Teriparatide: A New Agent for Treating Osteoporosis

Special Report


Richard S. Bockman, MD, PhD

Attending Physician, Hospital for Special Surgery
Associate Senior Scientist, Hospital for Special Surgery

  1. Background
  2. Key Evidence
  3. Clinical Use/Commentary

 

Background

Teriparatide (pronounced teh-rih-PAH-ruh-teyed), a synthetic human parathyroid hormone (PTH 1-34), was recently approved by the 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 U.S. FDA-approved bone anabolic agent - one 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.

The parathyroid glands were first described in the medical literature in 1880 by Sandstrom. Collup worked with Eli Lilly and Co. to purify and prepare a stable preparation of the PTH hormone and demonstrated that use of the hormone could restore serum calcium level in animals whose parathyroid glands had been removed. The same benefit was demonstrated in humans by Albright. Unfortunately, continuous high dosing with PTH also was shown to increase osteoclast number and activity, leading to bone loss.

Dr. C. Tam was the first to demonstrate that intermittent low dosing with PTH leads to increased bone formation and trabecular volume by recruitment of new osteoblasts having increased life span and activity[1]. This paradox in the way PTH acts in continuous high doses vs. intermittent low doses is based on the rapid release of bone-building growth factors from osteoblasts vs. proliferation and activation of osteoclasts due to prolonged PTH stimulation. Thus, as with so many things in life, timing is everything.

Key Evidence

The key evidence on which the FDA approval was based was a double-blind, controlled trial of teriparatide involving 1637 postmenopausal women with prior vertebral fractures[2]. They were randomly assigned to receive 20 or 40 mcg. of PTH or placebo, self-injected subcutaneously daily. They were monitored with vertebral X-rays and DEXA. 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; therefore, 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 conclusions: "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. The 40-mcg dose increased bone mineral density more than the 20-mcg dose but had similar effects on the risk of fracture and was more likely to have side effects"[2].

Preclinical studies showed the development of osteosarcoma 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. Rat bones grow through their entire lifetime (in contrast to human closure of the epiphyses early in life), and the cancers developed at the ends of their bones where active linear growth was occurring.

Clinical Use/Commentary

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.

The current formulation requires daily self-injection; only those who are highly motivated, i.e. those with advanced osteoporosis, will likely be willing to use it and maintain compliance. Alternate routes of administration are being investigated.

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

As with estrogen, a decline in the BMD gain achieved begins shortly after the drug is discontinued. Thus, after teriparatide therapy, it would be wise to prescribe an agent, such as a bisphosphonate, to maintain the gain in BMD achieved. An argument can be made that the two agents should be taken together, and ongoing studies are looking at such a combination.

Whether repeat courses of therapy will be needed remains unknown and is not foreseen at the present time. The theory is that this "turboblast" of increased BMD will get patients beyond their acute osteoporotic problem, enabling subsequent maintenance with oral medications.

Both hypercalcemia and hypercalcuria are contraindications to teriparatide, and checks should be made before initiating therapy. The development of hypercalcemia during PTH treatment occurs in about 3 to 10% of patients on the drug and is most likely to occur early. Thus, a check should be made a week after initiating PTH; if hypercalcemia has occurred, it may resolve by itself - and a re-check should be performed after three to seven days. If hypercalcemia or hypercalciuria persists beyond seven days, discontinuation is advised. Reducing or stopping calcium and vitamin D supplements along with the PTH usually restores normal blood and urine calcium levels. In the trial discussed above, 0.7 % of the placebo group showed some elevation of uric acid vs. 2.8% in the treatment group, but no one developed a uric acid stone.

Physicians should also be aware of concomitant drug use. Because thiazide diuretics promote calcium retention, consider switching patients to a different diuretic class or monitor their serum calcium more closely. Vitamin D supplements, by increasing calcium absorption, and calcium itself also may be problematic. If the patient develops elevated serum calcium levels, supplementation should be reduced or eliminated. All patients in the trial discussed above received calcium and vitamin D supplements, and the majority had no problems. Attenuated doses of calcium, vitamin D and PTH can be tried to avoid hypercalcemia and/or hypercalciuria in the sensitive patient.


[1] Tam CS, Heersche JN, Murray TM, Parsons JA. Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: differential effects of intermittent and continuous administration. Endocrinology. 1982 Feb;110(2):506-12.

[2] Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001 May 10;344(19):1434-41.

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