Osteoporosis, the presence of either low bone mineral density or a history of a fragility fracture, is known to be associated with an increased risk of future fracture. Fracture prevention is possible through use of both nonpharmacologic and prescription treatments. Despite recent controversy regarding the safety of calcium supplementation and the appropriate dosing of calcium and vitamin D, calcium and vitamin D remain an important part of bone health. However, prescription osteoporosis treatments should be considered for those at higher risk for fracture, and there are currently several treatment options available.
Key points
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Osteoporosis can be diagnosed by measurement of bone mineral density or based on the history of a nontraumatic fracture.
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Osteoporosis treatment should be considered in all people with an increased risk of future fracture. Use of fracture risk assessment tools can assist in determining patients who would benefit from treatment.
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There are several therapies available for the treatment and prevention of osteoporosis. The optimal treatment option for each patient should be determined after weighing the benefits and potential risks associated with these medications.
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Further information is needed to assist clinicians in determining the duration of osteoporosis treatment and the potential role of an interrupted treatment regimen.
Introduction
Hip fractures and vertebral fractures are 2 of the most common fracture sites related to osteoporosis, and affect nearly 1 million persons in the United States annually. Moreover, nearly one-quarter of patients who endure a hip fracture die within a year of the fracture. An even larger proportion requires either extensive physical rehabilitation or a stay in a nursing home facility. In addition to the morbidity and mortality patients may experience after an osteoporotic fracture, there are significant health care costs associated with fractures. The estimated cost of osteoporosis-related fractures in 2005 was $19 billion, but this is estimated to increase to more than $25 billion per year in the next 2 decades. However, many of these fractures could be prevented if osteoporosis and fracture risk were assessed before a fracture and appropriate measures taken.
Introduction
Hip fractures and vertebral fractures are 2 of the most common fracture sites related to osteoporosis, and affect nearly 1 million persons in the United States annually. Moreover, nearly one-quarter of patients who endure a hip fracture die within a year of the fracture. An even larger proportion requires either extensive physical rehabilitation or a stay in a nursing home facility. In addition to the morbidity and mortality patients may experience after an osteoporotic fracture, there are significant health care costs associated with fractures. The estimated cost of osteoporosis-related fractures in 2005 was $19 billion, but this is estimated to increase to more than $25 billion per year in the next 2 decades. However, many of these fractures could be prevented if osteoporosis and fracture risk were assessed before a fracture and appropriate measures taken.
Definition of osteoporosis
Osteoporosis can be defined clinically by either:
- 1.
Low bone mineral density (BMD) (T-score of ≤ −2.5)
- 2.
A history of fragility fracture
BMD is measured by a central dual-energy x-ray absorptiometry (DXA) scan. BMD is presented as gram per centimeter squared, then translated into T-scores for postmenopausal women and men older than 50 years. Alternatively, Z-scores are used for premenopausal women and younger men. T-scores and Z-scores represent the patient’s BMD in relation to a 30-year-old normal reference and an age-matched reference, respectively, and the difference is presented as a standard deviation from the “normal” BMD. The World Health Organization (WHO) defines osteoporosis as a T-score of −2.5 and lower; osteopenia (or low bone density) as a T-score between −1.0 and −2.5; and normal bone density as a T-score of −1.0 and higher. In a younger population, Z-scores of −2.0 and lower reflect low BMD and any Z-score higher than −2.0 is normal.
Based on the WHO definition, osteoporosis can also be diagnosed based on a prior “osteoporotic” fracture. Other ways of describing an osteoporotic fracture include fractures that would not have typically occurred in a “normal” individual, or a “fragility fracture.” Fragility fracture is frequently described as a fracture occurring as the result of minimal trauma or a fall from standing height or less. All of these definitions are subjective and leave room for clinical judgment. A history of hip or vertebral fracture is sufficient for a diagnosis of osteoporosis and recommendation for treatment regardless of BMD, but most other prior fractures also convey an increased risk of future fracture. However, fractures in adults are commonly managed without consideration of future risk. Thus, the American Orthopaedic Association launched the “Own the Bone” program in 2009 in an effort to increase the awareness of fragility fractures as a teachable moment. The intent of the program is recognition of patients who have an initial fracture and to ensure that they have proper evaluation for osteoporosis and treatment where appropriate.
There is intentional movement away from the T-scores alone, which measure relative fracture risk, toward absolute fracture risk. The WHO developed a fracture risk assessment tool called FRAX, which allows for the addition of clinical information to BMD (or body mass index, if BMD is not available). FRAX integrates clinical risk factors, such as glucocorticoid use, smoking, alcohol use, family history of fracture, and prior fracture, into the determination of 10-year absolute fracture risk. These estimates of fracture risk can then be used to assist in determining treatment needed in patients with less clear indications or to discuss potential treatment benefits with patients. A similar but more patient-friendly tool called the Garvin Institute Fracture Risk Calculator can be downloaded at http://garvan.org.au/promotions/bone-fracture-risk/calculator/index.php .
Osteoporosis in men
In contrast to most diseases for which there is a relative abundance of data and emphasis on men’s health, the opposite is true for osteoporosis. In 2012, the Endocrine Society published clinical guidelines for the treatment of osteoporosis in men. Based on these guidelines, it is now recommended that all men at risk of osteoporosis or fracture obtain a DXA scan for screening. Based on age alone, men who are 70 years or older should undergo screening. In addition, men aged 50 to 69 should also undergo DXA evaluation if additional risk factors for osteoporosis are present ( Table 1 ). Based on the DXA findings, men with T-scores in the osteoporosis range or men with low BMD and other clinical risk factors for fracture should be initiated on an osteoporosis prescription medication.
| Men and women | Hyperparathyroidism |
| Untreated thyroid disease | |
| Chronic lung disease | |
| Chronic glucocorticoid use (>3 mo) | |
| Alcohol abuse (>3 alcoholic beverages daily) | |
| Smoking tobacco use | |
| Vitamin D insufficiency | |
| Low calcium intake | |
| Immobilization | |
| Anorexia nervosa | |
| Diabetes mellitus (types 1 and 2) | |
| Adrenal insufficiency | |
| Malabsorptive gastrointestinal disease (celiac, inflammatory bowel disease, gastric bypass, etc) | |
| Rheumatoid arthritis | |
| Systemic lupus erythematosus | |
| Ankylosing spondylitis | |
| Men | Hypogonadism |
| Gonadotropin-releasing hormone agonist treatment | |
| Women | Ovarian failure |
| Amenorrhea (hypogonadotropic hypogonadism) |
It is estimated that 30% to 60% of osteoporosis within men is secondary to another underlying condition. The most frequent secondary causes are glucocorticoid use or hypercortisolism (ie, Cushing syndrome or disease), excessive alcohol use, hypogonadism, vitamin D deficiency/low calcium intake, smoking, and family history of fracture. Other secondary causes combined account for approximately 15% of cases. In up to 40% of cases in men no secondary cause is identified, and the osteoporosis is considered either primary or idiopathic osteoporosis. Secondary causes (see Table 1 ) for osteoporosis and fracture should be assessed clinically (by history and physical examination) in all patients, and with laboratory evaluation when clinical suspicion is high. Treatment of secondary causes of osteoporosis is recommended. However, if a patient’s risk of fracture is high, pharmacologic osteoporosis treatment should be initiated as well. In lower-risk patients treatment of the secondary cause may be sufficient, but they should be monitored for future bone loss and fracture risk.
Risk of future fracture
Prior Fracture
Low-energy trauma fractures have historically been linked to osteoporosis, in part because of the increased risk of ensuing low-energy fractures. In one study, an increased risk of subsequent fracture was observed following any fragility fracture, with only 2 exceptions: rib fractures in men and ankle fractures in women. In a more recent study nearly all fragility fractures were significantly associated with future fracture among postmenopausal women. In this study, ankle fractures were associated with an increased risk of future fracture of weight-bearing bones and rib fractures were associated with a risk of future vertebral fracture. Of note, the associations between incident hip and vertebral fracture following prior hip and vertebral fractures, respectively, were significantly elevated (hazard ratio [HR] of 7.3 and 3.5, respectively).
In addition to findings that most fracture types increase the risk of future fracture, there is also evidence that even fractures associated with high-energy trauma pose a risk for future fracture. Several studies have shown that BMD is similar in those who have had prior fractures, regardless of the presence or absence of high-energy trauma. In several studies, individuals with fractures were 3 times more likely to have osteoporosis at 1 or more sites regardless of the degree of trauma at the time of fracture. It has also been shown that a relationship exists between high-trauma fractures and either low BMD or structural changes in bone in both women and men, comparable with the relationship seen in those who have had low-energy trauma fractures. These findings all suggest that any prior fracture as an adult (after age 50 years), regardless of the degree of trauma, may merit evaluation for underlying fragility and may be associated with an increased risk of future fracture.
Fracture prevention
Nonpharmacologic Treatment Options
Approximately 90% of hip fractures are caused by falls. Several modifiable factors that may mitigate the risk of a fall include a home-safety assessment, alcohol cessation, vision evaluation, medication review (specifically psychoactive medications), and assessment of orthostatic blood pressure. Studies of community dwellers have shown a significant reduction of falls and fractures following exercise intervention.
Direction of fall is an important predictor of hip fracture, lending support to the use of hip protectors. Hip protectors significantly reduce the force to the hip during a fall. A meta-analysis showed a slight reduction in the risk of hip fracture among nursing home or residential care patients randomized to a hip protector (relative risk [RR] 0.77, 95% confidence interval [CI] 0.62–0.97) but no significant benefit among community dwellers was found (RR 1.16, 95% CI 0.85–1.59). The differences may be explained by poor long-term adherence in both patient groups, and should be interpreted cautiously because of cluster randomization. Another trial randomized individual nursing home residents to a one-sided hip protector and, despite good adherence, found no reduction in hip fractures in the unprotected versus protected hip. Despite these inconsistent results, hip protectors may still be a safe and reasonable option.
Calcium and vitamin D
Randomized trials comparing calcium therapy alone versus placebo have shown no consistent benefit in the reduction of vertebral and nonvertebral fractures. These findings may be partially confounded by nonadherence with treatment, because other trials have shown that when adherence of 80% or better is achieved, calcium has been shown to reduce the risk of fracture (HR 0.66, 95% CI 0.45–0.97).
Most available studies of calcium are completed in combination with vitamin D supplementation. Although there is evidence that calcium and vitamin D reduce the risk of fracture, the benefit has not been seen in all populations. The type and amount of vitamin D supplementation likely play a role in the reduction of fracture risk.
Evidence associating vitamin D intake with fracture reduction exists. In a meta-analysis, oral vitamin D supplementation of any dose led to a 7% to 10% reduction of fracture risk in older people (HR for any nonvertebral fracture 0.93, 95% CI, 0.87–0.99; HR for hip fracture 0.90, 95% CI 0.80–1.01). However, in those subjects who took the highest vitamin D doses (median of 800 IU/d), the reduction of fracture risk was greater (HR for any nonvertebral fracture 0.70, 95% CI 0.58–0.86; HR for hip fracture 0.86, 95% CI 0.76–0.96). These data underscore the importance of the dose when recommending vitamin D supplementation.
In addition to its role in fracture reduction, vitamin D insufficiency has been found to be associated with risk of a fall and supplementation has been found to reduce the risk of falls, likely through improved musculoskeletal function. Two randomized clinical trials confirmed that vitamin D supplementation (cholecalciferol 700 IU daily) reduced the risk of a fall in elderly persons. The effect was shown even in persons with adequate 25-hydroxyvitamin D (25(OH)D) levels at the start of the study, and was found to be more prominent in the less active women studied. The US Preventive Services Task Force has recently published recommendations for fall prevention in older, community-dwelling adults, which include vitamin D supplementation along with exercise for fall prevention.
Vitamin D is important in bone health because of its ability to counterregulate parathyroid hormone (PTH), a promoter of bone loss, and its ability to stimulate intestinal and renal calcium absorption. In the setting of vitamin D deficiency, PTH levels typically increase, resulting in secondary hyperparathyroidism.
The optimal level of serum 25(OH)D remains unclear, as do the optimal doses of vitamin D for replacement and maintenance. Most agree that vitamin D deficiency can be defined as a 25(OH)D level of less than 20 ng/mL. Because a 25(OH)D level of less than 30 ng/mL is sometimes associated with PTH elevation, a serum 25(OH)D level of 30 ng/mL has been recommended by some. Vitamin D intoxication, leading to hypercalcemia, generally does not occur until 25(OH)D levels reach 150 ng/mL or higher, except in patients with primary hyperparathyroidism.
Because of the multiple confounders regarding the absolute benefit of calcium, it is recommended that persons take calcium and vitamin D supplements for general bone health but that these supplements should not be used alone for the reduction of fracture risk. The Institute of Medicine published recommendations for calcium and vitamin D usage in 2011 based on age and gender ( Table 2 ). These new recommendations state that women 51 years and older and men 71 years and older should aim to consume 1200 mg of calcium daily, whereas a daily intake of 1000 mg is recommended for women 19 to 50 and men 19 to 70 years of age. For vitamin D, the recommended daily intake is 600 IU daily for children and adults, but rises to a recommended dose of 800 IU daily for men and women 71 years and older.
| Age (y) | Institute of Medicine | Endocrine Society | ||
|---|---|---|---|---|
| Recommended Daily Allowance | Upper Daily Limit | Daily Requirement | Upper Daily Limit | |
| Calcium (mg) | ||||
| 19–50 | 1000 | 2500 | — | — |
| 51–70 | 1000 (men) 1200 (women) | 2000 | — | — |
| >70 | 1200 | 2000 | — | — |
| Vitamin D (IU) | ||||
| 19–70 | 600 | 4000 | 1500–2000 | 10000 |
| >70 | 800 | 4000 | 1500–2000 | 10000 |
Shortly after the recommendations from the Institute of Medicine were published, the Endocrine Society published recommendations for vitamin D dosing provided by an expert committee (see Table 2 ) . In these latter recommendations, the recommended daily intake of vitamin D was much higher (1500–2000 IU daily for men and women) than that proposed by the Institute of Medicine.
A concern has been raised regarding a potential association between calcium and vitamin D supplementation and cardiovascular risk. In a secondary analysis of a prospective, placebo-controlled study of calcium supplementation in postmenopausal women, an association between calcium supplements and myocardial infarction and composite cardiovascular disease was seen, but was attenuated after the addition of unreported cardiovascular events found in the national hospital admission database. Thereafter, meta-analyses also found an association between calcium supplements alone and increased cardiovascular risk, and this was further supported by the update of this meta-analysis that included calcium with or without concurrent vitamin D. By contrast, another meta-analysis refuted these findings and found no clear association between cardiovascular disease and calcium supplementation. Similarly, in a recent report no association was found between cardiovascular disease and calcium supplementation in women enrolled in the Nurses’ Health Study, including women taking higher daily doses of calcium (>1000 mg of calcium daily).
Based on these findings, it is appropriate to assess each patient’s daily calcium consumption. If a patient is consuming fewer than 3 servings of calcium-rich foods or beverages daily (ie, milk, yogurt, cheese, calcium-fortified orange juice, and so forth), calcium supplementation should be considered. Goal daily calcium intake should be between 1000 and 1500 mg per day, divided. Care should be taken to avoid oversupplementation because of the risk of nephrolithiasis and, potentially, cardiovascular disease. Unlike calcium, vitamin D is more difficult to obtain from common foods and beverages. Patients older than 70 years are also less likely to obtain adequate vitamin D through sun exposure. Therefore, supplementation is typically required. The recommended daily intake of vitamin D is a minimum of 800 IU daily, but many patients require 1000 to 2000 IU daily to maintain stores of vitamin D.
Pharmacologic Treatment Options
The initial question most clinicians have is: who should be treated? The second question is determining which treatment to begin. The National Osteoporosis Foundation has created some guidelines to assist with the first question ( Box 1 ), which rely on data obtained through imaging (DXA) and/or clinical risk factors for fracture. As such, a DXA is not essential in determining the need for treatment. Consequently, in a patient with a recent hip, vertebral, or other weight-bearing osteoporotic fracture, treatment should be initiated without the need for BMD measurement, if no other contraindications exist. Treatment also should be initiated in a patient without a prior fracture but who has other strong clinical risk factors for fracture.
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