Superiority of alfacalcidol over plain vitamin D in the treatment of osteoporosis


Plain vitamin D or active vitamin D in the treatment of osteoporosis: where do we stand today?
Johann Diederich Ringe


Osteoporosis is a major cause of morbidity and mortality worldwide and its prevention in order to avert fractures was considered of great importance in maintaining well-being and independence among the elderly. Strategies for osteoporosis prevention are well delineated, but research shows that the treatment options offered today could still be improved. The role of plain vitamin D (cholecalciferol) in bone health and the prevention of osteoporosis are well documented; however, as a treatment for osteoporosis, either with or without calcium, it has been shown to be ineffective. This is due in part to the strong negative feedback mechanisms in place in vitamin D-replete patients. However, other factors linked directly to ageing such as oestrogen depletion, reduced kidney or liver function may also be involved in reducing the body’s capability to activate plain vitamin efficiently. This is why active vitamin D analogues such as alfacalcidol, 1-α-(OH)D3, are of clinical interest. Alfacalcidol requires only one hydroxylation reaction to become active 1,25-(OH)2-vitamin D3, and the 25-hydroxylase catalyzing this reaction is found in the liver and also interestingly in osteoblasts suggesting a local effect. Registered for use in postmenopausal osteoporosis, in most countries worldwide, alfacalcidol has also shown efficacy in glucocorticoid-induced and male osteoporosis. The present review provides compelling evidence for the efficacy of this compound in the treatment of osteoporosis and prevention of fractures both in monotherapy and when combined with other osteoporotic drugs where additive effects are clear. The safety profile of alfacalcidol is shown to be highly acceptable and it is considered less likely to induce hypercalcaemia than another more widely used analogue, calcitriol. Therefore, it remains unclear as to why alfacalcidol is not more widely used in clinical practice.

Spontaneous or low-trauma fractures are often one of the first signs of osteoporosis, a chronic, initially, often silent disease, characterised by compromised bone strength, namely low bone density and weakened bone architecture [1]. Most commonly of the vertebrae, radius and hip, such fractures are a major cause of morbidity and mortality worldwide accounting for millions of disability-adjusted life years (DALYs) annually [2] and placing the healthcare budgets of every country under immense strain [3–5]. Osteoporosis occurs in all populations and at all ages but is most prevalent in the elderly [1] especially in postmenopausal females [6]. These are both considered to be primary osteoporosis and are type II (age-related) and type I (postmenopausal), respectively [1]. Secondary osteoporosis is osteoporosis occurring as a result of disease, medication and/or lifestyle [1]. Clinically, osteoporosis is diagnosed on the basis of a bone mineral density (BMD) assessment that is ≥ 2.5 standard deviations (SD) below the average value for healthy, young women [2]. This WHO definition was globally considered to provide the threshold for both diagnosis and intervention [2]. However, bone density as a measure was designed for epidemiological studies and its use as a marker for fracture in individuals and to measure treatment outcomes is disputed [7]. On an individual basis, many other factors may influence skeletal fragility including bone size, shape, micro-architecture and bone quality [8]. Guidelines suggest that BMD should be used in conjunction with the online assessment tools FRAX and QFracture to ascertain the true risk of fracture in an individual [9]. Due to its high morbidity, the prevention of osteoporosis and fractures is considered vital to the continued health, quality of life and independence of elderly people [2]. Yet while strategies for osteoporosis prevention are well delineated [6, 10], what really is the best treatment option?

Vitamin D3 (cholecalciferol)

Why is plain vitamin D not effective in the treatment of osteoporosis?

Alfacalcidol as an alternative to plain vitamin D

There is clinical evidence to support the use of alfacalcidol in osteoporosis

Additive effects are seen when alfacalcidol is used in combination with other anti-osteoporosis drugs

The safety of alfacalcidol compared with that of plain vitamin D


While the above evidence clearly supports the superiority of alfacalcidol over plain vitamin D in the treatment of osteoporosis, there still remain several unanswered questions as to why it is not used more frequently in clinical practice.
Plain vitamin D itself, with or without calcium, is not useful in either the prophylaxis or treatment of osteoporosis in subjects who are replete in vitamin D. A recent meta-analysis showed that poor evidence to justify the routine use of plain vitamin D in osteoporosis prevention [26]. Nevertheless, this is not always reflected in current treatment guidelines. The latest NOGG guidelines recommend that in postmenopausal women and men ≥ 50 years who are at increased risk of fracture, a daily dose of 800 IU of plain vitamin D should be advised (grade A recommendation) [56]. While these guidelines also consider calcitriol as an analog alternative to plain vitamin D, there is no mention of alfacalcidol, although alfacalcidol is considered safer than calcitriol in regard to the risk of undesirable events, i.e. hypercalcemia and hypercalciuria [81], and despite a plethora of studies carried out in the 1980s and 1990s that have repeatedly shown the efficacy of alfacalcidol in osteoporosis [78, 82]. When added to the results from newer studies of alfacalcidol in both monotherapy and in combination discussed in this review, the wealth of data leads the author to an unresolved question; what more needs to be done to advance the use of alfacalcidol in current practice?


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Fig. 1 Cumulative rates of all fractures and of hip fractures by a group. Numbers at risk of hip fracture are higher because they include participants who had another type of fracture, reproduced with permission from Grant 2005 [27]
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Fig. 2 Comparison of activation pathways of plain vitamin D (left) and alfacalcidol (right). Once ingested, alfacalcidol enters the blood circulation, and 25- hydroxylation in the liver produces the active form of the D hormone, 1,25(OH)2D3. Alfacalcidol activation is independent of vitamin D status, age, and kidney function. Alfacalcidol can also be activated directly in the bone where it increases mineralization locally
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Table 1 Results from three randomized trials that compared the effects of alfacalcidol with either vitamin D in monotherapy or in combination with calcium on osteoporotic endpoints, calcium absorption, lumbar BMD, and fractures [39, 50, 53]
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Alfacalcidol in treatment guidelines

Alfacalcidol is amongst the active vitamin D analogs registered in most countries worldwide for postmenopausal osteoporosis with data that also show its efficacy also in glucocorticoid-induced [75] and in male osteoporosis [43]. Daily oral administration is recommended at 1 μg/day. While widely used and studied in Japan and China [57, 72, 77, 79, 82], low recognition of its advantages exists in Europe and North America. Its use is, however, included in wider international guidelines for the diagnosis, management, and treatment of osteoporosis and established postmenopausal osteoporosis [45, 47].

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