Full Text: Introduction: D-Hormones Alfacalcidol and Calcitriol for Prevention and Treatment of Glucocorticoid/Inflammation-Induced Osteoporosis

Introduction

D-Hormones Alfacalcidol and Calcitriol for Prevention and Treatment of Glucocorticoid/Inflammation-Induced Osteoporosis

PHILIP N. SAMBROOK, MD,
Institute of Bone and Joint Research,
University of Sydney,
Sydney, Australia;
ERICH SCHACHT, PhD,
Department of Rheumatology and
Rehabilitation,
University Clinic Balgrist,
Zurich, Switzerland.
E-mail: erich.schacht@teva.de

Glucocorticoids (GC) are widely used in medical practice, where they play a major role in the treatment of asthma, inflammatory joint and bowel diseases, and in diseases affecting the central nervous system. The prevalence of this risk group who continuously take GC is about 0.5% of the total population and about 1.4% in patients aged > 55 years. Despite indisputable therapeutic advantages, longterm GC treatment is often overshadowed by side effects that can produce morbidity comparable to that of the original illness. One example is the development of osteoporosis (OP), which is known to occur both as a consequence of chronic oral GC administration and due to deleterious effects of the underlying disease on bone metabolism. Bone loss is highest in the initial months of therapy, and fracture incidence of GC/inflammation-induced OP is estimated to be between 30% and 50% of patients receiving this type of treatment long term. The dose-dependent increased risk of fracture starts with > 2.5 mg prednisolone daily¹.

The high and rapidly increasing fracture rate associated with GC/inflammation-induced OP cannot be explained alone by the respective loss of bone mineral density. It is suggested, however, that early negative influences on bone quality contribute to this increase in bone fragility and — very important — that the deleterious effect on muscle metabolism contributes, even after 3 months of GC therapy, to risk of falls and fractures. Moreover, after cessation of GC treatment, fall and fracture risks decline rather rapidly toward baseline¹.

It is well established that GC and underlying diseases affect bone and muscles through multiple mechanism pathways. One pathological pathway is the negative influence of vitamin D metabolism (Figure 1)².

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Figure 1. D-hormone deficiency in glucocorticoid/inflammation-induced osteoporosis.

Experimental data suggest that GC suppress expression of vitamin D-hormone receptors (VDR), inflammatory factors, e.g., tumor necrosis factor-a (TNF-a), and inhibit renal 1a-hydroxylase, and thereby the action of D-hormone in target organs is reduced^3,4. This is in accord with clinical findings that inflammatory diseases are associated with low serum D-hormone levels related to disease activity⁵ (Figure 1).

It is obvious that GC/inflammation-induced OP, with its high prevalence but very low associated use of medications against osteoporotic or fall-related fractures, is a vastly underestimated health problem worldwide. A therapeutic strategy should be started very early, optimally concurrent with the commencement of GC treatment lasting more than 6 months. The potential of D-hormone analogs for secondary prevention and treatment of established GC/inflammation-induced OP is also underestimated, despite an acceptable pathophysiological rationale, and fairly good experimental and clinical proof².

Some of the deleterious pharmacological effects of GC on bone, or possibly on muscles, can be counteracted directly by D-hormone analogs². In animal trials alfacalcidol increased bone quality and bone strength more effectively than plain vitamin D. This is important, based on the rapid decrease of bone quality in this type of OP. Importantly, D-hormone protects in vitro osteoblasts against TNF-a-induced apoptosis. This mechanism has been demonstrated in vivo in the inflammation-mediated osteopenia (IMO) model, an animal model that simulates bone loss in rheumatoid arthritis⁶. D-hormone analogs have very specific T cell immunoregulating properties, producing tolerogenic antigen-presenting cells, decreasing T helper cells, increasing suppressor cells, and inducing cytokine homeostasis through decreased proinflammatory and increased antiinflammatory cytokines⁷. These effects have been proven in several autoimmune disease models and in preliminary clinical investigations. The important role of intact VDR and sufficient D-hormone levels on muscle cell differentiation and metabolism has recently been shown in VDR gene-deleted mice⁸.

The dual action of alfacalcidol on bone strength and the proven efficacy in reduction of fall rate in at-risk elderly patients is of importance also in the prevention of GC/inflammation induced falls and fractures⁹. Low D-hormone serum levels (and/or less D-hormone action in target organs), increased parathyroid hormone (PTH) serum levels, increased cytokine serum levels, and decreased insulin-like growth factor-I serum levels in both groups are the correlation. Based on the same pathological factors of age-related and GC-induced reduction of muscle performance and increased fall risk, an efficacy of D-hormone on falls can also be expected in GC/inflammation-induced osteoporosis.

There is controversy as to whether D-hormone analogs would be more effective than plain vitamin D. D-hormone deficiency is better treated by D-hormone than by plain vitamin D since with reduction of VDR by glucocorticoids, only D-hormone analogs provide target organs with higher levels of D-hormone to activate VDR¹⁰.

Clinical studies and new metaanalyses show that D-hormone analogs are active in terms of prevention of bone loss (i.e., treatment of "high risk patients")^11-14. In patients with chronic inflammatory diseases, alfacalcidol is more effective than plain vitamin D in relation to bone resorption, reduction of PTH, improvement of muscle function, reduction of cytokines (TNF-a), and joint pain¹⁵. Especially in patients treated with higher GC dosages and/or insufficiently controlled inflammatory diseases, plain vitamin D is not efficient¹⁶. In established OP, alfacalcidol appears superior to plain vitamin D in terms of bone mass gain, as well as — very importantly —in terms of reduction in number of patients with new vertebral fractures and back pain¹⁷.

The most appropriate use of alfacalcidol is at commencement of a medium or high dose of oral GC, during oral GC treatment, especially during periods when high GC dosages are being utilized, e.g., in disease flares or after organ transplant, and, of course, in established GC/inflammation-induced OP.

There remain open questions as to whether D-hormone analogs can be used advantageously as adjuvant therapy in addition to disease modifying drugs, and whether regulation of cytokines is responsible for improvement in muscle function and pain relief, and for its advantageous use after organ transplant.

Interestingly, D-hormone analogs were equally active compared with alendronate in prevention of organ transplant- induced bone loss¹⁸. Surprisingly, new data suggest that D-hormones have a synergistic immunomodulatory effect in combination with routine therapy for immunosuppression, allowing reduction in doses of potent but toxic and expensive drugs, such as cyclosporine and glucocorticoids, required to prevent organ rejection, without any detectable change in episodes of rejection, infection, or death¹⁹.

Due to pleiotropic efficacy on bone, muscle, and the immune system, excellent tolerability, longterm safety, simple mode of administration, all of which promote longterm patient compliance, and the moderate daily cost, physiological alfacalcidol is an important treatment option in patients with glucocorticoid or inflammation-induced osteoporosis.

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