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8. A 54-year-old woman comes to your clinic for a routine visit. She has no active complaints. Her medical history is positive only for mild asthma and arterial hypertension. Her only medications are albuterol, which she administers with a measured-dose inhaler as needed, and an angiotensin-converting enzyme inhibitor. She smokes one pack of cigarettes a day. She has a strong family history of osteoporosis. Her physical examination is unremarkable. You have a discussion with her regarding her risk of osteoporo-sis, and you decide to obtain a dual-energy x-ray absorptiometry (DEXA) scan for screening. The results show a T score of –2.6. Her creatinine and albumin levels are normal, her liver function tests are normal except for a slightly elevated alkaline phosphatase level, and her calcium level is 11 mg/dl.

What is the most appropriate step to take next in the treatment of this patient?

❑ A. Start bisphosphonate, calcium, and vitamin D, and reassess in 6 months

❑ B. Measure the parathyroid hormone (PTH) level with a two-site immunoradiometric assay (IRMA, or so-called intact PTH) and assess 24-hour urinary calcium output

❑ C. Order CT scans of the chest and abdomen to look for an occult malignancy

❑ D. Start hormone replacement therapy with estrogens and progestins

Key Concept/Objective: To understand the appropriate initial evaluation of a patient with hyper-calcemia

This patient presents with mild, asymptomatic hypercalcemia. The most common cause of hypercalcemia in outpatients is hyperparathyroidism. The differential diagnosis of hypercalcemia is extensive. Once hypercalcemia is confirmed, the next step is to measure the serum PTH concentration. Several PTH assays are commercially available. The most commonly utilized test is the intact PTH. Other helpful tests include blood urea nitrogen (BUN), serum creatinine, alkaline phosphatase, and serum inorganic phosphorus assays;

an electrolyte panel; and an assessment of 24-hour urinary calcium output. If the levels of PTH are elevated or inappropriately normal, the hypercalcemia is said to be PTH mediat-ed. When PTH levels are suppressed, the hypercalcemia is said to be non–PTH mediatmediat-ed.

Patients with hyperparathyroidism typically have a serum calcium concentration of less than 12 mg/dl; mild to moderate hypophosphatemia; and non–anion gap acidosis (from renal tubular acidosis). Urinary calcium excretion is usually increased; in these patients, the reduction of fractional calcium excretion by PTH is overcome by the high filtered cal-cium load, which may result in nephrolithiasis. The levels of alkaline phosphatase can be elevated as well. Before starting a more extensive evaluation in this patient, it is necessary to exclude the possibility of primary hyperparathyroidism. (Answer: B—Measure the parathy-roid hormone [PTH] level with a two-site immunoradiometric assay [IRMA, or so-called intact PTH] and assess 24-hour urinary calcium output)

9. A 45-year-old man with a history of primary hyperparathyroidism comes to your clinic for a follow-up visit. He was diagnosed 3 years ago after routine blood tests revealed an elevation in calcium level. He has no complaints. Review of systems is negative, and his physical examination is unremarkable. His family history is negative for similar problems. His calcium level is 11.5 mg/dl. A DEXA scan shows a T score of –2 at the hip.

What is the most appropriate treatment regimen for this patient?

❑ A. Observation, with routine follow-up visits that include assessment of calcium levels and DEXA scans

❑ B. Start a bisphosphonate

❑ C. Refer to an experienced surgeon for parathyroid surgery

❑ D. Administer calcium, 1,000 to 1,500 mg/day, and vitamin D, 400 to 800 IU/day

Key Concept/Objective: To understand the surgical indications for hyperparathyroidism

Treatment of the patient with hyperparathyroidism must take into account the degree of the hypercalcemia, the presence of symptoms, and the severity of any end-organ damage.

Because many patients with hyperparathyroidism are either asymptomatic or minimally symptomatic, there is controversy over which patients require definitive therapy with sur-gery. The 2002 National Institutes of Health Workshop on Asymptomatic Primary Hyperparathyroidism defined the following indications for surgical intervention: (1) sig-nificant bone, renal, gastrointestinal, or neuromuscular symptoms typical of primary hyperparathyroidism; (2) elevation of serum calcium by 1 mg/dl or more above the nor-mal range; (3) marked elevation of 24-hour urine calcium excretion (> 400 mg); (4) decreased creatinine clearance (reduced by 30%); (5) significant reduction in bone density (T score < –2.5); (6) consistent follow-up is not possible or is undesirable because of coex-isting medical conditions; and (7) age less than 50 years. Because of this patient's age, sur-gery is indicated. (Answer: C—Refer to an experienced surgeon for parathyroid sursur-gery)

10. A 66-year-old woman presents to a walk-in clinic with muscle spasms. She complains that for the past 2 days she has had muscle spasms in her hands, arms, and legs. She has a medical history of cervical Hodgkin lymphoma, which was treated with radiation. She does not take any medications or vitamins.

On physical examination, the Trousseau sign is positive. Her calcium level is 6.8 mg/dl; the albumin level is normal.

On the basis of this patient's history, what is the most likely diagnosis, and what should be the treatment?

❑ A. Hypoparathyroidism secondary to radiation therapy; start PTH injec-tions

❑ B. Vitamin D deficiency secondary to poor intake and lack of sunlight;

start calcitriol

❑ C. Vitamin D deficiency secondary to poor intake and lack of sunlight;

start cholecalciferol

❑ D. Hypoparathyroidism secondary to radiation therapy; start calcium and calcitriol

Key Concept/Objective: To understand the most common causes of hypocalcemia and its treatment

Hypocalcemia is defined as a serum calcium level of less than 9 mg/dl. Hypocalcemia is most often related to disorders of the parathyroid glands. Removal of or vascular injury to the parathyroids during neck surgery can result in hypoparathyroidism, which is mani-fested by hypocalcemia, hyperphosphatemia, and inappropriately low concentrations of PTH. Autoimmune destruction of the parathyroid glands may be seen in other autoim-mune conditions, such as polyglandular syndrome type 1. Certain infiltrative diseases, such as hemochromatosis, may also adversely affect parathyroid function, as may external beam radiation to the neck. In this patient, the history of radiation to the neck suggests the possibility of hypoparathyroidism secondary to radiation injury. Despite the fact that vita-min D deficiency is common in elderly patients, serum calcium concentrations are usual-ly not severeusual-ly affected thanks to compensatory increases in PTH levels. In patients with symptoms associated with hypocalcemia (e.g., neuromuscular irritability), calcium volume should be repleted with a slow intravenous infusion of calcium salts. In most patients, vita-min D should also be provided. If dietary deficiency is suspected, plain cholecalciferol is adequate. In cases of hypoparathyroidism, however, calcitriol will be required. (Answer: D—

Hypoparathyroidism secondary to radiation therapy; start calcium and calcitriol)

11. A 55-year-old woman comes to your office with the results of a screening DEXA scan. Her T score is –2.7.

She has not had any symptoms and denies having any previous fractures. She underwent menopause 3 years ago. Six months ago, she underwent mammography and had a Pap smear, both of which were neg-ative. She has no family history of breast cancer. Her physical examination, including examination of the breasts, is normal. Her laboratory workup shows no evidence of conditions that are secondary caus-es of osteoporosis.

What is the most appropriate recommendation regarding the management of this patient's osteoporosis?

❑ A. Start bisphosphonate therapy, start calcium and vitamin D therapy, and recommend exercise

❑ B. Start hormone replacement therapy, start calcium and vitamin D ther-apy, and recommend exercise

❑ C. Start calcitonin, calcium, and vitamin D therapy, and recommend exercise

❑ D. Do not start therapy until the osteoporosis becomes symptomatic

Key Concept/Objective: To understand the appropriate management of osteoporosis

Osteoporosis is defined as decreased bone mass (or density) with abnormal skeletal microarchitecture that increases the risk of fracture. The diagnostic criteria of the World

Health Organization are based on the results of standardized bone mass measurements:

osteoporosis is present when the bone mineral density (BMD) is decreased to more than 2.5 standard deviations below that of a normal, young control population (T score).

Osteopenia is present when the BMD falls between –1.0 and –2.5 from peak bone mass. In patients with osteoporosis, an adequate amount of calcium should be provided. This patient should take 1,000 to 1,500 mg of calcium a day. Also, the patient should receive 400 to 800 IU of vitamin D. Osteoporosis is most often treated with antiresorptive agents;

these drugs include bisphosphonates, estrogen, selective estrogen receptor modulators (e.g., raloxifene), and calcitonin. All of these agents reduce fracture rates substantially, but estrogen and bisphosphonates appear to produce the greatest improvement in bone den-sity. Until recently, estrogen replacement therapy was widely recommended as first-line therapy for both prevention and treatment of osteoporosis. Advocates argued that estro-gen directly corrected the chief pathophysiologic defect of the menopause-estroestro-gen defi-ciency. They also cited other benefits, such as relief from vasomotor disturbances, mood swings, sleep disturbance, and urogenital atrophy. Estrogen therapy was also thought to offer cardiovascular benefits, possibly related to its positive effects on plasma lipid levels.

Recently, the multicentric Women's Health Initiative study was stopped prematurely because of a significant increase in the risk of breast cancer, myocardial infarction, strokes, and thromboembolic events. As a result of these findings, estrogen should no longer be considered the optimal first-line preventive or therapeutic agent for osteoporosis.

Bisphosphonates should be considered the optimal choice for the initial therapy for osteo-porosis. Calcitonin's effects on bone density appear to be weaker than those of estrogen or the bisphosphonates. Raloxifene can be used for osteoporosis prevention and treatment; it appears to have a less potent effect on bone density than either estrogens or bisphospho-nates. (Answer: A—Start bisphosphonate therapy, start calcium and vitamin D therapy, and recom-mend exercise)

For more information, see Inzucchi SE: 3 Endocrinology: VI Diseases of Calcium Metabolism and Metabolic Bone Disease. ACP Medicine Online (www.acpmedicine.com). Dale DC, Federman DD, Eds. WebMD Inc., New York, March 2003