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Endocrinology

Calcium and Phosphate Disorders

~15 min read8 sections

calcium phosphate PTH vitamin D

⭐ High-yield 🎯 Drill Endocrinology

Contents (8)

Overview
Pathophysiology
Etiology & Risk Factors
Clinical Presentation
Diagnosis
Treatment
Complications
High-Yield Pearls

High-Yield Pearls

Measure intact PTH first in any hypercalcemia: this single test splits the differential into PTH-dependent (primary hyperparathyroidism, FHH, lithium) and PTH-independent (malignancy, granuloma, vitamin D). It is the most commonly tested "next best step."
Outpatient vs inpatient rule: asymptomatic hypercalcemia found on routine labs in a well outpatient is primary hyperparathyroidism; symptomatic hypercalcemia of rapid onset in a sick, weight-losing patient is malignancy. Together they account for the large majority of cases.
The FHH trap: a young patient with lifelong mild hypercalcemia, a family history, PTH high-normal, and a urine calcium-to-creatinine clearance ratio <0.01 has an inactivating CaSR mutation. Parathyroidectomy is the wrong answer — it is benign and requires no treatment.
Check magnesium in refractory hypocalcemia: hypomagnesemia (alcoholism, PPIs, diarrhea, cisplatin) blocks both PTH release and renal PTH action. Calcium will not correct until magnesium is replaced.

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Calcium and phosphate homeostasis represents one of the most tightly regulated physiologic processes, maintained through the integrated actions of parathyroid hormone (PTH), calcitriol (1,25-dihydroxyvitamin D3), and renal and gastrointestinal mechanisms. Hypocalcemia and hyperkalemia occur with significant frequency in both ambulatory and hospitalized settings and carry substantial morbidity if not recognized and treated promptly. These disorders affect multiple organ systems—including the nervous system (neuromuscular excitability), cardiovascular system (arrhythmias, contractility), skeletal system (mineralization, bone turnover), and metabolism—making their recognition essential for clinical practice. The prevalence of calcium disorders in hospitalized patients approaches 15-20%, while phosphate abnormalities are common in chronic kidney disease and critical illness. Mastery of calcium-phosphate physiology is fundamental for the USMLE Step 2 CK examination and for competent clinical management across multiple specialties.

Calcium Homeostasis and PTH Regulation

The body contains approximately 1000-1200 g of calcium, with 99% stored in the skeleton as hydroxyapatite. However, only ~2.5 mmol/L circulates in plasma, existing in three forms: ionized calcium (physiologically active, ~45%), protein-bound calcium (primarily albumin-bound, ~40%), and complexed calcium (with citrate and phosphate, ~15%). The ionized calcium concentration is the physiologically relevant form and is tightly maintained between 4.5-5.3 mg/dL through negative feedback regulation by the calcium-sensing receptor (CaSR) on the parathyroid gland. When serum ionized calcium decreases by even 2-3%, the CaSR detects this change and triggers rapid secretion of PTH, which acts through three primary mechanisms: (1) stimulation of renal 1α-hydroxylase to increase calcitriol production, which enhances intestinal calcium absorption and mobilizes skeletal calcium; (2) direct stimulation of osteoclast-mediated bone resorption through osteoblast PTH receptor activation; and (3) increased renal tubular calcium reabsorption in the distal convoluted tubule and collecting duct while simultaneously increasing urinary phosphate excretion. This PTH-mediated correction typically restores normocalcemia within hours to days.

Phosphate Homeostasis and FGF23

Serum phosphate (normal 2.5-4.5 mg/dL) is regulated primarily by renal excretion under the control of FGF23 (fibroblast growth factor 23), a bone-derived phosphaturic hormone, and PTH. Approximately 80% of filtered phosphate is normally reabsorbed in the proximal tubule via sodium-phosphate cotransporters (NPT2a and NPT2c); PTH and FGF23 decrease expression of these transporters, increasing urinary phosphate excretion. When serum phosphate rises, FGF23 secretion increases to promote urinary phosphate wasting and simultaneously suppresses calcitriol production (reducing intestinal phosphate absorption). FGF23 requires α-klotho as a coreceptor for cellular signaling; thus, chronic kidney disease patients develop resistance to FGF23 as klotho becomes depleted, leading to hyperphosphatemia and secondary hyperparathyroidism. The interconnected regulation of calcium and phosphate is critical: hyperphosphatemia itself stimulates PTH secretion and increases FGF23 production, creating a complex feedback loop.

Vitamin D Metabolism and Calcitriol Synthesis

Vitamin D is obtained from dietary sources and skin synthesis via UVB exposure, where 7-dehydrocholesterol is converted to cholecalciferol (vitamin D3). In the liver, vitamin D3 undergoes 25-hydroxylation to form 25-hydroxyvitamin D [25(OH)D], which is the major circulating form and best indicator of total body vitamin D stores (normal 30-100 ng/mL). The renal 1α-hydroxylase then converts 25(OH)D to the active 1,25-dihydroxyvitamin D [calcitriol], which is tightly regulated by PTH (stimulation), FGF23 (inhibition), and serum calcium and phosphate. Calcitriol acts on the vitamin D receptor (VDR) in intestinal epithelial cells to increase expression of calcium-binding protein and apical calcium channels (TRPV5), enhancing intestinal calcium absorption from ~30% to >80% in vitamin D-replete states. Loss of functional renal tissue (as in chronic kidney disease) profoundly impairs calcitriol synthesis, leading to secondary hyperparathyroidism and mineral bone disease.

Mechanisms Driving Hypocalcemia

Hypocalcemia results from one or more of four fundamental mechanisms: (1) decreased PTH secretion or action (hypoparathyroidism, pseudohypoparathyroidism with end-organ resistance); (2) decreased calcitriol synthesis, occurring in chronic kidney disease, vitamin D deficiency, vitamin D-dependent rickets, or acquired conditions blocking 1α-hydroxylase (granulomatous diseases, FGF23-producing tumors); (3) decreased intestinal calcium absorption due to vitamin D deficiency, malabsorption, or dietary insufficiency; and (4) increased urinary calcium losses or sequestration, as seen in acute phosphate administration (complexation), massive blood transfusions with citrate, or EDTA chelation. In severe acute hypocalcemia, calcium shifts into the intracellular space or becomes sequestered in tissues (pancreatitis with fat necrosis, rhabdomyolysis with muscle necrosis), creating a functional deficit despite total body calcium depletion.

Mechanisms Driving Hypercalcemia

Hypercalcemia arises from excessive intestinal calcium absorption, increased bone resorption, or decreased renal excretion. PTH-mediated hypercalcemia occurs when autonomous parathyroid tissue secretes PTH independent of serum calcium feedback (primary hyperparathyroidism) or when there is tertiary hyperparathyroidism in chronic kidney disease patients after renal transplantation. Non-PTH-mediated hypercalcemia results from PTHrP (parathyroid hormone-related peptide) secretion by malignancies, which activates the PTH1 receptor in kidneys and bone, mimicking PTH effects but bypassing normal feedback control; from calcitriol overproduction by activated macrophages in granulomatous diseases (tuberculosis, sarcoidosis, histoplasmosis, coccidioidomycosis, berylliosis); or from osteoclast-activating factors (lymphokines, TNF-α, IL-6) produced by lymphoid malignancies (multiple myeloma, lymphomas). Thyroid hormone excess increases bone turnover and calcium mobilization, while vitamin A intoxication and vitamin D intoxication directly increase intestinal calcium absorption and bone resorption. Immobilization in young patients increases bone resorption acutely.

Phosphate Homeostasis Dysregulation

Hyperphosphatemia develops when renal excretion cannot match intake, occurring in acute kidney injury, chronic kidney disease (where GFR <15 mL/min), tumor lysis syndrome (massive phosphate release from dying cells), rhabdomyolysis, and severe hemolysis. Hyperphosphatemia itself is harmful: it binds ionized calcium, decreasing bioavailable calcium and stimulating PTH and FGF23 secretion; it promotes vascular calcification through loss of inhibitors (fetuin-A, MGP); and it drives secondary hyperparathyroidism. Hypophosphatemia (serum phosphate <2.0 mg/dL) causes impaired ATP production, decreased red blood cell 2,3-DPG (impairing oxygen delivery), and muscle weakness. Causes include malnutrition, alcoholism (with refeeding syndrome), hyperparathyroidism (PTH-driven urinary phosphate wasting), FGF23-producing tumors (oncogenic osteomalacia), hypophosphatemic rickets, and medications (phosphate binders, diuretics, corticosteroids).

Phosphatonin Axis and FGF23 Pathophysiology

In healthy individuals, serum phosphate rises slightly after meals, stimulating FGF23 secretion from osteocytes. FGF23 acts on klotho-expressing cells in the proximal tubule to reduce NPT2a expression, increasing urinary phosphate excretion and restoring normophosphatemia. FGF23 also inhibits 1α-hydroxylase and stimulates 24-hydroxylase, decreasing calcitriol production. In chronic kidney disease, progressive loss of nephrons leads to increased serum phosphate that stimulates more FGF23; additionally, declining klotho expression impairs FGF23 signaling, creating a vicious cycle. Genetic disorders of phosphate wasting (X-linked hypophosphatemic rickets, PHEX mutations; autosomal hypophosphatemic rickets, FGF23 mutations) demonstrate the critical role of the phosphatonin axis in skeletal health.

Hypocalcemia Etiologies

Hypoparathyroidism (Decreased PTH Production): Post-surgical hypoparathyroidism is most common, occurring after thyroid or parathyroid surgery due to parathyroid gland trauma or inadvertent removal. Autoimmune polyendocrine syndrome (APS-1) presents with autoimmune destruction of parathyroid tissue, often accompanied by Addison's disease and candidiasis. Infiltrative diseases (sarcoidosis, lymphoma, tuberculosis, hemochromatosis) can destroy parathyroid tissue. DiGeorge syndrome (22q11 deletion) involves parathyroid hypoplasia. Activating mutations of the calcium-sensing receptor (CaSR) cause autosomal dominant hypocalcemia, where the parathyroid glands "sense" lower set-point calcium and suppress PTH despite low serum calcium.

Pseudohypoparathyroidism (PTH Resistance): Type 1A is characterized by end-organ resistance to PTH due to GNAS mutations affecting Gs alpha protein signaling; patients present with high PTH levels but low-normal calcium and elevated phosphate. Short stature, round facies, subcutaneous ossifications, and brachydactyly are characteristic features (Albright hereditary osteodystrophy). Type 1B involves isolated renal resistance to PTH without the phenotypic features.

Vitamin D Deficiency: Inadequate sunlight exposure, dietary deficiency, malabsorption (celiac disease, Crohn's disease, cystic fibrosis, post-bariatric surgery), and dietary restrictive disorders are common causes. 25(OH)D <20 ng/mL indicates deficiency; <30 ng/mL indicates insufficiency.

Vitamin D-Dependent Rickets Type 1 (VDDR-1): Autosomal recessive mutation in 1α-hydroxylase (CYP27B1) prevents calcitriol synthesis. Presents with hypocalcemia, severe hypophosphatemia, elevated alkaline phosphatase, and rickets in infancy. PTH is markedly elevated. Responsive to calcitriol replacement.

Vitamin D-Dependent Rickets Type 2 (VDDR-2): Autosomal recessive vitamin D receptor (VDR) mutations cause end-organ resistance; patients have hypocalcemia, elevated calcitriol, and elevated PTH—the opposite biochemical pattern of VDDR-1. Alopecia is a characteristic feature. Unresponsive to calcitriol; may require supraphysiologic doses.

Chronic Kidney Disease and Secondary Hyperparathyroidism: Loss of functioning renal tissue impairs 1α-hydroxylase activity, decreasing calcitriol synthesis. Hyperphosphatemia and low calcitriol both stimulate PTH. Fibroblast growth factor 23 becomes elevated but signaling is impaired due to loss of klotho. Patients develop mineral bone disease with tertiary hyperparathyroidism developing over years.

Acute Phosphate Loading: Rapid IV phosphate administration, tumor lysis syndrome, or massive cellular breakdown (rhabdomyolysis, hemolysis) releases intracellular phosphate. Hyperphosphatemia complexes with calcium, reducing ionized calcium acutely.

Citrate-Induced Hypocalcemia: Rapid blood transfusion or fresh frozen plasma infusion introduces citrate (anticoagulant), which binds calcium, reducing ionized calcium. Hypothermia impairs citrate metabolism. Liver disease reduces citrate clearance.

Pancreatitis and Fat Necrosis: Acute pancreatitis causes release of pancreatic lipase into interstitial tissue, promoting saponification (fatty acid-calcium complexes) that sequesters calcium in the pancreatic bed and surrounding tissues. Hypocalcemia typically develops 2-3 days after onset.

Hypomagnesemia: Magnesium is required for normal PTH secretion and renal responsiveness to PTH. Hypomagnesemia (Mg <1.5 mg/dL) impairs both PTH release and PTH action at the kidney, causing refractory hypocalcemia. Must be corrected before calcium supplementation is effective. Common causes include diuretics, diarrhea, alcoholism, and medications (proton pump inhibitors, bisphosphonates).

Hypercalcemia Etiologies

Primary Hyperparathyroidism: Autonomous PTH secretion from parathyroid adenoma (~80% of cases), hyperplasia (~10%), or carcinoma (~1-2%). Most common outpatient cause of hypercalcemia. Often asymptomatic and detected on routine labs. Associated with PTH >65 pg/mL and elevated 1,25-dihydroxyvitamin D despite high calcium.

Malignancy (PTHrP-Mediated): Non-small cell lung cancer, breast cancer, ovarian cancer, and renal cell carcinoma commonly produce PTHrP. Creates a PTH-like biochemical picture (high calcium, low phosphate, high 1,25-OH vitamin D) but with PTH level suppressed and PTHrP elevated. Typically presents with symptomatic hypercalcemia and acute onset.

Granulomatous Diseases: Sarcoidosis is the most common; activated macrophages produce 1α-hydroxylase, converting 25(OH)D to calcitriol, causing hypercalcemia and hypercalciuria. Tuberculosis, histoplasmosis, coccidioidomycosis, berylliosis, and Crohn's disease are additional causes. Hypercalcemia persists despite normal PTH (suppressed by feedback) and elevated calcitriol.

Vitamin D Intoxication: Excessive supplementation or fortified milk intake can raise 25(OH)D to >150 ng/mL, overwhelming normal metabolism and causing hypercalcemia. Calcitriol is inappropriately elevated.

Vitamin A Intoxication: Chronic ingestion of retinoids (isotretinoin for acne, excessive supplementation) or acute toxicity causes osteoclast activation and hypercalcemia. Associated with hypervitaminosis A signs (dry skin, alopecia, pseudotumor cerebri).

Thyrotoxicosis: Excess thyroid hormone increases bone turnover and calcium mobilization acutely. TSH is suppressed; thyroid function tests confirm diagnosis.

Immobilization: Young patients with high bone turnover (fracture, spinal cord injury, prolonged immobilization) develop acute hypercalcemia due to uncoupling of bone formation from resorption. Risk factors include young age, normal or elevated PTH, and elevated 1,25-OH vitamin D.

Lymphoid Malignancies (PTHrP and Lymphokine Production): Multiple myeloma, Hodgkin lymphoma, and non-Hodgkin lymphoma produce lymphokines (IL-6, TNF-α, lymphotoxin) that activate osteoclasts. Myeloma may also produce PTHrP.

Thiazide Diuretics: Decrease urinary calcium excretion by volume depletion and enhanced proximal tubule reabsorption, unmasking mild hyperparathyroidism or increasing calcium in hypercalcemic states.

Tertiary Hyperparathyroidism: After renal transplantation, previously suppressed parathyroid glands may not respond to restoration of normal calcium, leading to autonomous PTH secretion and hypercalcemia despite normal renal function.

Acute Severe Hypocalcemia (<7 mg/dL with symptoms)

**Par

Step 1 — confirm the true calcium

Corrected calcium: add ~0.8 mg/dL to total calcium for every 1 g/dL that albumin falls below 4 g/dL. Hypoalbuminemia (cirrhosis, nephrosis, critical illness) lowers total but not ionized calcium — pseudohypocalcemia.
Ionized calcium: the confirmatory test whenever albumin, pH, or protein binding is deranged (alkalosis increases albumin binding and causes symptomatic hypocalcemia with normal total calcium; myeloma paraprotein causes the reverse).
Always pair with magnesium and phosphate: hypomagnesemia produces functional hypoparathyroidism and hypocalcemia refractory to calcium alone.

Step 2 — intact PTH is the branch point (Endocrine Society and AACE approach)

Hypercalcemia with high or inappropriately normal PTH: PTH-dependent — primary hyperparathyroidism, lithium, or familial hypocalciuric hypercalcemia. Distinguish with a 24-hour urine calcium-to-creatinine clearance ratio: <0.01 favors FHH, >0.02 favors primary hyperparathyroidism.
Hypercalcemia with suppressed PTH: measure PTHrP (solid tumors), 1,25-(OH)₂D (granulomatous disease, lymphoma), 25(OH)D (vitamin D intoxication), SPEP/free light chains (myeloma), TSH.
Hypocalcemia with low or inappropriately normal PTH: hypoparathyroidism (post-surgical, autoimmune, CaSR-activating mutation).
Hypocalcemia with high PTH: secondary — vitamin D deficiency, CKD, or PTH resistance (pseudohypoparathyroidism, in which phosphate is high despite high PTH).

Step 3 — phosphate handling and ancillary studies

Fractional excretion of phosphate / 24-hour urine phosphate: renal phosphate wasting (FEPO₄ above roughly 5%) in hyperparathyroidism, Fanconi syndrome, and FGF23 excess; measure FGF23 when tumor-induced osteomalacia or X-linked hypophosphatemia is suspected.
ECG: prolonged QT in hypocalcemia, shortened QT in hypercalcemia.
Imaging is for localization, never diagnosis: sestamibi scintigraphy, neck ultrasound, or 4D-CT only after biochemical confirmation of primary hyperparathyroidism.
DXA including the distal one-third radius (the cortical site preferentially lost to PTH) and renal imaging for stones, per the International Workshop criteria used to decide on parathyroidectomy.

Severe symptomatic hypocalcemia (tetany, laryngospasm, seizure, prolonged QT) — emergency

IV calcium salts: calcium gluconate is preferred peripherally (calcium chloride is sclerosant and reserved for central access/arrest); follow with a continuous calcium infusion, since a bolus corrects for only 1–2 hours.
Replete magnesium first or simultaneously: without magnesium, PTH secretion and renal PTH action fail and calcium will not correct.
Caution: in digoxin-treated patients, rapid IV calcium can precipitate arrhythmia; give slowly with monitoring.

Chronic hypocalcemia/hypoparathyroidism (Endocrine Society guideline)

Oral calcium plus active vitamin D: calcium carbonate (needs gastric acid; use calcium citrate on PPIs) with calcitriol, which bypasses the absent PTH-driven 1α-hydroxylation. Target low-normal serum calcium to limit hypercalciuria.
Thiazide diuretic and sodium restriction reduce urinary calcium losses; PTH analog therapy is reserved for patients uncontrolled on conventional therapy.

Hypercalcemia — sequence by severity

Volume expansion with isotonic saline first; hypercalcemia causes nephrogenic diabetes insipidus and volume depletion, which worsens it. Loop diuretics are not routine and are used only for volume overload.
Calcitonin for rapid but transient lowering (tachyphylaxis within ~48 hours).
IV bisphosphonate (zoledronic acid) is the definitive antiresorptive for hypercalcemia of malignancy per ASCO/NCCN supportive-care guidance; onset takes 2–4 days. Denosumab is the option in significant renal impairment or bisphosphonate refractoriness.
Glucocorticoids (prednisone) only for calcitriol-mediated hypercalcemia — granulomatous disease, lymphoma, vitamin D intoxication.
Hemodialysis for life-threatening hypercalcemia with renal failure.
Parathyroidectomy is the only cure for primary hyperparathyroidism; International Workshop/AAES criteria include symptomatic disease, calcium >1 mg/dL above normal, age <50, eGFR <60, nephrolithiasis/nephrocalcinosis, marked hypercalciuria, or T-score ≤ −2.5/vertebral fracture. Cinacalcet is medical therapy when surgery is declined.

Phosphate disorders

Hyperphosphatemia in CKD (KDIGO): dietary phosphate restriction and phosphate binders taken with meals, with KDIGO suggesting restriction of calcium-based binders in favor of sevelamer or lanthanum; add active vitamin D analogs or cinacalcet for secondary hyperparathyroidism.
Hypophosphatemia: oral or IV phosphate salts; anticipate refeeding syndrome in alcoholism/malnutrition. Burosumab, an anti-FGF23 antibody, treats X-linked hypophosphatemia.

Emergencies

Laryngospasm and generalized seizures in acute hypocalcemia: neuromuscular membrane destabilization lowers the threshold for depolarization; stridor or a witnessed seizure with a prolonged QT demands immediate IV calcium.
Hypercalcemic crisis (calcium roughly >14 mg/dL): obtundation, coma, volume depletion from nephrogenic diabetes insipidus, and shortened QT with bradyarrhythmia.
Calciphylaxis in dialysis patients: medial calcification and thrombosis of dermal arterioles from a high calcium–phosphate product; signaled by exquisitely painful retiform purpura progressing to necrotic eschar, with high mortality.
Tumor lysis syndrome: hyperphosphatemia complexes calcium, producing hypocalcemia plus acute kidney injury from calcium-phosphate deposition.

Complications of the disease

Nephrolithiasis and nephrocalcinosis: chronic hypercalciuria; calcium oxalate/phosphate stones and a falling eGFR.
Osteitis fibrosa cystica: unopposed PTH-driven osteoclastic resorption producing brown tumors, subperiosteal resorption of the radial phalanges, and a salt-and-pepper skull.
Rickets/osteomalacia: defective mineralization from vitamin D deficiency or phosphate wasting; elevated alkaline phosphatase, Looser zones, bowed legs, rachitic rosary.
Basal ganglia calcification and cataracts in long-standing hypoparathyroidism; parkinsonism or movement disorder is the clinical signal.
Peptic ulcer and pancreatitis with hypercalcemia (gastrin stimulation; intraductal calcium activating trypsinogen).
Vascular and valvular calcification in CKD-MBD, driving cardiovascular mortality — the reason KDIGO targets phosphate lowering.

Complications of treatment

Hungry bone syndrome after parathyroidectomy: abrupt PTH withdrawal lets remineralizing bone consume calcium, magnesium, and phosphate — profound, prolonged hypocalcemia.
Permanent hypoparathyroidism and recurrent laryngeal nerve injury after neck surgery.
Bisphosphonates: osteonecrosis of the jaw, atypical subtrochanteric femoral fracture, hypocalcemia, and acute kidney injury with rapid IV infusion.
Denosumab: severe hypocalcemia (especially in CKD) and rebound vertebral fractures or hypercalcemia after discontinuation.
Calcitriol/calcium therapy: iatrogenic hypercalciuria, stones, and renal impairment — the reason target calcium is low-normal.
Cinacalcet: hypocalcemia and nausea. Calcium-based binders: hypercalcemia and calcification burden.

Measure intact PTH first in any hypercalcemia: this single test splits the differential into PTH-dependent (primary hyperparathyroidism, FHH, lithium) and PTH-independent (malignancy, granuloma, vitamin D). It is the most commonly tested "next best step."
Outpatient vs inpatient rule: asymptomatic hypercalcemia found on routine labs in a well outpatient is primary hyperparathyroidism; symptomatic hypercalcemia of rapid onset in a sick, weight-losing patient is malignancy. Together they account for the large majority of cases.
The FHH trap: a young patient with lifelong mild hypercalcemia, a family history, PTH high-normal, and a urine calcium-to-creatinine clearance ratio <0.01 has an inactivating CaSR mutation. Parathyroidectomy is the wrong answer — it is benign and requires no treatment.
Check magnesium in refractory hypocalcemia: hypomagnesemia (alcoholism, PPIs, diarrhea, cisplatin) blocks both PTH release and renal PTH action. Calcium will not correct until magnesium is replaced.
Phosphate tells you the mechanism: PTH is phosphaturic, so PTH- and PTHrP-driven hypercalcemia comes with low phosphate. High calcium and high phosphate points to vitamin D excess, granulomatous disease, milk-alkali, or immobilization. High PTH and high phosphate with low calcium means resistance — pseudohypoparathyroidism or CKD.
Pseudohypoparathyroidism 1A vs pseudopseudohypoparathyroidism: both show Albright hereditary osteodystrophy (short fourth metacarpals, round facies, short stature); only 1A has the abnormal labs, reflecting maternal vs paternal imprinting of GNAS.
Buzzwords: Chvostek and Trousseau signs (Trousseau is the more specific), stones, bones, abdominal groans, psychiatric overtones, brown tumors, salt-and-pepper skull, Looser zones, and painful retiform purpura for calciphylaxis.
Distractor to avoid: loop diuretics are not first-line for hypercalcemia — the answer is isotonic saline first, then calcitonin for speed and a bisphosphonate for durability; glucocorticoids only when calcitriol-mediated (sarcoidosis, lymphoma).