Bone marrow is the soft, spongy tissue inside bones that produces blood cells. It is found in the hollow cavities of bones. There are two types of marrow - red marrow produces blood cells while yellow marrow stores fat. Certain drugs can cause bone marrow toxicity by damaging the blood cell production in the marrow. These include chemotherapy drugs, NSAIDs, antithyroid medications, and others. Side effects of bone marrow toxicity include cytopenia, a low blood cell count, which can increase risk of infection, bleeding, and anemia. Careful monitoring is needed when using these types of drugs.

1. Bone Marrow Toxicity
04/29/17bonemarrowtoxicity
1
BONE MARROW TOXICITY
PRESENTED BY:
VISHNU JATOTH
SHRIKANT KIRWALE

2. Bone Marrow
 Specialized type of soft, diffuse connective tissue; called myeloid
tissue
 Site for the production of blood cells
 Found in medullary cavities of long bones and in the spaces of
spongy bone
04/29/17bonemarrowtoxicity
2

3. Bone Marrow
 Two types of marrow are present during a person’s lifetime:
 Red marrow
 Found in virtually all bones in an infant’s or child’s, adults body
 Functions to produce red blood cells
 Yellow marrow
 As an individual ages, red marrow is replaced by yellow
marrow
 Marrow cells become saturated with fat and are no longer
active in blood cell production
04/29/17bonemarrowtoxicity
3

4. Bone Marrow
 The main bones in an adult that still contain red marrow include the
ribs, bodies of the vertebrae, the humerus, the pelvis, and the femur
 Yellow marrow can alter to red marrow during times of decreased
blood supply, such as with anemia, exposure to radiation, and
certain diseases
04/29/17bonemarrowtoxicity
4

5. Functions of Bone
• Support—bones form the framework of the body and contribute to
the shape, alignment, and positioning of the body parts
• Protection—bony “boxes” protect the delicate structures they
enclose
• Movement—bones with their joints constitute levers that move as
muscles contract
• Mineral storage—bones are the major reservoir for calcium,
phosphorus, and other minerals
• Hematopoiesis—blood cell formation is carried out by myeloid
tissue
04/29/17bonemarrowtoxicity
5

6. Regulation of Blood Calcium Levels
• Skeletal system serves as a storehouse for about 98% of body
calcium reserves
• Helps maintain constancy of blood calcium levels
• Calcium is mobilized and moves in and out of blood
during bone remodeling
• During bone formation, osteoblasts remove calcium from
blood and lower circulating levels
• During breakdown of bone, osteoclasts release calcium
into blood and increase circulating levels
04/29/17bonemarrowtoxicity
6

7. Regulation of Blood Calcium
Levels
 Skeletal system
 Homeostasis of calcium ion concentration essential for the
following:
 Bone formation, remodeling, and repair
 Blood clotting
 Transmission of nerve impulses
 Maintenance of skeletal and cardiac muscle contraction
04/29/17bonemarrowtoxicity
7

8. Regulation of Blood Calcium
Levels
 Mechanisms of calcium homeostasis
 Parathyroid hormone
 Primary regulator of calcium homeostasis
 Stimulates osteoclasts to initiate breakdown of bone
matrix and increase blood calcium levels
 Increases renal absorption of calcium from urine
 Stimulates vitamin D synthesis
04/29/17bonemarrowtoxicity
8

9. Regulation of Blood Calcium
Levels
 Mechanisms of calcium homeostasis
 Calcitonin
 Protein hormone produced in the thyroid gland
 Produced in response to high blood calcium levels
 Stimulates bone deposition by osteoblasts
 Inhibits osteoclast activity
 Less important in homeostasis of blood calcium levels than
parathyroid hormone
04/29/17bonemarrowtoxicity
9

10. Development of Bone
 Osteogenesis—development of bone from small cartilage
model to an adult bone
 Intramembranous ossification
 Occurs within a connective tissue membrane
 Flat bones begin when groups of cells differentiate into
osteoblasts
 Osteoblasts are clustered together in centers of ossification
 Osteoblasts secrete matrix material and collagenous fibrils
04/29/17bonemarrowtoxicity
10

11. Development of Bone
 Cont…..
 Large amounts of ground substance accumulate around
each osteoblast
 Collagenous fibers become embedded in the ground
substance and constitute the bone matrix
 Bone matrix calcifies when calcium salts are deposited
 Trabeculae appear and join in a network to form
spongy bone
 Apposition growth occurs by adding of osseous tissue
04/29/17bonemarrowtoxicity
11

12. Development of Bone
 Endochondral ossification
 Most bones begin as a cartilage model, with bone formation
spreading essentially from the center to the ends
 Periosteum develops and enlarges, producing a collar of
bone
 Primary ossification center forms
 Blood vessel enters the cartilage model at the midpoint of
the diaphysis
04/29/17bonemarrowtoxicity
12

13. Development of Bone
 Endochondral ossification
 Bone grows in length as endochondral ossification
progresses from the diaphysis toward each epiphysis
 Secondary ossification centers appear in the epiphysis, and
bone growth proceeds toward the diaphysis
 Epiphyseal plate remains between diaphysis and each
epiphysis until bone growth in length is complete
04/29/17bonemarrowtoxicity
13

14. Development of Bone
Endochondral ossification
 Epiphyseal plate is composed of four layers:
 “Resting” cartilage cells—point of attachment joining the
epiphysis to the shaft
 Zone of proliferation—cartilage cells undergoing active
mitosis, causing the layer to thicken and the plate to
increase in length
 Zone of hypertrophy—older, enlarged cells undergoing
degenerative changes associated with calcium deposition
 Zone of calcification—dead or dying cartilage cells
undergoing rapid calcification
04/29/17
bone marrow toxicity
14

15. Bone Growth and Resorption
 Bones grow in diameter by the combined action of osteoclasts
and osteoblasts
 Osteoclasts enlarge the diameter of the medullary cavity
 Osteoblasts from the periosteum build new bone around the
outside of the bone
04/29/17bonemarrowtoxicity
15

16. Repair of Bone Fractures
 Fracture—break in the continuity of a bone
 Fracture healing
 Fracture tears and destroys blood vessels that carry nutrients
to osteocytes
 Vascular damage initiates repair sequence
 Callus—specialized repair tissue that binds the broken ends
of the fracture together
 Fracture hematoma—blood clot occurring immediately after
the fracture, is then resorbed and replaced by callus
04/29/17bonemarrowtoxicity
16

17. Cartilage
 Characteristics
 Avascular connective tissue
 Fibers of cartilage are embedded in a firm gel
 Has the flexibility of firm plastic
 No canal system or blood vessels
 Chondrocytes receive oxygen and nutrients by diffusion
 Perichondrium—fibrous covering of the cartilage
 Cartilage types differ because of the amount of matrix present
and the amounts of elastic and collagenous fibers
04/29/17bonemarrowtoxicity
17

18. Cartilage
 Types of cartilage
 Hyaline cartilage
 Most common type
 Covers the articular surfaces of bones
 Forms the costal cartilages, cartilage rings in the trachea,
bronchi of the lungs, and the tip of the nose
 Forms from specialized cells in centers of chondrification,
which secrete matrix material
 Chondrocytes are isolated into lacunae
04/29/17bonemarrowtoxicity
18

19. Cartilage
 Types of cartilage
 Elastic cartilage
 Forms external ear, epiglottis, and eustachian tubes
 Large number of elastic fibers confers elasticity and
resiliency
 Fibrocartilage
 Occurs in symphysis pubis and intervertebral disks
 Small quantities of matrix and abundant fibrous elements
 Strong and rigid
04/29/17bonemarrowtoxicity
19

20. Cartilage
Growth of cartilage
 Interstitial or endogenous growth
 Cartilage cells divide and secrete additional matrix
 Seen during childhood and early adolescence while cartilage
is still soft and capable of expansion from within
04/29/17bonemarrowtoxicity
20

21. Cartilage
Growth of cartilage
 Appositional or exogenous growth
 Chondrocytes in the deep layer of the perichondrium
divide and secrete matrix
 New matrix is deposited on the surface, increasing its size
 Unusual in early childhood but, once initiated, continues
throughout life
04/29/17bonemarrowtoxicity
21

22. DRUGS THAT CAUSE
BONEMARROW TOXICITY
• CYTOTOXIC CHEMOTHERAPEUTIC DRUGS
• NSAIDS
• ANTI THYROID DRUGS
• BONEMARROW TRANSPLANTATION
04/29/17bonemarrowtoxicity
22

23. DRUGS THAT CAUSE ……
• vincristine
• zidovudine:
postmarketing,
uncommon
• zidovudine
• 6-mercaptopurine
• EDTA
• allopurinol
• amiodarone
• amitriptyline
• anthracycline
• azathioprine
04/29/17bonemarrowtoxicity
23
• carbamazepine
• chloramphenicol
• doxorubicin
• imatinib: uncommon
• imipramine
• methotrexate
• methyldopa
• metronidazole
• valproate
Cytopenia is a reduction in the number of blood
cells.

24. Azathioprine Induced
Pancytopenia
 Azathioprine is commonly used for management of lupus nephritis
 Mild myelotoxicity is a common side effect of azathioprine, however, severe
myelosuppression leading to pancytopenia is uncommon
 In vivo , it is converted, non-enzymatically, to 6-mercaptopurine, Further
metabolism of this drug involves various enzymes like, hypoxanthine
guanine phosphoribosyl transferase (HGPRT) thiopurine
methyltransferase, xanthine oxidase
 HGPRT is responsible for its bio-activation and converts it to 6-thioinosine
5-monophosphate which is further metabolized to 6-thioguinine nucleotides
(6-TGNs)
 6-GTNs get incorporated into DNA and RNA and are possibly, responsible
for cytotoxic effect
04/29/17
bone marrow toxicity
24

25. CDK FAMILY
among the first
targeted therapy
approaches
pursued
for the treatment
of cancer
Palbociclib
Palbociclib was recently approved by the FDA in combination with
letrozole for the treatment of first-line advanced breast cancer.
FLAVOPERIDOL

26. MEGALOBLASTIC ANEMIA
DHFRas
e
reductas
e
Inhibitors like
MTX,BARBITURATES,PHEN
YTOIN
Examination of peripheral blood shows an increase in the mean
corpuscular hemoglobin concentration.
VITAMINE B12, FOLATE CONCENTRATION CAN DIAGNOSE.

27. RIBAVARIN hepatitis C infection

28. Reference
• T.M. Fliedner, D. Graessle, C. Paulsen, and K. Reimers. Cancer
Biotherapy and Radiopharmaceuticals. July 2004, 17(4): 405-426
• GREGORY S. TRAVLOS, Normal Structure, Function, and Histology
of the Bone Marrow Toxicologic Pathology, 34:548–565, 2006
• Rinaldo Florencio-Silva et al: Biology of Bone Tissue: Structure,
Function, and Factors That Influence Bone Cells, BioMed Research
International Volume 2015 :52-65
• Kamakshi Rao, Drug-Induced Hematologic Disorders, chapter 24, section
2 , McGraw-Hill Education, 367, 2014.
• Wenyue Hu1, Tae Sung1, Bart A. Jessen1, Stephane Thibault1,
Martin B. Finkelstein2,Nasir K. Khan3, and Aida I. Sacaan1,
Mechanistic Investigation of Bone Marrow Suppression Associated
with Palbociclib and its Differentiation from Cytotoxic
ChemotherapiesPublished OnlineFirst December 2, 2015; DOI:
10.1158/1078-0432.CCR-15-1421
04/29/17bonemarrowtoxicity
28