A study published in The Lancet suggests that the combination of teriparatide (Forteo, Eli Lilly and Company) and denosumab (Prolia, Amgen) results in significantly increased bone mineral density (BMD) at the posterior-anterior lumbar spine compared with either drug alone. These results contrast with previous studies that showed that combinations of other osteoporosis treatments do not increase BMD.
Joy N Tsai, Endocrine Unit, Department of Medicine, Massachusetts General Hospital, Boston, USA, and others reported that attempts to improve the efficacy of osteoporosis therapies by combining them have proven to be “largely unsuccessful.” They explained: “Studies combining parathyroid hormone or teriparatide and bisphosphonates have reported no benefit compared with parathyroid hormone or teriparatide alone.”
Furthermore, the authors reported that the combination of teriparatide and the molecule osteoprotegerin (which inhibits RANKL binding to RANK – a similar mode of action to denosumab) was associated with increased BMD compared with either agent alone in a rat model but they added that this finding could not be consistently reproduced. Tsai et at commented: “To test the hypothesis that combined teriparatide and denosumab would have additive effects on BMD in human beings, we performed a randomised, controlled trial in postmenopausal women with osteoporosis.”
In the open-label study, postmenopausal women aged 45 or older with a high risk of fracture (T-score of -2.5 or less at the femoral neck, spine, or hip; or T-score of -2.0 with one additional risk factor) were randomised to receive teriparatide, denosumab, or a combination of both. Throughout a 12-month period, femoral neck, total hip, and spine BMD assessments were taken at baseline, three months, six months, and at 12 months.
Of 100 patients originally enrolled in the study, 94 were included in the analysis (six patients dropped out after baseline). The investigators found that the group that received the combination therapy had significant increased BMD at the spine compared with denosumab alone group (p=0.0005) or the teriparatide alone group (p=0.0139). They reported that combination therapy, compared with either drug alone, was also associated with significant increases in total hip BMD and in femoral neck BMD. Tsai et al added: “Moreover, the 12-month changes in femoral-neck and total hip BMD in the combination therapy group (4.2% and 4.9%, respectively) were greater than have been reported with approved therapies for postmenopausal osteoporosis.”
According to the authors, it is unclear why the combination of denosumab and teriparatide increased BMD compared with monotherapy but combinations of bisphosphonates and teriparatide did not. They noted: “The mechanisms underlying these differences are unclear but the larger increases in BMD we found might be at least partly explained by the net effects on osteoclast function.” Tsai et al explained that the combination therapy of teriparatide and denosumab was associated with acute and sustained suppression of bone resorption whereas in studies of bisphosphonate-based regimens, bisphosphonates alone suppressed bone resorption more than combination therapy.
Concluding the results of their study, the authors stated that more studies were needed to assess the effect of combination therapy on fracture reductions and explore different doses and duration of treatment. But, they added: “The results of this trial suggest that this specific combination of drugs could be a useful option in the treatment of patients with osteoporosis at especially at high risk of fracture.”