METABOLIC DISEASE
Normal bone metabolism
CALCIUM 99% in bone. Main functions- muscle /nerve function, clotting.
Plasma calcium- 50% free, 50% bound to albumin.
Dietary needs-kids- 600mg/day, adolesc.-1300mg/day, adult-750mg/day,
pregnancy-1500mg/day, breastfeeding-2g/day, # 1500mg/day
Absorbed in duodenum ( active transport) and jejunum (diffusion), 98%
reabsorbed in kidney prox. tubule, may be excreted in stool.
Calcium balance- positive first 3 decades then neg.
PHOSPHATE 85% in bone. Functions-metabolite and buffer in enzyme
systems.
Plasma phosphate mainly unbound. Daily requ. 1-1.5g/day
REGULATION OF CALCIUM AND PHOSPHATE METABOLISM
In all conditions except osteoporosis there is coupling of calcium metabolism
Origin
Factors

Factors

Effects on
intestine
Effects on
kidney
Effects on
bone
Effects on
[calcium]
PTH
peptide
chief cells
parathyroi
d gland

[Ca2+]
 [Ca2+]
 1,25...
No direct
affect,

absorption
of Ca
indirectly
via  1,25
 prodn of
1,25(OH)
D
reabsorp
tion of
calcium,

excretion
of
phosphate
Stimulates
osteoclast
s to
absorb
bone,
stimulates
recruitme
nt of
preosteocl
asts

Effects on
[phospha
te]

1,25(OH)
prox
tubule of
kidney
 [ ca2+]
[phos]
 PTH
 [Ca2+]
9 [phos]
 P0TH
absorpt
ion of Ca

absorption
of phos


para
follic.
cells of
thyroid
 [ca2+]
 [ca2+]
stimulates
reabsorpti
on of
bone
(osteoclas
tic)
inhibits
osteoclast
stic
reabsorpti
on of
bone
D
steroid
2
Calcitoni
n
transient

Oestrogen
Prevents bone loss
Corticosteroids Increased bone loss (reduced gut absorption, decreased bone formn/collagen
Growth Hormone Causes positive calcium balance
Growth factors
Insulin like growth factor; produced by osteoblasts, recruits osteoblasts
Transforming Growth factors; produced during bone resorption, stimulate
osteoblasts
IL1 and osteoclast activating factor; activate bone resorption
Prostaglandins; regulate both osteoblasts and osteoclasts
Metabolism of Vit D
Diet

7 Dehydrocholesterol
 skin
Vit D3 (Cholecalciferol)
liver
25-OH-Cholecalciferol


kidney
1,25 dihydroxycholecalciferol
24,25 dihydroxycholecalciferol (inactive)


Bone
(absorption of bone)
Small intestine
(absorption of calcium)
Disorders of Bone Mineralisation
Hypercalcaemia
Symptoms- ‘bones, moans, stones and abdominal groans’polyuria,
constipation,lethargy,disorientation,bony resorption+/- figrous replacement(osteitis
fibrosa cystica),weakness,CNS effects.
Primary hyperparathyroidismAge40-65
F:M2:1
Pathology
Adenoma/hyperplasia
Clinical features
often asymptomatic, only 10% have bone disease Moans, bones stones
and abdominal groans
Xrays
osteopenia, osteitisfibrosa cystica,brown tumours, subperiosteal
erosions (phalanges),pathological fractures. Calcification of soft
tissues
Blood results calcium,  PTH,  phosphate, alk. phosp. N/( increased with
osteitis fibrosa
Treatment
Parathyroidectomy beware hungry bone syndrome post op,
(hypocalcaemia due to brisk formn of new bone)
Secondary hyperparathyroidism
Parathyoid over secretion is a predictable response to chronic hypocalcaemia. Therefore found in
rickets and osteomalacia, accounting for some of radiological findings
Other causes of Hypercalcaemia
MENMalignancy,hyperthyroidism, addisons, steroids, peptic ulcers, kidney disease,
sarcoidosis
Hypocalcaemia
Causes neuromuscular instability (tetany, seizures, Chvostek’s sign). Cataracts,fungal
nail infections, Prolonged QT on ECG
Caused by low PTH or low Vit D
Primary hypoparathyroidism
Causes;
can be iatrogenic after thyroidectomy
Clinical Features;
fungal infections of nails, hair loss, vitiligo
Xrays;
skull Xrays, calcification of basal ganglia
Blood results;
low calcium, high phosphate
Pseudo hypoparathyroidism eg. Albright hereditary osteodystrophy
Incidence;
rare
Pathology;
genetic x linked dominant.lack of effect of PTH at target cell.
Clinical features;
obesity, diminished intelligence, short 1st 4th, 5th metacarpals
and metatarsals, exostoses, brachydactyly.
Blood tests;
normal or high PTH, low Ca, high phosphate
Renal Osteodystrophy
Pathology;
chronic renal failure, leads to failure to excrete phosphate, ass.
with long term dialysis.
Chronic renal disease
Glomerular damage

uremia
Tubular damage


phosphate retention

Hyperphosphatemia



Ectopic calcification
reduced synthesis of 1,25(OH)D3

reduced GI absorption of calcium


Increased serum calcium

secondary hyperparathyroidism


Hypocalcaemia

rickets/osteomalacia

osteitis fibrosa


osteosclerosis
xrays;
Blood tests;
Treatment;
rugger jersey spine, soft tissue calcification
calcium normal or low, abnormal renal function, raised alk
phos.,
aimed at kidney disease
Rickets/ osteomalacia in adults
Failure of mineralisation of bone
Causes;
Nutritional deficiency- vit D
chelators of calcium- phytates, chelates
phosphorous
Antacid abuse, causing reduced dietary
phosphate binding
GI Absorption defects- Post gastrectomy
Biliary disease (reduced absorption of
ADEK)
Small bowel disease
liver disease
Renal tubular defects
Renal osteodystrophy
Miscellaneous causes
Clinical features;
Rickets tetany , convulsions, failure to thrive, listlessness, muscular flaccidity.
Flattening of skull(craniotabes), thickening of wrists from epiphyseal overgrowth,
bow legs, stunted growth, rickety rosary, spinal curvature, coxa vara, bowing, # of
long bones
Osteomalacia, aches and pains, muscle weaknessloss of height, stress #s
Xray findings:
Rickets; Thickening and widening of physes, cupping of metaphysis, bowing of
diaphysis, wide metaphysis.
Osteomalacia; Loosers zones- incomplete stress # with healing lacking calcium, on
compression side of long bones. Codfish vertebrae due to pressure of discs, trefoil
pelvis, due to indentation of acetabulae, stress #s
+ the Xray changes of 2ndary hyperparathyroidism
Blood tests;
Reduced calcium, reduced phosphate, increased alk. Phos. Diminished urinary
excretion of calcium,In vit D deficient rickets, 25 hcc also low. Calcium phosphate
productis normally 3. In rickets and osteomalacia is less than 2.4
eg.Vit D deficient rickets;
Due to lack of vit D
Histology- Swiss cheese trabeculae and widened osteoid seams
gross distortion at maturation zone of physis, poorly defined zone of calcification
Treatment- vitamin D (5000u) and Calcium (3g/day)
e.g. Hereditary vit D dependent rickets;
Rare
Autosomal recessive
Defect in 1 hydroxylation of vit D3 in kidney causing reduced 1,25 dihydroxy
cholecalciferol
Clinical features; similar to other causes of rickets but can be worse + baldness
Treatment; High levels of vit D
e.g. Vitamin D resistant rickets/ familial hypophosphataemic rickets;
X linked dominant
Impaired renal tubular reabsorption of phosphate
clinical features; similar to other types
Treatment; phosphate and vit D replacement
e.g Hypophosphatasia
AR Disorder
Low levels of alk phos. (makes inorg phospate, important for bone matrix formn)
Diagnosis, increased urinary phosphoethanolamine
Treatment, Phosphate therapy
Ideopathic Juvenile osteoporosis
Incidence;
Age
Pathology;
Blood tests;
Prognosis;
rare
8-14
Osteopenia, growth arrest
normal calcium and phosphate
spontaneous resolution
Osteopetrosis
Mild form AD, malignant form AR
Pathology;
Failure of osteoclastic and chondroclastic resorption secondary
to defect in thymus producing dense bone
Xrays;
Rugger Jersey spine, marble bone, ‘Erlenmyer flask’prox
humerus, /distal femur
Treatment;
Bone marrow transplant for malignant cases
Infantile Cortical Hyperostosis (Caffey syndrome)
Age;
0-9 months
Pathology;
Soft tissue swelling and bony cortical thickening post febrile
illness
Xrays;
periosteal reaction, ulnar/jaw
Diff diag;
child abuse, hypervitaminosis A, infection, scurvy
Prognosis;
Benign, self limiting
Connective tissue syndromes
Marfan Syndrome
Pathology;
Autosomal Dominant, disorder of alpha 1 unit of collagen
synthesis
Clinical findings;
Arachnodactyly, pectus deformities, scoliosis, spondylolisthesis, heartvalve
abnormalities, superior lens dislocation. Joint laxity, protrusio acetabuli
Management;
Joint laxity, conservatively, scoliosis and spondo. aggressively with surgery.Protrusio
acetabuli with triradiate cartilage fusion
Ehlos Danlos Syndrome
Pathology;
Autosomal Dominant, , skin laxity, joint hypermobility vascular fragility
Types;
11 types, , types 11 and 111 most common, least disabling
Treatment;
Physio, orthotics, soft tissue procedures fail
Homocystinuria
Pathology;
Investigations;
Autosomal recessive, inborn error of methionone metab.
Accumulation of homocysteine
Osteoporosis, marfanoid habitus, but with stiffening, inferior
lens dislocation. CNS effects
Increased homocysteine in urine.(cyanide nitroprusside test)
Implications;
Treatment;
Thrombosis ppted by minor procedures.
Vit B6 and reduced methionone diet
Clinical findings;