Endocrine Lecture 5: Bone Mineral Metabolism

How is primary hyperparathyroidism most often found?

Incidentally, by an elevated calcium level on routine screening by the PCP (asymptomatic hyperparathyroidism).

What is the most common cause of increased calcium in healthy outpatients?

Primary hyperparathyroidism.

What is the most common cause of primary hyperparathyroidism?

Single parathyroid adenoma (80%).

What percentage of primary hyperparathyroidism is caused by parathyroid hyperplasia?

20%.

Which genetic syndromes are risk factors for primary hyperparathyroidism?

MEN types 1, 2A and 4.

In which sex and age group is primary hyperparathyroidism most common?

Women, in the 7th decade.

Which two medications are risk factors for primary hyperparathyroidism?

Lithium and thiazides.

What mnemonic describes the classic signs and symptoms of primary hyperparathyroidism?

"Bones, stones, abdominal moans, and psychic groans."

What are the "bones" symptoms of hypercalcemia?

Muscle weakness, bone pain, osteopenia/osteoporosis.

What are the "stones" (renal) manifestations of hypercalcemia?

Nephrogenic diabetes insipidus, acute and chronic kidney function impairment, renal tubular dysfunction.

What are the "abdominal moans" of hypercalcemia?

Anorexia, nausea, vomiting, constipation, pancreatitis, peptic ulcer disease.

What are the "psychic groans" of hypercalcemia?

Decreased concentration, confusion, fatigue, stupor, coma, decreased DTRs.

What are the cardiovascular findings of hypercalcemia?

Shortened QT interval, bradycardia, hypertension.

What happens to the QT interval in hypercalcemia?

It is shortened.

What is osteitis fibrosa cystica?

The classic bone disease caused by severe, longstanding hyperparathyroidism.

Where is subperiosteal bone resorption seen on X-ray in osteitis fibrosa cystica?

The radial aspect of the middle phalanges.

What happens to the distal clavicles on X-ray in osteitis fibrosa cystica?

Tapering of the distal clavicles.

What is the classic skull X-ray finding in osteitis fibrosa cystica?

"Salt and pepper" skull.

What are brown tumors?

Bone lesions of osteitis fibrosa cystica caused by excessive osteoclast activity.

What is the initial and best test for diagnosing primary hyperparathyroidism?

Labs.

What is the calcium level in primary hyperparathyroidism?

Elevated (hypercalcemia).

What is the PTH level in primary hyperparathyroidism?

Elevated.

What is the phosphorus level in primary hyperparathyroidism?

Decreased.

What is the 24-hour urine calcium in primary hyperparathyroidism?

Normal or high (not needed for diagnosis; elevated suggests the disease).

What imaging helps identify a parathyroid adenoma?

Ultrasound of the thyroid/parathyroid.

Which sites should a DXA include in primary hyperparathyroidism?

Distal radius, hip, lumbar vertebrae.

What is the only long-term cure for primary hyperparathyroidism?

Surgical parathyroidectomy.

Which patients with primary hyperparathyroidism should have parathyroidectomy?

Symptomatic patients, or those with nephrolithiasis or fractures.

What serum calcium level makes an asymptomatic patient with primary hyperparathyroidism a surgical candidate?

>1 mg/dL above the upper limit of normal.

What bone density finding makes an asymptomatic patient with primary hyperparathyroidism a surgical candidate?

≥2.5 SD below peak bone mass.

What age makes an asymptomatic patient with primary hyperparathyroidism a surgical candidate?

Under 50.

What GFR makes an asymptomatic patient with primary hyperparathyroidism a surgical candidate?

GFR ≤60.

Besides calcium, bone density, age, and GFR, which two other findings make an asymptomatic patient a surgical candidate?

1. Nephrolithiasis 2. Previous fragility fracture

How are truly asymptomatic primary hyperparathyroidism patients managed?

Close lab monitoring, remain active, avoid immobilization, drink fluids, avoid aggravating hypercalcemia.

What surgery is done for a parathyroid adenoma?

Removal of the abnormal gland.

What surgery is done for parathyroid hyperplasia?

Removal of 3.5 of 4 glands.

When is medical management considered in primary hyperparathyroidism?

When the patient meets surgical criteria but cannot or will not have surgery.

What class of drug is cinacalcet?

CaSR (calcium-sensing receptor) activator.

What is the mechanism of cinacalcet?

Decreases PTH secretion.

When is cinacalcet used in primary hyperparathyroidism?

Symptomatic or severe hypercalcemia; initial therapy for symptomatic hyperparathyroidism or after failed parathyroidectomy.

When are bisphosphonates used in primary hyperparathyroidism?

For patients with osteoporosis (they can also temporarily treat the hypercalcemia).

What is hungry bone syndrome?

Post-parathyroidectomy rebound uptake of calcium and phosphorus by starved bones, pulling them from the blood.

What are the serum calcium and phosphorus levels in hungry bone syndrome?

Decreased calcium, decreased phosphorus.

In which patients is hungry bone syndrome usually seen?

Longstanding disease with extensive bone resorption.

What is started post-parathyroidectomy as soon as the patient can swallow?

Oral calcium and calcitriol.

How is severe or symptomatic post-op hypocalcemia treated after parathyroidectomy?

IV calcium, typically for 3-4 days post op, then switch to PO.

What is given pre-op to help prevent hungry bone syndrome?

IV calcitriol.

How often are serum calcium, creatinine, and eGFR monitored in primary hyperparathyroidism?

Annually.

How often is bone density monitored in primary hyperparathyroidism?

Every 1-2 years.

Which interim events in a non-op patient with primary hyperparathyroidism warrant surgery?

1. Low-trauma fracture 2. Kidney stones/hypercalciuria 3. Reduction in eGFR 4. Calcium persistently >1 mg/dL over ULN

Which asymptomatic primary hyperparathyroidism patients usually remain stable with follow-up?

Those with serum calcium below 11 mg/dL.

What is secondary hyperparathyroidism?

Another condition causes low blood calcium, so the parathyroid glands respond with increased PTH secretion.

In which patients is secondary hyperparathyroidism most commonly seen?

Chronic kidney disease.

How does renal disease cause secondary hyperparathyroidism?

Increased calcium excretion → PTH increases in response.

Besides CKD, which deficiency causes secondary hyperparathyroidism?

Vitamin D deficiency.

How is secondary hyperparathyroidism treated?

Treat the underlying cause; this can reverse the condition.

What is hypercalcemia?

Elevated serum calcium; entry of calcium into circulation exceeds urinary excretion/deposition into bone.

Which two causes account for 90% of hypercalcemia?

Hyperparathyroidism (most common) and malignancy.

Which medications cause hypercalcemia?

1. Thiazide diuretics 2. Lithium 3. Vitamin D (toxicity)

Which causes of hypercalcemia work through decreased renal excretion?

Thiazide diuretics and renal disease.

Which cause of hypercalcemia works through increased GI absorption?

Excess vitamin D3.

Which cause of hypercalcemia works through increased bone resorption?

Lytic bone lesions.

Are most patients with hypercalcemia symptomatic?

No; most are asymptomatic. Symptoms depend on the degree of hypercalcemia.

Hypercalcemia with bone pain is most likely due to what?

Primary hyperparathyroidism or malignancy.

Hypercalcemia with kidney stones is most likely due to what?

Primary hyperparathyroidism or sarcoidosis.

Why must total serum calcium be interpreted with caution?

Roughly 40% of serum calcium is protein bound, so abnormal albumin distorts the total calcium.

Which calcium measurement is more accurate and should be done when albumin is abnormal?

Ionized calcium.

What serum calcium defines mild hypercalcemia?

What serum calcium defines moderate hypercalcemia?

12-14 mg/dL.

What serum calcium defines severe hypercalcemia?

>14 mg/dL (frequently symptomatic).

Severe hypercalcemia is most commonly associated with what?

Malignancy.

What is the next test once hypercalcemia is confirmed?

PTH.

What does an elevated or upper-normal PTH suggest in hypercalcemia?

Hyperparathyroidism.

What does a low or low-normal PTH suggest in hypercalcemia?

Non-PTH-mediated hypercalcemia.

Which labs are obtained in hypercalcemia when PTH is low (

1. 25-hydroxyvitamin D 2. 1,25-dihydroxyvitamin D 3. PTH-related protein (PTHrP)

What does an elevated 25(OH)D suggest in hypercalcemia?

Ingestion of vitamin D.

What can cause an elevated 1,25-dihydroxyvitamin D in hypercalcemia?

Direct intake of the metabolite, or extrarenal production in granulomatous diseases or lymphoma.

What does an elevated PTHrP indicate?

Humoral hypercalcemia of malignancy.

When should PTHrP be measured?

Clinical evidence of malignancy (usually a solid tumor) and recent onset of hypercalcemia.

Do asymptomatic or symptomatic mild/moderate hypercalcemia require immediate treatment?

No.

Which factors that aggravate hypercalcemia should be avoided?

Thiazides, lithium, dehydration, high calcium diet, calcium supplements, vitamin D supplements.

Which hypercalcemia patients require treatment and admission?

Symptomatic hypercalcemia or severe hypercalcemia (usually above 14 mg/dL).

What is the first step in treating severe hypercalcemia?

IV fluid resuscitation with isotonic saline for 24-48 hours.

What is the initial drug given for severe hypercalcemia, and by what route?

Calcitonin IM/SQ every 6-12 hours.

How does calcitonin lower calcium in hypercalcemia?

Enhances renal calcium excretion and decreases bone resorption.

Why can calcitonin treatment not exceed 48 hours?

Tachyphylaxis.

What is the treatment of choice for long-term control of severe hypercalcemia?

IV bisphosphonates.

When do IV bisphosphonates reach maximum effect in hypercalcemia?

2-4 days (so they are combined with the more rapid IV saline and calcitonin).

What is the normal serum calcium range?

8.5-10.5 mg/dL.

What is the most common cause of hypocalcemia with decreased PTH?

Hypoparathyroidism (autoimmune/surgical).

What is the most common cause of hypocalcemia with elevated PTH?

Chronic kidney disease.

Besides CKD, which causes of hypocalcemia have elevated PTH?

Liver disease and vitamin D deficiency.

What is the PTH level in hungry bone syndrome?

Usually normal.

What are the mild acute symptoms of hypocalcemia?

Perioral numbness, paresthesias of hands/feet, muscle cramps.

What are the severe acute symptoms of hypocalcemia?

Carpopedal spasm, laryngospasm, focal or generalized seizures.

What is Chvostek's sign?

Facial muscle contraction after tapping the facial nerve.

What is Trousseau's sign?

Carpal spasm with blood pressure cuff inflation.

What happens to the QT interval in hypocalcemia?

Prolonged.

What cardiovascular findings occur in hypocalcemia?

Hypotension, prolonged QT, heart failure, arrhythmia.

Which PTH/phosphate pattern suggests hypoparathyroidism?

Low PTH, elevated phosphorus.