Recombinant 1-34 fragment of human parathyroid hormone [rhPTH(1-34), teriparatide] and recombinant human intact parathyroid hormone [PTH(1-84)] are effective stimulators of bone formation. They stimulate bone remodeling at the bone remodeling unit and bone modeling on quiescent bone surfaces. They induce a prompt increase in bone formation followed by a slower increase in bone resorption. As they strongly increase BMD in the trabecular compartment, the greatest increase in BMD is observed at the lumbar spine.

In the cortical sites, they slightly decrease areal BMD measured by DXA (one-third distal radius) and volumetric BMD measured by QCT (femoral neck, total hip). By contrast, they increase cortical bone volume at the radius and femoral neck [1,2]. In osteoporotic women with prevalent vertebral fractures, rhPTH(1-34) decreases the incidence of new vertebral fractures by 65 % and of non-vertebral fractures by 53 % [3].

In postmenopausal women with low BMD, PTH(1-84) decreased the incidence of vertebral fractures (but not of non-vertebral fractures) by about 60 % (4). The fracture incidence remained significantly decreased for at least 30 months after discontinuation of teriparatide treatment (5). However, these data should be interpreted cautiously, because during the follow-up after the discontinuation of teriparatide, patients and investigators were unblinded to the treatment and additional treatment for osteoporosis was allowed. The best candidates for the anabolic treatment are patients with pre-existing osteoporotic fractures, patients with very low BMD and those with unsatisfactory response to anti-resorptive therapy [6].

Teriparatide and PTH(1-84) increase BMD and reduce the risk of fracture mainly by stimulating bone formation, thus, by a different mechanism from that of BPs. Therefore, a logical question was whether joint use of two groups of drugs would provide therapeutic advantage. This point is important because the anabolic treatment necessitates daily subcutaneous injection. However, after one year of combination therapy of PTH(1-84) and alendronate, no synergy was observed and alendronate even attenuated the effect of PTH(1-84) on BMD [7].

In osteoporotic women taking alendronate for at least one year, continued alendronate plus rhPTH(1-34) subcutaneously daily for three month cycles alternating with three month periods without rhPTH(1-34) induced similar increase in BMD and in bone turnover marker (BTM) levels as continuous rhPTH(1-34) [8].

Treatment with oral alendronate (10 mg daily for 1 year) after 1-year treatment with PTH(1-84) allowed a further increase in BMD at the lumbar spine and the hip (2). These studies were made in small groups without assessment of the anti-fracture efficacy. However, they suggest that the therapeutic effect PTH may be obtained by less frequent administration of PTH with alendronate.

References

1. Zanchetta JR, Bogado CE, Ferretti JL, Wang O, Wilson MG, Sato M, Gaich GA, Dalsky GP, Myers SL 2003 Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis. J Bone Miner Res 18:539-543.
2. Black DM, Bilezikian JP, Ensrud KE, Greenspan SL, Palermo L, Hue T, Lang TF, McGowan JA, Rosen CJ 2005 One year of alendronate after one year of parathyroid hormone (1-84) for osteoporosis. N Engl J Med 353:555-565
3. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH 2001 Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434-1441
4. Greenspan SL, Bone HG, Ettinger MP, Hanley DA, Lindsay R, Zanchetta JR, Blosch CM, Mathisen AL, Morris SA, Marriott TB 2007 Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis: a randomized trial. Ann Intern Med 146:326-339
5. Prince R, Sipos A, Hossain A, Syversen U, Ish-Shalom S, Marcinowska E, Halse J, Lindsay R, Dalsky GP, Mitlak BH 2005 Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment. J Bone Miner Res 20:1507-1513
6. Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, Kendler DL, McClung MR, Miller PD, Olszynski WP, Orwoll E, Yuen CK 2005 Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 26:688-703
7. Black DM, Greenspan SL, Ensrud KE, Palermo L, McGowan JA, Lang TF, Garnero P, Bouxsein ML, Bilezikian JP, Rosen CJ 2003 The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med 349:1207-1215.
8.Cosman F, Nieves J, Zion M, Woelfert L, Luckey M, Lindsay R 2005 Daily and cyclic parathyroid hormone in women receiving alendronate. N Engl J Med 353:566-575