This document discusses various bone diseases and disorders. It begins by describing the different types of cells that make up bone, including osteoprogenitors, osteoblasts, osteoclasts, and osteocytes. It then discusses several specific bone diseases and disorders in more detail, including osteoporosis, Paget's disease, rickets/osteomalacia, hyperparathyroidism, and fractures. It also provides information on osteonecrosis, osteomyelitis, bone tumors, joint diseases like osteoarthritis and rheumatoid arthritis, and other conditions like gout. Throughout, it includes details on pathogenesis, morphology, clinical expression, and imaging findings for many of these diseases.

1. Bone Diseases
Remo George Ph.D., ABSNM, NMTCB(CNMT)

2. Cells of Bone
• OSTEOPROGENITOR (“STEM”)(TGFβ)
• OSTEOBLASTS (surface of spicule), under
control of calcitonin to take blood calcium
and put it into bone.
• OSTEOCYTES (are osteoblasts which are
now completely surrounded by bone)
• OSTEOCLASTS (macrophage lineage), under
control of PTH to chew up the calcium of
bone and put it into blood

3. Classical actions of vitamin D to
maintain serum calcium homeostasis
• Vitamin D is sole
factor that
stimulates
intestinal calcium
absorption
• Vitamin D and PTH
in concert
necessary to
mobilize calcium
from the bone and
conserve calcium
from urine.

4. Ultrastructure and function of osteoclasts.
• Multiple nuclei, abundant
mitochondria and large number of
vacuoles & lysosomes.
• Bone-resorbing osteoclasts form
ruffled borders and sealing zones
• The resorbing area under ruffled
border is acidic (vacuolar H+-
ATPase are localized)
• Enzymes cathepsin K, MMP9 and
TRAP secreted into resorption
lacuna degrade bone matrix
proteins
• Degradation products
endocytosed, packaged into
transcytotic vesicles and secreted
from functional secretory domain
• Numerous calcitonin receptors
and αvβ3 vitronectin receptors
• DC-STAMP and OC-STAMP involved
in cell–cell fusion of osteoclasts BoneKEy Reports (2014) 3, Article number: 495

5. Regulation of osteoclast differentiation
and function by osteoblastic cells
• Bone resorption-stimulating
factors act on osteoblastic cells
to induce membrane-associated
factor RANKL
• Osteoblasts constitutively
produce M-CSF
• Osteoclast precursors express
receptors RANK and c-Fms and in
the presence of RANKL and M-
CSF differentiate into osteoclasts
• Osteoblastic cells secrete decoy
receptor OPG, which inhibits the
RANKL–RANK interaction
between osteoblasts and
osteoclast precursors
• Multinucleated osteoclasts also
express RANK, and RANKL
induces the bone-resorbing
activity of osteoclasts via the
interaction with RANK
BoneKEy Reports (2014) 3, Article number: 495

6. Cells of Bone
A, Active osteoblasts synthesizing bone matrix proteins. The
surrounding spindle cells are osteoprogenitor cells.
B, Two osteoclasts resorbing bone. The smaller blue nuclei surrounded
by a halo of clearing in the dense pink lamellar bone are osteocytes in
their individual lacunae.
A B

7. Cells of the Bone

8. Bone Diseases
• Congenital Disorders of Bone and Cartilage
– Osteogenesis Imperfecta
– Achondroplasia and Thanatophoric Dwarfism
– Osteopetrosis
• Acquired Diseases of Bone
– Osteoporosis
– Paget Disease (Osteitis Deformans)
– Rickets and Osteomalacia
– Hyperparathyroidism
– Fractures
– Osteonecrosis (Avascular Necrosis)
– Osteomyelitis
– Pyogenic Osteomyelitis
– Tuberculous Osteomyelitis
• Bone Tumors
– Bone-Forming Tumors
– Cartilage-Forming Tumors
– Fibrous and Fibroosseous Tumors
– Miscellaneous Bone Tumors
• Joints
– Arthritis
– Osteoarthritis
– Rheumatoid Arthritis
– Juvenile Rheumatoid Arthritis
– Seronegative
Spondyloarthropathies
– Gout
– Pseudogout
– Infectious Arthritis
– Joint Tumors and Tumor-Like
Lesions
– Ganglion and Synovial Cysts
– Tenosynovial Giant Cell Tumor

9. Osteogenesis Imperfecta
• “Brittle” bone disease, too LITTLE bone
• Blue sclerae, Type 1 most common & mildest type
• Mutations in genes which code for the alpha-1 and alpha-
2 chains of COLLAGEN 1
• Mutations of COLLAGEN 2,10, 11 manifest themselves as
CARTILAGE diseases, ranging from joint cartilage
destruction to fatal sequelae

10. Dwarfism
• Achondroplasia, dwarf
(non-lethal)
• Thanatophoria, dwarf (lethal,
FGF-3 mutations)
• a point mutation (usually Arg for
Gly375) in the gene that codes
for FGF receptor 3 (FGFR3),
which is located on the short
arm of chromosome 4. In the
normal growth plate, activation
of FGFR3 inhibits cartilage
proliferation, hence the term
“achondroplastic”
• A MUTATION causes FGFR3 to be
constantly activated.
Achondroplastic “dwarf”
Short arms and extra folds of skin
Thanatophoric “dwarf”, often lethal
J. Nucl. Med. Technol. Sept.
1, 2013 vol. 41 no. 3 234-235

11. Osteopetrosis
• “Marble” bone,
increased bone, brittle,
sclerotic bone
• Carbonic anhydrase
deficiency resulting from
mutation in encoded CA2
gene, i.e., ↓ acid
• ↓ osteoclast resorption
• Bone-on-bone
appearance on
radiographs Medicine (Baltimore). 2015 Jun;94(22)

12. Osteoporosis
• “Peak” bone mass is early adulthood
• Normal decline, slow
• Osteoporosis is accelerated bone loss
• Factors:
– AGE
– Physical activity
– Estrogen withdrawal (menopause)
– Nutrition (Ca++)
– Genetics
Categories of
Osteoporosis
Nuc Med Rev 2012, 15, 2: 124–131
Patient 60 years old
with osteoporosis
complicated with
vertebral fractures

13. Paget’s Disease
• Matrix madness, Osteoblasts/-
cytes gone wild
• THREE PHASES:
• 1) Increased osteoclast
resorption
• 2) Increased “hectic” bone
formation (osteoblasts)
• 3) Osteosclerosis
• ELEVATED ALKALINE-
PHOSPHATASE
• ELEVATED urine
HYDROXYPROLINE
• CLINICAL: PAIN!!!
(MICROFRACTURES)
Radionuclide Biphosphonate Imaging

14. • VITAMIN D
deficiency/dysfunction
• Rickets:
– In children, prior to
epiphyseal fusion,
vitamin D deficiency
results in growth
retardation
associated with
expansion of growth
plate known as
rickets (cupping,
fraying, widening of
GP).
• Osteomalacia:
– In adults, Vit. D
deficiency leads to
hypocalcemia &
hypophosphatemia
resulting in poor
mineralization of
bone matrix proteins
Schematic representation of the main steps
of the vitamin D biosynthetic pathway,
where genetic aberrations may lead to
rickets and osteomalacia. The renal defect in
pseudo–vitamin D–deficiency rickets (PDDR)
is indicated by the break in the 1,25(OH)2D3
arrow arising in the kidney. The mutation
leads to insufficient synthesis of 1,25(OH)2D.
The left part of the figure represents a target
cell where schematic coupling of the ligand
to its receptor (VDR) takes place in the
cytosol or, more likely, in the nucleus. The
VDR then heterodimerizes with the RXR
receptor. For ease of representation, the RXR
ligand (9-cis retinoic acid) is not depicted.
The complex then binds to DNA to regulate
gene transcription. Various mutations
affecting either of the two VDR domains
(DBD, DNA-binding domain; LBD, ligand-
binding domain), depicted by the stippled X
over the receptor complex, cause hereditary
vitamin D–resistant rickets (HVDRR).
Rickets & Osteomalacia
Osteomalacia. To r/o
mets. The unusually
large number of rib
lesions raised the
suspicion of metabolic
bone disease rather
than metastases.

15. Hyperparathyroidism
• PRIMARY - (PTH adenoma)
– Entire skeleton
• OSTEITIS FIBROSIS CYSTICA (von
Recklinghausen’s disease (of
bone)
• “Brown” “Tumor”
• SECONDARY - (RENAL) (NOT
AS SEVERE AS 1º)
• TERTIARY - from chronic 20
Overview of the pathogenesis of secondary hyperparathyroidism.
PTH, parathyroid hormone; VDR, vitamin D receptors
Tertiary Hyperparathyroidism.
Diffusely increased uptake in
the lungs, stomach, and heart.

16. Fractures
• Types
– Complete, incomplete
– Closed, open (communicating)
– Comminuted (splintered, “greenstick”)
– Displaced (NON-aligned)
– PATHOGENIC, (non-traumatic, 2º to other disease, often
metastases)
– “STRESS” fracture
• Three Phases
1. HEMATOMA, minutes, days
2. SOFT CALLUS (“PRO”-CALLUS), ~1 week
3. HARD CALLUS (BONY CALLUS), several weeks
• COMPLICATIONS
– PSEUDARTHROSIS (non-union)
– INFECTION (especially OPEN [communicating] fractures)

17. Osteo/Avascular/Aseptic Necrosis
• Cause: ISCHEMIA
– Trauma
– Steroids
– Thrombus/Embolism
– Alcohol abuse
– Vessel injury, e.g., radiation
– Sickle cell anemia
– INCREASED intra-osseous
pressure vascular
compression
– Venous hypertension

18. Osteomyelitis
• Pyogenic: Staph, E. coli,
Pseudom, Kleb, Salmonella
– Hematogenous
– Contiguous, e.g., from a
nearby joint
– Direct implantation
• TB
– Usually blood borne
– TB of spine is known as
POTTS disease
• Syphilis
– CONGENITAL
– TERTIARY, “SABRE” shins
• DX: X-ray, 3-phase bone
imaging
Sabre Shins

19. BONE TUMORS
• BONE
– OSTEOMA (benign, solitary, middle age, skull/face common)
– OSTEOID OSTEOMA (benign, >2cm dia, nidus, appendicular
skeleton, teens/ 20s, M>>F, painful)
– OSTEOBLASTOMA (axial skeleton, no nidus)
– OSTEOSARCOMA (late teens, knees, metaphyses, painful)
• CARTILAGE
– OSTEOCHONDROMA (most common, cartilage & bone present,
hereditary, M>>F, pelvis/scapulae/ribs)
– CHONDROMA (pure hyaline cartilage)
– CHONDROBLASTOMA (rare, teens, M>>F, often knees, epiphyses)
– CHONDROMYXOID FIBROMA (Rarest of all, teens, males)
– CHONDROSARCOMA (malignant)
• FIBROUS
– FIBROUS CORTICAL DEFECT/NON-OSSIFYING FIBROMA (most
common, < 1cm, children >2, if >5-6cm then called non-ossifying
fibroma)
– FIBROUS DYSPLASIA (benign, 70% single bone, 27% poly-ostotic,
3% poly-ostotic with café-au-lait, endocrine disorders and
precocious puberty
– FIBROSARCOMA/MALIGNANT FIBROUS HISTIOCYTOMA
(metaphyses of long bones/ pelvis, lytic, fractures)
• MISC.
– Ewing’s “sarcoma” (neuroendocrine origin, chromosome
translocation 11 & 22 with EWS gene rearrangement, 2nd most
childhood malignancy, arise in medullary cavity of bone)
– Giant Cell Tumor (20s-40s, macrophage lineage)
– METASTASES (Prostate (M), breast (F), blastic or lytic?)

21. Joint Diseases
• “ARTHRITIS”
– DEGENERATIVE (OSTEOARTHRITIS)
– RHEUMATOID
• “JUVENILE” RHEUMATOID
• NON-INFECTIOUS: Ankylosing Spond.,
Reactive, Psoriasis, IBD
• INFECTIOUS: Supp., TB, Lyme, Viral
• GOUT (URATE)
• PSEUDOGOUT (PYROPHOSPHATE)
• Tumors (all are of synovium)
– Ganglion (Synovial Cyst), non-
neoplastic
– Giant Cell Tumor (Pigmented
VilloNodular Synovitis[PVNS]),
benign
– Synovial Sarcoma, malignant

22. Osteoarthritis
• Etiology/Risk
Factors: Age,
Trauma, Genes
• Pathogenesis:
Progressive
EROSION of
articular cartilage
• Morphology: X-
Ray, “eburnation”,
“joint mice”,
osteophytes
• Clinical
Expression: PAIN,
Limitation of
motion
Heberden’s Nodes in DIP

23. Rheumatoid Arthritis
• Chronic systemic inflammatory disorder
• Principally attacks the joints
• Nonsuppurative proliferative &
inflammatory synovitis
• Destruction of articular cartilage & ankylosis
of joints
• May affect many tissues and organs—skin,
blood vessels, heart, lungs, & muscles
• Morphology: Synovial lymphocytes,
macrophages, plasma cells, neutrophils,
osteoclasts, “pannus”, hyperemia,
rheumatoid “nodules”, vasculitis
• Clinical Expression: PAIN, Limitation of
motion, malaise, fatigue, rheumatoid factor
IgMIgG-Fc,
CLINICAL FEATURES :
• 1% of population, F>>M
• Morning stiffness, mean age 45 yrs
• “TYPICAL” hand /x-ray findings, MCP ulnar
deviation
• Symmetric arthritis
• SERUM RHEUMATOID FACTOR
ULNAR DEVIATION of MCP joints

24. RA vs OA

25. Juvenile Rheumatoid
Arthritis
• Begins BEFORE age 16, by
definition
• Unknown etiology, often genetic
component
• Generally LARGER joints than RA
• Often positive antinuclear
antibodies
Whole body bone scan
using technetium-99m
shows increased bone
uptake in the lesions of
a patient with juvenile
idiopathic arthritis.
J Pediatr. 2010 Nov;53(11):931-935.

26. Seronegative
Spondyloarthropathies
• ANKYLOSING SPONDYLITIS (aka,
“rheumatoid” spondylitis, or
Marie-Strumpell Disease [HLA-
B27] (M>>F)
• “REACTIVE” ARTHRITIS (follows
GU or GI infections)
– From osteomyelitis
– Usually suppurative
– GC, staph, strep, H. flu, E. coli,
Salmonella, viral
– fever, leukocytosis
• REITER SYDROME (urethral &
conjunctival inflammation too)
[HLA-B27]
• Arthritis associated with IBD
• PSORIATIC ARTHRITIS [HLA-B27]
Pathogenesis of ankylosing spondylitis

27. Bone Scintigraphy in Spondylolysis
• (A) Planar images are
normal in a 20-year old
gymnast with sever low
back pain and negative
radiographs and MRI
• (B) However, transverse
and coronal SPECT
images show focal
abnormal activity in
the right posterior
element of L5-S1
(arrow) consistent with
spondylolysis.
Nuclear Medicine: The Requisites, 4th Edn.

28. Gout
• Endpoint of HYPERURICEMIA
from ANY cause resulting in JOINT
deposition of monosodium urate
crystals (TOPHI)
• ACUTE
• CHRONIC
• 10% of population has
hyperuricemia (>7 mg/dl), but
only 1/20 of these has gout
Tophus area predominantly
containing crystals.
The fanning arrangements of MSU
crystals is suggestive of spherulitic
crystal formation in a constrained
space. Frozen section stained with
haematoxylin and eosin, ×400
magnification. Abbreviation: MSU,
monosodium urate monohydrate
On this image of chronic
tophaceous gouty arthritis,
extensive bony erosions are
noted throughout the carpal
bones. Urate depositions
may be present in the
periarticular areas.

29. HYPERURICEMIA  GOUT
• Age of the individual and duration of the hyperuricemia are factors. Gout
rarely appears before 20 to 30 years of hyperuricemia. M>>F
• Genetic predisposition is another factor. In addition to the well-defined X-
linked abnormalities of HGPRT, primary gout follows multifactorial
inheritance and runs in families.
• Heavy alcohol consumption predisposes to attacks of gouty arthritis.
• Obesity increases the risk of asymptomatic gout.
• Certain drugs (e.g., thiazides) predispose to the development of gout.
• Lead toxicity increases the tendency to develop gout

30. Classification of Gout
Clinical Category Metabolic Defect
Primary Gout (90% of cases)
Enzyme defects unknown (85%–90%
of primary gout)
■ Overproduction of uric acid
Normal excretion (majority)
Increased excretion (minority)
Underexcretion of uric acid with normal
production
Known enzyme defects—e.g., partial
HGPRT deficiency (rare)
■ Overproduction of uric acid
Secondary Gout (10% of cases)
Associated with increased nucleic
acid turnover—e.g., leukemias
■ Overproduction of uric acid with
increased urinary excretion
Chronic renal disease ■ Reduced excretion of uric acid with
normal production
Inborn errors of metabolism—e.g.,
complete HGPRT deficiency (Lesch-
Nyhan syndrome)
■ Overproduction of uric acid with
increased urinary excretion
HGPRT, hypoxanthine guanine phosphoribosyl transferase.

31. Pseudogout
• Gout: Monosodium Urate
• Pseudo-GOUT: Calcium Pyrophosphate
• PSEUDOGOUT is also called
CHONDROCALCINOSIS, or CPPD
(Calcium Phosphate Deposition
Disease)
• IDIOPATHIC, HEREDITARY, SECONDARY
• Secondary joint damage,
hyperparathyroidism,
hemochromatosis, hypomagnesemia,
hypothyroidism, ochronosis, and
diabetes

32. Joint Tumors
• BENIGN
– GANGLION (SYNOVIAL
CYST)
– GIANT CELL TUMOR of
TENDON SHEATH, aka
PVNS, Pigmented
VilloNodular Synovitis
• MALIGNANT
– SYNOVIAL SARCOMA
F-18-FDG-PET-CT in a 15-year-old boy with
synovial sarcoma in the right shoulder.