May is osteoporosis month.

During the past year, the field of osteoporosis has witnessed many significant developments that are paving the way for great future advancements in the management of this condition. In July 2002, the National Institutes of Health announced unexpectedly that it was terminating the arm of the Women's Health Initiative (WHI) study in which patients were assigned randomly to be administered either conjugated equine estrogen and medroxyprogesterone acetate therapy or placebo. This decision was made on the basis of conclusions drawn by the Data Safety Monitoring Board that the adverse effects of such medication regimens exceeded the potential benefits.'

The WHI study was designed to evaluate the long-term effects of various hormone replacement therapy (HRT) options. More than 160,000 postmenopausal women were recruited nationwide between 1993 and 1998 in centers across the United States. Each arm of the study was designed to examine the effects of a different HRT regimen. (1) It is important to emphasize that the National Institutes of Health terminated only the arm of the study in which the effects of conjugated equine estrogen and medroxyprogesterone acetate were being examined. That arm of the study included more than 16,000 patients. The other arms of the study are continuing, presumably because the potential adverse effects of those HRT regimens do not exceed the potential benefits. The results and potential impact of the WHI study were reviewed extensively in the September 2002 issue of Southern Medical Journal. (2-8)

HRT is not approved for the prevention of coronary artery disease, and although it is approved for the prevention of osteoporosis, caution should be exercised in administering it to patients. Patients should be monitored regularly, and the lowest effective dose should be prescribed for the shortest possible duration. (9) Debate continues regarding continuing long-term HRT in women who already have been on an HRT regimen for a number of years. As more evidence becomes available, however, a general consensus probably will emerge that discontinuation of long-term HRT is advisable. This theory is supported by the U.S. Food and Drug Administration requirement that all products containing estrogen, regardless of type and whether a product combines estrogen with progesterone, carry a highlighted warning (ie, inside a box on the label, the most significant cautionary warning) stating that the risk of heart attack, stroke, breast cancer, and blood clots is increased with the prolonged use of such products. (9)

In December 2002, the U.S. Food and Drug Administration approved the use of subcutaneous teriparatide (Forteo; Eli Lilly and Co., Indianapolis, IN) 20 [micro]g/d to treat patients with osteoporosis. Teriparatide is made up of the first 34 amino acids found in the N-terminal region of the human parathyroid hormone (PTH), which comprises a single chain of 84 amino acids. (10-13) It seems counterintuitive that PTH could be used to treat osteoporosis, because it is a wellknown fact that hyperparathyroidism increases bone resorption, which leads to osteoporosis. An important finding, however, showed that if PTH is administered for 1 or 2 hours per day as opposed to continuously, this intermittent administration stimulates the osteoblasts to a much greater degree than the osteoclasts, thus leading to a net increase in bone mass. (14-15) It is interesting to note that findings of an increase in bone density after the administration of PTH were reported as early as 1970 16-20 and that several studies have documented a positive effect of PTH in patients with osteoporosis. (21-32) It took more than 3 decades to apply this observation and make this therapeutic modality available to patients.

The availability of teriparatide represents a major landmark in the treatment of osteoporosis because it is the first therapeutic modality to target the osteoblasts specifically and increase the rate of bone formation as opposed to targeting the osteoclasts and reducing the rate of bone resorption. The effects of teriparatide are impressive, in terms of both increasing bone mass and reducing the risk of fracture. (21-31) The main disadvantage of teriparatide, however, is that it must be administered parenterally once per day. Because the effectiveness of teriparatide relies on PTH blood levels, which are expected to increase and decrease during a period of 1 to 2 hours, it is unlikely that an oral preparation will be made available. Nevertheless, it is possible that similar effects may be achieved with an intranasal preparation.

Clinicians must not forget that osteoporosis is largely a preventable condition. An adequate daily intake of calcium, sufficient physical exercise, and the avoidance of cigarette smoking are the mainstays of prevention. Regrettably, many Americans are at risk of developing osteoporosis because they do not follow these three guidelines. It is indeed ironic that the most affluent nation in the world remains disappointingly uneducated about the basics of healthy eating habits and that both obesity and osteoporosis are increasingly prevalent in the United States. In this society in which soda-dispensing machines prevail, it is becoming progressively more difficult to obtain milk or other dairy products. Although a great deal is known about the prevention of both osteoporosis and obesity, the medical community has not been successful in integrating this knowledge into the everyday lives of Americans. In this respect, we have not met our responsibility.

References

(1.) Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperbcrg C, Stefanick ML, et al; writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321-333.

(2.) Hamdy RC. Lessons learned from the Women's Health Initiative study. South Med J 2002;95:951-952 (editorial).

(3.) Watts NB. Lessons from the Women's Health Initiative. South Med J 2002;95:952-955 (editorial).

(4.) Jelovsek FR. A gynecologist's view of hormone replacement therapy in light of the Women's Health Initiative. South Med J 2002;95:955-957 (editorial).

(5.) Muse K. After the Women's Health Initiative: What to tell our patients. South Med J 2002;95:957-959 (editorial).

(6.) Alpert MA. Hormone replacement therapy to reduce cardiovascular risk: A concept whose time has passed? South Med J 2002;95:959-961 (editorial).

(7.) Peiris A, Iskandar S. Hormone replacement therapy and lipids: Time to reconsider our options? South Med J 2002;95:961-963 (editorial).

(8.) Krishnan K, Karnad AB. The rise and fall of hormone replacement therapy: Oncologists' views. South Med J 2002;95:963-965 (editorial).

(9.) Stephenson J. FDA orders estrogen safety warnings: Agency offers guidance for HRT use. JAMA 2003;289:537-538.

(10.) Brewer HB Jr, Fairwell T, Ronan R, Sizemore GW, Arnaud CD. Human parathyroid hormone: Amino-acid sequence of the amino-terminal residues 1-34. Proc Natl Acad Sci U S A 1972;69:3585-358.

(11.) Juppner HW, Gardella TJ, Brown EM, Kronenberg HM, Potts JT Jr. Parathyroid hormone and parathyroid hormone related peptide in the regulation of calcium homeostasis and bone development, in DeGroot LJ, Jameson JL (eds): Endocrinology: Parathyroid, Thyroid, Adrenal. Philadelphia, W.B. Saunders Co., 2001, vol 2, ed 4, pp 969-998.

(12.) Niall HD, Sauer RT, Jacobs JW, Keutmann HT, Segre GV, O'Riordan JL, et al. The amino-acid sequence of the amino-terminal 37 residues of human parathyroid hormone. Proc Natl Acad Sci USA 1974;71:384-388.

(13.) Potts JT Jr, Tregear GW, Keutmann HT, Niall HD, Sauer R, Deftos LI, et al. Synthesis of a biologically active N-terminal tetratriacontapeptide of parathyroid hormone. Proc Natl Acad Sci U S A 1971;68:63-67.

(14.) Dobnig H, Turner RT. The effects of programmed administration of human parathyroid hormone fragment (1-34) on bone histomorphometry and serum chemistry in rats. Endocrinology 1997;138:4607-4612.

(15.) Dobnig H, Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology 1995;136:3632-3638.

(16.) Kalu DN, Doyle FH, Pennock J, Foster GV. Parathyroid hormone and experimental osteoselerosis. Lancet 1970;1:1363-1366.

(17.) Podbesek R, Edouard C, Meunier PJ, Parsons JA, Reeve J, Stevenson RW, et al. Effects of two treatment regimes with synthetic human parathyroid hormone fragment on bone formation and the tissue balance of trabecular bone in greyhounds. Endocrinology 1983;112:1000-1006.

(18.) Reeve J, Meunier PJ, Parsons JA, Bernat M, Bijvoet OL, Courpron P, et al. Anabolic effect of human parathyroid hormone fragment on trabecular bone in involutional osteoporosis: A multicentre trial. Br Med J 1980;280: 1340-1344.

(19.) Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption: A hypothesis. Calcif Tissue Int 1981;33:349-351.

(20.) Tam CS, Heersehe JN, Murray TM, Parsons JA. Parathyroid hormone stimulates the hone apposition rate independently of its resorptive action: Differential effects of intermittent and continuous administration. Endocrinology 1982;110:506-512.

(21.) Cosman F, Lindsay R. Is parathyroid hormone a therapeutic option for osteoporosis? A review of the clinical evidence. Calcif Tissue in 1998;62475-480.

(22.) Cosman F, Nieves J, Woelfert L, Formica C, Gordon S, Shen V, et al. Parathyroid hormone added to established hormone therapy: Effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal. Bone Miner Res 2001;16:925-931.

(23.) Dempster DW, Cosman F, Kurland ES, Zhou H, Nieves J, Woelfert L, et al. Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: A paired biopsy study. J Bone Miner Res 2001;16:1846-1853.

(24.) Finkelstein JS, Klibanski A, Arnold AL, Toth TL, Hornstein MD, Neer RM. Prevention of estrogen deficiency-related bone loss with human parathyroid hormone (1-34): A randomized controlled trial. JAMA 1998; 280:1067-1073.

(25.) Hodsman AB, Fraher LJ, Watson PH, Ostbye T, Stitt LW, Adachi ID, et al. A randomized controlled trial to compare the efficacy of cyclical parathyroid hormone versus cyclical parathyroid hormone and sequential calcitonin to improve bone mass in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 1997;82:620-628.

(26.) Hodsman AB, Kisiel M, Adachi ID, Fraher LJ, Watson PH. Histomorphometric evidence for increased bone turnover without change in cortical thickness or porosity after 2 years of cyclical hPTH(1-34) therapy in women with severe osteoporosis. Bone 2000;27:311-318.

(27.) Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC. Increased bone formation by prevention of osteoblast apoptosis with paratliyroid hormone. J Clin Invest 1999;104:439-446.

(28.) Kurland ES, Cosman F, MeMabon 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;85:3069-3076.

(29.) Lindsay R, Nieves J, Formica C, Henneman E, Woelfert L, Shen V, et al. Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis. Lancet 1997;350:550-555.

(30.) Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engi J Med 2001;344:1434-1441.

(31.) Roe EB, Sanchez SD, Del Puerto GA, Pierini E, Bacchetti P, Cann CE, et al. Parathyroid hormone 1-34 and estrogen produce dramatic bone density increases in postmenopausal osteoporosis: Results from a placebo-controlled randomized trial. J Bone Miner Res 1999;14(Suppl 1): S137.