 Osteogenesis Imperfecta (Type I Collagen Disease) o Mutations interfere with acidification of the

o Brittle Bone Disease osteoclast resorption pit

o MC inherited d/o of CT: AD  Required for the dissolution of calcium
o Phenotypically heterogenous d/o d/t hydroxyapatite within the matrix
deficiency in type 1 collagen synthesis  Albers-Schonberg Disease – mild AD form
o MC affects bone, but also affects joints, eyes, of osteopetrosis – caused by mutation of
ears, skin, and teeth CLCN7 – encodes a proton-chloride
o Mutations in genes encoding alpha 1 and 2 exchanger on the osteoclast surface
chains of type 1 collagen required for resorption pit acidification
o Replacement of a glycine residue within the  AR cases – d/t TCIRG1 and CA2 (carbonic
triple helical domain with another AA anhydrase 2) mutation
o Collagen synthesis and EC transport require  Osteopetrosis d/t CA2 mutations are
triple helix formation – result in misfolding of accompanied by renal tubular acidosis, as
collagen polypeptides and defective assembly CA2 facilitates resorption pit acidification
of higher order collagen chains by osteoclasts and urinary acidification by
o Fundamental abnormality: too little bone – renal tubular epithelial cells
extreme skeletal fragility o Some are d/t mutations in IKBKG – encodes
o Other findings NEMO – required for osteoclastogenesis and
 Blue sclerae d/t decreased collagen osteoclast survival – regulated by NF-KB
content – sclera made translucent –  Causes X-linked anhidrotic ectodermal
underlying choroid can be partially dysplasia (multisystem disorder that
visualized includes osteopetrosis)
 Hearing loss – sensorineural and impeded o Morphology
conduction d/t abnormal middle and inner  Deficient osteoclastic activity → bones
ear bones lack a medullary canal and long bone ends
 Dental imperfections (small misshapen are bulbous and misshapen (Erlenmeyer
and blue-yellow teeth) – dentin deficiency flask deformity)
o Subtypes  Neural foramina are small and can
compress exiting nerves
I  Bone, teeth, joint, & ear disorders  Primary spongiosa (normally resorbed)
survive  Normal stature persists and fills the medullary cavity – (-)
 Blue sclerae room for the hematopoietic marrow and
II  Death, intrauterine/perinatal fx prevent the formation of mature
perinatal  Skeletal deformity trabeculae
lethal  Blue sclerae
 Deposited bone – woven (not lamellar)
III  Bone, teeth, and ear disorders
 Osteoclasts –
progressive,  GR, progressive kyphoscoliosis
normal/increased/decreased
deforming  Blue to white sclerae
IV  Moderate skeletal fragility o Clinical Features
survive  Short stature 1. AR
 Normal sclerae  Severe infantile osteopetrosis
 Evident in utero or soon after birth
 Fx, anemia, and hydrocephaly →
 Osteopetrosis postpartum mortality
o A group of rare genetic diseases characterized  If infant can survive, (+) cranial nerve d/os
by reduced bone resorption d/t deficient (optic atrophy, deafness, facial paralysis)
osteoclast development/function and repeated fatal infections d/t
 Leads to diffuse, symmetric skeletal leukopenia from reduced hematopoiesis
sclerosis  Compensatory hematopoiesis can lead to
o Misnomer – implies that bones are stone-like prominent hepatosplenomegaly
 Bones are actually brittle and fracture 2. AD
easily (chalk-like)
  Milder; may not be detected until  Craniofacial enlargement → leontiasis
adolescence or adulthood – incidental or ossea (lion face)
because of repeated fractures  Heavy cranium
o Tx: HSC transplantation  Platybasia and compression of the
 Osteopenia and Osteoporosis posterior fossa
o Osteopenia – decreased bone mass  Chalk stick-type fractures of the LE
o Osteoporosis – osteopenia severe enough to  Hypervascularity of Pagetic bone warms
significantly increase fracture risk the overlying skin
 Complication: sarcoma (fibro/osteo)
SDs below mean peak  Radiographic dx – enlarged with thick
bone mass in young adults coarsened cortices and medulla
Osteopenia 1 to 2.5  Active disease – wedge-shaped lytic
Osteoporosis > 2.5
leading edge
o Morphology
 Elevated serum AP
 Hallmark of osteoporosis – histologically
 Normal serum Ca and P
normal bone decreased in quantity
 Osteonecrosis (AVN)
 Postmenopausal - > affectation of bones
o MC causes: fractures and corticosteroid
with > SA – cancellous compartment of
administration
vertebral bodies
o Morphology
 Trabecular plates become perforated and
 Medullary infarcts – geographic in shape
thinned and lose their interconnections →
and involve both trabecular bone and
microfractures, vertebral collapse
marrow
 Senile – cortex thinned by subperiosteal
 Subchondral infarcts – triangular/wedge-
and endosteal resorption, and the
shaped segment with subchondral bone
Haversian systems are widened
plate as the base undergoes necrosis
o Clinical Features
 Cartilage remains viable with nutrients
 Can’t be reliably detected in plain
from SF
radiographs until 30-40% bone mass is lost
 Dead bone – empty lacunae surrounded
 Paget Disease (Osteitis Deformans)
by necrotic adipocytes
o Increased but disordered and structurally
 Released FAs bind Ca and form insoluble
unsound bone mass
Ca soap
o Stages
o Clinical Features
 Osteolytic
 Sx depend on location and extent of
 Mixed osteoclastic-osteoblastic
infarct
 Burned out quiescent osteosclerotic
 Subchondral – pain initially with activity,
(osteoblastic)
then becomes constant; collapse →
o Presents in late adulthood and more common
secondary OA
with increasing age  Medullary infarcts – small and clinically
o Morphology silent
 Hallmark: mosaic pattern of lamellar bone
that develops in the sclerotic phase
 Jigsaw-puzzle-like appearance d/t
prominent cement lines – join
haphazardly oriented units of lamellar
bone
 Abnormally large osteoclasts
o Clinical Features
 Monostotic in 15% cases
 MC involves the axial skeleton and
proximal femur
 Pain – microfracture or nerve compression