[Web Module] Endocrine System - Osteoporosis

What is osteoporosis?

A systemic skeletal disorder characterized by decreased bone mass density due to increased osteoclast activity and decreased bone formation.

It leads to diminished stature, bone fragility, and increased risk of bone fractures

What is the role of calcium within the body?

Involved in many metabolic processes, including:

-Cell membrane permeability and function

-Neuronal excitability and transmission of electrical impulses

-Contraction of cardiac, skeletal, and smooth muscle

-Conduction of electrical impulses in the heart

-Blood coagulation

-Platelet adhesion

-Hormone secretion

-Enzymatic activity

-Catecholamine release from adrenal medulla

-Release of chemical mediators

What is bone deposition?

Calcium derived from the diet is moved from the intestines into the bone through osteoblasts

This is mediated by calcitonin, which is released from the thyroid glands

What is bone resorption?

Unbound ionized calcium is moved from the bone into the bloodstream when serum calcium levels are low through osteoclasts

This is mediated by PTH, which is released from the parathyroid glands

What occurs to bone deposition vs resorption from childhood to adulthood?

Bone deposition is greater than bone resorption during childhood.

After 35 years, bone resorption is greater than bone deposition, resulting in weaker bones.

This is a normal part of aging

What is the cause and result of a calcium defiency?

Calcium deficiencies can be caused by a poor diet, hormone alterations, and medications (corticosteroids)

A calcium deficiency results in loss of bone mass, loss of structural function, and osteoporosis. This is because bone resorption is increased during low serum calcium levels, and bone resorption will continue even if it results in weaker bones

What are the three hormones involved in calcium metabolism?

Parathyroid hormone (increase calcium levels)

Calcitonin (decrease calcium levels)

Calcitriol (increase calcium absorption)

What is the role of parathyroid hormone in calcium metabolism?

Parathyroid hormone is released by the parathyroid gland during low serum calcium levels.

Parathyroid hormone causes:

1. Release of calcium from bone (activates osteoclasts)

2. Increased calcium reabsorption from kidneys

3. Increased absorption of calcium in small intestine

4. Stimulates production of calcitriol from the kidneys (increase calcium absorption)

What is the basic role of osteoblasts in calcium metabolism?

Increases bone deposition, decreases serum calcium levels

What is the basic role of osteoclasts in calcium metabolism?

Increases bone resorption, increases serum calcium levels

What is the role of calcitonin in calcium metabolism?

Calcitonin is released by the thyroid glands during high serum calcium levels

Calcitonin causes:

1 Addition of calcium to the bone (activates osteoblasts)

2. Decreased absorption of calcium in small intestine

Which hormone is released during low calcium levels?

Parathyroid hormone

Which hormone is released during high calcium levels?

Calcitonin

What type of feedback mechanism regulates calcium metabolism?

Negative feedback

Low serum calcium levels -> PTH / Calcitriol

High calcium levels -> Calcitonin

What is the role of calcitriol in calcium metabolism?

It is an active form of vitamin D that is released by the kidneys in response to PTH stimulation during low serum calcium levels.

Calcitriol causes increased intestinal absorption of calcium

Why is a vitamin D deficiency detrimental to bone health?

A vitamin D deficiency causes less calcitriol to be produced, resulting in less intestinal absorption of calcium.

A vitamin D deficiency also causes increased PTH release, causing increased bone resorption

What are common signs of osteoporosis prior to a bone fracture?

1. Shortened stature (measurable loss of height)

2 Spinal deformities

3. Back pain

What are common causes of osteoporosis?

1. Inadequate dietary calcium intake (increased bone resorption)

2. Inadequate calcium absorption

3. Vitamin D deficiency

4. Hypersecretion of PTH (increased bone resorption)

5. Hyposecretion of calcitonin (decreased calcium resorption, osteoblast activity)

What are alterable risk factors of osteoporosis?

Factors that can be controlled by the individual that increases risk of osteoporosis. They have less of an impact compared to unalterable risk factors of osteoporosis

1. Smoking (Increased calcium excretion)

2. Calcium and vit D deficiency (increased calcium resorption)

3. Sodium intake (increased calcium excretion and bone resorption)

4. Caffeine and Alcohol (increased calcium excretion)

5. Lack of exercise (lack of retention of calcium and decreased bone mass density)

What are unalterable risk factors of osteoporosis?

Factors that can not be controlled by the individual that increases risk of osteoporosis. They have a greater impact compared to alterable risk factors of osteoporosis

1. Being of the female gender

-> Advanced age

-> Prolonged absence of menstruation

-> Menopause

2. Fragility fractures after 40 yrs of age

3. Northern European (White) and South Asian ancestry

4. Having a small lean frame (small bones -> less bone mass)

5. FHx of osteoporosis

6. Chronic administration of glucocorticoids (greater than 3 months), inhibits bone deposition and increases bone resorption

What is the basic role of estrogen in maintaining bone density?

Estrogen limits osteoclast activity

What is the basic role of progesterone in maintaining bone density?

Progesterone stimulates osteoblast activity

How does menopause contribute to increased risk of osteoporosis?

During menopause, estrogen and progesterone production is decreased. This causes increased osteoclast activity (lower estrogen) and decreased osteoblast activity (lower progesterone), resulting in lower bone density

Which individuals should undergo bone mass density testing for osteoporosis?

Individuals 50 years or older who are either:

65 years of age or older

OR

Have one of the following risk factors

-Hx of fragility fracture after 40

-FHx of osteoporosis

-Chronic glucocorticoid therapy >3 months

-Hx of smoking or alcohol intake

-Low body weight

-Hx of rheumatoid arthritis

-Hx of premature menopause

-Hx of primary hyperparathyroidism

-Hx of hypogonadism

What is a bone mass density test?

A test with high sensitivity for diagnosing osteoporosis

A dual energy x-ray absorptionmetry is used to scan the lumbar and hip

Normal bone mass density signifies low 10-year risk of fracture, and the patient should undergo repeated bone mass density testing every 5 years.

Decreased bone mass density indicates a moderate or high 10-year risk for fracture, and the appropriate pharmacological treatments of lifestyle changes should be initiated

What should be the treatment if the patient is found to have normal bone mass density after a BMD test?

Normal bone mass density indicates low 10-year risk of fracture

The patient should repeat BMD testing every 5 years to monitor for changes

What should be the treatment if the patient is found to have decreased bone mass density after a BMD test?

Decreased bone mass density testing indicates a moderate to high 10-year risk of fracture

The appropriate lifestyle changes and pharmacotherapy should be initiated for patients with moderate risk depending on risk factors

For individuals with a high 10-year risk, the appropriate pharmacological treatment for increasing bone mass and mediating high fracture risk should be initiated

The patient should undergo repeated BMD testing every 1-3 years

What are the 6 pharmacological treatment options for osteoporosis?

Antiresorptive

1. Hormone replacement therapy

2. Selective estrogen receptor modulators

3. Biphosphonates

4. RANKL inhibitors

5. Sclerostin inhibitors

Anabolic agents

6. Parathyroid hormone

These pharmacological treatments should be used in conjunction with calcium and vitamin D supplements

What is hormone replacement therapy as a treatment for osteoporosis? (Use, Patients Used for, Adverse Effects)

Use

Hormone replacement therapy (estrogen + progesterone) is used as treatment of symptomatic menopause. As a secondary benefit, it provides prevention and treatment of osteoporosis

Patients used for

Hormone replacement therapy should only be used for patients with moderate to severe symptoms of menopause, and should not be prescribed solely for the treatment of osteoporosis

Adverse Effects

-Breast cancer

-Heart disease

-Stroke

Which patients should be prescribed hormone replacement therapy as a treatment for osteoporosis?

Hormone replacement therapy should only be used as treatment for patients with moderate to severe symptoms of menopause, and should not be prescribed solely for the treatment of osteoporosis

What are selective estrogen receptor modulators as a treatment for osteoporosis? (Use, Mechanism of action, Patients used for, Adverse Effects)

Use

Used to prevent and treat osteoporosis while preventing cancer risks associated with HRT

Mechanism of action

SERMS acts as an estrogen receptor agonist at beta-estrogen receptors in the bone, causing estrogen effects of inhibiting osteoclast activity and reducing rate of bone resorption

SERMS acts as an estrogen receptor antagonist at alpha-estrogen receptors in the breast and endometrial tissue, resulting in no risk of breast and uterine cancer

Patients used for

SERMS is used for patients with osteoporosis without menopause or post menopausal symptoms

Adverse Effects

-Leg cramps

-Hot flashes

-Rare side effect of venous thromboembolism

What is the mechanism of action of selective estrogen receptor modulators?

SERMS acts as an estrogen receptor agonist at beta-estrogen receptors in the bone, causing estrogen effects of inhibiting osteoclast activity and reducing rate of bone resorption

SERMS acts as an estrogen receptor antagonist at alpha-estrogen receptors in the breast and endometrial tissue, resulting in no risk of breast and uterine cancer

What are tissue selective estrogen complexes? (Use, Benefits)

Use

Tissue selective estrogen complexes combine selective estrogen receptor modulators (agonist at bone/antagonist at breast and endometrial) with synthetic estrogen. It is prescribed for postmenopausal patients with osteoporosis

Benefits

-Provides relief of menopausal symptoms (synthetic estrogen)

-Protects breast and endometrium from cancerous effects (antagonist action of SERMS)

-Provides positive effect on bone protection and osteoporosis prevention (agonist action of SERMS and synthetic estrogen)

What are the benefits of using tissue selective estrogen complexes?

Tissue selective estrogen complexes combine SERMS with synthetic estrogen

Benefits include

-Provides relief of menopausal symptoms (synthetic estrogen)

-Protects breast and endometrium from cancerous effects (antagonist action of SERMS)

-Provides positive effect on bone protection and osteoporosis prevention (agonist action of SERMS and synthetic estrogen)

What are bisphosphonates? (Use, Mechanism, Dose, Adverse Effects, Contraindications)

Use

Most commonly prescribed drug class for the prevention and treatment of osteoporosis.

Mechanism

Biphosphonates inhibit osteoclast activity and reduce bone resorption, causing increased bone mass density and overall bone strength

Dosage

Two options

1. Alendronate, Risedronate - Oral administration, 1x per week

-> Taken on an empty stomach with full glass of water

-> No other foods, beverages, or medications should be taken for 30 minutes post administration

2. Zolendronic acid - IV administration, annually

-> Less frequent dosage, lower abdominal adverse effects, increased adherence to medication

Patients should only be prescribed bisphosphonates for 5 years to avoid atypical femur fractures. 5 year dosage associated with long term skeletal retention and stable bone mass

Adverse Effects

-Atypical Femur Fracture -> >5 year dosage

-Abdominal pain

-Dysphagia

Contraindications

-Biphosphonates are cleared renally, therefore pts with renal dysfunction should be prescribed with an alternative

What is the mechanism of action of biphosphonates?

Biphosphonates inhibit osteoclast activity and reduce bone resorption, causing increased bone mass density and overall bone strength

What is the oral dosage option for biphosphonates?

Includes Alendronate and Risedronate

Administered orally once per week

The medication should be taken on an empty stomach with a full glass of water. The patient should not consume any other foods, beverages or medications for 30 minutes post administration.

Adverse side effects include abdominal pain, dysphagia, and AFF's if dose is prolonged after 5 years.

What is the IV dosage option for biphosphonates?

Includes Zolendronic acid

Administered IV on an annual basis

Good option for patients who want less frequent doses, less abdominal side effects, and better adherence. It is also more potent than the oral route

What are contraindications of biphosphonates?

Biphosphonates are cleared renally, therefore pts with renal dysfunction should be prescribed with an alternative (Denosumab)

Biphosphonates should not be administered for more than 5 years as it can result in atypical femur fractures

Why should biphosphonates not be administered for more than 5 years

Administration of Biphosphonates for longer than 5 years is linked to atypical femur fractures.

Typically, pain the the thigh or groin region precedes an AFF, so this should be regularly screened in patients who have taken biphosphonates for longer durations

What are RANKL inhibitors? (Use, Mechanism of Action, Dosage, Adverse effects)

Use

Used for prevention of bone fractures in post menopausal women due to osteoporosis or patients who experience AFFs from biphosphonates

Mechanism of Action

RANKL inhibitors prevent the binding of RANKL ligands from RANKL receptors, preventing promotion of osteoclast activity, maintaining bone density and preventing osteoporosis.

Dosage

Administered SUBQ twice a year

Adverse Effects

-Hypocalcemia

-Fatigue

-Asthenia

-GI disturbances

-MSK pain

-Skin lesions

-Increased risk of infectino

-AFFs

What is the use of RANKL inhibitors?

Used for prevention of bone fractures in post menopausal women due to osteoporosis or patients who experience AFFs from biphosphonates

What is the mechanism of action of RANKL inhibitors?

In estrogen deficiency (post menopausal), RANKL is upregulated, causing increased osteoclast formation and bone loss

RANKL inhibitors prevent the binding of RANKL ligands from RANKL receptors, preventing promotion of osteoclast activity, maintaining bone density and preventing osteoporosis.

What are sclerostin inhibitors? (Use, Mechanism of Action, Dosage, Adverse Effects, Contraindications)

Includes Romosozumab

Use

Used to treat osteoporosis in postmenopausal women

Mechanism of Action

In estrogen deficiency (post menopausal), sclerostin inhibitors are increased, increasing bone loss

Sclerostin inhibitors Inhibit sclerostin activity, a protein that inhibits osteoblast and bone formation, resulting in increased bone formation and decreased bone resorption

Dose

2x SUBQ injections per month in one year

Adverse Effects

-Joint pain

-Headaches

-Cardiovascular events

Contraindications

-Patients with cardiovascular disease

What is the mechanism of action of sclerostin inhibitors?

In estrogen deficiency (post menopausal), sclerostin inhibitors are increased, increasing bone loss

Sclerostin inhibitors Inhibit sclerostin activity, a protein that inhibits osteoblast and bone formation, resulting in increased bone formation and decreased bone resorption

What are contraindications of sclerostin inhibitors?

Sclerostin inhibitors can cause cardiovascular events and is thus not recommended to be prescribed to patients with cardiovascular disorders

What is synthesized parathyroid hormone as a form of treatment for osteoporosis? (Use, Mechanism of Action, Dosage, Adverse Effects)

Includes Teriparatide

Use

Prescribed to patients with severe osteoporosis who are not responding to other forms of treatment

Mechanism of Action

Intermittent administration of parathyroid hormone is known to increase osteoblast activity and stimulate bone deposition

Dosage

SUBQ for a period of no longer than 24 months

Adverse Effects

-Nausea

-Dizziness

-Leg cramps

What is the use of synthesized parathyroid hormone for osteoporosis treatment?

Prescribed to patients with severe osteoporosis who are not responding to other forms of treatment

What is the mechanism of action of synthesized parathyroid hormone for osteoporosis treatment?

Intermittent administration of parathyroid hormone is known to increase osteoblast activity and stimulate bone deposition