Parathyroid hormone (PTH) is an 84 amino acid polypeptide hormone secreted by the parathyroid glands located behind the thyroid gland. It is an important agent of control of blood calcium levels, and remodelling of bone. PTH increases blood calcium levels by its effect on bone, the intestine, and the kidneys. Teriparatide is a recombinant human form of PTH and is made up of 1 to 34 of the amino acid sequence of the N-terminal end of PTH. It is abbreviated to rhPTH(1-34). In Europe, it is marketed under the brand name Forsteo (Eli Lilly). It is administered as a 20mcg daily dose given by subcutaneous injection, into the thigh or abdomen.
Increased levels of PTH in conditions, such as in hyperparathyroidism, can cause a reduction in BMD and an increase in risk of fragility fracture. However intermittent controlled low levels of added PTH have an anabolic effect on bone.73, 74 This is
believed to be related to the mechanism of action of PTH on osteoblasts. PTH does not exert a direct action on osteoclasts, but exerts its resorptive action on bone through the RANKL-OPG pathway mediated by osteoblasts. PTH has a short half-life of only 4 minutes, and shortly after its release, there is an increase in osteoblast formation and inhibition of osteoblast apoptosis.75 With continuous release of PTH,
the osteoblasts commence recruitment and maturation of osteoclast precursors, resulting in an increase in the population of osteoclasts leading to bone resorption. When intermittent low levels, rather than continuous levels of PTH are administered, it results in an increase in osteoblasts rather than osteoclasts, which in turn results in an overall net increase of bone formation, and an increase in hydroxyapatite crystal heterogeneity.27, 74
Its development is of particular importance as it is the first anabolic bone agent shown to stimulate bone formation. The Food and Drug Administration (FDA) in the US approved Teriparatide for treatment of osteoporosis in 2002. It is licensed for no more than 2 years use, as animal studies have shown an increased incidence of
osteosarcoma related to long-term use.76-78 It is contraindicated in patients with a
history of osteosarcoma or metastatic bone disease. In the US, there have been two reported cases of osteosarcoma occurring in patients on Teriparatide, however over 430,000 people have been safely treated.78 Additional contraindications to the use of
teriparatide include hypercalcaemia and hyperparathyroidism.
Teriparatide has been shown in multiple studies to be an effective treatment for low BMD. Neer et al in 2001 in a randomised placebo control trial of 1,637 participants with a history of vertebral fracture investigated the effect of teriparatide on BMD and fracture risk reduction. The cohort was divided into 3 groups based on treatment: placebo (n=544), 20µg teriparatide (n=541) and 40µg (n=552) daily. They reported that compared to placebo there was an improvement in bone mineral density (BMD) in the lumbar spine of 13.7% in the 40µg group, and 9.7% in the 20µg group over a 21 month period. The improvement in BMD in the total hip was 3.6% and 2.6% in the 40mcg, and 20mcg groups, respectively. Teriparatide also reduced the risk of new vertebral fractures compared to a placebo by 65% and 69% in the 20µg and 40µg groups, respectively. A weakness of this study was that it was cut short following the publication of the reports of increased incidence of osteosarcoma in animal studies.76, 79
Chen et al in 2006 also reported good results with teriparatide use in a study of 1637 postmenopausal women. Subjects were observed over an 18-month period, and the authors found that teriparatide mediated increases in spine BMD accounted for between 30% to 41% reduction in new vertebral fracture risk.82
The EUROFORS (European Study of Forsteo) study was a 2-year, prospective, randomised study, conducted in 95 centres throughout 10 European countries. The study had two research aims. The first was to investigate three different treatment regimens after 1 year of Teriparatide, and the second was to investigate the effect of prior antiresorptive treatment.80, 81
The three different treatments investigated were a further year of Teriparatide, a year of Raloxifene (a selective oestrogen receptor modulator) therapy, and a year of no active treatment. In the group receiving 2 years of continuous Teriparatide therapy (n=305) a mean improvement from baseline in spine BMD of 10.7% and hip BMD of 2.5% was observed. In the Raloxifene group (n=100) there was an increase of 7.9% in spine BMD in the first year and no change in the second year. In the no active treatment group (n=102) there was an increase of 6.3% in the first year, and a decrease of 2.5% in the second year.81
In the second arm of the study, 503 patients in the 2 year Teriparatide course were divided into three groups: treatment naïve (n=84), pre-treated with anti-resorptive (AR) medication (n=134), and pre-treated and showing no response to AR medication (n=285). The mean BMD gain in the spine and hip was greatest in the treatment naïve group at 13.1% and 3.8%, respectively. In the pre-treated AR group the mean gain in spine BMD was 10.2%, and 9.8% in the pre-treated “non- responder” group. Hip BMD gain for both of these groups was 2.3%.80