• May 2, 2007, Antidepressant drugs: Update to the existing black box warning on the prescribing information on all antidepressant medications to include warnings about the increased risks of suicidal thinking and behavior in young adults ages 18 to 24 years old during the first one to two months of treatment.

Note from the National Guideline Clearinghouse (NGC) and the Institute for Clinical Systems Improvement (ICSI): For a description of what has changed since the previous version of this guideline, refer to Summary of Changes – July 2006.

The recommendations for the diagnosis and treatment of osteoporosis are presented in the form of an algorithm with 16 components, accompanied by detailed annotations. An algorithm is provided for Diagnosis and Treatment of Osteoporosis; clinical highlights and selected annotations (numbered to correspond with the algorithm) follow.

Class of evidence (A-D, M, R, X) and conclusion grade (I-III, Not Assignable) definitions are repeated at the end of the "Major Recommendations" field.

Clinical Highlights

• Discuss risk factors for osteoporosis and primary prevention with all patients presenting for preventive health visits. (Annotations #4, 5)
• Patients with a high pre-test probability of low bone mineral density (BMD) and future fracture should have bone density testing to further define their fracture risk. (Annotation #8, 9)
• Address pharmacologic options for prevention and treatment of osteoporosis with appropriate patients at risk for or who currently have signs and symptoms of osteoporosis. (Annotation #15)

Diagnosis and Treatment of Osteoporosis Algorithm Annotations

1. All Patients Presenting for a Preventive Visit

   Osteoporosis is the consequence of continued bone loss throughout adulthood, low achieved peak bone mass, or both. The guideline work group recommends maintaining peak bone mass for all patients. To achieve and maintain maximum bone density, patients should have risks for osteoporosis reviewed when they present to their provider offices. In addition to reviewing historical risk factors (discussed in Annotation #5, "Discuss Risk Factors for Osteoporosis and Osteoporotic Fracture"), it is important to record accurate serial height measurements with a stadiometer and observe posture for kyphosis. Patients with significant acquired kyphosis and/or a height loss of one inch should have lateral vertebral assessment with dual energy x-ray absorptiometry (DXA) or thoracic and lumbar spine radiographs and bone density testing.

   Evidence supporting this recommendation is of class: R

2. Patient With a Low-Impact Fracture

   Key Points:

   • Low impact fracture defines osteoporosis and requires therapy.

   Discuss osteoporosis risk with any adult who has a history of a low-trauma fracture that may be related to osteoporosis. For the purpose of this guideline, a low-impact fracture will be defined as a fracture occurring spontaneously or from a fall at a height no greater than the patient's standing height. This includes fractures from activities such as a cough, sneeze, or abrupt movement (e.g., opening a window), and patients who have vertebral compression fracture documentation on radiographs regardless of their degree of symptoms. Many adults do not realize that having one fracture in their adult lifetime indicates an increased risk of future fractures, especially in the first few years following the fracture, and may be an indication for bone density testing. This historical risk factor provides information that may be additive to bone mineral density information. The occurrence of a fracture, particularly in the limbs, is followed by accelerated bone loss, not completely reversible, which could lead to an increased risk of subsequent fracture. And, there may be mechanical influences caused by having had one fracture that increase subsequent risk by altering balance and increasing fall risk.

   Post-Fracture Recommendations

   • Consider all adults with a history of vertebral fracture, hip fracture, or distal forearm fracture at higher than average risk for a future fracture.
   • Review lifestyle risk factors for osteoporosis. Discuss adequacy of total calcium and vitamin D intake. Address home safety, fall prevention, and specific exercises for muscle strength.
   • Consider bone density testing in fracture patients willing to accept treatment.
   • Consider all men* and postmenopausal women with low impact fracture as candidates for pharmacologic and physical medicine treatment.
   • Women over age 70 with prior fracture are candidates for osteoporosis therapy even without bone density testing.

   *Although the best data available is on postmenopausal women, there may be a similar risk in men, and the guideline work group is including men in this guideline recommendation.

   Refer to the original guideline document for more information.

   Evidence supporting this recommendation is of classes: A, B, C, D, M, R

3. Patient On Chronic Glucocorticoid Therapy or Transplant Recipient

   Key Points:

   • Glucocorticoid therapy compounds fracture risk beyond that as determined by bone mineral density (BMD)

   Glucocorticoid Therapy

   Osteoporosis prevention and treatment measures and bone mineral density testing should be considered for anyone who is started on or has been on exogenous glucocorticoid therapy (at a dose of more than 5 mg prednisone or equivalent per day for 3 or more months). Osteoporosis prevention measures should also be considered for those who have been or can be expected to be on a daily high-dose inhaled glucocorticoid for several years. While it is never too late in the course of glucocorticoid therapy to prevent or treat osteoporosis, it is preferable to start preventive measures against bone loss when glucocorticoid therapy is started for two reasons. First, the greatest amount of bone is lost during the first several months of glucocorticoid use. Second, the risk of fracture at any given level of bone mineral density is greater in those on chronic glucocorticoid therapy than in those who are not on a glucocorticoid. That is, fracture risk is disproportionately increased in those with glucocorticoid-induced low bone density relative to those with low bone density associated with the aging process and/or the postmenopausal state.

   Refer to the original guideline document for information on bone mineral density loss and fracture associated with oral and inhaled glucocorticoids.

   Organ Transplantation

   Solid organ transplantation of all types and allogeneic bone marrow transplantation are associated with rapid bone loss after transplantation. In addition, many patients develop significant bone loss before transplantation.

   Refer to the original guideline document for more information on pre- and post-transplantation bone loss.

   Evidence supporting this recommendation is of classes: B, D

4. Discuss Primary Prevention of Fractures

   Key Points:

   • Healthy lifestyle discussion at primary prevention visits is important for osteoporosis prevention.

   Body Habitus

   Low body mass index (BMI) (less than 20) is a strong independent risk factor for osteoporosis and fracture. Weight less than 127 pounds, associated with small bones, is a risk factor for osteoporosis. Primary prevention should include counseling patients on achievement and maintenance of a healthy body weight (BMI between 20 and 25). A balanced diet including dairy products and appropriate nutrition should be discussed with patients. Also see Annotation #5, "Discuss Risk Factors for Osteoporosis and Osteoporotic Fracture."

   Evidence supporting this recommendation is of class: B

   Gonadal Hormonal Status

   Women who are prematurely hypogonadal and hypogonadal men who are at increased risk for fracture should be considered for replacement therapy. For further information, please see Annotation #14, "Consider Secondary Causes and Further Diagnostic Testing" as well as Annotation #15, "Address Options for Prevention or Treatment of Osteoporosis."

   Exercise

   Exercise is well known for its many benefits both short-term and long-term. Weight bearing and muscle strengthening exercises have been shown to be an integral part of osteoporosis prevention as well as a part of the treatment process.

   Three components of an exercise program are needed for strong bone health: impact exercise such as jogging, brisk walking, stair climbing; strengthening exercise with weights; and balance training such as Tai Chi or dancing.

   Refer to the original guideline document for more information.

   Evidence supporting this recommendation is of classes: A, C, D, R

   Smoking Cessation

   Smoking cessation counseling should be done at every visit. Discussion can include helpful strategies such as nicotine replacement therapy with patches, gum, etc. Bupropion and available smoking cessation classes may also be discussed. For more information on smoking cessation, please refer to the National Guideline Clearinghouse (NGC) summary of the Institute for Clinical Systems Improvement (ICSI) guideline, Tobacco Use Prevention and Cessation for Adults and Mature Adolescents.

   Alcohol Restriction

   Limit alcohol use to no more than two drinks per day. One drink equals 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of 80-proof distilled spirits. This limit will help to protect bone health and reduce the risk of falls. See Annotation #5, "Discuss Risk Factors for Osteoporosis and Osteoporotic Fractures."

   Calcium

   Adequate calcium intakes from food sources and supplements promote bone health. When food sources do not provide enough calcium, supplements can be used to meet this goal. Bioavailability of calcium in food sources and supplements is a factor in achieving daily calcium recommendations. Calcium supplement labels should indicate lead testing.

   Daily elemental calcium recommendations for healthy individuals include:

   National Academy of Sciences, Institute of Medicine (1997)

   • 9-18 years: 1,300 mg
   • 19-50 years: 1,000 mg
   • Over 50 years: 1,200 mg
   • Maximum limit: 2,500 mg

   However, for people with established osteoporosis, glucocorticoid therapy, pregnant or nursing women, or persons over the age of 65, it may be more appropriate to recommend 1,500 mg.

   Both low fractional calcium absorption and low dietary calcium intake have been associated with increased fracture risk. Since fractional calcium absorption is affected by multiple factors and decreases with age, adequate lifetime dietary calcium is an important recommendation for bone health.

   Generally, calcium absorption is similar from most foods, but calcium is poorly absorbed from foods rich in oxalic acid. An exception is soybeans. A variety of foods with calcium is recommended.

   Bioavailability from calcium supplements is affected by meals, dose size and tablet disintegration. For calcium carbonate, absorption decreases at doses greater than 600 mg, therefore supplements should be taken with meals and in divided doses. Taking calcium carbonate supplements on an empty stomach may increase the risk of kidney stones. Heavy metal levels in calcium supplements vary, with some supplements exceeding the acceptable level recommendation for bone health.

   Calcium slows age-related bone loss. [Conclusion Grade II, See Conclusion Grading Worksheet A -- Annotations #4 & 5 (Calcium) in the original guideline document]

   Calcium may reduce osteoporosis fracture risk. [Conclusion Grade III, See Conclusion Grading Worksheet A -- Annotations # 4 & 5 (Calcium) in the original guideline document]

   Evidence supporting this recommendation is of classes: A, D, R

   Vitamin D

   Adequate vitamin D intake supports calcium absorption and bone metabolism. Since sunlight exposure cannot be assumed to produce needed vitamin D, dietary sources are essential. Since many adults in northern climates are deficient in vitamin D, supplements are often needed to meet daily requirements. The following guidelines assume no vitamin D is synthesized from sunlight exposure:

   Institute of Medicine (1997)*

   • 19-50 years: 200 IU/day
   • 51-70 years: 400 IU/day
   • over 70 years: 600 IU/day
   • Maximum limit: 2,000 IU/day

   *These guidelines are currently under revision and the recommendation for adults will likely be significantly increased to 800-1,000 IU/day. Another study suggests at least 800 IU/day of vitamin D is needed for maximum suppression of parathyroid hormone (PTH), maximum absorption of calcium, and has been shown to prevent fractures in older adults. Supplementation should be made to maintain 25-OH vitamin D levels greater than 30 ng/mL.

   Although milk is the only dairy source of vitamin D, studies have demonstrated highly variable levels of vitamin D fortification in milk in both the U.S. and Canada. Other food sources of vitamin D are affected by the time of year they are harvested.

   Evidence supporting this recommendation is of classes: M, R

   Prevention of Falls

   Preventing falls reduces fracture risk. Modifying environmental, personal risk, and medication-related factors can be effective in reducing falls. Home visits may help with this. Hip protector pads for frail, elderly adults have been shown to reduce hip fractures in some studies, but not in others. Measures to decrease kyphotic posture and improve unsteady gait can decrease falls.

   Please, see Annotation #5, "Discuss Risk Factors for Osteoporosis and Osteoporotic Fracture."

5. Discuss Risk Factors for Osteoporosis and Osteoporotic Fracture

   The following are risk factors for osteoporosis and osteoporotic fracture:

   • Female gender
   • Advanced age (greater than age 65)
   • Body habitus (weight less than 127 pounds; or BMI less than or equal to 20)
   • Caucasian or Asian race
   • Personal or family history of fracture (first-degree relative)
   • Hypogonadism (estrogen or testosterone deficiency)
   • Sedentary lifestyle
   • Smoking
   • Excessive alcohol intake (more than two drinks per day)
   • Diet deficient in calcium or vitamin D without adequate supplementation
   • Increased likelihood of falling

   For a list of secondary causes of osteoporosis, please see Appendix A, "Secondary Causes of Osteoporosis" in the original guideline document.

   Risk factors for osteoporosis and fractures are fixed or modifiable. Some risk factors for osteoporosis are also risk factors for fracture independent of bone mineral density. They are important to know so they can be assessed and modified if possible.

   Advanced age, female gender, Caucasian and Asian race, and hypogonadal states are risk factors for osteoporosis. The only one of these that is modifiable is hypogonadism (with replacement therapy). African-American women have a decreased risk, partly because they begin menopause with a higher BMD and have a lower rate of bone loss after menopause. Of all these, age and prior fracture are also predictors of fracture independent of bone mineral density.

   Refer to the original guideline document for information on relationship of bone mineral loss with body habitus; family history of osteoporosis; cigarette smoking; sedentary lifestyle; alcohol, calcium, and vitamin D intake; and increased likelihood of falling.

   Evidence supporting this recommendation is of classes: A, B, C, D, M, R

6. Low Pre-Test Probability of Low BMD and Future Fracture

   The following individuals are at low risk of low bone density and future fracture; bone density testing in general is not recommended:

   1. Premenopausal women who have not had a fracture with minor trauma, are not on chronic glucocorticoid therapy, do not have secondary amenorrhea, and do not have a chronic disease associated with bone loss
   2. Eugonadal men who have not had a fracture with minor trauma, are not on glucocorticoid therapy, and do not have another chronic disease associated with bone loss
   3. Postmenopausal women under age 65 who have been on hormone replacement therapy since menopause and who do not have any significant additional risk factors.

7. Address/Reinforce Options for Prevention of Osteoporosis

   Osteoporosis is the consequence of continued bone loss throughout adulthood, low achieved bone mass, or both. Because of this, providers are encouraged to periodically review historical risk factors (see Annotation #4, "Discuss Primary Prevention of Fractures") and primary prevention strategies (see Annotation #5, "Discuss Risk Factors for Osteoporosis and Osteoporotic Fracture") with their patients. Preventive health maintenance exams provide an excellent opportunity for this review.

8. High Pre-Test Probability of Low BMD and Future Fracture

   Key Points:

   • Patients can be risk-stratified to determine the appropriateness of bone density testing.

   The following individuals are at sufficiently high risk for low bone mass and future fracture that a bone mineral density test is justified to further define that risk. This assumes that the individual being tested is willing to consider pharmacologic treatment for low bone mass documented on a bone density test. The first three of these indicate individuals at particularly high risk of bone loss and future fracture.

   1. Prior fracture with minor trauma (fall from standing height or less)
   2. Those who have been or are anticipated to be on glucocorticoid therapy for 3 or more months at a dose equivalent to or greater than 5 mg prednisone per day
   3. Radiographic osteopenia or vertebral deformity consistent with fracture
   4. All women 65 years of age or older
   5. Postmenopausal women less than age 65 with one of the following additional risk factors
      1. Body weight less than 127 lbs or a BMI of 20 or less
      2. History of nontraumatic fracture after age 45 in a first-degree relative
      3. Current smoker
      4. Not using hormone replacement therapy
      5. Surgical menopause, or natural menopause before age 40
   6. Chronic diseases known to be associated with bone loss (see  Appendix A, "Secondary Causes of Osteoporosis" in the original guideline document)
   7. Premenopausal women with amenorrhea greater than 1 year
   8. Men with hypogonadism more than 5 years
   9. Prolonged severe loss of mobility (unable to ambulate outside of one's dwelling without a wheelchair for greater than one year)
   10. Solid organ or allogeneic bone marrow transplant recipient
   11. Medications for malignancy are likely to cause bone loss in patients

   Refer to the original guideline document for more information.

   Evidence supporting this recommendation is of classes: C, D, M, R

9. Recommend Bone Density Assessment

   Key Points:

   • BMD measurement with DXA is the single best predictor of fracture risk as well as the best monitor of patient response to treatment.

   Measurements of BMD with DXA can predict fracture risk and allow for the identification of people who are at increased risk of fracture. Reviews of prospective cohort studies and case control studies have documented a direct relationship between decreasing BMD and increasing bone fracture risk. Additionally, there is strong evidence that stabilization or increases in BMD with therapy for osteoporosis are associated with substantial reductions in fracture incidence. Therefore, densitometry offers an objective measurement of a patient's response to treatment over time.

   Current practice is to describe an individual's bone mineral density as compared to a reference normal population. In this sense, a T-score is the number of standard deviations above or below the mean for a gender- and ethnicity-matched young adult healthy population. A T-score is calculated from the following equation:

   [(measured BMD - young adult population mean BMD) / young adult population SD]

   A Z-score is the number of standard deviations above or below the mean for gender-, ethnicity-, and age-matched healthy population. A Z-score is calculated from the following equation:

   [(measured BMD - age-matched population mean BMD) / age-matched population SD]

   Normal, low bone density (osteopenia) and osteoporosis are defined by the lowest of lumbar spine (at least two evaluable vertebrae required), femoral neck, and total femur T-score, according to the World Health Organization (WHO). The one-third radius site may be used if either the lumbar spine or femur is non-evaluable. Although the following classifications were originally drafted for Caucasian postmenopausal women, some controversy exists as to whether the same diagnostic criteria can be applied to other groups.

   • Normal*: A T-score greater than or equal to -1
   • Low bone density (osteopenia): A T-score between -1 and -2.5**
   • Osteoporosis: A T-score less than or equal to -2.5
   • The term "severe osteoporosis" is reserved for patients with both a fragility fracture(s) and a low bone density.

   * The absence of upper limits for BMD in the WHO criteria jeopardizes recognition of high BMD disease. This oversight requires correction using Z-scores. It has been proposed that Z-scores of localized BMD, at or above +2.5, warrant further study.

   ** Following a Position Development Conference on bone densitometry in 2005, the International Society of Clinical Densitometry recommends that the term "osteopenia" be retained, but "low bone mass" or "low bone density" are the preferred terms.

   For patients who decline bone density testing, reinforce osteoporosis prevention, consider gonadal hormone replacement therapy, and follow-up discussion of osteoporosis at future preventive visits.

   Universal bone densitometry screening of women age 65 and older is now recommended by nearly all specialty societies that have constructed guidelines for the diagnosis and management of osteoporosis, including the United States Preventive Services Task Force. Moreover, universal screening with bone densitometry followed by treatment of those found to have osteoporosis has been found to be highly cost-effective for women age 65 and older, including those residing in nursing homes.

   Refer to the original guideline document for more information.

   Evidence supporting this recommendation is of classes: C, D, M, R

10. Post-Test Probability

    Key Points:

    • BMD test results provide good information in predicting future fracture risk.
    • Other historical factors that relate to bone quality augment BMD data in modifying risk.

    Fracture risk in an individual patient is defined as the likelihood of sustaining an osteoporotic fracture over an interval of time. Current fracture risk is defined as the likelihood of an osteoporotic fracture in the patient's remaining lifetime years.

    Current fracture risk can be expressed in terms of absolute risk, relative risk, or incidence (annual) risk. Absolute fracture risk is the actual risk of fracture for a given patient. Relative risk of fracture is the ratio of the absolute risk of fracture for the patient compared to the absolute risk of fracture for a young adult-, gender-, and ethnicity-matched reference population. Relative risk of fracture is increased by 1.5 to 3.0 times for each 1.0 standard deviation decrease in bone density below the mean for young adults of the same gender and ethnicity. Fracture risk data in elderly postmenopausal women suggest that fracture prediction is nearly equal regardless of the skeletal site assessed or the type of technology used, with the exception that hip fracture risk is best predicted by proximal femoral bone mineral density measurement. Similar data are being accumulated for men, although the numbers of studies published so far are much smaller. Prospective data allows prediction of 10-year fracture risk based on age and bone mineral density alone in post-menopausal women. This risk must be adjusted according to other clinical findings.

    Evidence supporting this recommendation is of classes: B, C

12. Low Risk of Future Fracture

    Low fracture risk is clinically defined by a bone mineral density T-score above -1.0 (normal bone density by the WHO definition).

13. Increased Risk of Future Fracture

    Key Points:

    • The T-score is best used in combination with other patient information to predict a given patient's fracture risk.

    Even though osteoporosis is defined by a BMD T-score of less than -2.5, and osteopenia is defined as a T-score of -1 to -2.5, and the relative risk for fracture is directly correlated to T-score bone density, the absolute risk of fracture is not only related to bone density but also by bone quality and other non-bone density risk fractures for fracture.

    Some patients with very low T-scores will never sustain an osteoporotic fracture, whereas some patients with normal T-scores will have fractures. Patients who fall infrequently are less likely to sustain osteoporotic fractures.

    Previous osteoporotic fractures sustained by the patient, history of osteoporotic fractures sustained by the patient's family members, increased rate of bone turnover, the patient's risk of falling, and the use of medications that predispose to falling, also help predict future fracture risk.

    Bone mineral density is the single best predictor of future fracture. About 80% of the variance in bone strength and resistance to fracture in animal models is explained by bone mineral density, and numerous studies have demonstrated that fracture risk is predicted by bone mineral density.

    Patients found to have low risk of future fracture by bone mineral density testing should not automatically be assumed to remain at low risk of future fracture over their remaining lifetime years. Patients should be periodically reassessed by reviewing risk factors for osteoporosis, evaluating current primary prevention efforts, reviewing the clinical history for osteoporotic fractures subsequent to the initial bone density evaluation, and measuring bone mineral density. Clinical judgment must be used in determining the appropriate intervals between repeated measurements of bone mineral density over time. Whenever remeasure occurs, it is important to use the same densitometer. In some patients, such as those expected to have high bone turnover and rapid bone loss due to early postmenopausal status, initiation or continuation of steroid therapy, organ transplantation, or other causes, it may be appropriate to remeasure bone density as soon as 6-12 months after the initial measurement. In those patients not expected to have high turnover or rapid loss, it is appropriate to remeasure bone density at an appropriate interval, such as two to five years after the initial measurement, in order to detect patients who lose significant bone density over time.

14. Consider Secondary Causes and Further Diagnostic Testing

    Key Points:

    • A minimum screening laboratory profile should be considered in all patients with osteoporosis.

    At this time there is no consensus about the routine use of serum and/or urine markers of bone turnover in the evaluation of patients with osteoporosis. See the ICSI Technology Assessment Report #53, Biochemical Markers for Bone Turnover in Osteoporosis, for more information.

    Certain diseases are commonly associated with bone loss. These diseases are listed in Appendix A, "Secondary Causes of Osteoporosis," in the original guideline document. In broad categories, these include chronic inflammatory autoimmune conditions, endocrinopathies, malignancies, and malabsorptive states.

    Consider the following evaluation for the patient with osteoporosis without prior workup:

    • A biochemical profile that provides information on:
      • Renal function
      • Hepatic function
      • Calcium (important if starting an antiresorptive or anabolic agent)
        • elevated in hyperparathyroidism
        • decreased in malabsorption, vitamin D deficiency
      • Alkaline phosphatase
        • elevated in Paget's Disease, prolonged immobilization, acute fractures and other bone diseases
      • Phosphorus
        • decreased in osteomalacia
    • A complete blood count may suggest bone marrow malignancy or infiltrative process (anemia, low white blood cell count [WBC], or low platelets) or malabsorption (anemia, microcytosis, or macrocytosis).
    • An elevated sedimentation rate or C-reactive protein may indicate an inflammatory process or monoclonal gammopathy.
    • Thyroid-stimulating hormone (TSH) and thyroxine
    • 25-OH vitamin D (optimal level greater than or equal to 30 ng/mL to maximally suppress PTH secretion)
    • Intact parathyroid hormone
    • The 24-hour urinary calcium excretion on a high-calcium intake screens for malabsorption and hypercalciuria, a correctable cause of bone loss. Low 24-hour urine calcium suggests vitamin D deficiency, osteomalacia, or malabsorption due to small bowel diseases such as celiac sprue.

    Consider adding the following tests if clinically indicated: Osteoporosis and an age-matched bone density that is greater than one standard deviation below age-matched controls (Z-score <-1.0): In this population it is important to screen for treatable secondary causes of bone loss that may not be clinically evident in patients with a lower than expected bone density or premature osteoporotic fracture. (See Appendix A, "Secondary Causes of Osteoporosis" in the original guideline document for a comprehensive list of secondary causes of osteoporosis).

    • Testosterone (total and free) in men and estradiol in women; luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and prolactin if evidence of hypogonadotropic hypogonadism
    • Tissue transglutaminase if clinical suspicion for gluten enteropathy for low 25-OH vitamin D
    • 24-hour urinary free cortisol or overnight dexamethasone suppression test if clinical suspicion of glucocorticoid excess
    • Serum and urine protein electrophoresis, with a conditional immunoelectrophoresis

    Refer to Appendix A, "Secondary Causes of Osteoporosis" in the original guideline document for a table with the common causes of secondary osteoporosis.

    Evidence supporting this recommendation is of classes: D, R

15. Address Options for Prevention and Treatment of Osteoporosis

    Key Points:

    • Lifestyle adjustments are traditionally first-line therapy for osteoporosis prevention and treatment.
    • Bisphosphonates have the strongest data showing risk reductions in both vertebral and non-vertebral fractures.
    • Estrogen is considered first-line therapy for the prevention of osteoporosis in prematurely menopausal women under the age of 50.
    • Anabolic therapy with parathyroid hormone is indicated for patients with particularly high-risk for future fracture, and data shows reduction in vertebral and non-vertebral fracture.
    • Nasal calcitonin is not considered a first-line treatment for osteoporosis, but may be useful in some populations.
    • Selective estrogen receptor modulator (SERM) treatment with raloxifene has shown vertebral fracture risk reduction in postmenopausal osteoporosis.

    Please see the medication tables in Appendix B, "Recommended Pharmacologic Agents" of the original guideline document for specific information on pharmacologic agents for treatment and prevention of osteoporosis.

    Osteoporosis Prevention

    Estrogen has traditionally been considered first-line therapy for prevention of osteoporosis in prematurely menopausal women under the age of 50. If the only reason hormone therapy has been prescribed is for osteoporosis prevention, other therapies should be considered. If the decision is made to discontinue estrogen, a BMD should be obtained to determine if other bone loss prevention therapies are needed. Other medications for prevention include bisphosphonates and raloxifene.

    Osteoporosis Treatment

    Bisphosphonates have the strongest data showing risk reductions in both vertebral, hip, and other nonvertebral fractures. Other treatments include raloxifene (see SERM in this annotation) and calcitonin.

    Parathyroid hormone 1-34 (teriparatide) (PTH) is used for patients at highest risk for fracture. It could be first-line therapy for those patients.

    Post-transplantation Bone Loss

    Antiresorptive therapy and calcitriol may be effective at preventing bone density loss after transplantation. Considering the rates of bone loss after transplantation described in Annotation #3, bone mineral density testing should be performed every 6 months to one year until bone mineral density is shown to be stable or improving on therapies for osteoporosis. Studies demonstrate that standard calcium and vitamin D supplementation, with or without calcitonin, are not able to prevent bone loss after transplantation. Other studies indicate that pharmacologic vitamin D preparations or intravenous bisphosphonates, such as pamidronate, or zoledronic acid, or oral bisphosphonates, such as alendronate or risedronate are more likely to prevent bone loss after transplantation.

    Alternative and Complementary Agents for Prevention and Treatment of Osteoporosis

    There is conflicting data on a number of non-Food and Drug Administration (FDA) approved substances for possible use in prevention and treatment of osteoporosis. These include phytoestrogens, synthetic isoflavones such as ipriflavone, natural progesterone cream, magnesium, vitamin K and eicosapentaenoic acid. There is very limited data from randomized controlled trials of these agents for prevention or treatment of osteoporosis. A recently reported, multicenter randomized trial of ipriflavone showed no significant effect on bone density or risk of vertebral fractures.

    Evidence supporting this recommendation is of classes: A, B, C, D, M, R

    In addition to calcium, vitamin D, physical therapy, surgical repair, and radiologic intervention as appropriate, the therapies listed below may be used. Clinicians should be aware that patient compliance with adherence to osteoporosis therapy has been historically poor.

    Gonadal Hormone Therapy

    Female Gonadal Hormone Therapy

    The use of supplemental estrogen in the immediate postmenopause has been well accepted in preventing the rapid loss of bone that occurs in this interval.

    Supplemental estrogen not only retards accelerated bone loss, but has also been shown to create a gain in bone density. In the PEPI trial after 3 years, the women receiving hormone replacement therapy had a mean 5% gain in bone density in the spine and 2% in the hip compared to a 2% loss in the placebo group. Preliminary evidence suggests that the gain in bone mass may persist beyond the first few years. In one study, women on estrogen-progestin therapy showed a persistent increase in density over 10 years, reaching 13% over baseline.

    It is generally believed that estrogen therapy is most effective when started immediately after menopause. But estrogen therapy has also been shown to have a positive effect on bone mass long after menopause, creating gains of bone mass of 5 to 10% over baseline over 1 to 3 years.

    The protective effects of estrogen on bone density are lost quickly after estrogen is discontinued.

    Dose response effectiveness of hormone therapy on bone mass has recently undergone considerable scrutiny.

    Ultra-low estrogen supplementation has been shown to be effective in severely hypoestrogenic women in improving bone mass. Fracture data is pending.

    Refer to the original guideline document for more information on female gonadal hormone therapy.

    Male Gonadal Hormone Therapy

    The bone loss associated with male hypogonadism is reversed by testosterone therapy at least partly via aromatization to estrogen. Testosterone therapy, although not FDA-approved for osteoporosis, seems a reasonable first therapeutic intervention in men symptomatic with hypogonadism who do not have contraindications to the use of testosterone therapy.

    Evidence supporting this recommendation is of classes: A, B, C, D, M

    Bisphosphonates

    Treatment and Prevention of Osteoporosis in Postmenopausal Women

    Alendronate has been shown to increase bone mineral density and reduce the incidence of vertebral, hip, and non-vertebral fractures in postmenopausal women having existing vertebral fractures, and those with low bone mineral density (approximately 2.1 SD below peak) compared to placebo (calcium and vitamin D).

    Excellent clinical trial data based on BMD and bio-markers supports the use of oral bisphosphonates for preventing fractures in patients diagnosed with postmenopausal low bone density (osteopenia) or osteoporosis. The best clinical trials have been done with alendronate (Fosamax®), risedronate (Actonel®), and ibandronate (Boniva®). [Conclusion Grade I: See Conclusion Grading Worksheet B -- Annotation #15 (Bisphosphonates for Primary Osteoporosis) in the original guideline document]. (See Appendix B, "Recommended Pharmacologic Agents" in the original guideline document.)

    Note: there are case reports of bisphosphonate-associated osteonecrosis of the jaw most often following dental extraction with exposed jaw bone in cancer patients undergoing intravenous bisphosphonate therapy. The prevalence is estimated to be approximately one in one million for patients without cancer taking oral bisphosphonates.

    Treatment of Osteoporosis in Men

    Alendronate has been shown to increase bone mineral density at the spine, hip, and total body and prevents vertebral fractures and decreases in height for men with osteoporosis.

    Good clinical trial data support the use of alendronate for preventing bone loss in men diagnosed with osteoporosis. [Conclusion Grade I: See Conclusion Grading Worksheet B -- Annotation #15 (Bisphosphonates for Primary Osteoporosis) in the original guideline document].

    Treatment and Prevention of Glucocorticoid-Induced Osteoporosis

    Alendronate increases lumbar spine, femoral neck, trochanter, and total body bone mineral density in patients who require long-term (at least one year) glucocorticoid therapy at dosages of at least 7.5 mg daily.

    Risedronate has also been shown to increase bone mineral density in patients receiving glucocorticoid therapy. Treatment with risedronate 5 mg a day did have a trend of reduced fracture incidence.

    Clinical trial data supports the use of oral bisphosphonates for reducing bone loss in men and women diagnosed with glucocorticoid-induced bone loss. The best clinical trials have been done with alendronate (Fosamax®) and risedronate (Actonel®). [Conclusion Grade II: See Conclusion Grading Worksheet C -- Annotation # 15 (Bisphosphonates for Glucocorticoid-induced Bone Loss) in the original guideline document].

    Clinical trial data suggests that oral bisphosphonates may reduce fracture risk in men and women diagnosed with glucocorticoid-induced bone loss. [Conclusion Grade III: See Conclusion Grading Worksheet C -- Annotation #15 (Bisphosphonates for Glucocorticoid-induced Bone Loss) in the original guideline document].

    Post-transplantation

    Solid organ transplantation of all types and allogeneic bone marrow transplantation are associated with rapid bone loss after transplantation. In addition, many patients develop significant bone loss before transplantation.

    Several studies have shown that intravenous pamidronate (Aredia®) and zoledronate (Zometa®) may prevent bone loss after organ transplantation. A few small studies have evaluated oral bisphosphonate therapy in post-transplant patients.

    Evidence supporting this recommendation is of classes: A, C, D, R

    Selective Estrogen Receptor Modulator (SERM)

    The only SERM approved for the prevention and treatment of osteoporosis is raloxifene.

    Prevention and Treatment of Osteoporosis in Postmenopausal Women

    The MORE trial was a large 3-year randomized placebo-controlled study in postmenopausal women with osteoporosis. Raloxifene showed an increase in BMD and reduced the risk of vertebral fractures. The risk of non-vertebral fractures did not differ between placebo and raloxifene. There was an increased risk of venous thromboembolism compared with placebo (RR 3.1, 95% CI 1.5-6.2).

    The CORE 4-year trial extension of 4,011 women continuing from MORE (7,705) showed no difference in overall mortality, cardiovascular events, cancer or nonvertebral fracture rates.

    Calcitonin

    Treatment of Osteoporosis in Postmenopausal Women

    Nasal salmon-calcitonin 200 IU daily has shown a 33% risk reduction in new vertebral fractures compared with placebo (RR 0.67, 95% CI 0.47-0.97, p = 0.03). This occurred without significant effects on BMD. BMD measurements were not blinded to investigators and 59% (744) participants withdrew from the study early. Also, a dose response was not observed with respect to risk reduction of vertebral fractures.

    Post-transplantation

    Several studies have shown that nasal spray calcitonin has little effect on prevention of bone loss after organ or bone marrow transplantation.

    Refer to the original guideline document for information on anabolic agents, strontium, combination therapy (estrogen and bisphosphonates); comparative trials; calcitriol-1 25-OH vitamin D; and alternative and complimentary agents (phytoestrogens, ipriflavone, natural progesterone, magnesium, vitamin K, eicosapentaenoic and gamma-linolenic acid supplementation, and kampo formulae).

    Evidence supporting this recommendation is of classes: A, B, C, D

16. Follow-Up Testing After Pharmacologic Intervention

    Key Points:

    • Periodic follow-up central DXA on the same machine is recommended for following patients on pharmacologic therapy.
    • The testing interval varies from 6 to 24 months depending on the clinical situations.

    Sequential bone density testing using central DXA may be useful, and is generally recommended in monitoring drug therapy for the treatment of osteopenia or osteoporosis. Ideally, such testing should be performed at 12 to 24 months on the same machine as the pre-treatment bone density. A frequency as often as every 6 to 12 months may be indicated in the case of glucocorticoid treated patients or those on suppressive doses of thyroid hormone. Other patients at risk for accelerated bone loss include women at early menopause or those who have discontinued estrogen and are not on another bone protective agent*. The lumbar spine and the total proximal femur have the highest reproducibility and are the preferred sites for monitoring therapy. Changes in BMD should only be reported as significant if they exceed the "least significant change" for the DXA center. Stability or increase in BMD indicates successful therapy. A significant decline in BMD may require further investigation.

    A significant decrease in BMD on therapy may be due to:

    • Poor drug adherence
    • Improper medication administration technique in the case of bisphosphonates
    • A missed secondary cause of osteoporosis (e.g., hyperparathyroidism, malabsorption)
    • Inadequate calcium intake
    • Untreated Vitamin D deficiency
    • A true treatment failure due to the drug itself
    • Malabsorption of orally administered drugs

    Further follow-up BMD testing after stability or improvement over 3 to 4 years has been demonstrated is recommended by most experts. No study has been done as to whether follow-up BMD testing on therapy enhance fracture risk reduction but they may affect patient adherence to therapy. Therapy should not be withheld if follow-up bone density testing is not available.

    *Medicare provides coverage for bone densitometry with central DXA every two years to monitor osteoporosis therapy.

    Evidence supporting this recommendation is of classes: A, C, R

Definitions:

Conclusion Grades:

Grade I: The evidence consists of results from studies of strong design for answering the question addressed. The results are both clinically important and consistent with minor exceptions at most. The results are free of any significant doubts about generalizability, bias, and flaws in research design. Studies with negative results have sufficiently large samples to have adequate statistical power.

Grade II: The evidence consists of results from studies of strong design for answering the question addressed, but there is some uncertainty attached to the conclusion because of inconsistencies among the results from the studies or because of minor doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from weaker designs for the question addressed, but the results have been confirmed in separate studies and are consistent with minor exceptions at most.

Grade III: The evidence consists of results from studies of strong design for answering the question addressed, but there is substantial uncertainty attached to the conclusion because of inconsistencies among the results of different studies or because of serious doubts about generalizability, bias, research design flaws, or adequacy of sample size. Alternatively, the evidence consists solely of results from a limited number of studies of weak design for answering the question addressed.

Grade Not Assignable: There is no evidence available that directly supports or refutes the conclusion.

Classes of Research Reports:

1. Primary Reports of New Data Collection:

   Class A:

   • Randomized, controlled trial

   Class B:

   • Cohort study

   Class C:

   • Non-randomized trial with concurrent or historical controls
   • Case-control study
   • Study of sensitivity and specificity of a diagnostic test
   • Population-based descriptive study

   Class D:

   • Cross-sectional study
   • Case series
   • Case report
2. Reports that Synthesize or Reflect upon Collections of Primary Reports:

   Class M:

   • Meta-analysis
   • Systematic review
   • Decision analysis
   • Cost-effectiveness analysis

   Class R:

   • Consensus statement
   • Consensus report
   • Narrative review

   Class X:

   • Medical opinion

A detailed and annotated clinical algorithm is provided for Diagnosis and Treatment of Osteoporosis.

For information about availability, see the "Availability of Companion Documents" and "Patient Resources" fields below.

ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; e-mail: icsi.info@icsi.org; Web site: www.icsi.org.

ICSI's conflict of interest policy and procedures are available for review on ICSI's website at www.icsi.org.

Electronic copies of the updated guideline: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; Web site: www.icsi.org; e-mail: icsi.info@icsi.org.

• Diagnosis and treatment of osteoporosis. Executive summary. Bloomington (MN): Institute for Clinical Systems Improvement, 2006 Jul. 1 p. Electronic copies: Available from the Institute for Clinical Systems Improvement (ICSI) Web site.
• ICSI pocket guidelines. May 2005 edition. Bloomington (MN): Institute for Clinical Systems Improvement, 2005. 362 p.

Print copies: Available from ICSI, 8009 34th Avenue South, Suite 1200, Bloomington, MN 55425; telephone, (952) 814-7060; fax, (952) 858-9675; Web site: www.icsi.org; e-mail: icsi.info@icsi.org.

Electronic copies: Available in Portable Document Format (PDF) from the Institute for Clinical Systems Improvement (ICSI) Web site.

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