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Abstract

Osteoporosis is a common medical condition in older individuals, responsible for approximately 1.5 million fragility fractures in the USA each year. Alendronate sodium with cholecalciferol (vitamin D3) is a newly developed combination formulation for the treatment of osteoporosis in women and for increasing bone mass in men with osteoporosis. It complements the existing once-weekly dosage formulation of alendronate sodium alone, providing, in addition to alendronate, a 2800 international unit (IU) dose of cholecalciferol (vitamin D3), equivalent to 400 IU daily. Its efficacy in reducing fracture risk is expected to be at least as good as that of once-weekly alendronate given for the same indications.

Keywords

alendronate absorption bisphosphonate bone resorption calcium cholecalciferol falls fractures osteoporosis vitamin D3

Osteoporosis, the principal indication for bisphosphonate compounds, affects 44 million individuals in the USA (10 million of whom meet strict bone density criteria for diagnosis and 34 million with low bone mass, who actually account for the majority of osteoporotic fractures). Approximately 1.5 million osteoporotic fractures occur annually in the USA. The risk of an osteoporotic fracture in a woman aged 50 years approaches 50% in her remaining lifetime, exceeding the combined risk of developing several cancers, including breast cancer [1]. Many of these fractures produce both a substantial reduction in quality of life and increased mortality [2,3]. At the same time, inadequate vitamin D status is common in older adults in North America and Europe, and by some estimates approaches 80% of the population over the age of 60 years [4,5]. It is now recognized that vitamin D inadequacy aggravates osteoporosis by:

Contributing to bone loss [6]

Leading to increased bone remodeling (a fragility factor in its own right) [7]

Reducing lower-extremity neuromuscular function, thereby increasing the risk of falling [8 –10]

Overview of the market

Only a small fraction of postmenopausal women or older adults of both sexes receive treatment directed at reducing the risk of osteoporotic fracture. Even those who sustain such a fracture are often not defined as having osteoporosis; nor, after fracture repair, are they given treatment directed at reducing the risk of further fractures. Moreover, many individuals prescribed antiresorptive agents stop taking the medications within a few weeks or months of starting [11]. Partly for that reason and with the hope of increasing treatment adherence, dosage forms of bisphosphonates intended for once-weekly (or less frequent) administration have been developed and marketed over the past several years. Compliance with daily supplements of calcium and vitamin D is equally poor, as a recent population-based trial in the UK demonstrated [12].

The currently recommended daily intake of vitamin D in the USA is 200 international units (IU) up to the age of 50 years, 400 IU up to the age of 70 years and 600 IU thereafter [13]. However, since the publication of these recommendations in 1997, a great deal of additional work has been carried out demonstrating that these intakes alone are not sufficient to sustain vitamin D adequacy in most older individuals [14]. This is because, depending upon the serum 25-hydroxy-cholecalciferol (25(OH)D) value one wishes to maintain, daily utilization of the vitamin may need to be as much as 4000 IU or higher.

Vitamin D, as a nutritional supplement in its own right, is not commonly available in the supplement sections of most retail outlets, making it hard for patients to obtain. The principal forms of vitamin D supplementation have been multivitamin preparations (which typically contain 400 IU/dose) and calcium supplement preparations (which typically contain 200 IU per 500–600 mg calcium). Some of the supplements contain ergocalciferol (vitamin D2), which is less potent than cholecalciferol (vitamin D3). The combination of a bisphosphonate with supplemental vitamin D in a once-weekly formulation overcomes the barriers to self-supplementation with vitamin D and, at the same time, greatly decreases the need for daily pill taking and its associated problems.

Introduction to the compound

Alendronate

Alendronate is a nitrogen-containing bisphosphonate and the first such drug to be approved for an osteoporosis indication in the USA (1995). The drug has been used extensively for nearly 15 years with an impressive record of fracture-risk reduction and safety, particularly in women with postmenopausal osteoporosis and in individuals of both sexes with glucocorticoid-induced osteoporosis.

In common with the other nitrogen-containing bisphosphonates, alendronate concentrates on active bone-resorbing surfaces, where it is ingested by osteoclasts [15]. Within the cell, the nitrogen-containing bisphosphonates act as antagonists to farnesyl pyrophosphate synthase, the enzyme responsible for the synthesis of farnesyl diphosphate and geranylgeranyl diphosphate, the principal prenoid units that are attached to catalytic proteins, enabling their incorporation into key structural elements of working cells (principally the cell membrane or vesicular membranes within the cell) [16]. In preformed osteoclasts, one visible result is retraction of the ruffled border in the resorption pit (the active, working side of the osteoclast), together with shortened osteoclast lifespan. In addition, bisphosphonates in tissue culture reduce the development and maturation of new osteoclasts. Because of the 2–3-week lifespan of the osteoclast, as well as the long residence time of the bisphosphonates in bone, daily administration of bisphosphonates is not required for efficacy.

The net result of a therapeutic dosage level of the nitrogen-containing bisphosphonates is a substantial reduction in bone resorption [17]. Since resorption is the first step in the remodeling process, the high level of bone remodeling that is often characteristic of the postmenopausal and osteoporotic states [18] is reduced to approximately premenopausal levels [19]. Physiologically, bisphosphonates affect bone mass in several ways:

Stop or slow bone loss

Increase bone density by filling in of the remodeling space [20]

Shift bone balance at the remodeling locus from negative to positive, leading to slow, linear bone gain at the hip and spine for as long as 10 years of continuous treatment

The reduction in bone resorption produced by the oral bisphosphonates decreases one of the major inputs of calcium into the extracellular fluid (ECF), which is important for the maintenance of calcium homeostasis. This effect leads to a mild reduction in ECF calcium, usually within the normal range (sometimes dipping below under fasting conditions) [21]. This drop in ECF calcium, in turn, evokes an increase in parathyroid hormone (PTH) secretion, which leads to better conservation of calcium at the kidney and, through improved synthesis of calcitriol (1,25(OH)₂D), improved absorption of calcium from the diet. These latter effects help meet the calcium requirements created by the increased bone mineralization and improvement in bone balance that can accompany long-term bisphosphonate therapy. However, for these ancillary physiologic processes to operate effectively, there must be adequate calcium in the diet and it must be absorbed. All clinical trials of alendronate have excluded individuals with low vitamin D status (<9 ng/ml or 23 nmol/l), and have incorporated supplemental calcium along with the bisphosphonate. Thus, it is uncertain whether the drug would be able to exert its demonstrated efficacy if adequate dietary calcium were not available or if calcium absorption were defective.

Cholecalciferol

Cholecalciferol is a secosterol, normally synthesized in the skin by photoconversion of 7-dehydrocholesterol to previtamin D in response to ultraviolet (UV) radiation in the wavelength range of 280–320 nm (UV-B). Cholecalciferol is naturally present in only a few foods (principally oily fish) and the major source of the vitamin for most individuals is cutaneous synthesis, which, depending upon exposure, can easily exceed 10,000 IU/day. Vitamin D, whatever its source, is converted in the liver to 25(OH)D, which circulates in the blood attached to D-binding protein and is probably also bound in muscle. 25(OH)D is the precursor compound used by many tissues for controlled synthesis of calcitriol, a key component of the autocrine signaling mechanisms in many cells, important in regulating cell replication, differentiation and apoptosis [22,23].

The same 1-α-hydroxylation of 25(OH)D that produces calcitriol for autocrine regulation also occurs as an endocrine mechanism in the proximal tubular cells of the kidney, where synthesis of calcitriol is regulated by PTH, as well as by a low serum phosphorus concentration. These cells then secrete the synthesized calcitriol into the bloodstream, whence it travels to such tissues as the intestinal mucosa, where it is responsible for inducing the synthesis of a calcium-transport protein that upregulates calcium absorption. This latter step is the canonical function of vitamin D and is what is responsible for its antirachitic effects. The autocrine function, described briefly above, is probably more general and more primitive, but it has only been discovered relatively recently and much more needs to be learned about its importance in a variety of chronic diseases.

In additon to its effects on the calcium economy, vitamin D has been shown to decrease the risk of falls [9,10], an action that appears to be unrelated to its role in promoting calcium absorption. Additionally, there is a large body of literature showing associations between low vitamin D status and disorders such as prostate cancer, colon cancer, breast cancer, Type I diabetes, multiple sclerosis and even coronary artery disease [22,23].

Because of the long half-life of 25(OH)D in the body (in the order of 3 weeks) [24], daily administration of vitamin D is not required for clinical efficacy.

Alendronate plus cholecalciferol

The marketed once-weekly product contains alendronate sodium 70 mg and cholecalciferol 2800 IU. The alendronate dose has been approved since 2000 for once-weekly therapy, and the vitamin D dose is equal to seven-times the daily intake recommended for individuals aged 50–70 years [13]. Thus, the combination product provides a week's worth of both agents in a single dose.

Absorption & metabolism

Alendronate, like the other bisphosphonates, is poorly absorbed when taken orally, with absorption averaging approximately 0.6% of the ingested dose when taken on an empty stomach [15]. Absorption is even lower when food or beverages are ingested less than 30 min following the alendronate dose. Alendronate is not metabolized in the body and that fraction of the absorbed drug that is not bound to bone is excreted in the urine. Cholecalciferol, by contrast, is well absorbed with or without food. Pharmacokinetic studies of the combination dosage unit have demonstrated bioequivalence of alendronate as a component of the combined product with alendronate alone and, correspondingly, bioequivalence of cholecalciferol in the combined product with cholecalciferol alone [UNPUBLISHED DATA, MERCK & CO.]. Thus, neither component interferes with the absorption of the other.

Clinical efficacy

The clinical efficacy of alendronate has been demonstrated many times over [25 –27]. The drug leads to improved bone density, reduced bone remodeling and an approximately 50% reduction in fracture risk, including hip and spine fractures. Vitamin D, together with supplemental calcium, but without other pharmacologic therapy, in doses of 700–800 IU/day, has also been shown to reduce the risk of osteoporotic fractures by as much as 55% in individuals over the age of 65 years [28 –31]. Evidence of the efficacy of the new, combined formulation is limited to short-duration studies of remodeling suppression, indicating a comparable degree of remodeling biomarker reduction for both alendronate alone and alendronate with cholecalciferol [32].

Because of the fall-protective effect of vitamin D, as well as the resorption-suppressive effect of the bisphosphonate, it is possible that the combined formulation will be more effective than either component alone. However, there are no studies evaluating whether the combination is more efficacious in the treatment of osteoporosis than alendronate alone. Nevertheless, there is an emerging consensus that improving the vitamin D status of the elderly population would be beneficial, and the combination product contributes to that goal.

What is novel about this product is that, with a single oral dose per week and at no additional cost, patients get not only a potent bone active agent, but also vitamin D, without having to buy separate pills for each or having to remember to take them daily.

Safety & tolerability

The safety and tolerability profile of the combination product should be identical to that of the individual components. Preliminary clinical data are consistent with this conclusion [32]. Alendronate alone is capable of producing lower esophageal irritation, a side effect that tends to be minimized by the once-weekly dosage form, but which may nevertheless occur in isolated patients. Alendronate, like the other bisphosphonates, may also aggravate inflammatory bowel disease and, finally, rare cases of osteonecrosis of the jaw following tooth extraction have been reported [33]. This latter complication is observed mostly in individuals with cancer and poor oral hygiene who are receiving chemotherapy, following administration of intravenous aminobisphosphonates. The mechanism behind this serious complication is uncertain, but is likely to be due to more than (or in addition to) remodeling suppression (e.g., reduced angiogenesis).

The rare gastrointestinal side effects are local and acute, and subside as soon as treatment is stopped. However, the long residence time of the bisphosphonate in bone may mean that stopping treatment would not promptly reverse the pathogenetic mechanism for osteonecrosis of the jaw.

The vitamin D dosage in the combined product is equivalent to the ordinary, over-the-counter dosage typically found in multivitamin and calcium supplement preparations, and no adverse effects or tolerability issues are to be expected. The small minority of patients receiving bisphosphonates who may already be vitamin D replete would not be at risk using this combination product, since the vitamin D it contains would elevate serum 25(OH)D by less than 10 nmol/l (2.5 ng/ml) [14], an increment that would leave even individuals already two standard deviations above the population mean well short of values associated with toxicity. The only possible exception would be individuals with granulomatous diseases such as Boeck's sarcoid, in whom additional vitamin D may aggravate the hypercalcemia sometimes found in these patients. However, there is currently no reason to believe that the tolerability of the combination product would be different from that of the individual components.

Regulatory affairs

The combination product is approved in the USA, Mexico, Brazil and the European Union for the treatment of osteoporosis in women and for increasing bone mineral density in men with osteoporosis. Approval is pending in several other countries.

Conclusion

The combination of alendronate with cholecalciferol appears likely to represent an advance in osteoporosis therapy and prophylaxis since, in addition to the benefits associated with alendronate alone, it provides additional vitamin D, which the majority of individuals suffering from osteoporosis require. The vitamin D dosage is relatively modest and is not likely fully to normalize vitamin D status in many patients with osteoporosis by itself. However, given the increase in vitamin D fortification of a number of commonly consumed foods in the USA, it is becoming increasingly likely that full vitamin D normalcy may be approached by the sum total of a number of different inputs, one of which would be this once-weekly tablet containing alendronate and cholecalciferol.

Future perspective

Growing recognition of the importance of ensuring a sufficient calcium intake and optimal vitamin D status for the prevention and treatment of osteoporosis makes it likely that more combination dosage forms or packages will be developed for the antiresorptive, bone-active, pharmacologic agents. It would be logical, in the case of alendronate, for the vitamin D addition to be extended to the 35 mg alendronate once-weekly dosage form, now approved for the prevention of osteoporosis. In part, these combinations will be directed at improving patient adherence to optimal regimens, and partly at offsetting common physician inattention to the need for supplemental calcium and vitamin D in the treatment of most patients with osteoporosis.

Executive summary

Inadequate vitamin D status is common in patients with osteoporosis.

Alendronate sodium plus cholecalciferol (vitamin D3) is a combination product intended for once-weekly administration for the treatment of osteoporosis in women.

This product provides the once-weekly dosage already approved for alendronate, together with 2800 international units (IU) of cholecalciferol, equivalent to 400 IU/day.

Safety and tolerability of the combination are likely to be the same as for its components.

The cost is the same as for alendronate alone and the combination avoids the need to take an extra vitamin D pill.

References

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Alendronate plus Cholecalciferol for the Treatment of Osteoporosis

Abstract

Keywords

Overview of the market

Introduction to the compound

Alendronate

Cholecalciferol

Alendronate plus cholecalciferol

Absorption & metabolism

Clinical efficacy

Safety & tolerability

Regulatory affairs

Conclusion

Future perspective

References