Bone/Parathyroid Case 3

A 67-year-old Caucasian woman with vitamin D deficiency presents for follow-up of osteopenia. She has no history of vertebral, radius, or pathological fracture or family history of osteoporosis. A recent DXA scan revealed a bone mineral density with a T-score of -1.7 in the spine, and -2.0 in the left femoral neck. She takes calcium and vitamin D supplementation. She denies bone pain, history of kidney stones, anorexia, change in concentration, peptic ulcer disease or pancreatitis in the past. 

Laboratory test results at the time of the visit:  

Serum calcium = 11.2 mg/dL (8.2-10.2 mg/dL) (SI: 2.8 [2.1-2.6 mmol/L]) 

Serum phosphate = 2.8 mg/dL (2.3-4.7 mg/dL) (SI: 0.9 [0.7-1.5 mmol/L]) 

Serum creatinine = 0.80 mg/dL (0.6-1.1 mg/dL) (SI: 70.7 [53.0-97.2 µmol/L]) 

Glomerular filtration rate (estimated) > 60 mL/min per 1.73 m2 

Serum 25-hydroxyvitamin D = 30 ng/mL (30-80 ng/mL [optimal] (SI 74.9 nmol/L [74.9-199.7 nmol/L]) 

Serum intact PTH = 85 pg/mL (10-65 pg/mL) (SI: 85 ng/L [10-65 ng/L]) 

Serum albumin = 4.0 g/dL (3.5-5.0 g/dL) (SI: 4.0 g/L [35-50 g/L]) 

Serum magnesium, normal 

Urinary calcium = 450 mg/24 h (100-300 mg/24 h) (SI: 11.2 [2.5-7.5 mmol/d]) 

Urinary creatinine = 1.2 g/24 h (1.0-2.0 g/24 h) (SI: 10.6 [8.8-17.7 mmol/d]) 

Urinary volume = 1600 mL/24 h  

Question 1

Which of the following is the correct next step in management?

A. Continue to monitor calcium, 25-hydroxyvitamin D, PTH every 3-6 months.
B. Increase vitamin D supplementation, repeat calcium, 25-hydroxyvitamin D, PTH in 3 months.
C. Refer to surgery for preoperative localization and parathyroidectomy.
D. Start cinacalcet 30 mg daily and repeat calcium, albumin, creatinine and PTH in 2 weeks.
E. Refer to medical genetics for assessment of Familial Hypocalciuric Hypercalcemia (FHH).
Incorrect!
Correct!
Correct Answer
C. Refer to surgery for preoperative localization and parathyroidectomy.

This patient presents with a clinical constellation of hypercalcemia, elevated PTH with a replete 25-hydroxyvitamin D level, that is suggestive of primary hyperparathyroidism. Additionally, she has clear evidence of hypercalciuria with a fractional excretion of calcium [FeCa] = 0.026; FeCa = (urine calcium x serum creatinine)/(serum calcium x urine creatinine), which further supports a diagnosis of primary hyperparathyroidism rather than familial hypocalciuric hypercalcemia (FHH). The fractional excretion of calcium, also termed the urine calcium to creatinine ratio, can be used to distinguish primary hyperparathyroidism and FHH. A FeCa < 0.01 in a vitamin D-replete individual is highly suggestive of FHH rather than primary hyperparathyroidism (ratio usually > 0.02 in primary hyperparathyroidism. In an analysis of five large studies combining 165 patients with FHH and 197 patients with primary hyperparathyroidism, a FeCa < 0.01 had a sensitivity for FHH of 85% and a specificity of 88% with a positive predictive value (PPV) of 85% (1-3). This effectively rules out answer E.  

This patient currently does not have any symptoms to suggest primary hyperparathyroidism, but does meet surgical criteria for parathyroidectomy. For asymptomatic individuals who meet the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism guidelines, surgical intervention is recommended as opposed to observation (4, 5). Therefore, answers A, B, and D are incorrect. 

Patients need to meet only one of the following criteria for surgery (with our patient’s findings in bold):  

  • Serum calcium concentration of 1.0 mg/dL (0.25 mmol/L) or more above the upper limit of normal 

  • Skeletal indications:  

  • Bone density at the hip, lumbar spine, or distal radius htat is more than 2.5 standard deviations below peak bone mass (T-score < -2.5) 

  • Previous asymptomatic vertebral fracture (by radiograph, computed tomography [CT], magnetic resonance imaging [MRI], or vertebral fracture assessment).  

  • Renal indications: 

  • Estimated glomerular filtration rate (eGFR) < 60 mL/min 

  • Twenty-four-hour urinary calcium > 400 mg/day (> 10 mmol/day).  

  • Nephrolithiasis or nephrocalcinosis by radiograph, ultrasound, or CT.  

  • Age less than 50 years 

This patient currently has primary hyperparathyroidism by lab studies, and has two indications for parathyroidectomy. It is important to note that she does not have any contraindications to surgery that are mentioned in the question stem, therefore, cinacalcet (answer D) would not be the most appropriate next step in management.  

References: 

1. Sywak MS, Knowlton ST, Pasieka JL, et al. Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery 2002;132:1013.  

2. Walker MD, McMahon DJ, Inabnet WB, et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab 2009;94:1951.  

3. Walker MD, Silverberg SJ. Parathyroidectomy in asymptomatic primary hyperparathyroidism: improves “bones” but not “psychic moans”. J Clin Endocrinol Metab 2007;92:1613. 

4. Bilezikian JP, Brandi ML, Eastall R, et al. Guidelines for the management of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab 2008;93:3462. 

5. Silverberg SJ, Clarke BL, Peacock M, et al. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop.  J Clin Endocrinol Metab 2014;99:3580.  

This patient presents with a clinical constellation of hypercalcemia, elevated PTH with a replete 25-hydroxyvitamin D level, that is suggestive of primary hyperparathyroidism. Additionally, she has clear evidence of hypercalciuria with a fractional excretion of calcium [FeCa] = 0.026; FeCa = (urine calcium x serum creatinine)/(serum calcium x urine creatinine), which further supports a diagnosis of primary hyperparathyroidism rather than familial hypocalciuric hypercalcemia (FHH). The fractional excretion of calcium, also termed the urine calcium to creatinine ratio, can be used to distinguish primary hyperparathyroidism and FHH. A FeCa < 0.01 in a vitamin D-replete individual is highly suggestive of FHH rather than primary hyperparathyroidism (ratio usually > 0.02 in primary hyperparathyroidism. In an analysis of five large studies combining 165 patients with FHH and 197 patients with primary hyperparathyroidism, a FeCa < 0.01 had a sensitivity for FHH of 85% and a specificity of 88% with a positive predictive value (PPV) of 85% (1-3). This effectively rules out answer E.  

This patient currently does not have any symptoms to suggest primary hyperparathyroidism, but does meet surgical criteria for parathyroidectomy. For asymptomatic individuals who meet the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism guidelines, surgical intervention is recommended as opposed to observation (4, 5). Therefore, answers A, B, and D are incorrect. 

Patients need to meet only one of the following criteria for surgery (with our patient’s findings in bold):  

  • Serum calcium concentration of 1.0 mg/dL (0.25 mmol/L) or more above the upper limit of normal 

  • Skeletal indications:  

  • Bone density at the hip, lumbar spine, or distal radius htat is more than 2.5 standard deviations below peak bone mass (T-score < -2.5) 

  • Previous asymptomatic vertebral fracture (by radiograph, computed tomography [CT], magnetic resonance imaging [MRI], or vertebral fracture assessment).  

  • Renal indications: 

  • Estimated glomerular filtration rate (eGFR) < 60 mL/min 

  • Twenty-four-hour urinary calcium > 400 mg/day (> 10 mmol/day).  

  • Nephrolithiasis or nephrocalcinosis by radiograph, ultrasound, or CT.  

  • Age less than 50 years 

This patient currently has primary hyperparathyroidism by lab studies, and has two indications for parathyroidectomy. It is important to note that she does not have any contraindications to surgery that are mentioned in the question stem, therefore, cinacalcet (answer D) would not be the most appropriate next step in management.  

References: 

1. Sywak MS, Knowlton ST, Pasieka JL, et al. Do the National Institutes of Health consensus guidelines for parathyroidectomy predict symptom severity and surgical outcome in patients with primary hyperparathyroidism? Surgery 2002;132:1013.  

2. Walker MD, McMahon DJ, Inabnet WB, et al. Neuropsychological features in primary hyperparathyroidism: a prospective study. J Clin Endocrinol Metab 2009;94:1951.  

3. Walker MD, Silverberg SJ. Parathyroidectomy in asymptomatic primary hyperparathyroidism: improves “bones” but not “psychic moans”. J Clin Endocrinol Metab 2007;92:1613. 

4. Bilezikian JP, Brandi ML, Eastall R, et al. Guidelines for the management of primary hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin Endocrinol Metab 2008;93:3462. 

5. Silverberg SJ, Clarke BL, Peacock M, et al. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop.  J Clin Endocrinol Metab 2014;99:3580. 

Bone/Parathyroid Case 2

A 76 year-old woman is referred for evaluation of multiple non-traumatic vertebral compression fractures developing over the past year. She was initially diagnosed with osteoporosis at age 58 years, with her lowest T-score of -3.2 at her lumbar spine. She was treated with alendronate for one year, but because of significant gastroesophageal irritation, she switched to intravenous zoledronic acid once a year for the next three years without symptoms, followed by a 6-year drug holiday.

Once her bone density began to decrease after 6 years off treatment, she received a second three-year course of intravenous zoledronic acid, again without symptoms.  After completing her second course of zoledronic acid, her bone density did not increase as much as it did with her first course, and her primary care physician switched her to denosumab 60 mg subcutaneously every six months. Because her bone density increased significantly after four years of denosumab treatment, her physician discontinued denosumab. One year after her last dose of denosumab, she developed severe back pain without a fall or other injury, and her spine films showed new vertebral compression fractures at L1, L3, and L4.

Question 1

The most likely reason for the patient's multiple atraumatic vertebral compression fractures over the last year is which of the following?

A. Stopping denosumab therapy without starting other therapy
B. Lack of adequate calcium and vitamin D supplementation
C. Loss of previous antiresorptive effect of zoledronic acid
D. Persistent low bone mineral density after treatment
E. An unrecognized secondary cause for bone loss
Incorrect!
Correct!
Correct Answer
A. Stopping denosumab therapy without starting other therapy

Bisphosphonate therapies give long-lasting protection against postmenopausal bone loss.  Oral bisphosphonate therapies are typically given for three to five years, followed by up to a five-year drug holiday as long as the femoral neck bone density is above -2.5 and the patient has not had a fracture while on therapy. Intravenous zoledronic acid is given once yearly for up to three years and then followed by a three-year drug holiday, unless the patient has femoral neck bone density less than -2.5 or has sustained a low-trauma fracture on therapy. Bisphosphonate therapy is not usually stopped if the post-treatment T-score is less than -2.5 or a fracture has occurred while on therapy.

Antiresorptive osteoporosis therapies other than bisphosphonates lose their effect soon after therapy is discontinued. Because of this, bone formation and resorption typically increase toward baseline within the next several months after stopping therapy, leading to higher turnover bone loss if nothing else is given. Phase 2 clinical trial data showed that markers of bone formation and bone resorption both rebound above baseline within 6 to 12 months of stopping denosumab. High bone turnover may allow perforation of bony trabeculae and rapid bone loss leading to vertebral structural weakness and subsequent vertebral fractures. As a result of an increased risk of multiple vertebral fractures. 

Bisphosphonate therapies give long-lasting protection against postmenopausal bone loss.  Oral bisphosphonate therapies are typically given for three to five years, followed by up to a five-year drug holiday as long as the femoral neck bone density is above -2.5 and the patient has not had a fracture while on therapy. Intravenous zoledronic acid is given once yearly for up to three years and then followed by a three-year drug holiday, unless the patient has femoral neck bone density less than -2.5 or has sustained a low-trauma fracture on therapy. Bisphosphonate therapy is not usually stopped if the post-treatment T-score is less than -2.5 or a fracture has occurred while on therapy.

Antiresorptive osteoporosis therapies other than bisphosphonates lose their effect soon after therapy is discontinued. Because of this, bone formation and resorption typically increase toward baseline within the next several months after stopping therapy, leading to higher turnover bone loss if nothing else is given. Phase 2 clinical trial data showed that markers of bone formation and bone resorption both rebound above baseline within 6 to 12 months of stopping denosumab. High bone turnover may allow perforation of bony trabeculae and rapid bone loss leading to vertebral structural weakness and subsequent vertebral fractures. As a result of an increased risk of multiple vertebral fractures. 

Bone/Parathyroid Case 1

A 34 year-old woman comes to the emergency department for evaluation and management of postsurgical hypoparathyroidism. Her serum calcium is 6.8 mg/dL (normal, 8.9 to 10.1 mg/dL) two days after undergoing subtotal thyroidectomy for a unicentric 2.5-cm right thyroid lobe papillary cancer, without evidence of metastatic lymph nodes. She tolerated her surgery without difficulty but developed mild symptoms of tingling paresthesias at her fingertips, toe tips, and lips, and muscle cramps, beginning about six hours after surgery. She was sent home on calcium carbonate 500 mg twice daily, but her tingling paresthesias worsened over the next 24 hours. Her laboratory studies during her emergency department evaluation showed her serum phosphate increased at 6.4 mg/dL (normal, 2.5 to 4.5 mg/dL), serum creatinine normal at 1.0 mg/dL, and parathyroid hormone (PTH) undetectable.

Question 1

What treatments should be offered acutely to this patient with newly diagnosed symptomatic hypoparathyroidism?

A. Infusion of calcium gluconate given by diluting 10 mL of 10% calcium gluconate solution in 100 mL D5W (5% dextrose in water) over 5-10 minutes and repeat as needed
B. Begin oral calcium citrate 600 mg elemental calcium two tablets twice daily as soon as she can begin oral intake
C. Begin magnesium oxide 400 mg twice daily
D. Begin calcitriol 0.25 mg twice daily
E. All of the above
Incorrect!
Correct!
Correct Answer
E. All of the above

Patients with new-onset postsurgical hypoparathyroidism commonly present to the emergency department within several days of surgery with hypocalcemia, hyperphosphatemia, normal serum creatinine, and a low or undetectable parathyroid hormone level. Most patients with acute hypoparathyroidism are symptomatic, like this patient, with tingling paresthesias around their fingertips, toe tips, and lips, and experience muscle cramps or tetany.

Chvostek's sign, Trousseau's sign, and prolonged QT interval on their electrocardiogram may be seen. Repletion of their deficiencies with supplementation of intravenous calcium followed by oral calcium, both active and nutritional vitamin D, and magnesium, if needed, is usually sufficient to minimize their symptoms and signs. Doses are titrated up every few days until serum calcium is in the 8.0 to 8.5 mg/dL range, with improved symptoms, serum 25-hydroxyvitamin D are in goal range, and serum magnesium is normal.

Patients with new-onset postsurgical hypoparathyroidism commonly present to the emergency department within several days of surgery with hypocalcemia, hyperphosphatemia, normal serum creatinine, and a low or undetectable parathyroid hormone level. Most patients with acute hypoparathyroidism are symptomatic, like this patient, with tingling paresthesias around their fingertips, toe tips, and lips, and experience muscle cramps or tetany.

Chvostek's sign, Trousseau's sign, and prolonged QT interval on their electrocardiogram may be seen. Repletion of their deficiencies with supplementation of intravenous calcium followed by oral calcium, both active and nutritional vitamin D, and magnesium, if needed, is usually sufficient to minimize their symptoms and signs. Doses are titrated up every few days until serum calcium is in the 8.0 to 8.5 mg/dL range, with improved symptoms, serum 25-hydroxyvitamin D are in goal range, and serum magnesium is normal.