Osteoporosis is defined by the World Health Organization (WHO) as a bone mineral density (BMD) value for the hip, spine, or wrist of 2.5 standard deviations (SD) or more below the mean for healthy young white women, or a T-score of less than or equal to –2.5.¹ The disease is characterized by an increased risk of fractures, which can result in pain, diminished quality of life, decreased physical mobility and independence, inability to work, and increased burden on caregivers. ^2,3

Prevalence and Impact

Osteoporosis is considered a global problem. Currently, an estimated 75 million people have osteoporosis in Europe, the United States and Japan.⁴ This figure is projected to double within 50 years. ⁴ In addition, around 225 million people in Europe, the United States and Japan have osteopenia (defined as a T-score between –1 and –2.5).⁵ Due to demographic changes, the greatest increase in the number of people with osteoporosis will be in Asia and Latin America.⁴ It is projected that about 50% of all osteoporotic hip fractures will occur in Asia by the year 2050.⁴

Worldwide, the financial cost of osteoporosis is equally high. Within the European Union, over 3,500 million Euros (approximately US$3,976 million) each year are needed for the direct hospital costs of hip fractures alone. ⁶ Hospital costs following hip fracture in some non-European countries in 1996 included approximately US$60 million in Hungary, US$500 million in Australia, US$5,700 million in the United States, and US$9,359 million in Japan.⁶ The cost per person also varies, for instance, from US$12,000 in Australia to US$8,700 in Lebanon.⁶ These figures only represent the direct hospital costs; primary, outpatient and institutional care may multiply the real cost of hip fractures by 2.5.⁶

Hip fractures are considered the greatest burden as they nearly always require admission to the hospital, are fatal in about 20% of cases, and produce permanent disability in about half the patients.⁷ By 2050, the number of hip fractures is expected to increase about three- or-four-fold from the estimated 1.7 million in 1990.⁷

Diagnosis

Studies have shown that a reduction in BMD is the most important predictor of osteoporosis-related fractures in both men and women. Accordingly, the World Health Organization has identified the following categories based on BMD as compared with healthy young adult mean values. ⁸

• Normal BMD (T-score value greater than –1 standard deviation [SD])
• Osteopenia (T-score between –1 and –2.5 SD)
• Osteoporosis (T-score less than or equal to –2.5 SD)
• Established osteoporosis (T-score less than –2.5 SD and 1 or more fractures)

Current Treatments and Guidelines

The US Food and Drug Administration has approved estrogen, parathyroid hormone (teriparatide), bisphosphonates (alendronate and risedronate), raloxifene, and calcitonin for osteoporosis treatment and/or prevention.⁹

The National Osteoporosis Foundation has issued the following guidelines for the prevention, diagnosis, and treatment of osteoporosis in postmenopausal white women¹⁰:

• Counsel all women on the risk of osteoporosis and related fractures.
• Advise all patients to consume adequate amounts of calcium (at least 1200 mg/day, including supplements if necessary) and vitamin D (400 to 800 IU per day for individuals at risk of deficiency).
• Recommend regular weight-bearing and muscle-strengthening exercise to reduce the risk of falls and fractures.
• Advise patients to avoid tobacco smoking and excessive alcohol intake.
• Recommend BMD testing to all women aged 65 and older.
• Recommend BMD testing to younger postmenopausal women who have one or more risk factors (other than being white, postmenopausal, and female).
• Recommend BMD testing to postmenopausal women who have suffered a fragility fracture to confirm the diagnosis and determine disease severity.
• Initiate therapy to reduce fracture risk in postmenopausal women with BMD T-scores by central dual x-ray absorptiometry (DXA) below –2 in the absence of risk factors and in women with T-scores below –1.5 if one or more risk factors are present.
• Consider postmenopausal women with vertebral or hip fractures candidates for osteoporosis treatment.
• Current pharmacologic options for osteoporosis prevention and/or treatment are bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens and/or hormone therapy, parathyroid hormone (PTH 1-34), and raloxifene. ¹⁰

Role of RANKL in Osteoporosis

Receptor activator of nuclear factor kappa B ligand (RANKL) is the final common mediator that regulates bone remodeling. RANKL is the primary mediator of osteoclast formation, function and survival. RANKL, produced by osteoblasts and other cells, causes osteoclast precursors to form and differentiate into active (mature) osteoclasts. RANKL also has been implicated in altering the adherence of osteoclasts to the bone surface and suppresses apoptosis of mature osteoclasts. ^11,12 The body naturally produces a protein called osteoprotegerin (OPG) that neutralizes the effects of RANKL, keeping the bone loss process in check. ^11,13,15

Excess RANKL activity drives bone destruction across a broad range of conditions. In osteoporosis, RANKL has direct catabolic effects on cortical and trabecular bone including reductions in bone density, volume and strength. ^16-21 In preclinical studies, RANKL caused the increased bone resorption and bone loss associated with animal models of postmenopausal and male osteoporosis.

To determine if RANKL plays a role in mediating the increase in bone resorption in early postmenopausal women, an in vitro study was performed comparing results of estrogen-deficient, early postmenopausal women with two estrogen-replete control groups. The authors demonstrated that RANKL is increased by estrogen deficiency and decreased by estrogen sufficiency. These results suggest that RANKL may play a major role in mediating increased bone resorption and bone loss following menopause. ²²

In a separate study, estrogen treatment was found to stimulate the production of OPG by osteoblast lineage cells in vitro. These findings suggest that a local increase in OPG levels in the bone micro-environment may be an important component of the mechanism(s) by which estrogen reduces osteoclast activity and bone loss. ²³

In preclinical models, RANKL inhibition has been shown to increase cortical and trabecular bone density, volume and strength. ^16,17,24

• Observations across a wide range of animal disease models have confirmed that RANKL inhibition reduced osteoclast activity and that this effect was reversible. ^17,25,26
• RANKL inhibition had no direct adverse effect on osteoblast numbers. ²⁷
• These actions led to increased density, volume, and thickness of cortical and trabecular bone, resulting in significant increases in measurements of bone strength in these animals. ^16,17,24

Scientists are currently investigating RANKL inhibition as a novel therapeutic approach.

For more information on the OPG/RANK/RANKL pathway and its role in bone health, see the section on RANKL Inhibition.

References

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