNF
• Increased number of monocytes
• Increased cytokines lead to increased osteoclast
development and lifespan
She underwent a DXA scan, which revealed
spine and femoral neck BMD T-scores of -1.5
and -2.9, respectively.
b. How will you interpret the DXA scan report according to WHO
Diagnostic Categories for Osteoporosis and Low Bone Mass?
• Osteopenia: BMD between -1.0 and – 2.5 SD below
the norm for young healthy adult of same sex (T score < 1.0 and > - 2.5).
• Osteoporosis: BMD – 2.5 SD or below (T score < - 2.5)
In this Patient
• Spine : osteopenia
• Femoral neck : severe osteoporosis
BMD testing
• The definition of osteoporosis developed for World
Health Organization (WHO) is based on bone
densitometry
• Normal bone mass is defined as BMD above or below 1
standard deviation (SD) from the premenopausal mean
value (T-score), osteopenia as BMD below -1SD but
above -2.5 SD and osteoporosis as BMD below -2.5 SD
DXA
• Non-invasive
• Takes only 10-15 minutes, and exposes patients to
only a small amount of radiation (less than one tenth
of the amount of a chest x-ray)
• do not provide any information about bone
architecture
• Screening for osteoporosis should be performed with
BMD testing by DXA if available, and not more
frequently than every 2 years. (Ref: ACPM 2009)
DXA for Pakistanis
• Availability and access to DXA machines is an issue in
Pakistan
• There were only 16 DXA machines across Pakistan as reported
by IOF in 2007
• This number has risen but there is need of increasing this more
especially in public care settings
• The expense of DXA scans makes them unavailable for the
majority even if the machine is made accessible (average cost
of DXA being ~PKR 3500)
c. What laboratory investigations will you
order to exclude secondary causes of
osteoporosis?
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TSH
PTH
HbA1C/glucose
Urinary cortisol/ ACTH
Creatinine
Autoimmune Antibody panel
FSH, LH, Testosterone, estrogen
Secondary Osteoporosis
Slides courtesy of Dr Sabiha Waseem, Canada
Causes of Secondary Osteoporosis
Endocrine or metabolic
causes
Rheumatological Hematologic diseases
diseases
• Diabetes mellitus
• Rheumatoid
• Myeloma
(type 1)
arthritis
• Monoclonal
• Acromegaly
• Ankylosing
gammopathy of
• GH deficiency (rare)
spondylitis
undetermined
• Athletic amenorrhea
• Systemic lupus
significance
• Premature menopause
erythematosus • Lymphoma/leukemi
• Hemochromatosis
a
• Hyperadrenocorticism
• Systemic
• Hyperparathyroidism
mastocytosis (rare)
• Hyperprolactinemia
• Disseminated
• Thyrotoxicosis
carcinoma
• Chemotherapy
Collagen/genetic
disorders
• Ehlers-Danlos
syndrome
• Glycogen storage
diseases
• Homocystinuria
• Hypophosphatasia
• Marfan syndrome
• Osteogenesis
imperfecta
Causes of Secondary Osteoporosis
(cont)
Medications
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Cyclosporine (Sandimmune)
Excess thyroid hormone
Glucocorticoids
GnRH agonists
Methotrexate (Rheumatrex)
Phenobarbital
Phenothiazines
Phenytoin (Dilantin)
Heparin, prolonged treatment
Proton pump inhibitors,
prolonged treatment
Nutritional
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Anorexia nervosa
Alcoholism
Calcium deficiency
Chronic liver disease, Liver
cirrhosis, Chronic biliary
tract obstruction
• Gastric operations
(Gastrectomy)
• Malabsorption syndromes,
celiac disease, IBD
• Vitamin D deficiency
Diagnostic tests in the work-up of
secondary osteoporosis.
Diagnostic test
• History and physical exam
Purpose
• To identify risk factors for
fractures, the underlying disease,
and potential drugs
• Dual-energy X-ray
absorptiometry (lumbar spine and • To quantify bone mineral density
hip)
• To detect prevalent vertebral
fractures
• Spinal X-rays
• To exclude osteolytic lesions or
tumors
d. Using FRAX what is the ten year
probability of fracture (%) in her?
• 3.7 % major osteoporotic
• 0.3% hip fracture
(Using WHO FRAX Indian version)
Fracture Risk Assessment Tools
• Qualitatively predict the 10-year fracture probability of
hip and major osteoporosis related fractures and can be
used to define cost effective intervention strategies for
primary and secondary fracture prevention
Various Tools :Most of these are
based on non-Asian population
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WHO Fracture Risk Assessment Tool (FRAX)
Garvan Institute fracture risk calculator (Garvan)
Q fracture Scores (Qfracture)
Simple calculated osteoporosis risk estimation (SCORE)
Age, BOdy size, No Estrogen (ABONE)
OSteoporosis Index of RISk (OSIRIS)
Study of Osteoporosis Fractures-Study Utilizing Risk Factors
(SOFSURF)
Osteoporosis self-assessment tool (OST)
National Osteoporosis Foundation (NOF) guidelines
Weight-Only–EPIDOS (WO-E)
Osteoporosis Risk Assessment Instrument (ORAI)
No Tool in Pakistan
• Unfortunately no such tool is available for Pakistan where the risk factors
are different from the Caucasians
• Osteoporosis screening questionnaires have thus far not been validated in
Pakistani community
• However, a new version of FRAX is available which can calculated fracture
probability for 26 countries
• Data from Singapore, which is a multi-ethnic country, is also represented on
the FRAX tool
• The calculator provides separate data for Chinese, Malay and Indian
population of Singapore
• The Singapore, Indian data can easily be extrapolated to the population
living in India or neighboring countries.
e. Name the group of medicines most
commonly prescribed in such patients.
• Calcium supplements
• Vitamin D
• Bisphosphonates
 Alendronate (Fosamax)
 Risedronate (Actonel)
 Ibandronate (Boniva)
 Zoledronic acid (Reclast)
• Hormone Replacement Therapy
Thank You and Best Of Luck