Teriparatide A Review of its Use in Osteoporosis

Recombinant teriparatide (Forteo (TM); Forsteo (TM)) is an anabolic (bone forming) agent. Studies have shown that subcutaneous teriparatide 20 mu g/day is effective in women with postmenopausal osteoporosis, men with idiopathic or hypogonadal osteoporosis and patients with glucocorticoid-induced osteoporosis. Teriparatide improves bone mineral density (BMD) and alters the levels of bone formation and resorption markers; histomorphometric studies showed teriparatide-induced effects on bone structure, strength and quality. Subcutaneous teriparatide 20 mu g/day administered over a treatment period of 11-21 months was effective in reducing the risk of fractures in and in improving BMD in men with idiopathic or hypogonadal osteoporosis, women with postmenopausal osteoporosis and patients with glucocorticoid-induced osteoporosis. Furthermore, the beneficial effects of teriparatide on vertebral fracture prevention and BMD appear to persist following treatment cessation. Teriparatide is generally well tolerated and treatment compliance rates are favourable. However, current limitations on the length of treatment and the high acquisition cost mean that teriparatide is best reserved for the treatment of patients with osteoporosis at high risk of fracture, or for patients with osteoporosis who have unsatisfactory responses to or intolerance of other osteoporosis therapies. Pharmacological Properties Teriparatide is the 1-34 N-terminal fragment of human parathyroid hormone (PTH) and appears to contain all the anabolic properties of the full-length PTH. Both teriparatide and endogenous PTH mediate their biological effects via specific, high-affinity membrane cell-surface receptors expressed on osteoblasts and renal tubular cells. Both molecules bind to the receptors with the same affinity and exert the same physiological effects on bone and kidney. Unlike antiresorptive agents (e.g. bisphosphonates and raloxifene) that inhibit bone resorption and preserve existing bone architecture, teriparatide stimulates osteoblastic activity and new bone tissue formation. Increases in levels of bone formation markers occur earlier than increases in bone resorption markers, creating the `anabolic window'. The early changes in biochemical markers of bone formation may correlate with improvements in bone structure and BMD. The effects of teriparatide on calcium and phosphorous metabolism are consistent with those seen with endogenous PTH (transient increase in serum calcium and decrease in serum phosphate). Subcutaneous teriparatide is rapidly and extensively absorbed and has an absolute bioavailability of 95%. Peak serum concentration was achieved approximate to 30 minutes after administration of subcutaneous teriparatide 20 mu g in healthy volunteers and in postmenopausal women with osteoporosis, after which time concentrations declined to nonquantifiable levels within 3 hours. Teriparatide is not expected to accumulate in bone. Subcutaneous teriparatide has a half-life of approximate to 1 hour, which reflects the time required for absorption from the injection site. It is eliminated via hepatic and extra-hepatic clearance. No metabolism or excretion studies have been undertaken for teriparatide; however, it is believed that peripheral metabolism of endogenous parathyroid hormone occurs largely in the liver, followed by excretion via the kidneys. In the EU, teriparatide is not recommended for use in patients with severe renal impairment. Therapeutic Efficacy In large, well designed clinical trials, teriparatide was effective in reducing fracture risk, increasing BMD values (particularly at the lumbar spine) and increasing bone turnover marker levels in male idiopathic or hypogonadal osteoporosis, and in postmenopausal and glucocorticoid-induced osteoporosis. In a large, pivotal, placebo-controlled, double-blind clinical trial in women with postmenopausal osteoporosis, subcutaneous teriparatide 20 mu g/day over a median of 21 months' duration effectively reduced vertebral and nonvertebral fracture risk (but not hip fractures), and increased markers of bone formation over markers of bone resorption leading to increases in lumbar spine, femoral neck and total hip BMD. Significantly fewer recipients of teriparatide 20 mu g/day than placebo had at least one new vertebral fracture (5% vs 14%; relative risk reduction of 65%). Subgroup analyses of data from this trial showed that teriparatide was effective in women with varying degrees of disease severity, and that efficacy was independent of age, renal function, pretreatment BMD values, or the number or severity of prior vertebral fractures. Teriparatide 20 mu g/day was more effective in increasing lumbar spine BMD values after 6-24 months' treatment in women with postmenopausal osteoporosis than the antiresorptive comparators, alendronate or calcitonin. Both teriparatide and alendronate had positive effects on BMD, but these were significantly greater with teriparatide than with alendronate. When teriparatide was combined with raloxifene in postmenopausal women, the teriparatide-mediated effect on bone resorption appeared to be attenuated, with a net effect of increasing bone formation. After 6 months' treatment, the increase in cross-linked C-telopeptide of type I collagen, a bone resorption marker, was significantly smaller with raloxifene plus teriparatide than the increase observed with teriparatide monotherapy. However, when teriparatide was added to an existing alendronate or raloxifene regimen, significant increases from baseline were observed in lumbar spine and total hip BMD, but overall, coadministration did not appear to enhance the activity of either agent as monotherapy. Switching to teriparatide after antiresorptive therapy in postmenopausal women results in further increases in BMD. Similarly, on cessation of teriparatide, administration of an antiresorptive capitalizes on teriparatide-induced increases in BMD. Teriparatide 20 mu g/day was more effective than placebo in increasing lumbar spine (primary endpoint) and femoral neck BMD, but not total hip BMD, after a median of 11 months' treatment in men with either idiopathic or hypogonadal osteoporosis. In patients with glucocorticoid-induced osteoporosis, teriparatide 20 mu g/day over 18 months was more effective in increasing lumbar spine BMD than alendronate. Bone formation marker levels were also significantly increased with teriparatide, but were significantly decreased with alendronate. Significantly fewer vertebral fractures occurred in teriparatide recipients than in alendronate recipients. Pharmacoeconomic analyses suggest that teriparatide is only cost effective in postmenopausal women with severe osteoporosis and is dominated by alendronate in all other scenarios. Tolerability Subcutaneous teriparatide 20 mu g/day was generally well tolerated during clinical trials of a median of 21 months' duration in patients with osteoporosis. The adverse events most commonly reported in teriparatide recipients were pain in limb, nausea, headache and dizziness. Serious adverse events were uncommon, were not significantly different between groups receiving teriparatide and comparator agents and were mostly deemed to be unrelated to study drugs. There were no reports of osteosarcoma during clinical trials (follow-up < 2 years) and the incidence of other malignancies did not differ between teriparatide and placebo recipients. The US prescribing information contains a black box warning regarding the increased incidence of osteosarcoma associated with teriparatide treatment. Since commercial launch of teriparatide in 2002, one case of osteosarcoma in a teriparatide-treated patient has been reported; however, causality between teriparatide and the osteosarcoma could not be established. Increases in alkaline phosphatase levels have been reported infrequently with teriparatide therapy. Teriparatide is contraindicated in the EU and the US in patients with unexplained elevations of alkaline phosphatase as this may indicate Paget's disease of bone.