乌鸦传媒

SAN FRANCISCO -- Patients who discontinue the osteoporosis drug denosumab (Prolia) have an increased fracture risk that major clinical trials did not reflect, recent case reports documented.

The fractures were accompanied by increases in markers of bone turnover, consistent with a rebound effect following discontinuation of denosumab. With recognition of the fracture risk, clinicians can take steps to minimize the rebound effect and reduce the fracture risk, Nancy E. Lane, MD, of the University of California Davis in Sacramento, said here at the meeting.

"Discontinuation of denosumab was not associated with an increase in incident osteoporotic fractures in phase II and III studies," said Lane. "However, the studies were short term and underpowered for incident fractures."

If a patient discontinues treatment with denosumab, "consider switching to another antiresorptive agent, like a bisphosphonate. Less potent antiresorptive agents may work -- such as SERMs, calcitonin, and estrogen -- but they haven't been tested," she added. "It is essential to discuss with patients the increased fracture risk with discontinuation of treatment with denosumab."

The case reports were part of a review of recent developments in the management of osteoporosis. Lane also discussed clinical development of the sclerostin-targeted antibody romosozumab and the parathyroid hormone-related protein abaloparatide (Tymlos).

One of the case reports discussed by Lane involved a 48-year-old woman with hormone receptor-positive breast cancer, who . Three months after stopping the drug, the patient complained of back pain after slipping, but not falling. Six months after discontinuation, spinal MRI revealed multiple compression fractures.

The second report involved a 51-year-old woman with , who also discontinued denosumab after 3 years of treatment. A 6-month assessment showed deterioration of the patient's T-score, and 2 months later she complained of severe back pain after bending to open a refrigerator drawer. MRI showed three vertebral fractures.

The previously unrecognized fracture risk introduced a caveat to the clinical experience with an "amazing drug" that has rapid and potent antiresorptive activity, achieving particularly notable reductions in the risk of spinal fractures, said Lane. Aside from the rebound fracture risk, the principal safety issues with denosumab consist of cellulitis, "a few cases" of osteonecrosis of the jaw and atypical femoral fractures, and hypocalcemia, which can be avoided with concomitant use of calcium and vitamin D.

Whereas the rebound fracture risk after denosumab discontinuation appears manageable, a late-emerging safety issue derailed the progress of another promising osteoporosis drug. Romosozumab is a first-in-class inhibitor of sclerostin, a naturally occurring inhibitor of the Wnt signaling pathway that leads to bone formation. As previously reported, two large randomized phase III trials showed that the anti-sclerostin antibody significantly reduced the risk of new vertebral fractures, including a head-to-head comparison against a bisphosphonate control.

However, continued follow-up in the , comparing romosozumab and alendronate, showed a small but statistically significant increase in the risk of serious cardiac events among patients treated with the anti-sclerostin antibody. The FDA subsequently rejected Amgen's application for approval of the drug. The European Medicines Agency is now considering a for romosozumab.

Postmenopausal women with osteoporosis have an , an association documented in multiple studies, said Lane. Whether romosozumab truly added to the risk remains open to debate. Recent studies have shown that in addition to its negative regulatory effect on bone formation, sclerostin has a vascular effect: . Moreover, preclinical studies documented new blood-vessel formation following exposure to sclerostin.

"Is this what's going on in patients? I can't really say," said Lane. "But it's clear that one of sclerostin's biologic functions is to stimulate new blood vessel formation, and who knows whether that's going to connect to cardiovascular disease."

Clinicians do have abaloparatide (Tymlos) as a new therapeutic option to offer selected patients. In a turn of events, as compared with romosozumab, the FDA for patients with high-risk osteoporosis (history of multiple fractures, lack of response/benefit with other agents), but the EMA .

Support for the FDA approval came primarily from the phase III , which involved 2,463 women with postmenopausal osteoporosis. Patients were randomized to abaloparatide, teriparatide (Forteo), or placebo. Both active drugs significantly reduced fracture incidence as compared with placebo, slightly more so with abaloparatide (86% versus 80% for teriparatide). Markers of bone turnover declined significantly more with abaloparatide, which also was associated with a lower incidence of hypercalcemia as compared with teriparatide.

Though not the primary endpoint, the incidence of wrist fracture was significantly lower with abaloparatide and associated with a significantly greater increase in wrist bone mineral density.

"Abaloparatide is out there, looks equivalent to teriparatide, maybe just a touch better," said Lane. "But remember: if you grow bone, whether with denosumab or teriparatide, you can't just walk away. When patients discontinued abaloparatide, they went on maintenance with alendronate, which maintained the bone mass gained with abaloparatide and actually increased it just a bit and maintained the reduction in fractures."

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