Endocrine Regulation of Bone Mineral Homeostasis: PTH, Vitamin D, FGF23, and Clinical Implications

Major endogenous regulators of bone mineral homeostasis.

PTH, Vitamin D (1,25[OH]₂D), FGF23

Minor endogenous regulators of bone mineral homeostasis.

Calcitonin, adrenal steroids, gonadal steroids

Source of PTH.

Parathyroid glands (chief cells)

Length of PTH molecule.

84 amino acids (active hormone); precursor 115 aa

What regulates PTH release?

↓ Ca²⁺ (stimulates), ↑ phosphate (stimulates); inhibited by ↑ Ca²⁺, calcitriol, FGF23

Effect of PTH on bone.

↑ RANKL expression by osteoblasts → ↑ osteoclast activation → ↑ bone resorption → ↑ serum Ca²⁺, ↓ phosphate

Effect of PTH on kidney.

↑ Ca²⁺ reabsorption, ↓ phosphate reabsorption, ↑ calcitriol synthesis

Effect of PTH on intestine.

Indirect ↑ Ca²⁺ and phosphate absorption (via calcitriol)

Therapeutic PTH analogs.

Teriparatide (1-34 aa), rhPTH 1-84 (Natpara), Abaloparatide (PTHrP analog)

Dosing effect of PTH.

Intermittent small doses → ↑ bone formation; chronic high doses → ↑ bone resorption

How does PTH indirectly regulate osteoclasts?

Stimulates osteoblasts to secrete RANKL, which activates osteoclast precursors

What blocks RANKL activity?

Osteoprotegerin (OPG) secreted by osteoblasts/osteocytes; Denosumab (monoclonal antibody to RANKL)

What is Sclerostin?

Protein that blocks Wnt signaling; Romosozumab antibody blocks sclerostin → ↑ bone formation

Vitamin D3 (cholecalciferol) source.

Skin (UV light)

Vitamin D2 (ergocalciferol) source.

Plants

Vitamin D activation pathway.

Liver: 25-hydroxylation → calcifediol; Kidney: 1α-hydroxylation → calcitriol (active form)

Major effects of calcitriol.

↑ Ca²⁺ and phosphate absorption (intestine), ↑ renal reabsorption, ↑ bone mineralization (normal dose), ↑ bone resorption (high dose)

Regulation of calcitriol synthesis.

Stimulated by PTH; inhibited by phosphate, FGF23, and calcitriol itself

Source of FGF23.

Osteocytes and osteoblasts in bone

Effect of FGF23 on vitamin D.

Inhibits calcitriol synthesis

Effect of FGF23 on phosphate.

↓ renal phosphate reabsorption (inhibits NaPi transporters) → ↓ serum phosphate

Clinical use of FGF23.

No clinical use

Source of calcitonin.

Parafollicular (C cells) of thyroid

Effect of calcitonin on bone.

Inhibits osteoclast activity → ↓ bone resorption

Effect of calcitonin on kidney.

↑ renal Ca²⁺ and phosphate excretion

Overall effect of calcitonin.

↓ serum Ca²⁺ and phosphate

Clinical use of calcitonin.

Osteoporosis (less common), Paget's disease, hypercalcemia (ancillary therapy)

Effect of glucocorticoids on bone.

Antagonize vitamin D, ↓ Ca²⁺ absorption, ↑ renal Ca²⁺ excretion, ↓ bone formation → osteoporosis

Effect of estrogens on bone.

Prevent postmenopausal bone loss, maintain osteoblast/osteocyte survival, ↓ osteoclast activity

Effect of SERMs on bone.

Raloxifene, Bazedoxifene: mimic estrogen effects on bone, anti-estrogen in breast/uterus

Effect of androgens on bone.

Support bone formation and bone mass maintenance

Bisphosphonate mechanism.

Analog of pyrophosphate; bind hydroxyapatite → inhibit osteoclasts → induce osteoclast apoptosis

Examples of bisphosphonates.

Etidronate (rarely used), Alendronate, Pamidronate, Risedronate, Ibandronate, Zoledronate

Side effects of bisphosphonates.

Esophageal/GI irritation (oral), hypocalcemia, rare osteonecrosis of jaw

Clinical use of bisphosphonates.

Osteoporosis, Paget's disease, hypercalcemia of malignancy

Denosumab mechanism.

Monoclonal antibody to RANKL → inhibits osteoclast formation and activity

Denosumab administration.

Subcutaneous injection every 6 months

Denosumab use.

Osteoporosis, bone loss from cancer therapy

Calcimimetic mechanism.

Activate Ca²⁺-sensing receptor in parathyroid → ↓ PTH secretion

Example of calcimimetic.

Cinacalcet (Sensipar)

Clinical use of calcimimetics.

Secondary hyperparathyroidism, parathyroid carcinoma

Other agents affecting bone.

Plicamycin (Mithramycin, rarely used), Thiazide diuretics (↓ renal Ca²⁺ excretion), Fluoride (stabilizes hydroxyapatite), Strontium ranelate (antiresorptive + anabolic)

Clinical implications of hyperparathyroidism.

↑ PTH → hypercalcemia, bone pain, cognitive dysfunction

Clinical implications of osteomalacia/rickets.

↓ Vitamin D or defective metabolism → poor bone mineralization (adults = osteomalacia; children = rickets)

Clinical implications of osteoporosis.

Abnormal bone loss → fractures, spinal deformities

Clinical implications of Paget's disease.

Disordered bone remodeling → enlarged, deformed, fragile bones

Causes of hypercalcemia.

Hyperparathyroidism, cancer, hypervitaminosis D, sarcoidosis, thyrotoxicosis, milk-alkali syndrome, adrenal insufficiency

Treatment of hypercalcemia.

Saline diuresis ± furosemide, bisphosphonates, calcitonin, gallium nitrate, phosphate (last line), glucocorticoids

Causes of hypocalcemia.

Hypoparathyroidism, vitamin D deficiency, chronic kidney disease, malabsorption

Symptoms of hypocalcemia.

Tetany, cramps, seizures, neuromuscular excitability

Treatment of hypocalcemia.

Calcitriol (vitamin D metabolite), calcium supplements (Ca carbonate orally, Ca gluconate IV), rhPTH or teriparatide in hypoparathyroidism

Causes of hyperphosphatemia.

Renal failure, hypoparathyroidism, vitamin D overdose

Treatment of hyperphosphatemia.

Limit dietary phosphate, use phosphate binders (e.g., calcium supplements)

Causes of hypophosphatemia.

Hyperparathyroidism, vitamin D deficiency, malabsorption

Treatment of hypophosphatemia.

Oral phosphate preparations (e.g., Fleet Phospho-soda)