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

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-κB 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 fractures5^,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!