Rationale for active vitamin D and analogs in the treatment of osteoporosis

In 1981, Chugai Pharmaceutical succeeded in marketing alfacalcidol, a prodrug of calcitriol, as a therapeutic agent for renal osteodystrophy. In 1983, Chugai succeeded in extending the application of alfacalcidol to the treatment of osteoporosis as well. Clinicians in Japan have accepted alfacalcidol as a remedy for osteoporosis. However, the use of calcitriol and its analogs for the treatment of osteoporosis is still controversial. Some misunderstandings exist internationally about the efficacy of the active form of vitamin D for the treatment of osteoporosis. It is important to emphasize that patients with osteoporosis have intestinal calcium malabsorption and dysfunction in renal activation of vitamin D. When massive doses of parent vitamin D were administered to OVX rats, bone mass increased, but surprisingly, many porotic area were observed in the cortical bone. On the other hand, administration of alfacalcidol increased physiological bone without porotic observation. It is necessary to give the active form of vitamin D, D-hormone, with an RDA-equivalent supply of calcium. Alfacalcidol forms physiological strong bones that are hardly fractured by regulating calcium and bone metabolism. We proposed a new vitamin D analog, 2beta (3-hydroxypropoxy)calcitriol [ED-71] as a therapeutic drug for osteoporosis, which is more potent than calcitriol. ED-71 is now being investigated in phase 2 clinical studies in Japan. ED-71 will appear as more improved drugs for osteoporosis until 2010.     

The effects of calcitriol on falls and fractures and physical performance tests

There is an increase in the incidence of falls with aging and about 10% of falls lead to fractures. Nearly all hip fractures are due to falls and hip fractures are the most severe of the osteoporotic fractures because they lead to a 20% mortality rate and a loss of independent living in 50% of cases. Although there are multiple factors associated with falls, our interest is the role that vitamin D metabolism plays in the pathogenesis of falls. Recent clinical trials show that both vitamin D and the metabolite calcitriol reduce the number of falls by 30-40% in elderly subjects. This should also reduce the number of fractures. In European studies, the decrease in falls could be attributed to an improvement in the muscle weakness that often accompanies vitamin D deficiency. However, in the studies using calcitriol there was no vitamin D deficiency, so the mechanism of its efficacy is less clear. It could be due to increased muscle strength, an improvement in the neurological control of balance or both. Understanding these mechanisms would allow us to search for analogs of vitamin D that act more selectively on muscle and on the central nervous system.     

A new active vitamin D analog,ED-71, causes increase in bone mass with preferential effects on bone in osteoporotic patients

As a candidate for active vitamin D analogs that have selective effects on bone, 1alpha,25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71) has been synthesized and is currently under clinical trials. In ovariectomized rat model for osteoporosis, ED-71 caused an increase bone mass at the lumbar vertebra to a greater extent than 1alpha-hydroxyvitamin D3 (alfacalcidol), while enhancing calcium absorption and decreasing serum parathyroid hormone levels to the same degree as alfacalcidol. ED-71 lowered the biochemical and histological parameters of bone resorption more potently than alfacalcidol, while maintaining bone formation markers.An early phase II clinical trial was conducted with 109 primary osteoporotic patients. The results indicate that oral daily administration of ED-71 (0.25, 0.5, 0.75, and 1.0 microgram) for 6 months increased lumbar bone mineral density in a dose-dependent manner without causing hypercalcemia and hypercalciuria. ED-71 also exhibited a dose-dependent suppression of urinary deoxypyridinoline with no significant reduction in serum osteocalcin. These results demonstrate that ED-71 has preferential effects on bone with diminished effects on intestinal calcium absorption. ED-71 offers potentially a new modality of therapy for osteoporosis with selective effects on bone.     

Vitamin D in the aging musculoskeletal system: an authentic strength preserving hormone

Until recently, vitamin D was only considered as one of the calciotrophic hormones without major significance in other metabolic processes in the body. Several recent findings have demonstrated that vitamin D plays also a role as a factor for cell differentiation, function and survival. Two organs, muscle and bone, are significantly affected by the presence, or absence, of vitamin D. In bone, vitamin D stimulates bone turnover while protecting osteoblasts of dying by apoptosis whereas in muscle vitamin D maintains the function of type II fibers preserving muscle strength and preventing falls. Furthermore, two major changes associated to aging: osteoporosis and sarcopenia, have been also linked to the development of frailty in elderly patients. In both cases vitamin D plays an important role since the low levels of this vitamin seen in senior people may be associated to a deficit in bone formation and muscle function. In this review, the interaction between vitamin D and the musculoskeletal components of frailty are considered from the basic mechanisms to the potential therapeutic approach. We expect that these new considerations about the importance of vitamin D in the elderly will stimulate an innovative approach to the problem of falls and fractures which constitutes a significant burden to public health budgets worldwide.     

Alfacalcidol restores cancellous bone in ovariectomized rats

Active vitamin D metabolites have been demonstrated to reduce vertebral and hip fractures in elderly patients. A number of in vitro and in vivo pre-clinical studies have suggested that vitamin D may effectively stimulate osteoblastic activity and exert an anabolic effect on bone. The current study was designed to further explore the ability of an active vitamin D analog to restore bone in a skeletal site with established osteopenia in ovariectomized (OVX) rats. Female Sprague Dawley rats at five months of age and 8 weeks after sham ovariectomy or ovariectomy were randomly divided into 7 groups with 10 per group. At the beginning of the treatments, one group of sham-operated rats and one group of OVX rats were sacrificed to serve as baseline controls. Another group of sham-operated rats and one group of OVX rats were treated with vehicle for 4 weeks. The OVX rats in the remaining groups were treated with alfacalcidol at 0.05, 0.1 or 0.2 microg/kg/d by daily oral gavage, 5 days/week for 4 weeks. As expected, estrogen depletion caused high bone turnover and cancellous bone loss in lumbar vertebra of OVX rats. Alfacalcidol treatment at 0.1 or 0.2 but not 0.05 microg/kg/d increased serum calcium and phosphorus in OVX rats as compared with vehicle treatment. In addition, serum parathyroid hormone was suppressed, whereas serum osteocalcin was increased by alfacalcidol at all dose levels. Furthermore, histomorphometric data of 2nd lumbar vertebral body revealed that cancellous bone volume in OVX rats treated with alfacalcidol at 0.1 or 0.2 microg/kg/d was increased to the level of sham-operated rats treated with vehicle. This increment in cancellous bone mass was accompanied by increases in trabecular number and thickness and a decrease in trabecular separation. Moreover, osteoclast surface and number were significantly decreased, whereas bone formation variables such as mineralizing surface and bone formation rate were significantly increased in alfacalcidol- treated OVX rats compared with those of vehicle-treated OVX rats. Finally, a linear regression analysis showed that alfacalcidol treatment dose-dependently altered most of the variables measured in the current study. In conclusion, alfacalcidol completely restores cancellous bone by stimulating bone formation and suppressing bone resorption in lumbar vertebra of OVX rats when the treatment is started at an early phase of osteopenia. The evidence of increased bone formation by alfacalcidol treatments further supports the notion that active vitamin D metabolites or their analogs may exert anabolic effects on bone.     

Vitamin D analogs and bone

Vitamin D analogs increase intestinal calcium absorption, and have been shown to possess antiresorptive and also bone anabolic properties in vivo. Therefore, the pharmacological profile of vitamin D analogs would be well suited for the treatment of osteoporosis. However, the calcemic side effects of this compound class, especially at higher doses, have hampered their wide use in osteoporotic patients. Nevertheless, the clear potential for bone anabolic properties together with oral availability have stimulated the interest in this substance class, and there is an active search for bone selective vitamin D compounds. After an overview of the physiological functions of vitamin D in bone, this article focuses on the effects of acute and chronic administration of pharmacological doses of vitamin D analogs on bone in animal models and humans. Furthermore, the endocrinological, cellular, and microanatomical mechanisms involved in the skeletal actions of vitamin D analogs are discussed. The final section briefly reviews the available data on possible bone selective vitamin D analogs.     

Bone marrow levels of 25 hydroxy vitamin D are not depressed in cases of hip fracture compared with controls

There is little information on tissue as distinct from plasma levels of vitamin D metabolites in cases of hip fracture compared with controls. Femoral neck fractures in the elderly are associated with increased cortical remodelling and endosteal resorption, leading to regional increases in porosity and reduced cortical thickness. Vitamin D metabolites play a central role in the maintenance of normal serum calcium levels and may, through interactions with parathyroid hormone, exert an important influence on bone structure. To investigate whether hip fracture might be associated with tissue vitamin D deficiency, we have measured by radioimmunoassay the levels of 25 hydroxy vitamin D (25 (OH)D) in bone marrow samples extracted from the proximal femurs of 16 female subjects who had suffered fracture (mean age = 82.1 years, standard error (se) 1.9) and nine sex matched post mortem controls (mean age = 83.8 years, se 2.5). Twenty five (OH)D concentrations were significantly greater in the fracture cases (median = 3.7, IQR = 2.5–3.9 ng/g) than in the control group (median = 1.5, IQR = 0.9–2.3 ng/g; P = 0.0007, non‐parametric Wilcoxon/Kruskal–Wallis test). It was suggested in the 1970s that bone loss and hip fracture risk in the UK were driven by vitamin D deficiency. Our results suggest that the alterations in femoral neck bone microstructure and remodelling in hip fracture cannot be assigned to the single cause of relative deficiency of vitamin D. Vitamin D deficiency or insufficiency may nevertheless increase remodelling and loss of bone tissue and contribute causally to a minority of hip fractures. Copyright © 2013 John Wiley & Sons, Ltd.     

Combined therapies in osteoporosis: bisphosphonates and vitamin D-hormone analogs

During the last two decades, the development of new, highly effective therapeutics (e.g. bisphosphonates, SERMs, strontium ranelate and PTH) has significantly extended the spectrum of osteoporosis therapy. However, the interest of combining bone-active agents and/or Vitamin D and calcium is still being debated, and is restricted to a very marginal set of compounds (Alendronate and native Vitamin D). On the other hand, Vitamin D-hormone analogs, calcitriol, and alfacalcidol, have repeatedly demonstrated their effectiveness in being valuable alternatives compared to native Vitamin D in this setting. A growing amount of data documents the pre-clinical and clinical efficacies of combinations of bisphosphonates with calcitriol, or with alfacalcidol in primary and secondary osteoporosis. This exhaustive review of the available animal and clinical data aimed at comparing the theoretical with demonstrated absolute and relative benefits of those therapeutic approaches. Most of the pre-clinical and clinical data in PMOP suggest significant, clinical improvements in response to combination therapies versus monotherapies in postmenopausal osteoporosis. As a investigated by most of the currently available trials, a daily dose of alendronate 10 mg or a weekly dose of Alendronate 70 m plus alfacalcidol 0.5-1.0 microg daily plus alfacalcidol 0.5 microg seems to surpass other combinations when BMD and bone metabolism markers are considered. A synergy with bisphosphonates in reducing the fracture episodes may lie in the pleiotropic effects of D-hormone analogs on musculoskeletal, immunological and neurological systems. Negative interactions between both drugs have not yet been reported, while a reduction of hypercalcuria episodes has been noted in combination therapies, as compared to monotherapies involving high doses of Vitamin D, calcitriol, or alfacalcidol. Based on the possible reduction of periodic safety checks of calcemia, an improved compliance could then be expected, which would, in turn, generate a better end result. However, to document this, long-term, high quality comparative studies with factorial designs are needed to determine which role this alternative should play in the management of postmenopausal, male, and glucocorticoid-induced osteoporosis.     

Vitamin D and osteoporosis-related fracture

The age-related decline in mass and quality of bone (osteoporosis) and muscle (sarcopenia) leads to an exponential increased risk for osteoporosis-related fracture with advancing age in older adults. As vitamin D inadequacy plausibly causally contributes to these declines, optimization of vitamin D status might reduce the deterioration of bone and muscle function with age. Putative mechanisms by which vitamin D inadequacy may increase fracture risk include both direct and indirect effects on bone and muscle. However, controversy currently clouds the role(s) of vitamin D in osteoporosis-related fracture, the amount of vitamin D required and the optimal 25-hydroxyvitamin D level. This review provides an overview of current knowledge and suggests a clinical approach to vitamin D status in older adults with, or at risk for, osteoporosis-related fracture. These recommendations are likely to evolve as additional data becomes available.     

Novel nonsecosteroidal vitamin D3 carboxylic acid analogs for osteoporosis, and SAR analysis

Novel vitamin D(3) analogs with carboxylic acid were explored, focusing on a nonsecosteroidal analog, LG190178, with a bisphenyl skeleton. From X-ray analysis of these analogs with vitamin D receptor (VDR), the carboxyl groups had very unique hydrogen bonding interactions in VDR and mimicked 1α-hydroxy group and/or 3β-hydroxy group of 1α,25-dihydroxyvitamin D(3). A highly potent analog, 6a, with good in vitro activity and pharmacokinetic profiles was identified from an SAR study. Compound 6a showed significant prevention of bone loss in a rat osteoporosis model by oral administration.     

Vestibular dysfunction in vitamin D receptor mutant mice

The vitamin D endocrine system is essential for calcium and bone homeostasis. Vitamin D deficits are associated with muscle weakness and osteoporosis, whereas vitamin D supplementation may improve muscle function, body sway and frequency of falls, growth and mineral homeostasis of bones. The loss of muscle strength and mass, as well as deficits in bone formation, lead to poor balance. Poor balance is one of the main causes of falls, and may lead to dangerous injuries. Here we examine balance functions in vitamin D receptor deficient (VDR−/−) mice, an animal model of vitamin D-dependent rickets type II, and in 1α-hydroxylase deficient (1α-OHase−/−) mice, an animal model of pseudovitamin D-deficiency rickets. Recently developed methods (tilting box, rotating tube test), swim test, and modified accelerating rotarod protocol were used to examine whether the absence of functional VDR, or the lack of a key vitamin D-activating enzyme, could lead to mouse vestibular dysfunctions. Overall, VDR−/− mice, but not 1α-OHase−/− mice, showed shorter latency to fall from the rotarod, smaller fall angle in the tilting box test, and aberrant poor swimming. These data suggest that VDR deficiency in mice is associated with decreased balance function, and may be relevant to poorer balance/posture control in humans with low levels of vitamin D.     

Vitamin D and aging: old concepts and new insights

Aging is a complex biological process driven by a selective class of molecules and pathways that affect overall deterioration of physiological functions to increase the risk of age-related diseases. A role of vitamin D in mammalian aging is well documented. Since vitamin D has an essential role in bone formation and mineralization, its deficiency results in impaired bone mineralization, such as rickets in children, osteomalacia in adults and osteoporosis in the aged population. Vitamin D replacement therapy therefore is one of the most commonly prescribed treatments for the elderly. Recent studies using genetically altered mouse models, such as in Fgf-23^−/− and klotho mutant mice, that exhibit altered mineral ion metabolism due to high vitamin D activities showed features of premature aging that include atherosclerosis, emphysema, osteopenia/osteoporosis, hypogonadism, soft tissue calcifications and generalized atrophy of organs; the pathologic effects of vitamin D in these mouse models are obvious, as diminution or genetic ablation of the vitamin D pathway ameliorated most of the above-mentioned phenotypes, by reversing mineral ion metabolism, and the resultant effect being prolonged survival of the mutant mice. These in vivo mouse studies, although subject to further molecular characterization, add new insights into the role of vitamin D in aging.     

Safety of treatment for subclinical osteomalacia in the elderly.

Forty one elderly patients admitted to hospital for acute illnesses were also found to have subclinical osteomalacia. Immediately before discharge, therefore, all were randomised to receive either vitamin D2 25 micrograms daily, alfacalcidol 0.5 micrograms daily, or placebo. Treatment was given for at least three months, those allocated to placebo then being switched to an active drug. Within the first three months of treatment with either of the active drugs most patients had exhibited a fall to normal in osteoid values. In only four treatment periods was there a mild increase in serum calcium concentration, and in no patient was this accompanied by deterioration in renal function. Any increase in serum creatinine concentration was invariably attributable to the underlying disease for which the patient had been admitted in the first place. Subclinical osteomalacia in the elderly may be corrected by relatively low doses of alfacalcidol (0.5 micrograms daily) or vitamin D2 (25 micrograms daily) given for three months. Such treatment is safe and not accompanied by a serious risk of hypercalcaemia or renal impairment.     

Vitamin D and fractures in the elderly

Osteoporosis and the subsequent fractures caused by this are a source of morbidity and mortality in the elderly population. It is also often the start of the cascade that culminates in frailty and dependence. Vitamin D has a direct relationship with the appearance of osteoporosis and with the risk of fractures. Receptors of this vitamin have also recently been described in other organs and systems of the body that are associated with muscle strength, cancer and overall mortality. Deficiency of this vitamin in the elderly population in Spain is very prevalent, both in the community and the hospitalised elderly. The diagnosis and treatment are straightforward and cheap. Its efficacy in the prevention of osteoporosis and in the appearance of fractures is perfectly demonstrated. In this review, we will look at the physiology and actions of this vitamin, as well as the principal studies that have demonstrated its effectiveness in the elderly population.     

The vitamin D story: a collaborative effort of basic science and clinical medicine

The discovery in 1919-1924 of vitamin D and its production in skin and foods by UV irradiation led to the elimination of rickets as a major medical problem. The identification and chemical preparation of vitamin D in the next decade provided large quantities of vitamin D to the physician for the treatment of a variety of metabolic bone diseases. Early in the 1960s, little was known about the function of vitamin D in causing mineralization of the skeleton, and hence in preventing the disease rickets in children and osteomalacia in adults. With the application of modern tools of biochemistry came the discovery that vitamin D must first be modified by 25-hydroxylation in the liver followed by 1 alpha-hydroxylation in the kidney to produce the vitamin D hormone 1 alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. This process is strongly feedback-regulated and is one of the major endocrine systems regulating plasma calcium and phosphorus concentrations. Furthermore, it is a major endocrine system regulating bone mass and state. With the chemical synthesis of 1,25-(OH)2D3 and many of its analogs has come the possibility of treating a number of metabolic bone diseases not previously managed adequately, such as vitamin D-resistant rickets, hypoparathyroidism, renal osteodystrophy, and osteoporosis. By using 1,25-(OH)2D3, considerable work has been carried out to understand how this hormone facilitates calcium transport across the intestinal membrane. Modern work is described on the molecular mechanism of action of the vitamin D hormone in eliciting the cellular responses that result in mineral homeostasis. The possible use of the vitamin D analogs to bring about differentiation of myelocytic-type leukemias and in the treatment of psoriasis has been an important new development. This paper will thus be a blend of basic science of the vitamin D system and the application of that information to the treatment of disease.     

Vitamina D y fracturas en el anciano

Osteoporosis and the subsequent fractures caused by this are a source of morbidity and mortality in the elderly population. It is also often the start of the cascade that culminates in frailty and dependence. Vitamin D has a direct relationship with the appearance of osteoporosis and with the risk of fractures. Receptors of this vitamin have also recently been described in other organs and systems of the body that are associated with muscle strength, cancer and overall mortality. Deficiency of this vitamin in the elderly population in Spain is very prevalent, both in the community and the hospitalised elderly. The diagnosis and treatment are straightforward and cheap. Its efficacy in the prevention of osteoporosis and in the appearance of fractures is perfectly demonstrated. In this review, we will look at the physiology and actions of this vitamin, as well as the principal studies that have demonstrated its effectiveness in the elderly population.     

Increase in Bone Mass After Correction of Vitamin D Insufficiency in Bisphosphonate-Treated Patients

ObjectiveTo assess the relative contribution of vitamin D insufficiency to loss of bone mineral density (BMD) in patients taking bisphosphonates.MethodsPatients were eligible for inclusion if they had osteoporosis or osteopenia and demonstrated a decline in BMD during the preceding year while taking stable doses of alendronate or risedronate, plus supplemental calcium and vitamin D. Patients with previously known secondary causes of osteoporosis were excluded from the study. Eligible patients underwent prospective measurement of bilateral hip and lumbar spine BMD by dual-energy x-ray absorptiometry, serum 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D, intact parathyroid hormone, osteocalcin, and thyroid-stimulating hormone (thyrotropin), and urinary calcium:creatinine ratio.ResultsAnnual BMD was assessed in 175 previously bisphosphonate-responsive patients with low BMD. Of the 175 patients, 136 (78%) had either a significant interval increase or no change in BMD, whereas 39 (22%) had a significant decrease. Of the 39 patients who lost BMD, 20 (51%) had vitamin D insufficiency (25-OHD < 30 ng/mL). After a single course of orally administered vitamin D₂ (500,000 IU during a 5-week period), the 25-OHD level returned to normal in 17 of the 20 vitamin D-insufficient patients and was associated with significant (P < .02) 3.0% and 2.7% increases in BMD at the lumbar spine and the femoral neck, respectively. Failure to normalize the serum 25-OHD level was associated with further loss of BMD.ConclusionVitamin D insufficiency was the most frequently identified cause of bone loss in patients with declining BMD during bisphosphonate therapy. Correction of vitamin D insufficiency in these patients led to a significant rebound in BMD. (Endocr Pract. 2008; 14:293-297)     

Effects of vitamin D2-fortified shiitake mushroom on bioavailability and bone structure

Bioavailability and bone loss inhibitory effects of vitamin D₂ derived from UV-irradiated shiitake mushroom were determined in vivo. The effect of the absence of ovaries on the bioavailability of vitamin D₂ and bone structure was also investigated. Sham operated (sham) and ovariectomized (OVX) rats were divided in 3 groups according to their diets, i.e. control: only vitamin D-deficient diets; UV(X): vitamin D-deficient diets with non-irradiated mushroom powder; UV(O): vitamin D-deficient diets with irradiated mushroom powder. The obtained results showed that vitamin D₂ from shiitake mushroom was able to increase bone mineral density and trabecular bone structure of femur bone as well as its bioavailability. The absence of estrogen induced adverse effects not only on bioavailability of vitamin D₂ but also on trabecular bone. In conclusion, vitamin D₂-fortified shiitake mushroom might help postmenopausal women increase vitamin D₂ bioavailability and retard trabecular bone loss.

Abbreviations: OVX: ovariectomized; 25(OH)D: 25-hydroxyvitamin D; 1,25(OH)2D: 1,25-dihydroxyvitamin D; BMD: bone mineral density; micro-CT: micro computed tomography; RSM: response surface methodology; RP-HPLC: Reverse phase-high performance liquid chromatography; MS/MS: tandem mass spectrometry; E2: estradiol; NTx: N-terminal telopeptide of type I collagen; BV/TV: bone volume/total volume; BS/BV: bone surface/bone volume; Tb.Th: trabecular thickness; Tb.Sp: trabecular separation.     

老年髋部骨折患者抗骨质疏松的治疗

髋部骨折往往与高发病率、死亡率以及沉重的经济负担相联系,也是再次骨折的一个主要危险因素。因此加强老年髋部骨折患者的抗骨质疏松治疗及预防再次骨折成为提高该类人群生活质量的必要和关键,其中均衡的营养、补充钙和维生素D是基础,及早进行抗骨质疏松药物治疗是关键,而消除骨质疏松的继发原因、治疗并存疾病、适当的锻炼及防止跌倒则是重要的补充。总之,加强老年骨质疏松的多学科综合管理能够获得很好的临床效果。本文就抗骨质疏松药物在老年髋部患者和那些具有跌倒高风险人群中的疗效予以综述,以期为老年骨质疏松的管理提供借鉴。