OsteoporosisQG.docx

Osteoporosis (8 questions KD) Need to know Interventions to minimize bone loss and reduce risk of fracture can be implemented throughout the entire lifespan Adquate calcium and Vitamin D intake based on age and sex is essential for best outcomes The most robust clinical data is for management of...

Osteoporosis (8 questions KD) Need to know Interventions to minimize bone loss and reduce risk of fracture can be implemented throughout the entire lifespan Adquate calcium and Vitamin D intake based on age and sex is essential for best outcomes The most robust clinical data is for management of osteoporosis in postmenopausal women. However, osteoporosis can also occur in men, younger women, and other special populations All patients presenting with osteoporosis should be evaluated for secondary causes, including medication-induced bone loss. Clinical assessment includes fracture history, bone mineral density (BMD), and the FRAX tool, which is used in a similar manner to the ASCVD risk calculator Pharmacotherapy mechanisms focus on reducing bone resorption, increasing bone formation, or both Severity of disease will determine whether to treat with an antiresorptive therapy or begin with an anabolic therapy, then transition to an antiresorptive Therapy may last 5-10 years, but this is not well defined In addition to the FDA-approved therapies for treatment of osteoporosis in postmenopausal women and men, several options are approved for prevention of osteoporosis in postmenopausal women only Understanding of best practices continues to evolve. At least 8 US organization have published treatment guidelines in the past 10 years Osteoporotic Fractures Wrist: more common in younger postmenopausal women; less disability, but negative effects on work and ADLs Vertebral: Most likely to be asymptomatic, undetected; Lead to height loss, deformity; I vertebral fracture = 5x risk for another Hip: Significant morbidity and mortality Bone Healthy Lifestyle Interventions from birth through old age Balanced nutrition, ideally starting from childhood Adequate calcium and Vit D intake Physical activity and resistance training exercises Avoid smoking and excessive alcohol intake Fall prevention Management of high-risk medications & chronic diseases Medication-induced Osteoporosis Long-term oral glucocorticoids Increase bone resorption AND decrease bone formation, calcium absorption Dose- and duration- dependent effects; highest risk at 5mg or more prednisone equivalent daily Select chemotherapeutics Aromatase inhibitors (ex. letrozole, anastrozole) reduce estrogen concentrations Calcineurin inhibitors (ex. cyclosporine, tacrolimus) increase osteoclast activity Patient Assessment: BMD Central DXA Scan (Dual-energy X-ray Absorptiometry) determines: Bone mineral density (BMD; g/cm^2) BMD T-score (diagnostic) and Z-score Generally targeted to post-menopausal females… no consensus on who, when, how often to repeat Osteopenia/Low BMD: T-score between -1.0 and -2.5 Osteoporosis: T-score -2.5 or below Fracture Risk Assessment Tool (FRAX) Evaluates 11 factors +/- BMD Estimates 10-year risks of hip fracture and any major fracture What is considered high risk? 10-year hip fracture risk > 3% 10-year major fracture risk >20% Validated for postmenopausal women to age 90 and men ages 50 to 90 Adjusted for race/ethnicity and global region (multiple version on website) Limitations Estimates risk for only about half of fragility fractures May underestimate risk in the most severe osteoporosis cases Antiresorptive: Calcium and Vitamin D Calcium considerations Prioritize dietary intake first (broccoli, milk, etc) Supplement to make up difference between dietary intake and recommended daily intake Calcium carbonate and citrate are the salts most commonly used Limit to 500mg or less in a single IR dose AE: constipation, GI, disturbance, potential for kidney stones Carbonate: 40% elemental calcium More elemental calcium per dose Requires acidic environment Citrate: 21% elemental calcium Best option for lower-acid stomachs (elderly, acid suppression, not taking with meals) Vitamin D Considerations Regular supplementation may not be sufficient because many older adults are deficient (serum level <20 ng/mL) Treatment goal: reach serum level >30 ng/mL Vit D3 may have advantage over D2 in increasing serum levels Current guidelines: 5000 units daily for 8-12 weeks until target reached followed by maintenance dose of 1000-2000 units daily (preferred over mega weekly doses) Adverse effects: typically, not observed at therapeutic doses and normal serum levels Bisphosphonates (-dronates)– typically a first line treatment option due to well-established track record in reducing the risk of fractures and improving bone density Class AE: GI effects (abdominal pain or acid reflux), muscle or joint pain, Osteonecrosis of the jaw (ONJ, rare), Atypical femoral fractures (AFF, rare) Monitoring parameters: BMD every 1-3 years while on tx Calcium and Vit D levels Adherence to therapy Duration of therapy: Optimal duration of therapy is not well established, but generally you may consider d/c after 5 years if BMD is stable, there have been no fractures, and short-term fracture risk is low CI: hypersensitivity to bisphosphonates, hypocalcemia, or abnormalities of the esophagus, CrCl <35mL/min Alendronate (Fosamax) PO Dosing Prevention: 5mg daily or 35mg weekly Treatment: 10mg daily or 70mg weekly Counseling Points Take on empty stomach Take with 6-8 oz of plain water Remain upright for at least 30 minutes with no oral intake (to avoid esophageal irritation) Avoid taking with other medicines Ibandronate (Boniva) - PO and IV – Postmenopausal women ONLY Dosing Prevention AND Treatment: 150mg monthly Treatment ONLY: 3mg IV Q3mo Counseling Points Take on empty stomach Take with 6-8 oz of plain water Remain upright for at least 60 minutes with no oral intake Avoid taking with other medicines Risendronate (Actonel) PO Dosing Prevention and Treatment: 5mg daily, 35mg weekly, or 150mg monthly Counseling Points Take on empty stomach Take with 6-8 oz of plain water Remain upright for at least 30 minutes with no oral intake Avoid taking with other medicines Zoledronic Acid (Reclast) IV Dosing: Prevention: 5mg IV infusion every 2 years Tx: 5mg IV infusion yearly IV administration avoids GI effects Denosumab (Prolia) Administered by a licensed healthcare provider Used in males and postmenopausal females Dose: 60mg SQ injection every 6 months MUST correct hypocalcemia before initiation REMS program for risks of hypocalcemia, atypical femur fractures (AFF), osteonecrosis of the jaw (ONJ), serious infection, and dermatologic reactions AE: injection site reactions, cellulitis, rash, eczema, arthralgia, back pain Monitoring parameters SCr, calcium phosphorous, magnesium pregnancy test Duration of therapy; not been established. If fracture risk remains high after 5-10 years of therapy, consider extending therapy or switching to an alternative. There is no data available for therapy use beyond 10 years CI: hypersensitivity to denosumab, preexisting hypocalcemia, pregnancy DI: corticosteroids, immunosuppressants, methotrexate Estrogen (Climara, Estrace, Prempro, Vivelle) Used for prevention in postmenopausal women CI: patients with current or history of DVT or PE Estrogen should be used for the shortest duration possible consistent with treatment goals Increased risk of endometrial cancer and risk of stroke and DVT AE: n/v, breast pain/tenderness, mood and/or weight changes Raloxifene (Evista) MOA: acts as an estrogen agonist in the bone to prevent bone loss and has estrogen antagonist activity in the breast and uterine tissues Selective estrogen receptor modulator (SERM) Decreases bone resorption, increasing bone mineral density and decreasing fracture incidence Increased VTE and stroke risk Educate patient to monitor for signs/symptoms of VTE CI: hx of or current venous thromboembolic disorders Concurrent use with systemic estrogen therapy is not recommended AE: flushing, leg pains, cramps, peripheral edema Bazedoxifene + CEE (Duavee) Selective estrogen modulator (SERM) MOA: provides relief of vasomotor symptoms and maintenance of bone mineral density in postmenopausal females Dose: Bazedoxifene/conjugated equine estrogens 20mg/0.45mg orally daily Used for prevention in postmenopausal women CI: pts with hx of venous thromboembolism Does NOT need to be combined with a progestin Calcitonin Dose: one spray (200 units) in one nostril daily or 100u SQ daily Used as tx in women who are 5 years postmenopausal May be used off label short term (4 weeks) to relieve osteoporotic pain AE: rhinitis, epistaxis PTH Anabolic (building back bone that patients have already lost) Injected SubQ daily by patient for up to 24 months Orthostasis with first few doses – administer sitting or lying down) Correct Vit D deficiency before initiation Monitor serum calcium during therapy Cumulative lifetime exposure to PTH analogs should not exceed 2 years Avoid in patients at increased risk for osteosarcoma, active or recent urolithiasis AE: Inj site rxns, N/HA/dizziness, joint pain, leg cramps, Hypercalcemia, hypercalciuria, hyperuricemia Teriparatide (Forteo) Approved for use in men and postmenopausal women Refrigerated pre-filled pen with 28 doses Administered in thigh or abdomen BBW: increased osteosarcoma rates observed in rats; human risk unk Abaloparatide (Tymlos) Approved for use only in postmenopausal women Pre-filled pen with 30 doses; stored at room temp after first dose Administered in periumbilical region Antiresorptive and anabolic Romosozumab Approved for use in postmenopausal women Administered SubQ by healthcare provider once monthly for 12 months Correct Vit D deficiency before initiation Monitor serum calcium during therapy Do not initiate in patients with MI or stroke in the past year BBW: increased risk of myocardial infarction, stroke and CV death AE: inj site rxns, hypersensitivity rxns, HA, arthralgia, muscle spasms, hypocalcemia, RARE: ONJ, AFF Treatment Considerations Who is eligible for pharmacotherapy to prevent osteoporosis? Postmenopausal women who have concern for development of osteoporosis but do not qualify for tx pharmacotherapy Goal is to prevent progression to osteoporosis and/or first fracture in patient who is at risk but doesn’t meet full diagnostic criteria Options are bisphosphonates, estrogens, and SERMs – all other options are NOT approved for prevention pharmacotherapy Who is eligible for pharmacotherapy to treat osteoporosis? Generally, postmenopausal women and men 50 & over who: Have a low-trauma fragility fracture OR have a T-score of -2.5 or lower OR have a T-score between -1 and -2.5 plus high fracture risk through assessment such as FRAX Goal: prevent new fractures in patient diagnosed with osteoporosis How is tx pharmacotherapy selected? Bisphosphonates are generally an appropriate first-line selection Denosumab is an acceptable alternate first-line option For severe cases, can bypass first-line and initiate anabolic therapy What is the expected duration and outcome of tx? Therapy end is not well defined; some guidance from FDA labeling Patients on bisphosphonates will tend to stabilize above baseline BMD for a longer period than other therapies Effects of all non-bisphosphonate therapies will wane rapidly after d/c (1-2 years) When anabolic therapy is indicated, following the antiresorptive for maintenance is generally recommended Can pharmacotherapies be combined? Combining two antiresorptives should be reserved for special cases, such as active bone loss in a woman who: Is already using hormone therapy for menopause (+bisphosphonate) Is already using raloxifene for breast cancer prevention As for different mechanisms, side effects likely outweigh benefits. Sequential therapy preferred over combo therapy Ex: teriparatide plus antiresorptive was more effective than antiresorptive alone, but less effective than teriparatide alone Let anabolic do its job first, then start antiresorptive Characteristics of Osteoporosis: Low bone mass; Fragile, deteriorated bones; Increased risk for fracture Who Gets Osteoporosis? Risk factors Age (particularly post-menopausal women) Lower body weight and muscle mass Women: early menopause, no pregnancy Men: low testosterone Caucasian or Asian ethnicity Smoking and high caffeine intake Low Ca and vitD intake Inadequate or excessive exercise Depression Certain medications Bone composition Bone is formed by inorganic bone material deposited on a framework of organic material Organic component = osteoid (mostly collagen), inorganic component = hydroxyapatite (this is mostly calcium and phosphate) Cells Osteoblast: synthesize osteoid They become osteocytes (resident bone cells) when they are surrounded in bone matrix (osteocytes are derived from osteoblasts) Osteoclasts: bone resorption, secrete acids and proteolytic enzymes that break up all parts of bone Calcium and phosphorous absorption and distribution Mostly found in bone We only absorb 30% of our calcium from our diet We absorb 93% of phosphorous from our diet Principle regulators of Ca+2 and PO4-3 (we are better at absorbing phosphate than calcium – only about 30% of calcium is absorbed) Parathyroid hormone (PTH) increase serum Ca+2, decrease serum PO4-3 stimulates production of active vitamin D Vitamin D increase serum Ca+2 and PO4-3 inhibits production of PTH (negative feedback!) stimulates production of FGF23 Fibroblast growth factor 23 Decreases serum PO4-3 Inhibits production of active vitamin D Secondary regulators: calcitonin (net effect: decrease serum Ca and P), prolactin, growth hormone, insulin, thyroid hormone, glucocorticoids, sex steroids Parathyroid hormone (inCa, dePho) Peptide hormone (84 amino acids) Actions Net effect on bone: increasing resorption (THIS IS BAD; dissolving minerals and breaking down the matrix) Kidney: increases Ca2+ reabsorption, PO4-3 excretion, Increases production of active vitamin D Net effect: increase calcium, decrease phosphate Parathyroid hormone regulation Calcium  Within the parathyroid gland: calcium-sensitive protease capable of cleaving PTH into fragments  Calcium sensing receptor (CaR): calcium binds CaR, more Ca2+ less PTH Calcium bind CaR, more Ca2+ inhibits PTH Phosphate Calcium sensing receptor (CaR): increase PTH Phosphate binds Ca2+, so less free to bind CaR More phosphate, increases PTH secretion Active form of vitamin D (inhibits PTH) PTH action on bone Receptor for activating NF-κB (RANK) is an osteoclast protein whose activity is required for osteoclastic bone resorption Its natural ligand is a membrane-bound osteoblast protein called RANK ligand (RANKL) PTH acts on the osteoblast to induce RANKL RANKL binding to RANK increases both numbers and activity of osteoclasts (increase bone resorption) Paradoxical effect of PTH? Net effect of excess PTH is to increase bone resorption However, low and intermittent doses of PTH increase formation without first stimulating resorption (Indirect mechanism through growth factors like IGF-1) Teriparatide= Recombinant PTH (aas 1-34) for osteoporosis First drug for osteoporosis that stimulates bone formation given SC once daily Approved for use for only 2 yrs Black box warning: In rats, causes an increase in the incidence of osteosarcoma Adverse effects: joint pain, arthritis, muscle spasm Calcimimetics (mimic calcium) Cinacalcet – activates calcium sensing receptor (CaR) Activated CaR = negative feedback to PTH Blocks PTH secretion – useful for hyperparathyroidism Adverse effects: Diarrhea, nausea, vomiting, hypocalcemia (because turning off PTH, so inhibiting signal to release more calcium) Vitamin D too much = too much PTH = bad Vitamin D2 = ergocalciferol Vitamin D3 = cholecalciferol How is Vitamin D3 produced by the body? Skin Activation of vitamin D Liver: 25-hydorxylase enzyme adds hydroxyl group to 25th carbon Kidney: 1-alpha-hydroxylase enzyme adds hydroxyl group to 1st carbon This is a high site of regulation Effects of 1, 25 (OH)2 Vit D (AKA Vitamin D) Increase Ca+2 and PO4-3 absorption Inhibit production of PTH (Vit D provides negative feedback to PTH) Stimulates production of FGF23 Regulation of Vitamin D Both calcium and phosphate at high levels reduce amount of 1,25(OH)2D produced by kidney (inhibit what enzyme?) PTH stimulates production of 1,25(OH)2D (stimulates what enzyme?) 1-alpha hydroxylase FGF-23 inhibits production of 1,25(OH)2D (inhibits what enzyme?) 1-alpha hydroxylase Clinical use of vitamin D Vitamin D and 1,25(OH)2D as calcitriol are available for clinical use (1/2 life: 5-8 hrs) Analogs of 1,25(OH)2D also available – calcipotriene, doxercalciferol (32-37h), paricalcitol (5-7h) Adverse effects: ALL: hypercalcemia Effects on bone Facilitates PTH action Fibroblast Growth Factor 23 inhibits mineralization (want less of this) 251 amino acids, produced by osteoblasts and osteocytes Binds to FGF I and IIIc receptors in the presence of an accessory receptor Klotho Effects Inhibits formation of active vitamin D Inhibits phosphate reabsorption via interactions with sodium phosphate cotransporters Regulation of FGF23 1,25(OH)2D stimulates production of FGF23 High serum phosphate stimulates release of FGF23 Other regulators: Calcitonin Actions Bone: inhibit osteoclastic bone resorption (this is good)  Bone formation not impaired initially, but with time both formation and resorption are reduced Kidney: reduces reabsorption of both calcium and phosphate Net: decrease in serum calcium and phosphate Kinetics Human calcitonin ½ life ~ 10 minutes, salmon calcitonin longer Other regulators Glucocorticoids: antagonize vitamin D-stimulated intestinal calcium transport, stimulate renal calcium excretion, and block bone formation Estrogens: thought to reduce bone resorbing action of PTH, also has direct effects on bone HRT – estrogen long-term risky? Bisphosphonates (-dronate) Analogs of pyrophosphate in which P-O-P bond is replaced with nonhydrolyzable P-C-P bond “dronates” Etidronate (1st gen) Clodronate (1st gen) Tiludronate Alendronate (2nd gen) Fosamax Pamidronate (2nd gen) Aredia Ibandronate (2nd gen) Boniva Risedronate (3rd gen) Actonel Zoledronate (3rd gen) (Zoledronic acid) Reclast 2nd gen: contain a nitrogen group in side chain, 10-100x more potent than 1st gen 3rd gen: contain a nitrogen atom in heterocyclic ring, 10,000x more potent Bisphosphonate mechanism Used for disorders of bone remodeling (osteoporosis) as well as for hypercalcemia, cancer (via inhibiting Ras pathways) Bind hydroxyapatite, may block its dissolution Decrease osteoclastic bone resorption (this is GOOD): Localize to regions of bone resorption Inhibition of osteoclast activity Inhibit osteoclastic survival- alendronate, risderonate Increase osteoclast apoptosis Bisphosphonates Less than 10% of oral dose absorbed, reduced further by food ~1/2 of drug accumulates in bone, remainder excreted unchanged in urine Decreased renal function, esophageal motility disorders, and peptic ulcer disease are contraindications (last two- unless IV) Side effects: diarrhea, nausea, abdominal pain Esophageal ulcers – take with full glass of water and remain upright for 30 min Ibandronate: 60 minutes Osteonecrosis of the jaw (ONJ) Some potential for esophogeal cancer Bisphosphonates Alendronate (2nd gen) Fosamax IV (malignancy), Orally weekly or daily Pamidronate (2nd gen) Aredia IV (malignancy, Padget’s), Once weekly or monthly Ibandronate (2nd gen) Boniva Orally, once daily or monthly; IV every 3 months Risedronate (3rd gen) Actonel Orally, once daily or weekly Zoledronate (3rd gen) (Zoledronic acid) Reclast IV every year Denosumab: RANKL inhibitor (inhibit osteoclast differentiation to inhibit bone resorption this is good) Administered subcutaneously or orally Adverse effects: hypocalcemia, hypophosphatemia, serious infections (immunosuppression?), osteonecrosis of the jaw (ONJ), diarrhea, nausea/vomiting, fatigue, backache, pain in limbs, headache, low energy, nasopharyngitis Romosozumab-aqqg: Humanized monoclonal antibody (IgG2) Sclerostin inhibitor: Increases bone formation and to a lesser extent, decreases bone resorption Administered subcutaneously Short-term use (12 months) Adverse effects: arthralgia, headache, hypersensitivity reactions, hypocalcemia, ONJ, MI, stroke, cardiovascular death