Pathophysiology
I-29. Calcium & phosphate metabolism — effects on the skeletal system
カルシウム・リン代謝と骨格系への影響
Osteoporosis
- Systemic bone disease: low bone mass + breakdown of bone tissue → ↑fragility, pathological fractures (hip, wrist, vertebrae). One-year mortality after hip fracture 10–20% (immobilization).
Classification
- Primary: postmenopausal (lose 2–3%/yr) and age-dependent (both sexes).
- Secondary: drug-induced, primary hyperparathyroidism.
Postmenopausal vs Age-dependent
- Men: age-dependent remodeling of cortical bone (femur, wrist).
- Women: trabecular remodeling (postmenopausal → vertebrae) plus cortical (age-dependent → femur, wrist) → more severe.
- ~200× higher risk in Scandinavia vs Africa: genetic (estrogen receptor α, VDR polymorphisms) + environmental (low sun/vitamin D, sedentary, smoking, nutrition).
Bone Remodeling Regulators
- Estrogen: inhibits osteoclast differentiation and osteocyte sclerostin → osteoblasts secrete OPG (inhibits RANKL).
- RANKL (osteoblasts/osteocytes): binds pre-osteoclasts → osteoclast differentiation → resorption. Influenced by glucocorticoids.
- OPG: estrogen-stimulated, binds RANKL to block RANK-RANKL → inhibits osteoclasts. ↓OPG → osteoporosis.
Osteomalacia (bone softening)
- Decreased mineralization of newly formed osteoid at turnover sites.
- Via hypocalcemia, hypophosphatemia, or direct inhibition of mineralization.
- Symptoms: bone pain, muscle weakness, pseudofractures (fissures), fractures.
- Causes: hypophosphatemia (chronic severe vitamin D deficiency → secondary hyperparathyroidism), or chronic metabolic acidosis (releases bone Ca²⁺).
Secondary Osteoporosis — Causes
- Vitamin D/Ca²⁺ deficiency: low sun, malabsorption/diet.
- Endocrine: Cushing’s, hyperparathyroidism, hyperthyroidism, hypogonadism.
- Renal: CKD → can’t activate calcitriol → secondary hyperparathyroidism.
- Liver: deficiency (alcoholism) → can’t activate vitamin D.
- Drug-induced: glucocorticoids, GnRH agonists (↓estrogen, e.g. prostate cancer).
- Lifestyle: malnutrition (↑salt/phosphate), metabolic syndrome (↑resorption, ↓formation — elderly men with ↑CRP → vertebral compression fracture risk).
Vitamin K2 & Osteoporosis
- Needed for gamma-carboxylation of osteocalcin → enables bone Ca²⁺ uptake (uncarboxylated → no uptake).
- K2 ↑ vertebral BMD in postmenopausal osteoporosis. Sources: cheese, goose liver, green vegetables, probiotics.
一問一答
▶What is osteoporosis?
A systemic bone disease of low bone mass and breakdown of bone tissue → increased fragility and pathological fractures (hip, wrist, vertebrae).
▶How is osteoporosis classified?
Primary (postmenopausal and age-dependent) and secondary (drug-induced, primary hyperparathyroidism, and other conditions).
▶Why is osteoporosis more severe in women than men?
Women have both trabecular remodeling (postmenopausal → vertebrae) and age-dependent cortical loss (femur, wrist), whereas men mainly have age-dependent cortical bone loss.
▶How does estrogen protect bone?
It inhibits osteoclast differentiation and osteocyte sclerostin, and stimulates osteoblast OPG (which inhibits RANKL) → less resorption.
▶What is the RANKL/OPG system in bone remodeling?
RANKL (from osteoblasts/osteocytes) binds pre-osteoclasts → osteoclast differentiation/resorption; OPG (estrogen-stimulated) is a decoy that binds RANKL to block resorption. ↓OPG → osteoporosis.
▶What is osteomalacia and how does it differ from osteoporosis?
Osteomalacia is decreased mineralization of newly formed osteoid (bone softening), whereas osteoporosis is loss of total bone mass with normally mineralized bone.
▶What are the symptoms and main causes of osteomalacia?
Bone pain, muscle weakness, pseudofractures (fissures), and fractures; caused by hypophosphatemia (chronic severe vitamin D deficiency → secondary hyperparathyroidism) or chronic metabolic acidosis.
▶What endocrine conditions cause secondary osteoporosis?
Cushing's syndrome, hyperparathyroidism, hyperthyroidism, and hypogonadism.
▶How do renal and liver disease cause secondary osteoporosis?
CKD prevents calcitriol activation → secondary hyperparathyroidism; liver disease (e.g., alcoholism) impairs vitamin D activation → reduced calcium absorption.
▶Which drugs commonly cause secondary osteoporosis?
Glucocorticoids and GnRH agonists (which lower estrogen, e.g., in prostate cancer therapy).
▶Why is the 1-year mortality after a hip fracture so high?
It is 10–20%, largely due to complications of immobilization.
▶What genetic and environmental factors explain large geographic differences in osteoporosis risk?
Genetic (estrogen receptor α and VDR polymorphisms) plus environmental factors (low sun/vitamin D, sedentary lifestyle, smoking, nutrition).
▶What is the role of vitamin K2 in bone health?
It enables gamma-carboxylation of osteocalcin so bone can take up Ca²⁺; uncarboxylated osteocalcin cannot, and K2 raises vertebral BMD in postmenopausal osteoporosis.
▶How does chronic metabolic acidosis affect bone?
It releases buffering calcium from bone, contributing to demineralization/osteomalacia.
▶Which bone type and sites are affected by postmenopausal vs age-dependent osteoporosis?
Postmenopausal: trabecular bone → vertebrae. Age-dependent: cortical bone → femur and wrist.
▶How does the metabolic syndrome contribute to osteoporosis in elderly men?
It increases bone resorption and decreases formation; elderly men with elevated CRP have an increased risk of vertebral compression fractures.
▶How does glucocorticoid excess affect bone remodeling?
It influences RANKL signaling to favor osteoclast activity and impairs osteoblast function → bone loss (secondary osteoporosis).
▶What rate of bone loss occurs in postmenopausal osteoporosis?
About 2–3% per year.
▶What is the role of sclerostin in bone?
Sclerostin (from osteocytes) inhibits osteoblast bone formation; estrogen suppresses sclerostin, favoring formation.
▶What dietary sources provide vitamin K2?
Cheese, goose liver, green vegetables, and probiotics.