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Anabolic agents for osteoporosis have limited role so far



SAN FRANCISCO – Parathyroid hormone and parathyroid hormone–related protein analogs show promise for treating osteoporosis, but, for now, they’re reserved for the most severe cases.

Teriparatide, a parathyroid hormone analog, is the first treatment that stimulates bone formation instead of inhibiting bone resorption, but studies to date are too small to evaluate its effect on hip fractures, Jeffrey A. Tice, MD, said at the UCSF Annual Advances in Internal Medicine meeting.

Dr. Jeffrey Tice, professor of medicine in the division of general internal medicine at UCSF

Dr. Jeffrey Tice

Approved in 2002, teriparatide requires subcutaneous dosing of 20 mcg daily for up to 2 years, “which can be inconvenient,” said Dr. Tice, professor of medicine in the division of general internal medicine at the University of California, San Diego. Studies have demonstrated increased bone density in the spine by 10% and the hip by 3%, compared with placebo, over 18 months. In women with pre-existing vertebral fractures, the agent was found to reduce the incidence of vertebral fractures by 65% and nonvertebral fragility fractures by 53%. Adverse reactions include arthralgia, pain, and nausea.

Abaloparatide, a parathyroid hormone-related protein analog approved in April 2017, requires subcutaneous dosing of 80 mcg daily for up to 2 years and has been found to increase bone density in the spine by 11% and in the hip by 4%, compared with placebo, over 18 months. In women with pre-existing vertebral fractures, the agent was found to reduce the incidence of vertebral fractures by 86% and nonvertebral fragility fractures by 43%, but data are not adequate to evaluate its effect on hip fractures. Adverse reactions include hypercalciuria, nausea, hypercalcemia, orthostatic hypotension, tachycardia, and injection site reactions.

Studies to date have shown that combining either teriparatide or abaloparatide with an antiresorptive drug is less effective than either agent alone. However, both agents must be followed by an antiresorptive agent. “These drugs are expensive,” Dr. Tice said. “Right now, they’re reserved for patients with severe osteoporosis.”

The lifetime risk for osteoporotic fractures is 50% in women and 20% in men, and they cause significant morbidity and mortality. Among U.S. hospitalizations for women 55 years and older between 2000 and 2012, Dr. Tice noted, 4.9 million were for osteoporotic fractures, 3 million were for stroke, and 2.9 million were for myocardial infarction.

“Osteoporosis is a very common condition, but it’s under-recognized, in part because it’s a silent disease,” he said. “Only 20%-30% of patients with bone mineral densities less than –2.5 are treated in this country. And, 12 months after hip fracture, only 2% had a dual-energy x-ray absorptiometry [DXA] test, and only 15% were treated with an appropriate drug. We should be asking about fracture history, note vertebral fractures, treat those patients, and we should remember to use chart reminders for DXA.”

Clinical guidelines from the American College of Physicians and other groups recommend alendronate, risedronate, zoledronic acid, or denosumab as first-line therapy for women with osteoporosis. “There are no head to head trials to indicate which agent is best,” Dr. Tice said. “They reduce the fracture risk by 30%-50%, primarily in patients with an existing vertebral fracture or a T score below –2.5.” The use of hormone therapy and raloxifene are generally not recommended.

In a review published in the New England Journal of Medicine, researchers Dennis M. Black, MD, and Clifford J. Rosen, MD, estimated the number of patients needed to treat for 3 years to prevent various fractures (N Engl J Med. 2016 Jan 21;374[3]:254-62). They found that, for nonvertebral fractures, including hip, 35 patients need to be treated for 3 years to prevent one of those fractures, 90 patients for 3 years to prevent one hip fracture, and 14 patients for 3 years to prevent one vertebral fracture.

In the FIT trial, 20% of women taking alendronate lost BMD during the first year (JAMA. 1998 Dec 23-30;280[24]:2077-82). However, those same patients had a 50% fracture reduction, and 92% regained the lost bone mineral density (BMD) by the next measurement. “Using DXA to measure BMD after 1 year of therapy does not accurately predict what will happen over time or reflect fracture reduction,” Dr. Tice said. “Effective treatment for osteoporosis should not be changed because of loss of BMD during the first year of use.”

A rare but potential harm from treatment with bisphosphonates includes osteonecrosis of the jaw, which is believed to affect only 1 in 10,000 patients who are treated for 10 years. Most of these cases (94%) were caused by IV bisphosphonates. Only 4% of cases were being treated for osteoporosis, and 60% were caused by tooth extraction. Because of this, a dental exam is recommended before starting patients on bisphosphonate therapy, but this small risk of osteonecrosis of the jaw “is not a reason to stop bisphosphonate therapy,” Dr. Tice said.

Other concerns include an increased risk for atrial fibrillation that has been observed in randomized, controlled trials of zoledronate and alendronate. “There has been no association in other trials,” Dr. Tice said. “This is likely a chance finding, likely spurious.”

Reports of an increased risk of esophageal cancer from bisphosphonate use have also been suggested, but these come from case series and from two conflicting cohorts of data. “This is most likely not a real finding but is a concern because of clinical reports of esophagitis associated with oral bisphosphonates,” he said.

Another concern from long-term bisphosphonate use is the development of atypical femoral fractures, a subtrochanteric fracture with atypical features. “These are transverse fractures of the femur and are likely a real effect of bisphosphonates,” Dr. Tice said. “They are characterized by transverse fractures, cortical thickening, and the 10-year risk is about 1:200. It’s similar to a stress fracture, and it’s often preceded by pain.”

To bring perspective on the risk of developing an atypical femoral fracture, Dr. Tice offered a comparison. If 1,000 women are treated for 3 years with zoledronic acid, it will prevent 71 vertebral fractures, 11 hip fractures, and 18 other fractures. “So, the best estimate is that you would cause 0.1 atypical femoral fractures,” he said. “That really means that, for every one atypical femoral fracture caused, you’ve prevented 110 hip fractures. So, yes, there’s a risk of harm – but there is so much more benefit.”

Dr. Tice reported having no relevant financial disclosures.

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