After Denosumab Discontinuation, Alendronate Superior to Raloxifene at Maintaining BMD Gains
Key findings
- This open-label, randomized trial enrolled 51 postmenopausal women with osteoporosis who completed one year of denosumab, then transitioned to alendronate or raloxifene for one year
- Alendronate, but not raloxifene, was able to maintain suppression of bone remodeling similar to what was achieved during treatment with denosumab
- At the end of the 24-month study period, bone mineral density at the lumbar spine and total hip was significantly increased in the denosumab-to-alendronate group compared with the denosumab-to-raloxifene group
- Overall bone density at the femoral neck and wrist was similarly maintained in both groups, and bone density remained above the pre-denosumab baseline in both treatment groups at all sites measured
- Raloxifene may be a suitable, although probably inferior, option after denosumab therapy for patients who cannot tolerate bisphosphonate use or decline it
Denosumab use increases bone mineral density (BMD), improves bone microarchitecture, and significantly reduces fracture risk in people with osteoporosis. Once denosumab is discontinued, those benefits are rapidly lost. Still, trials have demonstrated the preservation of BMD for at least 12 months after patients transition from short-term denosumab to a bisphosphonate, either alendronate or zoledronate.
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Sabashini K. Ramchand, MBBS, a research fellow in the Endocrine Unit of the Endocrinology Division at Massachusetts General Hospital; Joy Tsai, MD, and Benjamin Z. Leder, MD, endocrinologists and physician-investigators in the Division; and colleagues conducted the first prospective trial to assess the efficacy of a selective estrogen receptor antagonist in this setting.
In their comparison of alendronate and raloxifene published in Osteoporosis International, they say raloxifene can be considered for some patients, as BMD remained above pre-treatment baseline at all sites with both drugs. However, alendronate could better suppress bone remodeling and maintain denosumab-induced gains in BMD.
Methods
From November 2018 to January 2020 at Mass General, 51 women with osteoporosis who were >36 months postmenopausal and at increased risk of fracture were enrolled in the open-label, randomized Comparison of Alendronate or Raloxifene following Denosumab (CARD) study.
They received denosumab 60 mg subcutaneously at months 0 and 6, followed by either alendronate 70 mg weekly or raloxifene 60 mg daily starting at month 12 and continuing for one year. All patients also received daily calcium and vitamin D.
Markers of Bone Remodeling
The primary outcome was between-group differences in serum biochemical markers of bone remodeling. After discontinuation of denosumab, levels of C-telopeptide of type I collagen (CTX) and procollagen N-propeptide of type I collagen (PINP):
- Gradually increased and returned to baseline levels over six to 12 months in the denosumab-to-raloxifene group
- Remained suppressed at all time points in the denosumab-to-alendronate group
No overshoot in bone remodeling markers was observed in either group.
Bone Mineral Density
From months 12 to 24, BMD:
- Remained above the pre-denosumab baseline in both treatment groups at all sites measured (lumbar spine, total hip, femoral neck, and distal one-third of the radius shaft)
- Was maintained at all measured sites in the alendronate group
- Was maintained at the femoral neck and wrist but decreased at the lumbar spine by 2.0% (P=0.003) and at the total hip by 1.2% (P=0.008) in the raloxifene group
The mean differences in BMD change in the alendronate group compared with the raloxifene group were 2.9% (P<0.001) at the lumbar spine, 1.2% (P=0.02) at the total hip, 0.6% (P=0.6) at the femoral neck, and 0.3% (P=0.6) at the wrist.
Raloxifene: An Option for Some
Raloxifene may be a suitable, although probably inferior, option after denosumab for some patients who cannot tolerate bisphosphonate use or decline it. Before prescribing raloxifene, clinicians should consider its potential off-target effects, such as increased risk of venous thromboembolic events and hot flashes.
In addition, raloxifene has been shown to reduce rates of vertebral fracture but not non-vertebral fracture, so it may not be suitable for patients at high risk of the latter.
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