Teriparatide
Recombinant 1-34 N-terminal fragment of human parathyroid hormone [rhPTH(1-34), teriparatide] is an effective stimulator of bone formation when administered intermittently.
Teriparatide has been shown to stimulate bone formation through bone remodeling primarily and to a much lower extent through bone modeling on quiescent bone surfaces, by increasing the number of osteoblasts and their activity [1]Langdahl, B., S. Ferrari, and D.W. Dempster, Bone modeling and remodeling: potential as therapeutic targets for the treatment of osteoporosis. Ther Adv Musculoskelet Dis, 2016. 8(6): p. 225-235.
. This induces a prompt increase in bone formation followed by a slower increase in bone resorption. As it strongly increases bone mineral density (BMD) in the trabecular compartment, the greatest increase in BMD is observed at the lumbar spine [2]Neer, R.M., et al., Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med, 2001. 344(19): p. 1434-41.
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In osteoporotic women with prevalent vertebral fractures, observations show that teriparatide decreases the incidence of new vertebral fractures by 65% and of non-vertebral fractures by 35% [2]Neer, R.M., et al., Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med, 2001. 344(19): p. 1434-41.
. In postmenopausal women with a vertebral fracture, the risk of a new vertebral fracture was observed to be lower in teriparatide-treated patients compared to the risedronate-treated ones [3]Kendler, D.L., et al., Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet, 2018. 391(10117): p. 230-240.
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The effect of teriparatide on hip fracture was not evaluated due to the small number of fractures occurring during the clinical trials. However, a recent meta-analysis suggests an overall reduction of hip fractures by 56% [4]Diez-Perez, A., et al., Effects of teriparatide on hip and upper limb fractures in patients with osteoporosis: A systematic review and meta-analysis. Bone, 2019. 120: p. 1-8.
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Maintenance of BMD and anti-fracture efficacy after TPT depends on the subsequent administration of bisphosphonates or other anti-resorptives.
The recommended dose is a subcutaneous injection of 20µg/day for people at high risk of fracture, especially of vertebral fracture, including patients with a previous vertebral fracture. Regulatory authorities have limited the duration of teriparatide administration to 24 months in Europe and in the USA.
Common adverse events reported by patients include nausea, hypercalcemia, headache and dizziness. Due to the increased incidence of osteosarcoma seen in rats when very high doses of teriparatide were administered over a long duration, the use of teriparatide is not recommended for individuals at increased risk of osteosarcoma. Therapy is also contraindicated in people with renal impairment and in conditions characterized by abnormal high bone turnover.
Abaloparatide
Abaloparatide is a 34-amino acid synthetic peptide. It is an analogue of parathyroid hormone-related protein (PTHrP), selected to be a selective activator of the parathyroid hormone receptor (PTH1R).
Compared to placebo, abaloparatide was shown to increase BMD at the lumbar spine, femoral neck, and total hip [5]Leder, B.Z., et al., Effects of abaloparatide, a human parathyroid hormone-related peptide analog, on bone mineral density in postmenopausal women with osteoporosis. J Clin Endocrinol Metab, 2015. 100(2): p. 697-706.
. Results from phase 3 of the ACTIVE trial observed that a significantly greater proportion of postmenopausal women treated with abaloparatide experienced an increase in hip BMD compared to those treated with teriparatide [6]Miller, P.D., et al., Bone mineral density response rates are greater in patients treated with abaloparatide compared with those treated with placebo or teriparatide: Results from the ACTIVE phase 3 trial. Bone, 2019. 120: p. 137-140.
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In postmenopausal patients with osteoporosis, abaloparatide decreased new vertebral fractures by 86% and 80%, respectively, whereas the relative risk reduction in nonvertebral fractures reached 43% [7]Miller, P.D., et al., Effect of Abaloparatide vs Placebo on New Vertebral Fractures in Postmenopausal Women With Osteoporosis: A Randomized Clinical Trial. JAMA, 2016. 316(7): p. 722-33.
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The recommended dose of abaloparatide is a subcutaneous injection of 80µg/day. The use of abaloparatide is not recommended for individuals at increased risk of osteosarcoma.
Abaloparatide is approved for the treatment of postmenopausal women with osteoporosis at high risk for fracture in many countries, including US, Japan and the European Union.
The most common side effects reported by patients are nausea, headache and dizziness, hypercalciuria.
Romosozumab
Romosozumab is a humanized monoclonal antibody against sclerostin. Sclerostin, encoded by the SOST gene, is a secreted protein by the osteocyte and inhibits bone formation.
Romosozumab (210mg every month sc) has been shown to increase bone formation and decrease bone resorption [8]Padhi, D., et al., Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res, 2011. 26(1): p. 19-26.
. At 1 year, romosozumab reduced the incidence of new vertebral fractures and clinical fractures by 73% and 36%, respectively [9]Cosman, F., et al., Romosozumab Treatment in Postmenopausal Women with Osteoporosis. N Engl J Med, 2016. 375(16): p. 1532-1543.
. The reduction in non-vertebral fractures did not reach significance against placebo in the FRAME study but this was explained by a very low risk of non-vertebral fractures in the overall study population. Pre-planned subgroup analyses among non-Hispanics and/or higher risk subjects indeed demonstrated a 40% significant reduction of non-vertebral fractures as well [10]Cosman, F., et al., FRAME Study: The Foundation Effect of Building Bone With 1 Year of Romosozumab Leads to Continued Lower Fracture Risk After Transition to Denosumab. J Bone Miner Res, 2018. 33(7): p. 1219-1226.
. In FRAME, transition from romosozumab to denosumab in year two lead to a continuous increase in BMD and a further decrease in fracture risk.
In the ARCH study, the selected women were a high risk of fracture. After 1 year of treatment, romosozumab reduced the risk of vertebral and clinical fracture by 37% and 28%, respectively, compared to alendronate [11]Saag, K.G., et al., Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis. N Engl J Med, 2017. 377(15): p. 1417-1427.
. During the second and third year, when all women were treated with alendronate, women previously on romosozumab had a significant decrease in all fracture types compared to alendronate alone.
Similar to denosumab, romosozumab effects are reversible when the treatment is stopped, hence the therapy will need to be administered in sequence with an anti-resorptive.
Especially during the first year of the ARCH study, serious cardiac ischemic and cerebrovascular events appeared more often in the romosozumab group compared to the alendronate one, where a lower risk than expected was observed. Contrastingly, these cardiovascular effects were not seen in the FRAME study.
Romosozumab is approved for osteoporosis treatment in postmenopausal women at high risk of fracture in many countries including US, Japan, South Korea, Canada, Australia and Europe.