Teriparatide(Synthetic peptide)

Osteoporotic fractures, especially in elderly people, represent a health concern as they are associated with increased morbidity and mortality together with an increased economic burden for the society. During the past 20 years a great effort has been done in order to reduce the risk of fracture and many drugs are now available for this purpose, but osteoporosis is still regarded as an inevitable consequences of the aging process. Osteoporotic fractures occur most frequently in the spine and hip and with lower frequency in the wrist, pelvis, and upper arm. They are associated with significant morbidity and those of the hip and spine are also associated with excess mortality. The correct diagnosis and the adequate treatment of osteoporosis can reduce fracture risk. Together with well known anti-resorptive agents (like bisphosphonates, oestrogen and selective oestrogen receptor modulators) in the past few years anabolic therapy with parathyroid hormone (PTH) has become available for the treatment of severe osteoporosis. Human recombinant intact parathyroid hormone (PTH 1-84) and human recombinant PTH peptide 1-34 (Teriparatide) belong to this group of agents.This paper will review PTH actions together with the anabolic effect of PTH 1-84 both in reducing fracture risk and in promoting fracture healing. Although in primary hyperparathyroidism bone catabolism prevails on bone anabolism, PTH remains a potent stimulator of osteoblasts and its anabolic properties can be seen when it is given at a low dosage and intermittently. Intermittent PTH can stimulate bone formation to a greater extent and earlier than bone resorption, thus creating the so called "anabolic window".The TOP study demonstrated that PTH 1-84 is able to reduce the risk of a new fracture in patients with prevalent vertebral fractures, but the same effect was also seen on the incidence of the first fracture in women without fractures at baseline. Moreover PTH produced a continuous increase of bone mineral density, particularly in the cancellous bone. A positive effect of PTH has been described also on fracture healing, consisting both by a shortened time for fracture repair and by an improving of all the parameters of callus formation and development. Although most of the evidence has been obtained in animals some recent studies in humans confirmed, at least in part, these findings. In elderly patients with osteoporosis and fractures PTH treatment may reduce the healing time, improve clinical outcomes and reduce the time of immobilization together with the risk of complications.

The effect of teriparatide (TPD) on bone turnover is initially exuberant but then diminishes. TPD is thought to stimulate bone formation by down-regulating the expression of specific Wnt antagonists, such as of sclerostin and Dickkopf-1 (DKK1).

Our objective was to determine whether long-term treatment with TPD is associated with increasing serum levels of either sclerostin or DKK1.

Ancillary observation was made of patients participating in a randomized clinical trial. PATIENTS, INTERVENTION, AND OUTCOMES: Fifty-five women with postmenopausal osteoporosis were randomly allocated to treatment for 18 months with either TPD 20 μg daily or placebo.

In the TPD group, both N-propeptide of type I collagen and C-terminal telopeptide of type I collagen rose significantly by 108 and 175% within the first 6 months. At month 18, the mean values decreased significantly compared with month 12 (-10 and -12%, respectively), but they were still significantly higher than baseline (+84 and 152%, respectively). Sclerostin remained stable over the entire study period in both groups. DKK1 did not change during the first 6 month of treatment, but only in the active group, it rose significantly at month 12 (median change +26.9%) and remained elevated at month 18 (+29.7%), at the time when the pharmacological effect of treatment with TPD appeared to be declining.

Long-term (>12 months) treatment with TPD is associated with an increase in serum levels of DKK1 that might be associated with the appearance of declining effect on bone formation markers.