Postmenopausal Osteoporosis

Postmenopausal osteoporosis:
What’s new and what’s next

Director, University Bone Health and Osteoporosis Center, Professor of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio

National guidelines and the new FRAX^® algorithm help clinicians decide who should be screened and treated for osteoporosis, but these important tools augment—rather than replace—clinical judgment. For treatment, clinical trial fracture endpoints provide the best evidence to support the use of a specific agent, as well as therapy duration and potential utility of combination therapy for some patients.

How important is bone density?

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength, predisposing an individual to increased risk of fracture.¹ Bone strength is a function of bone mineral density (BMD) and the more difficult to describe bone “quality.” Because BMD can be measured in the clinic, it remains the best available metric to identify at-risk patients and to monitor response to treatment. Also, in untreated patients, BMD is strongly related to increasing fracture risk.² The commonly used T-score compares a woman’s BMD with the mean value for young, healthy women. For every 1 standard deviation below the mean, the fracture risk roughly doubles. BMD is a continuous measure. The World Health Organization (WHO) has established cut-points to define osteoporosis, osteopenia (or low bone mass, as some prefer to describe it), and normal BMD.³ The fracture risk at the ends of the “osteopenia” continuum differ greatly—as does management. An individual whose T-score is just below –1.0 is an unlikely candidate for pharmacologic therapy; a patient with a score between –2.0 and –2.5 might benefit from treatment, particularly if she has additional risk factors.

Deciding who to test

The US Preventive Services Task Force’s (USPSTF) evidence-based recommendations advise routine osteoporosis screening for women aged 65 years and older and women aged 60 to 64 years who are at increased risk of fractures,⁴ based on weight (<70 kg [154 lb]) and no current use of estrogen therapy. The USPSTF takes no position on screening younger postmenopausal women regardless of risk. The National Osteoporosis Foundation (NOF) recommends screening otherwise healthy women at age 65 (and men at age 70) but also screening younger postmenopausal women and men aged 50 to 70 with risk factors such as a family history of osteoporosis, cigarette smoking, low body weight, or a prior low-trauma fracture as an adult.⁵

The recommendation for routine screening for women at age 65 years was based on the number needed to treat (NNT) and number needed to screen to prevent hip or vertebral fractures. Osteoporosis and fracture are uncommon in younger women: to prevent 1 hip fracture among women aged 50 to 54 years with osteoporosis, approximately 7500 women would require screening, and approximately 225 women with osteoporosis would need treatment.⁶ At age 65, more people have osteoporosis, and age is a powerful independent risk factor for fracture: at the same level of BMD, a 70-year-old has twice the risk of fracture as does a 50-year-old.

Treatment decisions: The muddle in the middle

Most professional organizations agree that a woman with a T-score of –2.5 or below is an appropriate treatment candidate; one with a T-score above –1.5 is not.^7-9 Less consensus exists about the management of a patient with a T-score between –1.5 and –2.5: Should additional risk factors should be considered? Or treatment implemented?

The National Osteoporosis Risk Assessment enrolled more than 200,000 women aged 65 years and older who had never been diagnosed with osteoporosis. All participants received a peripheral BMD test. One year later, they were asked if they had had a fracture.¹⁰ As bone density decreased, fracture risk increased; however, more than half of the fractures occurred in women with T-scores above –2.5. Clearly, a new strategy was needed to identify women who would benefit from therapy.

New guidelines, new tools

In 2008, the NOF published comprehensive updated guidelines (TABLE). The old guidelines did not describe how to weigh risk factors for patients with T-scores between –1.5 and –2.0. The new guidelines direct clinicians to use FRAX^®, an online tool to estimate fracture risk in patients. (See “The WHO Fracture Risk Assessment Tool”.)

For patients who will be treated with a pharmacologic agent, the guidelines remind clinicians to test for secondary causes of osteoporosis, which usually entails a complete blood count, chemistry panel, 25(OH)-vitamin D, and a 24-hour urine test for calcium and creatinine.⁵

Comparison of National Osteoporosis Foundation Guidelines

Fundamental measures for bone health

Weight-bearing exercise, calcium, and vitamin D are basic measures.

Exercise. Walking, particularly while carrying light weights to add resistance, provides a weight-bearing exercise during which gravity and muscle action combine to strengthen bone.

Calcium. Currently, 1200 mg of calcium per day from all sources is recommended for adults aged 50 and older. Dietary calcium intake must be estimated before deciding to supplement. The diet of an average 50-year-old supplies half of her calcium needs, so for many people, only 700 to 1000 mg of supplemental calcium are needed per day. Excess calcium is unlikely to be beneficial; one study reported that women who received calcium supplementation had an increased risk of myocardial infarction,¹¹ although other studies do not confirm these results.^12,13

Vitamin D. A meta-analysis of 5 studies showed that vitamin D supplementation reduced the risk of falling among elderly individuals, suggesting that vitamin D may have neuromuscular effects.¹⁴ Epidemiologic studies suggest that high levels of vitamin D are associated with reduced risk of cancer, multiple sclerosis, rheumatoid arthritis, type 1 and type 2 diabetes, and depression.

Vitamin D insufficiency is common in the United States, with a mean 25(OH)-vitamin D level of 30 ng/mL or below; significant racial differences in vitamin D levels have been reported.¹⁵ For optimal bone health, serum 25(OH)-vitamin D should be between 30 and 60 ng/mL, although higher levels are probably better.¹⁶ Toxicity is unlikely below 100 ng/mL. Supplementation with 1000 IU of vitamin D per day raises the blood level about 10 ng/mL; 2000 IU/d appears to be a safe upper limit for most people, and even higher doses are often safe and sometimes necessary.

Approved agents for bone health

The FDA has approved agents for the prevention or treatment (ie, fracture prevention) of postmenopausal osteoporosis, as well as for the treatment of glucocorticoid-induced osteoporosis in women and men. Regarding “prevention” of osteoporosis, there is no evidence that treatment to prevent bone loss in a 50-year-old will change that person’s fracture risk at age 75; therefore, fracture reduction is the outcome of greater interest to many clinicians. The approved drugs can be grouped by mechanism of action into antiresorptive or anabolic agents.

Antiresorptive drugs

Antiresorptive drugs change the balance of bone remodeling in favor of bone formation. Although the average increase in bone density is modest, fracture risk reduction is quite robust. An analysis of fracture risk in randomized trials of risedronate showed that the increase in BMD with treatment explained less than 20% of the reduction in fracture, and the decrease in bone resorption explained only about half of the reduced risk.¹⁷ These results suggest that antiresorptive agents lead to changes in unmeasured bone properties that account for the balance of improved bone strength. In the clinic, this means that a repeat bone density test 1 to 2 years after starting treatment that shows either stable or increasing BMD is evidence of a benefit from treatment; a test that shows significant loss is concerning.

In research, bone density and bone turnover markers are intermediate endpoints and do not necessarily translate into fracture reduction.

Selecting an agent. Of the FDA-approved agents, only alendronate, risedronate, and zoledronic acid have shown evidence of reducing the risk of hip and other nonvertebral fractures. No evidence demonstrates the effect of the other approved antiresorptive agents— calcitonin, raloxifene, and ibandronate—on nonvertebral fractures. Thus, evidence-based practice suggests that the bisphosphonates alendronate, risedronate, and zoledronic acid should be first-line agents.

Safety concerns. Adverse effects do occur in a minority of patients who take bisphosphonates. Oral administration may irritate the esophagus; intravenous or oral high-dose formulations can cause flu-like symptoms. Hypocalcemia and adverse renal effects may occur with intravenous bisphosphonates in patients with reduced kidney function. Predose serum calcium and creatinine tests are recommended before intravenous therapy; oral bisphosphonates should not be used in patients with reduced creatinine clearance (<35 or 30 mL/min, depending on the agent).

Rare complications of bisphosphonate use include musculoskeletal pain, atypical fractures, oversuppression of bone turnover, and osteonecrosis of the jaw. The latter affects cancer patients, who receive much higher doses of these agents. The American Dental Association has well-balanced information sheets (www.ADA.org) for patients.

Importantly, 3 studies have shown that long-term treatment appears to be safe.^18-20

Drug holidays. These have been suggested to address some safety concerns. Agents continue to be released from bone for a period after treatment discontinuation and therefore provide extended benefit.

The Fracture Intervention Trial Long-term Extension (FLEX) study enrolled patients who took alendronate for 5 years in a different study and rerandomized them to either placebo or alendronate for the next 5 years.² At 10 years, the cumulative incidence of clinical vertebral fractures was reduced by 55% in the patients treated for 10 years compared with those treated for only 5 years (FIGURE). No overall differences in nonvertebral fractures or morphometric fractures were seen between the 2 groups. A subgroup analysis of women who started the second 5-year period with a T-score of less than –2.5 showed a 50% reduction in nonvertebral fractures, suggesting that patients with severe osteoporosis should continue treatment for at least 10 years. For patients with mild osteoporosis for whom treatment was beneficial after 5 years, a drug holiday may be appropriate. As the FIGURE shows, the cumulative incidence of clinical vertebral fracture diverges about 2 years after discontinuing alendronate; therefore, a drug holiday should probably be limited to 1 to 2 years, after which treatment should resume.

Other antiresorptive agents. Raloxifene, an estrogen agonist/antagonist, has been shown to reduce the risk of vertebral fractures. It is approved for prevention and treatment of postmenopausal osteoporosis, and reducing the risk of breast cancer in women with postmenopausal osteoporosis and those at high risk of breast cancer. Side effects include hot flushes, night sweats, and leg cramps as well as increased risk of venous thromboembolic events.

Drug combinations with antiresorptives. The combination of a bisphosphonate with estrogen or raloxifene produces slightly greater gains in bone density compared with use of a single agent; no additional antifracture effects have been established. Given the additional cost and potential for side effects, use of a single agent may be preferable, with some exceptions. Using estrogen to control menopausal symptoms may provide sufficient bone protection. Adding a bisphosphonate may be appropriate.

Parathyroid hormone

Teriparatide, a recombinant form of parathyroid hormone (PTH), has been approved by the FDA to reduce vertebral and nonvertebral fractures. To date, this drug has not been shown to reduce hip fractures. Continuous PTH breaks down bone. However, animal studies show that intermittent PTH is anabolic for bone. Intermittent PTH improves microarchitecture, produces favorable changes in bone geometry, and reduces fracture risk.²¹

Given in this way, PTH also increases spine bone density dramatically, producing 2- to 3-fold greater gains in bone density than the antiresorptive drugs.²² As with antiresorptives, the gains in bone density with PTH do not explain the drug’s protective effect. Patients in a trial of PTH were given either 20 mcg, 40 mcg, or placebo.²² At the higher dose, patients experienced a relative increase of 40% in spine BMD compared with the patients who received the lower dose (13% vs 9% change in BMD), but no real difference in fracture risk reduction was seen between the 2 treatment groups.

Considerations for patient selection. Teriparatide is expensive, requires daily subcutaneous injections, and may produce more side effects than other agents, so it is often reserved for patients with unusually severe osteoporosis or those patients who continue to have bone loss on bisphosphonate therapy.

Combination with teriparatide. Teriparatide is most often used as monotherapy to reduce risk of fracture. Combination with estrogen or raloxifene does not provide additional benefit.²³ When combined with alendronate, a potent antiresorptive drug, the anabolic effects of teriparatide are attenuated.^24,25 The effect on bone strength is unknown; small studies have not included fracture endpoints.

Teriparatide is indicated for 2 years or less; for patients who cannot take a bisphosphonate, its use only postpones future decision making. For patients who are candidates for bisphosphonate therapy, an agent with broad-spectrum antifracture efficacy is appropriate after 2 years of anabolic therapy.

The future of bone health

Clinicians can expect new PTH analogs that are inhaled or absorbed transdermally. Related therapeutic agents may include PTH-related peptide and calcilytics, compounds taken orally to stimulate endogenous parathyroid hormone secretion.

Phase 3 trials of the new estrogen agonists/antagonists lasofoxifene and basedoxifene have been completed.

Strontium, a high atomic weight mineral, substitutes for calcium in bone, making bone more dense, although not necessarily stronger. Strontium ranelate is available in Europe but not in the United States. Here, patients can buy other salts of strontium (citrate or carbonate) without a prescription. Use should probably be discouraged until evidence shows that it improves bone strength.

Denosumab is under review by the FDA, with a decision expected soon. This osteoprotegerin analog is taken subcutaneously twice per year. Robust data from a large clinical trial show reductions in spine, hip, and nonvertebral fracture.²⁶ Further down the pipeline are cathepsin K inhibitors, which inhibit an enzyme that works with osteoclasts, and an antibody to sclerostin, which would promote differentiation of precursor cells into osteoblasts.

Conclusion

Screening for osteoporosis should begin at age 65 for most women and earlier for higher-risk women. Pharmacologic intervention is indicated for everyone with osteoporosis, defined as either a clinical diagnosis from fracture or a T-score of –2.5 or below. It is also indicated for individuals with low bone mass who are at risk for fracture using the FRAX^® calculator. Pharmacologic treatment selection should be individualized to the patient and based on evidence of fracture reduction rather than changes in intermediate endpoints.

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