Disorders of calcium and bone metabolism

1. Olivia Baugh MD Chief Resident Disorders of calcium and bone metabolism

2. Parathyroid dependent • Primary hyperparathyroidism • Familial hypocalciurichypercalcemia • Thiazide-induced hypercalcemia • Lithium • Parathyroid independent • Malignancy • Vitamin D intoxication • Granulomatous disorders (sarcoidosis, lymphoma) • Miscellaneous Hypercalcemia

3. Commonest cause of hypercalcemia, more common in females • 80% will be caused by a single parathyroid adenoma • 15% hyperplasia • 5% multiple adenomas • Rarely caused by parathyroid cancer • Familial hyperparathryoidism is associated with MEN1 and MEN 2A, and usually see hyperplasia Primary hyperparathyroidism

4. Usually asymptomatic • Symptoms: • Polyuria, polydipsia • Nephrolithiasis, nephrocalcinosis • Fatigue, weakness, myopathy • Depression • Osteopenia, osteoporosis, bone pain, pathologic fractures symptoms

5. Labs: • Usually mild hypercalcemia • Normal phosphate • Increased or inappropriately normal PTH • Increased urinary calcium excretion • Imaging • Loss of cortical bone, see subperiosteal bone resorption (on radial borders of phalanges) • “salt and pepper” appearance of skull • Osteitisfibrosacystica (fibrous replacement of resorbed bone) • Brown tumors (collections of osteoclasts in poorly mineralized bone) • Renal stones TESTS

10. Parathyroidectomy is treatment of choice • Adenoma requires resection, localize with sestimibe scan • Hyperplasia can be treated with subtotal parathyroidectomy, leaving 50gm of tissue intact • Reversible, mild asymptomatic hypocalcemia is common in the early postop period, however if pt’s already have bone disease, correction of hyperparathyroidism may lead to prolonged hypocalcemia • Conservative therapy used in elderly or mild uncomplicated disease, indications for excision are calcium level greater than 1 unit above normal range, nephrolithiasis, thinning bones, or pronounced hypercalciuria treatment

11. Autosomal dominant • Patients have an abnormal set point of the calcium-sensing receptor in the parathyroid glands and renal tubules • Labs: mild hypercalcemia, normal or slightly increased PTH, low urinary calcium, family history, calcium-creatinine clearance ratio of less than 0.01 • No intervention as complications do not develop Familial hypocalciurichypercalcemia

12. Mild hypercalcemia Caused by: dehydration, decreased renal calcium clearance, possible increased PTH Hypercalcemia usually resolves in a few weeks after stopping the thiazide More likely to occur in patients with underlying hyperparathyroidism Thiazide induced

13. Raises the threshold of inhibition of PTH secretion by serum calcium PTH inappropriately normal or increased Hypercalcemia resolves after lithium discontinuation lithium

14. You are asked to evaluate a 25-year-old woman with hypercalcemia, fatigue, and weakness, which have been ongoing for the previous 3 months. Laboratory data include the following: serum calcium 10.2 mg/dL, PTH 5.2 pmol/L (1-5.2 pmol/L), and urinary calcium excretion 40mg/24h (20-275mg/24 h). She is not known to be taking any medication, and there is no history of nephrolithiasis or fracture. Which of the following is indicated? • A. parathyroidectomy • B. measurement of 25-0H-vit D • C. parathyroid imaging • D. calculation of fractional calcium excretion and thiazide screen • E. measurement of PTHrP Question

15. This patient has elevated serum calcium with a normal PTH level (not suppressed). This is compatible with primary hyperparathyroidism but you would expect an increased urinary calcium excretion level. Hypercalcemichypocalciuria is familial but the same clinical picture and lab studies can be seen with thiazide administration. This patient also had hypokalemia and was taking diuretics for weight loss. Hypocalcemia accompanies elevated PTH due to 25-OH-D deficiency but this patient has hypercalcemia. Answer D

16. Hypercalcemia of malignancy • Acute, severe and life-threatening • Commonest cause in hospitalized patients • Due to destruction of bone by mets or paraneoplastic disease (PRHrP) • Hypercalcemia resolves after malignancy treatment in paraneoplastic disease • Serum PTH is low Parathyroid-independent hypercalcemia

17. Hypercalcemia Hypercalciuria Renal insufficiency Soft tissue calcification Hypercalcemia may persist for months after vit D is discontinued due to fat stores Can also occur in vit A intoxication Vitamin d intoxication

18. Vitamin D-dependent granulomas and some lymphomas express high concentrations of 1 alpha-hydroxylase enzyme that generates 1,25-dihydroxyvitamin D 25-OH-vit D is normal level 1,25-(OH)2-vit D is increased Treat with glucocorticoids Sarcoidosis, granulomatousdz, lymphoma

19. Hyperthyroidism enhances bone turnover and may lead to bone loss, see hypercalciuria • Resolves with treatment of thyrotoxicosis • Addisonian crisis causes dehydration and increased albumin concentration • Treat with glucocorticoids • Immobilization causes increased bone turnover Miscellaneous causes

20. A 64-year-old woman is referred for evaluation of hypercalcemia detected on routine testing 2 days ago. She is asymptomatic, but her serum calcium is elevated (13.4 mg/dL). A chest radiograph shows mediastinallymphadenopathy. Which test result does NOT support a diagnosis of granuloma-associated hypercalcemia? • A. normal serum phosphate concentrations • B. PTH 4.8 pmol/L (1-5.2 pmol/L) • C. undetectable PTH-related peptide (PTHrP) • D. 25-OH-D 30 ng/mL • E . 1,25-(OH)2-D >70pg/mL Question

21. Asymptomatic hypercalcemia in an otherwise asymptomatic patient is most often caused by primary hyperparathyroidism. If the parathyroid glands are normal, secretion of PTH is suppressed by hypercalcemia. Granulomas and some lymphomas express 1-alpha-hydroxylase and activate vitamin D to produce excess 1,25-(OH)2-D, the mediator of hypercalcemia. 25-(OH)-D levels are typically normal. Answer B

22. Saline rehydration • Loop diuretics • Pamidronate (IV bisphosphonate) inhibits bone resorption and has a prolonged effect on calcium concentration • Dialysis if pt has renal failure • Calcitonin rarely used due to modest effect and rapid onset of tachyphylaxis (rapid decrease in response to the drug over a short period of time) Hypercalcemia management

23. Results from surgical damage to the parathyroid glands, autoimmune disease, infiltration (Wilsons or hemochromatosis), or congenital disease (DiGeorge syndrome, also see thymicaplasia), hypomagnesemia impairs secretion and action of PTH (functional hypoparathyroidism) • Hypocalcemia symptoms include: Chvostek and Tinel signs • Pseudohypoparathyroidism is due to end-organ resistance to PTH due to a receptor defect (short stature, round face, short metacarpals and metatarsals, calcification of the basal ganglia and mild mental retardation) Hypoparathyroidism

24. Parasthesias, carpopedal spasm, laryngeal stridor, convulsions, prolonged QT interval, cataracts, alopecia, malabsorption, mucocutaneouscandidiasis (in DiGeorge) • Hypocalcemia and hyperphosphatemia with normal renal function • PTH is low in hypoparathyroidism and elevated in psuedohypoparathyroidism • Determine level of ionized calcium and Mag • High PTH with low calcium can also suggest vit D deficiency Making the diagnosis

25. IV calcium for acute, severe disease with continuous EKG monitoring Oral calcium for chronic disease with vit D Thiazide diuretics to decrease amount of calciuria Phosphate binders Goal calcium level is 8.5mg/dL and urinary calcium level is less than 300 mg/24 h therapy

26. Osteopenia is bone mass 1-2.5 standard deviations below the mean peak bone mass • Osteoporosis is bone mass value of greater than 2.5 standard deviations below the mean • Causes: menopause, senile osteoporosis • Secondary: hypogonadism, hyperparathyroidism, hyperthyroidism, hypercortisolism, malnutrition, malabsorption, neoplasia, bone collagen abnormalities • Drugs: heparin, MTX, corticosteroids, GnRH analogues osteoporosis

27. Bone fracture NORMAL calcium, phosphorus, alkaline phosphatase A decrease of 1 standard deviation from the mean peak bone density leads to double the fracture risk Diagnose with bone densitometry Features of osteoporosis

28. Estrogen replacement is the therapy of choice in post-menopausal women with no contraindications (give with progesterone if pt still has her uterus to prevent endometrial hyperplasia) Oral bisphosphonates Calcium and vit D supplements Calcitonin nasal spray Treatment

29. Affects 3% of the population over 45 • Abnormal osteoclasts increase rate of bone resorption • Most commonly affects the sacrum, spine, femur, tibia, skull, and pelvis (bone scan is sensitive test) • Increased alkphos, (may be over 1000; also used as a marker to therapy) pain and deformity are used to diagnose • Complications: hydrocephalus, nerve entrapment, high-output cardiac failure, hypercalcemia, hypercalciuria Paget disease (osteitisdeformans)

30. Bisphosphonates IV or oral (preffered over calcitonin due to tachyphylaxis over time) Orthopedic surgery to correct deformity or treat pain Neurosurgical intervention for nerve entrapment Treatment of paget disease