METABOLIC DISEASES OF BONE

A Review for MD Pathology

Source: Robbins, Cotran & Kumar - Pathologic Basis of Disease

1. OSTEOPENIA AND OSTEOPOROSIS

Definition

• Osteoporosis: bone mass >2.5 SD below mean peak bone mass in young adults (T-score ≤ -2.5)
• Osteopenia: 1 to 2.5 SD below the mean (T-score -1.0 to -2.5)

Classification (Table 26.3)

Pathogenesis

1. Age-related changes (Senile Osteoporosis - "low-turnover" form): Osteoblasts show reduced proliferative and biosynthetic capacity and attenuated response to growth factors.
2. Reduced physical activity: Osteocytes act as mechanosensors - reduced mechanical loading decreases WNT signaling, which normally suppresses sclerostin (a WNT inhibitor). With less mechanical stimulation, sclerostin is up-regulated, decreasing WNT signaling and thereby reducing osteoblast activity.
3. Calcium and Vitamin D deficiency: Dietary calcium deficiency and reduced intestinal calcium absorption (partly due to decreased active vitamin D production with aging) stimulate PTH release, which increases bone resorption.
4. Reduced estrogen levels (Postmenopausal Osteoporosis - "high-turnover" form):
   • Estrogen normally suppresses osteoclast activity by reducing RANKL production and increasing OPG (osteoprotegerin) by osteoblasts.
   • Estrogen also inhibits cytokines (IL-1, TNF, IL-6, M-CSF) that promote osteoclast differentiation.
   • Loss of estrogen after menopause increases osteoclast activity disproportionately, causing accelerated bone resorption.
5. Genetics: Polymorphisms in genes encoding the vitamin D receptor, type I collagen, IL-6, and other mediators influence peak bone mass.

Morphology

Clinical Features

• Vertebral fractures (thoracic and lumbar): pain, loss of height, kyphoscoliosis, lumbar lordosis
• Femoral neck and pelvic fractures: immobilization, pulmonary embolism, pneumonia - responsible for >50,000 deaths/year (US data)
• Blood calcium, phosphorus, and alkaline phosphatase are usually normal
• Plain X-rays cannot reliably detect loss until 30-40% of bone mass is lost
• Best screening: Dual-energy X-ray Absorptiometry (DEXA) and quantitative CT

Treatment

• Exercise, calcium and vitamin D supplementation
• Bisphosphonates (anti-resorptive - first line)
• Denosumab (anti-RANKL antibody) - effective in postmenopausal osteoporosis
• Menopausal hormone therapy (estrogen) - limited use due to DVT/stroke risk

2. OSTEOMALACIA AND RICKETS

Definition

• Rickets - occurs in children; interferes with deposition of bone in growth plates
• Osteomalacia - adult counterpart; bone formed during remodeling is undermineralized, predisposing to fractures

Pathogenesis

• Vitamin D is required for intestinal calcium and phosphate absorption
• Deficiency leads to low serum calcium/phosphate, inadequate mineralization of osteoid
• Causes include: nutritional deficiency (most common in India), malabsorption, renal failure (inability to form active 1,25-(OH)₂-D₃), liver disease, anticonvulsants

• Disorganized, widened growth plates
• Softening of bones (craniotabes, rachitic rosary, Harrison sulcus, genu varum/valgum)

Clinical Features of Rickets

• Craniotabes - softening of skull
• Rachitic rosary - costochondral junction enlargement
• Harrison sulcus - indentation along the lower chest (diaphragm pull)
• Frontal bossing, delayed fontanelle closure
• Genu varum (bow legs) or genu valgum (knock knees)
• Tetany from hypocalcemia

3. HYPERPARATHYROIDISM

Definition

Pathogenesis of Bone Changes

1. Osteoclast activation (indirectly via increased RANKL on osteoblasts) → bone resorption and calcium mobilization
2. Increased calcium resorption by renal tubules
3. Increased urinary phosphate excretion
4. Increased synthesis of active Vitamin D (1,25-(OH)₂-D) by renal α-1 hydrolase → increased intestinal calcium absorption and bone calcium mobilization (via RANKL on osteoblasts)

Types

• Autonomous PTH secretion (usually from parathyroid adenoma)
• Elevated PTH is directly responsible for bone changes

• Chronic renal failure → low 1,25-(OH)₂-D → hypocalcemia → compensatory ↑PTH
• Combination of elevated PTH + inadequate 1,25-(OH)₂-D + hyperphosphatemia + metabolic acidosis = Renal Osteodystrophy

Morphology (Osteitis Fibrosa Cystica)

• Increased osteoclastic resorption along all bone surfaces (endosteal, periosteal, intracortical)
• Peritrabecular fibrosis and marrow fibrosis
• Brown tumors (focal collections of osteoclasts, fibrous tissue, and hemosiderin-laden macrophages from repeated microhemorrhages - yellow-brown color due to hemosiderin)
• Cyst formation - as brown tumors degenerate

Renal Osteodystrophy

• Osteopenia (from secondary hyperparathyroidism)
• Osteomalacia (from deficiency of active vitamin D)
• Growth retardation in children
• Hyperphosphatemia contributes by binding calcium, worsening hypocalcemia
• Metabolic acidosis also promotes bone loss

4. PAGET DISEASE OF BONE (Osteitis Deformans)

Definition

Epidemiology

• Usually presents in late adulthood (rare under 40 years)
• ~1% of the US population >40 years
• Common in UK, central Europe, Greece, Australia, USA
• Rare in native Scandinavians, Chinese, Japanese, Africans
• Decreasing incidence over the past 30 years in some countries

Pathogenesis

• ~60% of familial cases and 10% of sporadic cases: germline mutations in SQSTM1 gene (encodes sequestosome-1) → increased NF-κB activity → increased osteoclast activity
• Activating mutations in RANK and inactivating mutations in OPG cause some juvenile cases
• Possible viral trigger: chronic infection of osteoclast precursors by measles or other RNA viruses (paramyxovirus hypothesis) - not firmly established

Three Phases of Paget Disease

Morphology

• Cortical thickening and trabecular coarsening
• Characteristic "picture frame" vertebra on X-ray
• Bowing of long bones (especially tibia - "sabre shin")
• Skull: thickened, cotton-wool appearance
• Bone is increased in size, hypervascular, and prone to fracture

• Mosaic pattern of lamellar bone - irregularly shaped pieces of bone separated by prominent cement lines, creating a jigsaw/mosaic appearance
• Abnormally large, multinucleated osteoclasts in active phase

Clinical Features

• Many patients are asymptomatic (incidental finding on imaging or elevated alkaline phosphatase)
• Bone pain (most common symptom)
• Bone deformity: bowing of femur/tibia, frontal bossing (skull)
• Pathologic fractures (chalk-stick fractures in long bones)
• Nerve compression: deafness (VIII nerve), spinal stenosis, cranial nerve palsies
• High-output cardiac failure - due to increased vascularity (AV shunting in bone)
• Elevated serum alkaline phosphatase (ALP) - hallmark biochemical finding
• Normal serum calcium and phosphate (in uncomplicated cases)

Complications

1. Osteosarcoma (~1% of Paget cases - most serious complication; high-grade; poor prognosis). Fibrosarcoma and chondrosarcoma are less common.
2. Giant cell tumor - develops in pagetic bone
3. Pathologic fractures
4. Hearing loss (auditory foramen involvement)
5. High-output heart failure

Laboratory Findings in Paget Disease

Treatment

• Bisphosphonates (reduce osteoclast activity) - first-line
• Calcitonin (alternative)
• NSAIDs for pain

SUMMARY TABLE: Metabolic Bone Diseases at a Glance