THERAPY IN PRACTICE

Drugs Aging 2006; 23 (8): 617-625 1170-229X/06/0008-0617/$39.95/0 2006 Adis Data Information BV. All rights reserved.

The Problem of Low Levels of Vitamin D and Osteoporosis

Use of Combination Therapy with Alendronic Acid and Colecalciferol (Vitamin D3)
Sol Epstein
Doylestown Hospital, Doylestown, Pennsylvania, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 617 1. The Health Impact of Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618 2. Treatment of Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 618 3. Other Components of Managing Osteoporosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619 4. Role of Vitamin D in Skeletal Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 619 5. Vitamin D Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620 6. Vitamin D Measurement and Reference Range . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 620 7. Prevalence of Low Vitamin D Status . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 8. Rationale for Combining Alendronic Acid and Vitamin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 621 9. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 622

Abstract

Osteoporosis and fragility fractures are common in the elderly population and represent a large public health burden. Non-pharmacological recommendations for the management of osteoporosis include modification of lifestyle behaviours, increased weight-bearing exercise and consumption through dietary or supplement sources of adequate amounts of calcium and vitamin D. Although current guidelines include recommendations on calcium and vitamin D intake, patients frequently do not take sufficient amounts, even when supplements are provided free of charge. Vitamin D is essential for mineral metabolism, and low levels are associated with impaired skeletal metabolism and neuromuscular function. Nutritional sources of vitamin D are limited, and supplementation is usually necessary. A high prevalence of low vitamin D levels has been reported in a number of populations worldwide, including women being treated for osteoporosis and those with fragility fractures. At present, bisphosphonates are the most commonly prescribed pharmacological treatments for osteoporosis, and alendronic acid is the most frequently prescribed bisphosphonate. A nitrogen-containing bisphosphonate, alendronic acid has demonstrated anti-fracture efficacy at vertebral and non-vertebral skeletal sites, including the hip, in addition to long-term safety and efficacy. Weekly administration of alendronic acid takes advantage of the pharmacokinetics of the drug and osteoclast biology to optimise treatment, and may improve patient adherence. Combining alendronic acid 70mg and colecalciferol (vitamin D3) 2800

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IU in a single, once-weekly tablet has the advantage of combining the proven efficacy of an established bisphosphonate, alendronic acid, with the amount of vitamin D currently recommended for osteoporosis management.

1. The Health Impact of Osteoporosis Osteoporosis, a skeletal disorder characterised by compromised bone strength predisposing a person to an increased risk of fracture,[1] is common in the older population: in the US, over half of people >50 years of age are estimated to have either osteoporosis or low bone mass.[2] In general, approximately half of women and one-third of men >60 years of age are estimated to have osteoporosis.[3] Over 10 million people in the US currently have osteoporosis, and this number is expected to increase over the next few decades.[2] Similar projections elsewhere in the world reinforce the importance of osteoporosis as a large and growing international public health concern.[4,5] More than 55 million people in Europe and Japan are estimated to have the disorder,[6] together with approximately 2 million Australians[3] and 3.5 million Canadians.[7] Because of increased life expectancy and increasing numbers of people reaching 65 years of age, by 2040 the population >65 years of age in the European Union (EU) is expected to double.[8] Similar to population trends in the US, the greatest rate of growth in the EU is expected to be among people >80 years of age: the size of this group which is at high risk for fracture is expected to triple by 2040.[8] Comparable demographic changes have been projected for Canada and Australia.[3,7] By 2050, it has been estimated that the population aged 80 years will be largest in Asia, i.e. approximately 88 million or 57% of the worlds total.[9] Fragility fractures, the clinical consequences of osteoporosis, cause excess mortality and morbidity, as well as economic and social cost.[10-14] Hip fracture, the most important osteoporotic fracture, is associated with approximately 20% excess mortality, loss of functional independence in the majority of survivors, and nearly 75% of fracture-related healthcare expenditure in the elderly.[10,11] Relative to 1990 figures, worldwide hip fracture incidence is
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anticipated to more than double by 2025 and to nearly quadruple by 2050 as a consequence of increases in both the numbers of elderly and the incidence of fracture at a given age.[9] 2. Treatment of Osteoporosis Postmenopausal osteoporosis is characterised by accelerated bone turnover, a persistent remodelling imbalance in which resorption exceeds formation, and progressive loss of bone mineral density (BMD) and microarchitecture. This cascade of processes reduces bone strength and increases the risk of fragility fracture. The objective of treatment is to decrease fracture risk, and this is accomplished by reducing elevated turnover and arresting or reversing bone loss. A number of modifiable risk factors for osteoporosis have been identified, and comprehensive management guidelines address these as well as pharmacological therapy.[1,7,8,10,15-17] Adequate weight-bearing exercise, adequate calcium and vitamin D intake from dietary or supplement sources and modification of other lifestyle behaviours are among these recommendations. In many cases, however, these measures are insufficient and definitive pharmacological treatment is necessary. At present, among pharmacological options, bisphosphonates are the drugs of choice for the prevention and treatment of osteoporosis.[18] The primary mechanism of action of bisphosphonates is inhibition of osteoclast activity.[19] Slowing of resorption restores remodelling balance, allowing catch up of bone formation and more complete mineralisation of remodelling sites, thereby increasing bone density and mechanical strength.[19,20] Remodelling occurs continuously at multiple sites in the skeleton, with a new resorption site initiated approximately every 8 seconds and about one million sites active at any given time.[21] The osteoclast lifespan at each remodelling site is approximately 2
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weeks.[21] Bisphosphonates bind to mineral at active remodelling sites and remain there for longer than the typical osteoclast lifespan.[22,23] Thus, weekly administration interrupts the resorption process before it can progress very far, and clinical trials have shown the equivalence of daily and weekly treatment with both alendronic acid[24] and risedronic acid[25] with respect to markers of bone turnover and BMD. Recently, a once-weekly tablet that contains alendronic acid 70mg and colecalciferol (vitamin D3) 2800 IU has become available for use in osteoporosis treatment. This addresses two aspects of osteoporosis management, i.e. vitamin D intake and definitive pharmacological treatment with an agent shown to have anti-fracture efficacy. A number of clinical trials have demonstrated that alendronic acid treatment reduces bone turnover to premenopausal levels, increases both BMD and bone strength and decreases the risk of fracture.[26-29] Equivalence of weekly and daily administration with alendronic acid was predicted on the basis of bone physiology and drug pharmacokinetics, and these regimens have been shown to have equivalent efficacy, safety and tolerability.[24,30,31] Onceweekly administration provides continuous, stable suppression of bone turnover, as the drug residence on bone surfaces exceeds osteoclast lifespan; however, less frequent (intermittent) or suboptimal dosage of bisphosphonates may not sustain suppression of resorption and may, as a consequence, be less effective.[32] In addition, most (~84%) patients in a randomised trial (among those who expressed a preference) preferred weekly over daily administration.[33] Furthermore, 87% said that weekly administration was more convenient than daily administration and 84% said that weekly administration would allow them to achieve better long-term adherence.[30,33] These findings were confirmed in a second study of similar design.[34] 3. Other Components of Managing Osteoporosis Calcium and vitamin D are recognised as essential nutrients throughout life for growth and mainte 2006 Adis Data Information BV. All rights reserved.

nance of the skeleton, and osteoporosis management guidelines include recommendations for counselling patients regarding adequate intake of both from dietary or supplement sources.[1,7,15,16,35] Prescribing information for anti-resorptive medications also includes recommendations regarding calcium and vitamin D nutrition. Calcium is the primary mineral of bone, and its effective absorption depends on vitamin D.[36] At present, the Institute of Medicine has recommended that the intake of calcium for all adults >50 years of age should be at least 1200mg (30 mmol) per day and that of vitamin D at least 400 IU (10g) per day.[36] Unfortunately, many patients fail to take the recommended amounts of vitamin D, and have low serum vitamin D levels as a result (see section 7). 4. Role of Vitamin D in Skeletal Metabolism The biologically active form of vitamin D (1,25-dihydroxyvitamin D [1,25-(OH)2D]) is, more accurately, a hormone. Amongst other functions, vitamin D is an essential component of physiological mechanisms that maintain serum calcium and phosphorus levels within a narrow range.[37] In addition to increasing the efficiency of calcium and phosphorus absorption from the intestine and increasing renal reabsorption, vitamin D plays an important regulatory role in skeletal metabolism, since bone is the largest source of calcium for maintenance of appropriate serum levels. Increased risk of fracture with low levels of vitamin D and decreased risk with vitamin D supplementation have been observed in many,[38] but not all,[39-41] studies. However, results of a recent meta-analysis suggest a doserelated effect of vitamin D supplementation on fracture risk.[38] Even under conditions of vitamin D repletion, fractional calcium absorption from the intestine is approximately 3040%; this drops to 1015% when vitamin D levels are low.[42] If calcium intake is insufficient to maintain appropriate serum calcium levels, vitamin D acts through both activation of osteoblasts (these, in turn, produce receptor activator of nuclear factor-B ligand [RANKL], which
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stimulates osteoclast activation, maturation and differentiation) and stimulation of the release of parathyroid hormone (PTH), which increases bone resorption, thereby liberating calcium from bone.[43-45] 5. Vitamin D Metabolism Whereas calcium is present in many foods and adequate intake can be obtained from the diet, dietary sources of vitamin D are limited and fortification of foods is uncommon in many areas.[46] Thus, sunlight is the primary source of vitamin D[47,48] apart from nutritional supplements. Exposure of the skin to UVB in sunlight leads to cutaneous synthesis of colecalciferol from precursors.[43] Colecalciferol is transported to the liver, where it is converted to 25hydroxyvitamin D [25-(OH)D]. Serum 25-(OH)D is biologically inactive and is the main circulating form of vitamin D; because it increases in proportion to intake, it is the standard measure of vitamin D status. Further conversion to the active hormone, 1,25-(OH)2D, takes place in the kidney.[43] This conversion is under tight feedback control: PTH, hypocalcaemia and hypophosphataemia increase formation of 1,25-(OH)2D, while 1,25-(OH)2D inhibits its own formation.[49] If dietary intake of vitamin D and sunlight exposure are low, 25-(OH)D levels are also low, leading to slightly lower serum 1,25-(OH)2D and calcium levels; this, in turn, results in increased PTH secretion, which is why elevated PTH levels may indicate low vitamin D status.[50] Circulating vitamin D compounds are generally protein-bound, largely to vitamin D-binding protein.[43] Protein-bound vitamin D compounds are biologically inactive and, because of their limited uptake by cells and limited metabolism, have relatively long half-lives.[49] Circulating vitamin D-binding protein levels are about 20 times higher than concentrations of vitamin D compounds, and this excess capacity serves to limit the possibility of vitamin D toxicity.[49] 1,25-(OH)2D acts via a specific nuclear vitamin D receptor to perform its biological functions.[51] Vitamin D receptors are distributed widely in the body: in addition to their presence in tissues in 2006 Adis Data Information BV. All rights reserved.

volved in calcium metabolism (kidney, parathyroid glands, bone and intestine), vitamin D receptors have been identified in such locations as skin, muscle, cells of the immune system, cells of the haematopoietic system, male and female reproductive tissues, pancreas, lung, heart and vascular tissue.[51,52] Although this genomic pathway is responsible for most of the biological activity of vitamin D, recent evidence suggests that some activity may be mediated by cell surface receptors, but these are incompletely characterised and the relevance of this pathway is not universally accepted.[49] 6. Vitamin D Measurement and Reference Range Vitamin D status is assessed by measuring serum 25-(OH)D; however, what constitutes an adequate vitamin D level is poorly defined. Several assays are currently available: of these, high-performance liquid chromatography is the accepted gold standard, but radioimmunoassay and chemiluminescent protein-binding assay techniques are also used by laboratories. The reference range for an assay is often defined as the mean value, plus and minus two SD, of measurements in a healthy population. Clearly, a reference range for vitamin D derived in this way will depend on the population studied the age, skin pigmentation, nutritional habits, season, latitude and sun exposure of the people tested. Since many people have 25-(OH)D levels that are less than ideal (see section 7), the current reference ranges may not be appropriate. Some have proposed that serum 25-(OH)D levels >30 ng/mL (75 nmol/L) may be needed for optimal health.[53] As noted previously, elevated serum PTH is one indicator that vitamin D levels are low. A number of studies have reported that serum PTH increases progressively as serum 25-(OH)D levels fall below ~30 ng/mL.[54-58] Consistent with this, Heaney[42] reported that levels <32 ng/mL (80 nmol/ L) were associated with decreased calcium absorption. Variation among serum 25-(OH)D assays and among laboratories using the same assay has been documented in several reports.[59-65] This variability
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confounds both diagnosis and the assessment of therapeutic effects, as well as making comparisons among studies more difficult. As a consequence, consensus has not yet been reached regarding the optimal range of serum 25-(OH)D levels. 7. Prevalence of Low Vitamin D Status Severe vitamin D deficiency in children causes rickets; in adults, secondary hyperparathyroidism, osteomalacia, bone pain and proximal muscle weakness are the clinical consequences. Clinical cases of rickets or osteomalacia have become uncommon in the last century; however, some data suggest that their incidence has risen in recent years.[66] Notably, breastfed infants may be at risk if the maternal intake of vitamin D is inadequate.[67] Osteomalacia in adults is sometimes treated by a short course of ergocalciferol (vitamin D2) in doses as high as 50 000 IU orally once to three times weekly until deficiency is corrected and mineralisation is normalised;[68] such doses are considerably higher than those recommended for routine supplementation. Ergocalciferol is less than one-third as potent as colecalciferol,[68] but no toxicity has been associated with daily doses of colecalciferol as high as 10 000 IU (250g).[46,69-71] In recent years, it has become apparent that chronic low vitamin D that is less severe can also have profound skeletal and neuromuscular consequences. Low vitamin D [measured as serum 25-(OH)D] is associated with increased bone resorption and consequently also has implications for the development and progression of osteoporosis.[50] Low serum 25-(OH)D has also been associated with lower extremity muscle weakness, increased sway and increased risk of falling.[72-77] A number of epidemiological studies, conducted in diverse populations, have demonstrated that low vitamin D is very common among young,[78,79] adult,[54,79-82] and elderly[50,81,83-87] populations, regardless of latitude. Others have reported very low vitamin D levels in elderly patients hospitalised with hip or other fractures.[63,88-93] Two independent literature surveys[50,94] identified more than 83 studies in which vitamin D status in cohorts of elderly men and
2006 Adis Data Information BV. All rights reserved.

women was assessed; the prevalence of low vitamin D was as high as 86%. The importance of vitamin D in skeletal health is recognised in guidelines for the management of osteoporosis;[10,15,35,95,96] despite this, vitamin D levels are less than ideal in most patients being treated for osteoporosis. Gaugris and colleagues,[94] in their systematic review, reported that between 12% and 76% of osteoporotic populations had extremely low serum 25-(OH)D levels, i.e. <12 ng/mL (30 nmol/L), while 5070% of patients with a previous history of fractures had levels <15 ng/mL (37 nmol/L). Two additional recent reports are illustrative. In a survey conducted at 61 sites across North America among 1536 osteoporotic women who were receiving pharmacological treatment for osteoporosis, 52% had serum 25-(OH)D levels <30 ng/ mL (75 nmol/L); only 59% of the women reported using vitamin D supplementation of at least 400 IU/ day.[58] In a similar study of 1244 osteoporotic women (63% of whom were being treated with antiosteoporosis medication) conducted in 18 countries, including several considered to be equatorial, only 39% of women were taking at least 400 IU/day of vitamin D and 59% had serum 25-(OH)D levels <30 ng/mL (75 nmol/L).[97] Importantly, vitamin D levels were measured in each of these studies at a single laboratory using the same assay, which improved the reliability of comparisons. 8. Rationale for Combining Alendronic Acid and Vitamin D The currently recommended intake of vitamin D for adults is 400 IU (10g) per day.[36] Vitamin D is fat-soluble and accumulates in certain tissues, where it is gradually released. Because the half-life of 25-(OH)D is 1 month or longer, daily supplementation is not required, and doses of 2800 IU per week are equivalent to 400 IU/day.[70] As mentioned in section 2, alendronic acid is also effective when given weekly. Food and beverages other than water reduce the bioavailability of alendronic acid because they contain ionic compounds that strongly bind the drug, thereby preventing or markedly reducing its absorpDrugs Aging 2006; 23 (8)

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tion.[98] Because vitamin D is not a charged molecule, it can be combined with alendronic acid in a single tablet for weekly administration. The combination tablet provides efficacy equivalent to that of alendronic acid alone, with the additional benefit of increasing serum 25-(OH)D levels.[98,99] The combination of alendronic acid and vitamin D in a single once-weekly pill offers important advantages. The bioavailability of each compound in the combination pill is similar to that of the compounds taken individually.[98] Most patients with osteoporosis have low vitamin D levels, and many do not take the recommended amounts of supplemental vitamin D, despite recommendations in the prescribing information for osteoporosis treatments. A recent survey has shown this to be the case even when vitamin D is provided free to patients filling prescriptions for pharmacological osteoporosis therapy.[100] This may be less of a problem with drugs that have relatively modest effects on BMD,[101] but the more potent nitrogen-containing bisphosphonates have relatively greater effects on bone mineralisation. Combining 2800 IU (70g) of colecalciferol with alendronic acid ensures that patients with osteoporosis take the amount of vitamin D that is currently recommended as an essential component of osteoporosis management. Adherence, which can be challenging for older patients who may be taking multiple medications, is facilitated by combining the two compounds in a tablet to be taken only once a week.[102,103] 9. Conclusion Comprehensive management of osteoporosis includes a number of measures, including modification of lifestyle risk factors, weight-bearing exercise, appropriate nutrition, adequate intake of calcium and vitamin D and, in many patients, definitive pharmacological treatment. Vitamin D inadequacy is common, even among patients being treated for osteoporosis, and adherence to use of supplements is poor, even when they are provided free of charge to the patient. The combined alendronic acid-colecalciferol tablet provides the proven anti-fracture
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efficacy of alendronic acid, together with the minimum recommended amount of vitamin D. Acknowledgements
Dr Epstein has served as a consultant for Merck, RocheGlaxoSmithKline, Novartis and NPS Pharmaceuticals, has received honoraria from Merck, Roche-GlaxoSmithKline and NPS Pharmaceuticals, and has been the recipient of unrestricted educational grants for continuing medical education programmes from Merck, Amgen, Roche and Novartis. The author has received no funding from any source to produce the article. The author wishes to acknowledge useful discussions with Dr Lois E. Wehren during the preparation of this manuscript.

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Correspondence and offprints: Professor Sol Epstein, 595 West State Street, Doylestown, PA 18901, USA.

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Drugs Aging 2006; 23 (8)