Osteoporosis: 9 Questions Physicians Often Ask

Osteoporosis is a common disease characterized by low bone mineral density (BMD) and poor bone quality that reduces bone strength and increases the risk of fragility (low-trauma) fractures.¹ The lifetime risk of fracture at age 50 years is about 53% in women and 21% in men.² In 2005, more than 2 million osteoporosis-related fractures occurred in the United States; direct health care costs totaled nearly $17 billion.³ Vertebral fractures and hip fractures are associated with increased morbidity and mortality.⁴

Despite the availability of good clinical tools for identifying patients at risk for fracture, osteoporosis is underdiagnosed in clinical practice. This is the case even in patients who have already sustained a fragility fracture and are at very high risk for future fracture.

Osteoporosis also is undertreated, even though many prevention and treatment options have become available. Even when patients are treated, many do not take medication correctly or for a sufficient duration to reduce fracture risk. Of those patients who start therapy, the persistence rate at 1 year is typically 50% or lower.⁵ Poor persistence is associated with poor clinical outcomes (fractures) and increased health care costs.

The vast majority of patients with osteoporosis can be treated effectively. Key clinical decisions involved in the management of the disease include selection of patients for bone density testing, evaluation for factors contributing to low bone mass, identification of patients likely to benefit from treatment, recommendation of specific nonpharmacological and pharmacological therapies, and determination of how treatment is monitored. When physicians and their patients are educated about osteoporosis and have a full understanding of the risk and consequences of osteoporotic fractures, management decisions are most likely to result in successful clinical outcomes (Table 1). In this article, I address common clinical decision points by responding to questions that often arise in the primary care setting.

Who should have a bone density test?

1. The International Society for Clinical Densitometry (ISCD) has developed comprehensive guidelines for bone density testing (Table 2).⁶ The organization also has created standards for acquisition, analysis, and interpretation of the test results. The ISCD Official Positions are an essential reference for bone densitometrists and a helpful guide for primary care physicians caring for patients who are at risk for osteoporosis. The unifying consideration is that a bone density test should be ordered only when it is likely to play a role in patient management decisions.

All women 65 years and older and men 70 years and older should be considered for bone density testing. Others who should be considered include women in menopaus- al transition and postmenopausal women younger than 65 years and men younger than 70 years who have risk factors for fracture (eg, a family history of osteoporosis, cigarette smoking, a personal history of fragility fracture, and use of a medication known to have adverse skeletal effects).

The only technology that can be used for diagnostic classification is dual-energy x-ray absorptiometry (DXA). Technologies that can predict fracture risk include quantitative ultrasonography, quantitative computed tomography (QCT), peripheral QCT, and peripheral DXA. Only DXA and QCT are clinically useful for monitoring changes, provided that the precision error has been measured according to standard methods. T-score values measured by QCT are lower than T-scores measured by DXA.

How is a diagnosis of osteoporosis established?

2. Assuming that other causes of skeletal fragility have been eliminated, 1 of 2 methods may be used. A densitometric diagnosis of osteoporosis is made according to the criteria of the World Health Organization (WHO) when a DXA-measured T-score (the standard deviation [SD] difference between the patients BMD and that of a young-adult reference population) is 22.5 or lower at the hip (total hip, femoral neck); the posteroanterior lumbar spine (preferably L1-L4); or, if measured, the forearm (33% radius) (Table 3).⁷ The WHO diagnostic criteria may be applied to women in menopausal transition, postmenopausal women, and men 50 years and older.

For younger women and men, the Z-score (the SD difference between the patients BMD and that of an age- and ethnicity-matched reference database) is preferred. The WHO classification should not be used, because the relationship between BMD and fracture risk is not well established in these groups.

T-scores should not be used in children or adolescents, because comparing their BMD with that of an adult population that has already achieved peak bone mass would be inappropriate. A clinical diagnosis of osteoporosis may be made indepen- dently of the T-score by DXA when there is a history of fragility fracture. Diagnostic classification is useful for communicating disease-state information to the patient and may be needed for billing and determination of treatment benefits. A patient who is given a diagnosis of osteoporosis may gain a better understanding of its implications by observing the consequences (eg, fractures, disability, death) in others who have the same diagnosis. In the United States, a diagnosis code is required for payment for medical services and insurance coverage for treatment often requires a specific diagnosis.

How should patients who have low BMD be evaluated?

3. Baseline laboratory studies for all patients with osteoporosis or low bone mass are useful for detecting previously unrecognized factors that may be contributing to poor skeletal health. They also may help determine the potential safety of specific drugs being considered for therapy.

There is no consensus guideline for standard laboratory evaluation, but there are helpful tests for all patients. These include serum calcium, phosphorus, and alkaline phosphatase levels (results may be abnormal in some types of metabolic bone disease, such as osteomalacia and malignancy); creatinine level (chronic kidney disease may result in skeletal disease and may affect the choice of drug therapy); complete blood cell count (may be abnormal with multiple myeloma or other malignant conditions); and 24-hour urinary calcium level (hypocalciuria in patients with adequate calcium intake and good renal function suggests malabsorption; hypercalciuria is associated with osteoporosis and an increased risk of nephrolithiasis).

The measurement of serum 25-hydroxyvitamin D often helps the evaluation because suboptimal levels are common. For optimal skeletal health, many experts recommend attaining a level of at least 30 ng/mL.

In older patients, consider ordering serum protein electrophoresis to evaluate for multiple myeloma. Measuring thyroid-stimulating hormone helps identify patients who are taking an excessive dose of thyroid medication. For patients with hypercalcemia, further evaluation should include a measurement of serum parathyroid level. For unusual clinical situations, other laboratory tests or double tetracycline transiliac nondecalcified bone biopsy may provide useful information.

How is fracture risk assessed?

4. DXA combined with clinical risk factors for fracture provides a better estimate of fracture risk than DXA or clinical risk factors alone. Numerous clinical risk factors are associated with an increased risk of fracture⁸; those that have been best validated in large long-term observational studies are listed in Table 4.⁹ The most robust predictors of fracture are low BMD, advanced age, and previous fragility fracture. Fracture risk approximately doubles for every SD decrease in BMD and every decade advance in age, as well as in the presence of a fragility fracture. Fracture risk has been expressed as relative risk (the risk compared with that in a reference population, expressed as a ratio, such as “the relative risk of fracture is 2 times that of an age-matched population with normal BMD”). Now the field is moving rapidly toward expressing fracture risk as absolute risk (fracture probability over a defined period, such as “5% 10-year probability of hip fracture”). Fracture probability provides a better estimate of fracture risk for clinical applications, because relative risk may vary according to the comparator population that is selected.

Who should be treated?

5. Treatment guidelines of the National Osteoporosis Foundation (NOF)8 recommend that postmenopaus-al women and men age 50 and older be treated if at least one of the following conditions is met: a hip or vertebral (clinical or morphometric) fracture; a T-score of 22.5 or less at the femoral neck, total hip, or lumbar spine; or a T-score between 21.0 and 22.5 with other prior fracture, secondary causes associated with high risk of fracture (eg, glucocorticoid use, total immobilization), or a 10-year probability of hip fracture of at least 3% or a 10-year probability of any major osteoporotic fracture of at least 20%, based on the US adaptation of the WHO fracture risk algorithm (FRAXª, http://www.shef.ac.uk/FRAX/, accessed June 25, 2008).

FRAX uses the femoral neck T-score measured by DXA with easily obtainable clinical risk factors for fracture to calculate 10-year fracture probability. It is likely that the FRAX software will soon be incorporated into DXA systems, so that fracture probability may become part of the DXA printout in the future. It is important to note that FRAX fracture risk calculations are validated only in untreated postmenopausal women and men age 50 and older. FRAX should not be used in premenopausal women, men under age 50, children, or treated patients.

The NOF has used US-specific data on fracture risk, economic consequences of fracture, and societal willingness to pay to calculate cost- effective intervention thresholds. In deciding whom to treat, clinicians must consider additional factors that apply to individual patients. Such considerations include comorbidities, patient preferences, expected adherence to therapy, and affordability and availability of medications.

How should patients be treated?

6. Counsel all patients, including those with normal BMD, on the importance of regular physical activity, adequate intake of calcium and vitamin D, and avoidance of cigarette smoking and excessive alcohol use. Try to minimize their exposure to medications known to be toxic to bones and those that may cause sedation, hypotension, or disequilibrium. Frail patients at high risk for falls may benefit from physical therapy or activities (eg, tai chi) that can improve muscle strength and balance. Impaired hearing or limited vision also may contribute to fall risk and, when possible, should be corrected. If fracture risk is sufficiently high, pharmacological therapy should be considered.

Oral bisphosphonates are the most frequently used drugs in the management of osteoporosis. Those approved by the FDA and available for clinical use are alendronate (10 mg/d or 70 mg/wk orally), risedronate (5 mg/d, 35 mg/wk, 75 mg monthly on 2 consecutive days, 150 mg/mo orally), or ibandronate (150 mg/mo orally). All these agents increase BMD, reduce bone turnover, and decrease the risk of vertebral fractures.¹⁰ Alendronate and risedronate also have been shown to reduce the risk of nonvertebral fractures and hip fractures. These drugs must be ingested with a glass of plain water soon after awakening on an empty stomach after an overnight fast, followed by upright posture and postdose fasting (for at least 30 minutes with alendronate or risedronate and 60 minutes with ibandronate).

Two injectable bisphosphonates are FDA-approved for the management of postmenopausal osteoporosis-ibandronate (3 mg every 3 months, injected over 15 to 30 seconds) and zoledronic acid (5 mg every 12 months, injected over at least 15 minutes). Other FDA-approved pharmaceutical options are raloxifene (60 mg/d), a selective estrogen receptor modulator (SERM) that has been proved to reduce vertebral fracture risk and the risk of invasive breast cancer in high-risk women; salmon calcitonin (200 IU, intranasally, once daily); and teriparatide (20 µg/d by self-administered subcutaneous injection; maximum treatment period, 24 months), the only approved anabolic agent for the management of osteoporosis. These medications are listed with their indications in Table 5.

Each drug plays a role in osteoporosis prevention or treatment or both in properly selected patients, and each has its own profile of potential benefits and risks. The drugs cannot be ranked in terms of comparable efficacy, because no completed head-to-head clinical trials with fractures as a primary end point have been published. Ultimately, the best drug for a patient may be the one most likely to be taken, because poor compliance and persistence with therapy are major obstacles to achieving full drug benefits.⁵

An oral bisphosphonate usually is first-line therapy in appropriately selected patients. However, the recent availability of injectable bisphosphonates with long dosing intervals makes these agents attractive alternatives for patients who cannot take oral bisphosphonates and a possible consideration for primary therapy. Raloxifene most often is used in postmenopausal women younger than 65 years in whom the risk of thromboembolic and cardiovascular disease is not high and hot flashes are not a problem, especially those at high risk for breast cancer. Consider nasal calcitonin in women with osteoporosis who are at least 5 years postmeno- pausal and unable or unwilling to use other approved treatments. Teripara- tide is reserved for patients at high risk for fracture and usually is followed by an antiresorptive drug, such as a bisphosphonate.

How should patients be monitored for response to therapy?

7. The response to therapy is commonly assessed by repeating DXA of the spine and hip at least 1 year after the start of therapy. An acceptable response is considered to be stability or an increase in BMD, both of which have been associated with a reduction in fracture risk in clinical trials. Patients who have bone loss equal to or greater than the “least significant change,” calculated according to recognized standards,¹¹ are candidates for a thorough evaluation to search for factors contributing to bone loss.¹² A suboptimal response to therapy may be the result of poor compliance, inadequate calcium or vitamin D intake, malabsorption, bone-toxic medications, or the development of a previously unrecognized disease or conditions with adverse skeletal effects. Measurement of bone turnover markers (eg, N- and C-telopeptide in patients taking antiresorptive therapy) may be used to evaluate drug effect on bone metabolism, which occurs sooner than changes in BMD.¹³ However, standards for their clinical use have not yet been established.

For how long should patients be treated?

8. The decision to start therapy is easier to make than the decision to stop therapy or suggest a “drug holiday.” There are no consensus guidelines on stopping therapy.

As a group, the bisphosphonates are known to have a long skeletal half-life; therefore, patients who have been taking bisphosphonates for several years probably will have some residual effects for an undefined period after discontinuation. Alendronate, the bisphosphonate that has been studied most extensively, appears to be safe and effective for as long as 10 years.¹⁴ Oversuppression of bone turnover, resulting in “brittle bones” with increased fracture risk or poor fracture healing, has been a theoretical concern since the introduction of the bisphosphonates. However, it does not seem to be a legitimate clinical concern.

The estrogens, SERMs, salmon calcitonin, and teriparatide may be expected to lose their benefits soon after discontinuation. Prudence suggests continuing treatment for as long as fracture risk is high, heeding FDA labeling that restricts teriparatide use to no more than 24 months until contradictory evidence becomes available, and considering no more than a 1-year holiday in patients who have taken alendronate for at least 5 years and are not currently at very high risk for fracture.¹⁵

When should patients be referred to a specialist?

9. Most physicians are well qualified to manage the majority of patients with osteoporosis. However, consider referral to an osteoporosis specialist when the complexities of care exceed your comfort level. Common reasons for referral include significant BMD loss while the patient is receiving therapy, recurring fractures during therapy, fractures occurring with normal BMD, and unexplained skeletal-related laboratory test results. The American Association of Clinical Endocrinologists has identified specific indications for referral (Table 6).¹⁶

References:

REFERENCES:
1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785-795.
2. van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiology of fractures in England and Wales. Bone. 2001;29:517-522.
3. Burge R, Dawson-Hughes B, Solomon DH, et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005-2025. J Bone Miner Res. 2007;22:465-475.
4. Cooper C. The crippling consequences of fractures and their impact on quality of life. Am J Med. 1997;103(2A):12S-19S.
5. Cramer JA, Gold DT, Silverman SL, Lewiecki EM. A systematic review of persistence and compliance with bisphosphonates for osteoporosis. Osteoporos Int. 2007;18:1023-1031.
6. Binkley N, Bilezikian JP, Kendler DL, et al, International Society for Clinical Densitometry. Official positions of the International Society for Clinical Densitometry and Executive Summary of the 2005 Position Development Conference. J Clin Densitom. 2006;9:4-14.
7. World Health Organization. Assessment of frac-ture risk and its application to screening for post-menopausal osteoporosis. Geneva: WHO; 1994.
8. National Osteoporosis Foundation. ClinicianÕs Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National Osteoporosis Foundation; 2008.
9. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int. 2005;16:581-589.
10. Cranney A, Guyatt G, Griffith L, et al. Meta-analyses of therapies for postmenopausal osteoporosis, IX: summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev. 2002;23:570-578.
11. Lenchik L, Kiebzak GM, Blunt BA; International Society for Clinical Densitometry Position Development Panel and Scientific Advisory Committee. What is the role of serial bone mineral density mea-surements in patient management? J Clin Densitom. 2002;5(suppl):S29-S38.
12. Lewiecki EM. Nonresponders to osteoporosis therapy. J Clin Densitom. 2003;6:307-314.
13. Srivastava AK, Vliet EL, Lewiecki EM, et al. Clinical use of serum and urine bone markers in the management of osteoporosis. Curr Med Res Opin. 2005;21:1015-1026.
14. Bone HG, Hosking D, Devogelaer JP, et al. Ten yearsÕ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350:1189-1199.
15. Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927-2938.
16. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003 [published correction appears in Endocr Pract. 2004;10:90]. Endocr Pract. 2003;9:544-564.
17. Hodgson SF, Watts NB, Bilezikian JP, et al. American Association of Clinical Endocrinologists 2001 Medical Guidelines for Clinical Practice for the Prevention and Management of Postmenopausal Osteoporosis. Endocr Pract. 2001;7:293-312.