High-Dose Drug Combo Excels in Osteoporosis, but Cost a Barrier

The combination of two osteoporosis drugs — the potent antiresorptive drug denosumab (Prolia, Amgen) and a high dose of the bone-growth stimulating teriparatide (Forteo, Lilly) — substantially improves bone mineral density (BMD) at levels exceeding those seen with any other treatment, offering potentially effective treatment for those with osteoporosis at high risk of fragility fractures, say the authors of a new study.

"The combination of denosumab and high-dose teriparatide results in large increases in areal BMD and volumetric BMD of the hip and spine resulting in increases in estimated bone strength, which has not been achieved with any previously evaluated monotherapy or combination therapy approaches," they stress in their article, published online August 22 in the Lancet Diabetes & Endocrinology.

"Considering that skeletal integrity cannot be fully restored in most patients with established osteoporosis at present, this 40-µg regimen [of teriparatide] is likely to provide benefits for women at the highest risk of fragility fracture," write Joy N. Tsai, MD, Endocrine Unit, Massachusetts General Hospital, Boston, and colleagues, detailing results of the DATA-HD trial.

According to an accompanying editorial, the new study supports recent Endocrine Society guidelines that advise grading people according to their risk of fracture to determine the most appropriate therapy.

"[These results] indicate the possibility of refining treatment for patients with osteoporosis at high risk of fracture and personalizing treatment for these patients beyond the one-size-fits-all approach currently used (ie, predominantly prescribing bisphosphonates)," writes Sundeep Khosla, MD, Mayo Clinic College of Medicine, in Rochester, Minnesota.

Cost Currently Prohibitive but Generic Teriparatide on Horizon

A key caveat for the combination therapy, however, is cost.

Based on current pricing estimates, a 15-month regimen with the higher dose of teriparatide could run to approximately $76,000, and, according to Khosla, "the experience of most clinicians in the United States is that gaining insurance company approval for combination therapy for osteoporosis is virtually impossible."

However, the US patent for teriparatide expires in August 2019, opening the door for potential generic preparations that could make the combination regimen more affordable for patients.

Tsai told Medscape Medical News: "We agree that insurance issues may limit the use of this regimen and are hopeful that an affordable generic teriparatide formulation will be available."

DATA-HD Examines Higher Dose of Teriparatide

Tsai and colleagues explain by way of background that, in contrast with many other chronic, age-related diseases, osteoporosis remains a disease primarily treated with monotherapy.

And although the number of osteoporosis therapies has expanded substantially over the past two decades, currently available antiresorptive and anabolic medications typically achieve only modest increases in BMD or reductions in nonvertebral fracture rates.

In a previous trial published in 2013, the Denosumab and Teriparatide Administration (DATA) study, the same authors looked at the same combination and found denosumab was able to fully inhibit the effects of bone resorption induced by teriparatide while allowing for bone formation by teriparatide, boosting the effects on hip and spine BMD compared with either drug alone.

For the DATA-HD trial, they sought to determine the effects of a higher dose of teriparatide (40 µg versus 20 µg, the standard FDA-approved dose used in DATA).

The new study included 76 postmenopausal women with osteoporosis randomized between October 2014 and June 2016 to the 20-µg (n = 39) or 40-µg (n = 37) teriparatide injection dose daily for 9 months.

And at 3 months, both groups started denosumab 60 mg by subcutaneous injection every 6 months for 12 months.

At 15 months, among 69 participants who completed at least one post-baseline visit, those in the 40-µg teriparatide group showed significantly greater increases in mean areal BMD compared with the 20-µg group (17.5% vs 9.5%; P < .0001).

Greater increases were also observed in the 40-µg group in mean femoral neck areal BMD (6.8% vs 4.3%; P = .04) and total hip areal BMD (6.1% vs 3.9%, respectively; P < .0001).

Benefits Outweigh Risks in Those at Very High Risk of Fracture

The most common adverse events were joint pain, occurring in 38% of patients in the 20-µg teriparatide group and 46% in the 40-µg group, and fatigue, reported in 31% and 38%, respectively.

Nausea was reported in 43% of patients in the 40-µg group versus 21% in the 20-µg group. No deaths were reported.

"Reassuringly, the most common symptoms seen in our trial are similar to the ones seen in a larger phase 3 trial (assessing 20- and 40-µg doses of teriparatide)," first author Tsai told Medscape Medical News.

And any concerns about the potential side effects of higher doses do appear to be outweighed by the benefits to those with a high fracture risk, Khosla told Medscape Medical News.

"Although common, the nausea and joint pain [with the high-dose teriparatide combination] tend to be mild and physicians generally have the patient take the injections at night so they do not interfere with normal activities."

"So yes, for the patient at very high risk of fracture, the benefits likely do outweigh the risks," Khosla noted.

He added that another critical issue to consider with the high-dose combination therapy is the need to treat patients with sustained anti-resorptive therapy following combination treatment to prevent the loss of BMD increases that were gained.

"Those data are pending, but denosumab is such a potent inhibitor of bone resorption that, biologically, the expectation is that it would prevent bone loss upon completion of combination treatment," he said.

The study was supported by the Dart Family Foundation, National Institutes of Health, and National Institute of Arthritis and Musculoskeletal and Skin Diseases. Tsai and Khosla have reported no relevant financial relationships. Disclosures for the other authors are listed in the article.

Lancet Diabetes Endocrinol. Published online August 22, 2019. Abstract, Editorial

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