CME/CE

MAY 2008

Improving Treatment Success in Postmenopausal Osteoporosis

Raymond Cole, DO, CCD

Numerous pharmacologic regimens are now available to treat postmenopausal osteoporosis, each with its advantages and disadvantages. This allows the health care provider to individualize therapy in terms of dosing schedule, route of administration, and side effects as well as specific medical goals—helping to optimize patient adherence and satisfaction.

Continuing Medical Education

GOAL To optimize osteoporosis treatment in women through appropriate drug selection and attention to adherence. OBJECTIVES To promote supplementation and other lifestyle measures to prevent osteoporosis and fractures. To explore the similarities and differences among osteoporosis treatment regimens with regard to indications, dosing, route of administration, and side effects. To develop strategies for maximizing adherence to therapy. ACCREDITATION This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Albert Einstein College of Medicine and Quadrant HealthCom Inc. Albert Einstein College of Medicine is accredited by the ACCME to provide continuing medical education for health care providers. This activity has been peer reviewed and approved by Brian Cohen, MD, Professor of Clinical ObGyn, Albert Einstein College of Medicine. Review date: April 2008. It is designed for ObGyns, primary care physicians, and nurse practitioners. Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit™. Health care providers should only claim credit commensurate with the extent of their participation in the activity. Participants who answer 70% or more of the questions correctly will obtain credit. To earn credit, see the instructions on page 55 and mail your answers according to the instructions on page 56. CONFLICT OF INTEREST STATEMENT The “Conflict of Interest Disclosure Policy” of Albert Einstein College of Medicine requires that authors participating in any CME activity disclose to the audience any relationship(s) with a pharmaceutical or equipment company. Any author whose disclosed relationships prove to create a conflict of interest, with regard to their contribution to the activity, will not be permitted to present. The Albert Einstein College of Medicine also requires that faculty participating in any CME activity disclose to the audience when discussing any unlabeled or investigational use of any commercial product, or device, not yet approved for use in the United States. Dr Cole reports that he is a consultant to and on the speakers bureau for: Novartis Pharmaceuticals Corporation, F. Hoffman-La Roche Ltd., and GlaxoSmithKline. He is on the speakers bureau for Eli Lilly and Company. All disclosures reported by the author present no conflict of interest to this article. The author reports no discussion of off-label use. Dr Cohen reports no conflict of interest. The staff of CCME of Albert Einstein College of Medicine have no conflicts of interest with commercial interest related directly or indirectly to this educational activity.

Osteoporosis is a highly prevalent condition; approximately 50% of postmenopausal US women will experience an osteoporotic fracture within their lifetime.1 Effective therapies are available, but diagnosis and treatment are lagging. Moreover, even when patients are treated, adherence is problematic.

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NONPHARMACOLOGIC MANAGEMENT

Nonpharmacologic management—including risk reduction via lifestyle changes—is essential for all postmenopausal women, regardless of bone mineral density (BMD).

Supplementation

Although osteoporosis risk reduction generally focuses on calcium supplementation, adequate vitamin D levels are also essential—especially in women with additional risk factors (Table 1). Adult serum values of vitamin D₃ should be at least 30 ng/mL, but many inactive older women may have suboptimal levels. Both calcium and vitamin D supplementation can improve BMD, but data supporting their utility in preventing fractures are mixed. Dietary intake and supplementation for adult women over 50 years of age should total at least 1200 mg/d of calcium and 800 to 1000 IU/d of vitamin D₃. Exposure to 15 min/d of sunlight helps to maintain vitamin D values, but effects may be limited by sun block use.

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TABLE 1. Risk Factors for Osteoporosis2

Lifestyle and Fall Prevention

Several lifestyle measures can promote skeletal health, including moderate alcohol and caffeine intake, avoidance of smoking, and maintaining a healthy body weight. Diet should consist of grains, fruits, vegetables, low-fat dairy products, beans, and meat. Adults should have a minimum of 30 min/d of exercise, with strengthening and weight-bearing activities. To prevent fractures due to falls, balance training should be added to exercise.

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PHARMACOLOGIC MANAGEMENT

Selection of an appropriate drug regimen for osteoporosis requires consideration of safety, tolerability (including convenience of administration), and efficacy (Table 2). The National Osteoporosis Foundation (NOF) has just released new Clinical Guidelines in the Clinician’s Guide to Prevention and Treatment of Osteoporosis. The following synopsis of the guidelines (available in their entirety at www.nof.org/professionals/NOF_Clinicians_Guide.pdf) recommends initiation of treatment in:

• those with hip or vertebral (clinical or morphometric) fractures.
• those with BMD T-scores <-2.5 at the femoral neck, total hip, or spine by dual-energy X-ray absorptiometry, after appropriate evaluation.
• postmenopausal women and in men age ≥50 with low bone mass (T-score -1 to -2.5, osteopenia) at the femoral neck, total hip, or spine and 10-year hip fracture probability ≥3% or a 10-year all major osteoporosis-related fracture probability of ≥20% based on the US-adapted WHO absolute fracture risk model.2

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TABLE 2

The World Health Organization (WHO) recently developed a 10-year risk of fracture tool called FRAX (at www.shef.ac.uk/FRAX) which helps predict the risk of osteoporotic fracture using clinical risk factors and BMD, if available. This tool incorporates fracture risk assessment and cost-effectiveness into decisions about treatment to help health professionals worldwide identify patients at high risk of fracture who may require pharmacologic treatment.

The FRAX algorithm provides information indicating a 10-year fracture probability and guidance for determining treatment in health care systems. This is calculated by entering patient information into the Web site. Age, sex, weight, height, information on prior fragility fracture, parental history of hip fracture, current tobacco smoking, long-term use of glucocorticoids, rheumatoid arthritis, daily alcohol consumption, other causes of secondary osteoporosis, and femoral neck BMD, if available, are entered into the FRAX tool.

Estrogen/Hormone Therapy

Estrogen therapy (ET) alone and estrogen/progestin hormone therapy (HT) have demonstrated efficacy in reducing osteoporotic fracture risk. However, as both HT and ET have been linked to an increase in incidence of breast cancer and venous thrombotic events, their usage for osteoporosis has significantly declined. Although ET/HT is approved to prevent osteoporosis, the FDA recommends that women first consider other regimens.

Raloxifene

The selective estrogen receptor modulator raloxifene can reduce vertebral fracture risk by 30% to 50%.3 Raloxifene is also FDA-approved for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and/or at high risk for breast cancer. It is associated with an increased risk of thromboembolic disease (eg, deep venous thrombosis, pulmonary embolism, stroke, retinal vein thrombosis)—necessitating a "black-box" warning. Raloxifene is indicated for both prevention and treatment of postmenopausal osteoporosis.

Calcitonin

Calcitonin can reduce vertebral fractures by 33% in postmenopausal women with a history of compression fractures, even though spinal BMD gain is negligible. However, this effect does not extend to nonvertebral and hip fractures.4 Calcitonin is indicated for the treatment (not prevention) of osteoporosis in women who are at least 5 years postmenopausal, especially in those experiencing bone pain.

Teriparatide

Teriparatide (parathyroid hormone) can reduce the incidence of vertebral fractures by 65% in postmenopausal women with preexisting vertebral fractures, and increase BMD at the spine (9.7%) and hip (2.6%).5 A black-box warning cites an increased risk of osteosarcoma in rats that is dose- and duration-dependent. Treatment should be limited to 2 years, as subsequent safety and efficacy are unknown. Teriparatide is FDA-approved for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture. Therapy is generally followed by bisphosphonate treatment to preserve new bone growth.

Bisphosphonates

Alendronate.—Alendronate has proven effective in increasing BMD in a dose-dependent manner. A meta-analysis found that nonvertebral fractures were reduced in postmenopausal women with low BMD and no previous fractures, and vertebral fractures were prevented across patient populations.6 Weekly dosing is as effective as daily dosing, and preparations are available that combine alendronate with vitamin D₃. The FDA recently approved the first generic version of alendronate.

Risedronate.—Risedronate has demonstrated a 41% relative risk reduction in new vertebral fractures and a 39% reduction in nonvertebral fractures, increasing BMD such that bone growth was his-tologically normal.7 It has also shown a 30% reduction in hip fractures—40% with low BMD and 60% with low hip BMD and a history of one or more vertebral fractures.8 Weekly dosing is as effective as daily dosing. A formulation featuring one risedronate tablet per week with calcium carbonate the other 6 days of the week may help patients to remember to take their medication.

Ibandronate.—Ibandronate has demonstrated a relative risk reduction of 52% in new vertebral fractures, and an increase in spinal BMD of about 3% as early as 6 months.9 In patients with low hip BMD, there was a 69% relative risk reduction in nonvertebral fractures.10 Monthly oral dosing has produced BMD increases in the spine (6.8%) and hip (4.2%).11 Monthly ibandronate has been found to be particularly effective in early postmenopausal women with low BMD.12

Postmenopausal women using intravenous (IV) ibandronate injections have shown BMD increases of 6.3% in the spine and 3.1% in the hip.13 Ibandronate IV has been associated with a lower incidence of side effects, and may be preferable in patients who use many medications or have problems with oral bisphosphonates. Hypocalcemia, hypovitaminosis D, and other disturbances of bone metabolism must be effectively treated before starting ibandronate IV therapy. Patients must also take supplemental calcium and vitamin D. Ibandronate IV is indicated for the treatment (not prevention) of osteoporosis in postmenopausal women.

Zoledronic Acid.—Zoledronic acid IV infusion is a once-yearly treatment. It has been shown to reduce spinal fractures by 70% and hip fractures by 41%, with BMD increases of 6.7% and 6%, respectively.14 The benefits for BMD and bone turnover were equal to those of daily bisphosphonate dosing, and the once-yearly dosing may confer significant adherence benefits. As with ibandronate, disturbances of bone metabolism must be addressed before starting therapy. Patients should also take 1500 mg/d of elemental calcium in divided doses and 800 IU/d vitamin D₃, particularly in the 2 weeks postdosing. Zoledronic acid is indicated for the treatment (not prevention) of postmenopausal osteoporosis.

Precautions and Side Effects

To maximize absorption and minimize adverse gastrointestinal events, oral bisphosphonates should be taken first thing in the morning on an empty stomach with 8 oz of plain water (no other food, liquids, or medicine), and patients must remain upright for at least 30 minutes (alendronate and risedronate) to 60 minutes (ibandronate). Most side effects from IV bisphosphonates are mild or moderate, and decrease with each subsequent injection. Any reactions usually subside within several days.

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ADHERENCE

Adherence has two components: compliance in taking the medication properly, and persistence in taking the medication over the long term. The consequences of poor adherence are highly detrimental in osteoporosis management; conversely, adherent patients have been shown to experience a 16% lower fracture rate than nonadherent patients.15 With regard to dosing schedule, weekly bisphosphonate use has demonstrated significantly longer persistence than daily use, and more weekly users met predetermined criteria for good compliance than did daily users.16

In addition, significantly more patients preferred monthly ibandronate (71.4%) than weekly alendronate (28.6%). Patients who chose monthly dosing cited greater ease of long-term use, convenience, and tolerability—suggesting that monthly dosing may promote adherence.17 When monthly ibandronate was compared with weekly alendronate, persistence was 56.6% and 38.6%, respectively.18

Polypharmacy for multiple chronic conditions in older patients substantially challenges adherence to osteoporosis treatment regimens. Drug-related adverse events in this population may also exacerbate existing comorbidities, further decreasing adherence. It has been found that one year after initiating treatment, 45% of patients stop filling their osteoporosis prescriptions; older age and increasing numbers of comorbid conditions and medications unrelated to osteoporosis treatment all predicted lower adherence.19

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CONCLUSION

The aging of the US population, the asymptomatic nature of early BMD loss, and patients’ failure to raise the issue mandate that heath care providers address prevention, diagnosis, and therapy proactively. Effective osteoporosis education is necessary to correct common misperceptions, such as the belief that increasing calcium and vitamin D intake and exercising will rebuild lost BMD; it is the health care provider’s responsibility to explain that only pharmacotherapy can significantly increase BMD and protect against fractures. Relating osteoporosis to loss of independence, hunched posture, hip fracture, and confinement to a nursing home can also have a positive impact on adherence.20 Regular reinforcement during office visits improves adherence as well. To truly individualize therapy, the health care provider must listen to the patient, ask about personal preferences, and seek to accommodate her needs with a medically appropriate drug. The best treatment regimen is the one that the patient will follow.

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Raymond Cole, DO, CCD, is Clinical Assistant Professor, Department of Internal Medicine, Michigan State University College of Osteopathic Medicine, East Lansing, MI; and Director of the Osteoporosis Testing Center of Michigan, Brooklyn, MI.

References

1. National Osteoporosis Foundation web site. www.nof.org. Accessed January 10, 2008.
2. The Clinician’s Guide to Prevention and Treatment of Osteoporosis. National Osteoporosis Foundation Web site. www.nof.org/professionals/NOF_Clinicians_Guide.pdf. Accessed March 11, 2008.
3. 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. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999; 282(7):637-645.
4. Chesnut CH 3rd, Silverman S, Andriano K, et al. A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures Study. PROOF Study Group. Am J Med. 2000;109(4):267-276.
5. 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(19): 1434-1441.
6. Cranney A, Wells G, Willan A, et al. Meta-analyses of therapies for postmenopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev. 2002;23(4): 508-516.
7. 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. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999; 282(14):1344-1352.
8. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group. N Engl J Med. 2001;344(5):333-340.
9. Chesnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004; 19(8):1241-1249.
10. Recker RR, Weinstein RS, Chesnut CH 3rd, et al. Histomorphometric evaluation of daily and intermittent oral ibandronate in women with postmenopausal osteoporosis: results from the BONE study. Osteoporos Int. 2004;15(3): 231-237.
11. Reginster JY, Adami S, Lakatos P, et al. Efficacy and tolerability of once-monthly oral ibandronate in postmenopausal osteoporosis: 2-year results from the MOBILE study. Ann Rheum Dis. 2006;65(5): 654-661.
12. McClung MR, Wasnich RD, Recker R, et al. Oral daily ibandronate prevents bone loss in early postmenopausal women without osteoporosis. J Bone Miner Res. 2004;19:11-18.
13. Emkey R, Zaidi M, Lewiecki EM, et al. Two-year efficacy and tolerability of intermittent intravenous Ibandronate Injections in postmenopausal osteoporosis. The DIVA Study. [Abstract] Presented at the 70th Annual Scientific Meeting of the American College of Rheumatology, Nov 12-17, 2005, San Diego, CA.
14. Zometa (zoledronic acid) package insert. East Hanover, NJ: Novartis Pharmaceuticals; 2005.
15. Caro JJ, Ishak KJ, Huybrechts KF, Raggio G, Naujoks C. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int. 2004;15(12):1003-1008.
16. Cramer JA, Amonkar MM, Hebborn A, Altman R. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin. 2005;21(9):1453-1460.
17. Emkey R, Koltun W, Beusterien K, et al. Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO). Curr Med Res Opin. 2005;21(12): 1895-1903.
18. Cooper A, Drake J, Brankin E; the PERSIST Investigators. Treatment persistence with once-monthly ibandronate and patient support vs. once-weekly alendronate: results from the PERSIST study. Int J Clin Pract. 2006;60(8):896-905.
19. Solomon DH, Avorn J, Katz JN, et al. Compliance with osteoporosis medications. Arch Intern Med. 2005;165(20):2414-2419.
20. Cole R, Wright W, Dore R, Gold D. Analysis of physician/patient communication con-cerning osteoporosis treatment. 2006 Inter-national Osteoporosis Foundation World Congress on Osteoporosis, June 2-6, 2006, Toronto, Canada.

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