Introduction: There have been many forms of treatment for osteoporosis developed, including the popular estrogen therapy, selective estrogen-receptor modulators, biphosphates, calcitonin, vitamin D, and calcitriol. All of these have been shown to reduce bone resorption by osteoclasts and thus increase bone mass. However, normal bone mass is never regained.
Parathyroid hormone, or it's amino-terminal fragments (it is unknown which part of the molecule is responsible for its effects), works to decrease bone resorption, and increase bone formation and mass, thus partially reversing bone loss. However, this is only true when administered on a daily basis subcutaneously due to transient increases in serum levels. Continuous administration actually lead to an increase in bone resorption and decrease in bone mass, as parathyroid hormone is known to stimulate the activity of osteoclasts (Martini, 2006).
Prediction: parathyroid hormone treatment will provide protection against fractures; both vertebral and non-vertebral.
Materials & Methods:
The prediction was tested using postmenopausal women who had had previous vertebral fractures. During the transition to menopause, the body reduces its secretion of estrogens, which stimulate the activity of osteocytes and the production of new bone matrix (Martini, 2006). While the average age of menopause, defined by one year cessation of menstruation, is 51, those with early onset are at increased risk for osteoporsis (Cummings et al., 1985). The presence of a prior vertebral fracture actually increases the risk of another at least 4-fold (Ettinger et al., 1999) thus making these women a good experimental group. The 1637 women chosen for the study had to possess several criteria:
- they must have been menopausal for at least 5 years.
- they must have had one moderate or two mild vertebral fractures.
- they must be capable of walking (i.e. have sufficient bone mass).
- bone mineral density (hip or lumbar spine) at least 1 SD below the normal mean value if less than two moderate fractures.
- exclusion of women with illnesses that affect bone or calcium metabolism.
All women were given a daily regime, consisting of calcium supplements and vitamen D, to ensure consistant nutrient consumption. For the first two weeks of the study, women had self-administered daily injections of placebo. After this, random selection placed the women into one of three experimental groups:
- Those who continued to receive the placebo
- Those who received 20µg of recombinant human parathyroid hormone
- Those who received 40 µg of recombinant human parathyroid hormone
Each group continued with their self-administered daily injections.
Tests were done at the beggining, throughout, and at the end of the study.
Radiographs of the thoracic and lumbar spine were graded as:
- Normal (i.e. normal height)
- Mildly deformed (i.e. decrease in height of 20 to 25%)
- Moderately deformed (i.e. decrease in height of 26 to 40%)
- Severely deformed (i.e. decrease in height of more than 40%)
Bone mineral density was measured in several locations, as well as the total-body bone mineral using Hologic, Lunar, and Norland dual-energy x-ray absorptiometry. Osteoporosis is defined by the reduction in bone mass it creates. Therefore any sigficant changes seen, even if no significant change in the frequency of fractures is found, suggests that the parathyroid hormome is in fact working, and may help after a longer treatment period.
Results:
New vertebral fractures were found in:
- 14 % of the women in the placebo group
- 5 % of the women in the 20-μg parathyroid hormone group (35% risk of fracture)
- 4 % of the women in the 40-μg parathyroid hormone group (31% risk of fracture)
New non-vertebral fragility fractures were found in:
- 6 % of the women in the placebo group
- 3 % of those in each parathyroid hormone group (relative risk = 47 and 46% respectively)
Figure 1. Cumulative Proportion of Women Assigned to Receive Placebo or Parathyroid Hormone (1-34) (PTH) at a Daily Dose of 20 µg or 40 µg Who Had One or More Nonvertebral Fractures (Panel A) and the Cumulative Proportion Who Had One or More Nonvertebral Fragility Fractures (Panel B) during the Study. (from https://content.nejm.org/cgi/content/full/344/19/1434#F1)Comparison with Placebo results:
Increases in bone density was observed with both the 20-μg and 40-μg parathyroid hormone doses; results were variable among the different regions tested, but ranged from 3% in the femoral head to 13% in the lumbar region.
20-μg and 40-μg parathyroid hormone doses increased total-body bone mineral by 2-4%.
The 40-μg parathyroid hormone doses did, however, lead to decreased bone density of the radial shaft slightly (2%).
Occasional minor side effects included:
- headaches
- nausea
Conclusion:
Treatment of postmenopausal women with daily injections of parathyroid hormone:
- Decreased the risk of both vertebral and non-vertebral fractures.
- Increasing bone density in the femoral neck, vertebrae, and increase of total-body bone mineral density.
- Few side-effects were found.
- The 40-μg parathyroid hormone dose increased bone density more than the 20-μg parathyroid hormone dose.
It is important to note that, while the 40-μg parathyroid hormone dose did increase bone density more, the risks of fracture were similar. Because more side-effects were observed with the higher dosage, 20-μg of parathyroid would be a sensible daily dosage for postmenopausal women.
Overall I thought the study was well done, concise, and interesting! This is good news for postmenopausal women and may become a very popular form of treatment for osteoporosis. Reducing the risk of fractures is essential, as they can lead to both loss of mobility and loss of independence, as well as an earlier death.
The paper was well organized with sufficient tables and graphs, as well as easy to read and understand.
Figure 2: Preotact; a reusable fixed-dose pen for daily subcutaneous injections of parathyroid hormone ( 71.4 µL doses) by Nycomed and NPS Pharmaceutical now available (2003). (from http://www.ypsomed.com/en/346.html)
References:
Cummings , SR, JL Kelsey, MC Nevitt, and KJ O'Dowd. "Epidemiology of osteoporosis and osteoporotic fractures." Epidemiol Rev 7(1985): 178-208.
Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. "Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: Results from a 3-year randomized clinical trial." JAMA 282(1999): 637-645.
Martini, Frederic H.. Fundamentals of Anatomy & Physiology. 7th ed. San Francisco: Pearson Education Inc., 2006.
Neer, Robert M., Claude D. Arnaud, Jose R. Zanchetta, Richard Prince, Gregory A. Gaich, Jean-Yves Reginster, Anthony B. Hodsman, Erik F. Eriksen, Sophia Ish-Shalom, Harry K. Genant, Ouhong Wang, Bruce H. Mitlak, Dan Mellstrom, Erik S. Oefjord, Ewa Marcinowska-Suchowierska, Jorma Salmi, Henk Mulder, Johan Halse, and Andrzej Z. Sawicki. "Effect of Parathyroid Hormone (1-34) on Fractures and Bone Mineral Density in Postmenopausal Women with Osteoporosis." The New England Journal of Medicine 344 (2001): 1434-1441.
