CLINICAL CHEMISTRY 2​​ ​ ​

●​ Parathyroid Hormone (PTH)

Calcium and Phosphate Homeostasis

Hypocalcemic Agent (Decrease Blood Calcium Levels)​

Serum calcium and phosphate levels are tightly regulated to

ensure proper function of neural, muscular, and organ systems. ●​ Calcitonin

These minerals play essential roles in:

Organs Involved in Calcium and Phosphate
●​ Nerve conduction
Homeostasis​

●​ Muscle contraction
●​ Cardiac output ●​ Skin: Synthesizes Vitamin D3 (cholecalciferol)

●​ Bone and teeth formation ●​ Liver: Converts Vitamin D3 to 25-hydroxy vitamin D

●​ Biochemical processes (energy metabolism, DNA & ●​ Small Intestine: Absorbs dietary calcium and phosphate

RNA synthesis) ●​ Skeleton: Stores and releases calcium and phosphate

●​ Parathyroid Glands: Regulate calcium levels via PTH
NOTE: Imbalances can lead to significant clinical consequences. ●​ Kidneys: Excrete calcium, regulate phosphate levels,
and activate vitamin D
Calcium and Phosphate Distribution
Vitamin D (Calciferol)

Calcium (Extracellular Cation)​

●​ 99% stored in bones and teeth

●​ 1% found inside cells
●​ Key roles:
○​ Muscle contraction
○​ Nerve conduction ●​ Forms:
○​ Cardiac output ○​ Vitamin D2 (Ergocalciferol) – Found in edible
mushrooms
Phosphate (Intracellular Anion)​
○​ Vitamin D3 (Cholecalciferol) – Produced in the
skin, found in diet (INACTIVE FORM)
●​ 85% stored in bones and teeth ●​ Functions as a hormone rather than a classic vitamin
●​ 15% inside cells ●​ Sources:
●​ Functions: ○​ Sunlight (UVB exposure)
○​ Similar to calcium ○​ Diet (fortified milk, liver, seafood)
○​ Biochemical processes ○​ Supplements
○​ Energy metabolism (ATP) ●​ Target Organs:
○​ DNA & RNA synthesis ○​ Intestines – Increases calcium and phosphate
absorption
Hormonal Regulation of Calcium and Phosphate ○​ Kidneys – Enhances calcium reabsorption
Metabolism ○​ Bones – Stimulates bone resorption for calcium
release
Hypercalcemic Agents (Increase Blood Calcium Levels)​
●​ Toxic at high levels, leading to hypercalcemia and
nervous system effects
●​ Vitamin D

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Calcium Homeostasis | Pre-Final | Lecture ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Prepared by: nielisyu
 ●​ Synthetic Analogs (e.g., Paricalcitol) used in chronic
kidney disease

Parathyroid Hormone (PTH)

Calcium metabolism is regulated by three primary organ systems:

the gastrointestinal (GI) tract, the kidneys, and bone. These
●​ Smallest endocrine gland in the body, located behind
systems work together to maintain calcium homeostasis through
the thyroid
complex interactions involving vitamin D, parathyroid hormone
●​ Typically four glands, but individuals may have three or
(PTH), and fibroblast growth factor 23 (FGF23).
one without affecting PTH production
●​ Functions similar to Vitamin D, with the additional role
of influencing enzyme activity to produce more active Gastrointestinal (GI) Regulation
vitamin D
●​ Normal intestinal function is essential for calcium
●​ Enhances Vitamin D secretion
absorption.
●​ NOT PART OF THYROID GLAND
●​ Disorders affecting the intestine (e.g., short bowel
syndrome, celiac disease, gastric weight loss surgeries)
Physiologic Effects of Vitamin D & PTH
can impair calcium absorption.
●​ Adequate dietary calcium, vitamin D availability, and
metabolism are required for optimal absorption.
●​ 1,25(OH)2D plays a key role in calcium absorption from
the small intestine.
●​ Dietary phosphate can bind calcium in the intestine,
forming calcium phosphate, which is insoluble and
nonabsorbable.
●​ Calcium carbonate is used as a phosphate binder in

●​ Stimulate calcium absorption in the kidneys renal failure patients to limit phosphate absorption.

●​ Increase calcium and phosphate reabsorption in the

intestines Role of Kidneys
●​ Increase bone resorption of calcium and phosphate
●​ The kidneys are critical in calcium metabolism, and renal
failure leads to disordered calcium-phosphate balance.
Calcium, Phosphate, PTH, and Vitamin D Feedback
Mechanism ●​ Impaired hydroxylation of 25-hydroxy vitamin D reduces
active 1,25(OH)2D, leading to poor calcium absorption.
●​ Low blood calcium → PTH secretion → Bone ●​ Diseased kidneys fail to excrete phosphate, causing
resorption + Increased intestinal/kidney absorption hyperphosphatemia, which stimulates PTH and FGF23
→ Restores normal calcium levels secretion.
●​ High blood calcium → Inhibition of PTH secretion → ●​ FGF23 inhibits 1α-hydroxylation of vitamin D, further
Decreased calcium mobilization and increased decreasing 1,25(OH)2D and causing hypocalcemia.
excretion ●​ Chronic renal failure can elevate PTH, and a high
●​ High phosphate levels → Reduced 1,25(OH)2D calcium/phosphate product leads to mineral precipitation
formation → Decreased intestinal calcium absorption in tissues.
●​ PTH increases renal calcium reabsorption, reducing
Regulation of Calcium Metabolism calcium loss in normal conditions.
●​ Hypercalcemia, as seen in primary
hyperparathyroidism (PHPT), overwhelms renal
reabsorption, leading to increased calcium excretion and
kidney stone formation.

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Calcium Homeostasis | Pre-Final | Lecture ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Prepared by: nielisyu
 ●​ The stimulus for calcitonin release is the opposite of its
Bone Physiology
function (high calcium levels trigger its release to lower

●​ Bone serves as a major repository for calcium, calcium levels).

phosphate, and magnesium.

●​ Bone turnover or remodeling is a regulated process Diseases Associated with Abnormal Calcium Levels
balancing formation (osteoblasts) and resorption
(osteoclasts). Hypercalcemia Causes​
●​ Osteoblasts mediate bone formation, while osteoclasts
handle resorption. ●​ Cancer
●​ 1,25(OH)2D and PTH act on osteoblasts, which in turn ●​ Hyperthyroidism
regulate osteoclast activity. ●​ Iatrogenic causes
●​ Imbalance between formation and resorption results in ●​ Multiple Myeloma
bone mass loss, increasing fracture risk (e.g., ●​ Hyperparathyroidism
osteoporosis). ●​ Sarcoidosis

Bone Turnover Markers​ Hypocalcemia Causes​

●​ Resorption markers: Hydroxyproline, N-telopeptides, ●​ Calcitonin excess

C-telopeptides, Cross-links, TRAP. ●​ Hypoparathyroidism

●​ Formation markers: Bone-specific alkaline phosphatase ●​ Alkalosis

(BSAP), Osteocalcin, Procollagen N-terminal extension ●​ Renal failure

peptides. ●​ Vitamin D deficiency

Types of Bone​ Metabolic Bone Diseases

●​ Cortical bone: Found in the long bone shafts (e.g., RICKETS AND OSTEOMALACIA​
femur), strong yet lightweight.
●​ Trabecular bone: Found in the axial skeleton (e.g., ●​ Both result from vitamin D deficiency.
vertebrae), with a honeycomb-like structure for ●​ Rickets affects growing bones in children, leading to
weight-bearing. permanent skeletal deformities.
●​ Disease-specific bone loss: PHPT preferentially affects ●​ Osteomalacia affects adults post-skeletal maturation and
cortical bone, while postmenopausal osteoporosis does not cause deformity.
primarily affects trabecular bone. ●​ Both conditions involve secondary
hyperparathyroidism.

Calcitonin ●​ Fractures may occur due to poor bone structure.

●​ Hypocalcemia may develop if secondary
●​ Produced in the parafollicular cells (C-cells) located hyperparathyroidism is inadequate.
beside follicular cells in the thyroid.

Functions​

●​ Lowers calcium levels in the blood by:

○​ Inhibiting calcium absorption in the intestines.
○​ Promoting calcium excretion in the urine
(kidneys).
○​ Inhibiting osteoclast formation and stimulating
osteoblast activity (bones).

Target Organs​

●​ Intestines – reduces calcium absorption.

●​ Kidneys – increases calcium excretion.
●​ Bones – inhibits resorption, enhances deposition.

General Concept​

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Calcium Homeostasis | Pre-Final | Lecture ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Prepared by: nielisyu
Clinical Presentation​ Common Signs of Osteoporosis​

●​ Decrease in height over time

Clinical Presentations of Rickets & Osteomalacia ●​ Hunched or stooped posture
Rickets Osteomalacia ●​ Back pain, especially lower back pain, secondary to
collapsed vertebra
Skeletal pain and Not as dramatic
deformities, bow legged ●​ Easier than usual bone fracturing

Fracture susceptibility Diffuse skeletal pain Glucocorticoid-Induced Osteoporosis​

Weakness and hypotonia Bone tenderness
●​ Glucocorticoids inhibit osteoblasts and increase
Disturbed growth Fractures
osteoclast activity
Ricketic rosary (prominent Gait disturbances ●​ Commonly used for asthma, rheumatoid arthritis, lupus,
costochondral junctions) (wadding)
Harrison’s groove and organ transplant rejection
(indentation of lower ribs) ●​ Treatment: Bisphosphonates (alendronate,
Hypocalcemia Proximal muscle weakness risedronate)

​
​ Diagnosis of Osteoporosis​
​
Risk Factors​
●​ No specific lab test for osteoporosis

●​ Poor diet (low vitamin D intake) ●​ Diagnosis based on:

●​ Minimal sun exposure ○​ DEXA scan (Bone Mineral Density - BMD)

●​ Living indoors ○​ WHO Fracture Risk Assessment Tool

○​ Presence of fragility fractures
Diagnosis​
DEXA Scan Interpretation​

●​ Blood test for 25-hydroxy vitamin D

●​ Elevated PTH and low calcium confirm diagnosis ●​ Normal: T-score between -1.0 and +1.0
●​ Osteopenia: T-score between -1.0 and -2.5
Vitamin D Metabolism Defects​ ●​ Osteoporosis: T-score ≤ -2.5

Preventive Measures​
●​ Rickets can occur despite adequate vitamin D due to
genetic defects in:
○​ Vitamin D metabolism ●​ Reduce risk factors: Stop smoking, limit alcohol

○​ Vitamin D receptor (abnormal ligand binding, ●​ Fall prevention: Handrails, hip pads, walkers

DNA binding, transcriptional activation) ●​ Ensure adequate calcium (1,200-1,500 mg/day) and

●​ Treatment: 1,25(OH)2D (calcitriol) supplementation vitamin D (400-800 IU/day)

Medications​
OSTEOPOROSIS​

1.​ Bisphosphonates (First-line therapy)

●​ Bone thinning due to higher breakdown than formation
○​ Examples: Alendronate, Risedronate,
●​ Not associated with vitamin D deficiency
Ibandronate, Zoledronate
○​ Side effects: GI ulceration, osteonecrosis of
the jaw, atypical femur fractures
2.​ Selective Estrogen Receptor Modulators (SERM)
○​ Example: Raloxifene
3.​ Hormonal Therapy
○​ Testosterone (men with hypogonadism)
○​ Estrogen ± Progestin (women)
4.​ Anabolic Therapy (Bone Formation Stimulation)
○​ Teriparatide (only for severe osteoporosis)
○​ Requires subcutaneous injection, used for 2
years
○​ Possible bone tumor risk (experimental
animals)

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Calcium Homeostasis | Pre-Final | Lecture ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Prepared by: nielisyu
 Feature Rickets Osteomalacia Osteoporosis

Serum Low Low No

Calcium/Phosp biochemical
hate changes

Gender Both (unless More common More common

Prevalence X-linked) in females in
postmenopaus
al women &
elderly

Bone Poor Decreased No defect in

mineralization mineralization mineralization mineralization
& cartilage at
growth plate

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Calcium Homeostasis | Pre-Final | Lecture ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ ​ Prepared by: nielisyu