OSTEOPOROSIS

Greenspan SL, Bone HG, Ettinger MP, et al, for the Treatment of Osteoporosis with Parathyroid Hormone Study Group. Effect of recombinant human parathyroid hormone (1–84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med. 2007;146:326–339.

Teriparatide (Forteo) is a synthetic portion (1-34) of the parathyroid hormone (PTH) molecule that is identical in sequence to the biologically active segment of the 84-amino acid human PTH.

It has been shown to prevent fracture in women with low bone mineral density (BMD). Teriparatide is the only anabolic bone agent approved for clinical use; all other pharmacotherapies are antiresorptive.

The study by Greenspan and associates—the Treatment of Osteoporosis with Parathyroid Hormone, or TOP trial—involved the full-length PTH molecule (1–84) and provides evidence that it, too, can prevent vertebral fracture in women who have low BMD (FIGURE 2). This agent is used in Europe but not yet available in the United States.

TOP was an 18-month, randomized, double-blind, placebo-controlled, parallel-group study of 2,532 women with low BMD at the hip or lumbar spine. It was conducted at 168 centers in nine countries.

The primary outcome measure was new or worsened vertebral fracture; secondary outcomes were changes in BMD and safety. The trial investigated the safety of recombinant PTH and its effect on the incidence of vertebral fractures in postmenopausal women with osteoporosis.

FIGURE 2 Fracture-prone bone responds to PTH

PTH prevented vertebral fracture in women with low BMD, existing fractures, or both.

Women had very low BMD, or low BMD and existing fractures

Participants were postmenopausal women aged 45 to 54 years. They had a BMD 3 standard deviations or more (T-score ≤ -3.0) below the mean peak bone mass of young adult women at the lumbar spine, femoral neck, or total hip, with no vertebral fractures, or they had a BMD T-score of -2.5 and 1 to 4 vertebral fractures. Postmenopausal women aged 55 years or older were included if their BMD T-score was -2.5 and they had no vertebral fractures, or if their BMD T-score was -2.0 and they had 1 to 4 vertebral fractures before enrollment. The women were given 100 μg of recombinant human PTH or placebo daily, as well as calcium (700 mg/day) and vitamin D₃ (400 U/day).

PTH reduced the risk of new fractures or prevented worsening of existing fractures. The reduction in relative risk (RR) for vertebral fracture was 0.42 (95% CI, 0.24–0.72; P=.001). Women who received PTH had an increase in mean BMD of 6.9% at the spine (95% CI, 6.4–7.4) and 2.1% at the hip (95% CI, 1.7–2.5). Adverse events included a higher incidence of hypercalciuria, hypercalcemia, and nausea.

Although it is unlikely that many gynecologists will be ordering or monitoring injectable PTH therapy, we should be aware of the data. All too often such therapy is not even considered for women with severe osteoporosis (T-score < -2.5 and preexisting fracture), who may be excellent candidates.

Long-term alendronate users can sometimes take a “drug holiday”

Black DM, Schwartz AV, Ensrud KE, et al, for the FLEX Research Group. Effects of continuing or stopping alendronate after 5 years of treatment. The Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial. JAMA. 2006;296:2927–2938.

As early as 2002, Greenspan and colleagues³ demonstrated that women on alendronate for 21 months maintained femoral-neck BMD through 15 months of crossover to placebo. This study by Black and associates, known as the FLEX trial, is a long-term extension of the Fracture Intervention Trial (FIT). A total of 1,099 women who had participated in FIT and taken alendronate for 5 years were then randomized to one of two doses of alendronate or placebo for an additional 5 years. To qualify for the FLEX trial, all women had to have low bone mass at the beginning of FIT. The average age of women in the FLEX trial was 73 years. The primary outcome was total hip BMD; secondary outcomes were BMD at other sites and biochemical markers.

Women who remained on alendronate maintained a higher BMD of the hip and spine than women on placebo, but all patients’ levels remained at or above pretreatment levels of 10 years earlier. The same was true for markers of bone remodeling. The cumulative risk of nonvertebral fractures did not differ between the two groups (19% for placebo, 18.9% for alendronate; RR, 1.0; 95% CI, 0.76–1.32). The risk of clinically recognized vertebral fractures was lower in the women who continued alendronate (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24–0.85), but there was no significant reduction in morphometric vertebral fractures.