Hyperparathyroidism (1 of 11)

1 Patient presents w/ signs & symptoms suggestive of hyperparathyroidism

2 DIAGNOSIS Is hyperparathyroidism confi rmed?

Yes

3 4 No EVALUATION ALTERNATIVE Determine etiology DIAGNOSIS

Primary Secondary Tertiary Transient Neonatal Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism Hyperparathyroidism

A Surgery B Pharmacological therapy • Cinacalcet © MIMSC FOLLOWUP

Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS.

B1 © MIMS 2019 Hyperparathyroidism (2 of 11)

1 HYPERPARATHYROIDISM

• Caused by excessive parathyroid hormone (PTH) production • Primary hyperparathyroidism is the most common endocrine cause of hypercalcemia in ambulatory patients • Occurs more in women than in men aged >50 years old • 85-95% of primary hyperparathyroidism is due to adenoma • Sporadically arising solitary parathyroid adenoma is the most common primary hyperparathyroidism (PHPT) • Familial syndromes - 2nd most common cause of PHPT

HYPERPARATHYROIDISM • Renal failure - most common cause of secondary hyperparathyroidism

2 DIAGNOSIS

History • Complete history & physical examination including surgical procedures, medical conditions & medications • Check for thiazide diuretic & Lithium intake Signs & Symptoms • Usually related to elevated levels of PTH & serum calcium • Classic signs & symptoms include bone disease, kidney stones & hypercalcinosis • Constipation • Hypertension • Muscle weakness • Nausea • Polydipsia • Polyuria • Psychiatric symptoms (depression, anxiety, etc) • Signifi cant loss of appetite Complications • Parathyroid crisis - Also known as acute PHPT, parathyroid poisoning, parathyroid intoxication, parathyroid storm, hypercalcemic crisis - Excessive fl uid loss or severely limits the amount of fl uid they can consume - Sudden onset of life-threatening hypercalcemic episodes - Clinical manifestations are severe hypercalcemia-associated - Nephrocalcinosis or nephrolithiasis is frequently seen - Radiologic fi nding: Subperiosteal bone resorption - Laboratory fi ndings: Very high serum calcium levels, 20x above normal PTH levels - Aggressive fl uid resuscitation at a rate of at least 200 mL/hr of normal saline to promote renal calcium excretion & intravascular volume restoration - Once rehydrated, diuresis or dialysis w/ no or low calcium-containing dialysate may be added to inhibit reabsorption of calcium, as long as blood pressure remains stable • Impaired renal function • Nephrolithiasis • Bone disease - increased risk of bone fracture, osteopenia, osteoporosis or osteitis fi brosa cystica • Rheumatic symptoms - gout or calcifi cation of wrist or knee cartilage • Other chemical imbalance - decreased blood phosphate level or slightly increased magnesium level Urine tests 24-hour Urinary Calcium Level Measurement • Performed to exclude familial hypocalciuric hypercalcemia (FHH) • Used in renal complication risk assessment for asymptomatic PHPT • Elevated levels in young patients should raise suspicion on multiple endocrine neoplasia (MEN) syndrome & familial endocrinopathies • <200 mg/day (5.0 mmol/day) urinary calcium excretion - FHH or PHPT w/ concomitant vitamin D defi ciency is possible • <100 mg/day urinary calcium excretion - seen in approximately 75% of FHH patients Urinary Calcium© Excretion MIMS • Helpful in renal complication risk assessment for asymptomatic PHPT patients

B2 © MIMS 2019 Hyperparathyroidism (3 of 11)

2 DIAGNOSIS (CONT’D)

Serum Test Total Serum Calcium Concentration • Used for initial & repeat serum calcium measurements • Preferrably done on a fasted patient w/ minimal venous occlusion • Being done together w/ serum albumin measurement because it may infl uence the accuracy of total serum calcium concentration

HYPERPARATHYROIDISM - Adjusted to refl ect any abnormality in albumin - Compute for corrected calcium - Corrected calcium (mg/dL) = Measured total serum calcium (mg/dL) + 0.8 x (4.0 - serum albumin concen- tration (Patient)(g/dL)) - Corrected calcium (mg/dL) = Measured calcium (mg/dL) - measured albumin (g/dL) +4 Ionized Serum Calcium • Preferred for patients w/ asymptomatic PHPT in patients w/ normal serum albumin concentrations & absence of acid base imbalance • It has the advantage of not being aff ected by albumin levels • Adjunct to diagnosis in patients w/ presumed normocalcemic PHPT • Longstanding asymptomatic hypercalcemia is suggestive of PHPT Serum Parathyroid Hormone (PTH) Concentration • Uses an intact PTH (2nd generation PTH assay) or PTH 1-84 assays (3rd generation) • Concomittantly measured w/ serum calcium to diagnose hyperparathyroidism • Elevated PTH - 80-90% of PHPT patients • PTH w/ normal range - 24-hour urinary calcium excretion measurement should be done to help distinguish PHPT from FHH • PTH lower end of normal range - investigate for non-PTH-mediated cause of hypercalcemia Serum Phosphorus • May be in the lower normal range or decreased in cases of PHPT • Some patients may present w/ mild hyperchloremic acidosis Serum 25-hydroxyvitamin D (25(OH)D) • Useful to distinguish PHPT from other conditions • Insuffi ciency (<20 ng/dL) or frank defi ciency (<10 ng/dL) indicates a more active disease • Evidence showed PTH level reduction can occur in cases of insuffi cient correction of 25(OH)D • Increased urinary calcium excretion w/ vitamin D repletion - seen in mild PHPT w/ concomitant vitamin D defi ciency, elevated serum PTH & calcium w/ normal or low 24-hour urine calcium excretion • Low 25-hydroxyvitamin D is noted in secondary hyperparathyroidism due to vitamin D defi ciency Serum Creatinine • Diminished by hypercalcemia • eGFR of 60 mL/min - chronic kidney disease threshold for deciding which asymptomatic PHPT patient will benefi t from early surgical management Bone Markers • Eg Collagen crosslinks, osteocalcin, bone-specifi c alkaline phosphatase • Upper normal value or mildly elevated in asymptomatic PHPT • Severe cases presents w/ elevated bone markers Genetic Testing • Performed in patients suspected w/ familial form of PHPT, young patients & those w/ family history of PHPT, multigland involvement or clinical fi nding suspicious for multiple endocrine neoplasia type 1 (MEN1) • Approximately 10% patients w/ PHPT will have 1 out 11 genes mutation Imaging Studies Ultrasonography • Highly operator-dependent & high subjectivity in interpretation • Vital information for diagnosis can be detected when correlated w/ scintigraphy fi ndings • Cervical ultrasonography is utilized for excellent anatomic information but not for lesion identifi cation • Parathyroid adenoma appears as a homogenous well-demarcated mass, hypoechoic in contrast to hyperechoic thyroid tissue • Enlarged© inferior parathyroid adenomas MIMS are found immediately adjacent to the inferior pole of the thyroid lobes, thyrothymic ligament or upper cervical portion of the thymus • Enlarged superior parathyroid adenomas are usually found adjacent to posterior thyroid lobe which tends to migrate posteriorly & inferiorly

B3 © MIMS 2019 Hyperparathyroidism (4 of 11)

2 DIAGNOSIS (CONT’D)

Imaging Studies (cont’d) Single-proton Emission Computed Tomography (SPECT/CT) • 2nd-line modality in identifi cation of ectopic glands • Most valuable in identifying ectopic adenoma (except those located in the lower neck at the level of the shoul- ders & lesions close to or within the thyroid gland, hyperfunctioning gland not identifi ed during initial surgery • More successful modality in detecting retrotracheal, retro-esophageal & mediastinal adenoma • HYPERPARATHYROIDISM Mediastinal view - utilized to locate ectopic glands in the thorax • Jaw view - to locate undescended glands Magnetic Resonance Imaging (MRI) • Same as single-proton emission computed tomography (CT) • Indicated in pregnant patients w/ noninformative ultrasound results & identifi cation of ectopic parathyroid tissue 4D Computed Tomography (CT) • Powerful modality in identifying missed parathyroid glands & localization • Provides anatomic & function (perfusion) information • Axial views from jaw to aortic arch & perfusion studies should be included • Diff erentiates between perfusion characteristics, hyperfunctioning parathyroid gland, & status of parathyroid glands & other neck structures are visualized • When used w/ ultrasound shows 94% sensitivity & 90% specifi city in lateralizing hyperfunctioning parathyroid glands & 82% sensitivity in localizing to the correct quadrant of the neck Parathyroid Positron Emission Tomography (PET) • Tracers utilized: - 18F-fl uorodeoxyglucose - used for the identifi cation of pituitary adenomas - 11C-methionine - utilized in cases of problematic identifi cation of parathyroid site w/ conventional scintigraphy Double-tracer Parathyroid Scintigraphy • Also known as subtraction scanning • Parathyroid tracers are non-specifi c & absorbed by the thyroid gland as well; also used as myocardial perfusion tracers • Comparison w/ a second tracer is necessary • Application: - Detection of recurrent & persistent disease both in primary & secondary hyperparathyroidism - Improvement in initial surgical results in PHPT - Selection of appropriate surgical management for patients w/ PHPT • Parathyroid localization tracers utilized: - - 201 allous chloride (201Tl) - fi rst agent used to successfully visualize parathyroid glands in 1980s - 99mTc-sestamibi - used for parathyroid localization involving subtraction technique using 123I; Vitamin D therapy might reduce tracer uptake - 99mTc-tetrofosmin - an alternative to 99mTc-sestamibi for parathyroid subtraction scanning •  yroid scan tracers utilized: - 99mTc-pertechnetate - 123I - trapped & organifi ed by the thyroid; stable within the thyroid gland for long periods of time; uses at least 2 hours for adequate uptake by the thyroid gland Bone Mass Density • Determine reductions in bone density in PHPT patients • Essential part of disease management • Aids in confi rmation of trabecular involvement in asymptomatic PHPT • Approaches: Dual-energy x-ray absorptiometry (DXA), vertebral X-ray, vertebral fracture assessment (VFA), trabeculaar bone score (TBS) by DXA or high-resolution peripheral quantitative computed tomography (HRpQCT) • Bones to© be assessed: Spine, hip & distalMIMS ⅓ of forearm

B4 © MIMS 2019 Hyperparathyroidism (5 of 11)

2 DIAGNOSIS (CONT’D)

Invasive Methods Selective Venous Sampling (SVS) • Most sensitive localization procedure • Highly operator-dependent • Catheterization of common femoral vein or iliac vein to obtain PTH baseline values & internal jugular vein or multiple veins (neck & mediastinum) for lateralization

HYPERPARATHYROIDISM • Venograms should be obtained in 2 planes to delineate the precise anatomic location of sampled vessels • 2-fold elevation in PTH value compared to baseline denotes a positive localization study • Limited by procedure cost, adverse reactions (ie renal failure & anaphylactic reaction to contrast medium), & operative complications (ie bleeding, infection, pseudoaneurysm & AV fi stula) Ultrasound-guided Fine Needle Aspiration/Biopsy • Cytologic confi rmation & PTH biochemical assay should be done to samples • Confi rms the presence of PTH & diff erentiate it from other structures • Useful in the diff erential diagnosis of intrathyroidal parathyroid adenoma from a thyroid nodule • Positive PTH FNA, surgical reexploration should be done • Preoperative FNA of parathyroid glands should not be done due to theoretical risk of parathyroid cell seeding

3 EVALUATION

Classifi cation of Hyperparathyroidism Primary Hyperparathyroidism (PHPT) • An autonomous parathyroid hormone (PTH) overproduction resulting from either an adenoma or hyperplasia of parathyroid tissue • 2 molecular defects in sporadic parathyroid adenoma - Cyclin D1 gene inversions - leads to cyclin D1 overexpression causing cell proliferation - MEN1 mutations - accounts for approximately 20-30% of sporadic parathyroid tumors & found in familial parathyroid adenomas • Genetic syndromes associated w/ familial parathyroid adenomas - Multiple endocrine neoplasia, type 1 (Werner’s syndrome) & 2 (Sipple’s syndrome) - due to germline mutations of MEN1 & RET - Familial hypocalciuric hypercalcemia - a rare autosomal dominant disorder caused by loss-of-function mutation in parathyroid calcium-sensing receptor gene (CASR) leading to decreased extracellular calcium sensitivity - Neonatal severe PHPT - rare disorder developing shortly after birth aff ecting either homozygous or heterogenous mutation of the calcium-sensing receptor gene - Hyperparathyroidism-jaw tumor syndrome - Aff ects adults; an autosomal dominant disorder characterized by fi brosseous jaw tumors & parathyroid adenoma; Polycystic kidney disease, renal hamarthomas & Wilms tumor can also be observed in aff ected patients - Familial isolated hyperparathyroidism- has no specifi c features but are thought to be an occult expression of MEN type I • May occur during pregnancy - Causes spontaneous abortion, intrauterine growth restriction, supravalvular aortic stenosis, still birth & neonatal tetany - Neonatal tetany is a result of fetal parathyroid gland suppression by high levels of maternal circulation which readily crosses the placenta during pregnancy & most common initial sign of maternal hyperparathyroidism - Functional hypoparathyroidism occurs after birth in infants of mothers w/ PHPT due to hypercalcemic states while in utero - Aff ected infants can develop hypocalcemia & tetany in 1st few days of life - Initial symptoms: Abdominal symptoms, muscle weakness, disorientation, coma & death - Other complications: Prematurity, spontaneous abortion, intrauterine growth restriction, still birth - Decreased risk of obstetric complication has been seen in patients who undergo surgery for hyperparathyroidism - Surgical© intervention can be done aroundMIMS 2nd trimester

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3 EVALUATION (CONT’D)

Classifi cation of Hyperparathyroidism (cont’d) Primary Hyperparathyroidism (PHPT) (cont’d) • Clinical manifestations: - Musculoskeletal: Bone disease & bone pain secondary to bone fractures weakened by osteopenia, osteoporosis or osteitis fi brosa cystics, Brown tumors/cysts, muscle aches, weakness, fatigue - Renal: Nephrocalcinosis, nephrolithiasis w/ attendant pain & obstructive uropathy, chronic renal insuffi ciency & renal function abnormalities leading to polyuria & secondary polydipsia HYPERPARATHYROIDISM - Gastrointestinal: Abdominal pain, constipation, nausea, vomiting, peptic ulcers, pancreatitis & gallstones - Neurocognitive: Depression, lethargy, seizure, anxiety, depression, cognitive dysfunction, nervousness, mild emotional disturbances, frank psychosis - Cardiac: Aortic &/or mitral valve calcifi cations, hypertension Secondary Hyperparathyroidism • Caused by any condition giving rise to chronic hypocalcemia leading to compensatory PTH overactivity • Other causes: Inadequate dietary calcium intake, steatorrhea, vitamin D defi ciency • In cases of chronic renal insuffi ciency, decrease in phosphate excretion leads to elevation of serum phosphate levels which directly depresses serum calcium levels eventually leading to parathyroid gland stimulation • Clinical manifestations: Renal osteodystrophy, calciphylaxis Tertiary Hyperparathyroidism • Persistence of autonomous hypersection of parathyroid hormone after secondary hyperparathyroid hormone is corrected • Development of hypercalcemia refractory to medical management in patients w/ secondary hyperparathyroidism Transient Neonatal Hyperparathyroidism • Occurs in infants of mothers w/ idiopathic or surgically-induced hypoparathyroidism or pseudo hypoparathyroidism • Caused by chronic intrauterine exposure to hypocalcemia which results to fetal parathyroid gland hypoplasia

4 ALTERNATIVE DIAGNOSIS

Other Causes of PHPT • Parathyroid adenoma • Parathyroid carcinoma • Parathyroid hyperplasia Other Causes of Secondary Hyperparathyroidism Resulting to Hypocalcemia • Bone resorption inhibition - use of bisphosphonates • Calcium defi ciency • Chronic hyperphosphatemia • Chronic kidney disease - most common • Malabsorption • Postrenal transplantation • Pseudohypoparathyroidism - due PTH resistance • Vitamin D defi ciency Other Causes of Hypercalcemia • Familial hypocalciuria hypercalcemia (FHH) • Granulomatous disorders (eg sarcoidosis, Wegener granulomatosis) • Malignancy (eg bone metastasis, lung cancer, lymphoma, multiple myeloma, pheochromocytoma, metastatic tumors w/ osteolysis) • Medications (eg Lithium therapy, thiazide diuretics, antiestrogens, Aminophylline) • Milk-alkali syndrome • Renal failure (tertiary hyperparathyroidism) • Prolonged immobilization • Vitamin© D intoxication MIMS

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PREVENTIVE MEASURES

• For patients taking thiazide diuretics, discontinue for 2 weeks before serum calcium level measurement is repeated • Recommended for patients who do not undergo sugery - Avoid hypercalcemia-aggravating factors - Encourage physical activity to minimize bone resorption - Adequate hydration is encouraged to minimize nephrolithiasis risk - Moderate calcium intake (1000 mg/day) should be maintained HYPERPARATHYROIDISM - Moderate calcium restriction (<800 mg/day) is warranted in patients w/ high serum calcitriol concentration - Maintain moderate vitamin D intake (400-800 IU 24 hrly) to maintain 25-(OH)-D level of at least 20 or 30 ng/mL (50 or 75 mmol/L)

A SURGERY

Indications for Surgery: • Symptomatic PHPT (nephrocalcinosis, osteitis fi brosa cystica, nephrolithiasis) •  reshold value of serum calcium >1 mg/dL (>0.25 mmol/L) above the upper normal limit • 24-hour urinary calcium >400 mg/dL • Peri- or post-menopausal women & men aged ≥50 years old who have bone density T-score of ≤-2.5 at the lumbar spine, femoral neck, total hip, or distal ⅓ radius • Premenopausal women & men <50 years old w/ bone density Z-score of ≤-2.5 • Presence of vertebral fracture by x-ray or VFA w/ or without prior documentation • Creatinine clearance of <60 cc/min or when reduced by >30% in comparison w/ age-matched persons • Increased calcium-containing stone risk & marked hypercalciuria • Radiologic evidence of nephrocalcinosis or renal stones • Fragility fracture occurrence • Presence of neurocognitive &/or neuropsychiatric symptoms due to PHPT • Not desirable for medical surveillance Absolute Contraindication • Lack of confi rmation of diagnosis for persistent or recurrent PHPT • Inconclusive localization studies • Avoid blind explorations Preoperative Management • 1000-1200 mg daily intake of Calcium is recommended for adults & PHPT patients • Preoperative vitamin D repletion is advised but must be done w/ caution in patients w/ hypercalciuria • Preoperative voice evaluation including specifi c injury involving subjective & signifi cant voice changes or prior-at-risk surgery history Surgical Techniques Bilateral Neck Exploration • Standard surgical approach for most patients w/ PHPT • >95% long-term success rate w/ low rates of complications • Relies on visual & weight-based estimations of gland size to distinguish a single adenoma from multi-glandular disease • Preferred surgical technique in cases of discordant or non-localizing preoperative imaging • Suggested in cases of residual hyper-secreting tissue Radio-guided Minimally Invasive Parathyroidectomy • Achieves 97-99% cure rate when done w/ intraoperative PTH measurement to confi rm resection adequacy • Advantages: - Limits dissection - Faster recovery - Decreases postoperative discomfort - Less incision© length MIMS

Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS.

B7 © MIMS 2019 Hyperparathyroidism (8 of 11)

A SURGERY (CONT’D)

Surgical Techniques (cont’d) Radio-guided Minimally Invasive Parathyroidectomy (cont’d) • Preoperative imaging & other adjuncts are required prior to procedure • Indication: - Patient w/ high probability of solitary parathyroid adenoma w/ a signifi cant uptake on sestamibi scintigraphy

HYPERPARATHYROIDISM - Absence of thyroid nodules showing sestamibi uptake - Absence of familial hyperparathyroidism or MEN history - Absence of neck irradiation - Re-operation for persistent or recurrent hyperparathyroidism & ectopic adenoma Gamma-probe Guided Surgery • More sensitive than gamma camera • For patients undergoing bilateral neck exploration w/ negative preoperative scintigraphy • 2 types: - Minimally invasive approach - Bilateral cervical exploration • Advantages: - Easier surgical approach & shorter operation time - Verifi es the correct excision of the pathological tissue & success of surgery Concurrent  yroidectomy • Performed in patients for thyroid disease requiring resection, sporadic parathyroid cancer suspect, abnormal intrathyroid parathyroid gland removal or access improvement • Indication: Concomitant thyroid disease during parathyroidectomy for PHPT w/ isolated thyroid disease Immediate Postoperative Management • Monitor patient for complications (eg bleeding, hypocalcemia, vocal cord paralysis, laryngospasm) • Check: - Serum calcium concentration - reaches nadir within 24-36 hours post-surgery - Serum PTH level - within normal range within 30 hours post-surgery • Maintain low-calcium diet until normal serum calcium concentration is achieved • Seizure precaution should be observed at all times • “Hungry bone syndrome” - may develop in patients w/ large adenomas postoperatively - Associated w/ hypocalcemia, hypophosphatemia, & low urinary calcium excretion • Persistent hypercalcemia & elevated intact PTH levels post-surgery may indicated surgical failure Surgical Adjuncts Confi rmation of Resected Parathyroid Tissue • Frozen section analysis • Ex vivo parathyroid aspiration Gland Visualization • Methylene blue • Near infrared fl uorescence • Infrared spectroscopy Gland Localization • Intraoperative ultrasonography • Bilateral jugular venous sampling • Gamma-probe guidance Intraoperative Rapid PTH Test • Performed in minutes to detect any remaining abnormal glands which provides real-time parathyroid function assessment • Terminate surgery if >50% fall in intraoperative PTH levels • Full neck exploration may be necessary if <50% fall in intraoperative PTH levels to look for other hyperactive glands &© ectopic parathyroid glands (usuallyMIMS found in intrathyroid, retroesophageal, mediastinal)

Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS.

B8 © MIMS 2019 Hyperparathyroidism (9 of 11)

B PHARMACOLOGICAL THERAPY

Principles of  erapy • Goal: Normalize Calcium levels • Recommended for the following individuals: - Mildly elevated serum calcium levels (<1 mg/dL above upper normal limit) - No previous life-threatening hypercalcemic episodes - Normal bone & renal status

HYPERPARATHYROIDISM - Clinically asymptomatic, >50 years old - Poor surgical candidate - Inability to undergo surgery - Patient preference Bisphosphonates • Potent inhibitor of bone resorption • Useful to improve low bone mass in patients w/ untreated PHPT • Recommended for patients w/ PHPT & osteoporosis or those w/ low bone mineral density warranting intervention who opted not to undergo surgery • Increases bone mineral density after short term (2 years) therapy • Alternative treatment in mild hypercalcemia due to PHPT Alendronate • Given to patients w/ mild PHPT for 1-2 years • Increased bone density at the hip & lumbar spine but not radius • Studies showed 10 mg/day Alendronate eff ectively reverses bone loss in hyperparathyroidism Pamidronate • Most eff ective for acute treatment of hypercalcemia associated w/ PHPT • Given intravenously • Cannot be used as long-term treatment due to poor gastrointestinal drug absorption, PTH levels increases w/ increased renal tubular resorption & gastrointestinal calcium absorption Calcimimetic • Inhibits PTH secretion by activating calcium-sensing receptor in parathyroid gland • Used for poor surgical candidates to normalize serum calcium in patients w/ severe hypercalcemia • Preferred over bisphosphonates for patients who are unable to have surgery & whose primary indication for surgery is symptomatic &/or severe hypercalcemia w/ normal bone density Cinacalcet • Approved use in PHPT • Only approved calcimimetic for secondary hyperparathyroidism treatment • Used to treat hyperparathyroidism in ESRD patients on long-term dialysis • Oral administration peaks within 2-3 hours which lowers circulating PTH levels within the same period • Reduces serum calcium levels in PTCA patients particularly in unresectable diseases & those who underwent multiple operations without cure Vitamin D & Analogues • Aggressive supplementation is recommended for secondary hyperparathyroidism patients due to vitamin D defi ciency w/ normal renal function • Helps in suppression of the synthesis of PTH • Inhibits evolution of parathyroid hyperplasia • Adequate daily intake of 200 IU, 400 IU & 600 IU are recommended for adults up to 50 years, 51-70 years & ≥71 years respectively • For patients w/ vitamin D defi ciency, 50,000 IU weekly for 8 weeks or 3000 IU daily Vitamin D2 supplementation or 1000 IU daily Vitamin D3 is recommended • Caution must be observed as to high doses can lead to hypercalcemia • Vitamin© D analogues (Paricalcitol & Doxercalciferol)MIMS are less likely to cause hypercalcemia

Not all products are available or approved for above use in all countries. Specifi c prescribing information may be found in the latest MIMS.

B9 © MIMS 2019 Hyperparathyroidism (10 of 11)

C FOLLOW-UP

• Annual serum calcium, creatinine & eGFR assessment • 3-site dual energy x-ray absorptiometry scan should be done every 1-2 years • Bone mineral density assessment every 1-2 years in cases of chronic disorder • Radiograph or vertebral fracture assessment done in patients suspected w/ vertebral fracture (ie back pain, height loss) • 24-hour biochemical stone profi le done once indicated in suspected cases of renal nephrolithiasis or nephrocalcinosis HYPERPARATHYROIDISM • Abdominal imaging w/ radiography, CT or ultrasound is recommended in patients suspected w/ renal neph- rolithiasis or nephrocalcinosis

Dosage Guidelines

AGENTS AFFECTING BONE METABOLISM Drug Dosage Remarks

Alfacalcitriol Adjunct to tertiary hyperparathyroidism Adverse Reactions (alfacalcidol, management: • CV eff ects (cardiac arrhythmia, alpha-D3, Childn: hypertension); Dermatologic eff ects 1α-hy- Premature infants & neonates: (pruritus); Endocrine & metabolic droxyvit D3) 0.05-0.1 mcg/kg PO 24 hrly eff ects (decreased libido, hypercalcemia, hyperphosphatemia, <20 kg: 0.05 mcg/kg PO 24 hrly hypercholesterolemia, polydipsia, Adult: weight loss); GI eff ects (anorexia, Initial dose: 1 mcg PO 24 hrly constipation, dysgeusia, nausea, Maintenance dose: 0.25-1 mcg PO 24 hrly pancreatitis, vomiting, xerostomia); Elderly: 0.5 mcg PO 24 hrly GU eff ects (nocturia); CNS eff ects (headache, hyperthermia, drowsiness); Hepatic eff ects (increased serum ALT, increased serum AST); Ophthalmologic eff ects (conjunctivitis, corneal calcifi cation, photophobia); Resp eff ects (rhinorrhea) Special Instructions • Should be taken w/ food • Regular serum calcium monitoring while on treatment

©All dosage recommendations MIMS are for non-pregnant & non-breastfeeding women, & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. Not all products are available or approved for above use in all countries. Products listed above may not be mentioned in the disease management chart but have been placed here based on indications listed in regional manufacturers’ product information. Specifi c prescribing information may be found in the latest MIMS.

B10 © MIMS 2019 Hyperparathyroidism (11 of 11)

Dosage Guidelines

AGENTS AFFECTING BONE METABOLISM (CONT’D) Drug Dosage Remarks

Calcitriol Adult: Adverse Reactions Initial dose: 0.25 mcg PO 24-48 hrly, may • HYPERPARTHYROIDISM Dermatologic eff ects (skin rash); be increased by 0.25-1 mcg PO increments Endocrine & metabolic eff ects at 2-4 wkly intervals (polydipsia); GI eff ects (abdominal Usual dose: 0.5-1 mcg PO 24 hrly pain, nausea); Genitourinary eff ects Moderate to severe secondary hyper- (urinary tract infection); CNS eff ects parathyroidism in dialysis patient (headache) Initial dose: 0.5-4 mcg PO 3x/wk, may be Special Instructions increased by 0.25-1 mcg PO increments at • May be taken w/ or without food 2-4 wkly intervals • Take w/ food to minimize GI Max dose: 8 mcg PO 3x/wk discomfort • Plasma calcium monitoring while on treatment • Control plasma phosphate concentration while on treatment Paricalcitol Intact parathyroid hormone (iPTH) level Adverse Reactions ≤500 pg/mL: • Abdominal discomfort, acne, anorexia, 1 mcg PO/IV 24 hrly or 2 mcg PO/IV 3x breast tenderness, diarrhea, GI wkly disorders, hypercalcemia, iPTH level >500 pg/mL: hypocalcemia, rash 2 mcg PO/IV 24 hrly or 4 mcg PO/IV 3x Special Instructions wkly • May be taken w/ or without food • Monitor serum calcium levels

OTHER AGENTS AFFECTING METABOLISM Drug Dosage Remarks

Cinacalcet Initial dose: 30 mg PO 24 hrly Adverse Reactions Primary hyperparathyroidism: • CV eff ects (hypotension); Endocrine & Titrate every 2-4 wks through sequential metabolic eff ects (hypocalcemia, doses of 30 mg PO 12 hrly, 60 mg PO 12 hypercalcemia, dehydration, hrly, 90 mg PO 6-8 hrly as necessary to hypoparathyroidism); GI eff ects normalize serum calcium levels (abdominal pain, diarrhea, nausea, Secondary hyperparathyroidism in vomiting, anorexia, constipation); CNS chronic kidney disease patient on eff ects (headache, paresthesia, dialysis: depression, fatigue); Musculoskeletal eff ects (bone fracture, muscle spasm, Titrate every 2-4 wks through sequential weakness, myalgia); Respiratory eff ects doses of 30, 60, 90, 120 & 180 mg PO 24 (upper respiratory tract infection, hrly to target iPTH levels of 150-300 pg/mL cough, dyspnea) Special Instructions • Should be taken w/ food. Take shortly after meals • Swallow whole • Carefully monitor for hypocalcemia

All dosage recommendations are for non-pregnant & non-breastfeeding women, & non-elderly adults w/ normal renal & hepatic function unless otherwise stated. ©Not all products areMIMS available or approved for above use in all countries. Products listed above may not be mentioned in the disease management chart but have been placed here based on indications listed in regional manufacturers’ product information. Specifi c prescribing information may be found in the latest MIMS. Please see the end of this section for the reference list.

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