Case Presentation

Ms. D, a 65-year-old white woman, has just become eligible for Medicare. In her "Welcome to Medicare" letter, it is advised that she have a bone mineral density (BMD) test. Ms. D undergoes a dual energy x-ray absorptiometry (DXA) BMD screening at the spine and hip in accordance with recommendations of the US Preventive Services Task Force.¹ Her T-score is -1.8 at the spine and -2.1 at the femoral neck, which confers a diagnosis of osteopenia.

Audio Commentary by Dr. Siris

Decision Point 1. First-Line Intervention

What is/are the optimal first step(s) in managing this patient with osteopenia?

1. Review all of her clinical risk factors for osteoporosis and fracture
2. Perform a FRAX assessment to estimate her 10-year absolute risk for hip fracture and major osteoporotic fractures
3. Counsel on adequate calcium and vitamin D intake
4. Begin pharmacologic treatment with an antiresorptive agent

Answer: (a, b, and c) Osteopenia in and of itself does not necessarily require pharmacologic treatment, but treatment may be indicated depending on the results of further risk assessment. Clinical risk factors for osteoporosis and fractures should be reviewed, including medical and family history and prior laboratory test results. A FRAX assessment of her 10-year absolute risk for fracture also should be performed, and the patient should be counseled on the importance of adequate calcium and vitamin D intake for prevention of fractures.

If the FRAX score in this osteopenic patient indicates increased fracture risk, laboratory testing should be performed to identify secondary risk factors that could contribute to bone fragility. Initial laboratory tests should include evaluation of calcium, creatinine, thyroid-stimulating hormone, and 25-hydroxy vitamin D levels, as well as a liver function panel and complete blood count. Based on results of these tests, additional tests may be indicated, including 24-hour urine calcium level, parathyroid hormone, and other tests.

A number of factors are associated with increased risk for osteoporosis and fractures; a complete list of these risk factors is available in the National Osteoporosis Foundation (NOF) Clinician's Guide.² Some factors independently increase the risk of fracture more than other factors, as the World Health Organization determined through meta-analyses of several international epidemiologic studies.^3,4 In addition to age and body mass index, these factors include personal history of fracture after age 50 years,^5,6 parental history of fracture,⁷ current smoking status,^8-11 excessive alcohol consumption,^7,12,13 glucocorticoid therapy,^3,7,14,15 rheumatoid arthritis,^16,17 other secondary causes, and BMD at the femoral neck.^3,17

With these clinical risk factors, the clinician can use the FRAX fracture risk assessment tool to estimate the patient's absolute 10-year probability of hip fracture and the absolute 10-year probability of major osteoporotic fracture (ie, clinical spine, hip, forearm, or proximal humerus).^2,17 FRAX is intended and validated for use only in patients who have not been treated and are currently not on treatment for osteoporosis.² It is applicable in postmenopausal women and men between 40 and 90 years of age, and includes for the US population, white, black, Hispanic, and Asian ethnicities.¹⁸

The NOF Clinician's Guide and others have pointed out that, because FRAX incorporates clinical risk factors along with hip BMD, it is especially useful in identifying those patients in the very large group diagnosed with osteopenia who are at higher risk of fracture and therefore most likely to benefit from treatment.^2,4,19 Although no studies of this treatment decision strategy have been performed, it is recommended by the NOF. FRAX also helps identify patients with comorbid conditions that increase the risk of fracture.⁴ It is beneficial for educating patients about how fracture risk increases with additional risk factors (eg, smoking, prior fracture, glucocorticoid therapy) and motivating them toward lifestyle changes.²⁰ A patient's fracture risk can be obtained using FRAX even in the absence of BMD data, although including hip BMD data is preferred. This emphasizes the importance of clinical risk factors in predicting increased risk of fracture.²⁰

Audio Commentary by Dr. Siris

Based on an analysis of US fracture data and a cost-effectiveness analysis, the NOF Clinician's Guide recommends consideration for pharmacologic therapy if FRAX assessment shows the absolute 10-year risk of hip fracture is ≤3%. The NOF also recommends consideration for pharmacologic therapy if the absolute 10-year risk of major osteoporotic fractures is ≤20% on FRAX assessment.²

Irrespective of whether the patient is a candidate for pharmacologic therapy, she should be counseled on the importance of adequate calcium and vitamin D intake, as these two nutrients are required for maintaining bone health throughout life.²¹ More than 99% of the body's calcium is stored in the bones and teeth. When the intake of calcium is insufficient, bone tissue is resorbed from the skeleton to maintain the body's serum calcium level. The National Academy of Sciences recommends that women older than age 50 years have a daily calcium intake of at least 1200 mg/day, preferably through diet, with supplements if necessary.²² The NOF supports this recommendation.² It should be noted that calcium intake of more than 1200 to 1500 mg/day does not provide additional benefit and may increase the risk of developing kidney stones or cardiovascular disease.²

Vitamin D is essential for the absorption of calcium, as well as bone and muscle health. Especially in older individuals, vitamin D insufficiency may lead to muscle weakness, predisposing to falls, a major risk factor for fracture. The NOF recommends a daily intake of 800 to 1000 IU of vitamin D₃ for adults older than age 50 years.² Exposure to sunlight is the most common source of vitamin D, followed by dietary consumption (eg, fatty fish, egg yolks, and fortified foods, such as cereals); however, because both of these sources are usually inadequate, particularly for persons older than age 50 years, a supplement is frequently required to obtain sufficient vitamin D intake.²

Audio Commentary by Dr. Siris

Case Continues

Although Ms. D is generally healthy, she was hospitalized 3 years earlier for a deep venous thrombosis (DVT) after a flight to Australia. Her only prescription medication is a statin for elevated cholesterol. A review of her clinical risk factors reveals that her father sustained a broken hip at age 80 years. She weighs 130 lb and is 63 in tall. All other FRAX clinical risk factors are negative. Figure 1 illustrates her FRAX assessment,¹⁸ and shows that her absolute 10-year risk of hip fracture is 1.8% and major fractures is 26%.

Figure 1. Ms. D's FRAX Assessment.¹⁸

With permission from the World Health Organization (WHO). Available at: http://www.shef.ac.uk/FRAX.

Based on the patient's FRAX assessment, her risk of major osteoporotic fracture (a combination of hip, clinical spine, proximal humerus, and distal forearm) exceeds the suggested treatment threshold of 20%. This is largely due to the presence of a hip fracture in her father, because without that risk factor, her FRAX risk for hip and major osteoporotic fracture would have been 1.7% and 14%, respectively, which do not meet the recommended thresholds for treatment.

Ms. D's physician confirms that she is getting 1200 mg of calcium each day from dietary sources and a calcium supplement, and that her vitamin D intake is in the recommended range of 800-1000 IU/day. A 25-hydroxy vitamin D level, when measured, is 35 ng/mL, which is within the normal range (ie, >30 ng/mL).

Decision Point 2. Pharmacologic Therapy

What pharmacologic therapy would you select for Ms. D?

1. A bisphosphonate
2. Teriparatide
3. Hormone replacement therapy (HRT)
4. Raloxifene
5. A combination of a bisphosphonate and raloxifene

Answer: (a is preferred) Many therapies have been approved for the management of osteoporosis (Table 1). Of the available options, a bisphosphonate is probably the preferred option for this particular patient.

Table 1. FDA-Approved Agents for Treatment of Osteoporosis.

^aRefer to individual prescribing information for specific dosing information.
^bAvailable in generic formulation.
^cAt the time this newsletter was developed, zoledronic acid had just received FDA approval for prevention of postmenopausal osteoporosis; details regarding this use were still pending.

Most of the studies that evaluated reduction in risk of fracture as an endpoint enrolled women with established osteoporosis based on BMD criteria and/or history of prior fracture, typically prior vertebral fracture. As yet, there are no clinical trials to prove that patients who are osteopenic and at high risk for fracture as assessed by FRAX criteria will derive the same benefit with regard to fracture risk reduction. However, as noted above, the NOF Clinician's Guide does recommend treatment for patients in this population.²

Audio Commentary by Dr. Siris

Oral bisphosphonates include alendronate, ibandronate, and risedronate. According to the FDA-approved labels,^24,25,27 ibandronate reduces the incidence of vertebral fractures, alendronate reduces the incidence of vertebral and hip fractures, and risedronate reduces the incidence of vertebral and nonvertebral osteoporotic-related fractures, as supported by a number of clinical trials.^44-49 Available data on fracture reduction in osteopenic patients are limited to small subgroup analyses from larger trials. In a subgroup analysis of the Fracture Intervention Trial, alendronate significantly reduced the risk of clinical and radiographic vertebral fractures, but did not significantly affect risk of all clinical fractures, in patients who had a femoral neck T-score in the range of -2.5 to -1.6 at baseline.^45,50 A post hoc subgroup analysis of patients in four risedronate trials who had femoral neck T-scores between -1 and -2.5 showed a significant reduction in fragility fractures—a composite of morphometric vertebral and osteoporosis-related nonvertebral fractures.⁵¹ Side effects of all oral bisphosphonates include gastrointestinal effects (dysphagia, esophagitis, ulcer), very rare cases of osteonecrosis of the jaw with long-term use, and visual disturbances.²

Approved dosing regimens and dosing frequencies vary from one oral bisphosphonate to another, and there are options for daily, weekly, or monthly dosing. Most, but not all, patients prefer less-frequent dosing.³⁸ When prescribing any oral bisphosphonate, it is important to provide patients with clear instructions regarding proper administration in order to facilitate absorption and minimize any potential for esophageal irritation. Oral bisphosphonates should be taken with a full glass (6–8 oz) of plain water after arising in the morning and 30 minutes (60 minutes for ibandronate) before eating, drinking, or taking other medications.^23,25,27 Patients should avoid chewing or sucking on the tablets. ^23,25,27 Clinicians should also tell patients to remain upright—that is, sitting or standing, not lying down—for at least 30 minutes (60 minutes for ibandronate) after administration. ^23,25,27

Zoledronic acid, a once-yearly intravenous bisphosphonate, is indicated for the treatment of osteoporosis in postmenopausal women,²⁹ and was FDA approved in early June 2009 for prevention of osteoporosis.⁵² According to the FDA-approved label, when used for treatment it reduces the incidence of vertebral, hip, and nonvertebral osteoporotic fractures.^29,53,54 It also reduces the incidence of subsequent fractures in individuals who have recently sustained a low-trauma hip fracture.²⁹ Following the first infusion of zoledronic acid, 32% of clinical trial patients experienced an acute phase reaction (arthralgia, headache, myalgia, fever), which may be ameliorated by acetaminophen.²

Ibandronate administered intravenously once every 3 months demonstrated statistically superior increases in total hip, femoral neck, and trochanter BMD compared with daily oral ibandronate.²⁶ According to the prescribing information, intravenous ibandronate reduces vertebral fracture incidence in postmenopausal women with osteoporosis.²⁶ Although incidence rates of gastointestinal side effects were only slightly lower with intravenous ibandronate versus oral ibandronate,²⁶ in clinical practice, intravenous ibandronate is frequently used in patients who are unable to tolerate the gastrointestinal side effects of oral ibandronate.

Teriparatide—a daily injection of recombinant parathyroid hormone 1-34—reduces the risk of vertebral and nonvertebral fractures in postmenopausal women with osteoporosis who are at high risk of fracture.^43,55 According to the prescribing information, high-risk patients are those with history of fracture or multiple risk factors for fracture, those who fail or are intolerant of previous therapies, and those considered high risk based on physician assessment.⁴³ Thus, it is at the clinician's discretion to decide whether Ms. D's 26% chance of major osteoporotic fracture in the next 10 years constitutes high enough risk to warrant teriparatide. However, given the high cost of teriparatide compared with oral bisphosphonates, it is not unreasonable to reserve teriparatide for those at the highest risk levels.

In the Multiple Outcomes of Raloxifene Evaluation (MORE) study, the selective estrogen receptor modulator raloxifene significantly lowered the risk of vertebral fractures, but not nonvertebral fractures, compared with placebo in postmenopausal women with osteoporosis.^56-58 In a post hoc subgroup reanalysis of the MORE trial, benefits in terms of reduction in vertebral fracture risk were found to apply to patients with osteopenia defined by total hip BMD.⁵⁹ It is also noteworthy that raloxifene has also been FDA approved to reduce the risk of breast cancer in postmenopausal women with osteoporosis.³⁰

Raloxifene is dosed once daily at any time of day with or without food.³⁰ Common side effects of raloxifene include hot flashes, leg cramps, and peripheral edema.³⁰ Raloxifene is also associated with an increased risk of benign uterine polyps, DVT, pulmonary embolism, and retinal vein thrombosis, and women with coronary heart disease or who are at risk of major coronary events may have an increased risk of death due to stroke while taking raloxifene.^30,60 Even with long-term use, it has not been found to increase risk of myocardial infarction, stroke, endometrial hyperplasia, or postmenopausal bleeding, and raloxifene lowers total and low-density lipoprotein cholesterol.^60,61 Ms. D is not a good candidate for raloxifene because of her history of DVT and may be better served by an agent with proven efficacy in reducing both vertebral and nonvertebral fractures.

HRT is FDA-approved for prevention of postmenopausal bone loss.^34-42 A conjugated estrogen and medroxyprogesterone product was shown in the Women's Health Initiative (WHI) to be effective in reducing the risk of vertebral, hip, and lower arm/wrist fractures in postmenopausal women, the majority of whom did not have osteoporosis by BMD criteria.⁶² However, it should be noted that HRT use is recommended only if needed for relief of menopause-related symptoms.² It is not indicated for the prevention of bone loss alone, in the absence of menopausal symptoms. The decline in use of hormonal therapies in osteoporosis is attributable to additional findings from the WHI that after a mean of 5.2 years of use, women have an increased risk of coronary heart disease events, stroke, invasive breast cancer, and pulmonary emboli.⁶³ In this case study, HRT is not indicated because Ms. D is not experiencing hot flashes or other menopausal symptoms. Furthermore, she is 65 years old, has a history of DVT, and is being treated for hyperlipidemia, so HRT may further increase her cardiovascular risk.

More than one therapy generally is not recommended, particularly for initial therapy. The NOF Clinician's Guide notes that combination therapy, such as that with a bisphosphonate and raloxifene, may modestly increase BMD compared with monotherapy, but the overall effect on fracture risk is unknown.^2,64

Case Continues

After a discussion about the indications, benefits, and side effects of each agent and their modes of administration and cost, Ms. D accepts the suggestion to begin a weekly oral bisphosphonate.

Decision Point 3. Follow-Up

How would you follow this patient?

1. Follow up with phone call in 2 to 3 months to check on adherence to therapy
2. Perform a test of a marker of bone resorption in 6 months
3. Schedule a follow-up DXA to take place in 6 months
4. Schedule a follow-up DXA to take place in 1 year
5. Schedule a follow-up DXA to take place in 2 years

Answer: (a and d) The patient should receive a follow-up phone call in 2 to 3 months from the clinician or a staff person specifically assigned to handle patient follow-up phone calls. A follow-up DXA should be scheduled to take place in 1 year to monitor response to therapy. Medicare will cover follow-up DXA measurements at 2-year intervals. Most Medicare providers will cover a 1-year follow-up DXA in a patient newly started on treatment. If the follow-up DXA measurement shows either an increase in or maintenance of BMD, it may be interpreted as the patient having a response to treatment. BMD that is increased or maintained implies that treatment is working, and bone strength is improved. Because improvement in bone strength cannot be measured directly, a lack of bone loss or an increase in BMD is a surrogate for evidence that the bone is stronger.

Follow-up contact is important for monitoring adherence. An analysis of more than 18,000 women taking pharmacotherapy for osteoporosis reported that nearly 50% were nonadherent at 3 months after starting therapy. At 1 year, approximately 75% of patients were nonadherent, and nearly 50% had discontinued treatment.⁶⁵ Studies have shown that oral bisphosphonate taken at <50% of the recommended dosage affords no antifracture benefit, whereas refill compliance approaching >75% provides a marked increase in the fracture risk reduction benefit.⁶⁶

Bone turnover markers are very valuable in clinical trials, but generally are not helpful in individual patients because of both assay and biological variability in these markers that make results difficult to interpret. There are no guidelines for the use of bone turnover markers to monitor response to therapy in postmenopausal women.⁶⁷

The NOF Clinician's Guide recommends that follow-up DXA be performed at 2 years to monitor the patient's response to therapy;² however, many clinicians believe that a follow-up DXA at 1 year after treatment initiation is reasonable in order to give the patient some clinical feedback about their response to treatment. A 6-month follow-up is too soon to provide useful information, and it would not be reimbursed. Follow-up DXA otherwise is likely to be covered by Medicare in most areas in the United States when it follows initiation of osteoporosis treatment. If the local Medicare provider does not cover a 1-year follow-up in this patient's situation, a 2-year follow-up DXA should be planned, as recommended in the NOF Clinician's Guide.² If the initial posttreatment 1-year follow-up is possible, the next DXA can be performed 2 years later.

Conclusion

The FRAX fracture risk assessment tool is an essential component in the management of patients diagnosed with osteopenia. By incorporating clinical risk factors predictive of increased fracture risk, FRAX enables the clinician to identify those osteopenic patients who are at higher risk of fracture and likely to obtain benefit from therapy, as demonstrated with this case. This case also emphasizes other strategies for optimal patient management: counseling patients on adequate calcium and vitamin D intake to maintain bone health and performing appropriate follow-up to monitor adherence and response to therapy.

References

1. U.S. Preventive Services Task Force. Screening for osteoporosis in postmenopausal women. Ann Intern Med. 2002;137:526-528.


2. New Clinician's Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation. http://www.nof.org/professionals/clinicians_guide.htm. Accessed May 18, 2009.


3. World Health Organization. WHO Scientific Group on the Assessment of Osteoporosis at Primary Health Care Level. Summary Meeting Report. Brussels, Belgium, 5-7 May 2004. http://www.who.int/chp/topics/Osteoporosis.pdf. Accessed May 19, 2009.


4. Siris E, Delmas PD. Assessment of 10-year fracture risk: a new paradigm with worldwide application [editorial]. Osteoporos Int. 2008;19:383-384.


5. U.S. Department of Health and Human Services. Chapter 8: Assessing the risk of bone disease and fracture. In: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD. http://www.surgeongeneral.gov/library/bonehealth/chapter_8.html. Accessed May 19, 2009.


6. Johnell O, Kanis JA, Oden A, et al. Fracture risk following an osteoporotic fracture. Osteoporos Int. 2004;15:175-179.


7. U.S. Department of Health and Human Services. Chapter 3: Diseases of bone. In: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD. Available at: http://www.surgeongeneral.gov/library/bonehealth/chapter_3.html. Accessed on: May 19, 2009.


8. Law MR, Hackshaw AK. A meta-analysis of cigarette smoking, bone mineral density and risk of hip fracture: recognition of a major effect. BMJ. 1997;315:841-846.


9. Honkanen R, Tuppurainen M, Korger H, Alhava E, Saarikoski S. Relationship between risk factors and fractures differ by type of fracture: a population-based study of 12,192 perimenopausal women. Osteoporos Int. 1998;8:25-31.


10. Jacqmin-Gadda H, Fourrier A, Commenges D, Dartigues JF. Risk factors for fractures in the elderly. Epidemiology. 1998;9:417-423.


11. Kanis JA, Johnell O, Oden A, et al. Smoking and fracture risk: a meta-analysis. Osteoporos Int. 2005;16:155-162.


12. Laitinen K, Lamberg-Allardt C, Tunninen R, Karonen SL, Ylikahri R, Valimaki M. Effects of 3 weeks' moderate alcohol intake on bone and mineral metabolism in normal men. Bone Miner. 1991;13:139-151.


13. Felson DT, Zhang Y, Hannan MT, Kannel WB, Kiel DP. Alcohol intake and bone density in elderly men and women. The Framingham Study. Am J Epidemiol. 1995;142:485-492.


14. Van Staa TP, Leufkens HG, Cooper C. The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis. Osteoporos Int. 2002;13:777-787.


15. U.S. Department of Health and Human Services. Chapter 6: Determinants of bone health. In: Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD. Available at: http://www.surgeongeneral.gov/library/bonehealth/chapter_6.html. Accessed on: May 19, 2009.


16. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of prior corticosteroid use and fracture risk. J Bone Miner Res. 2004;19:893-899.


17. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX^TM and the assessment of fracture probability in men and women from the UK. Osteoporosis Int. 2008;19:385-397.


18. World Health Organization. FRAX^® WHO Fracture Risk Assessment Tool. Available at: http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=9/. Accessed on: May 20, 2009.


19. Dawson-Hughes B, Tosteson ANA. Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the USA. Osteoporos Int. 2008;19:449-458.


20. Roux C. Optimal use of FRAX [editorial]. Joint Bone Spine. 2009;76:1-3.


21. Sunyecz JA. The use of calcium and vitamin D in the management of osteoporosis. Ther Clin Risk Manag. 2008;4:827-836.


22. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food, and Nutrition Board, Institute of Medicine. Calcium. In: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, DC: The National Academies Press; 1997. Available at: http://books.nap.edu/catalog.php?record_id=5776. Accessed on: May 19, 2009.


23. Fosamax [package insert]. Whitehouse Station, NJ: Merck & Co; February 2008.


24. Fosamax Plus D [package insert]. Whitehouse Station, NJ: Merck & Co; February 2009.


25. Boniva [package insert]. Nutley, NJ: Roche Laboratories; November 2008.


26. Boniva Injection [package insert]. Nutley, NJ: Roche Laboratories; February 2007.


27. Actonel [package insert]. Cincinnati, OH: Procter & Gamble Pharmaceuticals; April 2008.


28. Actonel with Calcium [package insert]. Cincinnati, OH: Procter & Gamble Pharmaceuticals; January 2008.


29. Reclast [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; March 2009.


30. Evista [package insert]. Indianapolis, IN: Eli Lilly and Company; October 2008.


31. Miacalcin [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; June 2006.


32. Fortical [package insert]. Minneapolis, MN: Upsher-Smith Laboratories; June 2006.


33. Miacalcin Injection [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; November 2002.


34. Premarin [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; May 2008.


35. Estrace [professional information]. Available at: http://www.drugs.com/pro/estrace.html. Accessed on: May 18, 2009.


36. Ogen [professional information]. Available at: http://www.drugs.com/pro/ogen.html. Accessed on: May 18, 2009.


37. Climara [package insert]. Wayne, NJ: Bayer HealthCare Pharmaceuticals; June 2007.


38. Estraderm [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; January 2005.


39. Vivelle [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; August 2004.


40. Activella [package insert]. Princeton, NJ: Novo Nordisk; December 2006.


41. Femhrt [package insert]. Rockaway, NJ: Warner Chilcott; January 2005.


42. Prempro/Premphase [package insert]. Philadelphia, PA: Wyeth Pharmaceuticals; June 2008.


43. Forteo [package insert]. Indianapolis, IN: Eli Lilly and Company; June 2008.


44. Black DM, Cumming SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348:1535-1541.


45. Cummings SR, Black DM, Desmond E, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the fracture intervention trial. JAMA. 1998;280:2077-2082.


46. Liberman UA, Weiss SR, Bröll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med. 1995;333:1437-1443.


47. Delmas PD, Recker RR, Chesnut CH III, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporosis Int. 2004;15:792-798.


48. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA. 1999;282:1344-1352.


49. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group. Osteoporosis Int. 2000;11:83-91.


50. Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM. Effect of alendronate on vertebral fracture risk in women with bone mineral density T scores of -1.6 to -2.5 at the femoral neck: The Fracture Intervention Trial. Mayo Clin Proc. 2005;80:343-349.


51. Siris ES, Simon JA, Barton IP, McClung MR, Grauer A. Effects of risedronate on fracture risk in postmenopausal women with osteopenia. Osteoporosis Int. 2008;19:681-686.


52. FDA approves Reclast^® to prevent osteoporosis in postmenopausal women with convenient less frequent dosing [news release]. Basel, Switzerland. Novartis newsroom. June 1, 2009. Available at: http://www.novartis.com/newsroom/media-releases/en/2009/1318842.shtml. Accessed on: June 4, 2009.


53. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822.


54. Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809.


55. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434-1441.


56. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. JAMA. 1999;282:637-645.


57. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87:3609-3617.


58. Siris ES, Harris ST, Eastell R, et al. Skeletal effects of raloxifene after 8 years: results from the Continuing Outcomes Relevant to Evista (CORE) Study. J Bone Miner Res. 2005;20:1514-1524.


59. Kanis JA, Johnell O, Black DM, et al. Effect of raloxifene on the risk of new vertebral fracture in postmenopausal women with osteopenia or osteoporosis: a reanalysis of the Multiple Outcomes of Raloxifene Evaluation trial. Bone. 2003;33:293-300.


60. Martino S, Disch D, Dowsett SA, Keech CA, Mershon JL. Safety assessment of raloxifene over eight years in a clinical trial setting. Curr Med Res Opin. 2005;21:1441-1452.


61. Jolly EE, Bjarnason NH, Neven P, et al. Prevention of osteoporosis and uterine effects in postmenopausal women taking raloxifene for 5 years. Menopause. 2003;10:337-344.


62. Cauley JA, Robbins J, Chen Z, et al. Effects of estrogen plus progestin on risk of fracture and bone mineral density: The Women's Health Initiative randomized trial. JAMA. 2003;290:1729-1738.


63. Roussouw JE, Anderson GL, Prentice RL, et al, for the Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-333.


64. Johnell O, Scheele WH, Lu Y, Reginster J-Y, Need AG, Seeman E. Additive effects of raloxifene and alendronate on bone density and biochemical markers of bone remodeling in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87:985-992.


65. Weycker D, Macarios D, Edelsberg J, Oster G. Compliance with drug therapy for postmenopausal osteoporosis. Osteoporos Int. 2006;17:1645-1652.


66. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81:1013-1022.


67. Szulc P, Delmas PD. Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis.
    Available at: http://www.springerlink.com/content/68512w6g74n6vx67/. Accessed on: May 19, 2009.