Teriparatide: A New Drug for Osteoporosis

Teriparatide (pronounced teh-rih-PAH-ruh-teyed) is a synthetic version of human parathyroid hormone. It was recently approved by the U.S. FDA for the treatment of osteoporosis and will soon be commercially available from Eli Lilly and Company under the brand name Fortéo. Teriparatide is a breakthrough in osteoporosis therapy because it is the first drug that builds bone rather than just slowing bone loss. The Hospital for Special Surgery has participated in key clinical trials of the drug and I have been a consultant to Lilly in that context. So we have a good sense of its usefulness and patient responses.

Osteoporosis Background

While bone seems rock hard, it is a living tissue, constantly renewing itself. Osteoclasts are the cells involved in bone breakdown; osteoblasts are those involved in building new bone. If the balance of breakdown/buildup gets thrown off, bones can become thin and fragile. Our bone health can be assessed by a non-invasive methodology that measures bone mineral density.

We build bone throughout childhood. Bone mass peaks in our 20s, then slowly declines. After age 50, thin bones may present serious problems, particularly in women after menopause, because estrogen plays a pivotal role in maintaining bone density. Osteopenia is moderate low bone density, a warning sign. Osteoporosis is severe low bone density and puts you at significant risk for bone fractures, especially of the back and hip.

Understanding Parathyroid Hormone

Bone density is intimately involved with the parathyroid glands, which are located behind the thyroid gland in the throat. The glands secrete parathyroid hormone (abbreviated as PTH), a key hormone that regulates calcium metabolism - and calcium is critical to bone mineral density.

However, the timing of how your body receives PTH is critical. People with excessive production of PTH have increased numbers of osteoclasts - the cells involved in bone breakdown - leading to bone loss. In the early 1980s, a researcher discovered that giving intermittent, low doses of PTH recruits new osteoblasts - the bone-forming cells -leading to increased bone formation.[1] This discovery paved the way for developing PTH as a treatment for osteoporosis.

Thus, teriparatide is given by injection once a day - in the same way that people with diabetes give themselves an insulin injection. Teriparatide is active in the blood for a very short period of time, thus yielding the very brief exposure to the bone cells that promote bone density.

Research Evidence

The key research on which the FDA approval of teriparatide was based was a double-blind, controlled trial of teriparatide involving 1,637 postmenopausal women with prior vertebral fractures - bone breaks in their backs.[2] The women were randomly assigned to receive 20 or 40 mcg. of PTH or placebo (a dummy injection), self-injected daily. They were monitored with vertebral X-rays and DEXA - the best way to monitor bone density. Side effects were minor - nausea (9%), headache (8%), and leg cramps (3%).

The higher dose of teriparatide increased vertebral BMD by 14%, and the lower (now FDA-approved) dose yielded an average 10% increase in the lumbar spine BMD, as well as an increase in hip BMD of 2.8%

The risk of new vertebral fractures was reduced by 65% in the group that got the approved dose of 20 mcg. Such fractures occurred in 14% of the women on placebo group and in 5% and 4%, respectively, of those on 20 and 40 mcg of PTH.

There were only four hip fractures in placebo group vs. one in the approved dose group; so no definitive statement could be made with regard to hip fracture reduction. However, the impact of PTH on total non-vertebral fractures - including hip, wrist, rib, foot, ankle, arm, pelvis, etc. - yielded a statistically significant relative risk reduction of 53%.

The study concluded that "Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated." [2]

One concern of researchers has been early experiments that showed the development of osteosarcoma (a rare bone cancer) in rats, but this is not believed to be relevant in humans. Doses three to sixty times those given to humans were given to the rats over the course of their lifetime. Further, rat bones grow in length through their entire lifetime; however, in humans, our bone ends close relatively early in life. The rat cancers developed at the ends of their bones, precisely where bone stops growing in late adolescence in humans. That's why the researchers do not believe that a two-year period of PTH treatment in older adults is likely to cause bone cancer.

How PTH Will Be Used

Forteo is indicated for the treatment of postmenopausal women with osteoporosis who are at high risk for fracture. These include women with a history of prior fragility fractures. The relevance of osteosarcoma development in rats treated with Forteo is unknown but requires that the prescribing physician carefully weigh the potential benefits and risks in an individual patient. Specifically, the following categories of patients thought to be possibly at increased risk for osteosarcoma should not be treated with Forteo: patients with Paget's Disease of bone, pediatric patients, patients with a history of skeletal irradiation, and patients with bone metastases or prior history of bone cancers. The current FDA-drug insert indicates that the effects of Forteo on fracture risk in men have not been studied.

Because it requires daily self-injection, only those who are highly motivated, i.e. those with advanced osteoporosis, will likely be willing to use it.

The safety and efficacy of Forteo have not been evaluated beyond two years of therapy, consequently, treatment beyond two years is not recommended.

Thus, after the two years of teriparatide therapy, physicians will likely prescribe one of the drugs already shown to slow bone loss and help maintain the increased BMD gained from PTH treatment. This may well be a bisphosphonate, such as alendronate or risedronate. Researchers are now studying whether extra benefits will occur if PTH is taken together with a bisphosphonate.

Whether repeat courses of therapy will be needed remains unknown. The theory is that this "turboblast" of increased BMD will get patients beyond their acute osteoporotic problem, enabling subsequent maintenance with oral medications, such as the bisphosphonates

Contraindications

Some people should not take teriparatide. These include people who have too much calcium in their blood (hypercalcemia) or in their urine (hypercalcuria). Your doctor should check to make sure you don't have these problems before initiating PTH therapy.

Sometimes hypercalcemia develops during PTH treatment - in about 3 to 10% of patients on the drug. Because it is most likely to occur early in therapy, your doctor may do a blood test about a week after initiating PTH. If hypercalcemia has occurred, it may resolve by itself - so your blood may need to be re-checked at intervals to make sure. If it does not resolve and reaches problematic levels, PTH will be discontinued.

Drug Interactions

Because thiazide diuretics - one type of "water pill" - promotes calcium retention in the body, your doctor may switch you to a different diuretic class or monitor your calcium blood levels more closely if you take PTH.

Vitamin D supplements increase calcium absorption, and calcium is a key bone building block. That's why they are recommended to people who have osteopenia or osteoporosis. But when taken with PTH, they might lead to excessively high calcium levels. If you develop hypercalcemia during PTH therapy, your doctor will recommend that Vitamin D supplements be reduced or eliminated. By the way, all patients in the key research trial discussed above received calcium and vitamin D supplements, and the majority had no problems.

What Should You Do?

If you are over 50, discuss osteoporosis with your doctor and get your bone density checked. If you have low bone density, follow your doctor's treatment recommendations. If your osteoporosis is severe - especially if you have had fractures, your doctor may decide to consider treatment with teriparatide. If it is prescribed, it's worth using - even though it means daily injections. It's an exciting new treatment for osteoporosis - the first US-FDA-approved drug to actually build bone.