Bone Physiology & Metabolic Bone Disease

Bone Cells and the RANK-L Switch

Osteoblasts build. Osteoblasts, of mesenchymal origin, secrete osteoid (type I collagen) and alkaline phosphatase, which promotes mineralization. Serum alkaline phosphatase (ALP) is therefore a bone-formation marker that rises whenever turnover accelerates.

Osteoclasts chew. Osteoclasts are multinucleated cells of monocyte/macrophage origin. Sealed against the bone surface, they pump acid, which depends on carbonic anhydrase II, to dissolve mineral and secrete cathepsin K to digest collagen. Osteocytes, osteoblasts embedded in matrix, act as mechanosensors that sense load.

RANK-L/OPG axis. Osteoblasts control osteoclasts. RANK-L on osteoblasts binds RANK on osteoclast precursors, driving their differentiation and activation. Osteoprotegerin (OPG) is a decoy receptor that soaks up RANK-L and BLOCKS resorption. PTH and vitamin D raise RANK-L; estrogen cuts RANK-L and boosts OPG, so estrogen loss at menopause tips the balance toward resorption. Denosumab is an anti-RANK-L antibody that acts like OPG.

Remodeling. Bone is continuously remodeled by coupled osteoclastic resorption and osteoblastic formation. PTH is biphasic: CONTINUOUSLY high PTH is catabolic (net resorption), whereas INTERMITTENT pulses are anabolic, which is why daily teriparatide builds bone.

Mineral Regulation: Vitamin D and PTH

Vitamin D activation. Cholecalciferol made in sun-exposed skin or absorbed from the diet is activated in two steps: 25-hydroxylation in the LIVER (25-hydroxyvitamin D, the storage form measured to judge status), then 1α-hydroxylation in the KIDNEY, stimulated by PTH and low phosphate, to active 1,25-dihydroxyvitamin D (calcitriol). Calcitriol raises intestinal calcium and phosphate absorption, supplying the mineral needed to mineralize osteoid. Deficiency underlies rickets and osteomalacia.

PTH. Chief cells release PTH when ionized calcium falls. PTH increases bone resorption through RANK-L, increases distal tubular calcium reabsorption, decreases proximal tubular phosphate reabsorption, and stimulates renal 1α-hydroxylase. The net effect is calcium up and phosphate down. FGF23 from osteocytes also lowers phosphate and suppresses 1α-hydroxylase.

Too Little Bone vs Too Little Mineral

Osteoporosis. Reduced bone MASS with NORMAL mineralization; trabecular bone suffers first. Type I is postmenopausal, when estrogen loss increases osteoclast activity; type II is senile, affecting both sexes with age. Glucocorticoids, smoking, alcohol, and low body weight add risk. Serum calcium, phosphate, PTH, and ALP are ALL NORMAL. Fractures involve vertebral bodies (compression, height loss, kyphosis), the hip, and the distal radius (Colles fracture).

Osteomalacia and rickets. Low vitamin D impairs MINERALIZATION, leaving soft osteoid that bends and fractures. Adults develop osteomalacia with bone pain and pseudofractures (Looser zones). Children develop rickets: bowed legs, rachitic rosary (enlarged costochondral junctions), craniotabes (soft skull), and widened growth plates. Labs show low vitamin D, low or low-normal calcium that drives PTH up (secondary hyperparathyroidism), low phosphate, and HIGH ALP. Causes include poor intake or sun exposure, fat malabsorption, and liver or kidney disease. X-linked hypophosphatemic rickets instead reflects renal phosphate wasting from excess FGF23 activity (PHEX mutation), with normal calcium.

Osteomalacia = defective mineralization (low vitamin D); osteoporosis = low mass with normal mineralization and normal labs.

Osteopetrosis and Paget Disease

Osteopetrosis (marble bone disease). Failed OSTEOCLAST resorption, classically from a carbonic anhydrase II mutation that leaves no acid to dissolve bone (and also causes renal tubular acidosis). Bones become dense yet brittle and fracture easily; femurs take an Erlenmeyer-flask shape. Bone crowds out the marrow, causing pancytopenia and extramedullary hematopoiesis, and narrowed foramina compress cranial nerves, causing blindness and deafness. Serum calcium, phosphate and ALP are usually normal, but the severe infantile form can cause hypocalcemia. Because osteoclasts are marrow-derived, hematopoietic stem-cell transplant is curative.

Paget disease of bone. Localized, disordered high-turnover remodeling in older adults: frantic osteoclast activity followed by chaotic osteoblast activity, producing thick but weak bone with a mosaic (jigsaw) lamellar pattern. Stages run lytic, then mixed, then sclerotic (burnt-out); a paramyxovirus trigger has been proposed. The signature lab is an ISOLATED high ALP with NORMAL calcium, phosphate, and PTH. Clues include increasing hat size, hearing loss, bone pain, and high-output heart failure from arteriovenous shunts in vascular pagetic bone; transformation to osteosarcoma is rare. Bisphosphonates are the treatment.

Parathyroid and Renal Bone Disease

Primary hyperparathyroidism. Usually a parathyroid adenoma: HIGH calcium, LOW phosphate, HIGH PTH, and often high ALP, remembered as "stones, bones, groans, and psychiatric overtones." Excess PTH, whether primary or secondary, ramps up osteoclastic resorption and produces osteitis fibrosa cystica: subperiosteal bone resorption and brown tumors. Brown tumors are radiolucent, osteoclast-rich, hemorrhagic cystic lesions colored by hemosiderin, not true neoplasms.

Renal osteodystrophy. In chronic kidney disease, phosphate excretion falls (HIGH phosphate) and renal 1α-hydroxylase activity drops (LOW active vitamin D, so LOW calcium). Low calcium and high phosphate drive secondary hyperparathyroidism, resorbing bone with HIGH PTH and HIGH ALP. Long-standing stimulation can make the glands autonomous (tertiary hyperparathyroidism), with PTH high even as calcium rises.

Drugs That Target Bone

Bisphosphonates. Alendronate and zoledronate are pyrophosphate analogs that concentrate in bone and induce osteoclast apoptosis by inhibiting farnesyl pyrophosphate synthase. They treat osteoporosis, Paget disease, hypercalcemia of malignancy, and bone metastases. Adverse effects are pill esophagitis (take upright, fasting, with water), osteonecrosis of the jaw, and atypical subtrochanteric femoral fractures.