Monday, August 27, 2012

Parathyroid hormone to treat achondroplasia? Part 2: medical and experimental use of PTH

In the last article we learned that the parathyroid hormone (PTH) and  the PTH-related-protein (PTHrP) have quite comparable structures (PTHrP is bigger, though) and work through the same receptor, thus producing fairly the same effects in their target cells and body tissues. We also observed that while PTH is a circulating hormone, PTHrP works locally where it is released. It is interesting to note that both proteins, given systemically, cause similar effects in bone health and interfere with calcium and phosphorus metabolism in a similar way (1).
Now, we will explore a bit more PTH natural functions and also take a look at the current medical use of PTH in bone diseases. But first, let me emphasize that we will not be going deep here; I just want to give the reader an idea about the research made with PTH and what we can learn from it, again to help us understand if PTH therapy could be an option for achondroplasia.
Before we start, let´s talk a bit about the PTH analogues. This is relevant because if we are trying to decide if PTH can be used to treat achondroplasia, we will need to choose the best candidate analogue. Currently, there are two of them being marketed for the treatment of osteoporosis. One is a copy of the natural hormone, comprising the original 84 amino acids (PTH 1-84). The other is called teriparatide (Forteo™ or Forsteo™, Ely Lilly), an analogue formed by the first 34 amino acids of the N terminal part of the hormone (do you remember I mentioned the protein terminals also in the last article?). PTHrP has also been target of research and there is at least one analogue in development, also for osteoporosis (2). Scientists have discovered that both PTH and PTHrP have in their respective chains several amino acid segments, almost all with distinct functions. For instance, teriparatide was conceived after the demonstration that this segment at the N-terminal part of the molecule had a particular strong anabolic function in the bone. Furthermore, the other segments’ properties have been understood as the reason why there are some differences in the observed effects in studies of PTH 1-84 and PTH 1-34 in calcium metabolism and cell proliferation rates. As an example, it seems that the lack of the C-terminal in PTH 1-34 would be accountable for the stronger pro-proliferative effect of this compound compared to the complete PTH (3). Save this information, it may be important in our context.
PTH controls calcium and phosphorus metabolism
PTH is produced by the parathyroid glands. Its main metabolic action is related to the control of the systemic availability (the blood amount) of calcium and phosphorus. It does this control by mobilizing calcium from its natural deposits, the bones or regulating its excretion (elimination) by the kidneys. When the amount of circulating calcium falls under a physiological cutoff (which is controlled by chemical sensors), PTH is released by the parathyroid and induces the mobilization of the calcium reserves in the bones while regulating its excretion by the kidneys. When the release of PTH is balanced, calcium is kept under good control in the blood. However, when the parathyroid is malfunctioning, either producing too much or too little PTH, there are consequences to the body. In hyperparathyroidism, bones become fragile due to the excessive reduction of the calcium deposits, which leads to osteoporosis. Renal stones are also a common finding in affected patients. In hypoparathyroidism, the lack of sufficient blood calcium also produces clinical consequences, such as muscle spasms and tetany.
PTH is a double edge knife in bone metabolism
We have just learned that PTH, in excess, can cause osteoporosis. So, why this hormone has been used for the treatment of osteoporosis? For more than a decade some PTH analogues have been available for the treatment of this condition. PTH has a dual mode of action in bone metabolism, by stimulating both bone building and bone resorption cells (osteoblasts and osteoclasts, respectively) at the same time. If given continuously PTH causes bone resorption (catabolism) by increasing the activity of osteoclasts over that of the osteoblasts, which leads to osteoporosis, like we see in hyperparathyroidism cases, while its intermittent use induces bone production (anabolism). That’s why the current approved scheme of PTH therapy in osteoporosis is a single daily dose, in what is described as an intermittent fashion.
Hormone replacement therapy is a reality, not true about PTH
For people with hypothyroidism, the best therapy is to replace the thyroid hormone. For patients with type 1 diabetes, where there is no insulin production by the pancreas, the current gold standard therapy is insulin replacement. For people with underproduction of growth hormone (GH) due to pituitary deficiency, use of GH is warranted. It is remarkable that the only major glandular hormone deficiency in which the therapy does not include the replacement of the lacking hormone is exactly the hypoparathyroidism.
PTH therapy in hypoparathyroidism
Although PTH has been only officially licensed to treat osteoporosis, it has been also tested in hypoparathyroidism. In short, hypoparathyroidism can be caused by two groups of disorders, classified as primary or secondary. If the disorder is being caused by a gland issue, then the cause is primary; when the cause of the hormone deficiency is caused by external factors, for instance thyroid surgery, then it is secondary. It is natural to think that PTH replacement could be an option for hypoparathyroidism. In fact, there have been studies working on that. Let’s start looking at those being performed by Dr Karen Winer’s group. This group has been working with children with hypoparathyroidism for years and has published some relevant papers (3-5). The first one, published in 2003, described the results of three year treatment of adults with hypoparathyroidism, showing that it was at least as good – and safe – as the standard therapy with calcitriol (a vitamin D analogue) and calcium. In two other more recent papers, they tested both short and long term PTH 1-34 therapy in children with hypoparathyroidism (4,5). Again, PTH has been showing to be as effective and safe as the standard therapy. Based in these and in other published studies, we could say that there is already evidence for the use of PTH replacement in individuals with hypoparathyroidism.
Experimental use of PTH therapy
PTH has been tested not only in bone but also in cartilage in animal models, based on the established effect this hormone has on chondrocyte proliferation (multiplication). One of these studies explored the effect of PTH in a model of articular cartilage lesion (6). In this case, PTH was given systemically, reached the cartilage and induced the regeneration of the damaged tissue.
Why this study is important? Because it shows that in a tissue very similar to the cartilage growth plate PTH, given from a distance (systemically), was able to reach the area of interest and exerted the expected action. Even taking in account that the articular chondrocytes are not exactly the same of those in the growth plate, the basic mechanism causing the effect is quite similar, i.e., chondrocytes start to proliferate under the stimulus produced by the binding of PTH to its receptor PTHR.
Other studies have been exploring PTH in tendon damage repair and bone fracture repair. All of them are based on the PTH proliferative/anabolic effects in the bone and cartilage.
In summary
     We have been visiting PTH properties to learn if it could be employed as a therapeutic option for achondroplasia. So far we saw that:
  • PTH has a close related molecule, called PTHrP, which differs from the hormone because it does not circulate in the blood in normal circumstances. On the contrary, it is a locally released protein;
  • PTH and PTHrP work activating cellular functions by binding to the same receptor in the chondrocyte cell membrane, the PTH receptor;
  • In the cartilage growth plate, the fundamental role of PTHrP is to maintain chondrocytes in a proliferative (multiplicative) state;
  • Mutations in the PTH receptor either reducing or enhancing the receptor activity cause disturbs in the growth plate;
  • FGFR3 gain-in-function mutations, such the one seen in achondroplasia, seem to reduce the local availability of PTHrP;
  • Used in clinical settings for osteoporosis in adults or in experimental grounds for hypoparathyroidism in adults and children, PTH has been showing a reasonably safe profile;
  • There is evidence that PTH, given systemically, reaches cartilage tissue and exerts its expected actions.
  • There are several PTH analogues in clinical use or under development right now. They may have distinct properties according to their size or structure.
Now, it is time to review the specific data about PTH and PTHrP in achondroplasia, which we will be doing in the next article. 

2. Hattersley G et al. BA058, a Novel hPTHrP Analog, Reverses Bone Loss and Improves Bone Strength in Ovariectomized Rats. Osteoporos Int 2012; 23 (Suppl 2):S77-8.

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