PTH (1-34): a novel anabolic drug for the treatment of osteoporosis.

Abstract: The management of osteoporosis has in the past included providing patients with an adequate source of calcium and vitamin D and consideration of some type of antiresorption therapy such as hormone replacement, SERM therapy, or bisphosphonate therapy. However, patients who have very low bone density and continue to have fractures while receiving these therapies need to consider being treated with the recently approved novel anabolic drug PTH (1-34) (Forteo). The osteoblast has the receptor for parathyroid hormone (PTH). When PTH (1-34) is given in a pulsatile fashion, for example a daily subcutaneous injection, it stimulates osteoblasts to make new bone. PTH (1-34) has been shown to markedly increase spinal bone density and increase hip bone density. In addition, the relative risk of having moderate vertebral fracture was reduced by 90%. Thus, PTH (1-34) offers an exciting new approach for the treatment of severe osteoporosis.

Key Words: anabolic drugs, osteoblast, osteoporosis, parathyroid hormone

**********

Parathyroid hormone (PTH) has always been recognized as an important calciotropic hormone responsible for maintaining serum calcium levels within the physiologically acceptable range. It accomplishes this by enhancing tubular reabsorption of calcium in the kidneys, increasing the renal production of 1,25-dihydroxyvitamin D [1,25(OH)[.sub.2]D], which, in turn, enhances intestinal calcium absorption, and by mobilizing bone calcium stores from the skeleton. PTH is considered to be a catabolic hormone for bone metabolism. The recent recognition that the osteoblast has a PTH receptor has provided a new insight into the anabolic role of PTH on the skeleton and the use of PTH and its active analog PTH (1-34) for treating osteoporosis.

Historic Perspective

The parathyroid glands were the last major organ to be recognized in humans. Ivar Sandstrom, a Swedish medical student, first discovered them in dogs in 1877, then verified their presence in humans. (1) In 1906, Jacob Erdheim concluded that PTH was related to calcium metabolism and bone disease. In a letter dated June 9, 1922, Eli Lilly and Company expressed general interest in "gland products" from the parathyroids. Dr. J.B. Collip had previously collaborated with Eli Lilly and Company in the development of insulin. A similar collaborative relationship was established between Collip and Lilly chemist H.W. Rhodehamel to prepare a purified extract, marketed by 1925 as Para-Thor-Mone. Para-Thor-Mone was presented as a "Hormone or hormones of the parathyroid gland, stabilized and standardized." (1,2) In 1929, Bauer, Aub, and Albright (3) administered parathormone to growing rabbits, cats, and rats to test their hypothesis that bone trabeculae acted as a reserve supply of calcium. The thought was that cancellous or trabecular bone was well suited as a reserve because it was most numerous at the epiphyseal ends of the bones, where the blood supply was greatest, and that the delicate, lace-like structure of trabecular bone, in close relation to the bone marrow, was well situated to receive calcium deposits in times of calcium excess and to give up calcium in times of calcium demand. During these experiments, they learned that although parathyroid extract had no effect on trabeculae in growing rabbits or kittens, the extract increased the number of trabeculae in rats. (3) Finally, in 1932, Selye (4) provided histologic evidence that bovine parathyroid extract from Eli Lilly and Company stimulated osteoblast production and bone formation.

Dobnig and Turner (5) reported that when PTH (1-34) was given as either a subcutaneous injection or infused 1 hour per day, it markedly increased trabecular bone parameters and percentage of osteoblasts compared with continuous infusion of PTH. Of great importance was their observation that PTH given either subcutaneously or 1 or 2 hours per day had little increase in the percentage of osteoclasts in the bone, whereas continuous infusion markedly increased the number of osteoclasts in male rat bone. These data set the stage for Sato et al (6) to demonstrate that ovariectomized monkeys had marked increases in vertebral strength and bone mass after receiving PTH (1-34) at 1 or 5 [micro]g/kg.

Clinical Utility of PTH for Osteoporosis

Lindsay et al (7) observed that postmenopausal women who received PTH (1-34) with hormone replacement therapy compared with women receiving hormone replacement therapy alone had a 13% increase in the density of the lumbosacral spine. An 8% overall increase was observed in total body mineral content. Roe et al (8) conducted a similar study and observed median increases above baseline in spinal bone mineral density (BMD) of 9.2%, 20.6%, 23.6%, and 29.2% at 6, 12, 18, and 24 months, respectively, in women receiving PTH (1-34) plus hormone replacement therapy compared with women receiving hormone replacement therapy only. PTH (1-34) in combination with hormone replacement therapy was also effective in increasing spinal bone density in women with glucocorticoid-induced osteoporosis. Lumbar spine BMD increased by 11.8% after 12 months of human parathyroid hormone (1-34) [hPTH (1-34)] treatment and was maintained at 11.9% above baseline at 24 months [which included 12 months off hPTH (1-34)] (P < 0.001). (9,10) PTH (1-34) was found to be equally effective in increasing BMD of the lumbar spine in men with idiopathic osteoporosis. A 5.9% increase was observed after 10 months (Fig. 1). (11)

The defining study that supported the Food and Drug Administration (FDA) approval that PTH (1-34) (Teriparatide) was an effective anabolic agent for the treatment of osteoporosis was reported by Neer et al. (12) A prospective, randomized, double-blinded, multinational trial of 1,637 postmenopausal women with prior vertebral fractures received either 20 or 40 [micro]g of recombinant human PTH (1-34) by once-daily subcutaneous self-injection for up to 2 years. The placebo group also received a once-daily subcutaneous injection of vehicle, and all participants received a supplement of 1,000 mg of calcium and 400 to 1,200 IU of vitamin D per day. Within 3 months, women receiving either 20 or 40 [micro]g of PTH (1-34) subcutaneously daily had an almost 4% increase in their BMD of the lumbar spine. This continued to increase, and after 18 months overall, there was a 10% and 15% increase, respectively, in spinal bone density for women receiving either 20 or 40 [micro]g of PTH (1-34) (Fig. 2A). There was no significant difference from baseline in the bone density at either skeletal site for the women receiving the placebo injection. Ninety-six percent of the patients treated with either dose of PTH (1-34) had significant improvement in lumbar spine BMD. At the end of the study, total hip BMD decreased by a mean of 1% in the placebo group but increased by 2.6% and 3.6% respectively in the women given PTH (1-34) at either 20 or 40 [micro]g, (Fig. 2). The femoral neck BMD decreased by 0.7% in the placebo group and increased by 2.8% and 5.1% in the women who received either 20 or 40 [micro]g of PTH (1-34). Total body calcium (bone mineral content) increased 1.9% and 2.8% for women receiving 20 or 40 [micro]g of PTH (1-34), compared with a decrease of 0.7% in the placebo group. Ten percent of women assigned to placebo had new vertebral fractures that were moderate to severe in degree, whereas only 1 to 2% of women assigned to treatment with PTH (1-34) had such a fracture. The relative risk corresponded to a 90% and 78% reduction in risk of having a moderate or vertebral fracture in women treated with 20 or 40 [micro]g of PTH (1-34), respectively (Fig. 3A). The absolute risk of fracture was reduced from 9.4 to 0.9% and 2.1%. For women who had two or more vertebral fractures, there was a corresponding 77% and 86% reduction in risk of having multiple vertebral fractures for women on either 20 or 40 [micro]g PTH (1-34) (Fig. 3). There was an average 1.11-cm fracture-associated height loss in the placebo group, compared with 0.21 cm and 0.31 cm losses for the women treated with PTH (1-34) at either 20 or 40 [micro]g, respectively. Similarly, PTH (1-34) reduced the risk of one or more nonvertebral fragility fractures by 53% and 54% respectively for women receiving 20 and 40 [micro]g of PTH (1-34).

[FIGURE 1 OMITTED]

[FIGURE 2 OMITTED]

Bone biopsy results demonstrated no woven bone, mineralization defects, hypercellularity, or abnormal architecture. There was a significant increase in trabecular bone volume, mineral apposition rate, or orthogonal intercept length compared with placebo (Fig. 4). There was no increase in cortical porosity in the group receiving 20 [micro]g of PTH (1-34).

Safety

Hypercalcemia was either absent or mild and transient, reoccurring 4 hours after the subcutaneous injection. The mean 24-hour urine calcium increased by 0.75 mmol/d (30 mg/d). No clinically adverse events were associated with increases in serum or urine calcium. The only significant adverse event was increased risk of leg cramping.

[FIGURE 3 OMITTED]

[FIGURE 4 OMITTED]

Black Box Warning

In a 2-year rat study wherein test subjects received 30 to 60 times the dose approved by the FDA for the treatment of osteoporosis, marked increases in bone mass were noted in addition to an increase in the number of bone proliferative lesions, including osteosarcomas. The rat skeleton has an exaggerated response to PTH (1-34). (13) It was well known that rats are prone to development of osteosarcoma and there-fore it was not surprising that PTH (1-34), which is an anabolic agent on osteoblasts, significantly increased the risk of osteosarcoma in rats who received 30 to 60 times the human dose from neonatal life for 2 years.

To put this into perspective, it is also well known that patients with long-standing primary hyperparathyroidism and patients with chronic renal failure who have markedly elevated levels of PTH for prolonged periods of time are not at increased risk of osteosarcoma. Thus, when the lack of a clinical association with primary hyperparathyroidism and osteosarcoma in humans in a large national cancer registry was noted, the FDA gave its approval for the use of PTH (1-34) for the treatment of osteoporosis in both men and women.

Conclusion

A single daily subcutaneous injection of PTH (1-34) has demonstrated remarkable improvement in the BMD of both hip and spine, one that is directly correlative with marked decreases in both vertebral and nonvertebral fractures. Recent studies that evaluated a combination of PTH (1-34) with 10 mg of alendronate daily suggest that combination therapy was less effective than PTH (1-34) or PTH (1-84) alone. (14,15) Clearly, PTH (1-34) offers physicians an exciting new medication as part of their armamentarium to treat osteoporosis. This drug should be used in both female and male patients who have failed other approved osteoporosis medications.

References

1. Breimer L, Sourander P. The discovery of the parathyroid glands in 1880: triumph and tragedy of Ivar Sandstrom. Bull Hist Med 1981;55:558-563.

2. Eknoyan G. A history of the parathyroid glands. Am J Kidney Dis 1995;26:801-807.

3. Bauer W, Aub AC, Albright F. Studies of calcium and phosphorus metabolism, V: a study of the bone trabeculae as a readily available reserve of calcium. J Exp Med 1929;49:145-161.

4. Selye H. On the stimulation of new bone formation with parathyroid extract and irradiated ergosterol. Endocrinology 1932;16:547-558.

5. 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.

6. Sato M, Westmore M, Clendenon J, et al. Three-dimensional modeling of the effects of parathyroid hormone on bone distribution in lumbar vertebrae of ovariectomized cynomolgus macaques. Osteporos Int 2000;11:871-880.

7. Lindsay R, Nieves J, Formica C, 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.

8. Roe EB, Sanchez SD, del Puerto GA, et al. Parathyroid hormone 1-34 [hPTH(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.

9. Lane NE, Sanchez S, Modin GW, et al. Parathyroid hormone treatment can reverse corticosteroid-induced osteoporosis. J Clin Invest 1998;102:1627-1633.

10. Lane NE, Sanchez S, Modin GW, et al. Bone mass continues to increase at the hip after parathyroid hormone treatment is discontinued in glucocorticoid-induced osteoporosis: results of a randomized controlled clinical trial. J Bone Miner Res 2000;15:944-591.

11. Orwoll E, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis. J Bone Miner Res 2003;18:9-17.

12. Neer RM, Arnaud CD, Zanchetta JR, et al. Recombinant human PTH [rhPTH(1-34)] reduces the risk of spine and non-spine fractures in post-menopausal osteoporosis. N Engl J Med 2001;344:1434-1441.

13. Mitlak BH, Williams DC, Bryant HU, et al. Intermittent administration of bovine PTH-(1-34) increases serum 1,25-dihydroxyvitamin D concentrations and spinal bone density in senile (23 month) rats. J Bone Min Res 1992;7:479-484.

14. Vegni FE, Corradini C, Privitera G, et al, the PaTH (Parathyroid Hormone and Alendronate) Study Investigators. Effects of parathyroid hormone and alendronate alone or in combination in osteoporosis. N Engl J Med 2004;350:189-192.

15. Finkelstein JS, Hayes MSN, Hunzelman JL, et al. The effects of parathyroid hormone, aleudronate, or both in men with osteoporosis. N Engl J Med 2003;349:1216-1226.

Michael F. Holick, MD, PHD

From the Vitamin D, Skin and Bone Research Laboratory, Section of Endocrinology, Diabetes, and Nutrition, Department of Medicine, Boston University School of Medicine, Boston, MA.

Funded by the Speaker's Bureau for Lilly, Merck and P & G. This work was supported in part by NIH grant MO1RR00533.

Reprint requests to Dr. Michael F. Holick, 715 Albany Street, M-1013, Boston, MA 02118. Email: [e-mail]

Accepted June 4, 2004.

RELATED ARTICLE: Key Points

* Parathyroid hormone (PTH) is a novel anabolic drug for osteoporosis.

* PTH (1-34) (Forteo) is effective in reducing vertebral and nonvertebral fractures.

* PTH (1-34) has been approved for the treatment of osteoporosis in both women and men who failed therapies.

* There are essentially no side effects from PTH (1-34) therapy.

* There is a black box warning for PTH (1-34) that is based on the fact that rats given large doses of PTH (1-34) have an increased risk of osteosarcoma.

* There is no evidence that PTH (1-34) causes bone cancer in humans.