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Guideline

Pharmacologic approaches to prevention and treatment

Recombinant human parathyroid hormone

Recombinant human parathyroid hormone

Recommendation 31

Grade

Recombinant human parathyroid hormone (teriparatide) treatment is recommended to reduce fracture risk in postmenopausal women with osteoporosis who have sustained a subsequent fracture while on antiresorptive therapy, or in those at very high fracture risk.

A

Recommendation 32

Grade

Recombinant human parathyroid hormone (teriparatide) treatment is recommended to reduce fracture risk in men aged over 50 years with osteoporosis who have sustained a subsequent fracture while on antiresorptive therapy, or in those at very high fracture risk.

C

Recombinant human parathyroid hormone (PTH) is approved in Australia in the form of hPTH(1–34), also known as teriparatide. Teriparatide acts predominantly on osteoblasts to increase new bone formation on trabecular and cortical surfaces by preferentially stimulating osteoblastic bone formation over osteoclastic bone resorption. Teriparatide acts to increase osteoblast lifespan by reducing osteoblast apoptosis (cell death) and inducing the recruitment and formation of new osteoblasts – the cells that make new bone. The bone-remodelling rate and the amount of bone deposited in each remodelling cycle is increased. Cancellous bone connectivity, trabecular thickness and cortical width are increased, as is periosteal bone formation, which is responsible for increasing cortical width and producing an increase in bone size. Skeletal mass and bone strength are also increased.1

Teriparatide increases lumbar spine and FN BMD and decreases vertebral and non-vertebral fractures in postmenopausal osteoporosis with prior fracture. Hip fracture risk has not been assessed.2 Teriparatide has also been shown to improve new, worsening and moderate-to-severe back pain and reduce height loss in patients who have sustained one or more new vertebral fractures.3 Teriparatide increases BMD at the lumbar spine and FN in men with osteoporosis, but there are no data on fracture reduction in this population.4,5

Teriparatide has been studied at a maximum continuous course of 24 months with beneficial effects on bone density and fracture risk. It is PBS subsidised for 18 months per lifetime per individual (TGA approved for 24 months) for patients with severe osteoporosis and a very high risk of fracture who have:

  • a BMD T-score of ≤–3.0
  • had two or more fractures due to minimal trauma
  • experienced at least one symptomatic new fracture after at least 12 months continuous therapy with an antiresorptive agent (eg bisphosphonate or denosumab).

Dizziness, leg cramps, nausea, injection reactions and headache are the most common side effects, occurring in up to 5% of patients. These are generally mild and do not require treatment discontinuation. Because transient hypercalcaemia has been noted, checking serum calcium shortly after treatment is recommended.2 Mild increases in uric acid without the development of acute gout and small increases in urinary calcium excretion without nephrolithiasis have been reported.6 Oncogenicity studies in rats treated with high doses of teriparatide for near-lifetime duration revealed an increased risk of osteogenic sarcoma.7 However, surveillance of human osteosarcoma cases has found no relationship with teriparatide.8

Evidence Statement

Treatment of osteoporosis in postmenopausal women

A systematic review reported 10 moderate- and good-quality RCTs (including seven double-blind RCTs) investigating the effectiveness of hPTH(1–34).2 One trial3 in that systematic review reported fracture risk as a primary outcome measure. The trial compared hPTH(1–34) to calcium in postmenopausal women, reporting a reduction in the risk of new vertebral fractures for hPTH(1–34) 20 mcg per day (RR 0.35; 95% CI: 0.22–0.55). The ARR for vertebral fractures was 9% and the ARR for non-vertebral fractures was 3% (RR 0.47; 95% CI: 0.25–0.88) for hPTH(1–34) 20 mcg per day.3 Six moderate-to-good quality RCTs reported in the systematic review compared PTH to placebo or an active comparator and reported BMD as an outcome measure.2 The duration of the trials was 1–3 years. Participants treated with hPTH(1–34) 20 mcg per day had significant increases in lumbar spine BMD of 9.7–10.3% and increases in FN BMD of 2.8–3.9%.

Treatment of osteoporosis in men

In a good-quality trial, men with idiopathic osteoporosis (n=23) were randomly assigned to hPTH(1–34) 25 mcg versus placebo.4 After 18 months, BMD increased significantly by 13.5% and 2.9% at the lumbar spine and FN, respectively. Total hip BMD did not change significantly, but there was a significant decrease of 1.2% at the distal radius.4 Another good-quality trial was conducted in men with low BMD who were predominantly hypogonadal (n=437).5 Participants were treated with 20 or 40 mcg hPTH(1–34) versus placebo with calcium and vitamin D. After 12 months, lumbar spine BMD increased by 5.4% with 20 mcg hPTH(1–34), compared with no change with placebo. There was no significant difference in fracture rate between hPTH(1–34) and placebo.5

Combination with antiresorptive therapies in postmenopausal osteoporosis

There is strong evidence that combination therapy with alendronate and teriparatide may blunt the anabolic effect of teriparatide on BMD.2 There are no fracture data comparing the effect of combination teriparatide and alendronate with that of teriparatide alone.2 An open-label RCT has compared the effect on BMD between teriparatide and denosumab alone, or in combination.9 At 24 months, combination treatment increased BMD at the lumbar spine and hip more than either treatment alone; the study was not powered to detect an effect on fracture rate.9

Safety

An increased risk of osteosarcoma was reported in a lifelong carcinogenicity study involving Fischer rats given high-dose hPTH(1–34) from infancy through senescence (from eight weeks to two years of age).7 Osteosarcoma was found with all doses and, in the lower dose ranges, was first detected after about 20 months of therapy. There have been no reports of osteosarcoma in clinical trial subjects and, conversely, after seven years of the Osteosarcoma Surveillance Study (an ongoing 15-year surveillance study initiated in 2003), there have been no osteosarcoma patients who have reported prior exposure to teriparatide.8 Nine trials investigating hPTH(1–34) reported post-dose hypercalcaemia (serum calcium >2.6 mmol/L) that ranged from 3% to 11% among patients taking hPTH(1–34) 20 mcg, compared with 0–3% among those taking the comparator.2 These episodes were mild, with serum calcium concentrations usually normalising within 24 hours and no clinical sequelae. There were no reported increases in renal stones. hPTH(1–34) 20 mcg was associated with a significant increase in patients experiencing dizziness (3%) and leg cramps (range 2–8%).

  • Teriparatide is given as a daily subcutaneous injection via a multidose pen device. (This may be an issue for those with poor hand function or those who are vision-impaired or needle-phobic.)
  • Teriparatide is generally restricted to patients at very high risk of fracture. However, the cost has fallen with the recent introduction of a teriparatide biosimilar (Terrosa™).
  • Due to possible increased background risk of osteosarcoma, teriparatide is not recommended for patients with Paget’s disease, prior skeletal irradiation, bony metastases or prior skeletal malignancies, or for those with metabolic bone diseases (other than osteoporosis) or pre-existing hypercalcaemia.
  • BMD decreases within 12 months of stopping teriparatide, unless followed by sequential treatment with an antiresorptive drug.
  1. Dempster DW, Cosman F, Parisien M, Shen V, Lindsay R. Anabolic actions of parathyroid hormone on bone. Endocr Rev 1993;14(6):690–709.
  2. Cranney A, Papaioannou A, Zytaruk N, et al. Parathyroid hormone for the treatment of osteoporosis: A systematic review. CMAJ 2006;175(1):52–59.
  3. Neer RM, Arnaud CD, Zanchetta JR, 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):1434–41.
  4. Kurland ES, Cosman F, McMahon DJ, Rosen CJ, Lindsay R, Bilezikian JP. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: Effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000;85(9):3069–76.
  5. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide therapy on bone density in men with osteoporosis. J Bone Miner Res 2003;18(1):9–17. [human parathyroid hormone (1–34)]
  6. Black DM, Bilezikian JP, Ensrud KE, et al. One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N Engl J Med 2005;353(6):555–65.
  7. Barbehenn EK, Lurie P, Wolfe SM. Osteosarcoma risk in rats using PTH 1–34. Trends Endocrinol Metab 2001;12(9):383.
  8. Andrews EB, Gilsenan AW, Midkiff K, et al. The US postmarketing surveillance study of adult osteosarcoma and teriparatide: Study design and findings from the first 7 years. J Bone Miner Res 2012;27(12):2429–37.
  9. Leder BZ, Tsai JN, Uihlein AV, et al. Two years of denosumab and teriparatide administration in postmenopausal women with osteoporosis (The DATA Extension Study): A randomized controlled trial. J Clin Endocrinol Metab 2014;99(5):1694–700.
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