Teriparatide

Teriparatide is a recombinant fragment of human parathyroid hormone, its active 1-34 portion. It binds to the type 1 PTH receptor, the PTH1R, a G protein-coupled receptor present on the surface of osteoblasts, osteocytes and kidney cells. By binding to it, it activates the Gs and Gq signalling pathways inside the cell, which trigger the bone response.

Its effect depends above all on the rhythm of administration. A single injection per day, at a low dose, stimulates bone formation more than its breakdown. This is the opposite of continuous exposure to parathyroid hormone, as in hyperparathyroidism, which instead promotes bone resorption. At the molecular level, teriparatide increases pro-osteoblastic factors such as IGF-1 and FGF2, releases the brake that sclerostin places on the Wnt/beta-catenin pathway, and raises the transcription factor Runx2, which directs cells towards the osteoblast lineage.

Teriparatide is aimed at severe forms of osteoporosis, when the risk of fracture is high. It is indicated in postmenopausal women at high risk of fracture, in men with primary osteoporosis or osteoporosis linked to a hormone deficiency, and in osteoporosis caused by corticosteroids. The label describes stimulation of new bone formation on trabecular and cortical surfaces, through a preferential action on osteoblasts rather than on osteoclasts.

This rebuilding translates into fewer fractures. In the pivotal trial in postmenopausal women, the risk of a new vertebral fracture fell from 14.3% on placebo to 5.0% on teriparatide, a relative reduction of about 65%. The risk of a new non-vertebral fragility fracture dropped from 5.5% to 2.6%, a relative reduction of about 53%.

The recommended dose is 20 micrograms per day, in a single subcutaneous injection. It is given in the thigh or the abdominal wall, each day at a regular time. The serum half-life after injection is about one hour: the product passes through quickly, and it is precisely this brief, repeated passage that carries the anabolic effect. Regularity of dosing therefore matters more than the exact time.

The first injections are given sitting or lying down, because a drop in blood pressure when standing up, orthostatic hypotension, can occur. Treatment is not stopped on one’s own initiative, because its benefit rests on continuity. Its duration is limited: beyond two years over a patient’s lifetime, it is only renewed if the risk of fracture remains or becomes high again.

Most of the reported effects remain close to what the placebo group experiences. Out of 691 patients per arm at the 20 microgram dose, pain was recorded in 21.3% (versus 20.5%), joint pain in 10.1% (versus 8.4%), nausea in 8.5% (versus 6.7%), dizziness in 8.0% (versus 5.4%), and fatigue in 8.7% (versus 6.8%). Two effects stand out a little more: leg cramps, 2.6% versus 1.3%, and syncope, 2.6% versus 1.4%.

The most characteristic biological effect is a transient rise in blood calcium, in the four to six hours after the injection. It affected 11% of treated women and 6% of treated men, versus 2% and 0% on placebo. This hypercalcaemia is most often mild and transient, and becomes persistent only in about 3% of patients at 20 micrograms per day. Teriparatide also raises blood uric acid: 3% of patients exceeded the upper limit of normal versus 1% on placebo, without any increase in cases of gout, joint pain or urinary stones.

The bone that teriparatide makes needs calcium and vitamin D to mineralise. In the trials, all women received 1000 mg of calcium and at least 400 IU of vitamin D each day, and this sufficient intake is recommended throughout treatment. Teriparatide increases urinary calcium excretion, but the frequency of hypercalciuria seen in the trials remained comparable to that of placebo. For phosphorus, single-dose studies show a transient urinary elimination and a mild, transient fall in the blood level, without any hypophosphataemia appearing in the clinical trials.

Calcium intake is managed according to blood calcium. If it rises during treatment, the approach is first to reduce the calcium provided by supplements before adjusting the teriparatide dose. Food remains the simplest way to regularly provide the calcium that bone needs, with vitamin D also coming from sun exposure.

One interaction calls for particular attention: in patients treated with digoxin, the transient rise in blood calcium can promote toxicity of this heart medicine, whose signs must be monitored. Biological monitoring of teriparatide includes a measurement of blood and urinary calcium before starting, a control blood calcium at one month and then according to clinical judgement, a measurement of bone mineral density at one year, and the possibility of following bone remodelling markers such as P1NP.

On long-term safety, an increased incidence of osteosarcoma was observed in treated rats, but this excess risk was not found in observational studies in humans, and data beyond two years of use remain limited. This is the reason why the duration of treatment is framed and its continuation reassessed according to the risk of fracture.