Biochemistry and Molecular Biology - Bone Health

Bone Metabolism and Regulation

Calcium Overview

Calcium is the most abundant mineral in the body. Approximately 99% of calcium is stored in the skeleton (bones and teeth) in the form of hydroxyapatite, represented by the formula 3Ca3(PO4)2 \cdot Ca(OH)2. The remaining 1% is present in body fluids and other tissues, specifically in the extracellular fluid (ECF).

Blood Calcium Levels

The normal blood calcium level ranges from 9-11 mg/dl, with an average of 10 mg/dl. Calcium in the blood is categorized into:

1. Diffusible Calcium (55%):

   • Ionizable (45%): The active form of calcium, $Ca^{2+}$.

   • Non-ionizable (10%): The inactive form of $Ca^{2+}$, complexed with citrate.

2. Non-diffusible (Non-ionizable) (45%):

   • The form is bound to plasma proteins, mainly albumin.

Hormonal Regulation of Calcium and Phosphate Levels

1. Parathyroid Hormone (PTH)

PTH increases blood calcium levels through:

• Absorption of calcium from the intestine.

• Reabsorption of calcium and excretion of phosphate by renal tubules.

2. Vitamin D

Vitamin D increases blood calcium levels by:

• Absorption of calcium from the intestine.

• Reabsorption of calcium by renal tubules.

• Mobilization of calcium from bones.

3. Calcitonin

Calcitonin is a hypo-calcemic hormone that decreases blood calcium by:

• Increasing calcium deposition in bones.

• Inhibiting osteoclast activity.

• Increasing calcium excretion in the kidneys.

Impact of Corticosteroids on Calcium Levels

Corticosteroids, such as cortisone, can affect calcium levels:

1. Reduced Intestinal Calcium Absorption: Corticosteroids block the intestine's absorption of calcium.

2. Increased Urinary Calcium Excretion: Corticosteroids promote calcium loss through urine.

3. Impaired Bone Formation: Corticosteroids reduce calcium absorption and increase bone breakdown, leading to decreased bone formation and increased risk of osteoporosis.

Role of Thyroid Hormones (T3 and T4) on Bone

1. Bone Growth and Development: Thyroid hormones stimulate bone growth during childhood and adolescence and promote maturation of the epiphyseal plate. T3 is the active form affecting bone cells directly.

2. Bone Remodelling: Thyroid hormones stimulate both osteoblasts (bone-forming cells) and osteoclasts (bone-resorbing cells).

3. Normal vs. Excess Levels:

   • At normal levels, thyroid hormones help maintain healthy bone turnover.

   • In excess (hyperthyroidism), osteoclast activity dominates, increasing bone resorption, leading to bone loss, decreased bone density, and risk of osteoporosis.

Factors Decreasing Calcium Absorption

1. Oxalic Acid and Phytic Acid: Foods high in oxalic acid (e.g., spinach, chard, chocolate) and phytic acid (whole-grain foods, high-fiber foods) reduce calcium absorption by binding with calcium to form unabsorbable salts like calcium oxalate.

2. Phosphorus: Excessive phosphorus in the diet causes precipitation of calcium in the form of calcium phosphate.

3. Caffeine and Certain Drugs: Caffeine, anticoagulants, cortisone, and thyroxine reduce calcium absorption.

4. Stress: Stress negatively affects HCl production in the stomach and normal digestive behavior, impairing calcium absorption.

Vitamin D: Types and Synthesis

Vitamin D is a group of fat-soluble vitamins derived from cholesterol. Vitamins D2 (ergocalciferol) and D3 (calcitriol) are the only ones with known biological actions in the human body.

Vitamin D Synthesis and Exposure

The skin synthesizes vitamin D when exposed to sunlight. Factors reducing exposure to the sun’s UVB rays, decreasing vitamin D3 synthesis, include:

• Long winters

• High altitude

• Sunscreen use

• Skin color (including tanned skin)

Less than 30 minutes of sun exposure can increase blood levels of vitamin D3 more effectively than orally taking 10,000 IU of vitamin D3.

Bone Mineral Density (BMD)

Bone mineral density (BMD) is a measurement of the amount of calcified tissue in grams per centimeter squared of bone tissue ($g/cm^2$). High BMD indicates greater bone strength, and BMD measurement helps predict the risk of bone fracture.

Vitamin D Toxicity

Vitamin D toxicity, though rare, can cause hypercalcemia (high calcium levels), leading to:

1. Excessive calcium excretion through urine, potentially causing kidney damage.

2. Calcification of blood vessels, particularly dangerous in the major arteries of the heart and lungs, which can cause death.

Vitamin D synthesis from sun exposure does not typically cause vitamin D toxicity due to the tightly regulated production of vitamin D3 in the skin.

Rickets and Osteomalacia

• Rickets (الكساح): Occurs in children due to vitamin D deficiency, reduced sunlight exposure, impaired vitamin D absorption (e.g., obstructive jaundice), or vitamin D activation (liver & renal failure). Risk factors include breastfeeding, black skin, and older age.

• Osteomalacia (لين العظام): Occurs in adults.

Prevention of Vitamin D Deficiency

• Infants: 400 IU/day

• Adults: 1000 IU/day

This deficiency is referred to as vitamin D-sensitive rickets. Vitamin D-resistant rickets involves hereditary mutations in the genes of the vitamin D receptor.

Osteoporosis (OP) ھشاشة العظام

Osteoporosis involves a gradual reduction in bone mineral density (BMD), leading to fractures. BMD is measured using DEXA scan (Dual Energy X-ray Absorptiometry).

Risk Factors for Osteoporosis

• Drugs (e.g., glucocorticoids, thyroid hormone)

• Age-related factors (senile osteoporosis, >70 years): Decreased osteoblast activity, decreased calcium intake, decreased sex hormones

• Post-menopause: Abrupt decrease in estrogen levels, increasing bone resorption. Women may experience bone loss of 3% per decade after menopause, increasing to 9%.

Causes of Osteoporosis Risk in the Elderly

1. Reduced calcium bioavailability.

2. Decreased kidney capacity to convert vitamin D to its active form.

3. Less effective skin synthesis of vitamin D and reduced sunlight exposure.

Postmenopausal Women and Bone Loss

Decreases in estrogen production cause increased bone resorption and decreased calcium absorption. Annual decreases in bone mass range from 3-5% in the first years of menopause, decreasing to less than 1% after age sixty-five.

Clinical Presentation of Osteoporosis

• Bone pain

• Fracture with minor trauma

• Late-stage symptoms: kyphosis & lordosis

• Tension headache

• Neck and shoulder pain

• Difficulty breathing, pain in the mid/lower back, chest

• "Texting Neck" aka Anterior Head Syndrome

Nonpharmacological Treatment for Osteoporosis

1. Minimal exercise, minimal sun exposure, avoiding WT loss >10%.

2. Restrict caffeine.

3. Stop smoking.

4. Eat food rich in calcium and vitamin D.

5. Prevention of falls.

Recommended Dietary Allowances (RDA)

Vitamin D

• 0-12 months: 10 mcg (400 IU)

• 1–13 years: 15 mcg (600 IU)

• 14–18 years: 15 mcg (600 IU)

• 19–50 years: 15 mcg (600 IU)

• 51–70 years: 15 mcg (600 IU)

• >70 years: 20 mcg (800 IU)

Calcium

• 0–6 months: 200 mg

• 7–12 months: 260 mg

• 1–3 years: 700 mg

• 4–8 years: 1,000 mg

• 9–13 years: 1,300 mg

• 14–18 years: 1,300 mg

• 19–50 years: 1,000 mg

• 51–70 years: 1,000 mg

• >70+ years: 1,200 mg

Vitamin D-Rich Foods

• Salmon

• Canned sardines

• Canned tuna

• Fresh shiitake mushrooms

• Egg yolk

• Fortified foods (milk, orange juice, yogurt, baby formula, cereal, and cheese)

Vegan Sources of Vitamin D

• Vitamin D supplements

• Plant-based fortified foods:

  • Soy, almond, or oat milk

  • Cereal

  • Margarine

  • Orange juice

Calcium-Rich Foods

• Milk (300 mg per 8 ounces)

• Greek yogurt (200 mg per 6 ounces)

• Dried figs (65 mg per 2 figs)

• Cooked broccoli (60 mg per cup)

• Oranges (55 mg per orange)

• Canned sardines with bones (325 mg per 3 ounces)

Vegan Sources of Calcium

• Canned baked beans

• Cooked broccoli rabe

• Fortified almond, soy, or rice milk

• Fortified fruit juices

• Tofu prepared with calcium

• Fortified cereal