Osteoporosis Student Version PDF 2024

Osteoporosis Janene Madras, Pharm.D., BCPS, BCACP **Need to know dosages forms The student is responsible for all the material in assigned chapters, this includes any reading materials reviewed in class and any assigned reading materials not reviewed in class. ...

Osteoporosis Janene Madras, Pharm.D., BCPS, BCACP **Need to know dosages forms The student is responsible for all the material in assigned chapters, this includes any reading materials reviewed in class and any assigned reading materials not reviewed in class.  Objectives The student will: Explain the different types, composition, and normal function of bone Define BMD, when the peak occurs, and who should be tested Explain the calcium and phosphorus absorption process Differentiate between osteoporosis, osteopenia, and normal bone mass Define the risk factors, presentation, nonpharmacological, and pharmacological treatments of osteoporosis Define mechanism of, prevention, and treatment of glucocorticoid induced osteoporosis Define mechanism of, prevention, and treatment of Paget’s disease Define mechanism of, prevention, and treatment of osteomalacia  Types and Composition of Bone Cortical (compact) bone: 80% - Surfaces of long and flat bones (ex: forearm, hip) - Forms compact shell around bone - Formed in layers and highly calcified → more structurally strong and protective Trabecular (cancellous) bone: 20% - Interior structure - Greatest bone turnover - High amount of osteoclasts and osteoblasts - Vertebrae, end of long bones, pelvis, wrist, ankle, ribs → most common sites of fracture  Types and Composition of Bone Bone contains minerals (50-70%), organic matrix (20- 40%), water (5-10%), lipids ( resorption - > 30-35 years old: resorption > formation Osteoblasts promote mineralization: release vesicles that provide Ca and phosphate, block mineralization inhibitors, provide nuclei for mineralization Osteoblasts regulated by calcitriol, estrogen, PTH, etc Osteoclasts: release enzymes and metabolic acids → digest and phagocytize bone matrix → release calcium and phosphate ions into circulation Normal aging: progressive decrease in osteoblasts and activity  RANKL Receptor activator of nuclear factor-κB ligand (RANKL) Cytokine needed for formation, function, survival of osteoclasts RANKL binds to RANK → fusion of osteoclast precursors into multinucleated cells, differentiate into mature osteoclasts, osteoclast attach to bone surfaces, osteoclast activate to resorb bone, osteoclast survival by preventing apoptosis  Bone Mineral Density Reflection of balance of resorption and formation Bone Mass: -  during 1st 30 years - Approaches peak in late teenage years - Slightly  during 3rd decade of life - Reaches peak around 20-30 YO (men reach higher peak bone mass) - Peak bone mass from genetics, nutrition, endocrine status, exercise, health during growth - Plateau period: constant bone formation turnover which approximates bone resorption - Start to lose bone in 3rd-4th decade - Women lose 0.3-5%/yr of cortical bone and 0.6-0.8% of cancellous bone, with menopause (due  estrogen &  bone resorption) women lose 2-3%/yr of cortical bone for next 8-10 years - Throughout life: women may lose 50% cancellous bone; 30% cortical bone (men: may lose 30% cancellous bone; 20% cortical bone)  Vitamin D Vitamin D and PTH maintain Ca homeostasis Maintain Ca homeostasis and stimulates mineralization by  Ca absorption (plays essential role in absorption of Ca) Vitamin D3 from sun and diet Vitamin D2 and D3 referred Vitamin D2 from diet (fortified milk) to as “vitamin D” Vitamin D → liver conversion → 25-hydroxyvitamin D → PTH stimulates renal conversion to 1 alpha, 25-dihydroxyvitamin D (calcitriol – active form) → promotes intestinal Ca & phosphorus absorption → blood → bone Stimulate bone matrix formation & bone maturation Level of plasma Ca that determines Ca balance  serum Ca →  PTH →  calcitriol →  intestinal absorption, renal tubular reabsorption, bone resorption PTH releases Ca & phosphate from bone (bone resorption) by increasing osteoclasts to reestablish homeostasis 3 functions of Vitamin D to maintain Ca levels: -  intestinal absorption of Ca, phosphorus, magnesium - Acts with PTH to maintain free Ca level in blood - Stimulate bone resorption depending on Ca level in blood  Vitamin D, PTH, Calcitonin, Phosphorus PTH and 1,25 (OH)2D promote formation and resorption partially by increasing osteoblasts and osteoclasts (excess PTH increases bone resorption) PTH and 1,25 (OH)2D increase renal Ca retention but PTH promotes renal phosphate excretion Calcitonin: released when high Ca levels,  intestinal Ca & phosphorus absorption, increases Ca kidney excretion, inhibits bone breakdown Phosphorus - Same absorption/resorption as calcium - Mineral in bone - Excess ingested absorbed and adjusted by kidney (kidneys excrete excess) - Controlled by PTH (controls kidney set point and decreases renal phosphorus reabsorption) O’Connell, MB. Pharmacotherapy 2002.  Calcium Constant flow of calcium: entering blood via GI absorption and skeleton, exiting blood to enter bone or get excreted Calcium balance dependent on GI absorption, bone demineralization, bone mineral formation, renal calcium clearance  PTH and Vitamin D PTH Vitamin D Intestine  Ca and phosphate  Ca and phosphate absorption by  1,25 absorption due to (OH)2D production 1,25 (OH)2D Kidney  Ca excretion,   Ca and phosphate phosphate excretion excretion due to 25 (OH)D and 1,25 (OH)2D Bone  Ca and phosphate  Ca and phosphate resorption with high resorption due to  1,25 doses, low doses  bone (OH)2D, bone formation formation may be  by 1,25 (OH)2D Net effect on blood  Ca and  phosphate  Ca and phosphate levels  Osteoporosis Low bone mass, deterioration of bone tissue, disruption of bone architecture, compromised bone strength, increased risk of fracture Bone loss = resorption > formation Significant morbidity, mortality, cost Heavy economic burden Occurrence: - Most prevalent: postmenopausal white women - Hispanic women, men, children, premenopausal women Increases with age Fractures due to deterioration in trabecular and cortical bone Low BMD  fracture risk (but normal BMD can fracture, & some with osteoporosis do not fracture)  Radiologic and Ultrasound Quantification of Bone Loss BMD: establish or confirm diagnosis of osteoporosis & predict future fracture risk - Gold standard method: measure central skeletal BMD (hip and spine) by DEXA - Lower BMD → greater risk of fracture - Best predictor of fracture - But not all pts with low BMD have fractures; some pts with slightly low BMD have fragility fractures - Expressed: expected BMD for pt’s age and sex (Z-score), or "young normal" adults of same sex (T-score) - Difference between pt's score and norm is stated in SD above or below mean Every 1 SD below mean young-adult BMD = 2 times risk of fracture  Radiologic and Ultrasound Quantification of Bone Loss DEXA (dual energy X-ray absorptiometry): standard for measuring hip & spine BMD (2 major fracture sites) - Measuring BMD at hip or spine assesses fracture risk, diagnoses and osteoporosis and severity, and determine osteoporosis after low-trauma fracture - Recommended to measure lumbar spine, femoral neck, and total hip BMD and use lowest BMD to diagnose - Forearm (distal third of radius) is alternative if preferred areas listed above cannot be scanned - Used for osteoporosis diagnosis and monitoring - Accurate, short scan time, minimal radiation - WHO: reference standard is hip → hip BMD best predictor of hip fractures and predicts fractures at other skeletal sites - U.S. Preventive Services Task Force: hip (femoral neck), spine (lumbar) - Bone Foundation and Osteoporosis Foundation: lumbar spine, hip - AACE: lumbar spine, femoral neck, and total hip (one-third radius if indicated) - Femoral neck is part of hip (total hip is proximal femur areas: neck, trochanteric, and inter-trochanteric)  Radiologic and Ultrasound Quantification of Bone Loss Single energy x-ray absorptiometry (SXA): measure peripheral sites (ex: finger, heel) - Used in pharmacy/clinic - Screening tool - Predictive accuracy of fractures < hip BMD - Do not use for diagnosis and management - Younger postmenopausal women with no major risk factors  Osteoporosis Bone density data: T-scores and Z-scores Z score: number of SDs from normal mean BMD value for patients of same age, sex, ethnicity - Aid in diagnosis of osteoporosis (most useful for secondary causes, children, premenopausal women, men < 50 YO) - Z-score above -2.0 is within normal limits Bone mass classified on T score: number of SD an individual’s BMD is away from mean peak BMD for young, healthy adults (25-30 YO) of same sex, ethnicity  T-Score Normal Osteopenia Osteoporosis Severe Osteoporosis BMD Within 1 SD Between 1 and 2.5 SD or more of “young 2.5 SD below below that of normal” that of “young “young normal” adult normal” adult adult T- > -1 Between < -2.5 < -2.5 score (T-score at (-1) and (T-score at or and hx of -1.0 and (-2.5); also below -2.5) fragility above) stated as fracture -1.0 to -2.4 *Based on bone mass measurement at spine, hip, or wrist in white postmenopausal women *Applies to postmenopausal women and men 50 years and older  AACE 2020 Osteoporosis Guidelines Definition of Osteoporosis T-score < −2.5 in lumbar spine, femoral neck, total proximal femur, or 1/3 radius Low-trauma spine or hip fracture (not dependent on BMD) T-score between −1.0 and −2.5 and fragility fracture of proximal humerus, pelvis, or distal forearm T-score between −1.0 and −2.5 and high FRAX® (or TBS-adjusted FRAX®) fracture probability based on thresholds specific for country  Osteoporosis Categories/Pathophysiology Postmenopausal - Occurs in decade after menopause - Mainly affects trabecular bone - Mainly vertebral & distal forearm fractures - Lose 10-25% of bone - Estrogen receptors in bone tissue, intestine, kidney - Enhance osteoclast activity with estrogen deficiency - Higher estrogen → lower fracture risk - Menopause ≤ 40 YO → ↑ risk of low BMD  Osteoporosis Categories/Pathophysiology Age-related - Bone loss within few years after peak bone mass - Have  bone mass and quality of bone,  bone fragility - Affects trabecular and cortical bone - Vertebral, hip, wrist fractures  bone resorption with age - Decreased calcium and vitamin D intake - Vitamin D insufficiency from  sun exposure and absorption - Microarchitectural deterioration of bone - Sex hormone concentrations  Estrogen Deficiency Increase proliferation, differentiation, activation of new osteoclasts Increase survival of mature osteoclasts Increase calcium excretion Decrease calcium gut absorption  Osteoporosis Categories/Pathophysiology Secondary - Due to medications, smoking, alcohol, medical conditions (ex: chronic liver disease, hypogonadism) - Affects trabecular and cortical bone - Speculate when osteoporosis occurs in premenopausal women, men < 70 YO, no risk factors, multiple low trauma fractures (esp at young age), Z-score < -2.0, or bone loss despite adequate drug treatment and calcium supplementation - Drug Induced (refer to risk factor slide for more medications) Glucocorticoids (discuss later) Thyroid medications to normalize TSH to avoid bone loss Heparin > 15,000-30,000units/day for > 3-6 months → bone loss and fractures Phenobarbital, phenytoin:  vitamin D metabolism which causes osteomalacia  Osteoporosis in Men Less common - Higher peak BMD - Lose bone (in 30’s) at slower rate after peak - Reduced falls - Short life expectancy - Less fractures due to larger bone diameter More likely to die within 1st yr of hip fracture Due to  testosterone (which  estrogen), decreased body weight, alcohol, long-term steroid use, smoking, weight loss, age, androgen deprivation therapy 2012 Endocrine Society's "Osteoporosis in men: an Endocrine Society clinical practice guideline https://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20 Practice%20Guidelines/FINAL-Osteoporosis-in-Men-Guideline.pdf  Osteoporosis Risk Factors Lifestyle - Low calcium intake - High caffeine ( Ca excretion): limit < 1-2 servings/day - Cola beverage with or without caffeine (conflicting data) Caffeine and phosphoric acid - High salt and vitamin A intake - Alcohol use:  falls, poor nutrition (females: < 1-2 drinks/day; males: 2-3 drinks/day) - Smoking (active or passive) - Vitamin D insufficiency - Inadequate physical activity - Falling - Aluminum antacids - Immobilization - Thinness (< 127lb or BMI < 21kg/m2)  Osteoporosis Risk Factors Genetic Disorders, Rheumatic and Autoimmune Diseases, GI Disorders, and Hypogonadal States: refer to Bone Health and Osteoporosis Foundation guidelines and DiPiro for examples) Endocrine Disorders: - DM, hyperparathyroidism, obesity (refer to Bone Health and Osteoporosis Foundation guidelines and DiPiro for more examples) Hematological Disorders: - Sickle cell disease, leukemia (refer to Bone Health and Osteoporosis Foundation guidelines and DiPiro for more examples) Miscellaneous Diseases: - Alcoholism, depression, heart failure (refer to Bone Health and Osteoporosis Foundation guidelines and DiPiro for more examples)  Osteoporosis Risk Factors Medications (refer to Bone Health and Osteoporosis Foundation, AACE, DiPiro Book for more) – increased bone loss and/or fracture risk - Glucocorticoids - Lithium - Heparin or low molecular weight heparin - Chemotherapy - Anticonvulsants (ex: phenytoin, phenobarbital, valproic acid, carbamazepine) - Drugs alter Ca absorption: tetracycline, Al antacids - Drugs alter Ca elimination: loop diuretics (example: furosemide) - Aromatase inhibitors (ex: letrozole, anastrozole) - Medroxyprogesterone acetate (boxed warning on insert) - Cyclosporine - Tacrolimus - Barbiturates - PPI (long-term therapy) - Thiazolidinediones - SGLT 2 inhibitors - Protease inhibitors (nelfinavir, indinavir, saquinavir, ritonavir, lopinavir) - Excessive thyroid supplementation - SSRI  Risk Factors for Falling Environmental risk factors: - Low-level lighting, slippery outdoor/indoor conditions, obstacles in walking path, loose throw rugs, lack of assistive devices in bathrooms Medical risk factors: - Age, arrhythmias, female gender, medications (narcotic analgesics, psychotropics, anticonvulsants), previous fall, dehydration, orthostatic hypotension, impaired transfer and mobility, vitamin D insufficiency, malnutrition, poor vision (refer to Bone Health and Osteoporosis Foundation and AACE guidelines for more) Neuromuscular risk factors: - Poor balance, weak muscles, kyphosis, reduced proprioception (unconscious perception of movement and spatial orientation arising from stimuli within body) Fear of falling  Osteoporosis WHO and NOF FRAX®: calculate 10 yr probability of hip fracture and 10 yr probability of major osteoporotic fracture (vertebral, hip, forearm, or proximal humerus fracture) by using femoral neck BMD and these clinical risk factors: - Age (between 40-90 YO) - Gender - Weight (low body mass index) - Height (low body mass index) - Personal history of fracture in adult life - Femoral neck BMD - Parental history of hip fracture (mother/father) - Current smoking - Use of oral glucocorticoid use (> 3 months of prednisolone ≥ 5mg/day or equivalent doses of other glucocorticoids) - Rheumatoid arthritis - Secondary osteoporosis - Alcohol ≥ 3 drinks/day http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9  FRAX® U.S. adapted WHO algorithm most useful in identifying subset of pts in low bone mass (osteopenia: T-score -1.0 and -2.4 at femoral neck or spine) category most likely to benefit from treatment (treatment naïve pts) Not ideal if risk factors and low bone mass at spine but normal bone mass at hip (since spine bone mass not on algorithm and use not validated) → clinical judgment Used only for postmenopausal women and men ≥ 50 YO Not validated if currently or previously treated with medications for osteoporosis If no femoral neck BMD: total hip BMD may be substituted (cannot use non-hip BMD)  Bone Health and Osteoporosis Foundation (BHOF) 2022 BMD Testing Women ≥ 65 years-old and men ≥ 70 years-old Postmenopausal women and men 50-69 years-old (depending on risk factors) Postmenopausal women and men > 50 years-old who have had adult age fracture Use facility with accepted quality assurance measures Use same facility and same densitometry device if possible for every test  Bone Health and Osteoporosis Foundation 2022 Vertebral Imaging Women > 65 years-old with femoral neck T-score < -1.0 Women ≥ 70 years-old and men age ≥ 80 years-old if T-score < -1.0 at spine, total hip, or femoral neck Men 70-79 years-old if T-score < -1.5 at lumbar spine, total hip, or femoral neck Postmenopausal women and men ≥ 50 years-old with these risk factors: Fracture for any cause when adult Historical height loss ≥ 1.5 inches: difference between current height and peak height Prospective height loss ≥ 0.8 inches (2 cm): difference between current height and previously height measurement that was documented Recent or ongoing long-term glucocorticoid treatment Hyperparathyroidism  American Association of Clinical Endocrinologists 2020 Evaluation/BMD Testing Evaluate all postmenopausal women aged ≥ 50 years for osteoporosis risk All women ≥ 65 years old Postmenopausal women - History of fracture(s) without major trauma - Osteopenia identified radiographically - Starting or taking long-term systemic glucocorticoid therapy (≥ 3 months) Perimenopausal or postmenopausal women with osteoporosis risk factors and would consider medications: - Low body weight (< 127 lb or BMI < 20 kg/m2) - Long-term systemic glucocorticoid therapy (≥ 3 months) - Osteoporotic fracture family history - Early menopause (< 40 years old) - Current smoking - Excessive alcohol consumption Secondary osteoporosis Vertebral imaging indications: refer to guidelines  U.S. Preventive Services Task Force 2018 BMD Testing Screen women ≥ 65 YO, younger women whose fracture risk ≥ 65 YO white woman with no additional risk factors Postmenopausal women < 65 YO with at least 1 risk factor (ex: history of hip fracture in parent, smoking, excessive alcohol use, low body weight): determine to screen by risk assessment tool No recommendation for men  Osteoporosis Presentation Shortened stature (measure height → loss of height > 1.5inches increases vertebral fracture risk) Vertebral fracture: most common; occurs early, chronic pain & disability, cause height loss & kyphosis, cause increase risk of falls Hip fracture: most serious (women have 12-20% mortality within 2 years, men have higher mortality rate) - May not be able to live independently and need nursing home care Wrist, forearm fractures Kyphosis (excessive curvature of spine causing hunching of back) Lordosis (inward curvature of spine): aka widow’s hump Bone pain Immobility Thoracic fracture: cause restrictive lung disease Lumbar fractures: change abdominal anatomy → constipation, abdominal pain, distention, reduced appetite, premature satiety **Depression and lower self-esteem**  Patient Assessment Identify risk factors - Hx of nontraumatic adult fractures - Hx of nontraumatic adult fractures in 1st degree relative - Comorbid disease states - Diet - Surgery - Menstrual history - Physical activity - Alcohol - Smoking - Measure height annually - Falls and/or risk factors for falls - Prior and current medications - PE and labs to rule out secondary causes CBC, TSH, ESR, PTH, chem panel (Ca corrected albumin, phosphorus, alkaline phos), 25-hydroxyvitamin D, urine Ca (assess Ca absorption & elimin)-normal or elevated  Prevention of Osteoporosis Goals of Prevention - Enhance development of skeleton & maximize peak bone mass - Maintain BMD and prevent age-related bone loss - Prevent falls and fractures - Preserve skeleton integrity General Principles - Adequate calcium intake and good nutrition - Limit alcohol (not > 7 units/week and not > 2 units/6 hours) - Adequate vitamin D intake - Regular weight-bearing and muscle strengthening exercise - Quit smoking - Bisphosphonate: refer to glucocorticoid section - Periodic monitoring of thyroid function - Identify disease states cause osteoporosis - Identify patients who fell or predisposed to falling  Bone Health and Osteoporosis Foundation (BHOF) 2022 Treatment Candidates Treat postmenopausal women and men ≥ 50 YO: - Primary prevention T-score ≤ -2.5 at femoral neck, total hip, lumbar spine, 33% radius Osteopenia (T-score between -1.0 and -2.5) at femoral neck or total hip PLUS FRAX 10-year risk hip fracture ≥ 3% or major osteoporotic fracture ≥ 20% - Secondary prevention Hip or vertebra fracture (does not matter BMD value) Proximal humerus, pelvis, or distal forearm fracture PLUS osteopenia Individualized treatment decision if have proximal humerus, pelvis, or distal forearm fracture WITHOUT osteopenia or low BMD  AACE Osteoporosis Guidelines Treatment Candidates 2020 T-score between –1.0 and –2.5 in spine, femoral neck, total hip, or 1/3 radius and fragility fracture hip or spine T-score ≤ -2.5 in spine, femoral neck, total hip, or 1/3 radius T-score between –1.0 and –2.5 in spine, femoral neck, total hip, or 1/3 radius if FRAX® 10-year probability for major osteoporotic fracture is ≥ 20% or 10-year probability of hip fracture is ≥ 3% (in United States) or greater than country specific threshold in other countries/regions  AACE Osteoporosis Guidelines Treatment Candidates 2020 Apply and know these definitions to guidelines on later slides Very High-Risk Category - Recent fracture (within previous 12 months) - Fractures while taking medication for osteoporosis - Many fractures - Fractures while taking medication that effect skeleton (ex: long-term glucocorticoids) - Very low T-score (< -3.0) - High risk for falls - History of injurious falls - Very high fracture probability by FRAX® (ex: major osteoporosis fracture > 30%, hip fracture > 4.5%) or other validated fracture risk algorithm High risk category: osteoporosis diagnosis but not at very high fracture risk (defined above)  Treatment Goals Minimize bone loss/increase BMD Decrease falls Decrease fractures  Preventing/Reducing Falls/Nonpharmacologic Therapy Do not rush – avoid quick, jerky motions Exercise to strengthen muscles Remove or tape down loose rugs Clutter free rooms Clean up spills Do not wax floors Wear comfortable, well-fitting, nonskid, low-heeled shoes Avoid long clothes (ex: dresses) Nonskid mat in bathtub Grab bars in bathroom (tub, shower, toilet) Grab handrails installed on stairs, use/install rails in stairways Avoid stepstools Well lit halls, stairwells, porches, driveways, entrances (also by use of nightlights) Install treads on steps Use hip protectors or hip pads Use canes/walkers Remove extension cords, loose wires Review medications! Check and correct vision and hearing Refer to NAMS, AACE for more  Exercise Stimulates osteoblasts →  BMD Aerobic, weight bearing, and muscle strengthening exercises - Weight-bearing (work against gravity): improves muscle function - Aerobic: improves cardiovascular health Benefits: decrease falls, improve balance, muscle strength and mass, coordination, posture, range of motion, endurance, flexibility, agility, reduce bone loss Long-term exercise during youth  peak BMD Weight-bearing: walking, running, dancing, stair climbing Muscle strengthening: weight training, resistance exercise Running > walking Swimming and cycling may not be beneficial BHOF recommendation: 30 mins most days of week weight-bearing exercise and muscle strengthening 2-3 days/week Check with PCP before starting to exercise  Thiazide Diuretic Example: Hydrochlorothiazide  urinary Ca reabsorption →  Ca retention Cannot be prescribed solely for osteoporosis Could be used if osteoporosis and need diuretic and taking glucocorticoids with > 300mg of Ca excreted in urine over 24 hours  Fluoride Salts  BMD by stimulating osteoblasts at spine, but not as strong as normal bone, no hip protection May cause osteomalacia-like bone defect and loss of cortical bone as it increases trabecular bone May  nonvertebral fracture at high doses No fluoride products approved for prevention or treatment of osteoporosis Do not use Need concurrent, adequate dietary calcium or calcium supplementation - But need to time administration correctly since fluoride absorption may be reduced with co-administration of calcium  Pharmacological Agents Drugs decrease bone resorption (decrease bone loss) by inhibiting osteoclast activity - Calcium - Vitamin D - Estrogen - Bisphosphonates - Raloxifene - Calcitonin - Denosumab - Conjugated Estrogens and Bazedoxifene Drugs increase new bone formation (osteoblasts) - PTH  Calcium Supplements Calcium: delay BMD loss &  fractures when combined with vitamin D - Enhance mineralization of newly formed bone - Dairy products - In vegetables not absorbed (dark green leafy vegetables  Ca absorption due to oxalic acid) - Dietary preferred: Ca better absorbed from food than supplements → better to increase dietary than supplement but may be needed if low dietary intake (recommend food first) Calcium foods have essential nutrients not found in supplements - Avoid in uncontrolled hypercalciuria - Take in divided doses (if > 500-600mg/day) →  absorption (GI tract only absorbs 500-600mg/dose of Ca at one time) Divided doses of 500mg/dose (interval of at least 5 hrs between doses) - Take with fluids during or after meals low in fiber to increase absorption - Supplement doses calculated on quantity of elemental calcium, not amount of calcium salt in unit - Supplement dose and dietary intake should not exceed recommended daily amount - Use products labeled “USP Verified” - National Osteoporosis Foundation: dietary calculator to evaluate calcium in diet  Calcium Supplements Calcium - BHOF: men 50-70 YO have 1000mg/day elemental calcium; men > 71 YO have 1200mg elemental calcium - Women > 51 YO (BHOF, AACE): 1200mg/day elemental Ca (total calcium intake should not be more than 1500mg/day per AACE) - Refer to table in Pharmacotherapy Chapter for National Academy of Medicine (NAM) calcium allowances Calculate calcium in food serving: add “zero” to percentage of daily value listed on food label Ex: 8oz milk is 30% of daily value of calcium = 300mg Ca/serving Calculate vitamin D in food serving: multiply percent daily value listed on food label by 4 Ex: 20% vitamin D = 80 units  Calcium Supplements Generic name Brand Name % Ca Content per tablet Ca carbonate Os-Cal, Tums, 40% Viactiv Ca carbonate Tums 500 Ca citrate Citracal 21% Ca gluconate Kalcinate 9% Ca lactate None 13% Ca phosphate tribasic Posture 39% Calcium chloride 27%  Calcium Supplements Calcium sources - Calcium carbonate: 40% elemental Ca, antacid, take with food since needs to be stimulated from acid Achlorhydria or hypochlorhydria (elderly), taking H2RA or PPI: carbonate salt may be reduced Not as well absorbed as citrate or gluconate More likely to cause constipation and bloating - Ca citrate: less risk of kidney stone, absorption acid-independent and do not need to take with meals, suggestions of better absorption than carbonate May be better in achlorhydria, and taking H2RA (histamine 2 receptor antagonist) or PPI (proton pump inhibitor), inflammatory bowel disease May be less likely to cause GI problems - Unrefined oyster shells (other than Oscal brand), coral calcium: not recommend due to large amount of lead and other heavy metals (check label to see which type of calcium, not always specified)  Calcium Supplements Calcium can  absorption of medications - Tetracycline: administer tetracycline at least 2 hours before or 4-6 hrs after calcium -  absorption of quinolones, iron, bisphosphonates, thyroid supplements - Alendronate, risedronate: wait ½ hour before giving Ca Dietary fiber, fiber laxatives, antacids  absorption of calcium Adverse effects of supplements: constipation, abdominal cramping, bloating, diarrhea, flatulence Avoid > 2500mg/day of elemental calcium → hypercalcemia, hypercalciuria, urinary stones Contraindications: hypercalciuria (>300mg/24hr) not controlled by thiazide Caffeine:  Ca excretion  Vitamin D Needed to absorb calcium ( Ca absorption in GI tract and affects bone resorption) Improves muscle strength, balance; reduces risk of falling Alone does not decrease fracture rate Dietary sources: vitamin-D fortified milk, cereals, egg yolks, salt-water fish, liver, green vegetables, bread Usually 5-15 minutes daily exposure between 10AM and 3PM is often sufficient to fulfill body's vitamin D requirement - Except winter months - Use of sunscreen agents dramatically decreases body's absorption of vitamin D (sunscreen with SPF ≥ 8:  skin’s capability of making vitamin D by 97.5%) Refer to table in Pharmacotherapy Chapter for National Academy of Medicine vitamin D allowances Refer to Institute of Medicine Dietary Reference Intakes for Vitamin D (50-70-year-old females: 600 units/day)  Vitamin D Calcitriol (active form of cholecalciferol or vitamin D3): preferred Vitamin D3 1,000-2,000 IU/day to maintain optimal serum 25(OH)D level (AACE) Vitamin D > 50 years-old: 800-1000 units/day (BHOF) Adverse effects: hypercalcemia, hypercalcuria Severe renal disease or liver disease: use calcitriol (1 alpha, 25- dihydroxyvitamin D, activated form) → monitor Ca and serum Cr cause hypercalcemia Increase vitamin D metabolism: rifampin, phenytoin, barbiturates, valproic acid, carbamazepine Reduce vitamin D absorption: cholestyramine, colestipol, orlistat, mineral oil Increase aluminum absorption → avoid aluminum products  Vitamin D Bone Health and Osteoporosis Foundation 2022 Check 25-hydroxyvitamin D levels Maintain serum vitamin D level (≥ 30 ng/mL but ≤ 50 ng/mL) Supplemental vitamin D (800-1000 units/day) if needed > 50 years to obtain appropriate vitamin D level - Higher doses may be needed in some adults (malabsorption) - Healthy persons serum 25(OH) vitamin D ≥ 20 ng/mL may be adequate, but if known or suspected metabolic bone disease ≥ 30 ng/mL is appropriate - Prefers Vitamin D3 (cholecalciferol-produced in humans) VS Vitamin D2 - Vitamin D2 (ergocalciferol-produced from plants) may be preferred if strict vegan/vegetarian diet Adults with vitamin D deficiency: 50,000 units of vitamin D2 or vitamin D3 once a week (or daily dose of 7000 units vitamin D2 or vitamin D3) for 5-8 weeks to obtain 25(OH)D level 30 ng/ml → then 1000-2000 units/day or a dose required to keep target blood level (may need higher doses if have malabsorption)  AACE 2020 Vitamin D Measure serum 25-hydroxyvitamin D (25[OH]D) if at risk for vitamin D insufficiency, particularly if have osteoporosis Maintain serum 25-hydroxyvitamin D (25[OH]D) ≥ 30 ng/mL if osteoporosis (preferable range: 30-50 ng/mL) Adults with vitamin D insufficiency (20-29 ng/mL) or deficiency (< 20 ng/mL, respectively): 5,000 IU daily of Vitamin D3 for 8-12 weeks to achieve 25(OH)D blood level > 30 ng/mL - Then maintenance of vitamin D3 1,000-2,000 IU daily (or appropriate dose to maintain target 25(OH)D blood level) → higher doses may be needed if certain factors (ex: obesity, malabsorption, older patients) Higher does of vitamin D (e.g., 50, 000 IU) used only in NOT common clinical situations  Calcium and Vitamin D Calcium: maintains BMD but some have seen small increases in BMD (less than other medications) Vitamin D: small increase BMD, hip and nonvertebral fractures Both recommended for treatment and prevention in all premenopausal and postmenopausal women - Counsel on importance of calcium, vitamin D, exercise - Not have adequate calcium intake from diet → can use calcium supplements - Vitamin D  absorption of calcium from small intestine  Treatment and Prevention Categories Antiresorptive agents: Anabolic agent: stimulate inhibit osteoclastic bone bone formation resorption - Teriparatide - Alendronate - Abaloparatide - Risedronate - Ibandronate - Zoledronic acid - Raloxifene - Calcitonin - Estrogen - Denosumab  Bisphosphonates Alendronate (Fosamax®), risedronate (Actonel®), risedronate delayed release (Atelvia), ibandronate (Boniva®), Zoledronic acid (Reclast®) Etidronate (Didronel®), pamidronate (Aredia®) & tiludronate (Skelid®)– Paget’s Adsorb to bone hydroxyapatite & incorporated into bone → inhibit hydroxyapatite breakdown → inhibit osteoclast →  activity of osteoclasts → greater rate of bone deposition by osteoblasts (compete with osteoclasts) →  bone mass Incorporated into bone → long t½ lives (1-10 yrs) Maximal suppression occurs after about 3 months starting therapy Absorbed poorly from GI tract (0.5-5%) Alendronate & risedronate: prevention & treatment of postmenopausal osteoporosis, increase bone mass in men with osteoporosis, treatment of corticosteroid-induced osteoporosis in men & women  Bisphosphonates Oral ibandronate: treatment and prevention of postmenopausal osteoporosis IV ibandronate: treatment of osteoporosis in postmenopausal women IV zoledronic acid: treatment of osteoporosis in postmenopausal women, prevention of osteoporosis in postmenopausal women, increase bone mass in men with osteoporosis, treatment and prevention of glucocorticoid-induced osteoporosis if expected to be on glucocorticoids for at least 12 months  Bisphosphonates Alendronate treatment: 10mg/day or 70mg once a week Alendronate prevention: 5mg/day or 35mg once a week Risedronate treatment/prevention (Actonel): 5mg/day, or 35mg once a week, or one 75mg tablet on 2 consecutive days for total of 2 tablets monthly, or 150mg once a month Risedronate treatment (delayed release-Atelvia): 35mg once a week Fosamax plus D (alendronate/cholecalciferol): once-weekly tablet containing 70mg alendronate and 2800IU vitamin D3 representing 7 days worth of 400IU of vitamin D Risedronate plus calcium: includes 4 weeks of therapy → each week has 7 tablets (one 35mg once-a-week risedronate tablet & 6 tablets that each have 500mg Ca carbonate)  Bisphosphonates Ibandronate oral: 150mg once monthly (prevention & treatment) Ibandronate IV for postmenopausal osteoporosis: 3mg every 3 months over 15-30 seconds Zoledronic acid: 5mg IV infusion once a year for treatment (given over no less than 15 minutes) or every 2 years for prevention Etidronate: 400mg QD for 14 days followed by Ca 500mg (elemental) QD for 76 days (cycle repeated every 3 months) Etidronate: not approved for treatment or prevention of osteoporosis, alternative if have GI intolerance to other bisphosphonates, not as potent, cause osteomalacia Pamidronate IV: alternative if have GI intolerance to other bisphosphonates or cannot absorb oral bisphosphonates - Replaced by zoledronic acid and in some cases IV ibandronate  Bisphosphonates Greatest  BMD  vertebral, nonvertebral, hip fractures (zoledronic acid)  vertebral, hip fractures (alendronate)  vertebral, composite nonvertebral fractures (risedronate)  vertebral fractures (etidronate, ibandronate) Alendronate, risedronate, ibandronate - drugs used since selectively inhibit bone resorption High doses needed to impair bone mineralization Etidronate inhibits bone resorption and causes impairment in bone mineralization!! Pregnancy category C → use with caution in premenopausal women since can cross placenta and affect fetus bone development → must be counseled on appropriate contraception use  Bisphosphonates Adverse effects Esophageal ulcer Musculoskeletal pain Esophageal stricture Osteomalacia: etidronate (more when given continuously) Dyspepsia Osteonecrosis of jaw (mandibular or maxillary bone surgery, poor oral hygiene risk factors, Dysphagia other risk factors) - More with high dose IV therapy Acid regurgitation - Oral agents: a recommendation is to see dentist within 3 months of starting therapy, Abdominal pain proper dental hygiene, regular follow-up visits with dentist Nausea, diarrhea - IV and oral: a recommendation is for dental exam before starting therapy Arthralgia, HA, fever, myalgia, extremity pain (zoledronic) Hypocalcemia (more prone with Vitamin D deficiency): check baseline Ca and D levels Femur fractures Flu-like sx (IV ibandronate, zoledronic)  Some Risk Factors for Osteonecrosis of the Jaw Chemotherapy Bisphosphonates Denosumab Angiogenesis (formation of new blood vessel) inhibitors - Examples: Axitinib (Inlyta), Pazopanib (Votrient) Corticosteroids Cancer Radiotherapy Poor oral hygiene Pre-existing dental disease or infection Anemia Coagulopathy  Adverse Effects (Information from Lexi-Comp) Reports of esophagitis, dysphagia, esophageal ulcer, erosive esophagitis, esophageal stenosis, esophageal perforation, oropharyngeal ulcer - Risk factors: Not administering medication correctly Older age Concomitant use of NSAIDS or antithrombotic medications Prior gastrointestinal problems  Bisphosphonates Oral Administration (Alendronate, Risedronate, Ibandronate) Follow strictly since small amount is absorbed and adverse effects!! - Oral bioavailability < 1% in fasting state and  by food, beverages, medications, and taking it within 2 hours after a meal Take in AM with full glass (8 ounces) of plain water AT LEAST ½ hour (60 mins with ibandronate) before food, beverages, or other medications - Wait > 30 minutes before eating improves absorption (60 mins for ibandronate) - If food, beverages other than plain water, or other medications taken within 30 mins of alendronate/risedronate and 60 mins of ibandronate, absorption and effect reduced or eliminated Do not lie down, remain upright (seated or standing), for at least 30 minutes (60 mins with ibandronate) after taking medication and remain upright until after food consumed IV ibandronate, zoledronic acid: check Scr before each dose - Can use if GI contraindications or intolerances or oral bisphosphonate  Bisphosphonates Delayed Release Risedronate (Atelvia) - Take immediately following breakfast with at least 4 oz of plain water (delayed-release coating does not dissolve until after leaving stomach) - Do not lie down for 30 minutes afterwards - Once weekly Binosto: effervescent alendronate tablet once-weekly - Dissolve in 4 ounce plain, room temperature water (not mineral or flavored water) - Wait at least 5 mins after fizzing stops and stir for 10 secs before drinking - Take 30 minutes before 1st food, beverage, or medication of day - Do not lie down for at least 30 minutes after taking and until after 1st food of day  Bisphosphonates Missed Doses Alendronate once weekly missed dose: - Take 1 dose in the AM they remember - Do not take 2 doses on same day - Return to taking 1 dose once a week on originally scheduled day Oral ibandronate missed dose: - Do not take two tablets within same week - If next dose that is scheduled is 1-7 days away: wait to take until next dose that is scheduled - If next scheduled dose is >7 days away: take dose morning the person remembers, and then take it on originally scheduled day Refer to risedronate and other PIs for specifics on missed doses for each of its doses  Bisphosphonates Contraindications - Hypocalcemia (other bone & mineral metabolism disturbances) – treat before starting bisphosphonate therapy - Inability to sit or stand upright for at least 30 mins/60mins - Severe renal impairment (CrCl < 35ml/min alendronate and zoledronic acid (or advance renal impairment); CrCl < 30ml/min for risedronate and ibandronate) - Esophagus abnormalities which delay esophageal emptying (ex: stricture or achalasia-failure of esophageal sphincter to relax with swallowing) → alendronate package insert Precautions - Dysphagia, esophagitis, esophageal or gastric ulcers, Barrett’s esophagus - Hx of hypoparathyroidism → risk for hypocalcemia  Calcitonin Miacalcin®, Fortical® Peptide normally produced from C cells of thyroid, which inhibits osteoclasts &  bone resorption mainly from vertebral and femoral sites - Calcitonin inhibits PTH:  serum Ca → calcitonin released and bone resorption & osteoclasts inhibited Nasal formulation is used – less adverse effects than injection Indication: treatment of osteoporosis in women who are at least 5 years postmenopausal Dose: 200IU daily (alternate nostrils daily)  BMD, may  vertebral fractures Less effective FDA panel 2013: no longer use in women since little evidence that it works and may increase cancer risk Analgesic effects: may provide bone pain relief if acute fractures Refrigerate until opened, then stable room temp for 30 days  Calcitonin Adverse Effects (Nasal Formulation) Rhinitis Epistaxis Nasal irritation Nasal dryness Back pain Arthralgia Headache  Estrogen and Hormone Replacement Therapy Approved for prevention of osteoporosis Stabilize bone remodeling,  Ca absorption from GI tract, promote calcitonin synthesis,  number of Vitamin D receptors on osteoblasts, acts on osteoblasts and osteoclasts  BMD,  vertebral, nonvertebral and hip fractures (HRT: estrogen and progestogen)  BMD,  vertebral and hip fractures (ERT: estrogen) Decrease LDL and lipoprotein(a) Increases HDL and triglycerides (progestins  TG) Relieves hot flashes, sweating, arthralgias, myalgias (menopausal symptoms) Increase BMD less than bisphosphonates, denosumab, teriparatide but more than calcitonin and raloxifene  Disadvantages of Estrogen Increased risk of endometrial hyperplasia and endometrial cancer (if intact uterus) May increase breast cancer risk Weight gain Fluid retention Vaginal bleeding and spotting Breast enlargement and tenderness Increased risk of thrombosis **may have same risks as HRT**  Disadvantages of Progestin Edema Increased breast size Mastalgia (breast pain) Rash Acne Hirsutism Mood swings Depression Alopecia Headache Fatigue Irritability  Hormone Replacement Therapy Women's Health Initiative - Conjugated estrogen combined with medroxyprogesterone acetate  risk of MI, stroke, breast cancer, pulmonary emboli, DVT (in absence of data, all estrogen and estrogen-progestin products should be assumed to carry similar risks) Women's Health Initiative (estrogen-alone arm) - Estrogen-alone arm stopped after almost 7 years due to increased stroke - Did not appear to affect (either increase or decrease) heart disease or increase risk of breast cancer - Showed reduction in risk of hip fracture  Hormone Replacement Therapy Only use estrogen and HRT if benefits > risk!!!!!!! FDA: “When prescribing estrogen or HRT solely for prevention of postmenopausal osteoporosis, therapy should only be considered for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate.” Until more data, “because of the risks, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.”  Absolute Contraindications of Estrogen Breast cancer Undiagnosed vaginal bleeding Active thrombophlebitis or thromboembolic disorder Current endometrial cancer Active liver disease Known or suspected pregnancy  Relative Contraindications of Estrogen History of thrombophlebitis Thrombosis or thromboembolic disorders associated with prior estrogen use or pregnancy History of breast or endometrial cancer Gallbladder disease Strong family history of breast cancer Chronic liver disease Hypertriglyceridemia Endometriosis Varicose veins  Estrogen Agonist/Antagonist Raloxifene (Evista®) Approved for treatment and prevention of osteoporosis Estrogen agonist on bone, blood clotting, lipid metabolism Estrogen antagonist on endometrial and breast tissue Thought to reduce bone resorption and bone turnover  BMD and  vertebral fractures Does not stimulate endometrium → not associated with endometrial hyperplasia and progestin not needed  LDL and total cholesterol (no HDL effect) Adverse effects: hot flashes, venous thromboembolism, peripheral edema, leg cramps - Trial: did not significantly affect CHD risk in postmenopausal women with CHD or at increased CHD risk Secondary analysis: small increase risk of fatal stroke (p < 0.0499) more frequently if Framingham stroke risk score > 13 Boxed warning of venous thromboembolism & death from stroke  Estrogen Agonist/Antagonist Raloxifene (Evista®) Contraindications: active or history of venous thromboembolic event (DVT), pregnancy, may become pregnant, lactation Possibly NOT good candidates: high risk of stroke (ex: Framingham stroke risk score > 13), or coronary events, known CAD, PVD, atrial fibrillation, or history of cerebrovascular events Not recommend in women taking ERT/HRT Must be discontinued if immobilized or inactive for long periods of time (several hours or more, ex: hospitalizations) - D/C at least 72 hours before immobilization such as surgery Dose: 60mg/day without regard to meals (oral administration) ↓ levothyroxine absorption  Conjugated Estrogens and Bazedoxifene (Duavee®) Combination of conjugated estrogens with estrogen agonist/ antagonist indicated for prevention of postmenopausal osteoporosis in women with uterus One tablet daily without regard to meals for shortest period of time (oral administration) Muscle spasms, nausea, diarrhea, dyspepsia, upper abdominal pain, oropharyngeal pain, dizziness, neck pain Not studied > 75 YO or renal impairment: use not recommended BMI > 27 kg/m2 may have increased endometrial hyperplasia risk No fracture data No drug interaction studies Do not take progestins, other estrogens or estrogen agonist/antagonists  Conjugated Estrogens and Bazedoxifene (Duavee®) Contraindications: - Undiagnosed abnormal uterine bleeding - Known, suspected, or past history of breast cancer - Known or suspected estrogen-dependent neoplasia - Active or past history of venous thromboembolism - Active or past history of arterial thromboembolism - Hypersensitivity (angioedema, anaphylaxis) to estrogens, bazedoxifene, or any ingredients - Hepatic impairment or disease - Protein C, protein S, antithrombin deficiency or other thrombophilic disorders - Pregnancy, women who may become pregnant, nursing mothers  Conjugated Estrogens and Bazedoxifene (Duavee®) Boxed Warning Do not take additional estrogen Increased risk of endometrial cancer in female with uterus who uses unopposed estrogens Not used for prevention of CVD or dementia Women's Health Initiative estrogen-alone substudy: increased risks of stroke and DVT WHI Memory Study (WHIMS) estrogen-alone ancillary study of WHI: increased risk of probable dementia in postmenopausal women > 65 YO  Teriparatide (Forteo®) Biologically active N-terminal region (1-34) of human PTH Stimulates new bone formation, bone remodeling rate, osteoblast number and activity Treatment of postmenopausal women with osteoporosis at high risk for fracture Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture Treatment of men and women with glucocorticoid-induced (daily dose equivalent to ≥ 5 mg prednisone) osteoporosis at high risk for fracture High risk for fracture defined as: hx osteoporotic fracture, multiple risk factors for fracture, or failed/intolerant to other therapy  Teriparatide (Forteo®) Thought to increase trabecular bone (lumbar spine, femoral neck) more than cortical bone (distal radius) When stop treatment: bone loss rapid and consider alternative therapies Dose: SUB-Q (abdomen or thigh) 20mcg QD - Peak serum concentration in 30 mins & within 3 hrs is  to undetectable levels - Should sit or lye down when give 1st dose (orthostatic hypotension)  Teriparatide (Forteo®) Continuous exposure to  PTH levels for days →  osteoclast bone resorption Administration of PTH intermittently → stimulate bone formation > resorption  BMD,  risk of vertebral & nonvertebral fractures (fracture not studied in men) Treatment effects may be monitored by DXA after 18 months Each pen can be used for 28 days - Store in refrigerator at all times  Teriparatide Adverse Effects Osteosarcoma Hypotension/orthostatic hypotension (within 4 hrs of administration, resolves after few minutes to hours for 1st several doses) Nausea Dizziness Leg cramps Transient  serum Ca → monitor 1 month after start therapy → if Ca > 10.6 mg/ml  Ca intake to 1000mg/day → still elevated → lower dose by 25% or switch to every other day Ca therapy  uric acid  urinary calcium excretion Arthralgia Risk of kidney stones Pain at injection site  Teriparatide Contraindications Risk of osteosarcoma (bone tumor) - Do NOT use if open epiphyses, metabolic bone diseases including Paget’s, bone metastases or history of skeletal malignancies, prior external beam or implant radiation therapy of skeleton, hereditary disorders predispose to osteosarcoma Duration of use: 2 years (only consider using it > 2 years during a lifetime if continues or resumed to be high fracture risk) Preexisting hypercalcemia or hypercalcemic disorders (primary hyperparathyroidism) Kidney stones (risk vs benefit) Breastfeeding Pediatrics Pregnancy  Teriparatide Precautions Preexisting urolithiasis - potential exacerbation Hypotension Pregnancy – category C Severe renal insufficiency (no hepatic impairment studies) Digoxin therapy - hypercalcemia by teriparatide may predispose to digoxin toxicity Gout  Abaloparatide (Tymlos) Human parathyroid hormone related peptide [PTHrP(1-34)] analog Treatment of postmenopausal women with osteoporosis at high fracture risk Treatment to increase bone density in men with osteoporosis at high fracture risk or failed/intolerant to other osteoporosis medications 80 mcg subcutaneously once daily (periumbilical region of abdomen) Supplemental calcium and vitamin D if not adequate dietary intake ↑ BMD, ↓ risk of vertebral & nonvertebral fractures (data for women only) Adverse effects: - Orthostatic hypotension (dizziness, palpitations, tachycardia, nausea): initially administer sitting or lying down; sit or lie down if symptoms occur - Hypercalcemia: not use if hypercalcemia or hypercalcemic disorder (ex: primary hyperparathyroidism) - Hypercalciuria and urolithiasis: monitor urine calcium if hypercalciuria or active urolithiasis - Others: headache, fatigue, upper abdominal pain, increase uric acid - Osteosarcoma (see next slide) Before first use: store in refrigerator then store at room temperature up to 30 days Contraindications: hypersensitivity (also refer to what was stated on this slide)  Abaloparatide (Tymlos) Dose-dependent osteosarcoma increase (malignant bone tumor) in rats, unknown if cause in humans Do NOT use if increased osteosarcoma risk (ex: Paget's bone disease or unexplained alkaline phosphatase elevation, open epiphyses, bone metastases or skeletal malignancies, hereditary disorders predisposing to osteosarcoma, or prior external beam or implant radiation therapy of skeleton) NOT recommended: cumulative use of abaloparatide and PTH analogs (ex: teriparatide) for more than 2 years during lifetime  Denosumab (Prolia) RANK ligand (RANKL) inhibitor Fully human monoclonal antibody against receptor activator of nuclear factor- κB ligand (RANKL) Binds to RANKL (needed for formation, function, survival of osteoclasts) → denosumab inhibits RANKL from stimulating RANK receptor on osteoclasts’ surface and precursors → prevents osteoclast formation, function, and survival → reduce bone resorption and enhance cortical and trabecular bone mass and strength  Denosumab (Prolia) Approved for: - Treatment of postmenopausal women with osteoporosis at high risk for fracture (defined as history of osteoporotic fracture, or multiple risk factors for fracture; or failed or intolerant to other available osteoporosis therapy) - Treatment to increase bone mass in men with osteoporosis at high risk for fracture (defined as history of osteoporotic fracture, or multiple risk factors for fracture; or failed or intolerant to other available osteoporosis therapy) - Treatment to increase bone mass in men at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer - Treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer - Treatment of glucocorticoid-induced osteoporosis in men and women at high risk for fracture (guidelines published before receiving this indication)  Denosumab (Prolia)  vertebral, nonvertebral, hip fractures Administered by health care professional 60 mg every 6 months SUB-Q (upper arm, upper thigh, abdomen) Before administration, stored in refrigerator but then can remain at room temperature for 14 days Take calcium 1000mg/day and at least 400 IU vitamin D daily If stop treatment: bone loss rapid and consider alternative therapies Adverse effects: back pain, pain in extremity, hypercholesterolemia, musculoskeletal pain, cystitis, hypocalcemia, pancreatitis, osteonecrosis of jaw, serious infections, serious dermatologic reactions: seek immediate medical help (ex: cellulitis), atypical femoral fractures Contraindication: hypocalcemia (must correct before treatment), pregnancy, hypersensitivity  Denosumab (Prolia) Boxed Warning Advanced chronic kidney disease (eGFR < 30 ml/min/1.73m2) larger risk of severe hypocalcemia after denosumab is administered Severe hypocalcemia causing hospitalization, life-threatening events and fatal cases have occurred Chronic kidney disease-mineral bone disorder (CKDMBD) significantly increases hypocalcemia risk Evaluate for the presence of CKD-MBD before starting denosumab in persons who have advanced chronic kidney disease - Use of denosumab in in these persons needs to managed by healthcare provider who is an expert in diagnosis and treatment of CKD-MBD  Denosumab (Prolia) Advanced chronic kidney disease and predisposed to hypocalcemia and mineral metabolism problems (ex: hypoparathyroidism, thyroid surgery, parathyroid surgery, malabsorption syndromes, small intestine removed, treatment with other medications that lower calcium): monitor calcium, phosphorus, and magnesium 10-14 days of starting therapy Dental exam before treatment due to osteonecrosis of jaw - Preventative dentistry before treatment if osteonecrosis of jaw risk factors such as invasive dental procedures (ex: tooth extraction, dental implants, oral surgery), cancer, chemotherapy, corticosteroids, angiogenesis inhibitors, poor oral hygiene, co-morbid conditions (ex: periodontal and/or other pre-existing dental disease, anemia, coagulopathy, infection, ill-fitting dentures), etc Assess benefit vs. risk if taking immunosuppressive meds or impaired immune system →  of serious infections  Romosozumab (Evenity) Sclerostin inhibitor: protein in osteocytes that inhibits bone formation Treatment of osteoporosis in postmenopausal women at high risk for fracture (definition: osteoporotic fracture history, or multiple fracture risk factors; or failed or intolerant to other osteoporosis medications) Dose: - 2 separate subcutaneous (abdomen, thigh, upper arm) injections required to give total 210mg dose (2 syringes injected one after other) → administer once every month for 12 doses - Needs to be administered by healthcare provider - Need adequate Ca and vitamin D supplementation during therapy  vertebral and nonvertebral fractures ONLY give 12 monthly doses → use anti-resorptive medication if need osteoporosis therapy after this time period  Romosozumab (Evenity) Boxed Warning:  MI, stroke and CV death risk (monitor for these symptoms) Do NOT start if had MI or stroke within previous year Consider if benefits > risks if have other CV risk factors D/C medication if have MI or stroke while on therapy Contraindications: hypocalcemia (correct pre-existing BEFORE starting therapy), hypersensitivity to medication Some adverse reactions: arthralgia, headache, hypocalcemia, osteonecrosis of the jaw (routine oral examination before starting therapy), atypical fractures of femoral shaft, cardiac events, injection site reactions Renal Impairment: severe renal impairment (eGFR 15-29 mL/min/1.73 m2 or dialysis) →  hypocalcemia risk → monitor calcium and supplement with calcium and vitamin D  AACE Osteoporosis Guidelines Treatment Recommendations 2020 Females ≥ 50 YO: adequate total oral calcium dietary intake (diet and if needed supplement) of 1,200 mg/day At risk for low vitamin D and if have osteoporosis: measure serum 25- hydroxyvitamin D (25[OH]D) (NOT 1,25-dihydroxyvitamin D)→ low levels may affect osteoporosis medication efficacy - Osteoporosis diagnosis: keep 25-hydroxyvitamin D (25[OH]D) ≥ 30 ng/mL (range: 30-50 ng/mL) - Vitamin D3 supplementation (if needed): 1,000-2,000 IU/day usually needed to keep desired level - Serum 25[OH]D 20-29 or < 30 ng/mL: 5,000 IU/day vitamin D3 for 8-12 weeks to obtain 25(OH)D > 30 ng/mL (NOT vitamin D2) → then vitamin D3 1,000- 2,000 IU/day (or another sufficient dose)  AACE Osteoporosis Guidelines Treatment Recommendations 2020 Treatments if lumbar spine or femoral neck or total hip T-score < -2.5, fragility fracture history, or high FRAX score (10-year major osteoporotic fracture risk ≥ 20% or hip fracture risk ≥ 3%) (also refer to AACE Treatment Candidates 2020 slide) - Initial therapy for high risk/no prior fracture: Recommended: alendronate, denosumab, risedronate, zoledronic acid Alternative: ibandronate, raloxifene - Initial therapy for very high risk/prior fractures Very high fracture risk: advanced age, frailty, glucocorticoids, very low T scores, or increased risk of falls Recommended: abaloparatide, denosumab, romosozumab, teriparatide, zoledronic acid Alternative: alendronate, risedronate  AACE Osteoporosis Guidelines Treatment Recommendations 2020 High fracture risk (ex: postmenopausal female with no prior fracture and moderately low T-scores): may start oral medication Abaloparatide, denosumab, romosozumab, teriparatide, zoledronic acid (injectable medications): may consider initially if GI problems and may not be able to tolerate or absorb oral medications, cannot remember to take oral medications, problem with arranging oral bisphosphonate with other oral medications or daily routine, or very high fracture risk (ex: older female with many vertebral or hip fractures or with very low T-scores) Ibandronate or raloxifene: may be appropriate initially in some instances if need medications with spine efficacy Algorithm and Guideline https://www.sciencedirect.com/science/article/pii/S1530891X20428277 chrome- extension://efaidnbmnnnibpcajpcglclefindmkaj/https://pro.aace.com/pdfs/AACE_Postmeno pausal_Osteoporosis_Treatment_Algorithm_Update_022020.pdf  AACE Osteoporosis Guidelines Treatment Recommendations 2020 Sequential use of medications: D/C anabolic agent (abaloparatide, romosozumab, teriparatide) → treat with denosumab, bisphosphonate to prevent BMD loss and fracture Can switch from bisphosphonate to anabolic agent NOT recommended to switch from denosumab to anabolic agent (associated with loss of hip BMD) D/C denosumab → treat with bisphosphonate to prevent bone loss Prior use of antiresorptive then starting teriparatide: reduces hip BMD Does NOT recommend combination therapy (no benefit, more cost and adverse effects, etc.)  ACR 2022 Guidelines Sequential Therapy Denosumab, teriparatide, abaloparatide, romosozumab: need other medications after these medications are d/c Manuscript 2022 GIOP Guideline: https://rheumatology.org/glucocorticoid-induced-osteoporosis- guideline  Endocrine Society Osteoporosis Guidelines For Postmenopausal Women 2020 Low risk: no prior hip or spine fractures, BMD T-score at hip and spine both above -1.0, 10-year hip fracture risk < 3%, and 10-year risk of major osteoporotic fractures < 20% Moderate risk: no prior hip or spine fractures, BMD T-score at hip and spine (both above -2.5), 10-year hip fracture risk < 3% or risk of major osteoporotic fractures < 20% High risk: prior spine or hip fracture, or BMD T-score at hip or spine of -2.5 or below, or 10-year hip fracture risk ≥ 3%, or risk of major osteoporotic fracture risk ≥ 20% Very high risk: multiple spine fractures and BMD T-score at hip or spine of -2.5 or below  Endocrine Society Osteoporosis Guidelines For Postmenopausal Women 2020 High fracture risk: recommend initial treatment with bisphosphonates (alendronate, risedronate, zoledronic acid, ibandronate) - Ibandronate: NOT recommended to reduce nonvertebral or hip fracture risk - Denosumab: alternative initial treatment Very high fracture risk (ex: severe or multiple vertebral fractures): recommend teriparatide or abaloparatide for up to 2 years to reduce vertebral and nonvertebral fractures then treat with antiresorptive osteoporosis medications to maintain increased bone density Very high risk of fracture, such as those with severe osteoporosis (ex: low T-score < -2.5 and fractures) or multiple vertebral fractures: recommend romosozumab for up to 1 year to reduce vertebral, hip, and nonvertebral fractures High risk of fracture and low risk of DVT and bisphosphonates or denosumab NOT appropriate or have high breast cancer risk: recommend raloxifene or bazedoxifene to decrease vertebral fracture risk  Endocrine Society Osteoporosis Guidelines For Postmenopausal Women 2020 High fracture risk and meet criteria listed below: “suggest” menopausal hormone therapy (use estrogen-only medications in women with hysterectomy) to prevent all fracture types - < 60 YO or < 10 years past menopause, low DVT risk, bisphosphonates or denosumab not appropriate to use; bothersome vasomotor symptoms, additional climacteric symptoms, no contraindications, no prior MI or stroke; no breast cancer, fine with taking menopausal hormone therapy High fracture risk: “suggest” nasal spray calcitonin only in women who do NOT tolerate or if NOT appropriate to use raloxifene, bisphosphonates, estrogen, denosumab, abaloparatide, teriparatide Postmenopausal women with low BMD and high fracture risk with osteoporosis: suggest calcium and vitamin D in combination with osteoporosis medications For more information and ALGORITHM: https://academic.oup.com/jcem/article/104/5/1595/5418884 and https://academic.oup.com/jcem/article/105/3/587/5739968  Bone Health and Osteoporosis Foundation 2022 Treatment Recommendations Individualized treatment plans States in general the medications that are FDA approved - Alendronate, risedronate, ibandronate, zoledronic acid - ERT/HRT, raloxifene, conjugated estrogens/bazedoxifene - Teriparatide, abaloparatide - Denosumab - Romosozumab - Calcitonin Consider medication reduces vertebral AND non-vertebral fractures (alendronate, risedronate, zoledronic acid, denosumab, teriparatide, abaloparatide, romosozumab) instead of medication NOT shown these results (raloxifene, calcitonin, ibandronate) Begin antiresorptive medications after denosumab, teriparatide, abaloparatide, romosozumab is D/C If considering sequential therapy: begin with anabolic medication (ex: teriparatide, abaloparatide, romosozumab) followed by antiresorptive (less effect on BMD/bone loss if administered in the opposite order) aMajor clinical risk factors for fracture: advanced age, current smoker, low body weight or body mass index, personal history of fracture as an adult (after age 50 years), history of osteoporosis/low trauma fracture in a first-degree relative, excessive alcohol intake. Citation: Chapter 112 Osteoporosis, DiPiro JT, Yee GC, Michael Posey LL, Haines ST, Nolin TD, Ellingrod VL. DiPiro: Pharmacotherapy A Pathophysiologic Approach, 12e; 2021. Available at: https://accesspharmacy.mhmedical.com/content.aspx?bookid=3097&sectionid=271396715 Accessed: October 18, 2022 Copyright © 2022 McGraw-Hill Education. All rights reserved  BMD Follow-Up and Assessment Follow-Up Different Options Assess adherence and medication tolerance at each visit Option: hip and spine at one year, and if BMD is stable or improved, less frequent monitoring thereafter Option (AACE): repeat DXA every 1-2 years until findings are stable. Continue to follow-up DXA every 1-2 years or at less frequent interval depending on clinical situations. Follow-up with same facility, same machine. Option (U.S. Preventive Services Task Force): after 2 years of therapy Option (Bone Health and Osteoporosis Foundation): 1-2 years after starting or changing therapy (more frequent or less frequently depending on person – refer to guidelines) - BMD total hip, femoral neck, or lumbar spine  Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research (ASBMR) 2016 Reassess risk after 5 years of oral bisphosphonate (BP) or 3 years of intravenous BP Women with high risk (ex: older women, low hip T-score or high fracture risk score, previous major osteoporotic fracture, or who fracture on therapy): treat for up to 10 years (oral) or 6 years (intravenous) with periodic evaluation Atypical femoral fracture risk (NOT osteonecrosis of jaw) increases with duration of BP but benefits of decreasing vertebral fracture risk > risk of rare events in high-risk pts Women with NO high fracture risk after 3-5 years of BP: may consider 2-3 year drug holiday Need clinical judgement since limited evidence to base recommendations (only decreased vertebral fracture) in mainly white postmenopausal women Refer to article for more information about men and glucocorticoid-induced osteoporosis  Managing Osteoporosis in Patients on Long-Term Bisphosphonate Treatment: Report of a Task Force of the American Society for Bone and Mineral Research (ASBMR) 2016 Post-Menopausal Women Treated with oral (>5 years) or IV (>3 years) Hip, Spine, or Multiple other Osteoporotic Fractures Before or During Therapy Yes No Hip BMD T-Score < -2.5 or Reassess Benefits/Risks high fracture risk Consider continue BP or Yes No change to alternative therapy Reassess Benefits/Risks Consider Drug Reassess every 2-3 years Consider continue BP for Holiday up 10 year (oral) or 6 years Reassess every (IV) or change to 2-3 years alternative therapy Reassess every 2-3 years  How Long Should Patients Be Treated? AACE Recommendations 2020 Agree with ASBMR algorithm Abaloparatide, teriparatide used for 2 years then use bisphosphonate or denosumab Romosozumab used for 1 year then use bisphosphonate or denosumab Oral bisphosphonates: think about “bisphosphonate holiday” after 5 years if not at high risk (e.g.: T-score > -2.5 or no fractures) → continue to treat for 5 more years if high fracture risk Oral bisphosphonates: think about “bisphosphonate holiday” after 6-10 years in patients who are stable and higher-risk Zoledronic acid: think about drug holiday after 3 annual doses if high-risk or not high risk of fracture; continue up to 6 annual doses if very high-risk Non-bisphosphonate: may be used during “bisphosphonate holiday” if very high fracture risk  How Long Should Patients Be Treated? AACE Recommendations 2020 Non-bisphosphonate: drug “holiday” not recommended and treat as long as clinically needed - D/C denosumab → start another medication Stopping of “holiday” for bisphosphonate determined by each patient’s situations (risk of fracture, BMD, or bone turnover markers change) Ideal duration of “bisphosphonate holiday” not determined (need to monitor during “bisphosphonate holiday”) Bone binding affinity: zoledronic acid > alendronate > risedronate (“holiday” may be lengthiest after zoledronic acid, shortest after risedronate, intermediate after alendronate) Think about restarting medication if fracture or significant BMD loss occurs  How Long Should Patients Be Treated? Package Inserts Risedronate, alendronate, ibandronate, zoledronic acid: - Ideal duration not known - Safety and efficacy for osteoporosis treatment based on 3 years of data (risedronate, ibandronate, zoledronic acid) and 4 years (alendronate) - Everyone should have periodic re-evaluation of need to continue medication - Low fracture risk: think about D/C after 3-5 years - If d/c medication → periodically re-evaluate fracture risk  How Long Should Patients Be Treated? Bone Health and Osteoporosis Foundation 2022 Reassess person and BMD to consider drug holiday after 5 years of oral and 3 years of IV bisphosphonate if not at high fracture risk (T-score ≥ -2.5, no new fractures) - High fracture risk (ex: T-score ≤ -2.5 and/or recent fracture): continue bisphosphonate or alternative therapy with oral bisphosphonate up to 10 years and with yearly zoledronic acid up to 6 years Denosumab: NO drug holiday (quick bone loss → fractures) - Change to another antiresorptive (ex: bisphosphonate) after D/C denosumab to keep increase in bone density that occurred - Administering alendronate after denosumab: bone mass preserved - Administering teriparatide after denosumab: some loss of bone Assess every 1-2 years if person taking break from bisphosphonate Mention Endocrine Society Guideline recommends continue denosumab for 5-10 years contingent on risk of fracture Refer to guidelines for more information (algorithm and other information based on ASBMR guidelines)  Glucocorticoid Induced Osteoporosis  bone formation by inhibiting osteoblast formation;  bone resorption by  Ca excretion,  Ca absorption, stimulate osteoclasts;  estrogen and testosterone Largest bone loss within 1st 6 months of regimen then slower reduction continues with ongoing therapy Associated with all doses and formulations Use lowest dose for shortest duration (high daily and high cumulative doses increase risk of fracture-particularly vertebral fracture) Guideline applies to persons with and without rheumatic disease states taking ≥ 2.5 mg/day for > 3 months of glucocorticoid (prednisone) All adults taking prednisone > 2.5 mg/day for > 3 months: optimize intake of calcium and vitamin D based on age and lifestyle modifications (balanced diet, weight in appropriate range, stop smoking, regular weight-bearing or resistance exercises, < 2 alcoholic beverages/day) Risedronate, alendronate, zoledronic acid, denosumab, teriparatide: indicated for glucocorticoid-induced osteoporosis  ACR 2022 for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Guidelines Initial clinical fracture risk assessment in adults starting or continuing glucocorticoid ≥ 2.5 mg/day for > 3 months if no assessment of fracture risk or treated with osteoporosis medications (strong recommendation) - Initial assessment: ASAP within 6 months of starting glucocorticoids - Fracture risk assessment: dose, duration, glucocorticoid use pattern, alcohol, history of smoking, hypogonadism, fracture history, low body weight, weight loss that is significant, hip fracture in parent history, history of falls, thyroid disease, hyperparathyroidism, rheumatoid arthritis, malabsorption, chronic liver disease, inflammatory bowel disease, height loss - > 40 YO: BMD with vertebral fracture assessment (VFA) or spinal x-ray, FRAX → if prednisone > 7.5 mg/day FRAX with glucocorticoid correction (may not correct if dose > 30 mg/day of glucocorticoids) - < 40 YO: BMD with VFA or spinal X-Ray (NOT FRAX since not validated in this age) - Strongly recommend BMD < 40 years on glucocorticoids > 2.5 mg/day who have > 1 risk factors for osteoporosis  ACR 2022 for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Guidelines Major Osteoporotic Fracture (MOF) - > 40 YO and < 40 YO: spine, hip, wrist, humerus non-traumatic or pathological fractures Assessment of Clinical Fracture Risk - > 40 YO: history of taking glucocorticoid, falls, fractures, frailty, osteoporosis secondary causes, FRAX adjusted for glucocorticoid use, BMD with vertebral fracture assessment or spine x-ray - < 40 YO: history of taking glucocorticoid, falls, fractures, frailty, osteoporosis secondary causes, BMD with vertebral fracture assessment or x-ray of spine (not FRAX since not evaluated in this age range)  ACR 2022 for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Guidelines Risk Assessment Follow-Up During Use of Glucocorticoids - > 40 YO and < 40 YO: BMD with vertebral fracture assessment or x-ray of spine every 1-2 years during treatment of osteoporosis; BMD with vertebral fracture assessment or x-ray of spine every 1-2 years after treatment of osteoporosis is stopped FRAX Correction for Taking Glucocorticoid - > 40 YO: > 7.5 mg/day for glucocorticoid dose → multiply by 1.15 for 10- year risk of major osteoporotic fracture and by 1.2 for hip fracture risk - < 40 YO: FRAX not evaluated in this age group  ACR 2022 for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Guidelines Very High Fracture Risk > 40 YO: Previous fracture/fractures related to osteoporosis OR T-score ≤ -3.5 OR FRAX (adjusted for glucocorticoid) 10-year MOF risk ≥ 30% or hip ≥ 4.5% OR high glucocorticoid dose of ≥ 30 mg/day for > 30 days OR ≥ 5 gm/year < 40 YO: Fracture(s) history OR glucocorticoid ≥ 30mg/day OR cumulative ≥ 5 grams/year High Fracture Risk > 40 YO: T score ≤ -2.5 but > -3.5 OR FRAX (adjusted for glucocorticoid) 10-year MOF risk ≥ 20% but < 4.5% < 40 YO: No criteria Moderate Fracture Risk > 40 YO: FRAX (adjusted for glucocorticoid) 10-year MOF risk ≥ 10% and < 20%, hip > 1% and < 3% OR T score between -1 and -2.4 < 40 YO: Continuing to take glucocorticoid ≥ 7.5mg/day for ≥ 6 months AND Z score < -3 OR BMD loss that is significant (greater than least significant DXA change) Low Fracture Risk > 40 YO: FRAX (adjusted for glucocorticoid) 10-year risk of MOF < 10%, hip < 1%, BMD > -1.0 < 40 YO: Only risk factor is treated with glucocorticoids  ACR 2022 for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Guidelines (Know the Sections In White Font) Adults  40 YO with Moderate, High, or Very High Fracture Risk: - Dietary and supplemental calcium and Vitamin D optimization, lifestyle modification based on age - Weight bearing or resistance exercises, no smoking, no excessive intake of alcohol (< 2 servings/day) - Offer every adult patient osteoporosis medication if have medium, high, or very high risk of fracture (strong recommendation) - High or Very High fracture risk: treat with osteoporosis medication instead of treatment with calcium and vitamin D alone (strong recommendation) - High or Very High fracture risk: ORAL bisphosphonate (alendronate, risedronate, ibandronate) instead of no treatment (strong recommendation) - Very High fracture risk: PTH/PTHrP (PTH-related protein) agonists instead of anti-resorptive medications (denosumab, bisphosphonate) (conditional recommendation) - High fracture risk: denosumab or PTH/PTHrP instead of oral and IV bisphosphonate (conditional recommendation) - High fracture risk: IV or oral bisphosphonate, PTH/PTHrP, denosumab instead of romosozumab or raloxifene (conditional recommendation)  ACR 2022 for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Guidelines (Know the Sections In White Font) Adults  40 YO with Moderate, High, or Very High Fracture Risk (Continued): - High or Very High fracture risk: IV bisphosphonate, romosozumab, raloxifene instead of no treatment (conditional recommendation) - High or Very High fracture risk: NOT to use 2 different medications for osteoporosis (conditional recommendation) - Moderate fracture risk: oral or IV bisphosphonate, denosumab, PTH/PTHrP (no preference to these medications) (conditional recommendation) - Moderate fracture risk: NOT recommend romosozumab unless if NOT able to tolerate other medications (conditional recommendation) - NOT recommended: raloxifene (venous thromboembolism, fatal stroke), romosozumab (MI, stroke, death) only if NOT able to tolerate other medications (conditional recommendation) Adults  40 YO with Low Fracture Risk: dietary and supplemental calcium and Vitamin D optimization based on age, lifestyle modification (conditional recommendation); NOT recommend medications for osteoporosis (oral or IV bisphosphonate, PTH/PTHrP, raloxifene, denosumab, or romosozumab) (strong recommendation)  ACR 2022 for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Guidelines (Know the Sections in White Font) Adults less than 40 YO moderate or very high fracture risk: - Dietary and supplemental calcium and Vitamin D optimization based on age - Weight bearing or resistance exercises, no smoking, no excessive intake of alcohol (< 2 servings/day) - Oral or IV bisphosphonate, PTH/PTHrP, or denosumab (conditional recommendation) - NOT recommend raloxifene (venous thromboembolism, fatal stroke), romosozumab (MI, stroke, death) except if not able to tolerate other medications (conditional recommendation) Adults less than 40 YO with low fracture risk: dietary and supplemental calcium and Vitamin D optimization based on age, lifestyle modification (conditional recommendation); NOT recommend medications for osteoporosis (oral or IV bisphosphonate, PTH/PTHrP, raloxifene, denosumab, or romosozumab) (strong recommendation)  ACR 2022 for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis Guidelines Adults  40 YO with very high fracture risk as a result of taking  1 treatment courses of high-dose glucocorticoid (prednisone equivalent mean dose  30 mg/day for  30 days) or cumulative dose of glucocorticoid  5 gm in 1 year - PTH/PTHrP instead of anti-resorptives (conditional recommendation) - Oral bisphosphonate instead of no treatment (strong recommendation) - Denosumab and IV bisphosphonate instead of no treatment (conditional recommendation) - Raloxifene, romosozumab if NOT able to tolerate other medications (conditional recommendation) Adults < 40 YO taking  1 treatment courses of high-dose glucocorticoid (prednisone equivalent mean dose  30 mg/day for  30 days) or cumulative dose of glucocorticoid  5 gm in 1 year - Oral or IV bisphosphonate, PTH/PTHrP, denosumab (conditional recommendation) - Do NOT recommend raloxifene, romosozumab (conditional recommendation) - PTH/PTHrP and romosozumab: used only in adults who have growth plates that are closed - Denosumab: use with caution in growth plates that are open (inhibits growth long-bone) Refer to the guidelines for more information…. Manuscript 2022 GIOP Guideline: https://rheumatology.org/glucocorticoid-induced-osteoporosis-guideline  Paget’s Disease Bone remodeling - Excessive resorption ( amount of osteoclasts) then  in bone formation (dense, disorganized, & not effective mineralized bone matrix, weaker bone) → altered bone architecture → more prone to fracture or deformity 3 phases - 1st phase:  osteoclasts and bone resorption - 2nd phase: osteoblasts produce woven bone but mineralization not effective - 3rd phase: dense cortical & trabecular bone deposition but not organized, sclerotic, weaker Cause unknown Can affect any area (pelvic > femur > lumbar spine > thoracic spine > skull > tibia > humerus > cervical spine)  Paget’s Disease Most patients asymptomatic Some symptoms and complications - Bone pain from microfractures or osteoarthritis - Headache - Pain or neuropathy - Increased head size, bowing of limb or curvature of spine (kyphosis) - Hip pain - Cartilage damage - CHF (severe cases) - Kidney stones - Loose teeth (if involves jaw) - Hearing loss (if involves skull) - Osteosarcoma - Spinal stenosis Bone pain - Continuous - Increases at rest, weight bearing, bedtime, warm limbs  Paget’s Disease Radiographs most specific diagnostic test, bone scans can be done  serum bone specific alkaline phosphatase (indicates bone turnover and disease activity) No cure Treatment - Bisphosphonates: drug of choice since inhibit osteoclasts Zoledronic acid: 5mg IV infusion (single dose infusion): also need 1500mg elemental calcium and 800 IU vitamin D daily - Pyrexia, myalgia, headache, arthralgia, pain in extremity - Drug of choice if no contraindications: Endocrine Society Guidelines 2014 (most potent, extended duration of action) - Retreatment rarely needed within 5 years Alendronate: 40mg QD for 6 months (may need retreatment in 2-6 years, upper GI adverse effects since large dose) Risedronate: 30mg QD for 2 months (may need retreatment in 1-5 years, upper GI adverse effects since large dose) - Pamidronate (bisphosphonate): indicated for moderate-severe Paget’s but not used - Calcitonin SQ: not used, inject daily, flushing, nausea, relapse when stop treatment - Calcium and Vitamin D - Exercise, pain control  Osteomalacia  bone mineralization (Ca or phosphorus) of matrix → deformities of skeleton and decreased long bone growth - Children: rickets (delay in growth cartilage) - Adults: osteomalacia (absence/delay of newly formed bone collagen) “Soft bones” Osteoporosis: may be first sign of osteomalacia Some causes - Deficient in calcium and/or Vitamin D (most common) Vitamin D:  intake/sun, malabsorption, sunscreen use, dark skin pigmentation - Drug-induced: etidronate, anticonvulsants (phenytoin, primidone, carbamazepine, phenobarbital), rifampin, sodium fluoride, very large amount of Al antacids since inhibit intestinal phosphate absorption, phosphate- binding antacids -  serum Ca or phosphorus - Abnormal bone matrix - Renal disease - Hypophosphatemia (low dietary intake, phosphate-binding antacids)  Osteomalacia Pseudovitamin D deficiency rickets (used to be Vitamin D dependent rickets type I): genetic defect in 25-OH vitamin D 1 alpha-hydroxylase (enzyme that activates vitamin D) Hereditary vitamin D resistant rickets (used to be Vitamin D dependent rickets type II): deficiencies in vitamin D receptor or activity Vitamin D dependent resistant rickets (hereditary hypophosphatemic rickets): deficiencies in 25-OH vitamin D 1 alpha-hydroxylase & renal reabsorption of phosphate (primary problem) Renal disease: decreased 25-OH vitamin D 1 alpha-hydroxylase (enzyme that activates vitamin D)  Osteomalacia Clinical Presentation Bone pain Muscle weakness Malaise Skeletal deformities - Scoliosis, pigeon chest, kyphosis, spine shortening, leg bowing Tetany (severe muscle spasms)  calcium or phosphorus  vitamin D  alkaline phosphatase Can have no symptoms besides low BMD Bone biopsy – not usually done  Osteomalacia Treatment Depends on cause Osteomalacia treatment due to vitamin D deficiency: vitamin D and calcium - Do NOT treat with bisphosphonates, teriparatide, or other osteoporosis medications (may worsen low calcium levels and disease of bone)