Calcium lecture for medical student 2015

Calcium lecture for medical student 2015
Atchara Charoenpiriya MD. Endocrinologist Maharaj Hospital

Outline of Topics Calcium homeostasis Hypercalcemia and Hypocalcemia
Definition Clinical features Causes of hypercalcemia/hypocalcemia Cases demonstration Treatment

Distribution of Calcium
Blood calcium 10 mgs/100 mls Total body calcium 1000 mg 99% in bone 1% in blood, body fluids and intracellular calcium Blood calcium mgs ( ) /100 mls Non diffusible 3.5 mgs Diffusible 6.5 mgs Non diffusible 3.5 mgs Albumin bound 2.8 mg Globulin bound 0.7 mgs Diffusible 6.5 mgs Ionized 5.3 mg Complexed mgs: bicarbonate,citrate,phosphate, other Close to saturation point: tissue calcification, kidney stones Endotext online textbook

Regulation of Calcium and Skeletal Metabolism
Mineral Calcium Phosphate Magnesium Organ Systems Skeletal Kidney GI tract Hormones Calcitropic hormones: PTH, calcitonin, vit D, PTHrP Other hormones: Gonadal and adrenal steroids, thyroid hormones Growth factors and cytokines Calcium Endotext online textbook

Calcium 0.5-1 % 99% Corrected Ca PTH and 1,25(OH)2D Acidosis Alkalosis
An algorithm to correct for protein changes adjusts the total serum calcium (in mg/dL) upward by 0.8 times the de.cit in serum albumin (g/dL) or by 0.5 times the de.cit in serum immunoglobulin (in g/dL). Acidosis also alters ionized calcium by reducing its association with proteins. Acidosis Alkalosis Total Ca mg/dL 50% ionized 50% จับกับ negatively charged proteins(albumin, Ig), phosphate, citrate, sulfate

CALCIUM IN SERUM Regulated within narrow limits; approx mg/dl Less than 50% is ionized. Majority of the rest is bound to albumin. 0.8 mg/dl Ca change for each 1 gm/dl change in albumin. Ionization decreases in alkaline pH

PHOSPHORUS ดูดซึมทาง GI
Present in skeleton as hydroxyappatite and widely distributed in macromolecules Normal serum levels mg/dl in adults. Solubility product determines relationship between Ca and PO4 G.I. absorption is efficient, primarily in jejunum Renal excretion is regulated by PTH ดูดซึมทาง GI (ไม่ต้องอาศัย vitamin Dถึง65% แต่ถ้ามี vitamin D จะดูดซึมเพิ่มขึ้น) ขับออก/ดูดซึมกลับทาง kidney 80% ของ inorganic phosphorus ดูดซึมกลับทาง proximal tubule ผ่านทาง type 2 sodium phosphate transporter (NaPi 2a) FGF 23 85% สะสมอยู่ที่กระดูก ECF ~ Intracellular

Control of Mineral Metabolism by Parathyroid Hormone
Low serum Ca sensed through CaSRs Increased Ca and Pi Bone resorption PTH 1,25(OH)2D 25(OH)D Increased Ca reabsorption, decreased Pi reabsorption Increased Ca into serum (normal range restore) Decreased Pi

PTH (1–34) = biologic actions of the molecule
Active amino-terminal sequence PTH 7-84 uremic pt PTH/PTHrP receptor or PTH1R; PTH, PTHrP PTH-2 Receptor; PTH only

Actions of PTH Increase Ca2+, decrease PO42- In bone In kidney
Bone resorption; releases Ca2+ and PO42- Bone formation if intermittent administration In kidney Increased Ca2+ reabsorption Decreased PO42- reabsorption Increased hydroxylation of vitamin D

Kidney Filtered calcium Thiazide;  Ca
65% ถูกดูดซึมกลับที่ proximal tubules 20% ถูกดูดซึมกลับที่ cTAL (ถูกยับยั้งผ่านทาง Ca (CaSR)) 10% ถูกดูดซึมกลับที่ DCT (thiazide ออกฤทธิ์) Thiazide;  Ca Lower urinary calcium excretion by blocking a NaCl transporter Dietary Na loads,  distal Na delivery จาก loop diuretics, saline infusion reduce DCT calcium reabsorption PTH, vitamin D

Vitamin D Ergocalciferol (Vit D2) พืช Cholecalciferal (Vit D3) สัตว์
(7-dehydrocholesterol) Granulomas of sarcoidosis, TB, berylliosis, lymphoma 1α-hydroxylase

Control of Mineral Metabolism by Vitamin D
25-OHase Pi, Ca and other factors D3 25-(OH)D Intestine Increase absorption of Ca and Pi D2 PTH 1α-OHase 1,25-(OH)2D Tumor microenvironment Inhibit proliferation Induce differentiation Inhibit angiogenesis Bone Increase bone mineralization Immune cells Induce differentiation

Actions of vitamin D Kidney Bone Small bowel Parathyroid gland
Decreased Ca2+ excretion Bone Increased bone resorption Small bowel Increased Ca2+ and PO42- absorption Parathyroid gland Suppress PTH transcription gene and parathyroid growth

Intestinal absorption of Ca 1. Active (transcellular) 20-70%
Vitamin D Intestinal absorption of Ca 1. Active (transcellular) 20-70% คุมโดย 1,25(OH)2D ดูดซึมที่ duodenum และ proximal jejunum 2. Passive (paracellular) 5% ดูดซึมดีต้องใช้กรดช่วย ถ้าไม่มีกรด เช่น Achlorhydria  Ca citrate ดูดซึมแย่ลงกรณี pancreatic/ biliary insuff. (จับกับfatty acid, อาหาร)

Causes of Impaired Vitamin D Action
Vitamin D deficiency Impaired cutaneous production Dietary absence Malabsorption Accelerated loss of vitamin D Increased metabolism (barbiturates, phenytoin, rifampin) Impaired enterohepatic circulation Impaired 25-hydroxylation Liver disease Isoniazid Impaired 1 α-hydroxylation Hypoparathyroidism Renal failure Ketoconazole 1 α -hydroxylase mutation Oncogenic osteomalacia X-linked hypophosphatemic rickets Target organ resistance Vitamin D receptor mutation Phenytoin

Calcitonin Calcitonin is a peptide hormone secreted by the parafollicular or “C” cells of the thyroid gland It is synthesized as the preprohormone & released in response to high plasma calcium Calcitonin acts on bone osteoclasts to reduce bone resorption. Net result of its action is a decline in plasma calcium & phosphate

Bone cell types There are three types of bone cells: Osteoblasts are the differentiated bone forming cells and secrete bone matrix on which Ca++ and PO precipitate. Osteocytes, the mature bone cells are enclosed in bone matrix. Osteoclasts is a large multinucleated cell derived from monocytes whose function is to resorb bone. Inorganic bone is composed of hydroxyapatite and organic matrix is composed primarily of collagen.

Osteoblast Produce bone matrix Osteoclast Resorb bone matrix

Control of Osteoblast Activity
PTH Osteoblast IGF-I, others proliferation Increased Osteoblast Number Increased synthesis Of bone matrix Mesenchymal Stem cells differentiation

Control of Osteoclast Activity
Marrow Precursors (-) OPG Osteoblast differentiation (+) RANK ligand RANK Increased Bone Resorption activation Osteoclast Precursor Calcitonin Active Osteoclast Inhibits directly

Bone Remodeling Process
Osteoclasts Lining Cells Resorption Cavities The bone remodeling process begins when the cells lining the bone surface are activated to form osteoclasts. Osteoclasts secrete acid, which dissolves the bone mineral, to form resorption cavities (pits). Osteoblasts are recruited to the resorbed bone and secrete osteoid matrix, which is comprised mainly of collagen. Over time, the osteoid matrix becomes mineralized to form bone. Lining Cells Mineralized Bone Osteoblasts Osteoid Osteocyte Mechanosensor

The cycle of bone remodeling is carried out by the basic multicellular unit (BMU), comprising a group of osteoclasts and osteoblasts.

Principle Cells Regulating Bone Metabolism
Osteoblasts Bone forming cells derived from fibroblasts Synthesize and secrete collagen and other matrix proteins Synthesize and secrete alkaline phosphatase Govern bone mineral deposition Osteoclasts Bone resorbing cells derived from bone marrow cells (macrophages) Synthesize bone acid phosphatase Govern release of mineral from the skeleton

Hormonal control of bones

Hypercalcemia

Diagnostic approach of Hypercalcemia
Serum Ca History and PE Check blood draw technique, avoid venous stasis, and repeat serum Ca and check albumin or normal PTH Non PTH related PTH related Malignancy Vit D, A intoxication Granulomatous dis. Lytic bone Milk alkali Immobilization Adrenal insuff, hyperthyroidism Thiazide 1o hyperparathyroidism 3o hyperparathyroidism FHH Lithium Consider MEN I, IIA FHH =familial hypocalciuric hypercalcemia MEN =multiple endocrine neoplasia

Non PTH related PTH-rP Yes Solid tumor No  or normal cholecalciferol
High calcidiol (25OH VitD) High calcitriol (1,25 (OH)2 Vit D) Lytic bone, milk alkali, vit A toxicity, thiazide, aminophylline, estrogen, tamoxifen, thyrotoxicosis, pheochromocytoma, adrenal insuff, immobilization Granulomatous disease, malignant lymphoproliferative disease, vit D overdose Vit D overdose

Classification of Causes of Hypercalcemia
I. Parathyroid-related A. Primary hyperparathyroidism 1. Solitary adenomas 2. Multiple endocrine neoplasia B. Lithium therapy C. Familial hypocalciuric hypercalcemia II. Malignancy-related A. Solid tumor with metastases (breast) B. Solid tumor with humoral mediation of hypercalcemia (lung, kidney) C. Hematologic malignancies (multiple myeloma, lymphoma, leukemia) III. Vitamin D–related A. Vitamin D intoxication B. 1,25(OH)2D; sarcoidosis and other granulomatous diseases C. Idiopathic hypercalcemia of infancy IV. Associated with high bone turnover A. Hyperthyroidism B. Immobilization C. Thiazides D. Vitamin A intoxication V. Associated with renal failure A. Severe secondary hyperparathyroidism B. Aluminum intoxication C. Milk-alkali syndrome

1oHyperparathyroidism
80 % asymptomatic 20 % symptomatic 1% population 2% after 55yrs ♀>♂ 2-3:1 Etiology Solitary adenoma (rare; carcinoma) Hyperplasia; MEN1, MEN2A Hereditary hyperparathyroidism jaw tumor syndrome Familial isolated primary hyperparathyroidism Stones,Bones, moans, groans and tones

Hypercalcemia GI Neuromuscular -Constipation memory
-Nausea/vomiting -Constipation -Anorexia, wt. loss -Pancreatitis -Recurrent PU Neuromuscular -Impaired concentration, memory -Lethargy/ fatigue -Confusion-coma Renal stone -Nephrolithiasis -Nephrocalcinosis -Nephrogenic DI -Dehydration Hypercalcemia Skeleton -Bone pain, arthritis -Osteoporosis -Osteitis fibrosa cystica (in primary hyperparathyroidism) CVS -Hypertension -Shortened QT -Cardiac arrhythmia Others -Itching -Band keratopathy

Cystic brown tumors Sub-periosteal resorption

Tooth : loss of lamina dura
Clavicular resorption Skull : salt and pepper appearance Osteoporosis : compression fracture ofspine Tooth : loss of lamina dura

Hypercalcemia Extremely short QT interval and near loss of the ST segment…

Diagnosis High Ca Inappropriate  PTH DDx lithium therapy
Familial hypocalciuric hypercalcemia Family history of mild hypercalcemia (AD); abnormal CaSR Usual onset in young adulthood (<10 years old) Ratio of urinary calcium/urinary cr < 0.01 Tertiary hyperparathyroidism FHH involves excessive secretion of PTH, whereas Jansen’s disease is caused by excessive biologic activity of the PTH receptor in target tissues. CaSR = Calcium sensing receptor

Primary hyperparathyroidism
80-85% single parathyroid adenoma 15-20% hyperplasia < 0.5% carcinoma Standard surgical approach Exploration of all four parathyroid glands under general anesthesia Preoperative localization Ultrasonography Technetium-labeled sestamibi, with or without single-photon-emission CT In case of surgical failure or previous neck surgery or to identify the rare mediastinal parathyroid Adenomas are most often located in the inferior parathyroid glands, but in 6 to 10% of patients, parathyroid adenomas may be located in the thymus, the thyroid, the pericardium, or behind the esophagus.

After the removal of the parathyroid gland
Intraop. PTH If ↓ >50%, gland that has been well removed. If does not decrease by more than 50 %, the operation is extended to a more traditional one in a search for other overactive parathyroid tissue. Half life of PTH is 3-4 min. In hyperplasia, Remove 3 and ½ glands (subtotal) Total parathyroidectomy followed by autotransplantation of gland fragments in forearm

Postop. complication Hypoparathyroidism Hungry bone syndrome
Low PTH, normal to high phosphatemia More likely if all glands were removed May be transient or permanent Hungry bone syndrome Normal PTH, low phosphatemia Due to rapid deposition of calcium and phosphate into bone

Postremoval Serum and urinary Ca return to normal.
Rate of recurrence of kidney stones has been reduced by more than 90% after parathyroid surgery. Over a period of 3-4 yrs, Bone density improves, with the lumbar spine and hip regions typically showing increases of 12-14% without the need of antiresorptive therapy. Increases in bone density at vertebral spine can approach 20%. The density of the distal 1/3 radius changes little. No effect of parathyroidectomy for BP and renal impairment

FHH Inactivating mutation of Calcium sensor:
Parathyroid cell: higher serum Ca needed to shut off PTH secretion Renal tubular cell: increase urinary Ca reabsorption Autosomal dominant inheritance Homozygous: severe neonatal hypercalcemia Heterozygotes: asymptomatic mild hypercalcemia Distinguish HPT from FHH by FECa FHH: FECa < 0.01 HPT: FECa > Autosomal dominant hypocalcemia Activating mutation of Ca sensor Mirror image of FHH

FECa: Fractional Excretion Ca
FECa = CaU x CreatS CreatU x CaS CaU: urine Ca (mmol/d) CaS: serum Ca (mmol/L) CreatS: serum creatinine (mmol/L) CreatU: urine creat (mmol/d)

Malignancy related hypercalcemia
1.Humoral hypercalcemia of malignancy PTHrP Squamous cell CA lung, H&N, urogenital tract RCC, CA breast, pheo, carcinoid 2. Direct marrow invasion Leukemia, lymphoma, MM, metas.CA breast Osteoclast activating factor 3. 1,25(OH)2D B cell lymphoma 1α-hydroxylase 4. Ectopic PTH; very rare พบใน sarcoidosis, granulomatous dz Rx glucocorticoid

Other causes of hypercalcemia
Vitamin A intoxication Ingestion of vitamin A > 50, ,000 unit/d Vitamin D intoxication Ingestion of vitamin D > 50, ,000 unit/d 25(OH)D > 100 ng/mL Vitamin D stores in fat and vitamin D intoxication may persist for weeks after vitamin D ingestion is terminated. Immobilization Children, adolescents Paget’s disease Rx Steroid

Milk-Alkali Syndrome Excessive ingestion of calcium and absorbable antacids such as milk or calcium carbonate. Clinical presentations Acute, subacute, chronic Hypercalcemia, alkalosis, renal failure. The chronic form, termed Burnett’s syndrome The acute syndromes reverse if the excess calcium and absorbable alkali are stopped. The cycle of mild hypercalcemia Bicarbonate retention alkalosis renal calcium retention severe hypercalcemia

Treatment

Hypocalcemia

Definition of Hypocalcemia
Serum calcium < 8.5 mg/dL Albumin-corrected total Ca = measured total Ca (4.0−serum albumin)

Clinical Features Associated With Hypocalcemia
Neuromuscular inability Chvostek’s sign Endotext online textbook

Chvostek’s sign A = Chvostek I phenomenon B = Chvostek II phenomenon
0.5-1cm Grade 1-Twitching of the angle of the mouth Grade 2 -Additional twitching of the alae nasi Grade 3-Contraction of the orbicularis oculi Grade 4-Hemifacial contraction 2 cm Positive Chvostek’s sign ~ 25% of healthy individuals.

Neuromuscular inability Chvostek’s sign Trousseau’s sign Endotext online textbook

Trousseau’s sign 10 mmHg above SBP 3 minutes
Carpopedal spasm occurring after a few minutes of inflation of a sphygmomanometer cuff above systolic blood pressure. 10 mmHg above SBP 3 minutes Flexion of the wrist and MCP jts, hyperextension of the fingers, and flexion of the thumb on the palm

Neurological signs and symptoms Extrapyramidal sign Calcification of cerebral cortex or cerebellum Personality disturbance Irritability Impaired intellectual ability Nonspecific EEG changes Increase intracranial pressure Parkinsonism Choreoathetosis Dystonia spasm Neuromuscular inability Chvostek’s sign Trousseau’s sign Paresthesias Tetany Seizures (focal, petit mal, grand mal) Fatigue Anxiety Muscle cramps Polymyositis Laryngeal spasm Bronchial spasm Endotext online textbook

Ectodermal changes Dry skin Coarse hair Brittle nails Alopecia Enamel hypoplasia Shortened premolar roots Thickened lamina dura Delayed tooth eruption Increased dental caries Atopic eczema Exfoliative dermatitis Psoriasis Impetigo herpetiformis Mental status Confusion Disorientation Psychosis Psychoneurosis Smooth muscle involvement Dysphagia Abdominal pain Biliary colic Dyspnea Wheezing Endotext online textbook

Opthalmologic manifeatations Subcapsular cataracts Papilledema Cardiac Prolonged QT interval in EKG Congestive heart failure Cardiomyopathy Endotext online textbook

Causes of Hypocalcemia
Parathyroid-related Disorders Vitamin D-related disorders Other Causes Williams Textbook of Endocrinology, 11th edition

Parathyroid-related Disorders Absence of the parathyroid glands or of PTH: - Congenital: DiGeorge’s syndrome, X-linked or autosomally inherited hypoparathyroidism , Autoimmune polyglandular syndrome type I , PTH gene mutations - Postsurgical hypoparathyroidism - Infiltrative disorders: Hemochromatosis, Wilson’s disease, Metastases - Hypoparathyroidism following 131I ablation Impaired secretion of PTH: - Hypomagnesemia, Respiratory alkalosis , Activating mutations of the calcium sensor Target organ resistance: - Hypomagnesemia, Pseudohypoparathyroidism Williams Textbook of Endocrinology, 11th edition

Vitamin D-related Disorders Vitamin D deficiency: Dietary absence, Malabsorption Accelerated loss: Impaired enterohepatic recirculation, Anticonvulsant medications Impaired 25-hydroxylation: Liver disease , Isoniazid Impaired 1-hydroxylation Renal failure Vitamin D–dependent rickets type I Oncogenic osteomalacia Target organ resistance Vitamin D–dependent rickets type II, Phenytoin Williams Textbook of Endocrinology, 11th edition

Other Causes Excessive deposition into the skeleton: Osteoblastic malignancies , Hungry bone syndrome Chelation: Foscarnet, Phosphate infusion, infusion of citrated blood products, Infusion of EDTA-containing contrast reagents, Fluoride Neonatal hypocalcemia: Prematurity, Asphyxia, Diabetic mother , Hyperparathyroid mother HIV infection: Drug therapy, Vitamin D deficiency, Hypomagnesemia, Impaired PTH responsiveness Critical illness: Pancreatitis, Toxic shock syndrome, Intensive care unit patients Williams Textbook of Endocrinology, 11th edition

Evaluation History a history of neck surgery: surgical hypoparathyroidsm a family history of hypocalcemia: suggests a genetic cause presence of other autoimmune endocrinopathies (e.g., adrenal insufficiency) or candidiasis: autoimmune polyendocrine syndrome type 1. Immunodeficiency and other congenital defects: DiGeorge syndrome N Engl J Med 2008, 359;4:

Genetic Syndromes and Other Inherited Forms of Hypoparathyroidism
Familial hypocalcemia with hypercalciuria(AD) Familial isolated hypoparathyroidism (AD/AR) X-linked hypoparathyroidism Autoimmune polyendocrine syndrome type 1 (APS-1) Syndrome of hypoparathyroidism, deafness, and renal anomalies Syndrome of hypoparathyroidism, growth and mental retardation and dysmorphism DiGeorge, or velocardiofacial syndrome Mitochondrial disorders with hypoparathyroidism N Engl J Med 2008, 359;4:

Genetic Abnormalities and Hereditary Hypoparathyroidism
Isolated Polyglandular autoimmune syndrome DiGeorge syndrome, or the velocardiofacial syndrome Defective development of both the thymus and the parathyroid glands Autosomal dominant hypocalcemia Gain-of-function of CaSR (ตรงข้ามกับ FHH) Kearns-Sayre syndrome Ophthalmaplegia and pigmentary retinopathy MELAS syndrome mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes

Evaluation Physical Examination
assessment of neuromuscular irritability by testing for Chvostek’s and Trousseau’s signs a neck scar: postsurgical cause of hypocalcemia candidiasis and vitiligo: APS-1 generalized bronzing and signs of liver disease: hemochromatosis growth failure, congenital anomalies, hearing loss, or retardation: genetic disease. N Engl J Med 2008, 359;4:

Evaluation Laboratory testing serum total and/or ionized calcium
albumin phosphorus magnesium creatinine intact PTH 25-hydroxyvitamin D (25[OH]vitamin D) levels N Engl J Med 2008, 359;4:

Causes of Hypocalcemia Serum concentrations of markers
PTH ALP Phosphate 25-(OH)D Commom Postsurgical hypoparathyroidism L N H Autoimmune hypyoparathyroidism Vitamin D deficiency N or H Renal disease N or L Rare Parathyroid hormone resistance Vitamin D resistance Autosomal dominant hypocalcemia Hypomagnesemia Sclerotic metastasis Other Hungry bone syndrome, critical illness, intravenous bisphosphonate BMJ 2008, 336;

Algorithm for requesting investigations to elucidate the cause of hypocalcemia
Low or normal High Low Normal Low BMJ 2008, 336;

CASE 1 24 years old man Present at emergency department with a complaint of progressive muscle cramping, circumoral numbness and paresthesias for 3 days. Diarrhea 3 days ago. Past history of papillary CA thyroid with lymph node metastasis, post total thyroidectomy and 131I ablation Current medicine: Eltroxin (0.1µg) 2x1 oral ac CaCO3 (1250) 1×3 oral pc

Physicalc exmination - Neck scar - Chvostek’s signs is positive. - Carpopedal spasm ECG:

Diagnosis Severe symptomatic hypocalcemia Acute diarrhea
Papillary CA thyroid with lymph node metastasis post total thyroidectomy and 131I ablation

Laboratory Hypoparathyroidsm BUN/Cr 13/1.1 mg/dL
Na 141 mmol/L K 2.87 mmol/L Cl 99 mmol/L CO mmol/L Ca 4.2 mg/dL PO4 7.3 mg/dL Mg 1.8 mg/dL alb 4.1 g/dL ALP 66 U/L Hypoparathyroidsm

Postsurgical hypoparathyroidism
Permanent postsurgical hypoparathyroidism: - insufficient PTH to maintain normocalcemia 6 months after surgery % of total thyroidectomies The occurrence of hypoparathyroidism depend on: - the surgeon’s experience - extent of thyroid resection and nodal dissection for cancer - underlying thyroid disease: with the presence of substernal goiter, cancer, or Graves’ disease increasing the risk. - one or more parathyroid glands are not identified intraoperatively - the procedure is a reoperation N Engl J Med 2008, 359;4:

Vitamin D Calcium Other agents Management

Acute Management Agent Formulation and dose Comments Calcium gluconate
1g of calcium gluconate (10 ml of solution/ 93 mg of elemental calcium); dilute with ml of 5% dextrose in water; infuse 1 or 2 g slowly, each over a period of 10 min. Followed by a slow infusion of calcium; 10 g of calcium gluconate in 1 liter of 5 % dextrose in water, infused at a rate of (1-3) mg/kg of BW/ hr. -with ECG and clinical monitoring - Injection of calcium gluconate will increase the serum calcium level for only 2 or 3 h N Engl J Med 2008, 359;4:

Acute Management Agent Monitor therapy Calcium gluconate
- The serum calcium level should be measured frequently in order to monitor therapy (e.g., every 1 to 2 hr initially) while the infusion rate is being adjusted and until the patient’s condition has stabilized, and then every 4 hr. - Intravenous infusions are generally tapered slowly (over a period of 24 to 48 hr or longer) while oral therapy is adjusted. N Engl J Med 2008, 359;4:

Long-term Management Calcium salts Agent Formulation and dose Comments
Calcium carbonate - 40% elemental Ca by weight - begin with 500–1000 mg of elemental calcium; at least 1–2 g of elemental Ca(3 times/d) generally required - constipation - best absorbed with meals and with acid present in the stomach Calcium citrate - 21% elemental Ca by weight - patients with achlorhydria, taking a proton-pump inhibitor N Engl J Med 2008, 359;4:

Long-term Management Vitamin D metabolites Agents dose Time to
onset of action offset of Comments Vitamin D2 or vitamin D3 25, ,000 IU once daily 10-14 d 14-75 d Dose adjustment every 4 wk 1,25-dihydroxy vitamin D3 (calcitriol) µg, 1-2 time/d 1-2 d 2-3 d Most active metabolite of vitamin D 1α-hydroxyvitamin D3 (alfacalcidiol) 0.5–3.0 μg (5μg) once daily 5-7 d Rapidly convert to 1,25(OH)D3 Dihydrotachysterol 0.2–1.0 mg once daily 4-7 d 7-21 d N Engl J Med 2008, 359;4:

Long-term Management Thiazide diuretics
Added to prevent or control hypercalciuria; combined with a low-salt diet ( Na=80–100 mmol/d) to promote calcium retention Doses are increased as tolerated Adverse events include: hypokalemia and hyponatremia Agents dose Comments Hydrochlorothiazide 25–100 mg per day Doses at high end of these ranges are usually needed Amiloride and hydrochlorothiazide (Moduretic) 50 mg of hydrochlorothiazide combined with 5 mg of amiloride Potassium-sparing diuretics may be used to prevent hypokalemia N Engl J Med 2008, 359;4:

The goals of therapy Serum calcium: 8-8.5 mg/dL
A 24 hr urinary calcium level: below 300 mg/day A calcium-phosphate product: below 55 Annual slit-lamp and opthalmoscopic examinations N Engl J Med 2008, 359;4:

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