Fragility Fracture (Case 43)

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Chapter 51
Fragility Fracture (Case 43)

Paul Sack MD

Case: The patient is a 67-year-old woman with a history of hypertension and osteoarthritis of the knees who presents to the emergency department after falling and fracturing her left hip. She lost her balance in her kitchen after turning and fell on her left hip. She had immediate pain and could not put any weight on her left leg. A radiograph revealed a femoral neck fracture of her left femur. She reports a wrist fracture 3 years ago after falling in her kitchen. This fracture was treated by an orthopedist in the outpatient setting. She has never had a dual-energy x-ray absorptiometry (DXA) scan performed. She occasionally takes a multivitamin, but does not take any additional calcium. She also takes atenolol for her hypertension. She is married and has two children. She went through menopause at the age of 44 years and was only briefly on hormone replacement therapy for 2 years. She has one or two alcoholic beverages on the weekends. She has never smoked tobacco.

Differential Diagnosis

Primary osteoporosis	Osteomalacia	Multiple myeloma
Secondary osteoporosis	Paget disease	Multiple myeloma

Speaking Intelligently

The most common cause of a fragility fracture, a fracture that occurs with no or minimal trauma, is low bone density or osteoporosis. Unfortunately, osteoporosis does not cause symptoms until a fracture has occurred. Therefore, routine screening with a DXA scan is recommended for all patients at risk. The other main causes of a fragility fracture, such as multiple myeloma, Paget disease, and metastatic cancer, are usually fairly obvious with plain radiographs. Once the diagnosis of osteoporosis has been established, either on the basis of the DXA scan or by a clinical history of an osteoporotic fracture, the focus should be on prevention of the next fracture. This includes educating the patient about how to reduce the risk of a fall, ruling out secondary causes of bone loss, ensuring an adequate amount of calcium and vitamin D intake, and using prescription medications to help rebuild bone density and strength.

PATIENT CARE

Tests for Consideration

• 25-OH Vitamin D: This is the inactive or storage form of vitamin D. The vitamin D level should be at least above 32 ng/mL, and some experts are arguing for even higher levels. It is not recommended to check the active form (1,25-dihydroxyvitamin D3) in patients with normal kidney function. In patients with vitamin D deficiency as indicated by a low 25-OH vitamin D level, the active vitamin D can sometimes still be in the low normal range.	$55
• Intact PTH: In the setting of a normal or low calcium level, an elevated PTH level may indicate vitamin D deficiency. This is known as secondary hyperparathyroidism. If the PTH is inappropriately elevated in the setting of an elevated calcium level, the diagnosis is primary hyperparathyroidism.	$59
• Calcium: The serum calcium concentration is tightly regulated in the body. PTH and vitamin D play an essential role in this regulation. Remember to correct the calcium if the albumin is not within the normal range.	$12
• Alkaline phosphatase: An elevated alkaline phosphatase can be found in both Paget disease and severe vitamin D deficiency (osteomalacia).	$12
• Testosterone (in men): Testosterone deficiency causes bone loss. A level less than 300 ng/dL should cause some suspicion for hypogonadism. A full evaluation of this should follow, including a free testosterone, FSH, LH, and prolactin.	$36
• TSH: A screening TSH level should be ordered in all patients with decreased bone density. Some patients with subclinical or mild hyperthyroidism may not have obvious symptoms, but the increased bone turnover associated with hyperthyroidism can lead to bone loss.	$24
• Cushing syndrome evaluation: This evaluation is not done routinely, but if the patient has the classic findings of Cushing syndrome or has unexplained early bone loss, it should be considered. This can be achieved with a 1-mg dexamethasone suppression test, a midnight salivary cortisol level, or a 24-hour urine for free cortisol.	$23, $23, $24
• Celiac disease evaluation: If you suspect malabsorption because of symptoms or if the patient continues to have low vitamin D levels despite aggressive replacement, celiac disease should be considered. IgA anti-tissue transglutaminase and IgA endomysial antibody levels are blood tests to evaluate for celiac disease.	$85
• Serum protein electrophoresis (SPEP) and/or urine protein electrophoresis (UPEP): If multiple myeloma is suspected, these tests will confirm or exclude the diagnosis.	$15, $25

IMAGING CONSIDERATIONS

→ Plain films should be the first imaging tool for a fragility fracture. If osteoporosis is suspected, DXA should be the screening of choice. The other studies may be indicated depending on the diagnosis.	$45
→ DXA scan: The DXA scan is the most appropriate test to screen for osteoporosis. The mineral density of bone in the hips and spine (central skeleton) is assessed, and this density is expressed in grams per square centimeter. It is then compared to normal bone density (people with the same ethnicity and sex, but in their 20s, when bone density is at its peak). A standard deviation is calculated and expressed as a “T-score.” A T-score of zero indicates that the patient’s bone density is the same as the patient’s theoretical peak bone mass. A T-score greater than zero indicates a more dense bone, and a T-score less than zero indicates a less dense bone. A normal T-score is greater than –1.0. A T-score between –1.0 and –2.4 is considered osteopenia. A T-score of –2.5 or less is labeled osteoporosis. Another calculation is the Z-score, which compares the patient’s bone density to an age-matched reference group. While the T-score at the spine and hip are helpful in making the diagnosis of osteoporosis and estimating future fracture risk, it is important to understand that osteoporosis can also be diagnosed based on clinical information. If the patient has a fragility fracture and other causes have been ruled out, osteoporosis is the diagnosis regardless of the T-score on the DXA scan. It is still important to obtain the bone mineral density, so that it can be followed as the patient is treated.	$104
→ Peripheral bone density measurements: DXA, x-ray absorptiometry, and ultrasonography of the heel, wrist, or hand are less accurate than the DXA scan. However, the equipment is much cheaper and more portable than the DXA machine, so these techniques are commonly used at health fairs or for screening patients before they have a DXA scan. A low T-score on one of these tests can predict risk for fracture, but it is recommended not to make a diagnosis or decide on medications until a true DXA scan is performed on the hip and spine. A distal radius bone mineral density scan is sometimes useful in patients with hyperparathyroidism or hyperthyroidism, as this site is more sensitive to the rapid bone turnover associated with these conditions.	$46
→ Plain radiographs: The DXA scan is able to measure bone density, but plain radiographs are needed to look for compression fractures of the spine or other fractures. For example, if a patient presents with height loss and known osteoporosis, it is appropriate to order radiographs of the spine. A skeletal survey with plain films may show lytic lesions from multiple myeloma. Paget disease can also be easily identified on plain films.	$75
→ CT scan: If there is an area of concern on the radiograph, a CT scan may be useful in further defining the lesion.	$334
→ Nuclear bone scan: This study is indicated to find areas of active Paget disease or if metastatic cancer to the bone is suspected.	$247
→ MRI: This may be used if the suspected fracture is not seen on plain radiographs. In addition, it is used to assess the spine in patients with multiple myeloma.	$534

Clinical Entities

Medical Knowledge

Primary Osteoporosis
Pφ	Primary osteoporosis is defined by a significantly low bone density without identification of any secondary causes. Bone loss starts to occur after the third decade of life but accelerates with the loss of estrogen or testosterone. Therefore, women are much more likely to have osteoporosis after menopause as a result of their advancing age and low estrogen. Genetic factors, calcium intake, and age are important determinants of one’s bone density as well.
TP	Osteoporosis is typically a silent disease and is usually found on routine screening with a DXA scan. The first symptom is usually a fracture. Therefore, patients who have a suspicious, low- or no-trauma fracture should be screened for osteoporosis.
Dx	A T-score of –2.5 or less defines osteoporosis. In addition, a clinical diagnosis of osteoporosis can be made if the patient has a fragility fracture in the absence of other causes of that fracture. One can calculate the patient’s future fracture risk by using a calculation tool called FRAX (Fracture Risk Assessment Tool, found at http://www.shef.ac.uk/FRAX). This gives a 10-year estimated risk for a hip fracture or any osteoporotic fracture. This calculation uses the bone mineral density at the femoral neck as well as clinical information about the patient, including age, sex, weight, tobacco use, alcohol intake, family history of hip fracture, prior personal history of fracture, rheumatoid arthritis, secondary causes of osteoporosis, and steroid use. Treatment should be considered when the 10-year risk is above 3% for a hip fracture and 20% for any fracture.
Tx	All patients with primary osteoporosis should receive an adequate amount of calcium and vitamin D. This generally means 1500 mg of calcium a day and at least 800–1000 IU/day of vitamin D. Bisphosphonates are the first-line prescription medication for osteoporosis. These medications decrease bone resorption (breakdown by osteoclasts) while allowing bone formation to continue. This results in a net increase in bone density. Examples of oral bisphosphonates are alendronate, risedronate, and ibandronate. Zolendronate and ibandronate can be given as IV medications for those who cannot tolerate the gastrointestinal side effects of the oral bisphosphonates. Teriparatide is an anabolic agent, given as a daily subcutaneous injection, that increases bone formation and is indicated for those patients with extremely poor bone density who are at very high risk for fracture. Another antiresorptive medication, denosumab, was approved for treatment of osteoporosis in 2010. Denosumab is a RANK ligand inhibitor that is given as an IM injection twice a year. See Cecil Essentials 76.

Osteoporosis Secondary to Medical Conditions
Pφ	Hyperthyroidism, primary hyperparathyroidism, and glucocorticoid excess states (either endogeneous from Cushing syndrome or exogenous from prolonged use of high-dose steroids) all can cause increased bone turnover. Because bone formation takes much longer than bone resorption, the net effect in all of these conditions is decreasing bone density. Both estrogen and testosterone deficiencies can also lead to increased bone turnover and bone loss.
TP	Hyperthyroidism presents with tachycardia, weight loss, tremor, palpitations, anxiety, and heat intolerance. Primary hyperparathyroidism is usually silent and is diagnosed only with an elevated calcium and intact PTH level. Cushing syndrome presents with central weight gain, uncontrolled hypertension and diabetes, excessive fat pads above the clavicle and in the posterior neck, central large and purplish stretch marks, and proximal muscle weakness. Cushing syndrome may also be asymptomatic and must be considered in unusual cases of unexplained low bone density. Estrogen deficiency is obviously an issue in an older woman, but a younger woman with anovulation and hot flashes should be evaluated with lab work for estrogen deficiency.
Dx	Hyperthyroidism is diagnosed with a suppressed TSH and elevated T4 levels. Primary hyperparathyroidism is diagnosed with an elevated calcium level and an elevated PTH level. Cushing syndrome from exogenous steroids is a clinical diagnosis. Endogenous steroid production can be evaluated with one of three tests: midnight salivary free-cortisol levels (which should be low in a normal patient), 24-hour urine collection for free cortisol, or a 1-mg dexamethasone suppression test in which the early-morning cortisol should be low after midnight administration of dexamethasone. Testosterone and estrogen deficiencies are found by checking those blood levels.
Tx	Treatment of the hyperthyroidism, hyperparathyroidism, or Cushing syndrome is paramount is restoring normal bone density. Calcium and vitamin D are essential in these patients. Use of bisphosphonates may be considered immediately or after observing the bone density progression after the disease state has been normalized. Testosterone replacement in a hypogonadal man is recommended unless there are contraindications such as prostate cancer, benign prostatic hypertrophy, or polycythemia. Estrogen replacement is an excellent way to increase bone density in a woman, but it is no longer recommended because of an increased risk of malignancy and cardiovascular diseases. See Cecil Essentials 66, 67, 74.

Osteomalacia
Pφ	Osteomalacia is a disease of poor mineralization of newly formed bone, most commonly caused by vitamin D deficiency. Vitamin D is essential in the process of intestinal absorption of calcium. Inactive vitamin D is formed in the skin in the presence of ultraviolet B irradiation. It is then hydroxylated first in the liver and then to its active form in the kidney. Vitamin D can also be found in certain foods naturally and can be taken as supplements. Vitamin D deficiency is more common in areas of the world that do not have as many hours of sunlight. Malabsorption syndromes, like celiac disease, are also a major risk for vitamin D deficiency.
TP	Vitamin D deficiency in children is called rickets and causes severe bony deformities. In adults, vitamin D deficiency may only manifest as low bone density.
Dx	25-OH vitamin D levels are the most sensitive means to determine vitamin D deficiency. Levels should be >30 ng/mL to be considered normal. Measuring the active form, 1,25-dihydroxyvitamin D3, does not add to the evaluation unless there is kidney dysfunction or concerns of other rare vitamin D resistance syndromes.
Tx	Osteomalacia caused by vitamin D deficiency is treated with oral vitamin D. Prescription concentrations of vitamin D should be initially used. Ergocalciferol is the most common medication and contains 50,000 IU per tablet. This can be given weekly until the vitamin D levels are >30 ng/mL. Maintenance therapy can be with either monthly ergocalciferol or nonprescription vitamin D at much lower dosages. There are numerous combinations of calcium and vitamin D available. It is easy also to find vitamin D supplements without calcium. The recommended dietary allowance for vitamin D for most people is 600 IU/day, but in those patients who are deficient in vitamin D (<30 ng/mL), the dose may need to be increased until normal levels are reached. Many experts recommend at least 1000 IU/day in patients with osteoporosis. Another option for vitamin D repletion is the fatty oils of certain fish like cod (cod liver oil). Calcium must also be part of the treatment of osteomalacia. Calcium carbonate or calcium citrate at 1200–1500 mg/day in divided doses should be given long term. See Cecil Essentials 75.

Paget Disease
Pφ	Paget disease is a disorder of bone turnover that is localized to only a few areas of the body. The process begins with excessive bone resorption followed by an increase in bone formation. The resulting bone is less strong, more disorganized, and more vascular than the normal bone, and it is susceptible to fracture. The cause is unknown, although both genetic and environmental factors may contribute. It usually affects more than one site of the skeleton.
TP	Paget disease is usually asymptomatic and diagnosed after a workup of an elevated alkaline phosphatase level. Patients with symptomatic Paget disease may present with pain, warmth, bony deformities, and osteoarthritis at the site. A fracture may be the first sign of Paget.
Dx	An elevated alkaline phosphatase level is the blood test result that suggests Paget’s disease. However, an elevated alkaline phosphatase level can also be seen in severe osteomalacia, liver disease, and metastatic cancers to the bone. A GGT (γ-glutamyl transpeptidase) level should be checked if the alkaline phosphatase level is elevated. An elevated GGT indicates a hepatic origin of the alkaline phosphatase elevation, while a normal GGT points toward a skeletal etiology. A nuclear bone scan can then identify hypermetabolic areas of the skeleton. This should be followed with radiographs of the affected areas to make sure there is no evidence of cancer at these sites.
Tx	The active bone turnover of Paget disease can be halted with bisphosphonates. Oral daily alendronate for 6 months, or daily risedronate for 2 months, is approved for this disease; a one-time zolendronate IV infusion is the most effective. The arthritis and bony deformities will not improve with treatment. These must be individually treated based on symptoms. See Cecil Essentials 77.

Multiple Myeloma
Pφ	Multiple myeloma is a plasma cell neoplasm. The bone lesions of multiple myeloma are caused by activation of the osteoclasts and increased bone resorption.
TP	The presentation can be varied. Multiple myeloma usually presents with bone pain but can also present with anemia, hypercalcemia, pathologic fractures, renal failure, and/or spinal cord compression.
Dx	The diagnosis may be suspected from other laboratory studies but SPEP and UPEP are the best tests for confirming the diagnosis. A skeletal series, including the skull, is necessary to determine the extent of the disease affecting the bones. An MRI may be useful to evaluate the spine and spinal cord.
Tx	Although multiple myeloma is not curable, it can be treated with chemotherapy and bone marrow transplantation. Bisphosphonates have been found to be helpful in fracture prevention. See Cecil Essentials 51.

a. Osteogenesis imperfecta: This is a genetic disorder that is characterized by an abnormality of type 1 collagen that results in bone fragility. It is usually diagnosed in childhood.

b. Metastatic cancer to the bone: Most cancers have the potential to metastasize to the bone, but common cancers include lung, breast, and prostate. The areas of metastasis can lead to fractures at that site.

Practice-Based Learning and Improvement: Evidence-Based Medicine

Title
Fracture risk reduction with alendronate in women with osteoporosis: The Fracture Intervention Trial

Authors
Black DM, Thompson DE, Bauer DC, et al., for the Fit Research Group

Institution
Multiple sites

Reference
J Clin Endocrinol Metab 2000;85:4118–4124

Problem
What is the reduction in fracture risk in women with established osteoporosis while on alendronate?

Intervention
Women with an existing vertebral fracture and women with a T-score less than –2.5 were randomly assigned placebo or alendronate at 5 mg/day for the first 2 years and then 10 mg/day for another 2–3 years. Bone mineral density by DXA scan and new fractures were evaluated yearly.

Quality of evidence
Level I

Outcome/effect
There was a significant reduction of clinical fractures in patients receiving alendronate for both women with an existing vertebral fracture and women without a vertebral fracture who had osteoporosis on DXA scan. Vertebral fractures were reduced by 45%, hip fractures by 53%, and wrist fractures by 30%.

Historical significance/comments
This study showed that pharmaceutical treatment of high-risk patients, even those who have already had significant fractures, can greatly benefit patients by reducing their risk for future fractures.

Interpersonal and Communication Skills

Educate Patients about the Implications of a Fragility Fracture

Fragility fractures can result in significant morbidity. The initial goal is to address the acute fracture, but at some point early in the process the underlying cause of the fracture must be determined. Having just undergone major surgery to repair a fracture, some patients will not understand why it is necessary to have additional blood work, a bone density scan, and other radiographic studies. It is important to explain that the initial goal was to fix the fracture, and now it is essential to identify the underlying cause so as to prevent future fractures. Osteoporosis is the most common disease causing the fracture, and while it is not as concerning as metastatic cancer or multiple myeloma, the physician must ensure that the patient understands the importance of treating this silent disease. Without this understanding, most patients will not follow through with the basic treatments of calcium and vitamin D.

Professionalism

Show Commitment to Professional Excellence

It is the physician’s role to promptly identify patients at risk for osteoporosis and initiate treatment for their low bone density. The National Osteoporosis Foundation (NOF) and the American Association of Clinical Endocrinologists (AACE) recommend DXA scans for all women over the age of 65 years, because the risk of fracture begins to increase dramatically in this age group. In addition, a DXA scan should be done in any postmenopausal woman with other risk factors such as family history, vitamin D deficiency, or previous fracture. Those patients on chronic steroids, who have primary hyperparathyroidism, and who have had a suspicious fracture or significant height loss, should also be screened. However, many DXA scans are ordered on patients who do not meet these criteria. While men have significantly less risk for an osteoporotic fracture, there are still millions of men with osteoporosis who are at risk for fracture, but there are no guidelines (and therefore poor insurance coverage) for screening DXA scans. There are elderly men, especially those with risks such as testosterone deficiency, who should have DXA scans. Well-meaning physicians are ordering these tests in premenopausal women who have no major risks or symptoms. Even when decreases in bone density are found in these women, it is unclear what treatment is most beneficial when they are still young. Therefore, it is imperative for physicians to understand the DXA scan and to be educated as to the limitations and the usefulness of this test in certain patients.

Systems-Based Practice

Accountable Care Organizations Should Enhance Quality and Reduce Costs

Management of fragility fractures requires that all members of the patient’s health-care team are working together to enhance quality in a cost-effective manner. Introduced as part of the new health-care reform legislation in March 2010, Accountable Care Organizations (ACOs) are being created to provide better care for individuals, better health for populations, and slower increases in costs through improvements in care.1 In an ACO, a set of health-care providers will share responsibility for the quality and cost delivered to a defined population of patients; these providers can include a hospital, a group of primary-care providers, specialists, and possibly other health-care professionals. Together these providers will manage the continuum of care across different institutional settings, including outpatient, inpatient, and possibly post-acute care. ACOs are meant to control the growth of costs while maintaining or improving the quality of care of a population of patients by using evidence-based medicine. The incentives of an ACO are different from the current fee-for-service reimbursement system: the focus of the ACO will be to streamline its processes of care while exceeding the norm on quality and outcomes. If the ACO spends less than projected, all members share in bonus payments.