What happens when there’s not enough parathyroid hormone (PTH), or when there’s too much? How is the skeletal system impacted? These were questions international expert Professor John Bilezikian, a Silberberg Professor of Medicine and Pharmacology at the College of Physicians and Surgeons, Columbia University, discussed during a recent talk at Amgen One’ Bone Academy conference in Melbourne.
“Our understanding of the interconnected role this molecule plays should shape the way we treat each disease,”1 began Prof. Bilezikian. “It’s one molecule that impacts the skeletal system in a variety of ways depending on level and timing.”
What happens when PTH is too low
“We know hypoparathyroidism, characterised by not enough PTH typically presents after neck surgery, as an autoimmune disease and rarely as a genetic disease (e.g. DiGeorge syndrome) or as infiltrative disease (e.g. Wilson’s disease),”2,3 explained Prof. Bilezikian. “While we see effects in other body systems when you lack parathyroid hormone (PTH), we also see corticalisation of trabecular bone, effectively turning it into a ball of cement.4,5 Yet, this seems to translate as no increased risk of overall fracture risk.”6,7
One challenge he highlighted is that “current treatments for hypoparathyroidism (that is calcium, vitamin D, thiazide diuretics) do not address the underlying cause of disease.” While there is one treatment registered by the US Food and Drug Administration that replaces precisely what is missing – a full length recombinant PTH called rhPTH(1-84),8 it is not currently available in Australia. However, even in the US it is only for patients not well controlled on calcium and active forms of vitamin D alone and where the risk of osteosarcoma outweighs the potential risk.9
What happens when PTH is too high?
“Our understanding of hyperparathyroidism has evolved from a disease of bones, groans and stones to one that can present with more subtle biochemical and densitometric signatures at first,”10 noted Prof. Bilezikian. “Although the disease hasn’t changed, our understanding of it has, leading to recognition of three distinct phenotypes: symptomatic, asymptomatic and normocalcaemic primary hyperparathyroidism.”
Prof. Bilezikian explained how advances in imaging technology has meant clinical manifestations can now be explained by changes occurring in the skeletal microstructure. “For instance, looking at BMD alone in patients with primary hyperparathyroidism, you might expect no increased risk of vertebral fractures and an increased risk at non-vertebral sites. However, in reality there is an increased risk of both.11 This is because excess PTH leads to trabecularisation of cortical bone, compromising its structural integrity.”12
While not indicated for primary hyperparathyroidism, treatments “which have been shown to moderate serum calcium or BMD such as oestrogen, raloxifene and denosumab had no effect on PTH,” Prof. Bilezikian explained.13-15 Cinacalcet is the only treatment that reduces PTH, but on its own has no effect on BMD.16-18 When combined with bisphosphonates, BMD can be improved.”19
A little history about PTH and osteoporosis
“It’s been a journey to get to where we are today with our understanding and management of osteoporosis – and it couldn’t have been done without understanding the role PTH plays in the other two diseases,” explained Prof. Bilezikian.
Here’s a few things Prof. Bilezikian noted along the way:
“For the first 20 years or so, the field was dominated by drugs that prevent microstructural deterioration, add mineral content to bone, but do not help to reconstruct the skeleton.”
“The attempt to improve skeletal microstructure as a treatment for osteoporosis began with the development of a drug that was thought to do the opposite! We thought too much PTH was bad for bone.”
“It turns out that PTH is not always bad for bone after all.20 During the time that the symptomatic phenotype of primary hyperparathyroidism was being well characterised (1930-1960), another set of observations was leading to another conclusion: PTH alone might serve an anabolic function on trabecular bone but a catabolic function at cortical bone (“borrowing from Peter to pay Paul”).21-24 It seemed timing and dose may be the factors which decide whether it has an anabolic or catabolic effect.23 What we saw was when used at low dose, intermittently with rapid ‘on’ and ‘off’ kinetics PTH may actually be anabolic.”24
“The final irony is that teriparatide doesn’t exist as a hormone or a metabolic product – despite being a subset of the PTH molecule itself. While it has anabolic effects, its period of anabolic activity is relatively short. To explore the ability to bind the PTH1R receptor in its R0 configuration (which is associated with a more prolonged binding of the ligand than the RG conformation teriparatide binds to), a new molecule, abaloparatide (not registered for use in Australia) is currently under investigation.25 As well as not requiring refrigeration, this molecule will be of interest in the future as an alternative to teriparatide.”
This article was sponsored by Amgen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Amgen.
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- Powers J, et al. J Bone Miner Res. 2013;28:2570-2576.
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- Rubin MR, et al. Bone. 2010;46:190-195.
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- Eller-Vainicher C, et al. J Am Geriatr Soc 2018;66(3):518-524.
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- Faggiano A, et al. Endocrine 2011;39(3):283-287.
- Silverberg SJ, Bilezikian JP. J Clin Endocrinol Metab 1996;81(6):2036-2040.
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- Tay D, et al. Br J Clin Pharmacol 2018’84(2):252-267.