The following cases and commentary, which involve osteoporosis, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 15).
Case 1: Elderly man with osteoporosis
A 72-year-old man is evaluated for a two-week history of low back pain. The patient has a history of alcoholism but stopped drinking alcohol 10 years ago. He also has stage 3 chronic kidney disease and a 50-pack-year smoking history. Current medications are hydrochlorothiazide, ramipril, and a multivitamin.
On physical examination, vital signs are normal. Lumbar lordosis, decreased mobility and spasm of the paravertebral muscles, and tenderness to palpation at L4-L5 are noted. Neurologic screening examination findings are normal.
Laboratory studies show calcium 9.0 mg/dL (2.25 mmol/L), creatinine 2.1 mg/dL (185.6 µmol/L), phosphorus, 3.2 mg/dL (1.0 mmol/L), parathyroid hormone 50 pg/mL (50 ng/L), testosterone 400 ng/dL (13.9 nmol/L), 25-Hydroxy vitamin D 34 ng/mL (85 nmol/L), and estimated glomerular filtration rate 40 mL/min/1.73 m2.
A radiograph of the lumbosacral spine shows a compression fracture of L4. A dual-energy x-ray absorptiometry scan shows a T-score of −3.0 in the lumbosacral spine and −3.2 in the left hip.
Which of the following is the best treatment for this patient?
Case 2: Low back pain and height loss
A 56-year-old woman is evaluated for a 2-year history of chronic low back pain. She also has had a 2-cm (0.8-in) height loss during this period. Medical history is remarkable for chronic obstructive pulmonary disease requiring intermittent high doses of prednisone. Current medications are albuterol and ipratropium bromide inhalers; prednisone, 20 mg/d; vitamin D, 800 U/d; and calcium, 1500 mg/d.
On physical examination, temperature is normal, blood pressure is 135/80 mm Hg, pulse rate is 100/min, respiration rate is 24/min, and BMI is 28. Breath sounds are distant with an occasional wheeze. There is back tenderness. Neurologic examination findings are unremarkable.
Laboratory studies show normal serum calcium, phosphorus, parathyroid hormone, and vitamin D levels.
A radiograph of the spine shows a compression fracture of the T8 vertebra. A dual-energy x-ray absorptiometry scan reveals a T-score of −2.2 in the lumbosacral spine and −2.5 in the left hip.
Which of the following is the best treatment for this patient?
B. Increased dosage of vitamin D (to 1000 U/d)
Case 3: Young woman with fragility fracture
A 33-year-old woman comes for follow-up examination for a left fibula fracture due to a fall 1 week ago. She has hypertension and stage 5 chronic kidney disease treated with home hemodialysis. Medications are lisinopril, sevelamer, epoetin alfa, paricalcitol, and kidney vitamins.
On physical examination, temperature is normal, blood pressure is 130/70 mm Hg, pulse rate is 88/min, and respiration rate is 12/min. BMI is 29. Cardiopulmonary examination is normal. An arteriovenous fistula is present in the left forearm. Except for a cast on her left leg, musculoskeletal examination is normal and reveals no bone pain.
Laboratory studies show hemoglobin 10.3 g/dL (103 g/L), albumin 3.5 g/dL (35 g/L), phosphorus 5.8 mg/dL (1.9 mmol/L), calcium 8.4 mg/dL (2.1 mmol/L), parathyroid hormone 700 pg/mL (700 ng/L), alkaline phosphatase 330 U/L.
Which of the following is the most likely cause of this patient's bone disease?
A. Adynamic bone disease
B. Avascular necrosis
D. Secondary hyperparathyroidism
Case 4: Pituitary adenoma
A 58-year-old man is evaluated for possible osteoporosis. He recently underwent removal of a 1.6-cm nonfunctioning pituitary adenoma and was placed on levothyroxine therapy.
On physical examination, vital signs are normal. Examination of the neck reveals no palpable goiter. The testes are small and soft.
Laboratory studies show follicle-stimulating hormone <1.0 mU/mL (1.0 U/L), luteinizing hormone <1.0 mU/mL (1.0 U/L), testosterone 50 ng/dL (1.7 nmol/L) and thyroxine (T4), free 1.2 ng/dL (15.5 pmol/L).
A dual-energy x-ray absorptiometry scan shows T-scores of −2.5 in the left hip and −2.6 in the lumbar spine.
In addition to calcium and vitamin D supplementation, which of the following is the most appropriate initial treatment for this patient?
C. Decreased dosage of levothyroxine
Case 5: Adenoma removal and osteoporosis
A 55-year-old woman is evaluated in the surgical recovery room for tetany. Two hours ago, she had a single large parathyroid adenoma removed. Preoperative skeletal radiographs showed subperiosteal bone resorption of the distal phalanges, femoral and spinal osteopenia, and osteoporosis in the radius.
She is treated with intravenous calcium and improves.
Laboratory studies (before calcium therapy) show albumin 4.2 g/dL (42 g/L), calcium 6.0 mg/dL (1.5 mmol/L), phosphorus 1.8 mg/dL (0.58 mmol/L) and parathyroid hormone 20 pg/mL (20 ng/L).
Which of the following is the most likely diagnosis?
A. Hungry bone syndrome
C. Permanent hypoparathyroidism
D. Vitamin D deficiency
Answers and commentary
Correct answer: A. Alendronate.
This patient with T-scores of −3.0 in the lumbosacral spine and −3.2 in the left hip has osteoporosis and should be treated with alendronate. Osteoporosis is a silent skeletal disorder characterized by compromised bone strength and an increased predisposition to fractures. The following risk factors are associated with osteoporosis in men:
- Prolonged exposure to certain medications, such as corticosteroids, anticonvulsants, some cancer drugs, and aluminum-containing antacids
- Chronic disease affecting the kidneys, lungs, stomach, and intestines
- Smoking, excessive alcohol use, low calcium intake, and inadequate physical exercise
- Older age (bone loss with increasing age)
- Heredity and race (with white men seeming to be at greatest risk)
The diagnosis and treatment of any underlying medical condition affecting bone health are essential to preserve bone health. Medications that cause bone loss should be identified, evaluated, and stopped, if possible. Unhealthy habits, such as smoking, excessive alcohol intake, and inactivity, should be changed and vitamin D and calcium supplementation begun. A regular regimen of weight-bearing exercises in which bone and muscles work against gravity should be encouraged. Weight lifting or using resistance machines can also be recommended because they appear to help preserve bone density. The U.S. Food and Drug Administration (FDA) has approved three antiresorptive medications (the bisphosphonates alendronate, risedronate, and zoledronate) and the anabolic agent teriparatide as treatment of male osteoporosis. Bisphosphonates are not recommended for use in patients with an estimated glomerular filtration rate less than 30 mL/min/1.73 m2.
Calcitonin is currently FDA-approved for the treatment of osteoporosis in women (but not men) who are at least 5 years postmenopausal. It has been shown in clinical trials to decrease bone loss and decrease risk of vertebral fractures; however, it has not been shown to reduce nonvertebral or hip fractures. Alendronate would be a more effective agent in this patient.
When osteoporosis is due to hypogonadism, testosterone replacement therapy should be considered unless there are contraindications. However, this patient's testosterone level is already normal.
Teriparatide is a recombinant human parathyroid hormone and a potent anabolic bone agent. Teriparatide is FDA-approved for treatment of postmenopausal osteoporosis in women at high risk of fracture and for treatment of hypogonadal or primary osteoporosis in men with high risk of fracture. Teriparatide is more expensive then bisphosphonates and requires subcutaneous injection. Treatment with teriparatide is limited to a maximum of 2 years (concerns related to risk of osteosarcoma) and is contraindicated in patients with a history of bone malignancy, Paget disease of bone, hypercalcemia, or history of skeletal irradiation. Given its cost, subcutaneous route of administration, long-term safety concerns, and the availability of other agents, teriparatide is generally not used as a first-line drug for treatment of osteoporosis.
- The bisphosphonates alendronate, risedronate, and zoledronate and the anabolic agent teriparatide are approved by the U.S. Food and Drug Administration to treat male osteoporosis.
Correct answer: D. Risedronate.
This patient with corticosteroid-induced osteoporosis should be treated with risedronate. Bone loss induced by exogenous corticosteroids is the most common form of secondary osteoporosis. The extent is determined by the dose and duration of therapy. Both risedronate and alendronate have been shown to increase bone mineral density (BMD) in patients treated with corticosteroids. In addition, both agents decrease the risk of new vertebral fractures by up to 70%. A dual energy x-ray absorptiometry scan to assess BMD should be performed at the initiation of corticosteroid therapy. An oral bisphosphonate, such as risedronate or alendronate, which are specifically approved as therapy of corticosteroid-induced osteoporosis by the U.S. Food and Drug Administration (FDA), should be started in patients in whom the BMD is already low. Recently, an annual intravenous infusion of zoledronate was also approved by the FDA as therapy of corticosteroid-induced osteoporosis. All patients also should receive appropriate calcium and vitamin D therapy.
Calcitonin decreases bone resorption by attenuating osteoclast activity. Its use may be beneficial in decreasing pain associated with acute or subacute fracture, but because of the availability of other medications that have better efficacy in fracture reduction, calcitonin is not considered a first-line treatment for osteoporosis and is not FDA approved for the treatment of corticosteroid-induced osteoporosis.
The prevention and treatment of corticosteroid-induced osteoporosis includes oral calcium supplementation (1500 mg/d) and oral vitamin D (800 U/d). The patient is on sufficient dosages of both vitamin D and calcium.
Raloxifene is a selective estrogen receptor modulator with suppressive effects on osteoclast and bone resorption and is associated with an increase in bone mass and decreased vertebral fractures. It is not recommended for use in premenopausal women or in women taking estrogen replacement therapy. Adverse effects include an increased risk of thromboembolism, fatal stroke, and increased vasomotor symptoms. It is not FDA approved for the treatment of corticosteroid-induced osteoporosis and would also be inappropriate for this patient because of its adverse effect profile.
- Oral bisphosphonates are the therapy of choice for corticosteroid-induced osteoporosis; all patients with corticosteroid-induced osteoporosis should also receive adequate calcium and vitamin D supplementation.
Correct answer: D. Secondary hyperparathyroidism.
Chronic kidney disease (CKD) is associated with progressive alterations in mineral and bone metabolism that can cause bone disease. In patients with end-stage kidney disease (ESKD), the kidney's inability to excrete phosphorus leads to hyperphosphatemia. Loss of kidney function also is associated with 1,25-dihydroxyvitamin D deficiency. Hyperphosphatemia along with decreased 1,25 dihydroxy-vitamin D levels result in hypocalcemia, which leads to direct stimulation of parathyroid hormone secretion. Furthermore, decreased 1,25 dihydroxyvitamin D levels cause increased production of parathyroid hormone. Therefore, bone disease due to secondary hyperparathyroidism, the most common bone pathologic finding seen in patients with ESKD, develops. This patient's hyperphosphatemia, hypocalcemia, and elevated serum parathyroid hormone and alkaline phosphatase levels are consistent with secondary hyperparathyroidism.
Adynamic bone disease commonly occurs in patients with ESKD and may cause fractures. However, unlike bone disease associated with secondary hyperparathyroidism, adynamic bone disease is often associated with hypoparathyroidism caused by excess vitamin D intake and/or calcium loading. This condition usually manifests as bone pain accompanied by a serum parathyroid hormone level below 100 pg/mL (100 ng/L) and a normal alkaline phosphatase level.
Osteoporosis is defined by low bone mass, which is associated with reduced bone strength and an increased risk of fractures. Osteoporosis occurs most commonly in postmenopausal women but may develop secondary to drugs such as corticosteroids and anticonvulsants. Osteoporosis does not affect the concentrations of serum calcium, phosphorus, or alkaline phosphatase.
Avascular necrosis is caused by transient or permanent lack of blood supply to bone, which causes death of bone and bone marrow infarction that results in mechanical failure. Patients typically present with chronic bone pain and not fracture.
- Bone disease due to secondary hyperparathyroidism commonly occurs in patients with end-stage kidney disease and may be associated with elevated serum parathyroid hormone and alkaline phosphatase levels, hyperphosphatemia, and hypocalcemia.
Correct answer: D. Testosterone.
This patient had a clinically nonfunctioning pituitary adenoma with secondary hypogonadism and osteoporosis. He should be treated with testosterone replacement therapy. Hypogonadism is a prevalent secondary cause of male osteoporosis. Hypogonadism increases the skeletal sensitivity to parathyroid hormone and decreases intestinal calcium absorption. Because testosterone is aromatized to estradiol, it can be regarded as a prohormone for estradiol in the bone. Low bone mass in men with hypogonadism can be improved with androgen replacement, and bisphosphonates are effective in men regardless of their gonadal status. Anabolic therapy with teriparatide can likewise increase bone mineral density. Supplementation with calcium and vitamin D is also advisable.
Bromocriptine is useful for therapy of prolactinomas but has little utility for treatment of clinically nonfunctioning pituitary adenomas and will not treat this patient's osteoporosis.
Calcitonin can increase bone mass and is associated with a reduction in vertebral but not nonvertebral fracture rate. It is not as effective as bisphosphonate therapy and will not treat this patient's extraskeletal hypogonadal symptoms. Furthermore, calcitonin is not approved by the U.S. Food and Drug Administration as therapy of male osteoporosis.
Subclinical thyrotoxicosis can accelerate osteoclastic resorption of bone. Because this patient's free thyroxine (T4) level falls in the normal range, there is no need to decrease the levothyroxine dosage.
- Hypogonadism is a prevalent secondary cause of male osteoporosis.
Correct answer: A. Hungry bone syndrome.
This patient most likely has hungry bone syndrome. Hypocalcemia frequently occurs after removal of a hyperfunctioning parathyroid adenoma because of suppressed secretion of parathyroid hormone (PTH) by the remaining parathyroid tissue. The associated hypoparathyroidism is usually transient because the healthy parathyroid glands recover function quickly, generally within 1 week, even after long-term suppression. Transient postoperative hypocalcemia may be exaggerated or prolonged in patients, such as this one, who had marked preexisting hyperparathyroid bone disease. In these patients, the surgically induced reduction of previously elevated serum levels of PTH results in an increased movement of serum calcium and phosphorus into “hungry bones” for the purpose of remineralization. Treatment with calcium and a short-acting vitamin D metabolite may be required until the bones heal.
Both osteomalacia and vitamin D deficiency cause secondary hyperparathyroidism with elevated PTH levels. This patient's normal serum PTH level argues against these diagnoses.
Permanent hypoparathyroidism in patients treated for primary hyperparathyroidism is rare, developing in approximately 1% of these patients. The incidence of permanent hypoparathyroidism is greatly increased with repeated neck surgery for recurrent or persistent hyperparathyroidism, with subtotal parathyroidectomy for parathyroid hyperplasia, or with neck surgery performed by inexperienced surgeons.
- Hungry bone syndrome with severe hypocalcemia and hypophosphatemia can occur after removal of a parathyroid adenoma in patients with significant hyperparathyroid bone disease.