Sie sind auf Seite 1von 10

Small Group Session

Calcium/ Bone Metabolism

Case Discussion 1
A 44-year-old white man is scheduled for a vasectomy. His past medical history is remarkable
for two episodes of nephrolithiasis.
A routine preoperative chemistry profile is normal except for a serum calcium level of 11.6
mg/dL (Normal: 8.4 - 10.6) and a phosphorus concentration of 1.7 mg/dL (Normal: 2.5 - 4.5). His
serum ionized calcium is 1.52 mmol/L (Normal: 1.12 - 1.23), his serum creatinine measures 1.0
mg/dL, and his albumin is 3.8 g/dL (Normal 3.5-5.0 g/dL)
His physical examination is unremarkable: Blood pressure 112/72 mmHg, pulse 72 bpm,
height 70 inches, weight 169 pounds.
Questions
1. What is the most likely etiology of this man's hypercalcemia? What are the differential
diagnoses for hypercalcemia?
2. Should he go to surgery, or should it be postponed until this problem is resolved?
3. What laboratory tests would you order to confirm your diagnosis?
4. Which one of the following statements regarding parathyroid hormone is UNTRUE?
a.
b.
c.
d.
e.

PTH stimulates renal synthesis of 1,25(OH)2 vitamin D3.


It shares biologic activity with PTH-related protein.
It acts directly on the gut to increase Ca2+ absorption.
It promotes reabsorption of calcium from the glomerular filtrate.
Levels may be elevated in pseudohypoparathyroidism and osteomalacia.

5. What treatment or treatments are available for this man's condition?


6. What additional diagnostic tests can be done that might aid in the treatment?
7. He wants to know if there is a pill available as treatment. What do you tell him?
8. He wants to know the consequences of no treatment.
9. Should all patients with hyperparathyroidism be treated?
10. The 99mTc-sestamibi study showed increased uptake in the left lower pole, suggestive of
left lower parathyroid adenoma. This was easily resected by the surgeon. Postoperatively,
he is found to be hypocalcemic, with ionized calcium of 1.02 mmol/L (Normal: 1.15 1.32). He is asymptomatic. What are some explanations for the hypocalcemia? What is
the treatment?

Small Group Session

Calcium/ Bone Metabolism

Case Discussion 2
A 73-year-old woman presents to your office on referral from an orthopedic surgeon. She
recently suffered a compression fracture of L2, causing significant back pain. X-rays reveal old
compression fractures of L1 and T12. She had a hysterectomy and bilateral salpingooophorectomy at age 32 for uterine leiomyomas and has never received estrogen replacement.
Medications include verapamil for hypertension, a multivitamin and levothyroxine 150 mcg daily
which she has taken for over 30 years for a "low thyroid".
The physical examination reveals a thin woman with a slightly kyphotic posture. Her height and
weight are 57 inches (62 in her younger years) and 115 pounds, respectively. The remainder of
her examination is unremarkable. Recent laboratory studies include: Hemoglobin 13.2 g/dL
(Normal: 12 -14), Calcium 9.2 mg/dL (Normal: 8.2 - 10.2), BUN 8 mg/dL (Normal 4 - 20),
Creatinine 0.8 mg/dL (0.5 - 1.5), TSH 0.12 mlU/L (Normal: 0.25 - 4.5).
Questions
1. What is the definition of osteoporosis? How does it differ from osteomalacia?
2. What are the risk factors for osteoporosis?
3. The most accurate method of measuring bone density among the following is:
a.
b.
c.
d.
e.

Bone scan
Dual-energy x-ray absorptiometry (DXA)
Lateral spine x-ray
MRI of the spine
Single-photon absorptiometry (SPA)

4. Routine laboratory studies in patients with osteoporosis are most likely to


demonstrate (choose one):
a.
b.
c.
d.
e.
f.
g.

Hypocalcemia
Hypercalcemia
Low serum vitamin D levels
Anemia
High alkaline phosphatase
Abnormal serum protein electrophoresis
None of the above

5. What diagnostic workup would you like to perform in this patient?


6. What is your interpretation of the bone mineral density (BMD) DXA study?
L1-4 BMD is 0.59 g/cm2, T-score -4.1 or -4.1 SD below young-normal, same
gender, Caucasian reference population, Z-score -1.8 or 1.8 SD below age,
same gender, and race or ethnic matched reference population.
7. What is FRAX and how does it assist clinicians decide who to treat?
8. What treatment modalities are available?

Small Group Session

Calcium/ Bone Metabolism

Case Discussion 3
A 59-year-old woman is new to your practice after she moved three months ago from Seattle,
Washington to South Florida. Shortly before her move, her previous internist had called and
informed her of an elevated PTH level. He told her, she may have primary
hyperparathyroidism.
She is feeling well and her present and past medical history is rather unremarkable. Her last
menstrual period was 7 years ago and she was on hormone (estrogen/progestin) replacement
therapy for 4 years. She stopped the treatment about 3 years ago. She denies any personal or
family history of kidney stones, gastric or duodenal ulcers or non-traumatic fractures. She
exercises for about 45 minutes on a daily basis.
On physical examination, she is a well-developed, tall and slender Caucasian woman with a
rather fair complexion. Her blood pressure is 124/ 78 mmHg with a heart rate of 68 bpm. She is
5 11 (180 cm) tall and has a body weight of 164 pounds (74.5 kg; BMI 23) She exhibits normal
posture and gait. The remainder of her physical examination is unremarkable.
She presents the test results her previous internist had obtained in Seattle. The report shows an
intact PTH level of 115 pg/mL (normal range 10-65), a serum calcium concentration of 9.0
mg/dL (normal range 8.5-10.2), a serum phosphorus of 2.7 mg/dL (normal range 2.4-4.5), an
albumin of 4.1 g/dL (normal range 3.7-4.5) and an alkaline phosphatase of 145 U/L (normal
range 30-110). AST, ALT, bilirubin and serum creatinine were all within the normal range.
Her DXA bone mineral density test obtained 4 months ago revealed a T-score of -2.4 measured
at her lumbar spine and T-score of -2.0 at her hip.
Questions
1. Does this woman have primary hyperparathyroidism? Could there be other causes for
her elevated serum PTH?
2. Do you need to order additional laboratory test(s) to confirm the diagnosis?
3. Why does she have a low bone mineral density?
4. How do you treat her condition?
5. Would you recommend treating her osteopenia with a bisphosphonate?
6. Is surveillance of this patients condition needed and, if so, what tests would you order to
monitor the effectiveness of the therapeutic intervention?
7. What are consequences, if this patient does not receive adequate treatment?
8. What are causes leading to this condition?

Small Group Session

Calcium/ Bone Metabolism

ANSWERS to Case 1
1. What is the most likely etiology of this man's hypercalcemia?
Primary hyperparathyroidism: This is the most likely cause of hypercalcemia in an
asymptomatic outpatient (incidence about 1:800); more likely than malignancy, vitamin D
intoxication, milk-alkali, sarcoidosis or drugs (thiazides, lithium).
The hypercalcemia is
generally mild but can be rather profound, with values in the 13-14 mg/dL range or
occasionally even higher. The low serum phosphorus is consistent with hyperparathyroidism
or PTHrP from malignancy. Other diseases to consider are sarcoidosis and familial
hypocalciuric hypercalcemia. Malignancy is the most common cause of hypercalcemia in ill
hospitalized patients.
Differential Diagnosis of Hypercalcemia:
V
I
T
A
M
I
N
S

Vitamins
Immobilization
Thyrotoxicosis
Addison's disease
Milk alkali syndrome
Inflammatory disorder
Neoplastic
Sarcoidosis

T
R
A
P

Thiazides
Rhabdomyolysis
AIDS
Parathyroid disease
Parenteral nutrition
Pagets
Pheochromocytoma

2. Should he go to surgery, or should it be postponed until this problem is resolved?


This man has likely had modest hypercalcemia for years. There is little risk of undergoing an
outpatient surgery such as a vasectomy, so surgery may proceed.
3. What laboratory tests would you order to confirm your diagnosis? Intact serum
parathyroid hormone (PTH) level to see if calcium is caused by this, and urine calcium
excretion to exclude familial hypocalciuric hypercalcemia (FHH) with low urinary calcium
excretion (low FECa- under 1%).
FHH is an uncommon, genetically transmitted disorder. It is characterized by mild
asymptomatic hypercalcemia, normal or less often mildly elevated PTH levels, and low
fractional excretion of calcium. It is most frequently confused with primary
hyperparathyroidism, and patients may undergo parathyroidectomy of 1-3 glands, only to
have the hypercalcemia persist. Parathyroid hyperplasia often occurs, confusing the
diagnosis. Calcium:creatinine (Ca:Cr) clearance ratio is usually > 0.01 in
hyperparathyroidism and < 0.01 (<1%) in FHH. Presently, there are no genetic markers of
FHH; it would have been helpful to screen first-degree relatives in this patient, but this is
impossible since he is adopted. To calculate Ca:Cr clearance, four values are needed: 24hour urine calcium (fasting random specimen may be substituted), 24-hour urine creatinine
(or random specimen), Serum calcium (since 40% is bound to protein, the kidney only filters
60%. Serum Ca x 0.6 is the value to use), serum creatinine.
FECa = [UCa /SCa ] / [UCr /SCr ] x 100 If <1%, then consider FHH.

Small Group Session

Calcium/ Bone Metabolism

Give Laboratory values: Repeat serum calcium, 11.8 mg/dL (Normal: 8.4 10.6); Albumin 3.8 mg/dL; repeat phosphorus, 1.6 mg/dL (Normal: 2.5 - 4.5); PTH
(intact), 207 pg/mL (Normal: 15 -65); 24-hr urine calcium 400 mg, urine creatinine
1200 mg/d.
4. Which one of the following statements regarding Parathyroid hormone is UNTRUE?
(c.) It acts directly on the gut to increase Ca 2+ absorption. The actions of PTH on the
intestine are indirect and are mediated by calcitriol. PTH enhances synthesis of calcitriol
(1,25(OH)2D3) by stimulating 1-hydroxylase. It has similar biologic actions as the PTHrelated protein secreted in small amounts in normal individuals and by certain tumors. The
two share minimal structural homology, however. PTH and PTHrP act directly to promote
calcium reabsorption in the kidney, but PTHrP does not stimulate the 1-hydroxylase - all
new calcium comes from bone with this mechanism.
5. What treatment or treatments are available for this man's condition? The only cure for
primary
hyperparathyroidism
is
parathyroidectomy. About
80%
of
primary
hyperparathyroidism is due to a solitary adenoma; 18% is due to four-gland hyperplasia.
Parathyroid carcinoma is quite rare (1-2%). Medical therapy with a calcimimetic such as
cinacalcet (Sensipar) can reduce PTH concentrations and hypercalcemia while on
treatment. Other medications such as the bisphosphonates inhibit calcium resorption from
bone but have no effect on the kidney. These can prevent the development or worsening of
osteoporosis. Estrogens occasionally have minimal effect in postmenopausal women, but
this does not normally correct the hypercalcemia. Medications that promote calcium
reabsorption (e.g., thiazide diuretics) should be discontinued. Given this man's history of
renal stones, parathyroidectomy was recommended.
6. What additional diagnostic tests can be done that might aid in the treatment? If
possible, preoperative localization of parathyroid tissue is a worthwhile goal. However, it is
not necessary for an experienced parathyroid surgeon. Ultrasound is sometimes useful for
locating a large adenoma but gives no information about function.
A relatively new technique for parathyroid scanning is the use of 99mTc-sestamibi (MIBI, 2methoxy-isobutyl isonitrile, Cardiolite). 99mTc-MIBI accumulates in both the thyroid and the
parathyroid glands, with a peak activity at 4 - 6 minutes, and accumulates in the
mitochondria. Since parathyroid adenomas have large numbers of mitochondria per cell, the
washout rate of activity from the thyroid gland exceeds the washout rate from parathyroid
adenomas. This compound appears to be best for the localization of parathyroid tissue.
Remember that imaging procedures are used only to aid in surgical resection, not to
establish the diagnosis. This must be done biochemically. During surgery, many are now
measuring PTH levels with a "quick" assay to confirm that the offending gland(s) are
removed.
7. He wants to know if there is a pill available as treatment. What do you tell him?
Medical therapy with a calcimimetic such as cinacalcet (Sensipar) can reduce PTH
concentrations and hypercalcemia while on treatment. These compounds bind to the
calcium-sensor receptor, mimic calcium action, and diminish PTH synthesis and secretion.
They do not have calcium-like action in other tissues. The drug is FDA-approved for

Small Group Session

Calcium/ Bone Metabolism

secondary hyperparathyroidism of renal failure and parathyroid cancer, but it is used offlabel in some patients with primary hyperparathyroidism.
It has also been shown that treatment of PHPT with oral bisphosphonates can prevent
further bone loss, though it does not normalize calcium levels or PTH levels.
8. He wants to know the consequences of no treatment. Consequences of no treatment
include osteoporosis, osteitis fibrosa cystica, peptic ulcer disease (relationship
controversial), calcium kidney stones, parathyroid crisis (sudden onset of severe
hypercalcemia).
9. Should all patients with hyperparathyroidism be treated? Surgery is indicated in
symptomatic hypercalcemia, osteitis fibrosa cystic, fragility fractures due to secondary
osteoporosis caused by hyperparathyroidism, patients with kidney stones and those
unwilling or unable to be monitored. According to the Proceedings of the 2008 Third
International
Workshop
on
Asymptomatic
Primary
Hyperparathyroidism,
parathyroidectomy is recommended in patients with asymptomatic primary
hyperparathyroidism with:
serum calcium 1.0 mg/dl > upper normal limit
creatinine clearance < 60 ml/min
DXA BMD T-score -2.5
Age < 50 years
10. This man's 99mTc-sestamibi study showed increased uptake in the left lower pole,
suggestive of left lower parathyroid adenoma. This was resected easily by the
surgeon. Postoperatively, he is found to be hypocalcemic, with ionized calcium of
1.02 mmol/L (Normal: 1.15 -1.32). He is asymptomatic. What are some explanations for
the hypocalcemia? What is the treatment? Given hypersecretion of PTH from a solitary
adenoma, the other three glands are usually atrophied. Therefore, transient hypocalcemia
may occur right after surgery until the other glands "wake up". It may take several days for
this to fully resolve. If he is not symptomatic, the best approach is simply to watch him. He
can go home and come into the laboratory for daily calcium determinations. Intravenous
calcium should be avoided unless the patient is severely symptomatic, as this will delay
recovery of the remaining parathyroid glands.
Patients with hyperparathyroidism can also have a "hungry bone syndrome", in which
normalization of the PTH results in the highly active bone "stealing" calcium from the serum.
This can often be predicted by the presence of a high alkaline phosphatase before surgery
and is treated with oral elemental calcium 1.5 g daily. It may last for several weeks to
months. If the patient remains hypocalcemic with no improvement after several days, the
possibility that the other parathyroids have been damaged must be considered.
Measurement of an intact PTH level easily differentiates hypoparathyroidism from the
hungry bone syndrome, as it should be low in the former, normal in the latter.
His hypocalcemia resolved in 2 days, consistent with suppression of the other three glands.

Small Group Session

Calcium/ Bone Metabolism

ANSWERS to Case 2
1. What is the definition of osteoporosis? Osteoporosis is the most common metabolic bone
disease and is characterized by decreased bone mass and deterioration of the bone
microarchitecture, with consequent decreased bone strength and increased susceptibility to
fracture. This woman has radiographic evidence of compression fractions, and, in the
absence of other causes (e.g., metastatic cancer), this is diagnostic of osteoporosis.
As many as 25 million people in the United States have osteoporosis, and complications
result in considerable morbidity and mortality and constitute a major health expense.
Osteoporosis is asymptomatic until fractures occur; the diagnosis is often made only when
osteopenia and/or crush fractures are seen on x-rays. Unfortunately, at least 30% of bone
mineral must be lost before changes are seen on conventional x-rays. Osteoporosis may be
diagnosed using current high-accuracy techniques to measure bone mass.
How does it differ from osteomalacia? Osteomalacia is characterized by normal amounts
of collagenous bone matrix with deficient mineralization. Osteoporosis is caused by a
decrease in bone mass and deterioration of the microarchitecture. Both are separate causes
of osteopenia (low bone mass) and are treated quite different.
2. What are the risk factors for osteoporotic fracture?
Age - most important determinant of bone mass; loss of bone may begin as early as age 30.
Female sex - Women have lower DXA BMD (age, size matched) than men at all ages and
sites. Age-specific rates for hip fractures are two to three times higher in women than in
men.
Bone mineral density.
Race - less common in blacks than in fair-skinned Caucasians and Asians.
Lean body build Slender Built- less common in obese individuals (increased compartment
for sex steroid aromatization, "force of gravity").
Alcohol ingestion.
Cigarette smoking.
Postmenopausal women (especially early or surgically induced); bone loss in elderly women
is also accelerated by age factors.
Hypogonadism in males. Prolonged amenorrhea.
Decreased calcium intake. Current recommended calcium intake in the United States is
between 1000 and 1500 mg/day. The average calcium intake of middle-aged and elderly
women in the U.S. is only 550 mg/day. A relationship between fractures and h/o low calcium
intake has been established.
Secondary diseases such as rheumatoid arthritis and medical conditions such as bariatric
surgery.
Medications such as glucocorticoids.
Parental history and personal history of fragility fractures.
3. The most accurate method of measuring bone density among the following is:
(b) Dual-energy x-ray absorptionmetry (DXA) is the procedure of choice and can measure
bone density with excellent precision (1 - 2%). It is highly accurate, non-invasive, and
relatively quick and it gives relatively low radiation exposure. Ultrasound of the calcaneous is
often used as a screening test, but a DXA should be performed for a final diagnosis (WHO

Small Group Session

Calcium/ Bone Metabolism

diagnostic criteria only uses DXA of spine, hip, forearm).


A radionuclide bone scan may be useful in looking for occult fractures or metastatic disease
but gives no quantitative measurement of bone mass. Lateral spine films may show
compression fractures but are very inaccurate in quantifying bone mass; 30% of bone mass
must be lost before osteopenia is evident. MRI does not provide quantitative information.
QCT (quantitative CT) is quite accurate but more expensive than DXA and produces greater
radiation exposure.
4. Routine laboratory studies in patients with osteoporosis are most likely to
demonstrate:
(g) None of the above. Routine laboratory studies are usually normal in osteoporosis.
Secondary causes (e.g., hyperparathyroidism, excess cortisol or thyroid) and multiple
myeloma should be excluded, particularly if anemia, high serum globulins, venous
thrombosis or neuropathy are present.
5. What diagnostic workup would you like to perform in this woman? In an uncomplicated
patient with osteoporosis, laboratory studies are usually completely normal. Secondary
causes always need to be excluded, however; it is inadequate to simply place a patient with
multiple compression fractures on bisphosphonates without doing a basic workup. Normally,
a CBC, electrolytes, and a basic metabolic panel should be checked.
Patients with anemia may have a hematologic disorder such as multiple myeloma.
If serum calcium is low, investigation for vitamin D deficiency should be undertaken.
25(OH)-vitamin D is the most sensitive marker. Low serum phosphorus often
accompanies vitamin D deficiency. Severe vitamin D deficiency resulting in low
serum calcium is uncommon. However, mild vitamin D deficiency is rather prevalent,
particularly in the older population. It is characterized by normal serum calcium levels
and mildly elevated PTH.
If hypercalcemia exists, intact parathyroid hormone (PTH) should be measured; if
elevated, hyperparathyroidism is the most likely etiology. The benefit of measuring
serum PTH in a normocalcemic patient is controversial; many are concerned about
subclinical hyperparathyroidism (elevated PTH with normal calcium).
Urine calcium can be measured. If 24-hour excretion is high (> 400 mg) as a primary
mechanism, a thiazide diuretic can be added (this reduces calcium excretion).
Fractures due to multiple myeloma and diffuse metastasis of malignant tumors in the elderly
can be often misdiagnosed as caused by osteoporosis.
6. What is your interpretation of the DXA study of bone mineral density (BMD)? Severe
osteoporosis is defined as the presence of a clinical fragility fracture and the DXA diagnosis
of osteoporosis. Review differences between T score and Z score.
7. What is FRAX and how does it assist clinicians decide who to treat? Explain the
FRAX algorithm 10-year risk of Major and Hip fractures and NOF Guidelines for costeffective therapeutic intervention that are inclusive of FRAX.
8. What treatment modalities are available? Oral calcium & vitamin D (inhibits PTH),
raloxifene, bisphosphonates, calcitonin, daily subcutaneous synthetic/recombinant PTH.
This patient has subnormal TSH and should take a smaller dose of L-thyroxine.

Small Group Session

Calcium/ Bone Metabolism

ANSWERS to Case 3
1. Does this woman have primary hyperparathyroidism? Could there be other causes for
her elevated serum PTH? The patient may have primary hyperparathyroidism but we need
to perform further testing in order to determine the cause of the high PTH. Primary
hyperparathyroidism usually presents with elevation of PTH levels along with calcium levels
that are either elevated or in the upper limit of normal. Prolonged hyperparathyroidism can
lead to osteoporosis and mild elevation of alkaline phosphatase. Vitamin D insufficiency
(<30 ng/ml) and deficiency (<10 ng/ml) can also present with mild PTH elevations, but never
with hypercalcemia. Vitamin D levels usually decline with age, in the winter months and in
individuals with darker skin. Low vitamin D concentrations are associated with osteoporosis,
increased risk of falls, and fractures. Its treatment is very important not only for a healthy
musculoskeletal system but for immune and cardiovascular system as well.
2. Do you need to order additional laboratory test(s) to confirm the diagnosis? The best
way to check levels vitamin D is measuring the 25-hydroxyvitamin D (25OHD or calcidiol)
levels, which reflect vitamin D storage. A 24 hour urine collection for calcium may also be
helpful since usually it is low in these patients.
3. Why does she have a low bone mineral density? As levels of vitamin D fall, calcium
absorption from the gut decreases leading to a rise of PTH levels. This compensatory rise in
PTH levels results in excessive bone resorption that, over time, can cause bone loss
depicted on DXA by low bone mass (osteopenia) and eventually osteoporosis.
4. How do you treat the problem? The treatment consists of vitamin D supplementation. The
recommended Institute of Medicine RDA doses for calcium are 1,000 to 1,200 mg a day
and, depending on the vitamin D levels, large doses of vitamin D might be necessary.
Cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2) can be used. Because the
absorption and metabolism of Vit D are variable and sun exposure is difficult to quantify,
plasma levels of Vit D are useful in assessing Vit D status in patients with osteoporosis and
monitoring response to supplementation. Optimal serum concentration is >30 ng/ml (80
nmol/L). However, it should be noted there is considerable controversy about the optimal
level of plasma 25D (should discuss IOM report and editorials in journals critical of this
report). 1,25 hydroxy-vitamin D Calcitriol (1,25 OH Vit D ) which is active Vit D, is not
recommended because may cause hypercalcemia and hypercalciuria necessitating close
monitoring and adjustment of calcium intake and calcitriol dose. In patients with normal
absorptive capacity, for every 40 IU (1 mcg) of D3, serum 25OH Vit D increase by
approximately 0.3 0.4 ng/ml. If levels < 20 ng/ml, initial treatment with vit D2 50,000 IU
weekly for 6-8 weeks is recommended, and lower doses thereafter.
5. Would you recommend treating her osteopenia with a bisphosphonate?
Usually we correct Vit D levels first. Treatment with a bisphosphonate in a patient with
hypovitaminosis D can lead to hypocalcemia, as these drugs will reduce bone resorption
which in these cases may be the main source of calcium. If the patient has osteoporosis or
multiple risk factor for developing osteoporosis (lean body, cigarette smoker, excessive
alcohol intake, prolong therapy with glucocorticoids or anticonvulsants meds, etc) we would
suggest treatment soon after vitamin D levels are corrected.

Small Group Session

Calcium/ Bone Metabolism

6. Is surveillance of this patients condition needed and, if so, what tests would you
order to monitor the effectiveness of the therapeutic intervention? Levels of Vit D
should be monitored 3 months after initiating therapy.
7. What are consequences, if this patient does not receive adequate treatment? If Vit D
deficiency is not treated, patients may develop osteoporosis, fractures, be at increased risk
for falls and eventually hypocalcemia.
8. What are causes leading to this condition? Vitamin D deficiency most commonly results
from inadequate intake of vit D, lack of sun exposure, malabsorption (Crohns disease,
sprue, bariatric surgery) or underlying gastrointestinal disease.