MINNEAPOLIS – Combining the antiresorptive denosumab with the anabolic agent teriparatide increased bone mineral density more than either drug alone in postmenopausal women at high fracture risk in the ongoing DATA study.
At 12 months, the combination of denosumab (Prolia) and teriparatide (Forteo) significantly increased bone mineral density (BMD) by 8.9% at the spine, 4.5% at the femoral neck, and 4.9% at the total hip.
The increases in BMD observed in the combination group are larger than those seen in prior combination anabolic and antiresorptive trials, Dr. Benjamin Z. Leder reported at the annual meeting of the American Society for Bone and Mineral Research.
The DATA (Denosumab, Teriparatide or Both for the Treatment of Postmenopausal Osteoporosis) trial is the first to study denosumab in combination with an anabolic agent. Prior trials combining teriparatide and bisphosphonates have shown inconsistent effects on BMD or, in some cases, a blunting effect of the anabolic agent.
The mechanisms underlying the additive effects of denosumab and teriparatide are unclear, but they may be related to the ability of denosumab to fully block teriparatide’s pro-resorptive effects while still allowing for continued modeling-based bone formation and, perhaps, an expansion of the anabolic window, said Dr. Leder, an endocrinologist with Massachusetts General Hospital in Boston.
"If these results persist in the second year of therapy and are confirmed in larger studies, the combination of these two agents may eventually prove to be a beneficial treatment in patients who are at particularly high risk of fracture," he said.
The trial randomized 100 women aged 45 years or older who were at least 3 years post menopause to daily teriparatide 20 mcg subcutaneous or denosumab 60 mg subcutaneous every 6 months or both. All patients received calcium 1,200 mg and vitamin D 400 IU.
Enrollment criteria were a BMD T-score of –2.5 or less at any anatomic site or a T-score of –2 or less with one risk factor (fracture or parental hip fracture after age 50, prior hyperthyroidism, inability to rise from a chair with arms elevated, or current smoker) or a T-score of –1 or less with a history of fragility fracture.
Patients were excluded if they had received oral bisphosphonates in the past 6 months; glucocorticoids for more than 14 days in the past 6 months; and any prior use of teriparatide, strontium, or parenteral bisphosphonates.
Patients were stratified by age and spine BMD. The 94 evaluable patients had an average age of 66 years.
At 12 months, the average increase in total hip BMD was 0.7% with teriparatide, 2.5% with denosumab, and 4.9% with combination therapy. Femoral neck BMD increased 0.8%, 2.1%, and 4.5% and spine BMD increased 6.2%, 5.5%, and 8.9%, respectively.
At the distal one-third of the radius, there was a decrease in BMD of 1.8% with teriparatide, an increase of 1.7% with denosumab, and a gain of 2.5% with the combination, Dr. Leder said. The difference in BMD was significant between the combination and teriparatide groups (P less than .001) but not between the combination and denosumab groups.
Changes in bone density were not significantly different between bisphosphonate-naive patients and those with prior bisphosphonate exposure.
Bone formation biomarker analysis showed significant suppression of osteocalcium with denosumab monotherapy at 3 months that continued through the 12-month study, while there was no change at 3 months and a more modest suppression thereafter in the combination group, he said.
Denosumab monotherapy significantly inhibited procollagen type I N-terminal propeptide at 3 and 6 months, but both groups were similar at 12 months.
The data on bone turnover marker C-telopeptide of type I collagen were distinct, with suppression identical in the denosumab alone and combination groups, Dr. Leder observed.
During a discussion of the study, Dr. Leder said bone biopsies were not available but that data at the distal radius and tibia that have not yet been analyzed "may provide some additional idea of what is going on, specifically in the trabecular and cortical compartments."
Session comoderator Dr. Aliya Khan, director of the calcium disorders clinic at St. Joseph’s Healthcare, McMaster University in Hamilton, Ont., said in an interview that the results shouldn’t be universally applied, but "if someone has a fracture, we can certainly consider this approach."
She went on to say that "combination therapy may be a way to improve bone strength, and it may actually enable us to avoid conditions such as atypical femoral fractures, which appear to be associated with oversuppression of bone remodeling."
Eli Lilly and Amgen sponsored the trial. Dr. Leder reported consulting for Amgen and Merck. Dr. Khan reported no disclosures.