Assignment #4 - Review of a paper on Parathyroid Hormone

Paper:

Kurland, E.S., Cosman, F., McMahon, D.J., Rosen, C.J., Lindsay, R., Bilezikian, J.P. (2000). Parathyroid Hormone as a Therapy for Idiopathic Osteoporosis in Men: Effects on Bone Mineral Density and Bone Markers. The Journal of Clinical Endocrinology & Metabolism, 85(9): 3069-3078.
Summary:

Osteoporosis is a common and well-known condition primarily affecting post-menopausal women. There are, however, a significant proportion of cases in which osteoporosis affects middle-aged men, consuming more than 2 billion dollars in health care costs and accounting for 20% of fractures in the U.S. annually. Of all male cases, 40% are determined to be idiopathic; that is, with unknown determinate cause.

It is important that male cases and female cases be approached differently because the disease causing mechanisms are speculated to be quite different. Female osteoporosis has symptoms caused by factors that increase bone turnover, whereas idiopathic male osteoporosis involves depressed bone turnover, though the mechanisms causing this decrease are yet to be determined. Although antiresorptive medications, like estrogen and calcitonin, may be effective in female forms of the condition, they are proving to be inefficient or unsuitable to treat affected males. The nature of a low bone-turnover pathological is state requires an anabolic agent to restore or rebuild lost materials.

This study was conducted over an 18 month period with 23 male subjects diagnosed with idiopathic osteoporosis. Their ages ranged from 30 to 68 with a mean age of 50. All patients recieved 1500 mg of calcium and 400 units of vitamin D each day, and ten randomly chosen subjects of this group recieved 400 units of PTH in addition to this regimen. Every 3 months serum, urine and bone markers for turnover were analysed, while every 6 months bone densities were measured at three points commonly affected by osteoporosis in men; hip, lumbar spine and radius (forearm).

Parathyroid hormone is known to stimulate bone resorption when serum calcium is low by indirectly stimulating osteoclast bone cells to resorb bone. PTH acts on the osteoblast, or bone forming cells, which then stimulate osteoclasts to proliferate. While it may seem counterintuitive that treating osteoporosis patients with PTH would increase bone density, administering PTH was found to significantly reverse the effects of bone loss in the hip and lumbar spine in male patients as compared to control subjects. After 18 months, lumbar spine bone mass increased by 13.5% (p<0.001),>

The results observed in this study along with other studies have led to the conclusion that PTH stimulates skeletal dynamics in males with osteoporosis associated with low bone turn-over, by increasing bone mass in hip and spine. The experimenters thus conclude that PTH has potential as an anabolic agent to treat male idiopathic osteoporosis.

Critique

- The paper was well written and related the value of discovering anabolic treatments for male forms of osteoporosis as they are often overlooked and underestimated in their prevalence.

- The experimental design was excellent in terms of reducing error/bias. Subjects were placed into groups randomly, and within these groups well matched on clinical characteristics such as age, BMI, smoking, exercise and previous drug history. The subjects to recieve PTH treatment were chosen randomly from the groups. The study was double-blind and placebo-controlled.

- The researchers cited a previous study that had measured similar features of this PTH regimen and obtained success, however there were considerable flaws in the experimental design. This study was done as a follow-up with some variations in an attempt to fix the experiment to determine if their results were significant.

- In terms of changing the initial protocol, 2 of the 10 patients treated with PTH were found to have elevated serum calcium during the course of the experiment. The dosage for these patients was diluted to normalize calcium levels, yet they do not explain how this change affected the measurement of serum calcium levels that they found not to be significant during treatment. They cited the decreased dose while noting that even by lowering the amount of PTH given, bone density still rose for these subjects.

Possible Future Experiments:

Question: What is the effect on other bones of the body that could be affected by osteoporosis in male subjects?

- It would be useful to undertake more extensive studies of other bones, typically those under postural stress like the femur, to determine if there would be increased bone mass or no change like that of the radius in the study. It would be a huge setback if the treatment were to be marketed and it was found that some bones had increased densities while other had losses.

Question: Though the treatment worked for the three bones studied, did the overall bone mass measured for the individuals rise significantly?

- This could easily be measured as there are instruments available as compact as special scales to measure bone mass of the entire body. However, it is unknown if the bone density increases would have been significant when the entire body was taken into consideration.

Assignment #3 - Function and Pathology of Parathyroid Hormone

Function of Parathyroid Hormone

Parathyroid hormone functions to maintain calcium homeostasis by elevating concentrations through a variety of mechanisms when calcium-sensing receptors detect a drop in serum levels (Griffin & Ojeda, 2004). PTH also functions to decrease concentrations of phosphate ions by reducing phosphate reabsorption in kidney tubules; thus levels are lowered when phosphate is lost in urine (Hadley & Levine, 2006).

In order to raise serum Ca2+ and lower PO4-3, parathyroid hormone acts either directly or indirectly through mechanisms that incorporate bone, kidney and intestines (Hadley & Levine, 2006). These actions can be categorized as follows:


PTH on bone

PTH plays a role in mineral metabolism in order to raise serum calcium should it become low. As PTH is known to release calcium from bone into plasma, at first it seems counterintuitive that stromal osteoblast cells of the bone marrow are stimulated in the presence of the hormone. However, in response to PTH the osteoblast cells will increase expression of RANKL, a molecule that will bind to the RANK receptor on osteoclast precursor molecules, causing them to differentiate into mature cells. The creation of new osteoclasts increases bone resorption, a process that releases free Ca2+ to the serum (Hadley & Levine, 2006). This breakdown of bone, or osteolysis, also releases phosphate into circulation, but at lesser amounts than that of phosphate leaving the body through excretion.





PTH on renal tubules of the kidney

Parathyroid hormone also increases reabsorption of calcium in the proximal tubule of the kidney (Hadley & Levine, 2006).

PTH on intestine, indirectly through kidney

PTH stimulates the kidney to activate vitamin D by up-regulating the enzyme responsible for converting 25-hydroxy vitamin D, to its active form (1,25-dihydroxy vitamin D) in a hydroxylation reaction (Griffin & Ojeda, 2004). The active form of vitamin D is then able to absorb more calcium in the intestine.




Pathology

Hyperparathyroidism:

Overactivity of one or more parathyroid glands leading to excessive PTH secretion (Griffin & Ojeda, 2004). The excess PTH causes a marked increase in bone resorption and calcium absorption in the intestine leading to hypercalcemia in the blood as well as low phosphate levels.
Symptoms include those connected to high plasma calcium levels, for example, renal stones as a result of excessive calcium in the kidney and neurological symptoms since calcium plays such a large role in the nervous system. Weak bones and osteoporosis-like state are also associated with hyperparathyroidism due to a net resorption of minerals from the bones.


Causes include adenomas or PTH-secreting tumors, classified as primary hyperparathyroidism, overactive osteoclasts or a significantly higher production of active vitamin D than normal. In this case, the overactive gland can be surgically removed or calcitonin supplements given to maintain calcium homeostasis.

Hyperparathyroidism effects

Hypoparathyroidism:

Decreased activity of parathyroid glands resulting in low PTH levels and hypocalcemia (Griffin & Ojeda, 2004).

Low serum calcium can be dangerous because most cells, including neurons, require calcium to exert any effect on bodily functions. Thus, many neurological and neuromuscular symptoms are seen, such as seizures, nerve and skin pain, tetany of muscles and muscles spasms, including those muscles in the pharynx.

Hypoparathyroidism can result due to the accidental removal of one or more parathyroid glands during surgery (i.e. during a thyroidectomy). Autoimmune disorders may result in destruction of the parathyroid glands as well as affecting other organs. DiGeorge syndrome is a genetic disorder resulting in deletion of the locus coding parathyroid glands. A severe vitamin D deficiency can also result in hypoparathyroidism, and is reversible by increasing vitamin D consumption. Idiopathic forms also exist and are caused by an autosomal recessive inheritance pattern. In addition, pseudohypoparathyroidism results in the same lowered blood calcium, but it is due to the target organs upon which PTH acts being resistant to the hormone. Diet modifications are important in treatment, and intravenous calcium may be given with caution.

References:

Griffin, J. E., Ojeda, S. R. 2004. Textbook of Endocrine Physiology. Oxford University Press, New York.

Hadley, M. E., Levine, J. E. 2006. Endocrinology, 6th Ed. Pearson Prentice Hall, New Jersey.