Indian Journal of Pharmacology Medknow Publications on behalf of Indian Pharmacological Society ISSN: 0253-7613 EISSN: 1998-3751 Vol. 36, Num. 1, 2004, pp. 48-49

Indian Journal of Pharmacology, Vol. 36, No. 1, Feb, 2004, pp. 48-49

Molecules of the Millennium

Novel agents in osteoporosis

Compiled by: H. D. Shah

Department of Pharmacology, L. M. College of Pharmacy, Navrangpura, Ahmedabad - 380009, India.

Code Number: ph04018

Osteoporosis is characterized by a decrease in bone mass and a deterioration in skeletal micro architecture. One of the major determinants of skeletal weakness is bone loss that occurs after menopause. The bone loss is a consequence of an increased osteoclastic resorption that is only partially compensated by a moderate rise in the rate of bone formation by osteoblasts.¹ The objective in treating established osteoporosis is to prevent further skeletal deterioration and to increase bone mass or improve bone micro architecture to reduce the risk of vertebral and/or peripheral fractures.²

Estrogen, calcitonin and early generation biphosphonates were considered effective and well tolerated agents for maintaining bone mineral density (BMD) of trabecular and cortical bone at premenopausal levels.³ However, primary prevention of osteoporosis initiated in the immediate post menopause is not yet considered a public health priority. None of the available medications have unequivocally demonstrated their ability to fully prevent the occurrence of new vertebral or peripheral osteoporotic fracture once the disease is established.

The newer therapeutic approaches for the prevention of postmenopausal osteoporosis have been selective estrogen receptor modulators (SERMs) and second and third generation biphosphonates). This article highlights some of these promising agents in the treatment of osteoporosis.

Raloxifene

SERMs are defined as compounds that produce estrogen agonism in one or more desired targeted tissues (eg. Bone, liver) together with estrogen antagonism and/or minimal agonism in reproductive tissues, such as the breast or uterus.⁴ Raloxifene and its hydrochloride salt form are benzothiophene derivatives. On a molecular basis, raloxifene activates the gene encoding transforming growth factor beta, which together with other growth factors and cytokines, induces production of osteoblasts and inhibits the activity of osteoclasts thereby shortening their life span.⁵

Raloxifene and estrogen have shown to inhibit with similar potency and magnitude, the interluekin (IL-6) induced differentiation and resorptive activity of mammalian osteoclasts.⁶ In the human-female derived SaOS-2 osteoblast-like cell line, raloxifene has been shown to stimulate creatine kinase activity, a marker of cell division in a dose dependent manner.⁵ The beneficial estrogen agonist like effects have been characterized extensively in ovariectomized rats and several clinical trials have been depicting the same.

The MORE (Multiple Outcomes of Raloxifene Evaluation) trial was a randomized, placebo controlled study of raloxifene 60 or 120 mg/day involving 7705 women who were atleast 2 years menopause.⁷ The primary end point of MORE was the determination of the percentage of women taking raloxifene who had at least one new vertebral fracture, as compared to the control group. Secondary end points were the relative risk (RR) of nonvertebral fracture, breast cancer and cardiovascular events. In overall cohort, the risk of nonvertebral fractures for raloxifene (60 mg/day and 120 mg/day) Vs placebo did not differ significantly (RR=0.9, 95% CI=0.8-1.1).⁸ However, while assessing separately women whose fracture severity grades, at baseline, corresponded to an estimated decrease in vertebral height of >40% (grade 3), raloxifene 60 mg/day significantly decreased the risk of new vertebral fracture (RR=0.73, 95% CI=0.54-0.99) and nonvertebral fracture (RR=0.53, 95% CI=0.29-0.99) at 3 years. It reduced the risk of estrogen receptor positive invasive breast cancer by 84% (RR=0.16, 95% CI=0.09-0.30).⁹ It also significantly reduced the risk of cardiovascular events in a subset of women with increased cardiovascular risk. Thus, it appears that raloxifene can be targeted to post menopausal women with osteopenia with a risk for hip fracture (RR=2.6) and to women aged 65 or older or at a high risk (RR 3.0) for hip fracture.

Strontium Ranelate

Strontium (Sr) is a trace element that is distributed throughout the geosphere and biosphere. Sr greatly stimulates the formation of steoid tissue and tends to repress the resorptive process in bones. Sr ranelate is composed of an organic moiety (ranelic acid) and 2 atoms of stable non radioactive Sr.

In vitro, Sr ranelate increased DNA synthesis by 3-4 fold in rat cell population enriched with fibroblast and preosteoblastic cells. It also increased collagen and non collagenic protein synthesis by 34% in mature osteoblast enriched cells. On basis of in vitro results, Sr ranelate appeared to have a particular profile characterized by an inhibition of bone resorption and stimulation of bone formation.¹⁰ Targeting this mechanism of action-uncoupling the bone remodeling process-presents a novel means to treat osteoporosis. Sr ranelate is the first agent with this potential to be investigated. In experimental studies, it was found to be linked to an increase in femoral bone mineral content (BMC) which was associated to an increase in trabecular number and an unchanged trabecualr thickness. Bone resorption was also slightly decreased. It was also found that Sr was able to prevent the changes in bone turnover induced by estrogen deficiency.¹¹

In a 24 moth, double blind placebo controlled, prospective, randomized study, daily oral doses of 125 mg, 500 mg or 1 gm of Sr ranelate was compared with placebo. In conclusion, the percent variation of lumbar adjusted BMD from baseline was +1.41% in group receiving 1gm/day Sr, that was significantly different as compared to 0.98% in placebo.¹² Significantly increasing BMD of the spine and femur in early postmenopausal women, 1g/day Sr ranelate as compared to placebo, did not induce any significant adverse reactions. In Sr ranelate, treated women, there was a dose-dependent depositiond into compact and cancellous bone, with significantly higher contents in new bone that in old one.

Sr ranelate is being investigated in a large phase 3 program initiated in 1996 that includes two extensive clinical trials for the treatment of severe osteoporosis. The Spinal Osteoporosis Therapeutic Intervention (SOTI) trial will assess the effect of Sr ranelate on the risk of vertebral fractures. The Treatment of Peripheral Osteoporosis Study (TROPOS) will evaluate the effect of Sr ranelate on peripheral (nonspinal) fractures.¹³ It is proposed that Sr ranelate is a new effetive and safe treatment of vertebral and nonvertebral osteoporosis, with a unique mechanism of action.¹⁴

Source: www.medscape.com

References

1. Meunier PJ, Slosman D, Delmas PD, et al. The strontium salt S-12911: a new candidate for the treatment of osteoporosis. Osteoporos Int 1996;6:S241.
2. Kaufman JM, Devogelaer JP, Raeman F, et al. Prevention and treatment of postmenopausal osteoporosis, National consensus of the "Belgian Bone Club." Clin Rheum 1997;16:343-5.
3. Reginster JY, Jupsin I, Deroisy R, et al. Prevention of postmenopausal bone loss by rectal calcitonin. Calcif Tissue Int 1995;56:539-42.
4. Kaufmann RF, Bryant HU. Effective therapeutic management of the postmenopausal state will be a cornerstone in strategies for preserving or improving women's health in the 21st century. Selective estrogen receptor modulators. Drugs New Prospect 1995;8:531-9.
5. Balfour JA, Goa KL. Raloxifene. Drugs Aging 1998;12:335-42.
6. Sato M, Rippy MK, Bryant HU. Raloxifene, tamoxifen, nafoxidine or estrogen effects on reproductive and non-reproductive tissues in ovariectomized rats. FASEB J 1996;10:905-12.
7. Ettinger B, Black MD, Mitlak BH, et al. Reduction of vertebral risk in postmenopausal women with osteoporosis treated with raloxifene. Results from a 3-year randomized clinical trial. JAMA 1999;282:637-45.
8. Maricic M, Adachi JD, Sarkar S, et al. Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteoporosis. Arch Intern Med 2002;162:1140-3.
9. Cauley JA, Norton L, Lippman ME, et al. Continued breast cancer risk reduction in postmenopausal women treated with raloxifene: 4-years results from the MORE trial. Breast Cancer Res Treat 2001;65:125-34.
10. Su Y, Bonet J, Deloffre P, Tsouderos Y, Baron R. The strontium salt S12911 inhibits the expression of carbonic anhydrase and the vitronectin receptor in chicken bone marrow cultures and bone resorption in mouse calvaria and isolated rat osteoclasts. J Bone Miner Res 1992;7:306.
11. Ammann P, Rizzoli R, Deloffre P, Tsouderos Y, Meyer JM, Bonjour JP. The increase in vertebral bone mass induced in intact rats by long-term administration of the strontium salt S12911 is directly correlated with vertebral bone strength. Osteoporos Int 1996;6:259.
12. Reginster JY, Deroisy R, Dougados M, Jupsin I, Colette J, Roux C. Prevention of early postmenopausal bone loss by strontium ranelate: a randomized, two-year, double-blind, dose-ranging, placebo-controlled trial. Osteoporos Int 2002;13:925-31.
13. Reginster JY, Spector T, Badurski J, et al. A short-term run-in study can significantly contribute to increasing the quality of long-term osteoporosis trials. The strontium ranelate phase III program. Osteoporos Int 2002;13:S30.
14. Reginster JY, Sawicki A, Devogelaer JP, et al. Strontium ranelate reduces the risk of hip fracture in women with postmenopausal osteoporosis. Osteoporos Int 2002;13:14.

Copyright 2004 - Medknow Publications on behalf of the Indian Pharmacological Society. Free, full-text articles also available from http://www.ijp-online.com