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Parathyroid hormone is naturally an 84-amino-acid polypeptide. There have been some studies with various forms of PTH. In 2002 the FDA approved recombinant PTH 1-34, with a chemical name of teriparatide made by Lilly with the brand name Forteo.
1-34 PTH is a useful addition to osteoporosis treatment. Like other new treatments, we really must know more about long-term side effects and benefits before using it for routine cases. At this point I would consider PTH in patients who had demonstrated low bone formation rates and low resorption rates, and who continue to have fractures despite other osteoporosis therapy. As more experience accumulates, the drug may be indicated for primary treatment in severe cases (T-score less than -3.5).
The largest clinical trial (Neer, see table below) showed that PTH 1-34 increased bone density and reduced fractures. These changes were seen regardless of baseline age or bone density.
These were inclusion criteria for the Neer study:
The only dose is 20 mcg/day, given by intermittent subcutaneous injection once a day using a special injection device.
At this time, until longer studies are available, the duration of treatment should be 18 to 24 months.
After the intermittent PTH is discontinued, patients should be treated for the next two years with an anti-resorping medication; otherwise the bone density will decrease after the PTH is discontinued. (Black DM, Kurland ES, Rittmaster R, Prince R)
Cosman showed that giving PTH1-34 in 3 month cycles (daily for 3 months, off for 3 months) for 15 months gave a similar increase in bone density as daily for 15 months. She recently reported (ASBMR 2005) that a year later (27 months from baseline) the patients were again given PTH for 3 months and again showed an increase in the bone density. The patients had been on alendronate at least a year prior to baseline and had remained on alendronate the entire time. This approach is very promising but has not been officially approved, and the drug was specially synthesized for their study and given at a slightly higher dose than teriparatide.
Osteosarcomas develop in about 50% of rats treated with high doses of intermittent PTH. This has not been shown in dogs or primates. So far teriparatide has been used in over 300,000 people. There has been one case of osteosarcoma which was reported in July 2006. The background incidence rate is one in 250,000 so one case is not unusual. Nevertheless, this drug should not be used in patients with a risk of bone cancer until there has been even more clinical experience.
PTH with other osteoporosis medicines:
It is logical to combine an anti-resorptive drug with an anabolic drug. Sometimes, however, the prior inhibition of osteoclast activity diminishes the anabolic effect, especially in cancellous bone. In cortical bone the combinations increase bone density more than PTH alone. A short-term study with raloxifene showed synergism when combining raloxifene with PTH.
Alkhiary studied rats and showed that daily subcutaneous administration of low-dose teriparatide, PTH (1-34), enhances fracture healing by increasing BMD, BMC, and strength, and produces a sustained anabolic effect throughout the remodeling phase of fracture repair.
Summary of bone biopsy findings
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The role of PTH in control of bone mass is still not really understood. PTH stimulates osteoblastic activity, especially on trabecular surfaces. It also stimulates osteoclastic activity. In some cases the anabolic effect predominates over the increased resorption, and osteosclerosis results. Intermittent spikes of PTH, such as given by daily injection, will cause more increase in bone formation than in bone resorption. This has been shown in rats. Furthermore, micro-array analysis has shown that different genes are expressed in bone cells that have been exposed to continuous PTH than those expressed after intermittent PTH (Onyia JE).
PTH has different effects on the cortical and trabecular bone. Patients with either primary or secondary hyperparathyroidism have increased bone density of the spine, but decreased cortical bone mass. Patients with osteoporosis treated with PTH showed increases at the spine but decreases at cortical sites, especially the radius. Total body calcium decreased about 2%. QCT images demonstrated increases in cancellous bone of the hip, and overall increased amount of cortical bone, but the cortical bone became more porous.
The anabolic actions of PTH diminish with time; after a mean of 19 months, the bone forming surface from bone biopsies is slightly lower than at baseline. Studies using 85-Strontium kinetics, however, suggest that other parts of the skeleton might still be forming bone even when the iliac crest has returned to baseline (Reeve).
Intermittent PTH suppresses apoptosis of the osteoblasts (Jilka) which is one reason there is a high bone formation rate. On the other hand, continuous PTH will increase the apoptosis (Turner). The mechanisms of the anabolic effect are not really certain; it appears that intermittent PTH can inhibit SOST (Keller H). Also, osteoblast PTHrP influences the action of PTH 1-34; in mice with heterozygous deficiency of PTHrP in osteoblasts, the anabolic effect of PTH is enhanced compared to wild-type mice (Miao D).
An interesting report by Shao JS demonstrated decreased vascular calcifications in genetically predisposed mice, after treatment with teriparatide. The mechanism was an inhibition in the transcription factor Msx, which resulted in decreased Wnt signalling. This suggests that intermittent PTH might have different effects on Wnt signalling, depending on the cell type.
Two recent reviews about PTH:
Hodsman AB. Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 2005;26(5):688-703.
Poole KE. Parathyroid hormone - a bone anabolic and catabolic agent. Curr Opin Pharmacol 2005;5(6):612-7.
