BMS 551 Skeletal Physiology & Pharmacology

#15 Skeletal Physiology & Pharmacology Part 3 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...

#15 Skeletal Physiology & Pharmacology Part 3 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 )  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.  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  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 Romosozumab targets an Targeted by drug Teriparatide, Bisphosphonates, osteocyte-derived Abaloparatide Denosumab protein Images copyright John Wiley & Sons, used with permission  What is osteoporosis? Normal Bone Mass Osteoporosis Image obtained from Medscape  What is osteoporosis? Bone mass is determined by DXA and expressed as the number of standard deviations from the reference cohort mean of young, healthy sex-matched adults. This is the patient’s “T-score.” Osteopenia Image adapted from American Bone Health, used with permission Humans generally attain peak bone mass in 20’s and begin losing bone mass in 40’s. Two choices for individuals to forestall osteoporosis: 1) attain higher peak bone mass and/or 2) slow the rate of bone loss in aging. 7  What is osteoporosis? In general, fracture risk is inversely related to bone mass Low bone mass :: High fracture risk High bone mass :: Low fracture risk* *Caveats exist – eg, osteopetrosis and type 2 diabetes mellitus Bone mass (g/cm2) Adapted from Manolagas et al 2010 8  What is osteoporosis? Age is a critical influencer of fracture risk… A patient’s low T-score is less important than their high fracture risk. This is an important distinction! Bone mass (g/cm2) Adapted from Manolagas et al 2010 9  Age-related osteoporosis  What do we know about age-related osteoporosis pathogenesis?  Osteogenic potential of osteoprogenitor cells declines with age  Osteocyte viability is reduced, therefore repair of microdamage is less efficient  Decreased physical activity and secondary causes of bone loss (eg, malnutrition, glucocorticoid usage, chronic inflammation) are more common later in life  Bone remodeling is less coupled with age  Bone formation rate decreases with age  Bone resorption rate likely increases with age  Age-related osteoporosis Bone mass loss ***Resorption out-paces formation***  Treating osteoporosis  When and for whom is pharmacotherapy appropriate?  National Osteoporosis Foundation offers these guidelines:  Postmenopausal women and men over 50 who present with any of the following:  T-score ≤-2.5 at the femoral neck or spine,  T-score between -1 and -2.5 at the femoral neck or spine and a 10-year probability of a hip fracture of ≥3% or a major osteoporosis-related fracture of ≥20% based on the US-adapted FRAX algorithm,  A hip or vertebral fracture. Original source available at this link. 14  Treating osteoporosis Watts et al 2010 15 Case Presentations 16  Case #1:  70 years old caucasian female  168 cm (about 5'6"), 68 kg (about 150 lbs)  No previous fx, No parent fx hip, No current smoking, No glucocorticoid, No RA, No 2nd OP, No excess alcohol  Femoral neck T-score = -2.7  Is this normal BMD, osteopenia, or osteoporosis?  Is pharmacotherapy justified?  Which drug is best? The American Association of Clinical Endocrinologists (AACE) offers these recommendations:  First line therapy: certain bisphosphonates (e.g., alendronate) or denosumab  FYI Only: other available anti-resorptive medications in US market: other bisphosphonates, calcitonin and raloxifene  For patients with very high fracture risk or in whom bisphosphonate therapy has failed: teriparatide [[Note: No current AACE recommendation regarding other anabolics]]  Calcium and Vitamin D supplements are recommended for all patients if dietary levels are inadequate Watts et al 2010 18  Bisphosphonates  Most commonly prescribed drug class for osteoporosis  Anti-resorptive therapy with oral and intravenous options  Dosing frequency varies from daily to monthly to yearly  Mechanism of action: incorporate into bone matrix and are internalized by osteoclasts during resorption, then inhibit osteoclastic activity or promote apoptosis -- reduces bone resorption rate  Highly specific for bone with minimal off-target effects  STEREOTYPICAL BISPHOSPHONATE: alendronate 19  Follow-up  The patient is placed on calcium/vitamin D supplements along with daily alendronate and encouraged to maintain an active lifestyle.  The patient returns two years later, has experienced no fractures, and her T score is the same as at the first visit (-2.7).  Has the therapy been successful?  What does this represent about her BMD?  Should she continue the bisphosphonate treatment? 20  Bisphosphonates  Length of bisphosphonate therapy should be determined by individual patient’s fracture risk  If risk if mild, AACE recommends a 1-2 year drug holiday after 3-5 years of treatment  High risk patients may be continued >5 years, with a possible 1-2 year holiday at 10 years  Drug holiday is recommended because of risk of adverse events  BMD and bone resorption markers should be monitored during the drug holiday and treatment restarted if BMD declines, bone resorption increases, or a fracture occurs. 21  Case # 2:  78 year old Latino male  178 cm (about 5'10"), 88 kg (about 210 lbs)  No previous fx, No parent fx hip, Yes current smoking, No glucocorticoid, No RA, No 2nd OP, Yes excess alcohol  Femoral neck T-score = -2.2  Is this normal BMD, osteopenia, or osteoporosis?  Is pharmacotherapy justified?  Follow-up  The patient is placed on calcium/vitamin D supplements along with daily alendronate, provided smoking cessation resources, encouraged to limit alcohol consumption and to maintain an active lifestyle.  The patient returns two years later, has stopped smoking and reduced alcohol intake, experienced no fractures, but his T score has declined to -2.8  The patient reports that he occasionally has GI irritation with alendronate so he doesn't take it daily 23  Which drug is best? Significant GI irritation with oral bisphosphonate administration (e.g., alendronate) is a major cause of patient non-compliance, which is circumvented by intravenous bisphosphonate administration. 24  Which drug is best? This patient's BMD is not exceptionally low......nor is his fracture risk exceptionally high...... consider choosing a drug with a non-oral route of administration and that has less frequent dosing. 25  Denosumab  SQ injection every 6 months  Anti-resorptive therapy: monoclonal antibody that targets RANKL and reduces osteoclastogenesis, thereby reducing the overall bone resorption rate  There is no consensus recommendation on length of therapy or drug holiday for denosumab 26  Denosumab RANKL RANK Receptor Denosumab Image adapted from del Fatorre et al 2012 27  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 Romosozumab targets an Targeted by drug Teriparatide, Bisphosphonates, osteocyte-derived Abaloparatide Denosumab protein Images copyright John Wiley & Sons, used with permission