High-dose teriparatide + denosumab improves BMD in postmenopausal women with osteoporosis
Combining high-dose teriparatide with denosumab may improve areal bone mineral density (aBMD) in postmenopausal women with osteoporosis, according to results of the phase IV DATA-HD* study.
“[W]e showed that combined treatment with teriparatide 40 μg and denosumab increases BMD at the hip and spine to a greater extent than a similar regimen with 20 μg teriparatide and denosumab,” said the researchers.
Seventy-six women with osteoporosis and high risk of fracture who were postmenopausal for ≥36 months were enrolled at the Massachusetts General Hospital, Boston, Massachusetts, US. They were randomized to receive daily subcutaneous teriparatide at 20 μg (standard dose; n=39) or 40 μg (high dose; n=37) for 9 months. At 3 months, all women initiated subcutaneous denosumab (60 mg) therapy every 6 months for 12 months. Sixty-nine women were included in the analysis (35 and 34 in the standard- and high-dose groups, respectively).
At 15 months, women who received high-dose teriparatide plus denosumab had greater increases in lumbar spine aBMD than those who received standard-dose teriparatide plus denosumab (mean increase 17.5 percent vs 9.5 percent, difference 8.1 percent; p<0.0001). [Lancet Diabetes Endocrinol 2019;doi:10.1016/S2213-8587(19)30255-4]
Women who received high-dose teriparatide also experienced a greater increase in femoral neck aBMD (mean 6.8 percent vs 4.3 percent, difference 2.5 percent; p=0.04) and total hip aBMD (mean 6.1 percent vs 3.9 percent, difference 2.2 percent; p<0.0001) compared with those who received low-dose teriparatide.
There were also significantly greater increases in volumetric BMD (vBMD) at 15 months among women who received high-dose vs standard-dose teriparatide, be it of the spine (mean increase 32.2 percent vs 13.3 percent, difference 18.2 percent; p<0.0001), femoral neck (5.2 percent vs 1.4 percent, difference 3.8 percent; p=0.030), or total hip (6.3 percent vs 3.1 percent, difference 3.1 percent; p=0.003).
Women who received high-dose teriparatide also had greater increases in spine strength (mean increase 33.3 percent vs 18.5 percent, difference 14.8 percent; p<0.0001) and total hip strength (7.9 percent vs 4.3 percent, difference 3.6 percent; p=0.007) at 15 months than standard-dose teriparatide recipients.
Although comparisons with other studies should be treated with caution, the increases in this study were higher than that achieved with other monotherapy or combination therapies, the researchers said.
Adverse event (AE) incidence was comparable between low-dose and high-dose teriparatide recipients (77 percent vs 78 percent), though serious AEs occurred more frequently in the low-dose group (n=7 and 2, respectively). Joint pain and fatigue were among the most common AEs in both the low-dose and high-dose groups (38 percent vs 46 percent [joint pain] and 31 percent vs 38 percent [fatigue]). Other common AEs were muscle cramp in the low-dose group (38 percent) and nausea in the high-dose group (43 percent).
“By contrast with many other chronic, age-related diseases, osteoporosis remains a disease primarily treated with monotherapy,” said the researchers.
While the mechanism behind the effects of the combination are not yet established, the answer may lie with “optimizing the balance between bone formation and bone resorption,” they said. “The findings … suggest that high-dose teriparatide stimulates even greater separation between bone resorption and formation than that of standard-dose teriparatide and that denosumab maintains its capacity to inhibit bone resorption even in the presence of high-dose teriparatide.”
They acknowledged that the results may be limited by the small, predominantly Caucasian study population, and single-centre design and called for studies assessing the fracture-reducing effects of the combination.
According to Dr Sundeep Khosla from the Mayo Clinic College of Medicine, Rochester, Minnesota, US, the likelihood of using the high-dose teriparatide-denosumab combination is low due to the need for off-label prescribing. However, it presents a crucial therapeutic option for certain patients such as those with high fracture risk. [Lancet Diabetes Endocrinol 2019;doi;10.1016/S2213-8587(19)30266-9]
He also highlighted the necessity of “sustained anti-resorptive therapy” following denosumab or combination therapy, based on evidence pointing to loss of BMD following anti-resorptive therapy discontinuation. [J Clin Endocrinol Metab 2019;104:1595-1622]