Endocrinology 2025 PDF

ENDOCRINOLOGY Sunday, December 1st, 2024 Dr. Patricia Palcu  Outline (Lecture) 1. Hypercalcemia 2. MEN Syndromes 3. Hyperthyroidism 4. Hypothyroidism 5. Thyroid Disease in Pregnancy 6. Osteoporosis & Metabolic Bone Disease – **CMAJ Guidelines 2023** 7. D...

ENDOCRINOLOGY Sunday, December 1st, 2024 Dr. Patricia Palcu  Outline (Lecture) 1. Hypercalcemia 2. MEN Syndromes 3. Hyperthyroidism 4. Hypothyroidism 5. Thyroid Disease in Pregnancy 6. Osteoporosis & Metabolic Bone Disease – **CMAJ Guidelines 2023** 7. Diabetes 8. Adrenal & Pituitary 9. Lipid Guidelines 10. Care for Transgender Patients 11. Reproductive Endocrinology 12. Thyroid Nodules & Cancer 13. Obesity Guidelines 2  Endocrinology 101 Before we start… Interpreting Labs: *Normal or inappropriately normal? Always think critically about what the pattern of hormones should be, not only whether a value is in the normal range 3  1. Hypercalcemia Resources: 2022 Hyperparathyroidism Guidelines from the Fifth International Workshop https://asbmr.onlinelibrary.wiley.com/doi/epdf/10.1002/jbmr.4677 Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus: https://pubmed.ncbi.nlm.nih.gov/27613721/ 4  MCQ 1 - 2025 An 85yoF with bony pain is referred for hypercalcemia. Meds: ramipril, atorvastatin, glargine, aspart. A CT scan done shows lytic lesions. sPEP, uPEP, FLC assay and malignant workup is normal. BMD does not show T-scores < -2.5 at any sites (including radius). A sestamibi scan shows a 1.3 cm parathyroid adenoma. Her nephrologist and ENT do not think she is candidate for parathyroidectomy due to her frailty and she has also declined surgery. What treatment option is best to medically manage Lab Values Reference Range Calcium = 2.74 2.1 -2.6 mmol/L her hypercalcemia? Phosphate = 0.90 0.70 - 1.5 mmol/L 1. IV fluids + furosemide Cr = 123 53 - 97 µmol/L 2. Calcium restricted diet 25OHD = 74 75 – 200 nmol/L 3. IV bisphosphonate PTH = 35 1.6-6.9 pmol/L 4. Cinacalcet Albumin = 40 35 - 50 g/L 5. Calcitriol 5  Calcium Physiology: Pearl 1 & 2 1. In a parathyroid-mediated 2. In a vitamin D mediated process, process, serum calcium and serum calcium and phosphate go phosphate go in the opposite in the same direction direction e.g. e.g. Hyperparathyroidism: ↑Ca ↓PO4 Osteomalacia: ↓Ca, ↓PO4 Vitamin D *Excess: ↑Ca, ↑PO4 Hypoparathyroidism: ↓Ca ↑PO4 (*ex. 1,25-hydroxyvitamin D excess from granulomatous disease) 6  Calcium Physiology: Pearl 3 & 4 3. When the calcium, phosphate 4. Magnesium deficiency reduces and PTH are all high, think kidney PTH secretion and causes PTH (reduced ability to excrete resistance. Therefore think of phosphate) hypomagnesemia in someone with apparent e.g. hypoparathyroidism (or inappropriately normal PTH). Tertiary Hyperparathyroidism (in long-standing renal failure): ↑Ca, ↑PO4 7  BONUS Read on own Lab Patterns in Calcium Problems Disorder Serum Calcium Serum PO4 PTH Urine Calcium Primary HyperPTH High Low High High Tertiary HyperPTH High High High High Pseudohypoparathyroidism Low High High Variable FHH High Low High Low ( 0.25 mmol/L above upper limit T-score 6.25 mmol/d (>250mg/d) in women or >7.5 mmol/d in men (>300mg/d) Stones or nephrocalcinosis by x-ray, ultrasound, or CT Suggest Surgery in those being monitored in follow-up if: Creatinine clearance < 60 mL/min (stage 3 CKD) Serum calcium consistently >0.25 mmol/L above upper limit Low trauma fracture (+/- VFA if indicated) A kidney stone (abdo imaging if indicated) Significant reduction in BMD (every 1-2 yrs) to T-score 3ml/min annually to 0.02 Urine Calcium (mmol/l) x [Serum Creatinine (umol/l) / 1000] Serum Calcium (mmol) x Urine Creatinine (mmol/l) 10 1o Hyperparathyroidism (PHPT):Medical Management If patient NOT a candidate for surgery (e.g. per ENT, or too frail for surgery) : Medical Management* ! Correct vitamin D deficiency/insufficiency: target serum 25-OH vit D to >75 nmol/L Calcium intake should be consistent with nutritional guidelines (1000-1200 mg/d) Bisphosphonates and denosumab if indicated i.e. high risk per Osteoporosis Guidelines Cinacalcet ($) is effective in reducing serum Ca and should be considered for symptomatic PHPT if surgery is not an option. May combine w BP or denosumab in selected pts (to reduce Ca AND increase BMD). *Bottom Line: Surgery is the only cure for PHPT. Never use medical mgmt as an alternative to surgery when patient is fit for OR. There is no fracture data (only BMD improvement) with the existing medical treatments. 11  2o & 3o Hyperparathyroidism Secondary Hyperparathyroidism – Appropriate increase in PTH release in hypocalcemia or vitamin D deficiency (most common) – PTH is appropriately working to absorb all the urine calcium/salvage calcium level – TIP #1 : Postop Gastric Surgery (ex. gastric bypass/bilroth/whipples surgery where a portion of stomach is removed) You CANNOT use Calcium Carbonate as a supplement (there is no acidity to absorb this!) = use Calcium Citrate – TIP #2: Pt w Renal disease (CKD) treat with Vitamin D, phosphate restriction, non-calcium phosphate binders Cinacalcet for 2o HPT in CKD on dialysis (with target PTH levels depending on CKD stage; often in consultation with Nephrology) – cost $$ prohibitive in many patients Tertiary Hyperparathyroidism – Longstanding hypocalcemia (appropriate stimulus for PTH release) à parathyroid glands can become autonomous – Usually in the setting of end-stage renal disease or post-transplant Indications for Surgery in Tertiary Hyperparathyroidism Refractory hyperPTH despite vit D analogues/ calcimimetics (No absolute #/PTH cutoff, KDIGO defines as PTH still rising, symptomatic) Hypercalcemia severe / symptomatic Remarkably the KDIGO 2017 Calciphylaxis guidelines don’t give a lot of guidance here, largely because there Progressive bone disease are no high quality RCTs showing difference in outcome of medical vs surgical therapy in this population. 13  * BONUS Read on own Hypoparathyroidism Guidelines 2022 Diagnosis: Hypocalcemia in the presence of undetectable, low or inappropriately normal PTH measured on two occasions >2 weeks apart Supported by high phosphorus and low (1,25)OH2 vitamin D Permanent postsurgical hypoPTH is defined as persisting >12 months after surgery Management: 1st line = Conventional therapy w/ oral calcium & active vitamin D (calcitriol or alfacalcidol) PTH therapy can be considered if conventional therapy insufficient  * BONUS Read on own Hypoparathyroid Differential Acquired – Hypomagnesemia à PTH resistance – Hypermagnesemia à reduce PTH synthesis/secretion – Post-surgical (common complication post-total thyroidectomy) or post- radiation – Infiltrative disease (sarcoid, amyloid, cancer metastasis) – Autoimmune polyglandular syndrome type 1 (APS-1) (Whitaker’s Triad: chronic mucocutaneous candidiasis, Addison’s disease, & hypoparathyroidism) - AIRE mutation Congenital – Pseudohypoparathyroidism (genetic mutation in GNAS gene) – DiGeorge Syndrome / 22q11.2 deletion syndrome : parathyroid agenesis – Note: Hypocalcemia outside of hypoparathyroidism can also occur in Extravascular sequestration – Hyperphosphatemia, Pancreatitis, Osteoblastic metastases  Lytic lesions caused MCQ 1 - 2025 by HyperPTH = “Brown tumors” An 85yoF with bony pain is referred for hypercalcemia. Meds: ramipril, atorvastatin, glargine, aspart. A CT scan done shows lytic lesions. sPEP, uPEP, FLC assay and malignant workup is normal. BMD do not have any T-scores 25%) = increased endogenous production of thyroid hormone (e.g. Graves disease, toxic multinodular goiter) Low radioactive iodine uptake = extra thyroid hormone without increased endogenous production à exogenous ingestion or inflammatory leak (e.g. acute, sub-acute, post-partum, or amiodarone-induced thyroiditis)* *RAIU may be falsely low if there is an interfering factor (e.g. recent iodine load via IV contrast or amiodarone, use of thionamide medications) 20 Hyperthyroidism – Pearl # 2 Ophthalmopathy = Graves disease (no matter what the RAIU result!) If the RAIU is low even with these clinical features, the test is usually unreliable because of: Ø CT scan (iodinated contrast) Patient with thyrotoxicosis/ untreated hyperthyroidism Ø Amiodarone (iodine load) requiring CT scan with contrast? Ø Iodine intake (e.g. kelp) Consider pre-treating with anti- thyroid drugs prior to CT. 21 Hyper/hypothyroidism – Pearl # 3 A big gland (goiter) usually means the thyroid is being stimulated Ø TSH (Hashimoto’s) Ø Thyroid receptor antibodies (Graves’) Ø B-hCG (pregnancy) A painful gland usually means the thyroid is inflamed Ø Thyroiditis 22 Hyperthyroidism – Pearl # 4 Use beta-blockers (e.g. propranolol) for symptomatic patients (“especially elderly, those with resting HR > 90 or CVD”) It takes 4-6 weeks to see full effect of anti- thyroid drugs (e.g. methimazole or propylthiouracil) 23 Hyperthyroidism – Pearl # 5 Treatment Options for Graves: thionamides, surgery (total thyroidectomy), or RAI ablation; latter two renders the patient hypothyroid à need levothyroxine replacement lifelong Medical Management: Use MMZ instead of PTU because less hepatotoxic EXCEPT in the following situations: Ø First trimester of pregnancy (risk of aplasia cutis & cleft palate) Ø Thyroid storm Ø Minor MMZ reactions (if severe, then shouldn’t use anti-thyroid drugs at all) 24  Counselling on Anti-Thyroid Drugs Drug Reaction MMZ PTU Action Management Notes Hepatotoxicity* YES YES (worse) STOP & can’t switch Discontinue if transaminases reach >3x ULN * *some transaminitis often also a result of thyrotoxicosis before ATD, but typically not 3x ULN Agranulocytosis YES (more likely dose YES (not dose STOP & can’t switch Granulocyte colony stimulating (look out for related) related) factor, steroids, antibiotics (if fever/sore throat!) febrile) and/or supportive care Vasculitis YES YES STOP & can’t switch (polyarthritis, purpuric Rx - Glucocorticoids or other skin lesions, immunosuppressive therapy pulmonary +/or renal) Serious allergic rxn YES YES STOP & can’t switch Assess and treat for anaphylaxis Minor reactions YES YES Can try switching (but (e.g. minor rash, GI (be careful that it isn’t (be careful that it probably not helpful) Rx anti-histamine for minor rashes symptoms, myalgias & vasculitis) isn’t vasculitis) arthralgias) 25  Other Graves’ Treatment Options RAI – Single dose of ablative radioactive iodine. – Contraindications: Pregnancy, breastfeeding, moderate-severe orbitopathy, thyroid cancer – Adverse effects: Worsened Orbitopathy, Thyroiditis – Delay pregnancy for 6 months after tx – If giving RAI with orbitopathy, should give steroids – Should be off methimazole for at least 2-3 days before radioactive iodine ablation Surgery - Patient should be euthyroid prior to surgery Graves’ Orbitopathy Artificial tears or ophthalmic gels Mild Selenium supplements x 6 months Moderate to Severe IV glucocorticoids + mycophenolate is the EUGOGO first-line treatment for those with ACTIVE GO if no contraindications (i.e. CHF, severe hyperglycemia). Alternative first-line regimen is IV glucocorticoids alone at higher doses Surgery only offered for stable INACTIVE GO (must be inactive >6 months) Teprotumumab – not yet approved in Canada Bartalena et al. 2021 Thyroid Association/European Group on Graves’ Orbitopathy Guidelines for Management of 27 Graves’ orbitopathy , Teprotumumab for the Treatment of Active Thyroid Eye Disease N Engl J Med 2020;382:341- 3  Thyroid Storm Think of this with a very sick patient with thyrotoxicosis (tachycardia, confusion, hyperthermia) The degree of T4 excess is not necessarily more than with other forms of hyperthyroidism Burch-Wartofsky Scale https://www.mdcalc.com/burch-wartofsky-point-scale-bwps-thyrotoxicosis *don’t memorize the calculations, know the clinical picture* COMPONENTS: Fever Neurological symptoms GI symptoms/hepatic dysfunction Tachycardia A. fib +/- Heart failure Precipitants (infection, surgery, trauma, iodine load, pregnancy; most common is medication non-adherence/discontinuation) 28  Thyroid Storm Treatment ABCs – get ICU involved early! Supportive care Beta-blockers (careful with hemodynamic status!!) E.g. Propranolol 60-80mg PO q4-6h, if unsure, start at lower Propranolol dose 20-40mg po q4-6hr [the intention is to reduce adrenergic drive] PTU* (usually 200 mg PO q4h) THEN Iodine Lugol’s iodine 10 drops q8h Should be given 1 hour after the loading dose of PTU Glucocorticoids (often AI co-exists, also helps to reduce fT4à fT3 conversion) *In Real Life: There is a shortage of PTU since 2020. PTU is preferred in Thyroid storm vs MMI because it blocks some peripheral conversion of T4 à T3. If unavailable at your hospital : give MMI 20mg q4-6h 29  MCQ 2- 2025 A 43-year-old woman presents with 3 months of palpitations, anxiety, increased bowel movements, and 4 kg weight loss. On examination, BP 128/70, HR 104 and regular, and thyroid feels firm. On eye exam, she has proptosis and conjunctival redness. Her thyroid tests and TRAb are pending. Which of the following statements about thyroid eye disease (TED) is TRUE? A) Smoking has no effect on the severity or progression of TED B) TED symptoms always improve after treatment of hyperthyroidism C) The most common initial symptom of TED is loss of vision D) TED can occur in both hyperthyroid and euthyroid patients A - smoking is known to significantly worsen the severity and progression of TED B - TED symptoms may persist or even worsen after treating hyperthyroidism, as TED has a separate course from thyroid hormone levels. C - most common initial symptoms are usually eye redness, irritation, and eyelid retraction. Vision loss occurs in more severe cases. D – TED can occur even in patients who are euthyroid. 30  4. Hypothyroidism Resources: 2014 ATA Hypothyroidism Guidelines https://www.liebertpub.com/doi/full/10.1089/thy.2014.0028 Canadian Task Force Guidelines 2019 “ recommends against screening* asymptomatic nonpregnant adults aged 18 years and older for thyroid dysfunction in primary care settings” *Screening = measure TSH https://canadiantaskforce.ca/guidelines/published-guidelines/asymptomatic-thyroid- dysfunction/ 31  Subclinical Hypothyroidism TSH above upper limit of normal with normal Free T4 Treat when: Ø TSH > 10 mIU/L * 1.6mcg x weight (kg) = typical starting dose; titrate every 4-6 weeks ** if cardiac disease (CAD) or frail elderly, can start at lowest possible dose (e.g. 25mcg po daily or 50mcg po daily to avoid risk of inducing AFib) Double-blind RCT of adults > 65 years with subclinical Consider treatment when: hypothyroidism (Stott DJ et al. NEJM 2017): Ø Symptomatic No apparent benefits to treating older persons with sub- Ø Goiter clinical hypothyroidism Ø Pregnancy/pregnancy-planning Choosing Wisely: routinely, we do not test for anti-TPO (also Ø Positive anti-TPO antibodies called anti-microsomal Ab), but in subclinical, can test to push your treatment decision 32  Myxedema Coma Severe hypothyroidism leading to: – Altered LOC / lethargy – Hypothermia Life-threatening SLOWING of – Hypotension function in multiple organs! – Bradycardia – Hyponatremia Diagnosis is clinical – but often see very low/undetectable FT4, – Hypoventilation high TSH 33 Myxedema Coma Treatment IV levothyroxine load 200-400mcg x1 followed by 1.6mcg/kg/d (this is the PO dose, multiply by 75% if given IV) – Lower dose should be considered if cardiac history or elderly – PO levothyroxine ~75% as potent as IV form IV glucocorticoids (HC 100mg IV Q8H) until AI ruled out IV liothyronine load 5-20mcg x1 followed by 2.5-10mcg Q8H Supportive measures (ICU monitoring, mechanical ventilation, fluids, warming) 34 5. Thyroid Disease in Pregnancy Subclinical Hypothyroidism Pre-existing Hypothyroidism Grave’s Disease Gestational Thyrotoxicosis 35 Subclinical Hypothyroidism in Pregnancy Simplified version of the 2017 ATA Guidelines TSH ≤ 2.5 TSH 2.5 – 4.0 TSH ≥ 4.0 (-)TPO Ab (+)TPO Ab (-)TPO Ab (+)TPO Ab Do not Do not Consider treat 4-10, Treat Treat treat treat definitely treat if >10 i v Pregnant women with TSH >2.5 mU/L should be evaluated for TPO-Ab v Once on treatment, target TSH ≤ 2.5 throughout the pregnancy v In Canada, we do not routinely screen TSH in asymptomatic pregnant women v If pre-existing hypothyroidism, need ~30-35% more LT4 as soon as pregnant i.e. extra LT4 pill on Sat and Sun (9 pills/week) 36 Upon delivery, go back to pre-pregnancy dose  Graves’ in Pregnancy 1. Anti-thyroidal medications are teratogenic a) PTU in 1st trimester (conversion ~1mg MMZ:20mg PTU), MMZ after that (or discontinue all ATDs if possible) b) Use the lowest possible dose (aim for T4 at high-normal range) 2. Check TSH-R Ab in 2nd trimester as can cross placenta - if >3x ULN, predicts risk of neonatal hyperthyroidism - Consult Pediatrics to see Newborn 3. Long-term treatment with β-blockers associated with IUGR, fetal bradycardia, and neonatal hypoglycemia 4. Watch for post partum exacerbations and post partum thyroiditis ATA Guidelines 2017 Gestational Transient Thyrotoxicosis In normal pregnancy, Thyroid Binding Globulin and total T4 increase by 7 wks GA and peak at 16 wks GA hCG stimulates the TSH receptor on the thyroid gland causing ↑thyroid hormone & ↓TSH The hCG effect may be even more pronounced in: Ø Hyperemesis gravidarum Ø Molar pregnancy Ø Multiple gestation Ø Choriocarcinoma 38 Gestational Transient Thyrotoxicosis Generally self-limited, improves by 14-18 weeks Treat hyperemesis if present Use B-blockers if really necessary for symptoms Do NOT give PTU or methimazole 39  GTT vs. Thyroid Pathology Differentiating thyroid pathology from GTT can be hard, but look for: Ø Ophthalmopathy and/or thyroid bruit (Graves) Ø Goitre (more likely Graves) Ø Thyroid receptor antibody positivity (Graves) Ø Nodules (Toxic multinodular goitre or Thyroid Adenoma) Ø History of hyperemesis (GTT) Ø History of thyroid disease (not GTT) Ø Possibility of molar pregnancy (GTT; get a pelvic U/S!) 40  6. Osteoporosis Highest yield resource: ***NEW 2023 Osteoporosis Canada Guidelines (Scope of Recommendations: Community-dwelling postmenopausal females & males aged 50 years +) https://www.cmaj.ca/content/195/39/E1333 Recommendations for screening for 1o prevention of Fragility Fracture – Canadian Task Force on Preventative Health Care – Theriault G et al. CMAJ 2023 195(18) E 639-E649. American College of Endocrinology (ACE), the American Association of Clinical Endocrinologists (AACE) guidelines for the diagnosis and treatment of Postmenopausal Osteoporosis (2020) https://pro.aace.com/sites/default/files/2020-05/Vol%2026%20Supplement%201%20(May%202020)%20GL-2019-0524_0.pdf Pharmacological Management of Osteoporosis in Postmenopausal Women(2019) https://www.endocrine.org/clinical-practice-guidelines/osteoporosis-in-postmenopausal-women 41  MCQ 3 - 2025 A 68 yo M presents to primary care. He has a history of COPD, still smoking and has had frequent exacerbations requiring hospitalization. A recent CXR done during exacerbation noted new vertebral fracture at T7. The patient has lab-work done, showing Ca 2.17, Alb 38, ALP N, TSH N, eGFR 48, PTH 11.7, 25-OH-Vit D 38 nmol/L A BMD/DXA Scan is done and FRAX is calculated at 16% 10 year risk of major osteoporotic fracture. Which of the following is appropriate to recommend at this time? a) Alendronate 70mg po q weekly b) Exercise and resistance training weekly c) Vitamin D 1000 IU daily d) Denosumab 60mg sc q 6 mos e) No treatment for moderate risk FRAX, recommend non-pharm therapy and adequate calcium and Vitamin D f) Calcium 1000 mg daily 42  Osteoporosis Canada 2023 Guideline IMR recommends following these screening recommendations over Canadian Task Force 43 S. Morin et al. CMAJ 2023  FRAX Tool (https://frax.shef.ac.uk/) Age BMI Previous fracture? Parent with fractured hip? Current smoking Glucocorticoids RA 2o osteoporosis - Conditions associated with OP - type I (insulin dependent) diabetes, osteogenesis imperfecta in adults, untreated long-standing hyperthyroidism, hypogonadism or premature menopause ( 3% hip fracture) superior for classification and treatment https://www.sheffield.ac.uk/FRAX/tool.aspx?country=19 CAROC (High risk = >20% fracture) https://osteoporosis.ca/wp-content/uploads/CAROC.pdf Note that either tool could potentially underestimate risk : recency of fractures, recurrent falls, other comorbidities or very low BMD at the lumbar spine and total hip sites 45  Who to Screen BMD 50–64 yr with a previous osteoporosis-related fracture or ≥ 2 clinical risk factors ≥ 65 yr with 1 clinical risk factor for fracture ≥ 70 yr Spine x-ray / vertebral fracture assessment ≥ 65 yr with T-score ≤ –2.5 (femoral neck, total hip or lumbar spine) 10-yr major osteoporotic fracture risk between 15% and 19.9% (moderate) Clinical signs: vertebral tenderness, height loss (historical 6 cm, prospective 2cm), occiput to wall > 5 cm, rib-pelvis < 2 fingers Clinical Risk Factors : Previous fracture after 40 yr Glucocorticoids (> 3 mo in the last year, prednisone dose > 5 mg daily) Falls, ≥ 2 in the last year Parent fractured hip Body mass index < 20 kg/m2 Secondary osteoporosis. Current smoking Alcohol ≥ 3 drinks/d 46  When to Treat: High Risk Hip, vertebra or ≥ 2 osteoporosis-related fractures 10-yr major osteoporotic fracture risk ≥ 20% ≥ 70 yo and have a T-score ≤ –2.5 (femoral neck, total hip or lumbar spine) o Before initiating pharmacotherapy, assess for secondary causes of osteoporosis: ALP (Paget's), PTH, Calcium/Alb/PO4 (parathyroid), Cr/eGFR (renal disease), TSH (hyperthyroidism), 25OH vitamin D (deficiency, malabsorption), Meds/Alcohol SPEP – vertebral #, anemia (MM), Eating disorders, Bariatric Surgery Hx, testosterone (hypogonadism), CRP (IBD), tTG-IGA (Celiac) etc. 47  Suggest Treatment: Moderate Risk 10-yr major osteoporotic fracture risk between 15-19.9% < 70 yr and have a T-score ≤ –2.5 (femoral neck, total hip or lumbar spine) Other treatment decision factors to consider: a fracture in the last 2 years (risk of subsequent fracture highest) ongoing risk factors 48  Pharmacotherapy for Osteoporosis CLASS Drugs Side effects Contraindications Rx Notes Bisphosphonate Alendronate 70mg po q wk Esophageal / GI intolerance CrCl 15% Those on Therapy: – 3 yr after starting Rx Those on Bisphosphonate Drug Holiday: – 3 yrs after stopping *BMD measurement may be repeated sooner/more frequently in people with new fracture, secondary causes of osteoporosis, or new clinical risk factors associated with rapid bone loss 51 Atypical Femoral Fractures (AFF) Thigh or groin pain on bisphosphonates = need to rule out AFF! (bilateral femur X-rays, if these negative consider bone scan / MRIcharacteristics: Clinical if high index suspicion)** Proximal femoral shaft fracture Atraumatic Chronic bisphosphonate use (risk increases as early as 3 years) Asian women high risk Prodromal thigh pain (in up to 70%) Can occur with denosumab and Radiographic Characteristics romosozumab as well Lateral cortical thickening Transverse fracture lines Absolute risk increase is small, ~1:1000 patient Beaking years on bisphosphonate, versus 1:50000 patient years off bisphosphonate  Management of AFF PREVENTION Drug holiday for oral/?IV bisphosphonate for 3-6 years TREATMENT Orthopedic surgery consult (for IM nail insertion) Image contralateral femur (early fractures may be asymptomatic) Stop bisphosphonate Ensure adequate vitamin D and calcium intake, address other clinical risk factors for falls and fractures Start teriparatide (if still meet OP treatment criteria) – Denosumab NOT a good option as still risk of AFF 53 Osteonecrosis of the Jaw ONJ Nonhealing wound in oral mucosa with exposed bone that lasts >8 weeks Risk 1 fracture or substantial bone density decline (e.g. ≥ 5%) – Despite adherence to an adequate course of treatment (typically >1 yr) Consider: 2o causes of osteoporosis, falls, BMD imprecision errors Do not use bone turnover markers or FRAX/CAROC for monitoring What to do: extend or switch therapy reassess for secondary causes and refer to OP expert When To Refer To Consultant with OP expertise/Fracture Liaison Service Recent fracture Uncertainty about fracture risk or treatment Possible secondary causes of osteoporosis Comorbidities that complicate management (e.g. CKD-MBD) Significant adverse effects from pharmacotherapy Inadequate treatment response 55 Treatment Summary 56  Evidence based Non-Pharm Interventions Exercise Functional & Balance Training (twice weekly) : ↓ fall related fractures Resistance Training (twice weekly): In combination with functional Caution: Twisting or Flexion of the spine in repetitive, rapid way Nutrition Vitamin D: 400 IU/d minimum, dosing to target 25-OH vitamin D level *75- 125 mmol/L Calcium: 1000 mg/d (males aged 51–70 yr) and 1200 mg/d (females > 50 yr & males > 70 yr), dietary sources preferred Supplemental Protein, vitamin K, magnesium: low evidence Other Smoking cessation, alcohol moderation 57  *Paget’s Disease of Bone BONUS Read on own Pathophysiology: focal ↑ in bone resorption by Indications for Treatment: very large osteoclasts, then ↑ osteoblastic – Symptoms – pain, compression, fracture activity producing a high rate of bone – Evidence of active disease with impending formation/turn-over. symptoms (high risk for fracture) – Hypercalcemia (usually should only happen if Initial Labs: ↑ serum total alkaline phosphatase patient is immobile) (ALP) +/- bone specific ALP, without other – ALP >2x ULN abnormalities – Pre-orthopedic surgery at or near site (i.e. Imaging: do plain film XRs first of suspicious areas, femoral Paget’s lesion for hip replacement) if asymptomatic do skeletal survey/series (look for First Line Treatment: IV zoledronic acid 5mg IV q1yr is thickened cortices with tunnelling & accentuated treatment of choice trabeculae) or Oral bisphosphonate can be used **NOTE DOSING** If the diagnosis is confirmed à bone scan should – alendronate 40 mg/day x 6 months be done to determine the extent of the disease. – Risedronate 30mg/day x 2 months Associated illness: 2nd Line Agent (if intolerant to bisphos) is – Hearing loss, compressive neuropathies, Calcitonin osteoarthritis, osteosarcoma Paget's Disease of Bone: An Endocrine Society Clinical Practice Guideline (2014)  MCQ 3 - 2025 A 68 yo M presents to primary care. He has a history of COPD, still smoking and has had frequent exacerbations requiring hospitalization. A recent CXR done during exacerbation noted new vertebral fracture at T7. The patient has labwork done, showing Ca 2.17, Alb 38, ALP N, TSH N, eGFR 48, PTH 11.7, 25-OH-Vit D 38 nmol/L A BMD/DXA Scan is done and FRAX is calculated at 16% 10 year risk of major osteoporotic fracture. Which of the following is appropriate to recommend at this time? (A) – Alendronate is indicated for this patient with new a) Alendronate 70mg po q weekly vertebral fracture and clinical risk factors (ongoing b) Exercise and resistance training weekly smoking) c) Vitamin D 1000 IU daily Exercise and resistance training is recommended at least d) Denosumab 60mg sc q 6 mos TWICE weekly per Osteoporosis Canada 2023. Vitamin D 1000 IU daily is insufficient to replace the e) No treatment for moderate risk FRAX, recommend degree of Vit D deficiency this patient has. non-pharm therapy and adequate calcium and Vitamin D Denosumab not preferred first line, additionally = High a) Calcium 1000 mg daily risk of hypocalcemia without correcting Vitamin D. This patient has a vertebral # so needs treatment. Calcium supplements are not recommended where patients can meet the recommended dietary intake of 1000 mg/d for a man. 59  7. Diabetes Highest yield resource: 2018 Diabetes Canada Guidelines http://guidelines.diabetes.ca/cpg + 2020 Diabetes Canada Updates: http://guidelines.diabetes.ca/2020-Update (Pharmacologic glycemic management of T2DM in adults) + 2021 Diabetes Canada Updates: http://guidelines.diabetes.ca/2021-Update (BG monitoring in adults & children with diabetes) + 2022 Diabetes Canada Updates: https://guidelines.diabetes.ca/2022-Update (T2DM Remission) + 2023 Diabetes Canada Updates: https://guidelines.diabetes.ca/2023-Update (Diabetes and mental health) OTHER – KDIGO CKD and Diabetes Guidelines 2023 Note: The chapter summaries are concise. 60  Diabetes - Diagnosis Diagnosis of Diabetes with any of : Fasting glucose ≥ 7mmol/L (Prediabetes: 6.1-6.9) OR HbA1c ≥ 6.5% (Prediabetes: 6.0-6.4%) OR 2h 75g OGTT ≥ 11.1 mmol/L (Impaired glucose tolerance: 7.8-11.0) OR Random glucose ≥ 11.1 mmol/L Type of Diabetes: Type1: insulin deficiency (pancreatic β cell destruction), DKA prone, Usually Anti-GAD/Anti- Islet Cell antibody + Type 2: insulin resistance (tissue resistance, secretory defect), metabolic syndrome Latent autoimmune diabetes in adults (LADA): type 2 diabetes who also have immune- mediated loss of pancreatic β cells Monogenic: familial autosomal dominant mutation leading to beta cell defects, neonatal or topical Nephropathy T1DM 5y after diagnosis Random Urine ACR Annual ACE or ARB of T1DM >20, OR 2 of 3 rpt first line T2DM At time of diagnosis ACRs >2mg/mmol SGLT2i and/or eGFR 20mg/mmol, OR eGFR 2mg/mmol Treatment to reduce risk of progression of Nephropathy: ACE inhibitor or ARB maximally tolerated dose Nonsteroidal MRA (finerenone) used in DM2 + GFR >25 + ACR >3 despite maximally tolerated RASi [KDIGO CKD 2024 Guidelines] – ↓progression CKD, ↓CV and renal death, ↓ AFib (CKD w T2DM)1,2 – *watch out for K levels. If >5.5 à consider binder – May use steroidal MRA (aldosterone, eplerenone) if CHF, Conn’s, refractory HTN with caution in reduced GFR 1 Pitt B et al N Engl J Med 2021;385:2252-2263. 2Bakris GL et al N Engl J Med 2020;383:2219-2229 Refer if: chronic progressive loss of renal function, ACR persistently >60, eGFR 21 >=5 >=0.2 1.4 Negative overdose SU level ++ Insulin autoimmune >>21 >>5 >>0.2 1.4 Positive Ab IGF2 Bromocriptine: older, more side effects, cheaper Side effects: nausea, nasal stuffiness, headache -> Surgery if medication resistant/visual compromise/mass effect/hemorrhage CMAJ September 16, 2003 169 (6) 575-581  BONUS Read on own Acromegaly Syndrome of growth hormone excess Examination: macrognathia, macroglossia, increased ring shoe/collar/glove size, OSA, coarsened facial features, gap between incisors, carpal tunnel, osteoarthritis, type 2 diabetes, visual field defects, cranial neuropathies – “spade like hands and feet” Screening Test: IGF-1 level Diagnostic Test (remember principles): 75 g glucose suppression Treatment: Surgical  Diabetes Insipidus Absence of ADH leads to inability to concentrate urine Presentation is polydipsia and polyuria, usually post-neurosurgery Ø Remember that the other possibility is benign dumping fluids from the OR! Ø Check urine osm: If urine osm > serum osm it is not DI. Diagnosis: – Hypernatremia, hyperosmolar plasma, inappropriately dilute urine – 24 hour urine to confirm polyuria – Water deprivation test Usually presents in post-sellar surgical patients – Can be triphasic (or have some or none of): 1. Transient Diabetes insipidus – Pituitary stunning post-operatively 2. SIADH – release of stored ADH 3. Permanent Diabetes insipidus – loss of posterior pituitary function  9. Lipids Overarching Guidelines: 2021 CCS Guidelines for Management of Dyslipidemia and Prevention of Cardiovascular Disease https://www.onlinecjc.ca/article/S0828-282X(21)00165-3/fulltext REVIEW THE LAST PAGE OF THE CCS LIPID GUIDELINE PDF that comes after all the references (see below)! BONUS Read on own  MCQ 6 - 2025 A 67 year-old man is referred for cardiovascular risk management. His PMHx is significant for symptomatic PAD. His medications include atorvastatin 40 mg po QHS. Latest lipid panel shows total cholesterol 3.2, HDL 0.95, LDL 1.7, TG 1.2, Apo-B 0.94. Which of the following would you add based on the 2021 CCS Lipid Guidelines? a. No medication needs to be added b. Icosapent ethyl 2g BID c. Ezetimibe 10mg daily d. Evolocumab 140mg q2 weeks CCS Lipid Guidelines: Who to Screen Women ≥40 years of age (or postmenopausal) Men ≥40 years of age Consider earlier in ethnic groups at increased risk such as South Asians or Indigenous individuals In women with pregnancy-related complication (GDM, HTN, Pre-term birth, Low BW), screen with complete lipid profile in late postpartum period (incr. risk of premature CVD and stroke 10-15yr post-delivery) Counsel all women with pregnancy related complication for incr. lifetime risk of ASCVD and reinforce healthy lifestyle behaviours. To assist in lipid-lowering pharmacotherapy decisions in this specific patient population, use CV age over 10yr risk calculators – CV age calculator: myhealthcheckup.com CCS Lipid Management Guidelines 2021 120 CCS New Lipid Guidelines: Who to Screen ALL patients with any of the following conditions regardless of age Clinical ASCVD Family Hx of Dyslipidemia Evidence of preclinical ASCVD (CACS or carotid CKD (eGFR 3) U/S abn) Abdominal aortic aneurysm (AAA) Obesity (BMI > 30kg/m2) Diabetes Inflammatory diseases (RA, SLE, PsA, AS, IBD) Hypertension HIV infection Current Smoker Erectile dysfunction Stigmata of dyslipidemia COPD Family Hx of premature CVD in 1st degree Hypertensive disorder of pregnancy relative 121  *Simplified CCS FH Diagnostic Criteria* BONUS Read on own CCS Position Statement on Familial Hypercholesterolemia – When FH is suspected: Diagnosis and Treatment Flow CJC 2014 122 CCS New Lipid Guidelines: HOW to Screen History, physical Lipid profile Non-fasting acceptable as long as TG ≤4.5 mmol/L (otherwise, do fasting) – Tchol, TG, HDL-c, LDL-c, non-HDL-c – Lipoprotein (a) “once” CCS: If Lp(a) >100nmol/L, needs earlier and more intensive behavioural modification +/- statin Fasting glucose, A1C eGFR OPTIONAL: apolipoprotein(B), Urine ACR if eGFR 5.0 mmol/L or apoB ≥ 1.45 g/L or non-HDL-c ≥ 5.8 mmol/L Or Familial hypercholesterolemia, or genetic dyslipidemia 20-40% ↓ in LDL for starting dose of statin; additional 6% ↓for each 2. Diabetes if: doubling of dose – Age ≥40y – Age ≥30y and duration of diabetes over 15yrs 22% RR of MACE ↓for each – Microvascular disease 1 mmol/L reduction in LDL-c 3. CKD if: – Age ≥ 50y and eGFR 50 years + CKD 1-2: statin. – MI or ACS, stable angina, documented CAD on angiography CKD 3-5: statin or statin/ezetimibe. – CVA/TIA/Carotid atherosclerosis (in line w CCS) – PAD, Claudication or ABI 3cm or previous aortic aneurysm surgery PRIMARY Prevention – Use CV Risk calculator, see future slides. Counsel on health/behaviour modification … AND THEN START STATIN! 124 CCS Lipid Guidelines: What if NO statin indicated condition? USE FRAMINGHAM RISK Smoking Cessation Healthy Diet >150 min a week of mod-vigorous intensity aerobic physical activity INT (10-19.9%) FRS/ HIGH FRS (>20%): - Initiate statin - If on max dose and LDL >2.0 mmol/L, apo B> 0.8 g/L or non-HDL-C >2.6 -> add ezetimibe If Low FRS 100nmol/L they get a statin! CCS Lipid Management Guidelines 2021 125  LDL-c Therapies – PCSK-9 inhibitors Examples: Alirocumab, Evolocumab High PCSK9i benefit: Mechanism of Action: PCSK-9 is a protein Recent ACS 2 arterial beds) of LDL or background therapy Symptomatic PAD Current indications: Recurrent MI – Heterozygous Familial Mi in past 2 yrs Hypercholesterolemia Previous CABG – Clinical atherosclerotic cardiovascular disease LDL ≥ 2.6 mmol/L or heterozygous HH – Homozygous Familial Lipoprotein (a) > 120 nmol/l Hypercholesterolemia  CCS Lipid Guidelines: Tx Summary Condition LDL apoB non- First Add-on #1 Add on #2 (statin indicated) goal goal HDL-C line* Rx ** ** LDL>5