Metabolic bone diseases

Question 1

Describe the composition of bones

Answer 1

A) Cells

1) Osteoclasts
2) Osteoblasts
3) Osteocytes (calms bone cells that are residing in their lacunae)
4) Osteoprogenitor cells

B) Extracellular matrix:

1) 40% organic (osteoid)

• Type 1 collagen (most important)
• Proteoglycan
• Osteocalcin/osteonectin
• Growth factors/cytokines

2) 60% inorganic
- Calcium hydroxyapatite

Question 2

Most CT disorders affects what?

Answer 2

Type 1 collagen which is the main protein found in the connective tissue of the body

1) Metabolism of type 1 collagen

2) Mutation of the gene that encodes for type 1 collagen

Question 3

Describe the normal histology of a bone

Answer 3

1) Osteocytes inside the lacunae in a normal resting condition (1-2 osteocytes surrounded by a white space)

2) Blood vessels are seen inside the bone marrow

Question 4

At which age is the bone density at its peak?

Answer 4

30 years

Question 5

What are the metabolic bone disorders?

Answer 5

They are a group of heterogeneous disorders characterized by abnormalities in calcium metabolism and/or bone cell physiology

• Calcium serum levels can be normal while there is a skeletal failure

Question 6

What are the different bone diseases caused by a disrupted bone metabolism?

Answer 6

A) Congenital bone diseases:

1) Osteogenesis imperfecta (“brittle bone disease” thin bone trabecula)

2) Osteopetrosis (“marble bone disease” thick bone trabecula)

B) Acquired diseases of bone development

1) Paget’s disease of bone

2) Hyperparathyroidism/Osteitis fibrosa cystica (parathormone controls calcium metabolism, high parathormone leads to calcium mobilization from the bone)

3) Osteomalacia/rickets (related to vitamin D deficiency)

4) Osteoporosis (decreased bone density, but the ratio of calcium to protein is normal “decreased protein quantity”), common in old age and post-menopausal woman

Question 7

What is the most common inherited disorder of connective tissue?

Answer 7

Osteogenesis imperfecta (brittle bone disease)

Question 8

What causes osteogenesis imperfecta?

Answer 8

• Genetic defects, which affect the body’s ability to make strong bones, as there is a deficiency in the synthesis of type I collagen
• The fundamental abnormality is too little bone resulting in extreme skeletal fragility

Question 9

Describe osteogenesis imperfecta

Answer 9

• Too little bone/brittle bone
• Genetic defect (in the collagen type 1 encoding genes), altering the body’s ability to make strong bones which is susceptible to fracture
• It has many subtypes that differ in their severity and the mode of inheritance (the classical mode of inheritance is the dominant type, but there is also a recessive type)

Question 10

Describe the different types of osteogenesis imperfect (brittle bone disease)

Answer 10

1) Dominant “classical” type: the person has too little type I collagen/poor quality of type I collagen due to a mutation of type I collagen genes (severe)

2) Recessive type: mutation in genes other than the one synthesizing type I collagen, but it interferes with the production of collagen (a problem in the metabolism of type I collagen)

• Both cases result in a fragile bone that breaks easily

Question 11

What are the symptoms of osteogenesis imperfecta?

Answer 11

• Symptoms can vary and can range from mild to severe (they can start appearing very early in infants or be delayed to adolescence if it is less severe)

1) Curved spine (can cause kyphosis)

2) Hearing loss

3) Triangular-shaped face with a broad forehead

4) The white of the eyes looks blue

5) Brittle teeth

6) Barrel-shaped rib cage

7) Short, small body; deformed bones

Question 12

What is osteopetrosis (stone/marble bone)?

Answer 12

• A group of extremely rare genetic diseases that are characterized by reduced bone resorption and diffuse symmetric skeletal sclerosis, resulting from the impaired formation/function of osteoclasts, as a result, bone modeling and remodeling are impaired resulting in skeletal fragility despite the increased bone mass
• Stone-like bones
• The problem is with the quality of the bone (as they will dissolve and ultimately break) and not its thickness (as osteoclasts are impaired, they won’t participate in bone turnover “removing old trabecula”)

Question 13

What are the consequences of osteopetrosis (stone/marble bone)?

Answer 13

1) Skeletal fragility

2) Hematopoietic insufficiency

3) Disturbed tooth eruption

4) Nerve entrapment syndromes

5) Growth impairments

Question 14

What are the effects of PTH on the homeostasis of calcium?

Answer 14

• It increases serum levels of calcium

1) Osteoclast activation, increasing bone resorption, and calcium mobilization

2) Increases the resorption of calcium by the renal tubules

3) Increases the urinary excretion of phosphates

4) Increases the synthesis of active vitamin D, 1,25(OH)2-D, by the kidneys, which in turn enhances calcium absorption from the gut and mobilizes bone calcium

Question 15

What is hyperthyroidism?

Answer 15

It is when the levels of PTH remain elevated despite it being high and functioning already

The excess calcium and phosphate in the serum will lead to excessive mobilization of calcium and phosphates from the bones, demineralizing the skeleton, this will be followed by increased osteoclastic activity, bone resorption, osteopenia, and rarefaction (diminished density)

• Peritrabecular and marrow will then fibrose which is associated with cyst formation
• This disease will start with (osteomalacia “loss of calcium/demineralization of the bone” then osteoporosis “loss of bone”)
• Both bone quality and quantity are affected

Question 16

What causes hyperthyroidism?

Answer 16

1) Primary hyperthyroidism: Autonomous parathyroid secretion (Due to hyperplasia, Due to functioning adenoma, Carcinoma of the gland)

2) Secondary hyperthyroidism: Due to an underlying renal or hypothalamic disease

Question 17

What are the clinical features of hyperparathyroidism (osteitis fibrosa cystica)?

Answer 17

1) Bone pain

2) Pathological fractures and deformities of long bones

3) Hypercalcemia and soft tissue metastatic calcification

Question 18

What are the two types of calcification?

Answer 18

1) Metastatic calcification:
- Present in case of increased calcium level (the most common sites are heart valves and alveoli)

2) Dystrophic calcification:
- normal serum calcium levels (deposition of calcium in dying tissues “necrotic tissue & tumors”)

Question 19

Osteitis fibrosa cystica is interrelated with what skeletal abnormalities?

Answer 19

• Osteoporosis and brown tumors
• Osteoporosis is generalized but is most severe in the phalanges, vertebrae, and proximal femur

Question 20

What is meant by dissecting osteitis?

Answer 20

When osteoclasts tunnel into and dissect centrally along the length of the trabeculae, creating the appearance of railroad tracks

Question 21

What is a brown tumor (one of the interrelated tumors with osteitis fibrosa cystica)?

Answer 21

Bone loss predisposes microfractures and secondary hemorrhage, which elicit an influx of macrophages and an ingrowth of reparative fibrous tissue creating a (brown tumor) mass, these lesion often undergoes cystic degeneration

• Its brown color is due to the vascularity, hemorrhage, and hemosiderin (which is engulfed by macrophages to give a brown color)

Question 22

What is the difference between adenoma/carcinoma and hyperplasia in relation to the parathyroid gland?

Answer 22

1) Adenoma/carcinoma: 1 enlarged parathyroid gland

2) Hyperplasia: 2-3 enlarged parathyroid glands

Question 23

What should we test for if the person has a normal parathyroid gland size and normal parathormone levels?

Answer 23

1) Checking the hypothalamus and the pituitary

2) Check the kidney

3) Check calcium and vitamin D levels

4) Check the bone density

Question 24

What is the hallmark of generalized osteitis fibrosa cystica (hyperparathyroidism)?

Answer 24

• If hyperparathyroidism is not managed, it can develop later on into a condition called generalized osteitis fibrosa cystica

1) Increased bone cell activity

2) Peritrabecular fibrosis

3) Cystic brown tumors

Question 25

What is osteoperosis?

Answer 25

• It is the increased porosity of the skeleton due to a reduction in bone mass
• It is a disorder where a reduction in the bone mass and associated structural changes leads to increased bone fragility and susceptibility to fractures
• It is a normal acquired disease where bone has normal mineralization

Question 26

What are the types of osteoporosis?

Answer 26

1) Localized (like disuse osteoporosis in a limb)

2) Generalized (affecting the entire skeletal system, it might be primary or secondary)

Question 27

What are the causes of secondary generalized osteoporosis?

Answer 27

1) Endocrine disorder: Hyperparathyroidism and Cushing’s syndrome

2) Neoplastic: Multiple myeloma and metastatic carcinoma

3) Gastrointestinal: Hepatic insufficiency, malnutrition, malabsorption, Vitamin C and D deficiency

4) Rheumatologic disease: Like rheumatoid arthritis

5) Drugs: Anticoagulants, anticonvulsants, chemotherapy, corticosteroids, lithium, and alcohol

6) Miscellaneous: Osteogenesis imperfect, immobilization, chronic destructive lung disease, and anemia

• In secondary osteoporosis, we treat the underlying condition

Question 28

What are the risk factors for osteoporosis?

Answer 28

1) Alcohol use

2) Use of corticosteroids

3) Low calcium levels

4) Low levels of estrogen

5) Smoking

6) Sedentary lifestyle

Question 29

What is the difference between osteopenia and osteoporosis?

Answer 29

Osteopenia is the beginning of osteoporosis

Question 30

What are the different forms of primary osteoporosis?

Answer 30

• When there is no underlying issue
• It is the commonest type of osteoporosis

1) Senile form: affects elderly people of both sexes

2) Postmenopausal form: occurs in women postmenopausal

• The whole skeleton is affected in both types

Question 31

Describe the morphology of primary osteoporosis

Answer 31

The cortex and trabeculae are thinned and the haversian systems widen (there is no change in the ratio of mineral to protein matrix)

• The affected bones are those which are weight-bearing and are more liable to fracture (like the vertebrae “especially postmenopausal” and the neck of the femur)
• Characterized by a decrease in total bone mass and density, decreased bone formation, and increased bone loss
• Total bone mass is an important determinant for the subsequent risk of osteoporosis, it is largely determined by personal factors (age, sex, and genetic factors) however external factors like physical activity, diet and hormonal status might play a role

Question 32

How does aging cause osteoporosis?

Answer 32

• Bone density is at its maximum at the third decade of someones life, after that each year an average of 0.7% is lost, due to the compensation of osteoblast with the resorptive activity of osteoclasts

1) Decreased replicative activity of osteoprogenitor cells

2) Decreased synthetic activity of osteoblasts

3) Decreased biological activity of matrix-bound growth factors

4) Reduced physical activity

Question 33

How does menopause cause osteoporosis?

Answer 33

It does it by the following steps:

1) Decreased serum estrogen
2) Increased IL-1, IL-6 & TNF levels
3) Increased expression of RANK & RANKL
4) Increased osteoclast activity

Question 34

What is the function of RANKL/RANK?

Answer 34

It is a signaling mechanism that regulates osteoclast formation, activation, and survival in normal bone modeling and remodeling and in a variety of pathologic conditions characterized by increased bone turnover, where osteoprotegerin comes and binds to RANKL preventing it from binding to RANK

• Thus the relative concentration of OPG and RANKL in bone is a major determinant of bone mass and strength

Question 35

Describe the relationship between OPG, PTH & RANKL

Answer 35

• PTH stimulates osteoblasts to secrete RANKL (activates osteoclasts)
• RANKL will then go to stimulate osteoclast precursor to become active
• OPG is a competitive inhibitor of RANKL, and thus it blocks the activation of osteoclasts
• PTH (involved in osteoclast activation) is secreted by some cancers like breast cancer

Question 36

What is the effect of physical activity on bone density?

Answer 36

The rate of bone loss is increased by decreased bone density (as seen in a paralyzed limb), on the contrary, physical activity increases bone mass and density as seen in athletes as mechanical forces are important stimuli for normal bone remodeling

Question 37

What are the different hormones that affect the bone density?

Answer 37

1) Estrogen deficiency stimulates osteoclastic activity leading to increased bone resorption

2) Testosterone deficiency is common in 1/3 of men with senile osteoporosis

Question 38

What are the clinical features of primary generalized osteoporosis (the commonest type)?

Answer 38

• Osteoporosis remains asymptomatic until skeletal fragility is advanced then:

1) Bone pain

2) Loss in height

3) Instability of the vertebral column occurs

4) Generally fractures occur after bending, lifting, or falling (fracture to the neck of the femur can lead to an increase in blood viscosity that might cause pulmonary embolism)

5) Immobility

6) Bruising, depression, and lower self-esteem

Question 39

How can we diagnose primary generalized osteoporosis?

Answer 39

• Requires complicated measures of bone density, it is difficult to diagnose as:

1) X-ray changes cannot be detected until 30%-40% of the bone mass is lost

2) The disease remains asymptomatic until skeletal fragility is advanced

3) Blood levels of calcium, phosphorus, and alkaline phosphatase are normal in uncomplicated osteoporosis cases

Question 40

What is Paget’s disease (osteitis deformans)?

Answer 40

• Usually begins in the fifth decade of life, chronic progressive disease
• Males are more affected than females
• More common in pet owners
• <30% of the patients will suffer its symptoms
• It is an inflammatory process, caused by a slow virus (paramyxovirus) that infects the osteoclasts

Question 41

What are the stages of Paget’s disease (Osteitis deformans)?

Answer 41

1) Initial osteolytic stage, characterized by excessive bone resorption

2) Mixed osteolytic-osteoblastic stage, ending with a predominance of osteoblastic activity

3) The osteoclastic stage, which is inactive, is characterized by the formation of osteoid

Question 42

What is the histologic hallmark of Paget’s disease?

Answer 42

• The mosaic pattern of lamellar bone
• The new bone formed in active disease is disordered and poorly mineralized, it is soft porous, and lacks structural stability and it is liable to fracture or deformity under stress

Question 43

Which bones are affected by Paget’s disease?

Answer 43

1) Monostotic in 155 of the cases, it might affect the tibia, ileum, femur, skull, vertebrae, or the humerus

2) Polystotic in 85% of the cases (more than one bone at the same time, eg spine, pelvis, and skull)

Question 44

What are the clinical features of Paget’s disease (osteitis deformans)?

Answer 44

1) In the early stage of the disease there are deformities of bones, kyphosis & the bending of the femur and tibia forward and outwards

2) Then the bones will harden and thicken

3) If the deformity occurred in the bones of the skull it might cause a headache, visual disturbance, and deafness

4) Back pain is common

5) Long bones of the legs might undergo chalk-stick fractures

6) Osteosarcoma can occur in <1% of patients

Question 45

How do we diagnose Paget’s disease (osteitis deformans)?

Answer 45

1) Blood:
- ALP (It is classically raised)
- Gamma-GT (Rules out the liver cause of increased ALP)

2) Bone scan:
- Shows an increased calcium uptake of calcium in affected bones

3) Urine:
- Often contains collagen due to the high bone resorption

4) X-ray:
- Lytic & sclerotic lesions (dark blob’s in the bone)
- Widening of the bone cortex
- Bone deformaties

Question 46

What is the treatment for Paget’s disease (osteitis deformans)?

Answer 46

• Based on the severity of the symptoms

1) Bisphosphonates (pamidronate, reduces osteoclasts activity “2 months can induce remission”)

2) Analgesia

3) Treat complications (joint replacement)