By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD
The FDA has approved teriparatide (rhPTH[1-34]) for the treatment of osteoporosis in men and women. The drug is a 34-amino-acid polypeptide that represents the biologically active portion of human parathyroid hormone. Teriparatide is produced by a recombinant DNA technique using Escherichia coli bacteria. The once-a-day injection will be marketed by Lilly under the trade name "Forteo."
Indications
Teriparatide is indicated for the treatment of postmenopausal women with osteoporosis at high risk of fracture. It is also indicated for the treatment of men with primary or hypogonadal osteoporosis at high risk of fracture.1
Dosage
The recommended dose is 20 mg daily given by subcutaneous injection into the thigh or abdominal wall. Patients and caregivers should be appropriately trained to administer the drug by a qualified health professional.1
Teriparatide is supplied as a 3-mL prefilled pen delivery device. The device delivers 20 mg per dose for 28 days. The device should be stored under refrigeration but not frozen.
Any unused solution should be discarded after 28 days.1
Potential Advantages
Teriparatide is a potent agent for bone formation (trabecular and cortical) by stimulating osteoblastic activity.1 This differs from other drugs that modify bone resorption by affecting osteoclast activity. In postmenopausal women, 20 mg daily increased bone mineral density (BMD) of the spine by 10% and femoral neck by 3%, reduced the risk of new vertebral fractures by 65% (5% vs 14.3%) and risk of nonvertebral fractures by 35% (6.3% vs 9.7%) at a median follow-up of 21 months.2 Increases in BMD are greater than that achieved with alendronate. In a comparative study, teriparatide, 40 mg daily, increased BMD of the lumbar spine by 12.5% at 3 months compared to 5.6% for alendronate 10 mg daily.3 The FDA-approved dose of 20 mg was not compared in this study but increase in BMD is estimated to be 9-10% based on a comparison of the 2 doses, 13.7% and 9.7% for 40 mg and 20 mg respectively.2
Potential Disadvantages
Teriparatide requires daily subcutaneous injection and must be stored under refrigeration. It has been shown to increase the incidence of osteosarcoma in rats in a dose- and duration-related manner. Teriparatide is therefore not recommended for patients at risk for osteosarcoma. These include patients with Paget’s disease, unexplained elevation of alkaline phosphatase, open epiphyses, or those who have had prior radiation of the skeleton.1 Patients with metabolic bone disease or with active or a history of skeletal malignancies also should not be treated with teriparatide. Pain and induration at the injection have been reported and appears to be related to the vehicle, not teriparatide.6 Side effects related to teriparatide included nausea (8.5% vs 6.7% for placebo), dizziness (8% vs 5.4%), and leg cramps (2.6% vs 1.3%). Mild hypercalcemia (>10.6 mg/dL on at least 1 occasion) has been reported in 11% of women on 20 mg/day compared to 2% in the placebo group.2 Transient symptomatic orthostatic hypotension (beginning within 4 hours of administration) and elevation of serum uric acid have also been reported. In clinical studies, 7.1% of patients discontinued therapy due to side effects compared to 5.6% for placebo. The use of teriparatide for longer than 2 years is not recommended.1
Comments
Teriparatide is an N-amino-terminal fragment of the human parathyroid hormone produced by recombinant DNA technology. Clinical studies involving 1085 subjects randomized to placebo or 20 mg showed that teriparatide increased BMD and reduced vertebral and non-vertebral fractures in postmenopausal women.1,2 It has also been shown to be effective in increasing BMD in men with osteoporosis (n = 437).4 After a median of 11 months on 20 mg daily, spine BMD increased by 5.9% above baseline, femoral neck by 1.5%, and whole-body mineral content by 0.6%. The effect of the drug on fracture risk in men has not been evaluated. Teriparatide does not increase BMD in the radius and actually decreased bone density at the one-third distal radius compared to alendronate.3 In these trials, patients received 1000 mg of calcium and at least 400 IU of vitamin D per day. The effect of teriparatide does not appear to be affected by baseline BMD, age, gonadal status (men), or disease severity.4,5 Teriparatide is generally well tolerated. Osteosarcoma has been reported in female rats, which prompted the early termination of the above trial. To date, no increase in risk of osteosarcoma in humans has been reported.
The wholesale cost of teriparatide is about $17 per day ($6200/yr).
Clinical Implications
Teriparatide is a potent agent effective in increasing BMD and reducing the risk of vertebral and nonvertebral fractures. This new drug may be suited for postmenopausal women or men with severe osteoporosis. Candidates may include those with a history of osteoporotic fracture, with multiple risk factors for fracture, or who have failed or are intolerant of other therapy.1 Bisphosphonates, namely alendronate or risedronate, are currently regarded as first-line agents in preventing or treating osteoporosis.6
References
1. Forteo Product Information. Eli Lilly and Company. November 2002.
2. Neer RM, et al. N Engl J Med. 2001;344:1434-1441.
3. Body JJ, et al. J Clin Endocrinol Metab. 2002;87: 4528-4535.
4. Orwoll ES, et al. J Bone Miner Res. 2003;18(1):9-17.
5. Marcus R, et al. J Bone Miner Res. 2003;18(1):18-23.
6. Brown JP, et al. CMAJ. 2002;167(10 suppl):S1-S34.
Dr. Elliott is Chair of the Formulary Committee, Northern California Kaiser Permanente and Assistant Clinical Professor of Medicine at the University of California-San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager at Kaiser Permanente in Oakland, CA.
The FDA has approved teriparatide (rhPTH[1-34]) for the treatment of osteoporosis in men and women.
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