What happens when denosumab is discontinued?
Miller and colleagues randomized postmenopausal women who had a lumbar spine T-score of –1.8 to –4.0 or a proximal femur T-score of –1.8 to –3.5 to one of the following arms:
- denosumab every 3 months (6, 14, or 30 mg)
- denosumab every 6 months (14, 60, 100, or 210 mg)
- open-label oral alendronate every week (70 mg)
- placebo.
After 24 months, women taking denosumab either:
- continued treatment at 60 mg every 6 months for an additional 24 months
- discontinued therapy
- discontinued treatment for 12 months and then reinitiated denosumab at 60 mg every 6 months for an additional 12 months.
The placebo cohort was maintained throughout this period.
Continuous, long-term denosumab increased BMD at the lumbar spine (9.4% to 11.8%) and total hip (4.0% to 6.1%). In contrast, discontinuation of denosumab was associated with a decrease in BMD of 6.6% at the lumbar spine and 5.3% at the total hip within the first 12 months. Retreatment with denosumab increased lumbar spine BMD by 9% from the original baseline values. Levels of bone turnover markers increased upon discontinuation of denosumab and decreased with retreatment. Adverse events occurred at similar rates in all treatment groups.
WHAT THIS EVIDENCE MEANS FOR PRACTICE
Among postmenopausal women who have low bone mineral density (BMD), long-term treatment with denosumab leads to gains in BMD and a reduction of markers of bone turnover. These effects are fully reversible upon discontinuation of the drug, but reoccur when treatment is restored.
In addition, switching from alendronate to denosumab produces a greater reduction in bone turnover than does continuation on the bisphosphonate.
Denosumab is a safe, extremely potent agent that will undoubtedly find a place in the ObGyn armamentarium, where it will join bisphosphonates, selective estrogen receptor modulators, and hormone therapy. The long dosing interval (every 6 months) should help increase compliance.
TSEC, a novel compound, enters development
Lindsay R, Gallagher JC, Kagan R, Pickar JH, Constantine G. Efficacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk postmenopausal women. Fertil Steril. 2009;92:1045–1052.
Although raloxifene is the only selective estrogen receptor modulator (SERM) approved by the FDA for prevention and treatment of osteoporosis, numerous other SERMs have been explored for this application. One new category of drug is the tissue selective estrogen complex (TSEC), which pairs a SERM with an estrogen. This was previously attempted unsuccessfully with raloxifene and 17β-estradiol. The ideal SERM–estrogen combination would have the positive attributes of both classes of drugs with fewer, or none, of the undesired effects. An appropriate TSEC would therefore alleviate hot flushes, treat vulvar and vaginal atrophy, and protect against bone loss without stimulating the endometrium and increasing the risk of breast cancer.
One third-generation SERM that has been investigated for its utility in this regard is bazedoxifene (BZA), which produced endometrial thickness and amenorrhea rates comparable to those of placebo. It also produced greater gains in BMD at the lumbar spine in a 2-year, randomized, double-blind, placebo-controlled trial.3 The incidence of new vertebral fracture was significantly lower with BZA than with placebo in a study of postmenopausal women with osteoporosis.4
Given these favorable data, a TSEC containing BZA and conjugated equine estrogen was designed as a potential new comprehensive menopausal therapy.
Substudies suggest bazedoxifene has promise
Lindsay and associates reported on two osteoporosis substudies of the Selective estrogen Menopause and Response to Therapy (SMART) Trial. The main study, which evaluated the incidence of endometrial hyperplasia at 12 months, will be reported elsewhere; it was a multicenter, double-blind, randomized, placebo-controlled phase 3 trial that enrolled 3,397 women.
Substudy I involved women who were more than 5 years postmenopausal, and Substudy II included women who were between 1 and 5 years postmenopausal. Eligible screened subjects were randomly assigned to one of the following treatment groups:
- bazedoxifene (10, 20, or 40 mg), each with conjugated equine estrogen (0.625 or 0.45 mg)
- raloxifene (60 mg)
- placebo.
To maintain blinding, the combination of BZA and conjugated equine estrogen was provided as a single, encapsulated tablet to match the placebo, as was raloxifene. Subjects were directed to take one tablet orally at approximately the same time each day for 2 years. The primary outcome for both substudies was a change in BMD at the lumbar spine, as measured by dual-energy x-ray absorptiometry.
In both substudies, BMD increased to a greater degree at the lumbar spine and total hip at all BZA-estrogen dosages than with placebo, and it increased to a greater degree at the lumbar spine at most BZA-estrogen dosages, compared with raloxifene.