Osteoporosis Presentation PDF

Osteoporosis PHM101H1- Pharmacotherapy 1: Foundations & General Medicine Chris Fan-Lun, BScPhm, ACPR, BCGP Pharmacy Clinical Coordinator. Sunnybrook Veterans Centre Adjunct Lecturer, Leslie Dan Faculty of Pharmacy March 22, 2024  Learning Objectives Describe the pa...

Osteoporosis PHM101H1- Pharmacotherapy 1: Foundations & General Medicine Chris Fan-Lun, BScPhm, ACPR, BCGP Pharmacy Clinical Coordinator. Sunnybrook Veterans Centre Adjunct Lecturer, Leslie Dan Faculty of Pharmacy March 22, 2024  Learning Objectives Describe the pathophysiology, clinical presentation, risk factors and complications of OP Review the clinical approach to assess OP (history; physical exam; biochemistry; imaging) Use OP Canada guidelines to support clinical decision-making in the use of pharmacotherapy to reduce fracture risk Bone – Major Functions Structural support Protection of organs Marrow – development and storage of blood cells Mineral storage (Ca, Mg, PO4) Bone Tissue Cortical (compact) – hard outer layer Trabecular (cancellous) – spongy inner layer  Bone Composition Osteoid: non-mineral, organic part of the bone matrix made of collagen and non- collagenous proteins Minerals: hydoxyapatite (Ca and PO4) and Mg - stiffness and strength Osteoblasts: bone forming cells Osteocytes and Lining cells: bone communication activities; formerly osteoblasts that become incorporated into bone matrix or cover the surface as lining cells Osteoclasts: bone resorbing cells Image source: International Osteoporosis Foundation. https://www.osteoporosis.foundation/health-professionals/about-osteoporosis  Bone Remodeling Cells Osteoclasts Adhere to bone and subsequently remove it by acidification and proteolytic digestion Osteoblasts Synthesize and secrete the organic matrix and regulate mineralization Mature cells in osteoid matrix become osteocytes, or cover the surface as lining cells (bone communication cells)  Bone Remodeling: Resorption and Formation  Osteoclast Cell Signaling Receptor activator of nuclear factor kappa β ligand(RANKL) Cytokine released by osteoblasts, osteocytes Stimulates progenitor cell differentiation to osteoclast Binds to RANK receptor on osteoclast precursors  initiates differentiation, osteoclast maturation -> bone resorption Inhibit RANKL release: Estrogen, Calcitonin Stimulate RANKL release: IL1;IL6; m-CSF; PTH; 1,25(OH)2D3 ; TGF-β; prostaglandin E2; TNF-α Estrogen: ↓ production of IL6, IL7, TNF-α, and m-CSF; ↑ production of IL-4, IL-10, TGF-β, and TGF-α Net effect: osteoclast apoptosis  Osteoblast Cell Signaling Parathyroid hormone (PTH), Parathyroid related protein(PTHrP) - ↑ osteoblast differentiation and activity Osteoprotegerin (OPG) - binds to RANKL, stopping bone resorption  Calcium Homeostasis Calcium absorption usually 30-35% – low vitamin D:10-15% Low calcium PTH released into circulation – ↑ PTH production – ↑ 1,25(OH)2D3 production Ca reabsorption by kidney – If insufficient to maintain serum Ca, bone resorption occurs Low PTH concentrations for a short time ↑ bone formation Calcitonin inhibit RANKL release -> ↓ osteoclast bone resorption Pathophysiology: Osteoclast and Osteoblast Mismatch Image source: International Osteoporosis Foundation. https://www.osteoporosis.foundation/health-professionals/about-osteoporosis  Osteoporosis Reduced bone strength and deterioration of bone -> ↑ risk of fractures Most common fractures associated with OP: – hip, spine, wrist, and shoulder WHO def’n: bone density < 2.5 SD below the mean for young healthy adults of the same sex i.e. T-score of – 2.5.  The Need to Look Beyond BMD Most fragility fractures occur in people with BMD in non-osteoporotic range Osteoporosis Diagnostic Criteria T-score: -2.5 or less OR Fragility fracture Osteopenia &  fracture risk Ax 10-yr probability ≥ 3 % for hip fracture ≥ 20 % for major osteoporotic fracture Cranney A, et al. CMAJ 2007; 177(6):575-580; Langsetmo L, et al. J Bone Miner Res 2009; 24(9):1515-1522; Endocr Pract. 2016;22(9):1111-8.  What is a Fragility Fracture? A fracture occurring spontaneously or following minor trauma such as a fall from standing height or less – Excluding craniofacial, hand, ankle and foot fractures Kanis JA, et al. Osteoporos Int 2001; 12(5):417-427; Bessette L, et al. Osteoporos Int 2008; 19:79-86. Osteoporosis Canada Epidemiology www.osteoporosis.ca. Facts & Stats. Accessed March 2,2024.  Consequences of Fracture ↑ Risk of: Impact:  Hospitalization  Loss of confidence  LTC  Fear of falling  Death  6 cm; measured loss < 2 cm) Low BMD Fragility fractures Back pain Kyphosis – dysphagia Image source: Osteoporosis Canada https://osteoporosis.ca ▶ Update to the 2010 Osteoporosis Canada Guideline ▶ Expanded recommendations on exercise and nutrition ▶ Guidance on treatment initiation, duration of therapy and monitoring ▶ Guidance on use of anabolic therapies  Clinical Assessment for Osteoporosis 1. Identifying risk factors 2. Assess for signs of undiagnosed vertebral fracture(s) Risk Factors  Previous fracture, after age 40 (low  Secondary osteoporosis trauma; fractures of hands, feet and  Parent fractured hip craniofacial bones are not considered OP fractures)  Current smoking  Alcohol ≥3 drinks/day  Glucocorticoids (> 3months in the last year; prednisone dose ≥5 mg daily)  Body Mass Index, 50 years 0.8g protein/kg/day) ▶ Choose whole grain foods Calcium-rich foods: milk products (milk, yogurt, cheese) fortified beverages (plant- based, orange juice) canned salmon (w/ bones) Vitamin D-rich foods: fatty fish (salmon, rainbow trout) fortified foods (cow’s milk, plant-based beverages) eggs Protein-rich foods: beef, pork, chicken, fish, eggs, milk products legumes, beans, nuts, seeds Health Canada 2022. https://food-guide.canada.ca/en/  Recommended Dietary Allowance Calcium Vitamin D Men Men & Women 51 – 70 yo 1000 mg/d 51 – 70 yo 600 IU/d >70 yo 1200 mg/d >70 yo 800 IU/d Women Health Canada recommends 400 IU/d 51 – 70 yo 1200 mg/d plus dietary sources over age 50 >70 yo 1200 mg/d *Upper limit: 4000 IU/d Health Canada 2022. https://food-guide.canada.ca/en/applying-guidelines/advice-vitaminmineral-supplementation/#vitamin-d What Types of Exercise Prevent Fractures ▶ Balance and functional training, with or without resistance training can prevent falls and may prevent fractures ▶ Resistance and impact exercise may improve BMD ▶ Exercise may improve physical functioning or QoL Sherrington C et al. Cochrane Database Syst Rev 2019 Jan;1(1):CD012424. Recommendations on Exercise for Fall & Fracture Prevention Balance Exercises Functional Exercises Shifting body weight to the limits of stability Exercises that improve ability to perform everyday tasks, or do activities for fun or fitness Reacting to things that upset one’s balance (eg. chair stands for sit-to-stand ability, stair- (eg. catching and throwing a ball) climbing to train for hiking). Maintaining balance while moving Resistance Exercises (eg. Tai chi) Major muscle groups (eg. upper and lower extremities, chest, shoulders, back) work against Reducing base of support (eg. standing on resistance (eg. squats, lunges and push-ups) one foot). Target abdominal and back extensor muscles ↑ exercise difficulty, pace, frequency, volume (sets, reps) or resistance over time Nonpharmacologic Interventions ▶ Balanced Diet – Foods First Approach ▶ Individualized approach may be needed ▶ Consult dietitian If receiving pharmacotherapy, individualize Ca and vit D Most individuals in pharmacotherapy trials received Vit D  400 IU/day + calcium up to 1000 mg/day OHIP Coverage of 25-OH Vit D Testing  Malabsorption syndromes  Osteopenia  Osteoporosis  Rickets  Renal diseases  Medications affecting vit D metabolism Risk-Based Pharmacotherapy Previous hip or spine fracture Or ≥ 2 fragility fracture events Risk  Pharmacotherapy Options Anti-Resorptive Anabolic (Inhibit osteoclast activity) (Stimulate new bone formation) Bisphosphonates Parathyroid Hormone Analog o ORAL: Alendronate; Risedronate o Teriparatide o IV: Zoledronic Acid RANKL Monoclonal Antibody Sclerostin Inhibitor o Denosumab o Romosozumab SERM o Raloxifene Menopausal Hormone Therapy (Estrogen + progestogen)  Pharmacotherapy Safety and Adherence Issues Bisphosphonates: ↑ risk of AFF* + ONJ** with long term use Denosumab: ↑ bone loss + vertebral fracture risk with delayed dose or discontinuation Anabolic agents: Injections; high cost; subsequent antiresorptive required to maintain BMD *AFF = Atypical Femur Fracture **ONJ = Osteonecrosis of the Jaw Approach to Pharmacotherapy  Approach to Pharmacotherapy Bisphosphonates People initiating therapy – first line therapy for most people Bisphosphonates* Oral bisphosphonates may be preferred, as drug coverage, costs and (Alendronate, access to an infusion centre may be barriers to zoledronic acid Risedronate, Zoledronic acid) Assess adherence and tolerance *Menopausal hormone therapy (MHT) is a suggested alternative for women < 60 yo or MHT - within 10 years after menopause who alternative for prioritize alleviation of substantial some menopausal symptoms postmenopausal Choice will also depend on individualized risks of menopausal hormone therapy, which consists of an females estrogen dose equivalent of conjugated equine estrogens of 0.625 mg daily (plus progestogen in those with an intact uterus)  Approach to Pharmacotherapy Denosumab – People initiating therapy second line option Bisphosphonates* (Alendronate, Risedronate, Zoledronic acid) Assess adherence and tolerance Contraindications or substantial intolerance or barriers to bisphosphonate Denosumab and commitment to long-term therapy “Denosumab may be preferred when there is a high burden of oral medications, gastrointestinal intolerance, contraindication to oral bisphosphonates or barriers to accessing intravenous zoledronic acid Despite the benefits of denosumab, a careful assessment of indications is required because of the risk of rapid bone loss and vertebral fractures with delayed dosing or discontinuation of denosumab. It is important to communicate the need for commitment to long-term therapy and the need to transition to alternative antiresorptive therapy if discontinuing denosumab.”  Approach to Pharmacotherapy Anabolic therapy People initiating therapy Recent severe vertebral Anabolic Therapy in select patients fracture or ≥ 2 vertebral (Teriparatide or Romosozumab) fractures and T-score ≤- Seek advice from consultant 2.5 Bisphosphonates* (Alendronate, Antiresorptive therapy after Risedronate, Zoledronic anabolic therapy acid) Assess adherence and tolerance Recent fracture - a fracture occurring within the past 2 yr. Severe vertebral fracture - vertebral body height loss of > 40%. Choice of anabolic therapy may depend on affordability and feasibility of injection schedule.  Approach to Pharmacotherapy Raloxifene – People initiating therapy last resort Recent severe vertebral Anabolic Therapy fracture or ≥ 2 vertebral (Teriparatide or Romosozumab) rather than no fractures and T-score ≤- Seek advice from consultant treatment for Bisphosphonates* 2.5 PM females (Alendronate, Risedronate, Zoledronic acid) Assess adherence and tolerance Contraindications or substantial intolerance or barriers to bisphosphonate Denosumab ⱡ and commitment to long-term therapy Raloxifene is suggested rather than no *Raloxifene should be used only in those treatment for females who have who are not at high risk of VTE. contraindications or substantial intolerance to, or who choose not to take, other suggested therapies  Treatment Duration - Bisphosphonates Bisphosphonates Initial Treatment for 3-6 years 6yr for individuals who have a history of hip, vertebral, or multiple non-vertebral fractures, or new or ongoing risk factor(s) for accelerated bone loss or Assess adherence and tolerance fracture Inadequate response or ongoing substantial concerns Extend or switch therapy for fracture Seek advice from consultant Stop therapy (drug holiday) Reassess 3 yr after stopping therapy Earlier reassessment for resumption of therapy may be appropriate for some individuals  Treatment Duration - Denosumab Long term uninterrupted therapy Q6 months injections should not be delayed by more than 1 month because of the risk of rapid bone loss and vertebral fractures Duration of therapy may be assessed after 6–10 yr Transition to alternative therapy if stopping Treatment Duration – Anabolic Therapies Teriperatide – Daily subcut injections for up to 24 months Romosuzamab – Monthly subcut injections for up to 12 months Consultant expertise warranted Anabolic therapy may depend on affordability and feasibility  Monitoring BMD may be repeated at a shorter interval if there are secondary causes of OP, new fracture or new clinical risk factors associated with rapid bone loss  Pharmacotherapy Workup Use risk assessment tool to determine your patient’s risk for fractures Should you recommend pharmacotherapy? What risk factors influence your decision? Consider secondary drug-induced causes Consider nonpharmacological and pharmacological interventions  Calcium and Vitamin D What are the benefits and risks? How much calcium (through diet and supplementation) is recommended? – Consider the type of calcium salt & elemental Ca2+ How much Vitamin D is recommended? – Consider the patient’s 25-OH-Vit D level  Pharmacotherapy Considerations When is the drug INDICATED? In Common and more serious (but rare) what type of pt? side effects, contraindications, drug interactions, dosage and administration issues How EFFECTIVE are they? Cost? How SAFE are they? Convenience? Frequency Can your patient be ADHERENT Administration Formulation specific to pharmacotherapy? Monitoring  Summary Identification of OP fracture risk factors is key Risk assessment tools: FRAX,CAROC Investigations: biochem, radiographic(BMD, spine X-ray, VFA) As risk increases, benefit of pharmacotherapy increases Bisphosphonates - first line for most  Initial duration = 3-6 yrs, consider drug holiday + reassess to resume MHT – alternative for females with menopausal symptoms  Summary Denosumab – alternative therapy  Uninterrupted long-term commitment to treatment  Transition to anti-resorptive agent if discontinuing Anabolic agents – upfront therapy for select higher risk pts  Accessibility and feasibility may limit use Raloxifene – last option for females  Not for individuals at high risk for VTE Monitoring of Therapy  Regularly assess adherence, tolerability, and new risk factors  Reassess BMD and fracture risk in 3 yrs (or earlier if secondary causes, new fracture, new risk factors)