Residency · Residency · Internal Medicine

Calcium Disorders and Metabolic Bone Disease

Overview

Calcium homeostasis involves a tightly regulated interplay of PTH, vitamin D, and calcitonin acting on bone, kidneys, and the GI tract. Serum calcium must always be corrected for albumin using the formula: corrected Ca equals measured Ca plus 0.8 multiplied by (4.0 minus albumin). Ionized calcium is the gold standard when albumin is abnormal or acid-base disturbances are present. Both hypercalcemia and hypocalcemia can be life-threatening emergencies. Metabolic bone disease, particularly osteoporosis, is a major public health concern with significant fracture-related morbidity and mortality.

Calcium Physiology

Ninety-nine percent of total body calcium resides in bone. Serum calcium is approximately 45% protein-bound (primarily to albumin), 10% complexed with anions, and 45% ionized (the physiologically active fraction). PTH increases calcium by stimulating bone resorption, increasing renal calcium reabsorption, and promoting synthesis of 1,25-(OH)2 vitamin D, which in turn increases GI calcium absorption. Vitamin D exists as 25-OH vitamin D (the storage form) and is converted to 1,25-(OH)2 vitamin D (the active form, calcitriol) by renal 1-alpha-hydroxylase. Calcitonin decreases calcium by inhibiting osteoclast activity but plays a clinically minor role.

Hypercalcemia

Definition

Hypercalcemia is defined as total calcium above 10.5 mg/dL or ionized Ca above 5.2 mg/dL. It is classified as mild (10.5-12.0), moderate (12.0-14.0), or severe (above 14.0, constituting hypercalcemic crisis).

Differential Diagnosis -- PTH-Dependent vs. PTH-Independent

PTH-dependent causes (PTH elevated or inappropriately normal) include primary hyperparathyroidism (PHPT), which is the most common cause of outpatient hypercalcemia (single adenoma in 85%, hyperplasia in 10-15%, carcinoma in less than 1%); familial hypocalciuric hypercalcemia (FHH), a benign condition with low urine calcium excretion from a CaSR mutation; lithium-induced hyperparathyroidism; and tertiary hyperparathyroidism in CKD or post-transplant patients.

PTH-independent causes (PTH suppressed) include malignancy (the most common cause of inpatient hypercalcemia), which acts through PTHrP-mediated humoral hypercalcemia (squamous cell cancers, renal cell, bladder), osteolytic metastases (breast, multiple myeloma, lung), or 1,25-vitamin D-mediated mechanisms (lymphoma). Granulomatous diseases (sarcoidosis, TB, fungal infections) produce hypercalcemia through extrarenal 1-alpha-hydroxylase generating elevated 1,25-vitamin D. Other causes include vitamin D toxicity (elevated 25-OH vitamin D), milk-alkali syndrome, thyrotoxicosis, immobilization, thiazide diuretics, adrenal insufficiency, and vitamin A toxicity.

Clinical Features -- "Stones, Bones, Moans, Groans, and Psychiatric Overtones"

Stones refers to nephrolithiasis and nephrocalcinosis. Bones encompasses bone pain, osteoporosis, and osteitis fibrosa cystica in PHPT. Moans represents abdominal pain, constipation, nausea, pancreatitis, and peptic ulcer disease. Groans includes fatigue, weakness, and muscle pain. Psychiatric overtones covers depression, confusion, psychosis, and coma. Cardiac manifestations include shortened QT interval and arrhythmias at very high levels.

<image>PTH-based diagnostic algorithm for hypercalcemia showing PTH-dependent causes (primary hyperparathyroidism, FHH) versus PTH-independent causes (malignancy, granulomatous disease, vitamin D toxicity)</image>

Workup

The key branch point is PTH level. If PTH is high or inappropriately normal, primary hyperparathyroidism is likely, and urine calcium should be checked to exclude FHH (calcium:creatinine clearance ratio below 0.01 suggests FHH). If PTH is suppressed, PTHrP, 1,25-vitamin D, 25-OH vitamin D, SPEP/free light chains, and a malignancy workup should be pursued. Phosphorus is low in PHPT and PTHrP-mediated hypercalcemia because PTH is phosphaturic. Elevated 25-OH vitamin D indicates vitamin D toxicity, while elevated 1,25-(OH)2 vitamin D points to granulomatous disease or lymphoma.

Treatment of Hypercalcemia

For acute or severe hypercalcemia (calcium above 14 or symptomatic), treatment proceeds stepwise. IV normal saline at 200-300 mL/h restores volume and enhances calciuresis. Calcitonin 4 IU/kg IM/SC every 12 hours provides rapid onset (hours) but develops tachyphylaxis within 48 hours. Zoledronic acid 4 mg IV over 15 minutes has onset in 2-4 days with duration of weeks and is first-line for hypercalcemia of malignancy; pamidronate 60-90 mg IV over 2-4 hours is an alternative. Denosumab is used for bisphosphonate-refractory hypercalcemia of malignancy or when renal impairment contraindicates bisphosphonates. Loop diuretics are used only after volume resuscitation and should be avoided in hypovolemic patients. Glucocorticoids (prednisone 20-40 mg/day) are effective for granulomatous disease and lymphoma-related hypercalcemia by inhibiting 1-alpha-hydroxylase. Dialysis is reserved for refractory cases, especially with renal failure or heart failure limiting fluid resuscitation.

Surgical indications for primary hyperparathyroidism include symptomatic disease (nephrolithiasis, osteoporosis, fractures), calcium more than 1 mg/dL above normal, age below 50, eGFR below 60 mL/min, T-score of -2.5 or below at any site or vertebral fracture, and 24-hour urine calcium above 400 mg/day with increased stone risk. Parathyroidectomy is curative in over 95% of cases.

<image>Stepwise treatment algorithm for acute hypercalcemia showing IV saline, calcitonin (bridging), bisphosphonate or denosumab, and adjunctive therapies based on etiology</image>

Hypocalcemia

Definition

Hypocalcemia is defined as corrected total calcium below 8.5 mg/dL or ionized Ca below 4.6 mg/dL. Correction for albumin and ionized calcium should always be checked if any doubt exists.

Etiologies

Hypoparathyroidism is the most common surgical cause (post-thyroidectomy, post-parathyroidectomy), with autoimmune, infiltrative, and magnesium deficiency as other causes (magnesium deficiency impairs both PTH secretion and end-organ response). Vitamin D deficiency may be nutritional, from malabsorption, from CKD (impaired 1-alpha-hydroxylase), or from liver disease. PTH resistance occurs in pseudohypoparathyroidism. Acute causes include pancreatitis (calcium saponification), massive blood transfusion (citrate binds calcium), tumor lysis syndrome (hyperphosphatemia), and rhabdomyolysis. Medications that cause hypocalcemia include bisphosphonates, denosumab, cinacalcet, foscarnet, and long-term PPIs.

Clinical Features

Neuromuscular irritability manifests as perioral numbness, paresthesias, muscle cramps, tetany, laryngospasm, and seizures. Chvostek sign (tapping the facial nerve producing ipsilateral facial muscle contraction) has sensitivity of only 10-30%. Trousseau sign (inflating a blood pressure cuff above systolic for 3 minutes producing carpal spasm) is more specific. Cardiac effects include prolonged QT interval with risk of torsades de pointes. Chronic findings include cataracts, basal ganglia calcification, and dental abnormalities.

Management

For severe or symptomatic hypocalcemia, calcium gluconate 1-2 g (10-20 mL of 10% solution) is administered IV over 10-20 minutes followed by a continuous infusion with close monitoring. Calcium gluconate is preferred over calcium chloride via peripheral IV due to less tissue necrosis risk. Magnesium must be checked and corrected because hypomagnesemia renders hypocalcemia refractory to treatment. Oral replacement uses calcium carbonate or citrate plus vitamin D (cholecalciferol for deficiency, calcitriol for hypoparathyroidism or CKD). Recombinant PTH (teriparatide) is used for chronic hypoparathyroidism refractory to calcium and vitamin D.

Osteoporosis

Screening

DXA scanning is recommended for all women at or above age 65 and men at or above age 70, with earlier screening when risk factors are present (prior fragility fracture, glucocorticoid use, low body weight, smoking, family history, rheumatoid arthritis). T-score interpretation classifies normal as -1.0 or above, osteopenia as -1.0 to -2.5, osteoporosis as -2.5 or below, and severe osteoporosis as -2.5 or below with fragility fracture.

FRAX Tool

The FRAX tool estimates 10-year probability of major osteoporotic fracture and hip fracture, incorporating clinical risk factors and femoral neck BMD. Treatment thresholds are 20% or higher for major fracture risk or 3% or higher for hip fracture risk.

Treatment

Non-pharmacologic measures include weight-bearing and resistance exercise, fall prevention (home safety, physical therapy, vision correction), calcium 1000-1200 mg/day (diet preferred) plus vitamin D 800-1000 IU/day, smoking cessation, and alcohol moderation.

Bisphosphonates are first-line for most patients. Options include alendronate 70 mg orally weekly, risedronate 150 mg orally monthly, and zoledronic acid 5 mg IV annually. Oral bisphosphonates should be taken with water, remaining upright for 30 minutes, on an empty stomach. A drug holiday may be considered after 5 years of oral or 3 years of IV therapy in non-high-risk patients, with reassessment by DXA. Rare risks include atypical femoral fractures and osteonecrosis of the jaw, both very rare at osteoporosis doses.

Denosumab (RANKL inhibitor) is given as 60 mg subcutaneously every 6 months, requires no renal dose adjustment and can be used in CKD. Critically, rebound vertebral fractures occur upon discontinuation, so transition to a bisphosphonate before stopping is mandatory. Hypocalcemia is a risk, especially in CKD or vitamin D deficiency.

Anabolic agents for severe osteoporosis or antiresorptive failure include teriparatide (PTH 1-34) at 20 mcg subcutaneously daily for 2 years (contraindicated in Paget disease, bone metastases, or prior radiation), abaloparatide (PTHrP analog) at 80 mcg subcutaneously daily for 2 years, and romosozumab (anti-sclerostin) at 210 mg subcutaneously monthly for 12 months (with a cardiovascular warning to avoid in recent MI or stroke). Anabolic therapy must always be followed by antiresorptive therapy to maintain gains. Raloxifene (a SERM) reduces vertebral fractures but increases VTE risk and is not first-line.

<image>Osteoporosis treatment algorithm showing initial assessment with DXA and FRAX, first-line bisphosphonate therapy, denosumab for CKD or bisphosphonate-ineligible patients, and anabolic agents for severe disease</image>

Glucocorticoid-Induced Osteoporosis

Steroids are the most common cause of secondary osteoporosis, with bone loss most rapid in the first 3-6 months. ACR guidelines recommend starting bisphosphonate prophylaxis for prednisone at 2.5 mg/day or higher expected for 3 or more months. Calcium and vitamin D supplementation should be ensured, with DXA monitoring during chronic steroid use.

Clinical Pearls

Magnesium must always be checked when treating hypocalcemia because magnesium deficiency impairs PTH secretion and causes end-organ resistance to PTH. Familial hypocalciuric hypercalcemia mimics primary hyperparathyroidism but does not require surgery; it is distinguished by 24-hour urine calcium and the calcium:creatinine clearance ratio. Denosumab rebound fractures are a critical safety concern, and the drug should never be stopped without a transition plan (typically a bisphosphonate). Hungry bone syndrome after parathyroidectomy can cause severe, prolonged hypocalcemia, requiring preparation with calcium and calcitriol preoperatively. Bisphosphonate drug holidays are appropriate for moderate-risk patients but not for high-risk patients (T-score of -2.5 or below, prior fragility fracture). QT prolongation from hypocalcemia can be mistaken for other causes, so calcium should always be checked in patients with prolonged QT.

References

• Bilezikian JP, et al. Primary Hyperparathyroidism. Lancet. 2018;391:168-178.
• Shoback DM, et al. Presentation of Hypoparathyroidism: Etiologies and Clinical Features. J Clin Endocrinol Metab. 2016;101:2300-2312.
• Eastell R, et al. Pharmacological Management of Osteoporosis in Postmenopausal Women. Endocr Rev. 2019;40:1182-1209.
• Buckley L, et al. 2017 ACR Guideline for Prevention and Treatment of Glucocorticoid-Induced Osteoporosis. Arthritis Rheumatol. 2017;69:1521-1537.
• Tsourdi E, et al. Discontinuation of Denosumab Therapy for Osteoporosis. J Clin Endocrinol Metab. 2017;102:1691-1700.

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