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Postmenopausal Osteoporosis: New Diagnostic Tool, New Drug, New Therapeutic Strategies

Powerful tools are available to identify patients at high risk for fracture and to lower that risk.

We have simple tests to identify patients at excess risk for fractures and good treatments to lower fracture risk. Unlike chronic conditions (such as hypertension and hyperlipidemia) that necessitate early detection and aggressive management because little or no end-stage therapy can be offered, for osteoporosis we have medications that lower fracture risk by 50% to 70% within 6 to 12 months of treatment initiation. Despite all this, osteoporosis remains underdiagnosed, and many affected women are not treated.

The North American Menopause Society (NAMS), in its 2010 Position Statement, says "All postmenopausal women should be assessed for risk factors associated with osteoporosis and fracture. . . . The goals of this evaluation are to evaluate fracture risk, to rule out secondary causes of osteoporosis, to identify modifiable risk factors, and to determine appropriate candidates for pharmacologic therapy."¹

NEW DIAGNOSTIC TOOL

The FRAX algorithms have given us a new tool for assessing fracture risk. The NAMS recommends pharmacologic treatment for patients with clinical (vertebral or hip fracture) or densitometric (T-score –2.5 or below) diagnoses of osteoporosis. Moreover, the NAMS recommends osteoporosis drug therapy for postmenopausal women with T-scores between –1.0 and –2.5 who have FRAX-calculated 10-year risk for major osteoporotic fracture (spine, hip, shoulder, or wrist) of 20% or risk for hip fracture of 3%.¹ This recommendation provides an appropriate focus on those patients who will benefit most from treatment.

NEW DRUG

Denosumab (Prolia) was approved by the FDA in June 2010 for treatment of postmenopausal women with osteoporosis who are at high risk for fracture. Denosumab, which is administered by subcutaneous injection twice yearly, is a human monoclonal antibody against the receptor activator of nuclear factor-B ligand (RANKL) that potently inhibits osteoclastogenesis. In a large clinical trial, denosumab lowered risk for spine, hip, and nonvertebral fractures.² This agent is likely to be chosen for patients with reduced renal function (no dose adjustment is required) and patients who have experienced musculoskeletal pain with oral bisphosphonates.

Denosumab now gives clinicians and women a choice among four drugs that have what I call "broad-spectrum" antifracture efficacy. All FDA-approved agents lower risk for new vertebral fractures, but not all lower risk for hip fracture specifically and nonvertebral fractures collectively. Hip fracture is the most serious consequence of osteoporosis and, with other nonvertebral fractures, accounts for >90% of costs associated with fractures; thus, agents that show evidence of "broad-spectrum" antifracture efficacy represent first-line choices.

FDA-approved pharmacologic treatments for osteoporosis are shown in Table 1. Three of the four that have "broad-spectrum" antifracture efficacy — alendronate, risedronate, and zoledronic acid — are nitrogen-containing bisphosphonates. Because bisphosphonates accumulate in bone and are released slowly after treatment is stopped (during a period of months or even years), the possibility of limiting treatment duration is reasonable.

After use in millions of patients, bisphosphonates have proven to be effective and generally safe. However, uncommon or rare associations have been reported in postmarketing surveillance, including osteonecrosis of the jaw, musculoskeletal pain, and atypical femur fractures.³ The lay press has published considerable discussion of these rare occurrences, often outside the context of the seriousness of osteoporosis and the benefits of treatment. For the vast majority of patients with osteoporosis, benefits of bisphosphonate therapy far outweigh its small risks. Because safety concerns occur so rarely and lack evidence of causal association, we do not believe that they should limit duration of therapy.

NEW THERAPEUTIC STRATEGIES

"Drug holidays" from bisphosphonate therapy have been a subject of considerable discussion. Following 3 years of treatment, stopping treatment but retaining lingering protection against fractures might be possible. When patients with osteoporosis stopped risedronate treatment after 3 years, although bone-mineral density fell and bone turnover markers rose during the subsequent year, the incidence of new vertebral fractures was lower by approximately half compared with that in patients who had received placebo.⁴ In patients with osteopenia who received alendronate for 5 years, subsequent nonvertebral fracture incidence was similar whether treatment was stopped after 5 years or was continued for an additional 5 years.⁵ In the same study, however, patients with osteoporosis who were treated for 10 years had approximately half the risk for clinical vertebral fractures^5,6 and nonvertebral fractures⁶ as did those who stopped treatment after 5 years.

Our therapeutic approach is shown in Table 2. For patients at high risk for fracture, we recommend 10 years of bisphosphonate treatment followed by a 1- to 2-year drug holiday before resuming the bisphosphonate, sometimes prescribing a nonbisphosphonate drug (teriparatide or raloxifene) during the time off from bisphosphonate treatment. For patients who are at lesser risk for fracture, we recommend a drug holiday after 5 years of treatment, ending the holiday if bone-mineral density decreases or a fracture occurs.

CONCLUSION

The good news: We have powerful tools to identify patients at high risk for fracture and to lower their fracture risk. The challenge: We must use what we have more effectively!

— Nelson B. Watts, MD

Dr. Watts is a Professor of Medicine at University of Cincinnati College of Medicine and Director of the University of Cincinnati Bone Health and Osteoporosis Center.

Published in Journal Watch Women's Health August 12, 2010

Citation(s):

1. Management of osteoporosis in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010 Jan/Feb; 17:25.

• Medline abstract (Free)

2. Cummings SR et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009 Aug 20; 361:756.

• Medline abstract (Free)

3. Watts NB and Diab DL. Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 2010 Apr; 95:1555.

• Original article (Subscription may be required)
• Medline abstract (Free)

4. Watts NB et al. Fracture risk remains reduced one year after discontinuation of risedronate. Osteoporos Int 2008 Mar; 19:365.

• Medline abstract (Free)

5. Black DM 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 Dec 27; 296:2927.

• Original article (Subscription may be required)
• Medline abstract (Free)

6. Schwartz AV et al. Efficacy of continued alendronate for fractures in women with and without prevalent vertebral fracture: The FLEX Trial. J Bone Miner Res 2010 May; 25:976.

• Medline abstract (Free)

Reader Remarks:

Review and add to remarks on this article

• postmenopausal osteoporosis
  Beth Molnar, Brisbane., 19 Aug 2010 8:32 AM EST
  A reminder that SSRI antidepressants, as a class, are associated with an increased risk of osteoporosis, as such drugs are... [more]
• osteoporosis
  Roger J Beneitone, 2 Sep 2010 12:43 PM EST
  how do we define low, moderate and high risk?
• Pharmaceuticals
  J Harper, Scotland, 9 Sep 2010 11:17 AM EST
  The impressive list of pharmaceutical sposors on the NAMS website substantially diminishes the authority and credibility of the position statement.... [more]
• Osteoporosis
  Peter F. Gray, 13 Sep 2010 11:06 AM EST
  How do we define low,moderate, and high risk patients. It is easy for high risk. But should we treat moderate... [more]
• Drug Holiday
  vinod naneria, 27 Sep 2010 12:18 PM EST
  It is a beautiful concept perticularly with increasing incidences of complications like fragility fractures, Ca oesophagus, atrial fibrilations etc. with... [more]

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