Oral daily PTH(1-34) tablets (EB613) in postmenopausal women with low BMD or osteoporosis: a randomized, placebo-controlled, 6-month, phase 2 study.

ABSTRACT

Anabolic treatment is indicated for high and very-high risk patients with osteoporosis, but acceptance is limited because current anabolic medications require subcutaneous injections. The purpose of this study was to assess the effects of a novel orally administered PTH tablet on serum markers of bone formation (PINP and osteocalcin), bone resorption (crosslinked C-telopeptide [CTX]), BMD, and safety in postmenopausal women with low BMD or osteoporosis. In this 6-mo, double-blind, placebo-controlled study, 161 patients were randomized to oral PTH tablets containing 0.5, 1.0, 1.5, or 2.5 mg or placebo daily. Biochemical markers were assessed at 1, 2, 3, and 6 mo and BMD of LS, TH, and FN was measured at 6 mo. Biochemical marker changes were dose dependent with minimal or no effect at the 2 lowest doses. At the highest dose (2.5 mg once daily), serum PINP and OC levels increased 30% within 1 mo after oral PTH initiation (P < .0001), remained elevated through 3 mo, and were back to baseline at 6 mo. In contrast, serum CTX levels declined 16% and 21% below baseline at 3 and 6 mo, respectively (both P ≤ .02). At 6 mo, 2.5 mg tablets increased mean BMD vs placebo of the LS by 2.7%, TH by 1.8%, and FN by 2.8% (all P ≤ .01). There were no drug-related serious adverse events. The most common adverse events were headache, nausea, and dizziness. In contrast to subcutaneous PTH, the oral PTH tablet appears to increase BMD rapidly by the dual mechanism of stimulating formation and inhibiting bone resorption. This might be the first effective oral anabolic alternative to subcutaneous administration for the treatment of low BMD or osteoporosis.

Despite the superior benefits of bone-building (anabolic) agents and guidelines supporting their use, these medications are used in a minority of patients for whom they are appropriate, in part because they require daily or monthly injections, which limit patient acceptance. An oral anabolic tablet has potential to address this substantial treatment gap. In this double-blind, placebo controlled, dose-finding randomized study, 161 postmenopausal women with low BMD or osteoporosis were treated with varying doses of the active part of PTH(1-34) or placebo given in daily oral tablets for 6 mo. The highest oral PTH tablet dose (2.5 mg) produced an increase in markers of bone formation while simultaneously decreasing the markers of bone breakdown. Significant gains in BMD of the spine and hip were observed at the end of the 6-mo study and there were no significant safety concerns. The 2.5 mg oral PTH tablet dose was well tolerated when patients were instructed to titrate up to the full dose. We conclude that this PTH tablet might be the first effective orally administered bone building medication and should be studied further in treatment of women with osteoporosis.