B102 Acquired diseases of bone development, Osteoperosis, Rachitis, and Osteomalacia

Question 1

Describe the two major types of osteoperosis and their morphology, where are fractures most frequent?

What is the third category of osteoperosis?

Answer 1

Senile osteoperosis, and Postmenopausal Osteoperosis, and Disuse osteoperosis/immobilized osteoperosis

Senile osteoperosis occurs in everyone as they age, both men and women. Peak bone density occurs at ~age 30. Bone density decreases 0.5% each year. Postmenopausal osteoperosis causes more severe progression of osteoperosis in women, and this group is at the highest risk, but both have the same morphology.

Biggest losses are in areas of the most trabecular bone which are the vertebral bodies and femoral neck. Fractures are thus most common in the vertebrae and hips.

In the vertebral bodies there is characteristic loss of horizontal bone trabecules and thickening of the verticle trabecules, with increased porosity and decreased osteoid.

Question 2

What causes senile osteoperosis, the molecular mechanisms?

What causes post-menopausal osteoperosis?

How frequent are post-menopausal fractures?

Answer 2

In general, it is due to a shift in the balance of resorption and deposition, towards resorption.

Age Related changes:

• Decreased proliferation and decreased functional activity of osteoblasts.
• Decreased deposition of growth factors in the bone.
• Osteoclast activity is retained, thus osteoclast actions are favored.
• Physical activity and bone loading suppresses Sclerositin expression in osteoblasts.
  
  • Sclerostin is inhibitory and proapoptotic, so normal bone loading suppresses SOST and increases osteoblasts survival and activity.
  • In senile patients, less activity, more osteoblast apoptosis.

Post-Menopausal changes

• Estrogen stimulates OPG release from osteoblasts, which inhibits RANK signaling.
• Low estrogen, decreased OPG levels
• The loss of estrogen also increases cytokine levels in the bone, IL-1, IL-6, and TNF
• These cytokines increase RANK/RANK-L action

Question 3

Why don’t we just use estrogen replacement therapy for post-menopausal women?

What are the main risks associated with oral contraceptives?

Answer 3

Becasue it can cause:

• Hypercoagulability
• Non-bacterial thrombotic emboli/endocarditis
• Polycystic ovary syndrome,
• Endometrial hyperplasia and cancer,
• Breast cancer

Estrogen causes a hypercoagulable state (estrogen contraceptives - risk of thrombosis)

It does this by increasing the production of coagulation factors by the liver (2 [prothrombin], 7, 9, and 10), and by inhibiting production of Antithrombin-III

Hypercoagulable states, and hyperestrogenic states are also a major risk factor for NBTE, Non-Bacterial Thrombotic Endocarditis. Forming small, thrombotic masses of fibrin and platelets on damaged valves (in the elderly these valves are very likely damaged). These thrombi have a high risk of embolization.

Oral contraceptives: OCPs lowers the risk of endometrial and ovarian cancers because of the progestin protective effect.
However, the relation between OCP and breast cancer is complicated and there are several conflicting studies about that. It’s generally believed that OCPs slightly increase the risk specially in those BRCA or family history positive patients.

Question 4

What is the clinical presentation and course of osteoperosis?

Answer 4

Thoracic and Lumbar vertebrae fractures are very common. These secondarily often cause kyphoscoliosis - kyphosis, extreme forward bending of the spine, scoliosis - sideways/lateral bending of the spine. which can cause compromised respiratory funciton.

Femoral neck fractures, with a high risk for pulmonary embolism and secondary pneumonia

DEXA scan of more than 1 std dev to the negative

Not reliably detectable by X-ray, until 30-40% of bone mass is already gone

Importantly, the lab values of calcium, phosphate, PTH, ALP, are all normal in osteoperosis.

Question 5

What are other factors influencing the development of osteoperosis?

Answer 5

Genetic factors:

• Certain Vitamin D receptor polymorphisms are associated with higher or lower peak bone density in adulthood, and thus affect rate of decline to osteoperosis
• Genetic variation in calcium uptake and PTH activity/response

Calcium intake and nutritional state:

• Subclinical calcium deficiencies are unfortunately very common in adolescents, and more common in girls than boys. This is a contributing factor to the increases rate in women.

Question 6

Secondary causes/risk factors for osteoperosis

Answer 6

Smoking

Alcoholism

Prolonged glucocorticoid therapy/cushing’s syndrome

Question 7

How is osteoperosis treated?

Answer 7

Adequate dietary calcium

Vitamin D supplementation

Physical exercise

Drugs that inhibit bone resorption

• bisphosphonates - induce apoptosis in osteoclasts.
• calcitonin
• estrogen, but has risks
• denosumab

Drugs that stimulate osteoblasts

• PTH, surprisingly, but in specific doses.

Question 8

Rickets and osteomalaciea caused by, pathogenesis

Answer 8

Vitamin D deficiency,

Hypocalcemia, Impaired bone mineralization.

Question 9

Rickets clinical presentation

Answer 9

Bowing of the legs

Frontal bossing

Pigeon breast deformity

Frontal bossing

Rachitic rosary of the osto-chondral rib joints, due to deposition of osteoid.