Issue: April 2021
Source: Healio interviews
Disclosures: Cohen and Shane report they have received study drugs from Amgen and Eli Lilly for FDA-supported trials.
March 10, 2021
5 min read
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Rarity complicates research, treatment for unexplained premenopausal osteoporosis

Issue: April 2021
Source: Healio interviews
Disclosures: Cohen and Shane report they have received study drugs from Amgen and Eli Lilly for FDA-supported trials.
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Osteoporosis, long considered a disease of older age, is estimated to affect about 25% of women aged at least 65 years, according to the CDC.

The disease is less common among premenopausal women; however, most reproductive-age women with low bone mineral density or a low-trauma fracture have a secondary cause, such as rheumatoid arthritis or Cushing’s syndrome. Rarer still is idiopathic premenopausal osteoporosis — bone fragility in young, otherwise healthy women with no secondary cause — estimated to affect fewer than 200,000 people in the U.S.

Shane is a professor of medicine and senior associate dean for student research at Columbia University College of Physicians and Surgeons in New York City.

Guidelines for the diagnosis and treatment of osteoporosis are based on bone mass for postmenopausal women, complicating screening for the condition in younger women, according to experts. Debate also continues about who should receive treatment and which therapies are optimal.

“Osteoporosis is more difficult to diagnose in premenopausal women because the use of DXA, which is one important way we diagnose it in postmenopausal women, is less accepted and less reliable for assessing short-term risk for fracture than it is for postmenopausal women,” Elizabeth Shane, MD, professor of medicine and senior associate dean for student research at Columbia University College of Physicians and Surgeons in New York City, told Healio. “Because we do not routinely use DXA in premenopausal women, [osteoporosis] is often diagnosed after a young woman has an unexplained fragility or low-trauma fracture after a fall or with an otherwise normal activity, like lifting a baby, where you would not expect a young woman to fracture.”

That diagnosis is often a judgment call by the treating clinician, Shane said — and even physicians debate how much trauma is reasonable for an osteoporosis label for a premenopausal woman.

“Young people can break bones,” Shane said. “It is difficult to discriminate between someone who really has a problem — bones that are not as strong as they should be for their age — and someone who experienced an overwhelming amount of trauma and their bone broke. It is harder and more controversial to make that diagnosis in a young woman vs. an older woman.”

Premenopausal fractures may be an important indicator of underlying poor bone quality and fracture risk in older age. Data from the Study of Osteoporotic Fractures demonstrate that women with a history of premenopausal fracture are 35% more likely to fracture during the postmenopausal years compared with women without a history of premenopausal fracture, according to a 2017 review published in Endocrinology & Metabolism Clinics of North America.

Adi Cohen

“People are more willing to call a low BMD for these women, in the context of other diseases, osteoporosis,” Adi Cohen, MD, MHS, associate professor of medicine and director of the Early-Onset Osteoporosis Center at Columbia University Irving Medical Center, told Healio. “When a woman without other conditions has low BMD, people are less willing to call it osteoporosis because we are not sure what the BMD means in terms of fracture risk prediction. However, our research suggests that low BMD in these women is meaningful and suggests deficits in  underlying bone structure.”

Treatment timing, type

There are currently no FDA-approved therapies for idiopathic premenopausal osteoporosis, and how to treat, when to treat, or whether to treat at all are all areas of continuing debate.

“It depends on the severity of their presentation,” Cohen said. “Certainly, women with vertebral fractures, hip fractures and recurrent fractures, and even those with low or declining bone density may be candidates for treatment.”

Not every young woman with osteoporosis should receive drug therapy, Shane said.

“We are not necessarily saying you need to intervene [with young women], aside from making an effort to have a calcium-rich diet, make sure the vitamin D level is sufficient and exercise,” Shane said. “With osteoporosis drugs, there are concerns.”

Among postmenopausal women, few patients receive appropriate treatment for osteoporosis, even after a fracture. The crisis in the treatment of osteoporosis is related to several factors, including fears and beliefs patients and physicians have about adverse effects of treatments.

“It is not an easy decision to embark on treatment for a premenopausal woman with osteoporosis,” Shane said. “But if you decide to initiate treatment, it is not as straightforward as just putting someone on alendronate for 5 years and then giving them a drug holiday or putting someone on Prolia. It is an evolution of therapies, a therapeutic plan that doesn’t just involve a one-off.”

Trials to assess the best type of therapy, and who should receive it, are challenging to conduct, Cohen said. Due to the rarity of the disease, small studies are the norm; trials will never be adequately powered to assess fracture endpoints with an osteoporosis therapy, Cohen said.

“For all of our studies on unexplained osteoporosis in premenopausal women, we recruit from all over the country and internationally,” Cohen said. “That is certainly harder during COVID-19, but it continues, still.”

In a phase 2 study published in February in The Journal of Clinical Endocrinology & Metabolism, Cohen and colleagues analyzed data from 41 premenopausal women with idiopathic osteoporosis assigned teriparatide (Forteo, Eli Lilly; n = 28) or placebo (n = 13) for 6 months. At 6 months, those assigned placebo switched to teriparatide therapy for 24 months; those initially assigned teriparatide continued for 18 months. Researchers evaluated between-group differences in areal BMD via DXA, bone turnover markers and bone formation rate.

At 6 months, areal BMD increased at the lumbar spine by 5.5% in the teriparatide group and by 1.5% in the placebo group (P = .007). At 24 months, teriparatide increased lumbar spine areal BMD by 13.2%, total hip BMD by 5.2% and femoral neck BMD by 5% (P < .001 for all).

More to learn

The researchers noted that, among 15 premenopausal women evaluated 2 years after completing teriparatide, they observed significant losses (4.8%) in lumber spine areal BMD, although declines at the total hip and femoral neck were small and not significant.

Those with significant bone loss were older (mean age, 46 years vs. 38 years) and had larger increases in areal BMD with teriparatide therapy.

“It was surprising that, even in the setting of estrogen sufficiency, there is some bone loss after cessation of teriparatide,” Cohen said.

The data raise questions about how protective estrogen levels are in premenopausal women, Cohen said.

Cohen and colleagues are completing a study that will assess using denosumab (Prolia, Amgen) after teriparatide, with the hope that the RANKL inhibitor could provide an even better continued response in the sequential treatment setting, Cohen said.

“Then, because denosumab cannot be stopped without another medication after that, we are studying bisphosphonate use to get people safely off denosumab in premenopausal osteoporosis situations,” Cohen said.

Shane said research shows typical BMD improvements of 20% to 30% at the lumbar spine during 2 years of teriparatide followed by 1 to 2 years of denosumab therapy — more than would be expected with antiresorptive therapy alone. Still, proving cost-effectiveness in terms of fracture prevention will always remain elusive with a cohort of younger women, she said.

“I don’t think we are ever going to know if it is effective or cost-effective in terms of fracture prevention because there are just too few of these women with this condition to conduct a fracture study,” Shane said. “In my view, the best sequence is anabolic therapy and then denosumab therapy. If you transition from an anabolic to a bisphosphonate, you do not see much more improvement in bone density. Here, we find an additional 5% improvement the first year after denosumab. You go from a very low place to, often, a ‘normal’ place. And then you have to figure out, how do you retain that? This is a process.”

References:

Cohen A. Endocrinol Metab Clin North Am. 2017;doi:10.1016/j.ecl.2016.09.007.

Cohen A, et al. J Clin Endocrinol Metab. 2020;doi:10.1210/clinem/dgaa489.

For more information:

Adi Cohen, MD, MHS, can be reached at ac1044@cumc.columbia.edu.

Elizabeth Shane, MD, can be reached at es54@cumc.columbia.edu.