Osteoporosis, Cushing Syndrome Case File

Osteoporosis, Cushing Syndrome Case File

Eugene C. Toy, MD, Gabriel M. Aisenberg, MD

Case 35

A 57-year-old man is referred to the internal medicine clinic for a right radius/ ulnar fracture that occurred 1 week ago from an incidental contact with the car door. X-rays showed marked demineralization of the bones. He also has fatigue, weakness, and a 20-lb weight gain over the last 2 years, particularly around the abdomen. He has noticed these symptoms for around 3 months. He denies suffering from any medical condition, although his last visit to a primary care provider was more than 5 years ago. He reports a 30 pack-year history of cigarette smoking and denies alcohol or illicit drug consumption. On examination, his blood pressure is 155/95 mm Hg, pulse rate is 80 beats per minute (bpm), respiratory rate is 20 breaths per minute, and temperature is 99 °F. His body mass index (BMI) is 28 kg/m2. His neck, abdomen, and upper back look full, with reddish-purple striae on his abdomen and thighs. His heart examination shows regular sounds S1 and S2, without murmurs or gallops. Lung examination shows a slightly decreased vesicular breath sound on the right hemithorax, without adventitious sounds. His abdomen is nontender and shows no organomegaly. His right arm is in a short arm cast. Laboratory tests show a hemoglobin A1c (Hb A1c) of 8.5%, serum sodium of 140 mmol/L (normal 135-145), serum potassium of 3.3 mmol/L (normal 3.5-5.1), and serum bicarbonate of 30 mmol/L (normal 24).

▶ What is the cause of the patient’s bony problem?

▶ What is the most likely diagnosis?

▶ What are your next diagnostic steps?

ANSWERS TO CASE 35 B:

Osteoporosis, Cushing Syndrome

Summary: A 57-year-old man presents with

• A history of heavy smoking
• Decreased bone mineral density (BMD) and recent fragility fracture
• Fatigue, weakness, and weight gain
• BMI of 28 kg/m2 (noted to be overweight)
• Hypertension, centripetal fat distribution, and reddish-purple striae
• Laboratory testing that shows hypokalemia, metabolic alkalosis, and elevated Hb A1c

Cause of bony problem: Likely osteoporosis or osteopenia due to high corticosteroid levels.

Most likely diagnosis: Cushing syndrome, possibly paraneoplastic.

Next diagnostic step:

• Once Cushing syndrome is suspected, one of three tests should be obtained: 24-hour urine-free cortisol (UFC), late-night salivary cortisol, or the low-dose (1 mg) overnight dexamethasone suppression test (DST).
• If any of the above is abnormal, obtain a chest x-ray or contrast-enhanced computed tomography (CT) of the chest. There is high suspicion for ectopic adrenocorticotropic hormone (ACTH) syndrome from a small-cell lung carcinoma due to the history of heavy smoking, rapid onset of symptoms, and evidence of mineralocorticoid excess (hypertension, hypokalemia, and metabolic alkalosis).
• Obtain an imaging study of the BMD, such as a dual-energy x-ray absorptiometry (DEXA) test.

ANALYSIS

Objectives

1. Recognize the diagnostic approach to suspected Cushing syndrome. (EPA 3)
2. Outline the differential diagnosis for Cushing syndrome. (EPA 2)
3. Identify treatment options for Cushing syndrome. (EPA 4)
4. Describe the criteria to diagnose abnormally low BMD, such as osteopenia and osteoporosis. (EPA 1, 3)

Considerations

This 57-year-old man presents with a fragility fracture (bone fracture with minor or no trauma) and radiographic evidence of decreased bone mineralization on x-ray. He also has many of the stigmata of corticosteroid excess, such as hypertension, central obesity, abdominal striae, hyperglycemia, and likely buffalo hump. Because of the smoking history, the Cushing syndrome may be due to a lung cancer secreting ACTH-like hormone (paraneoplastic syndrome), which stimulates the adrenal gland to produce excess corticosteroids. Another possibility is that there is an autonomous tumor (adenoma) of the adrenal cortex producing corticosteroids. The bony problem is likely due to the high levels of corticosteroids, which is the most common cause of secondary osteoporosis (not aged related); if the patient has an underlying lung cancer, bony metastasis to the arm is also possible. Cigarette smoking also predisposes to osteoporosis. The four most important issues for this patient are (1) suspecting Cushing syndrome based on the history and physical examination, (2) recommending the initial laboratory tests once Cushing syndrome is suspected, (3) determining the etiology of the Cushing syndrome, and (4) understanding other steps in management, including additional diagnostic tests and treatment options.

APPROACH TO:

Osteoporosis, Cushing Syndrome

DEFINITIONS

ACTH-DEPENDENT CUSHING SYNDROME: Cushing syndrome due to an ACTH-secreting pituitary adenoma or ectopic source.

ACTH-INDEPENDENT CUSHING SYNDROME: Cushing syndrome caused by an adrenal disorder.

BISPHOSPHONATES: Synthetic carbon phosphate compounds (alendronate, risedronate, ibandronate) that build bone mass by binding to pyrophosphatase in bone and by inhibiting osteoclast bone resorption.

CUSHING DISEASE: Cushing syndrome caused by an ACTH-secreting pituitary adenoma.

CUSHING SYNDROME: The signs and symptoms that develop when the body is exposed to excess glucocorticoids.

DEXAMETHASONE SUPPRESSION TEST: In normal individuals, supraphysiologic doses of glucocorticoids suppress the secretion of ACTH and cortisol. The low-dose (1-mg) DST is one of three tests obtained to confirm a diagnosis of Cushing syndrome. The high-dose (8-mg) DST is used to confirm the source of ACTH-dependent Cushing syndrome (ACTH-secreting pituitary adenoma or ectopic source).

OSTEOPENIA: BMD that is lower than normal and considered to be a precursor to osteoporosis. Often defined as a BMD T score of between −1 and −2.5.

OSTEOPOROSIS: Progressive systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue and leading to an increase in bone fragility and susceptibility to fracture. Often defined as a BMD T score of less than −2.5.

T SCORE: A BMD comparison against young healthy adults (in standard deviations [SDs] from the mean).

CLINICAL APPROACH TO CUSHING SYNDROME

Pathophysiology

Iatrogenic Cushing syndrome, the most common cause, results from glucocorticoid treatment of inflammatory conditions. Cushing disease, which results from an ACTH-secreting pituitary adenoma, is the most common endogenous cause, accounting for 60% to 70% of cases. Ectopic ACTH syndrome, which comprises 5% to 10% of cases, refers to nonpituitary tumors that secrete ACTH. Most cases are due to small-cell lung carcinomas or neuroendocrine tumors of the lung, pancreas, or thymus. Adrenocortical adenomas, which secrete cortisol, account for 10% to 15% of cases. Other causes of Cushing syndrome include adrenocortical carcinoma, primary pigmented nodular adrenocortical disease (may occur as part of Carney complex), bilateral macronodular adrenal hyperplasia, and tumors that secrete corticotropin-releasing hormone (CRH). Long-term excess corticosteroid exposure (whether endogenous or medications) alters calcium absorption and directly inhibits osteoblast activity and augments osteoclast activity.

Clinical Presentation

Signs and symptoms of Cushing syndrome depend on the degree and duration of cortisol exposure. Some patients may present with obvious features of cortisol excess, while others present with subtle findings. While many features of Cushing syndrome are present in the general population (eg, obesity), some features are more specific for cortisol excess. This includes reddish-purple striae, plethora (ie, red face), proximal muscle weakness, and unexplained bruising. Other symptoms of cortisol excess include menstrual irregularities, decreased libido, and neuropsychiatric manifestations such as depression, sleep disturbances, and cognitive impairment. Associated conditions include hypertension, diabetes, and osteoporosis. On physical examination, the patient may exhibit facial fullness, supraclavicular or dorsocervical fat pads, thin skin, lower extremity edema, acne, or hirsutism.

Step 1: Confirm the Diagnosis of Cushing Syndrome. Once Cushing syndrome is suspected, one of three tests should be obtained: 24-hour UFC, late-night salivary cortisol, or the low-dose (1-mg) overnight DST. Each test has high sensitivity but lacks ideal specificity, so false-positive results may occur. If the initial diagnostic test is positive, one of the remaining tests must be obtained to confirm the diagnosis.

24-hour UFC: Two measurements should be obtained due to variability in cortisol secretion. False-positive results may occur with high fluid intake (> 5 L/d) or conditions associated with hypercortisolism (eg, depression or alcohol dependence). False-negative results may occur in patients with chronic kidney disease. Excreted urine cortisol levels begin to decrease with a creatinine clearance less than 60 mL/min and decrease markedly with a creatinine clearance less than 20 mL/min.

Late-night salivary cortisol: In healthy individuals, cortisol levels peak in the morning (7-9 am) and fall to very low levels during sleep. Patients with Cushing syndrome typically lose this normal circadian rhythm. Salivary cortisol should be measured between 11 pm and midnight, and like UFC, two measurements should be obtained due to variability in cortisol secretion. False-positive results may occur in patients who use tobacco, as tobacco contains 11-beta-hydroxysteroid dehydrogenase type 2 inhibitor glycyrrhizic acid, which inhibits the conversion of cortisol to inactive cortisone. Late-night salivary cortisol may not be appropriate for shift workers or patients with variable sleep patterns.

The low-dose (1-mg) DST: In normal individuals, supraphysiologic doses of glucocorticoids suppress the secretion of ACTH and cortisol. For the low-dose DST, the patient takes 1 mg of dexamethasone between 11 pm and midnight. Cortisol is measured the following morning at 8 am. The Endocrine Society recommends using a diagnostic cutoff value of 1.8 μg/dL to maximize sensitivity (greater than 95%). Using this cutoff, the specificity is 80%, yielding a high false-positive rate. False-positive results may occur in women taking oral contraceptive pills, which increase cortisol-binding globulin, leading to higher serum cortisol levels. In addition, false-positive results may occur in patients taking medications (eg, itraconazole, ritonavir) that decrease clearance of dexamethasone by inhibiting CYP (cytochrome P450) 34A. False-negative results may occur in patients taking medications (eg, phenobarbital, phenytoin, rifampin) that accelerate the metabolism of dexamethasone by inducing CYP 34A.

Step 2: Determine the Etiology (ACTH-Independent vs ACTH-Dependent Cushing Syndrome). After a diagnosis of Cushing syndrome is confirmed, plasma ACTH should be measured to determine the etiology.

ACTH-independent Cushing syndrome: A suppressed ACTH level (< 10 pg/mL) indicates the presence of an adrenal disorder (eg, adrenal adenoma or adrenal carcinoma). CT or magnetic resonance imaging (MRI) of the adrenal glands should be obtained to determine the type of adrenal lesion.

ACTH-dependent Cushing syndrome: A normal or elevated ACTH level (> 10 pg/mL) indicates the presence of an ACTH-secreting pituitary adenoma (Cushing disease) or ectopic ACTH secretion. Since the majority (80%) of cases are due to Cushing disease, a pituitary-protocol MRI is typically performed as the next diagnostic test. If there is high clinical suspicion for ectopic ACTH secretion, CT or MRI of the neck, chest, or abdomen/pelvis may be obtained to identify the causal tumor. Although there is overlap in ACTH levels and clinical presentation, patients with ectopic ACTH syndrome typically present with more severe hypercortisolism and evidence of mineralocorticoid excess (eg, hypertension, hypokalemia, metabolic alkalosis, or edema).

Step 3: Confirm the Source of ACTH-Dependent Cushing Syndrome. It is often challenging to localize an ACTH-secreting microadenoma on MRI. An adenoma is identified on imaging in only 60% of patients with Cushing disease. A normal MRI does not exclude a diagnosis of Cushing disease. Small pituitary lesions (≤ 6 mm) occur in 10% of the general population, so the presence of a pituitary abnormality on MRI does not confirm the diagnosis. Additional testing should be obtained to confirm the source of Cushing syndrome prior to surgical resection.

Inferior petrosal sinus sampling (IPSS): The Endocrine Society recommends IPSS for patients without an obvious causal tumor (ie, pituitary adenoma > 6 mm). Blood from the pituitary drains into the inferior petrosal sinuses. During petrosal sinus sampling, blood is sampled from both petrosal sinuses and a peripheral vein simultaneously. The central-to-peripheral ratio of ACTH is greater than 2:1 in patients with Cushing disease. Because ACTH secretion can be intermittent, it is helpful to sample blood at regular intervals (2, 5, and 15 minutes) after CRH is administered. A ratio greater than 3:1 after CRH administration has a sensitivity and specificity of 94% for the diagnosis of Cushing disease.

The high-dose (8-mg) DST: Noninvasive testing may be sufficient to confirm a diagnosis of Cushing disease if a pituitary adenoma greater than 6 mm is identified. In patients with Cushing disease, ACTH secretion is partially resistant to feedback inhibition from glucocorticoids. ACTH and cortisol secretion do not respond to 1 mg of dexamethasone (low-dose DST), whereas secretion is partially suppressed following the administration of 8 mg of dexamethasone (high-dose DST). For the high-dose DST, the patient takes 8 mg of dexamethasone between 11 pm and midnight. Cortisol is measured the following morning at 8 am. A 50% reduction in the cortisol level from baseline indicates a positive result. The high-dose DST yields high sensitivity but low specificity for identifying patients with Cushing disease.

CRH stimulation test: For the CRH stimulation test, ACTH and cortisol are measured at baseline and then every 15 minutes for 1 to 2 hours after CRH is administered. In healthy individuals, CRH produces a 15% to 20% increase in ACTH and cortisol levels. This response is exaggerated in patients with Cushing disease. ACTH typically increases by greater than 50%, and cortisol typically increases by greater than 20%. No response is seen in patients with ectopic ACTH syndrome. The sensitivity and specificity are approximately 90% for the diagnosis of Cushing disease.

Treatment

The first-line approach to treatment is typically surgical resection of the causal tumor. For example, if an adrenal adenoma is found, surgery is usually the best option. Medical management may be considered in the following situations: (1) persistent hypercortisolism following surgery, (2) a tumor that cannot be resected (eg, ACTH-producing small-cell lung carcinoma with metastases), and (3) situations in which cortisol levels need to be rapidly decreased in severely ill patients. The medications listed in Table 35–1 are used to treat patients with ACTH-independent or ACTH-dependent Cushing syndrome.

Medications used to treat patients with ACTH-dependent Cushing syndrome include somatostatin receptor agonists and dopamine agonists. Pasireotide is a somatostatin receptor agonist that has a higher affinity for somatostatin receptor subtypes 1 and 5 than octreotide or lanreotide. ACTH-secreting pituitary adenomas have high expression of somatostatin receptor subtype 5. Pasireotide decreases ACTH secretion and may decrease tumor size. Octreotide has been used to treat ectopic ACTH syndrome. Some ACTH-secreting tumors express somatostatin receptor subtype 2.

The dopamine agonist cabergoline has high affinity for dopamine receptor subtype 2, which is expressed by most ACTH-secreting pituitary adenomas. It is occasionally used to treat ectopic ACTH syndrome. Cabergoline is typically less effective than other agents for the treatment of Cushing syndrome.

CLINICAL APPROACH TO OSTEOPOROSIS

Epidemiology

Osteoporosis is an important health issue because the resultant bone fractures cause a great deal of morbidity in chronic pain, loss of independence, and loss of function, as well as mortality. Risk factors for the development of osteoporotic fracture include advanced age, previous fracture, glucocorticoid therapy, rheumatoid arthritis, low body weight, loss of steroid hormone production (menopause or hypogonadism), current smoking, excessive alcohol, and parental history of hip fracture. The Fracture Risk Assessment Tool (FRAX) risk calculator is available online to assess the 10-year probability of fracture. Approximately 14% of white women and 3% to 5% of white men will develop osteoporosis in their lifetime. The prevalence is lower in African Americans and higher in Asians.

Pathophysiology

Osteoporosis can be either idiopathic or a manifestation of another underlying disease process. Probably the most common form of secondary osteoporosis is caused by glucocorticoid excess, usually iatrogenic steroid use for an inflammatory disease such as rheumatoid arthritis. Patients, both men and women, with rheumatoid arthritis are susceptible to accelerated bone loss with even low doses of glucocorticoids. Gonadal deficiency is another common cause, which is seen physiologically in menopausal women but is seen pathologically in women who are amenorrheic (eg, female athletes such as gymnasts or marathon runners) or as a result of hyperprolactinemia. Men with gonadal failure for any reason also are prone to develop osteoporosis.

Osteoporosis is a common feature of several endocrinopathies. Patients with hyperparathyroidism will develop osteoporosis because of increased calcium mobilization from bone. Long-standing hyperthyroidism, either naturally occurring, as in Graves disease, or as a result of excessive replacement of levothyroxine in patients with hypothyroidism, will also lead to accelerated bone loss. Malnutrition and nutritional deficiencies are causative and are often seen in patients with malabsorption; for example, most patients, both men and women, with celiac sprue have osteoporosis. Certain medications, such as cyclosporine, antiepileptics, heparin, and gonadotropin-releasing hormone inhibitors, among others, may accelerate bone loss.

Peak bone density occurs in young adulthood under the influence of sex steroid hormone production. Other influential factors include genetics, which may account for 80% of total bone density, adequate calcium intake, and level of physical activity, especially weight-bearing activity. After age 35, bone breakdown begins to exceed bone replacement, and this increases markedly after menopause as a consequence of increased osteoclast activity.

Treatment

Treatment of osteoporosis takes a multifaceted approach. The first is avoidance of medications or conditions that predispose to bone loss (smoking cessation, reduction of systemic steroid use, and attention to nutrition). Adequate calcium intake, 1000 mg/d for premenopausal women and adult men and 1200 mg with 400 to 800 IU of vitamin D per day for postmenopausal women, leads to decreased fractures. Steroid estrogen receptor modulators such as raloxifene can increase bone density and reduce fracture risk, as can the use of bisphosphonates, in combination with both calcium and vitamin D. Bisphosphonates can lead to severe esophagitis and must be used with caution in individuals with gastric reflux disease. Oral bisphosphonates should be taken on an empty stomach, with a large quantity of water, and the patient should remain in the upright position for at least 30 minutes. Intravenous bisphosphonates are now available that can be infused quarterly or annually. There is some concern about long-term effects of bisphosphonates, including risk of osteonecrosis of the jaw and paradoxical bone fragility causing atypical subtrochanteric femur fractures. Many experts recommend a drug holiday after 5 years of treatment for patients with stable BMD.

Weight-bearing physical activity decreases bone loss and improves coordination and muscle strength, which may prevent falls. Ensuring that patients can see adequately, that they use a cane or walker if needed, that throw rugs are removed, that patients have railings to hold onto in the shower or bath, or that they wear hip protectors can further decrease the risk of life-altering bone fractures.

CASE CORRELATION

• See also Case 6 (Hypertension, Outpatient) and Case 51 (Type 2 Diabetes Diagnosis and Management).

COMPREHENSION QUESTIONS

35.1 A 38-year-old woman is being seen in the office due to concerns about irregular menses and a 15-lb weight gain over the last 2 years. Menarche occurred at age 12. Menses were regular until 2 years ago. Physical examination is notable for a blood pressure of 140/90 mm Hg, facial fullness, hirsutism, and supraclavicular fullness. Which of the following is the best next step?

A. High-dose (8-mg) DST

B. Low-dose (1-mg) DST

C. Measure plasma ACTH

D. Pituitary-protocol MRI

35.2 A 62-year-old man was seen by his primary care provider 2 weeks ago for severe, sudden-onset back pain. On further evaluation, his provider noted new-onset hypertension, dorsocervical fullness, and reddish-purple striae on his abdomen. An x-ray confirmed a T12 compression fracture. Laboratory tests showed an elevated serum cortisol level not suppressed by dexamethasone and two elevated 24-hour UFC values. Which of the following is the best next step?

A. High-dose DST

B. IPSS

C. Measure plasma ACTH

D. Pituitary-protocol MRI

35.3 A 57-year-old woman was seen 3 weeks ago for a health maintenance appointment. She complained about weight gain and difficulty sleeping over the last year. Physical examination revealed new-onset hypertension and centripetal distribution of fat. Laboratory tests show a Hb A1c of 8%, two elevated late-night salivary cortisol values, and two elevated 24-hour UFC values. Plasma ACTH is less than 5 pg/mL (normal 10-60). Which of the following is the best next step?

A. Abdominal CT

B. Chest CT

C. Pituitary-protocol MRI

D. Neck CT

35.4 A 32-year-old man was seen for a 2-year history of decreased libido, weight gain, and anxiety. On further evaluation, he was found to have unexplained bruising and supraclavicular fullness. Laboratory tests show an elevated serum cortisol level not suppressed by dexamethasone and two elevated late-night salivary cortisol values. Plasma ACTH is 38 pg/mL (normal 10-60). Pituitary-protocol MRI is normal. Which of the following is the best next step?

A. Abdominal CT

B. Chest CT

C. Inferior petrosal sinus sampling

D. A 24-hour UFC

35.5 A 60-year-old woman presents to the office for the results of her DEXA scan, which was performed as routine screening. She has no history of fragility fractures. She has a T score of –1.5 SD at the hip and –2.5 at the spine. Which of the following is the most accurate interpretation of these results?

A. She has osteoporosis at the spine and osteopenia at the hip.

B. She has osteoporosis in both areas.

C. This is a normal examination.

D. She has osteoporosis of the hip and osteopenia at the spine.

E. You need to know the Z score.

35.6 A 70-year-old woman is being seen in your office for a routine annual examination, and you order a DEXA scan for BMD screening. The T score returns as –2.5 SD in the spine and –2.6 in the hip. Which of the following statements is most accurate regarding this patient?

A. This patient has osteopenia.

B. Estrogen replacement therapy should be started with an anticipated rebuilding of bone mass to near normal within 1 year.

C. Swimming will help build bone mass.

D. Bisphosphonates would reduce the risk of hip fracture by 30% to 50%.

ANSWERS

35.1 B. This patient exhibits several signs and symptoms concerning for Cushing syndrome, including weight gain, hypertension, irregular menses, facial fullness, hirsutism, and supraclavicular fat pads. The low-dose DST is one of three tests performed to confirm the diagnosis of Cushing syndrome. Plasma ACTH (answer C) is obtained to determine the etiology after a diagnosis of Cushing syndrome is established. The high-dose DST (answer A) is one of three diagnostic tests performed to confirm the source of ACTH-dependent Cushing syndrome (ACTH-secreting pituitary adenoma vs ectopic source). A pituitary-protocol MRI (answer D) would not be performed until after the diagnosis of Cushing is established. If Cushing syndrome is ruled out, other potential causes of the patient’s symptoms may include polycystic ovarian syndrome, and pelvic ultrasound may be useful to evaluate for this condition.

35.2 C. A diagnosis of Cushing syndrome is confirmed by the positive low-dose DST and two elevated 24-hour UFC values. Plasma ACTH should be measured to determine the etiology (ACTH-independent vs ACTH-dependent Cushing syndrome). A pituitary-protocol MRI (answer D), high-dose DST (answer A), or IPSS (answer B) may be obtained after a diagnosis of ACTH-dependent Cushing syndrome is established.

35.3 A. A diagnosis of ACTH-independent Cushing syndrome is established by the suppressed ACTH level. A CT of the adrenal glands should be obtained to determine the type of adrenal lesion. A pituitary-protocol MRI (answer C), chest CT (answer B), or neck CT (answer D) may be obtained to identify the source of ACTH-dependent Cushing syndrome.

35.4 C. This young man has clinical findings of corticosteroid excess based on decreased libido, weight gain, bruising, and supraclavicular fullness (fat pad). The elevated serum cortisol not suppressed with dexamethasone and two salivary cortisol levels confirms hypercortisolism. A 24 hour UFC is not necessary since Cushing syndrome has already been established using two tests. The next step is to determine whether this is an ACTH-dependent or independent process. Because of the normal serum ACTH levels, this patient has ACTH-dependent Cushing syndrome; ACTH-independent Cushing syndrome is associated with low levels of serum ACTH. The third step is to determine the source of the ACTH. Most of the time, it will arise from the pituitary gland, but can also result from an ectopic ACTH producing location. This patient has a normal MRI of the pituitary gland; however, this finding does not exclude a diagnosis of Cushing disease (pituitary adenoma) since MRI is only 60% sensitive in these patients; nevertheless, because the MRI is non-invasive, it is the initial test used. If the MRI is negative as in this patient’s situation, the more invasive IPSS (answer C) is recommended to distinguish between an ACTH-secreting pituitary adenoma versus a peripheral source of ACTH. IPSS assesses the ACTH levels of the veins draining the pituitary gland. If the IPSS shows low levels of venous ACTH, then an ectopic source of ACTH is responsible, and a CT of the neck, chest, or abdomen/pelvis (answers A and B) may be obtained. If the IPSS is positive for elevated ACTH, then affected patients usually undergo transsphenoidal surgery or medical management if surgery is not possible.

35.5 A. The T score is the number of SDs of a patient BMD from the mean of young, adult, white women. It is the standard measurement of BMD used by the World Health Organization. Osteopenia is defined as a T score of 1 to −2.4. A score of –2.5 SD is the definition of osteoporosis. A Z score is the number of standard deviations from the mean BMD of women in the same age group as the patient. Based on this terminology, the patient has osteoporosis of the spine (T score −2.5) and osteopenia of the hip (T score −1.5). The other answer choices (B, C, and D) are inaccurate assessments of the T score. Answer E (Z score) is age-matched evaluation and not used in the definition of osteoporosis/osteopenia. This patient would benefit from review of her diet, assessment of vitamin D intake and levels, cessation of anything that would compromise bone health, and recommendation of starting pharmacological therapy such as a bisphosphonate.

35.6 D. This patient has osteoporosis based on the DEXA scan findings of −2.5 and −2.6. Bisphosphonates would decrease her risk of hip fractures by 30% to 50%. Alendronate and risedronate have been associated with a lower all-cause mortality. Answer A (osteopenia) is defined as a T score between −1 and −2.5. Answer B (estrogen) primarily inhibits loss of bone mass, although not only can it help to build a modest amount of bone mass, but it may also be associated with increased thrombotic and cardiovascular risk; for this reason, osteoporosis is not an indication to start estrogen replacement therapy in postmenopausal women. Answer C (swimming) is not helpful; weight-bearing exercise, not swimming or bicycling, is important in preventing osteoporosis.

CLINICAL PEARLS

▶ Osteoporosis is a condition of decreased bone mass and microarchitectural abnormalities that predisposes the patient to fragility fractures.

▶ The T score is a common way of assessing clinical BMD. Osteoporosis is defined as T score of −2.5 or less.

▶ Osteopenia is defined as a T score of between −1 and −2.5.

▶ Chronic exposure to excessive corticosteroids is the most common cause of secondary osteoporosis.

▶ Bisphosphonates are the most common first-line agent for osteoporosis, but they do have some rare but significant side effects.

▶ Cushing syndrome refers to the signs and symptoms that develop when the body is exposed to excess glucocorticoids.

▶ Signs of Cushing syndrome include facial fullness, plethora (ie, red face), supraclavicular or dorsocervical fat pads, reddish-purple striae, proximal muscle weakness, and unexplained bruising.

▶ Once Cushing syndrome is suspected, one of three tests should be obtained: 24-hour UFC, late-night salivary cortisol, or the low-dose (1-mg) overnight DST. If the initial test is positive, one of the remaining tests must be obtained to confirm the diagnosis.

▶ After a diagnosis of Cushing syndrome is confirmed, plasma ACTH should be measured to determine the etiology (ACTH-independent vs ACTH-dependent Cushing syndrome).

▶ For ACTH-dependent Cushing syndrome, the source (pituitary vs ectopic ACTH syndrome) can be confirmed with additional testing, including IPSS, the high-dose (8-mg) DST, and the CRH stimulation test.

▶ The first-line treatment of Cushing syndrome is surgical resection of the causal tumor. Medical management may be considered in certain situations.

▶ Medications include steroidogenesis inhibitors (ketoconazole, metyrapone, etomidate, mitotane), a glucocorticoid receptor antagonist (mifepristone), somatostatin receptor agonists (pasireotide, octreotide), and a dopamine agonist (cabergoline).

REFERENCES

Bertagna X, Guignat L, Groussin L, Bertherat J. Cushing’s disease. Best Pract Res Clin Endocrinol Metab. 2009;23(5):607-623. 

Boscaro M, Armaldi, G. Approach to the patient with possible Cushing’s syndrome. J Clin Endocrinol Metab. 2009;94(9):3121-3131. 

Lindsay R, Cosman F. Osteoporosis. In: Jameson JL, Fauci AS, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 20th ed. New York, NY: McGraw Hill; 2018:2488-2504. 

Nieman LK, Biller BM, Findling JW, et al. The diagnosis of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(5):1526-1540. 

Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2015;100(8):2807-2831.

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