BMS 551 Skeletal Physiology & Pharmacology 4 of 4 PDF

#16 Skeletal Physiology & Pharmacology Part 4 of 4 J O N AT H A N L O W E R Y, P H D A SS 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 J LO W E RY @ M A R I A...

#16 Skeletal Physiology & Pharmacology Part 4 of 4 J O N AT H A N L O W E R Y, P H D A SS 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 J LO W E RY @ M A R I A N. E D U 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 LO W E RY )  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, Degrade bone Major Secrete bone matrix Mineral homeostasis matrix Function Osteoprogenitor → Monocyte/ Lineage Osteoprogenitor Osteoblast Macrophage Romosozumab Targeted by Teriparatide, targets an Bisphosphonates, drug Abaloparatide osteocyte-derived Denosumab protein Images copyright John Wiley & Sons, used with permission  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. 5 Case Presentations 6  Case #3:  54 year old Asian female  165 cm (about 5'5"), 59 kg (about 130 lbs)  Yes previous fx, Yes parent fx hip, No current smoking, Yes glucocorticoid, Yes RA, No 2nd OP, No excess alcohol  Femoral neck T-score = -1.1  Is this normal BMD, osteopenia, or osteoporosis?  Is pharmacotherapy justified? 7 Anti-resorptive drugs stabilize bone mass… … by reducing resorption. 8 Image adapted from Lewiecki 2011  Anti-resorptive drugs stabilize bone mass… … by reducing resorption. So what do you do with a patient with very low bone mass and/or very high fracture risk? 10 Image adapted from Lewiecki 2011  Anabolic therapies  Teriparatide, abaloparatide and romosozumab are FDA approved anabolic therapies available in the USA  Teriparatide and abaloparatide are delivered via daily SQ injection  Romosozumab is delivered via monthly SQ injection  AACE recommends teriparatide for patients with very low BMD (or high fracture risk) or in whom bisphosphonates have failed  Additional advice on usage of abaloparatide and romosozumab expected in the coming years 12  Teriparatide Pre-teriparatide 21 months teriparatide Costly and, historically, could not be given for more than 2 years due to osteosarcoma observed in animal models. FDA removed black box warning in late 2020 and now allows 2+ year duration for patients who remain at or return to having a high risk for fracture. 10/08/2024  Teriparatide Mechanism of action: Teriparatide is the active form of Parathyroid Hormone (PTH) Don’t get confused: Sustained PTH signaling leads to bone loss (eg, primary hyperparathyroidism) via promoting osteoclastogenesis Intermittent PTH (iPTH) signaling preferentially activates osteoblasts to increase bone formation rate 14  Follow-up  The patient is placed on calcium/vitamin D supplements along with daily teriparatide, and encouraged to maintain an active lifestyle.  The patient returns two years later and has gained BMD.  This patient is 56 years old… what do you do now?  “Rebound” bone resorption after teriparatide withdrawal  General recommendation is to switch to an antiresorptive therapy such as alendronate or denosumab 15  Case #4:  88 years old African-American female  168 cm (about 5'6"), 53 kg (about 115 lbs)  Yes previous fx, Yes parent fx hip, No current smoking, No glucocorticoid, No RA, No 2nd OP, No excess alcohol  Femoral neck T-score = -4.0  Is this normal BMD, osteopenia, or osteoporosis?  Is pharmacotherapy justified?  Romosozumab Mechanism of action: Monoclonal antibody targeting Sclerostin, thereby reducing inhibition of the Wnt pathway Primarily leads to increased bone formation rate and has some effect on decreasing bone resorption rate Contraindicated in patients with history of myocardial infarction in preceding year due to possible increase in risk of myocardial infarction, stroke and cardiovascular death – leading to a black box warning. Costly and cannot be given for more than 1 year, after which should be followed by an anti-resorptive therapy. 17  Summary of major osteoporosis therapies  NOF offers guidelines on when and for whom to initiate pharmacotherapy  Calcium and vitamin D supplementation is always recommended for patient’s whose dietary intake is insufficient  AACE recommends certain bisphosphonates (e.g., alendronate) and denosumab as first line drugs, with teriparatide reserved for patients with very low BMD or in whom bisphosphonates have failed  Bisphosphonates (e.g., alendronate) and denosumab are anti-resorptive therapies:  Bisphosphonates selectively incorporate into bone matrix, are internalized by active osteoclasts during resorption, then inhibit that osteoclast  Denosumab is a neutralizing antibody that targets RANKL and reduces osteoclastogenesis  A drug holiday is recommended for bisphosphonate therapy due to risk of atypical femoral fractures and ONJ (no similar recommendation for denosumab)  Teriparatide, abaloparatide and romosozumab increase bone formation rate by activating osteoblasts; romosozumab also inhibits osteoclasts. 18  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. A 3-year-old boy is brought to the pediatrician by his mother because he is not meeting speech developmental milestones. The mother feels this is due to impaired hearing. The child has a history of multiple bone fractures. Physical examination shows small, discolored teeth. X-ray indicates low bone mineral density. Which of the following is the most likely explanation for these findings? A. Mutation causing reduced expression of Sclerostin B. Elevated production of Growth Hormone C. Mutation causing reduced expression of COL1A1 D. Increased dietary intake of calcium A 42-year old female presents with complaints of fatigue and mild headaches. She reports that her feet and hands seem to be getting larger, requiring her ring to be sized up. Her family has noted that her facial features have changed and her physical appearance is notable for frontal bossing and enlargement of the mandible. Which of the following is most likely to be observed? A. High serum P1NP B. Low serum P1NP A 42-year old female presents with complaints of fatigue and mild headaches. She reports that her feet and hands seem to be getting larger, requiring her ring to be sized up. Her family has noted that her facial features have changed and her physical appearance is notable for frontal bossing and enlargement of the mandible. Which of the following is most likely to be observed? A. High serum Growth Hormone levels B. Low serum Growth Hormone levels A 68-year-old Hispanic male presents for an annual physical. He reports generally feeling well and has no complaints. A review of his medical history is unremarkable. A DXA scan reveals a femoral neck T score of -2.9. Which of the following, if any, is the most appropriate medication for this patient? A. Teriparatide B. Romosozumab C. Alendronate D. Further information is needed to make a decision about pharmacotherapy. E. No medication is warranted. A 72-year-old African American woman presents for an annual physical. She reports generally feeling well and has no complaints. A review of her medical history is unremarkable, with last menstrual period at age 54. A DXA scan reveals a femoral neck T score of -2.9. Laboratory analysis does not support a diagnosis of osteomalacia. Which of the following best explains this finding? A. Decreased serum levels of CTx B. Increased expression of RANK ligand C. Inhibition of Sclerostin D. Increased production of osteoprotegerin Adapted from Board Vitals