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MONTREAL -- A combination regimen of high-dose teriparatide (Forteo) and denosumab (Prolia) increased hip and spine bone mineral density (BMD) to a greater extent than standard combination therapy among postmenopausal women who were at high fracture risk, according to a randomized controlled study presented here at the .

The study included 69 women who were initially randomized to receive high-dose (40 µg/day) or standard FDA-approved dose (20 µg/day) teriparatide for 9 months. During months 3 to 15, the women also received denosumab (60 mg subcutaneously, every 6 months).

At month 15, patients who had received the high dose of teriparatide had an increase of 17.5% in spine BMD compared with 9.5% in the standard-dose group (P<0.001) as well as an increase of 6.1% in the total hip BMD compared with 3.9% in the standard-dose group (P<0.001), reported Benjamin Leder, MD, of Massachusetts General Hospital in Boston.

"Osteoporosis drugs increase BMD and reduce fracture rates modestly, but cannot fully restore skeletal integrity in most patients with advanced disease," Leder said.

Anabolic therapies are limited to 24 months of use by regulatory authorities, and antiresorptive agents also are generally used for finite periods.

"There remains an urgent need to develop regimens that rapidly and more fully restore bone strength in patients with significant osteoporosis," he said.

In the , the investigators demonstrated that with co-administration of denosumab and teriparatide, denosumab was able to fully inhibit teriparatide bone resorption while allowing for continued modeling-based bone formation. The dosages used in that study were 20 µg of teriparatide daily and 60 mg denosumab every 6 months.

The combination led to increases in spine and hip BMD that were greater and more rapid than could be achieved with either drug alone or with any currently available agent, he explained.

"We then hypothesized that combining denosumab with a larger anabolic stimulus would result in an even greater separation between bone resorption and bone formation, resulting in larger and more rapid gains in bone mass than those observed in the original DATA studies."

For the current analysis with higher-dose teriparatide, patients were required to have an elevated risk of fracture on the basis of a T score below -2.5, or below -2 with an additional clinical risk factor, or less than -1 with a history of fragility fracture.

The mean age of participants was 67, and most were white. A total of 50%-70% had a previous fragility fracture, and prior bisphosphonate use was reported by 50%-60%, with duration of use ranging from 45 to 64 months.

As with the spine and total hip BMD, the increase in bone density at the femoral neck at 15 months was 6.8% in the high-dose group compared with 4.3% in the standard-dose group (P=0.039).

"Of note, the separation between the standard- and high-dose groups appeared to be occurring primarily between 9 and 15 months, when both groups were receiving the same intervention of denosumab alone," Leder said. "This suggested that the prior treatment with the higher dose of teriparatide had an impact on what was happening between months 9 and 15."

For volumetric BMD as measured by quantitative CT, the change in trabecular spine density was more than twofold greater in the high-dose group (32% versus 13%). For total hip, the volumetric bone density change was 3.6% in the high-dose group versus 3% in the standard-dose group, while the corresponding numbers for the femoral neck were 5.2% versus 1.4%.

For markers of bone turnover, after an initial 3 months of teriparatide treatment, osteocalcin had increased by 254% in the high-dose group compared with 140% in the standard-dose group, while P1NP had risen by 402% versus 153%, and bone resorption increased by 159% versus 84%. At month 15, bone turnover markers were suppressed similarly in the two groups.

There were no reports of hypercalcemia.

"The increases in spine and hip bone density were significantly greater and in many cases double what can be achieved with currently available agents and even greater than what can be achieved with the investigational agent romosozumab," he concluded.

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