Osteoporosis & Bone Physiology Lecture

Bone Physiology & Pathophysiology

• Core functions of bone
  • Support: rigid scaffolding for extremities & body cavities.
  • Movement: muscle attachment points act as levers.
  • Mineral reservoir: stores Ca^{2+}, PO_4^{3-}, Mg^{2+} & Na^{+} for rapid systemic release.
  • Hematopoiesis: marrow hosts lymphoid, erythroid & mesenchymal stem-cell lineages.

Bone Anatomy

• Rigidity ⇄ Elasticity balance maintains strength & impact absorption.
• Cortical (Compact) bone
  • Dense, structural; < metabolic.
  • Shaft of long bones + outer shell of all bones.
  • Organized as osteons surrounding Haversian canals.
• Trabecular (Cancellous) bone
  • Porous, elastic; highly metabolic.
  • Vertebrae, pelvic & rib interiors, epiphyses of long bones.
  • Forms a lattice; resorption spaces more frequent.

Bone Cells

• Osteoblasts ("builders")
  • Derived from mesenchymal stem cells.
  • Lay down collagen matrix → mineralize to hydroxyapatite Ca{10}(PO4)6(OH)2.
  • Regulators: Wnt/β-catenin (↑), sclerostin (↓), reactive oxygen species (↓).
  • High physiologic apoptosis rate \approx 60\text{–}80\%.
• Osteoclasts ("chewers")
  • Multinucleated; fusion of monocyte/macrophage precursors.
  • Form ruffled border → secretes H^{+} & proteases → digests bone.
  • Regulators: RANK + RANK-L (↑), M-CSF (↑), ROS (↑); OPG = decoy ↓.
• Osteocytes ("sentinels")
  • Osteoblasts entombed in matrix; dendritic network senses strain & mineral status.
  • Major source of sclerostin → tonic inhibition of osteoblasts.

Bone Remodeling Cycle ("Activation–Resorption–Formation")

• Pre-osteoblasts release RANKL → binds RANK on osteoclast precursors.
• Osteoblasts simultaneously release OPG (decoy) to modulate signal.
• Activated precursors fuse → mature osteoclast; ruffled border resorbs bone.
• Osteoblasts migrate in, deposit collagen → mineralize → new bone.
• Fraction of osteoblasts become osteocytes; remainder undergo apoptosis.
• Each cycle leaves a tiny formation deficit; cumulative life-long loss ⇒ ↓BMD.

Osteoporosis Overview

• Definition: systemic skeletal disorder with compromised bone strength & ↑ fracture risk.
• Normal aging: gradual loss of bone mass; pathologic acceleration ⇒ osteopenia / osteoporosis.
• Fracture risk ≠ BMD alone—architecture, quality & falls all contribute.

Causes of Secondary Osteoporosis (Slide 11)

• Endocrinopathies: thyrotoxicosis, hyperprolactinemia, primary hyperparathyroidism, acromegaly, hypogonadism, Cushing/glucocorticoid excess.
• Medications: chronic glucocorticoids, GnRH agonists (ADT), certain anticonvulsants, excessive thyroid replacement.
• GI / Nutritional: vitamin D deficiency, chronic liver disease, celiac sprue, malabsorption.
• Other: alcoholism, osteogenesis imperfecta, rheumatoid arthritis, multiple myeloma, COPD, idiopathic hypercalciuria.
• (Apply Dr Russu’s classification: many are Type III – drug/disease induced; mechanism often ↑bone resorption, ↓formation, or impaired Ca/VitD balance.)

Therapeutic Categories for Osteoporosis

• Anti-resorptive
  • Bisphosphonates
  • SERMs / Estrogens
  • Denosumab (RANKL mAb)
  • Calcitonin (brief mention)
• Anabolic (bone-forming)
  • Teriparatide, Abaloparatide (PTH/PTHrP analogs)
  • Romosozumab (sclerostin mAb)
• Calcium-balance adjuncts: Ca^{2+} & Vitamin D supplementation.

Bisphosphonates

• Chemistry: analogues of pyrophosphate; P–C–P backbone resists hydrolysis.
  • Nitrogenous (N-BP) vs simple (non-N) subclasses.
• Pharmacodynamics
  • Adsorb to bone mineral; internalized by osteoclasts during resorption →
  • Impair ruffled border formation & adherence.
  • ↓H^{+} secretion & proteolysis.
  • Modestly ↓osteoblast / osteocyte apoptosis (minor anabolic aid).
• Subclass mechanisms
  • N-BP: inhibit farnesyl pyrophosphate synthase in the mevalonate pathway → defective prenylation, cytoskeletal collapse; accumulation of isopentenyl-PP ↑TNF (basis of IV acute-phase reaction).
  • Non-N BP: metabolized → ATP analogues with P–C–P substitution → non-functional ATP → osteoclast apoptosis.
• Limitations / ADRs
  • Coupled remodeling ⇒ bone formation also slows.
  • Etidronate: specific mineralization inhibition.
  • Oral bioavailability \approx 1\text{–}5\%—empty stomach, upright posture needed.
  • Common: GI reflux, esophagitis, ulcers, hypocalcemia, myalgia, flu-like (IV).
  • Rare/serious: osteonecrosis of jaw (ONJ), atypical subtrochanteric/femoral fractures, renal failure, uveitis/eye pain, new-onset A_{fib}.

Calcium Balance Agents

• Physiology recap
  • Serum Ca^{2+} tightly regulated (\pm1\%) by PTH (↑), calcitonin (↓), Vitamin D (↑ GI & renal absorption).
• Supplementation
  • Calcium salts ± Vitamin D used when dietary intake/absorption inadequate.
• Adverse effects
  • Ca^{2+}: hypercalcemia, hypercalciuria, nephrolithiasis; possible ↑CV events.
  • Vit D: hypercalcemia, nephrolithiasis; possible links to certain cancers & ↑falls at high doses.

PTH Analogs – Teriparatide & Abaloparatide

• Teriparatide: recombinant PTH 1\text{–}34.
• Abaloparatide: synthetic PTH-related peptide 1\text{–}34 analogue.
• Intermittent (daily) SC dosing → anabolic
  • Transient PTH-R stimulation → ↑osteoblast number & activity > osteoclast activation.
  • Preferential gain in trabecular bone; modest cortical thinning possible.
• ADRs / limits
  • Injection-site erythema, headache, nausea.
  • Hypercalcemia & hypercalciuria (monitor).
  • Osteosarcoma signal in rats → human use capped at 24 months lifetime.

SERMs & Conjugated Estrogens

• Raloxifene
  • ER agonist: bone; antagonist: breast; neutral: uterus.
• Bazedoxifene + CEE
  • ER agonist: bone; antagonist: uterus; minimal breast stimulation.
• Mechanisms
  • ↓osteoblast apoptosis; ↓osteoclastogenesis via ↑OPG.
  • ↑BMD; ↓vertebral fractures (non-vertebral data mixed).
• ADRs
  • Hot flashes (esp. raloxifene), leg cramps, peripheral edema.
  • ↑Risk of VTE (DVT/PE); possible ± CHD modulation.

Denosumab (RANK-L Inhibitor)

• Fully human IgG2 mAb; SC q6 months.
• Mimics OPG → neutralizes RANKL → ↓osteoclast formation/function.
• Effects: ↑BMD; ↓vertebral & hip fractures.
• ADRs
  • Rapid BMD loss & rebound ↑fracture risk if discontinued without follow-on therapy (do "exit plan").
  • Musculoskeletal pain, hypercholesterolemia, cellulitis/dermatologic infections.

Romosozumab (Sclerostin Inhibitor)

• Humanized mAb; monthly x12.
• Dual action
  • ↑Wnt/β-catenin signaling → ↑osteoblastogenesis (anabolic).
  • Secondary ↓resorption.
• Clinical results: ↑BMD; ↓vertebral & non-vertebral (incl. hip) fractures.
• ADRs & cautions
  • Injection-site reactions.
  • Rare ONJ, atypical femoral fractures (monitor dental health & thigh pain).
  • Possible ↑MI & stroke risk; avoid in recent CV events.
  • Must transition to anti-resorptive afterward to maintain gains.

Calcitonin (brief mention)

• Thyroid C-cell hormone; directly inhibits osteoclasts.
• Less potent vs modern agents; used when others contraindicated.

Integrative Thought Prompts (Exam Prep)

• Classify agents
  • Anabolic: teriparatide, abaloparatide, romosozumab.
  • Anti-resorptive: bisphosphonates, SERMs/estrogen, denosumab, calcitonin.
• Map to remodeling cycle
  • RANKL blockade (denosumab) → precursor stage.
  • Bisphosphonates → active osteoclasts at resorption phase.
  • SERMs/estrogen → osteoblast survival & OPG ↑ (formation/regulation phase).
  • PTH analogs & romosozumab → osteoblast recruitment/activation (formation).
• Secondary osteoporosis mechanisms
  • Glucocorticoids: ↓osteoblastogenesis, ↑osteocyte & osteoblast apoptosis, ↑RANKL.
  • Hyperthyroidism: accelerates remodeling cycle → net loss.
  • GnRH agonist ADT: hypogonadism → ↓estrogen/testosterone → ↑resorption.
  • Vitamin D deficiency / malabsorption: ↓Ca^{2+} absorption → ↑PTH → secondary hyperparathyroidism & bone loss.
  • Chronic liver disease: impaired VitD activation & IGF-1 ↓ → ↓formation.

Email Dr Livesey with remaining questions or schedule a meeting for personalized clarification.