Reduction of Falls in Elderly. The central role of Alfacalcidol in a multi-dimensional paradigm

Fractures in the elderly represent a major threat in terms of life expectancy and quality of life. Modern therapeutics in the fight against fractures in the elderly require pluripotent efficacy in both preserving bone mineral density and limiting falls. Indeed, epidemiological evidence has recently highlighted that agents with a targeted action on bone only may fail to prevent up to 50% of the fractures observed in patients over 60 years. Furthermore, there are growing fundamental and clinical evidences that native vitamin D is unable to reduce falls and fractures in vitamin-D replete patients and patient with deficient renal function. Dhormone analogs (Alfacalcidol and Calcitriol) have been scrutinized for two decades for their abilities to prevent BMD loss, fractures, and, more recently, falls. Alfacalcidol (1alpha (OH) D3), notably by bypassing the renal endogenous feedback loop regulation, is a synthetic vitamin D derivative with more favourable pharmacokinetic and tolerability profiles as compared to calcitriol (1,25 (OH)2 D3). Encouraging results from pilot studies have driven research, and led to modern data able to support a pseudo Copernician change by switching from supplementation with vitamin D to actively treat bone, muscle, and neurocoordination with Alfacalcidol. This systematic narrative review browses the current pilot, clinical and meta-analytical data to demonstrate, in an evidence-based fashion, that the D-Hormone analog Alfacalcidol is an excellent candidate in preventing falls and fractures to a greater extent as compared to native vitamin D. The continuum of evidence synthesized in this paper highlights the necessary change in medical paradigm to efficiently prevent fractures in the elderly, and opens new research pathways, notably in combination therapies with Alfacalcidol. AGE-RELATED FRACTURES; A MULTIFACTORIAL PARADIGM Clinical experience and epidemiological data demonstrate that mobility and balance are key determinants of improved quality of life in worldwide aging populations. Falls currently tends to be a primary outcome in clinical trials given their consequences, in terms of fractures, quality of life and psychological consequences, including deconditioning and kinesophobia. A significant number of osteoporotic fractures are associated with falls, independently of bone mineral density (BMD) 1. Fractures are of the most conservative outcome in the fight against osteoporosis. Recently it was shown that 54% of women aged 65 years or older with incident hip fractures were not osteoporotic 2. Established osteoporosis in older patients of both sexes is characterized by decoupled bone remodelling induced by a deficit in sex hormones, as well as by a somatopause (insulin-like growth factor [IGF]-deficit), but also by a lack of circulating vitamin D, a reduced synthesis of D-Hormone in the kidneys and bones and by a lack of receptors and/or receptor affinity for D-Hormone (VDR’s) in the target organs leading to increased parathormone (PTH) levels and a higher bone turnover 3. In parallel to decreased bone strength, a loss of muscle power and performance (sarcopenia), neuromuscular deficiencies, deterioration in gait and postural stability appears in the age of 65-70 years in both genders and are very common. These deficiencies, together with slower response times lead to an increase of intrinsic, non-syncopal, locomotoric falls with no or only minimal contributions of external obstacles during normal daily activities. Together with a higher incidence of bone loss, differences in the types of falls, more often sideways instead of forward, and therefore, the direct impact of force on the hip together with the loss of soft tissue covering also explain the increased in hip fractures in elderly people over the age of 75. There is a current consensus that the combination of reduced bone strength and increased fall risk account for most of the variability for the different types of age-, falland osteoporosis-related peripheral, and, to a lesser extent, Reduction of Falls in Elderly. The central role of Alfacalcidol in a multi-dimensional paradigm 2 of 14 vertebral fractures 45. PHYSIOLOGY OF FALLS: MUSCLE, KIDNEY, NERVES AND BONE INTERACTION Age-related sarcopenia is, besides of reduced physical activity, the consequence of a reduction of fast-twitch type II muscle fibres, decreased IGF-1 and increased cytokine levels, e.g., interleukin-6 (IL-6) and tumour necrosis factor-α (TNF-α). Increasing IL-6 and decreasing IGF-1 are synergistic factors for functional disability 6. High PTHlevels and low circulating D-Hormone levels also play major roles as proximal muscle weakness is associated with hyperparathyroidism, vitamin D metabolism disorders, diabetes, chronic inflammatory diseases and reduced kidney function 78. Vitamin D-Hormone receptors (VDR’s) have been found in skeletal muscles and nerves and are implicated in correct muscle contraction and relaxation and in muscle protein synthesis 910. Murine models of VDR depleted mice have confirmed that VDR’s absence causes a reduction of skeletal muscle fiber size based on an increased expression of myogenic regulation factors (Myf5, Myogenin, E2A) through which the strict regulated differentiation and maturation of muscle cells will be disturbed 11. The muscular abnormalities are independent from secondary, metabolic changes, e.g. hypocalcaemia or hyperparathyroidism, confirming the direct involvment of VDR’s. The fact that a treatment with D-Hormone of VDR-positive myoblasts in vitro downregulates the mentioned myoregulating transcription factors, points out in addition the important role of D-Hormone and VDR’s in muscle development 11. Older age is significantly associated with decreased VDR expression in human skeletal muscle tissue 12. A positive correlation was found between femoral muscle strength and function and D-Hormone serum levels in the elderly 1314. This interaction was strongly supported by the fact that higher D-hormone serum levels were correlated, on a clinical perspective, with lower fall rates in elderly women 15. These data suggest that the age-related and the corticosteroid/inflammation-induced decline in muscle strength and function and the increase of falls could be in part explained by a decrease of VDR’s and a decrease of DHormone in serum and/or at receptor level. Impaired renal function is detrimental to the activation of DHormone. Dukas et al. found in multivariate-controlled analyses that in community-dwelling elderly women and men over age of 70, a creatinine clearance (CrCl) of<65 ml/min, calculated from serum creatinine by the CockcroftGault formula, was significantly associated with low DHormone serum levels and with a significant four times increased risk of falls compared to participants with normal CrCl 16. It has been postulated that this increased risk of falls is due to the associated significant lower D-Hormone and/or increased PTH serum levels. To test this hypothesis it was investigated in a double-blind randomized study whether treatment with Alfacalcidol can reduce the high risk of fallers and the high risk of falls associated with low CrCl. As a result 36 weeks of treatment with Alfacalcidol (1 μg daily) significantly and safely reduced in community-dwelling elderly men and women with a CrCl of<65 ml/min the low CrCl associated high risk of falls by -71% compared to placebo 17. The treatment with Alfacalcidol was, compared to placebo, associated with a significant reduction in the number of fallers (OR 0.26, 95% Cl, 0.08-0.80, P=0.019) and a significant reduction of the number of falls (0.29, 95% Cl, 0.09-0.88, P=0.028). The treatment effect of Alfacalcidol became significant after 24 weeks in participants with a CrCl<65ml/min. Alfacalcidol reduced the frequency of fallers and falls to the frequency of fallers and falls observed in participants with a CrCl ≥ 65ml/min and normal DHormone serum levels, which supports the basic hypothesis of the role of low D-Hormone levels and high risk of falls 17 It was confirmed in a cross-sectional study that also in osteoporotic patients (5313 women and men) a CrCl of less than 65 ml/min is a significant and independent risk factor for falls 18. Furthermore it could be shown for the first time that a low CrCl is also associated with a significantly increased risk of vertebral, hip and radial fractures 18. Recently Dukas et al found a significant correlation between decreasing CrCl and lower performance in validated balance and muscle power tests, like chairrising-test, timed – up and go test and tandem stand 19. Furthermore they found that a low CrCl<65 ml/min is, independent from the performance in muscle and balance tests, a significant risk factor for falls. In addition the same group found for the first time an stepwise increased risk for fall-associated fractures with a decreasing CrCl associated with first a decrease of Dhormone serum levels (CrCl<70 ml (min) and second with an increase of PTH serum levels (CrCl<40 ml/min) 20. Ensrud et al. tested the hypothesis that community-dwelling older women (>65 years) with low CrCl, calculated by the Cockcroft–Gault formula, are at increased risk of hip and vertebral fractures 21. There was an independent, graded Reduction of Falls in Elderly. The central role of Alfacalcidol in a multi-dimensional paradigm 3 of 14 association between reduced renal function and the risk of hip fractures. Women with a less than 60 ml/min CrCl compared to women with normal renal function (>60 ml/min CrCl = 1.0 as reference) had an increased risk, adjusted for age, weight and calcaneal BMD, between 1.6 (45–59 ml/min CrCl: Hip fractures (Fx) OR, 1.6; 95% CI, 0.9–2.8) and 2.3 (<45 ml/min CrCl: Hip Fx OR, 2.3;95%CI, 1.2–4.7). The correlation between renal function and vertebral fractures was not significant. The increased risk of hip fractures induced by low CrCl can obviously not be sufficiently explained by renal-induced bone quality impai