by Meggie Alcantara
It is estimated that every 10-25 years, new bones replace old bones in our skeletal system.8 This is because bones are continuously being formed and degraded. 8 The main cells involved are the osteoclasts which are responsible for bone resorption or break down and osteoblasts which synthesize new bones to replace that which were broken down.14 One purpose of this bone remodeling is to repair microfractures in order for bones to adapt to stresses.8 This is why a simple fall would not result to a fracture and people can engage in sports and carry heavy loads for example.
However, as people age there is an increase in bone resorption due to an increase in osteoclasts.14Thus, the balance between bone resorption and synthesis is lost as more bones are degraded and individuals develop weak and brittle bones. One disease attributed to this condition is osteoporosis.
Osteoporosis increases the risk of low trauma fractures such as hip fractures and vertebral fractures because of low bone mineral density and a decrease in bone strength.7 In a study on prevalence of osteoporosis and fractures among Filipino adults, it was predicted that by 2020, 4 million will be at high risk for osteoporosis and by 2050, more than 10 million will be affected.10 It is estimated that by 2020, there will be 65,000 Filipinos with hip fractures and 175,000 by 2050.3
Denosumab
Many drugs are available to treat osteoporosis. These are either antiresorptive or anabolic (for bone synthesis). However, poor adherence to therapy is a major problem in treating osteoporosis.9 Some drugs may be expensive such as the bone forming Teriparatide while some are just tedious to take due to pre-administration requirements such as oral bisphosphonates like Alendronate which need fasting, ingestion of plain water, and post-dose fasting.9
A new drug created by Amgen to treat postmenopausal osteoporosis, Denosumab (trade name: Prolia), was approved by the U.S. Food and Drug Administration on June 2, 2010. It is the first biologic therapy for osteoporosis and is administered thru subcutaneous injection every 6 months.15
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| Bone Density Scanner |
While other osteoporosis drugs target osteoclasts, denosumab is a fully human monoclonal antibody that targets the Receptor Activator of Nuclear Factor- κB ligand (RANKL), blocking it’s binding to its receptor called Receptor Activator of Nuclear Factor- κB (RANK) which is found on pre-osteoclasts and osteoclasts.2,14 This inhibits the formation, activity, and survival of osteoclasts; thus, bone resorption associated to bone loss in osteoporosis is also inhibited.9 In a 2009 study on postmenopausal women with osteoporosis, 60mg of denosumab was given to subjects ages 60-90 every 6 months for 36 months2. Through annual lateral spine radiographs and diagnostic imaging, it was found that Denosumab reduced the risk of vertebral, nonvertebral, and hip fractures. 2 Furthermore, annual dual-energy x-ray absorptiometry also showed an increase in bone mineral density among the subjects. 2
RANKL and RANK
Denosumab targets RANKL by inhibiting its binding to its receptor RANK. Why focus on this ligand and receptor?
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| Mechanism of Denosumab on Osteoclasts |
Receptor Activator of Nuclear Factor- κB ligand (RANKL), a cytokine or signaling molecule, is composed of 316 amino acids synthesized by osteoblasts or T cells.1 Receptor Activator of Nuclear Factor- κB (RANK) is a 616 amino acid transmembrane receptor found in pre-osteoclasts and osteoclasts.6 RANKL and its receptor RANK control the differentiation, activation, and survival of osteoclasts—the cells responsible for bone resorption.12 When RANKL binds to RANK present in pre-osteoclasts, new osteoclasts are formed.12 In addition, RANKL that binds to RANK found in mature osteoclasts promotes their adherence to bone and prevents its apoptosis. 12 Although other hormones such as parathyroid hormone, vitamin D3, and TNF-α affect osteoclast formation, studies on RANKL and RANK knockout mice resulted in a complete lack of osteoclasts showing that only RANKL and RANK were absolutely necessary for osteoclast formation.4
Because osteoclasts are greater in number than osteoblasts in osteoporosis12, then it would follow that inhibition of osteoclast formation, activity and survival would mean a decrease in bone resorption and less incidence of fractures.
Is Denosumab better?
Denosumab has advantages over bisphosphonates. While bisphosphonates decrease bone resorption by inhibiting the activity and survival of osteoclasts, denosumab goes beyond by preventing the formation of new osteoclasts by its binding to pre-osteoclasts.2This is consistent with a study that found denosumab’s effect on bone resorption to be faster and more pronounced as shown by markers of bone resorption compared to Alendronate, a bisphosphonate.11 Denosumab also has a reversible effect on bone resorption as opposed to bisphosphonates which has long term effects since it is incorporated in bone matrix.9 Thus, the body is more responsive to Teriparatide after treatment from denosumab as compared to bisphosphonates as observed by an immediate increase in bone mass density.5 How Denosumab though compares with other drugs besides bisphosphonates must still be explored.
It should be noted however that Denosumab can only be administered for postmenopausal women and only when other osteoporosis medications are no longer effective. 13 This implies the potency of the drug as it is used as a last resort. The biggest drawback to denosumab however is the selling price Amgen has set for it. Priced at $825 per injection or $1,650 per year, Yaron Werber, an analyst, said that Amgen had “oncology indications in mind.”17 This is in light with Amgen targeting the drug as a treatment for bone loss in cancers such as prostate cancer and breast cancer. If denosumab in the future would be approved for such a use, then Amgen would make a huge profit from the drug since taking it monthly would sell at $19,800 annually per cancer patient who buys it.16
How would Denosumab fair for Filipinos?
Denosumab provides a novel approach to combat osteoperosis. Unlike its antiresorptive counterparts that target the osteoclast function, denosumab is more thorough in that is inhibits even osteoclast formation. The fact that denosumab is taken as a postmenopausal osteoporosis treatment for women who are unresponsive to other drugs shows its potency.
In theory, Denosumab would seem more beneficial for patients who prefer infrequent intake of medicines rather than a weekly or monthly dose since denosumab is only administered every 6 months. This may also be beneficial for people taking care of a family member with osteoporosis, especially those without caregivers. One need not take note of the specific time and day they would need to give the medicine nor frequent pharmacies to stock up on medications. In this way, more time can be spent on activities and responisbilities that they would otherwise have no time for because of constantly attending to their family member with osteoporosis. Because Denosumab also decreases the risk of fractures, then it’d follow that less money would be spent on hospitalization, surgery, and rehabilitation.15
However, given that Denosumab is being marketed at a selling price of $825 per injection, it does not appear to be a cheaper option especially for (many) Filipinos who cannot afford it. In an assessment of bone-health status of urban, low income women, 19.8% or 180 of 905 participants had osteoporosis.12 Although this data represents only one area of a city, it may give us an idea or estimate on the number of low income women affected in other cities. Alendronate--which is priced at around 800 pesos-- as compared to Denosumab would still be a cheaper option.
In the end, the best way to keep from spending on expensive medicines is staying healthy and reducing one’s risk of incurring osteoporosis. In the least, 30 minutes of walking daily combined with weights twice a week should be done to prevent bone loss. 12 An intake of 1000 mg of calcium as part of one’s nutrition is also important.17 Lastly, avoid smoking and excessive alcohol intake as these are risk factors for fractures.17
In a time where there seems to be “no room” to incorporate exercise in one’s daily schedule especially for those with demanding occupations, where cigarettes are easily accessible, alcohol is enjoyed even by young adults, and where there's a profusion of junk food and fast foods, a healthy lifestyle seems to be beyond one’s reach. In fact, a low bone mass has been observed even in premenopausal women indicating a high risk for osteoporosis even in young women.18 Although being and staying healthy may be a challenge, it is not impossible to achieve as s long as one makes a commitment to a healthier living.
References
1. Collin-Osdoby, 2004 as cited in Lewiecki, 2008:
Lewiecki, E. (2008). Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics, 2(4), 645-653.
2. Cummings, S.R., San Martin, J., McClung M.R., Siris, E.S., Eastell, R., Reid, I.R., … Christiansen, C. (2009). Denosumab for prevention of fractures in postmenopausal women with osteoporosis.The New England Journal of Medicine, 361 (8), 756-765.
3. Dela Rosa, Bonifacion, & Canetter, 2008 as cited in 2009 Philippine Audit:
The Asian Audit Epidemiology, Costs and Burdens of Osteoporosis in Asia- Philippines
4. Dougall, 1999; Kong, 1999; Li, 2000 as cited in Leibbrandt & Penninger, 2008:
Leibbrandt, A. & Penninger, J. (2008). RANK/RANKL: Regulators of immune responses and bone physiology. New York Academy
5. Geusens, P. (2009). Emerging treatments for postmenopausal osteoporosis – focus on denosumab.Clinical Intervensions in Aging, 4, 241;250.
6. Hsu et. al, 1999 as cited in Lewiecki, 2008:
Lewiecki, E. (2008). Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics, 2(4), 645-653.
7. Klibanski et. al, 2001 as cited in Lewiecki, E., 2008:
Lewiecki, E. (2008). Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics, 2(4), 645-653.
8. Leibbrandt, A. & Penninger, J. (2008). RANK/RANKL: Regulators of immune responses and bone physiology. New York Academy
9. Lewiecki, E. (2008). Denosumab: an investigational drug for the management of postmenopausal osteoporosis. Biologics, 2(4), 645-653.
10. Li-Yu, 2007 as cited in 2009 Philippine Audit:
The Asian Audit Epidemiology, Costs and Burdens of Osteoporosis in Asia- Philippines
11. McClung, 2006 as cited in Geusens, 2009:
Geusens, P. (2009). Emerging treatments for postmenopausal osteoporosis – focus on denosumab. Clinical Intervensions in Aging, 4, 241;250.
12. Miura, S., Saavedra, O.L., & Yamamoto, S. (2008). Osteoporosis in urban post-menopausal women of the philippines
13. Prolia Medication Guide as Approved by FDA. Retrieved from http://www.fda.gov/downloads/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/UCM214383.pdf
14. Romas, E. (2009). Clinical applications of RANK-ligand inhibition. Internal Medicine Journal, 39(2), 110-116.
15. The Asian Audit Epidemiology, Costs and Burdens of Osteoporosis in Asia- Philippines
16. The International Osteoporosis Foundation. (2009). Facts and statistics. Retrieved from http://www.iofbonehealth.org/facts-and-statistics.html
17. The Street. (2010, June). Amgen proposes premium price for prolia. Retrieved from http://www.thestreet.com/story/10771798/amgen-proposes-premium-price-for-prolia.html
18. Torralba, T.P. (2004). Clinical management of osteoporosis in the Philippines