DO NOT USE! Teriparatide (FORTEO) — A New Drug For Osteoporosis

Teriparatide (FORTEO) was approved by the Food and Drug Administration (FDA) in late November 2002 for the treatment of osteoporosis in postmenopausal women who are at high risk for fracture and to increase bone mass in men with osteoporosis, who are also at high risk for fracture.

Teriparatide is manufactured by Eli Lilly and Company of Indianapolis and is very similar to human parathyroid hormone, the hormone that is the primary regulator of calcium and phosphate metabolism in bone and kidney. Teriparatide is produced by recombinant DNA technology and it has 34 amino acids that are identical in sequence to human parathyroid hormone. The drug is administered by daily subcutaneous (under the skin) injection and is approved for a maximum of two years of use.

In women, the treatment outcome that was used to approve teriparatide was the occurrence of new, x-ray-diagnosed fractures of the vertebrae (the bones that make up the spine) referred to as vertebral fractures. Vertebral fractures are not broken bones in the common use of the phrase; rather they are defined as changes in the height of previously undeformed vertebrae seen on x-ray. Many such fractures are not necessarily symptomatic.

Women who were defined as being at high risk for fracture were those with at least one vertebral fracture before being treated with teriparatide.

Notice that for men teriparatide is not approved to treat osteoporosis, but rather to increase bone mass in men with osteoporosis who are at high risk for fracture. The definition of men at high risk for fracture is the same as for women, at least one vertebral fracture. The drug does increase bone mass in men but there are no data available at this time showing that teriparatide reduces the risk of fracture in men. In our opinion, the FDA should not have approved this drug for use in men without evidence that it reduces fracture risk in men.

Teriparatide was approved with a number of severe conditions and restrictions on its distribution and promotion because it caused osteosarcoma, a type of bone cancer, in laboratory animals. The professional product labeling, or “package insert,” for the drug contains a black box warning about osteosarcoma. A black box warning is the strongest type of warning that the FDA can require on a drug’s labeling. It is extremely unusual to see a new drug marketed with a black box warning. (The text of the black box warning can be found at the end of this article.)

Pharmacists must also distribute FDA-approved information written specifically for patients (known as a Medication Guide) with each new and refill prescription for teriparatide. The FDA can require a Medication Guide for those drugs that present a significant public health problem or when patients need additional information to use a drug safely and effectively. At this time, Medication Guides are required for only a small handful of drugs.

Eli Lilly also committed to the establishment of a post-approval safety surveillance program to evaluate whether there is an association between treatment with teriparatide and the occurrence of osteosarcoma in patients, since it was shown to cause this bone cancer in animals. Data collection for the program will begin within 90 days after the first marketed use of teriparatide. Progress reports will be submitted to the FDA at six months, one year and annually thereafter. The program is to last for ten years. We have serious concerns about this program, as described in the FDA’s approval letter for teriparatide. It remains to be seen whether or not, as the program is planned, it will actually detect a link between the drug and osteosarcoma (if one exists) in a timely manner.

In addition, Eli Lilly agreed to restricted initial marketing of teriparatide by a limited sales force with no direct-to-consumer (DTC) advertising, and restrictions on the distribution of free samples of the drug. Further, the company agreed to conduct a physician education program to emphasize that teriparatide is approved only to treat patients at high risk for osteoporotic fractures.

Because of our concerns about the safety of this drug in relation to its effectiveness, the Health Research Group testified before the FDA’s Endocrinologic Drugs Advisory Committee on July 27, 2001 to urge that the drug not be approved. The full text of this testimony can be found at www.citizen.org/publications/release.cfm?ID=6787.  We testified that the ability of teriparatide to cause cancer — in this case osteosarcoma — in rats was some of the most striking animal carcinogenicity data we had ever seen. Tumors developed in the animals at even the lowest dose level of teriparatide administered, which was 1.6 times the dose intended for humans.

In effectiveness studies, when teriparatide given with calcium and vitamin D was compared with placebo given with calcium and vitamin D, the risk of one or more new vertebral fractures was reduced from 14.3 percent in women given the placebo to five percent in those given teriparatide. Thus, the absolute difference in the risk of a new vertebral fracture with teriparatide compared to placebo was 9.3 percent. The risk of a new vertebral fracture with teriparatide relative to the risk with placebo was 65 percent. This result was statistically significant.

Using the absolute difference in risk of a new vertebral fracture, the number of patients that need to be treated with teriparatide for a period of 19 months — the length of the effectiveness studies — to prevent one new vertebral fracture can be calculated, and is 11 patients.

There is no direct comparison between teriparatide and the very popular and heavily promoted osteoporosis drug alendronate (FOSAMAX); however, a study published in the medical journal The Lancet in 1996 provides some basis for a comparison. In women similar to those in the teriparatide studies, the number that needed to be treated with alendronate to prevent one new vertebral fracture after 36 months of treatment was 14. This information is only given for context; the most valid type of information would be a direct head-to-head comparison of teriparatide to alendronate, which has not been done at this time.

One direct comparison of teriparatide to alendronate is available: cost. A 30-day supply of teriparatide is $515.79 at an online pharmacy, while 30 alendronate 10-milligram tablets, enough for 30 days, are $65.16. This is a difference of over $5,400.00 for one year of treatment.

The table below is taken from the FDA-approved professional product labeling for teriparatide and summarizes the sites of fractures, other than vertebral fractures, in women given teriparatide vs. a placebo. There were 541 women in the teriparatide group and 544 in the placebo group. The number of fractures at a particular site is given, and the percentage of the group represented by that number is reported in parentheses.

There are a number of groups of patients that should not use teriparatide, primarily those with an increased baseline risk of osteosarcoma, including:

• Paget’s disease of the bone.
• Unexplained high levels of alkaline phosphatase in the blood, which may mean the presence of Paget’s disease. If you are not sure, ask your doctor.
• Children or growing young adults.
• Patients who have had radiation therapy involving the bones.

In addition, patients who have ever been diagnosed with bone cancer or other cancers that have spread (metastasized) to the bones, have a bone disease other than osteoporosis, have too much calcium in the blood (hypercalcemia) or are pregnant or nursing should not use teriparatide.

Other common adverse reactions seen with teriparatide in clinical trials include nausea, dizziness, leg cramps and headache. Redness and swelling has also occurred at the injection site. Low blood pressure (orthostatic hypotension) that can lead to fainting has been seen with the first few doses of teriparatide. Elevations of calcium levels in both the blood and urine have also been reported.

What You Should Do

Teriparatide should not be used by men. Clearly, without evidence that teriparatide reduces fracture, the possibility of osteosarcoma outweighs any theoretical benefit of the drug.

Our recommendation for women is the same, but for different reasons. There is evidence of reduced fracture risk in both vertebral and non-vertebral locations; however, the absolute risk of vertebral fracture reductions is not large and many vertebral fractures are asymptomatic. Finally, alendronate appears to offer a comparable level of protection without the concerns of osteosarcoma.