Prevention and treatment of postmenopausal osteoporosis

Abstract

In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone loss, however there was no fracture data, even though it was thought to be effective. This continued until the Women's Health Initiative (WHI) study in 2001 that published data on 6 years of treatment with hormone therapy that showed an increase in heart attacks and breast cancer. Even though the risks were small, 1 per 1500 users annually, patients were worried and there was a large drop off in estrogen use. In later analyses the WHI study showed that estrogen reduced fractures and actually prevented heart attacks in the 50-60 year age group. Estrogen alone appeared to be safer to use than estrogen+the progestin medroxyprogesterone acetate and actually reduced breast cancer. At the same time other drugs were being developed for bone that belong to the bisphosphonate group and the first generation of compounds showed moderate potency on bone resorption. The second and third generation compounds were much more potent and in a series of large trials were shown to reduce fractures. For the last 15 years the treatment of osteoporosis belonged to the bisphosphonate compounds, most of which reduce fracture rates by 50 percent. With the exception of gastrointestinal irritation the drugs are well tolerated and highly effective. The sophistication of the delivery systems now allow treatment that can be given daily, weekly, monthly and annually either orally or intravenously. Bone remodeling is a dynamic process that repairs microfractures and replaces old bone with new bone. In the last 10 years there has been a remarkable understanding of bone biology so that new therapies can be specifically designed on a biological basis. The realization that RANKL was the final cytokine involved in the resorption process and that marrow cells produced a natural antagonist called Osteoprotegerin (OPG) quickly led to two lines of therapy. First OPG was used as a therapy to block RANKL was initially successful but later antibodies against OPG developed and this line of treatment had to be discontinued. The next step was to develop a monoclonal antibody against RANKL and this proved to be highly effective in blocking bone resorption. It led to development of a drug Denosumab that successfully reduces fractures and is now one of the therapeutic options for osteoporosis treatment. On the anabolic side bone biology research showed that osteocytes produces sclerostin an inhibitor of the anabolic WNT signaling pathway. Recent development of a monoclonal antibody against sclerostin has shown remarkable anabolic activity in bone showing large increases in bone density and fracture trials are now underway. The newer treatments for osteoporosis are likely to be based on our understanding of bone biology and the design of new highly specific compounds with fewer side effects. This review summarizes the diagnosis of postmenopausal osteoporosis and various available non-pharmacological and pharmacological therapies available for its management. This article is part of a Special Issue entitled 'Menopause'.

Keywords: BMD; Diagnosis; Osteoporosis; Risk factors; Treatment.

Figure 1

Cellular changes that occur with estrogen changes. + E depicts effects in presence of estrogen; -E depicts effects in absence of estrogen. IL-1 is Interleukin 1, TNF-Tumor Necrosis Factor, OPG-Osteoprotegerin. Estrogen decreases osteoclastogenesis and increases osteoclast apoptosis. Estrogen reduces osteoclastogenesis by suppressing IL-1 and TNF and increasing the sensitivity of stromal cells/preosteoblasts to IL-1, thus suppressing MCSF, RANKL, and perhaps most notably, IL-6. In addition, estrogen stimulates the production of OPG, the potent inhibitor of osteoclastogenesis. Estrogen also reduces the responsiveness of osteoclast precursors to RANKL. Estrogen also promotes osteoclastic apoptosis, thereby reducing osteoclast lifespan. This effect appears to be mediated by TGFβ.

Figure 2

Figure depicting the decline of total body Calcium with years since menopause.

Figure 3

Figure depicting the decrease of T score with age and simultaneous increase in fracture risk.

Figure 4

The International Osteoporosis Foundation and the National Osteoporosis Foundation have recommended that risk of fracture be expressed as a fixed-term absolute risk, for example the probability in percent over a 10-year period. This figure shows other BMD-independent risk factors for fracture that the IOF and NOF have integrated to establish absolute risk of fracture in men and women.

Figure 5

This figure depicts how risk factors multiply the fracture risk.

Figure 6

The Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) trial was a prospective, randomized, double-blind, placebo-controlled, multicenter trial that investigated the efficacy and safety of lower doses of conjugated equine estrogens (CEE) alone and with continuous medroxyprogesterone acetate (MPA) in early postmenopausal women (who were within 4 years of their last menstrual period).

Figure 7

Effect of tissue selective estrogen complex (TSEC) (CEE + Bazedoxifene) on lumbar spine and total hip BMD.

Figure 8

Although it is FDA-approved for osteoporosis prevention, but not treatment, results from the Women's Health Initiative (WHI) HT trials provide randomized clinical trial evidence for the efficacy of estrogen used alone (E only) or with a progestin (E+P) in reducing the incidence of hip, vertebral, nonvertebral, and total fractures as shown in this slide.

Figure 9

The relative risk (95% CIs) for vertebral fractures with each therapy is shown in this slide. Significant treatment effects were not seen for calcium and the P value for effect of calcitonin was 0.05. All other therapies significantly reduced the incidence of vertebral fractures. *Denosumab: * Cummings et al N Engl J Med. 2009

Figure 10

The relative risk (95% CIs) for nonvertebral fractures with each therapy is shown in this slide. Significant treatment effects were seen only with HT (including the WHI trial), alendronate (10–40 mg), risedronate and Tereperatide. *Denosumab: * Cummings et al N Engl J Med. 2009

Figure 11

Figure summarizing Sclerostin and Wnt 2 pathway. Sclerostin antibody binds and inhibits the anti-anabolic effect of inhibits sclerostin protein.