BMS 551 Skeletal Physiology & Pharmacology

#13 Skeletal Physiology & Pharmacology Part 1 of 4 J O N AT H A N L O W E R Y, P H D A S S I S TA N T P R O V O S T F O R R E S E A R C H & S C H O L A R S H I P A S S O C I AT E P R O F E S S O R O F P H Y S I O L O G Y...

#13 Skeletal Physiology & Pharmacology Part 1 of 4 J O N AT H A N L O W E R Y, P H D A S S I S TA N T P R O V O S T F O R R E S E A R C H & S C H O L A R S H I P A S S O C I AT E P R O F E S S O R O F P H Y S I O L O G Y [email protected] V I R T U A L O F F I C E H O U R S T H U R S D AY S 9 : 3 0 – 1 0 : 3 0 A M ( J L O W E R Y )  Concept Map for Lectures 13-16  Central Theme: Defects in bone material properties and/or cellular function underlie metabolic disease of bone.  Lecture 13: Matrix properties and bone formation  Lecture 14: Bone remodeling  Lecture 15: Osteoporosis diagnosis and pharmacology  Lecture 16: Osteoporosis pharmacology  Learning Objectives for Lectures 13 - 16 1. Identify the four major bone cell types and describe the lineage and markers (if discussed) for each. 2. Discuss the process of bone remodeling, detailing the function of osteocytes, bone lining cells, osteoclasts, and osteoblasts in this process. 3. Describe the net impact of changes in bone formation rate and/or bone resorption rate on bone mass and relate serum/urinary bone turnover markers to bone formation and resorption. 4. Describe the role of Sclerostin in osteocyte-dependent regulation of osteoblast activity and be able to identify the hallmarks of decreased Sclerostin expression or activity. 5. Discuss the impact of Growth Hormone on bone formation and be able to identify the hallmarks of elevated Growth Hormone expression. 6. Discuss how osteoblasts regulate osteoclastogenesis and how PTH impacts this process. 7. Relate how changes in the differentiation rate of osteoclasts may alter bone resorption rate. 8. Describe what osteoporosis is and its underlying pathophysiology. 9. Describe how osteoporosis is diagnosed, how it is evaluated, and its consequences. 10. List and apply the NOF guidelines when to initiate pharmacotherapy for osteoporosis. 11. Name the major FDA approved drugs (only the ones discussed) used for treating osteoporosis, identifying the mechanism of action of each. 12. List and apply the AACE guidelines on first line drugs for treating osteoporosis.  Why should you care about bones?  Major functions of the skeleton:  Structural support and locomotion  Primary location of hematopoiesis in adulthood  Storage of lipids  Reservoir for minerals and regulates kidney function  Participates in energy metabolism and satiety  Skeletal disorders are generally grouped into 2 types:  Non-metabolic (ex: trauma or injury such as osteoarthritis)  Metabolic (ex: low bone mass)  Why should you care about bones? Normal Bone Mass Osteoporosis USBJI: The prevalence of osteoporosis in US adults aged 50 and over [is] 11.0%, or roughly 12 million adults… The prevalence [is] significantly higher in women (16.5%) than men (5.1%). The overall prevalence of low bone mass [is] 44.5%, representing ~45 million adults.  Why should you care about bones? Fracture risk is inversely related to bone mass. Lower bone mass::Higher fracture risk Advanced age alone increases fracture risk. Advanced age::Higher fracture risk Adapted from Manolagas et al 2010 Why should you care about bones?  In the US, Hospitalizations for osteoporotic fractures exceeds those for heart attack, stroke, and breast cancer (1)  Up to 25% of hip fracture patients die within a year of their injury (2)  In the US, only 1 in 5 patients age 50 and above who suffer a hip fracture go on osteoporosis pharmacotherapy (3)  Compared to 1990, worldwide incidence of hip fracture is projected to increase by 310% in men and 240% in women by 2050 (4)  Black women with post-menopausal osteoporosis have significantly higher rates of mortality, debility, and destitution after fracture than white women (5)  Definition of “bone” Bone, the matrix Bone, the tissue Bone, the organ Lippincott’s Illustrated Reviews: Physiology Junqueira’s Basic Histology  Bone tissue organization (osteon) Adapted from the UCSD Histology Image Bank Lippincott’s Illustrated Reviews: Physiology  Bone material properties  The material strength of bone is due to  Packaging of collagen fibrils into fibers like rebar in concrete  Studding of collagen fibrils with hydroxyapatite crystals  Calcium phosphate  Bone material can be weakened by defects in packaging and/or mineralization Lippincott’s Illustrated Reviews: Physiology  Clinical Application of Bone Material Properties: Osteogenesis Imperfecta  Numerous mutations leading to defects in type 1 collagen expression, structure, packaging, or mineralization are linked to osteogenesis imperfecta (OI), also known as brittle bone disease.  OI is a long spectrum of symptoms that range from mild to severe types  Manifestations include low bone mass with inordinately high fracture risk, “blue” sclerae, poor bone quality, mineralization, dentinogenesis imperfecta  Most common form of OI is type I, which is due to heterozygous mutations that causes reduced COL1A1 expression  Pharmacological management aims to stabilize bone mass and reduce fracture risk  FYI only Clinical Application of Bone Material Properties: Osteogenesis Imperfecta Reeder & Orwoll 2006 Clinical Application of Bone Material Properties: Osteogenesis Imperfecta The Patient Project podcast interview with Jessica Minor is available at this link.  Clinical Application of Bone Material Properties: Osteomalacia and Rickets  Adequate calcium and phosphate levels are required for proper bone strength  Osteomalacia in adults  Rickets in children  Often with bowed legs or knock-knee  Both conditions are characterized by increased amounts of osteoid and low bone mineral density. Image created by Michael L. Richardson, M.D. Sept 28th, 2004; obtained from Wikipedia Commons; used with permission.  Bone remodeling Bone matrix suffers constant strain and stress, causing microdamage (cracks, fissures, etc). Maintaining bone quality requires continual repair of microdamage through a process called BONE REMODELING Collagen I fragments (CTx) Collagen I propeptide (P1NP) Lippincott’s Illustrated Reviews: Physiology  The players in skeletal physiology  Four bone cell types:  Osteoprogenitors  Osteoblasts  Osteocytes  Osteoclasts Junqueira’s Basic Histology  Osteoblasts and osteocytes RUNX2 is a gene target of the Bone Morphogenetic Protein (BMP) pathway whose transcription is induced by active BMP signaling in the MSC lineage. Adapted from Del Fattore et al 2012  Osteoblasts and osteocytes runx2 and other transcription factors Several molecular switches control the decision to become an osteoprogenitor instead of a chondroprogenitor Adapted from Del Fattore et al 2012  Osteoblasts and osteocytes runx2 runx2 runx2 osterix and other balp balp transcription col1a1 col1a1 factors rankl opg Active, mature osteoblasts secrete 1) bone matrix as uncalcified osteoid (type 1 collagen, COL1A1), 2) molecules involved in matrix mineralization such as bone-specific alkaline phosphatase (BALP), and 3) RANKL and OPG which regulate osteoclast formation. Adapted from Del Fattore et al 2012  Osteoblasts and osteocytes Monitoring osteoblasts diagnostically: Lab tests from serum/plasma/urine: Alkaline Phosphatase Bone-Specific Alkaline Phosphatase P1NP Others Bone biopsy with histomorphometry: Counting number of osteoblasts on bone surface Fluorescent dyes that incorporate into the bone matrix during mineralization Bone scintigraphy using technetium-99m Adapted from Del Fattore et al 2012 Osteoblasts and osteocytes  Osteoblasts have three choices:  Apoptosis (majority)  Inactivity to become bone lining cells (reversible upon need)  Enclose themselves in matrix and differentiate into osteocytes  What regulates osteoblast activity?  Wnt pathway  Growth Hormone pathway  PTH pathway  Clinical Application of Bone Turnover: Sclerosteosis and Van Buchem Disease  Two human diseases – sclerosteosis and Van Buchem Disease – indicate Wnt signaling promotes osteoblast activity  Both conditions are caused by overactivity of the Wnt pathway due to ineffective (or absent) action by the Wnt inhibitor Sclerostin Van Buchem Disease Janssens & Van Hul 2002  Clinical Application of Bone Turnover: Sclerosteosis and Van Buchem Disease  Two human diseases – sclerosteosis and Van Buchem Normal Van Buchem Disease Disease – indicate Wnt signaling promotes osteoblast activity  Both conditions are caused by overactivity of the Wnt pathway due to ineffective (or absent) action by the Wnt inhibitor Sclerostin Janssens & Van Hul 2002  Clinical Application of Bone Turnover: Sclerosteosis and Van Buchem Disease  Two human diseases – sclerosteosis and Van Buchem Disease – indicate Wnt signaling promotes osteoblast activity  Both conditions are caused by overactivity of the Wnt pathway due to ineffective (or absent) action by the Wnt inhibitor Sclerostin Janssens & Van Hul 2002  Clinical Application of Bone Turnover: Sclerosteosis and Van Buchem Disease  Two human diseases – sclerosteosis and Van Buchem Disease – indicate Wnt signaling promotes osteoblast activity  Both conditions are caused by overactivity of the Wnt pathway due to ineffective (or absent) action by the Wnt inhibitor Sclerostin  Sclerostin is inhibited by a neutralizing antibody called Romosozumab Janssens & Van Hul 2002  Clinical Application of Bone Turnover: Acromegaly  Over-secretion of Growth Hormone (typically from a pituitary adenoma) leads to high bone mass  Especially noticeable in face, hands and feet Molitch 1992  Clinical Application of Bone Turnover: Acromegaly P1NP levels are typically elevated in patients with acromegaly and decline after removal of pituitary adenoma Note: While GH-based therapies improve bone mass they are not recommended for osteoporosis but are available for treating short stature. More to come on GH and acromegaly in GEM course. Adapted from Godang et al 2016  Working summary of bone cell types and functions Osteoblast Osteocyte Osteoclast “Bob the Blast” “Sally the Cyte” “Carl the Clast” Mechanosensor, Mineral Major Function Secrete bone matrix Degrade bone matrix homeostasis Osteoprogenitor → Lineage Osteoprogenitor Monocyte/Macrophage Osteoblast Teriparatide, Bisphosphonates, Targeted by drug Abaloparatide Denosumab, Romosozumab Romosozumab Images copyright John Wiley & Sons, used with permission  Working summary of bone cell types and functions Osteoblast Osteocyte Osteoclast “Bob the Blast” “Sally the Cyte” “Carl the Clast” Mechanosensor, Mineral Major Function Secrete bone matrix Degrade bone matrix homeostasis Osteoprogenitor → Lineage Osteoprogenitor Monocyte/Macrophage Osteoblast Teriparatide, Bisphosphonates, Targeted by drug Abaloparatide Denosumab, Romosozumab Romosozumab Images copyright John Wiley & Sons, used with permission