Vitamin D is a key player in calcium homeostasis and bone health. Beyond these well-known effects, new data suggest that vitamin D deficiency potentiates a variety of chronic disease states, including diabetes, cancer, and depression. Extremely low vitamin D levels have been associated with osteomalacia and impaired muscle function, both core elements in the field of orthopedic surgery. Good muscle function and healthy bones are essential for fast rehabilitation and positive outcome after orthopedic surgery as well, especially for elderly patients seeking good physical function. Physical function is important for the preservation of independence in daily life and for the prevention of falls, which are associated with fractures and high mortality.
This review focuses on the role of vitamin D deficiency in elderly orthopedic patients.
Vitamin D; hypovitaminosis D; sarcopenia; fracture prevention
Vitamin D is a key player in calcium homeostasis and bone health. Beyond these well-known effects, new data suggest that vitamin D deficiency potentiates a variety of chronic disease states, including diabetes, cancer, and depression. Extremely low vitamin D levels have been associated with osteomalacia and impaired muscle function, both core elements in the field of orthopedic surgery. Good muscle function and healthy bones are essential for fast rehabilitation and positive outcome after orthopedic surgery as well, especially in elderly patients seeking a return to good physical functioning. Physical function is important for the preservation of independence in daily life and for the prevention of falls, which are associated with fractures and high mortality. This review focuses on the role of vitamin D deficiency in elderly orthopedic patients.
Vitamin D is a fat-soluble, secosteroid hormone required for proper regulation of many body systems and normal human growth and development (Hoffmann et al., 2015). Two common forms exist: vitamins D2 (ergocalciferol) and D3 (cholecalciferol). Vitamin D uptake or acquisition is regulated both through nutritional means (10–20%) and by the intradermal synthesis under the action of sunlight (80–90%). The main circulation form is 25-hydroxyvitamin D (25(OH)2D), the result of hydroxylation in the liver of vitamin D2 or D3. It is yielded into the biologically active form of vitamin D, calcitriol, or 1,25(OH)2D, through hydroxylation in the kidney. The active 1,25(OH)2D acts through specific vitamin D receptors to regulate calcium metabolism, differentiation, and division of various cell types (Holick and DeLuca, 1974).
The major source of vitamin D for most people is casual exposure of the skin to sunlight (Godar et al., 2011). When the precursor, 7-dehydrocholesterol, is exposed to ultraviolet light, it converts to previtamin D3 (Baggerly et al., 2015). Previtamin D3 undergoes nonenzymatic thermal transformation, which results in the production of vitamin D3 (Hoffmann et al., 2015). Due to the necessity of sun exposure and ultraviolet light, the endogenous synthesis can be affected by many different factors. Decreased synthesis of vitamin D can be attributed to high latitude, darker skin pigmentation, advanced age, and the use of sunblock and protective clothing (Adams et al., 1982; Clemens et al., 1982; Dowdy et al., 2010).
A limited number of foods naturally contain vitamin D, including fish, egg yolk, and offal such as liver. Because dietary intake of such foods is generally low in many countries, the use of supplements is important and should be recommended for groups prone to develop vitamin D deficiency such as infants and inactive elderly (Lips, 2007).
Circulating 1,25-(OH)-D concentrations are under homeostatic control, limiting the value of 1,25-(OH)-D as a nutritional marker of vitamin D status (Hill et al., 2013). Serum concentrations closely reflect the amount of vitamin D synthesized in the skin and ingested in the diet. For this reason, 25-OH-D is widely accepted as a good biomarker of vitamin D status (Hill et al., 2013). During winter months in countries with a geographies above 40 degrees northern or southern latitude, the skin is not capable of synthesizing vitamin D for as long as 4–5 months (Webb et al., 1988). Therefore, it is assumed that during winter the circulating 25-OH-D levels are related to late-summer concentrations, oral intake, and body stores (Hill et al., 2013).
Vitamin D status has been studied on all continents and in most countries of the world (van Schoor and Lips, 2011). The best determinant of the serum vitamin D status is the serum concentration of 25-hydroxyvitamin D (25-OH-D) (Lips, 2001). As yet, there is no consensus on what constitutes normal vitamin D levels (Perez-Lopez et al., 2011). Many studies suggest 30 ng/mL as an optimal level, whereas others suggest 40 ng/mL, especially under particular conditions such as cancer involvement (Grant et al., 2009). The Institute of Medicine of the US National Academies has recommended an increase in minimal daily requirements for vitamin D and also raised its recommendation of an upper limit on a safe dose of vitamin D to 4000 international units (IUs) per day (Perez-Lopez et al., 2011). The US Endocrine Society guideline defines vitamin D deficiency as a serum 25-OH-D level less than 20 ng/mL (50 nmol/L) and vitamin D insufficiency as 25-OH-D values between 21 and 29 ng/mL (Pramyothin and Holick, 2012).
Hypovitaminosis D has been described in several studies in numerous segments of the global population. It is estimated to affect more than 1 billion people of all races, age groups, and ethnic backgrounds (Mithal et al., 2009). High rates of vitamin D deficiency in particular have been described among the elderly. One British study revealed a lower vitamin D level in people 65 and older than in the general public (Glowacki et al., 2003; Hirani and Primatesta, 2005). In postmenopausal American women taking antiosteoporotic medicine, more than 50% showed inadequate low vitamin D levels (Glowacki et al., 2003). Even young and healthy cohorts are at risk of developing hypovitaminosis D. In an American study from 2004, 52% of Boston-based adolescents of Hispanic and African American origin were suffering from hypovitaminosis D (Gordon et al., 2004).
Data on vitamin D status among the German population frequently reveals low vitamin D levels. In 14,000 individuals between one and 79 years of age, 62% of adolescent boys, 64% of adolescent girls, 57% of men, and 58% of women demonstrated vitamin D levels below 20 ng/mL (Hintzpeter et al., 2008). A study of 1578 elderly care rehabilitation facility patients in Germany published in 2012 showed severe vitamin D deficiencies with values below 10 ng/mL in 68% of patients. Only 4% of the patients had levels in the target range of 30–60 ng/mL (Schilling, 2012).
Among inpatients of geriatric acute care units, lower vitamin D serum levels have been associated with a greater severity of chronic diseases, increased risks of acute decompensation, and a higher risk of in-hospital mortality (Annweiler et al., 2010; Beauchet et al., 2012; Sutra Del Galy et al., 2009). In line with this, hypovitaminosis D doubled the risk of hospitalization for more than 14 days in a geriatric acute care unit (Beauchet et al., 2013).
Although several studies reported a widespread rate of vitamin D deficiency, epidemic data on elderly orthopedic patients is scarce. Data revealing the prevalence of vitamin D insufficiency and deficiency in elderly patients may be of value for treating orthopedic surgeons and geriatricians to prevent potential negative consequences in the operative and postoperative settings to maintain good physical function and to preserve independence in daily life. We reported in 2013 on an association between hypovitaminosis D and elderly orthopedic patients in general and found a high prevalence of vitamin D deficiency and insufficiency in such patients in an orthopedic department in central Germany (Maier et al., 2015a; Sutra Del Galy et al., 2009). We were able to show not only that orthopedic patients with hip or vertebral fractures have low vitamin D levels but also that elderly orthopedic patients in general had such low levels. A novelty in this study was that mainly nonhospitalized elderly patients were tested. Extremely low vitamin D levels have been associated with osteomalacia and impaired muscle function, both core elements in the field of orthopedic surgery. Good muscle function and healthy bones are essential for fast rehabilitation and positive outcome after orthopedic surgery as well as good physical function, especially in elderly patients (LeBoff et al., 2008; Maier et al., 2013a).
Physical function is important for the preservation of independence in daily life and for the prevention of falls, which are associated with fractures and high mortality (Annweiler et al., 2010; Bischoff-Ferrari et al., 2005; Bruyere et al., 2007). Vitamin D depletion has been linked with impaired cognition and specific damage to executive functions and speed of information processing, which can directly impact the selection of postural control strategies and reaction to falls (Annweiler and Beauchet, 2015; Annweiler et al., 2010). Low vitamin D levels negatively affect muscle strength, which may impact fall patterns, their severity, and reaction to them (Hamilton, 2010). Furthermore, several studies showed that lower 25-OH-D serum levels are a risk factor for orthostatic hypotension, which was reported to deteriorate the functional autonomy of older patients and to have a close relation with mortality and morbidity in the elderly (McCarroll et al., 2012; Soysal et al., 2014). In a study of 546 elderly patients aged 65 and older, vitamin D deficiency was shown to be a factor in the development of orthostatic hypotension. The authors concluded that during the evaluation of orthostatic hypotension serum, 25-OH-D levels should be checked and detected deficiencies should be treated (Soysal et al., 2014).
Vitamin D plays a pivotal role in bone mineralization. Vitamin D deficiency results in decreased bone mineralization as well as secondary hyperparathyroidism and increased cortical bone loss. In certain cases, severe vitamin D deficiencies can lead to osteomalacia. An autopsy study of deceased with clinically healthy bones found histopathological signs of osteomalacia with vitamin D levels below 30 ng/mL in 25% of all bone samples taken. Of note, samples with correlating vitamin D levels above 30 ng/mL did not show any signs of bone pathology (Priemel et al., 2010).
The relationship between vitamin D status and osteoporosis is of growing interest. Vitamin D levels below 20 ng/mL lead to malabsorption of intestinal calcium, and osteomalacia in the elderly as well as rickets in children (Holick, 2007; Lips, 2001). Several studies revealed that vitamin D status influences various outcomes of osteoporosis (Dawson-Hughes et al., 2005; Nakamura et al., 2011). One serious outcome of osteoporosis is fracture. Hip fractures are one of the most common fractures of the elderly (Maier et al., 2013b). Recent studies suggest that measurement of vitamin D serum concentrations might serve as a biomarker for hip-fracture risks among elderly patients (LeBoff et al., 1999; Lopes et al., 2009; Nuti et al., 2004). Current studies have shown a widespread rate of vitamin D deficiency in women with hip fractures (Dhanwal et al., 2010; Nurmi et al., 2005). These fractures contribute significantly to morbidity and mortality of elderly. As many as 50% of seniors will have permanent functional disabilities after hip fractures, and as many as 20% will die within the first year after the primary event (Bischoff-Ferrari et al., 2008). Supplementation of vitamin D has been shown to reduce the risk of falls (Bischoff-Ferrari et al., 2009a) and hip fractures (Bischoff-Ferrari et al., 2012). One of the first randomized controlled trials investigating the efficacy of vitamin D supplementation to prevent fractures compared the effect of 1200 mg of calcium and 20 μg vitamin D daily versus placebos in 3270 French women averaging 84 years of age. Under supplementation, bone mineral density increased and the risk of hip and nonvertebral fractures was reduced (Chapuy and Meunier, 1996). The Randomized Evaluation of Calcium or Vitamin D (RECORD) study compared the effect of calcium and vitamin D, alone or in combination, and placebos in 5292 community-dwelling older women or men with low-trauma fractures. Over the 62-month follow-up, the authors found no difference in the incidence of hip fractures or other fracture types. A possible explanation for the missing effect of supplementation was found in the extremely poor compliance with supplementation, especially when this included daily calcium (Grant et al., 2005). The women’s health initiative study showed an improvement in bone mineral density with the combined supplementation of calcium and vitamin D. Among patients who were compliant with the supplementation scheme there was a significant reduction in the risk of hip fractures (Jackson et al., 2006). A meta-analysis by Bischoff-Ferrari et al. (2009b) suggested that after adjustment of the vitamin D dose the incidence of nonvertebral fractures decreased independently of additional calcium supplementation.
Vertebral fragility fractures are another common type of osteoporosis complication. So far, a distinct correlation between these fractures and vitamin D levels has been described (Cummings et al., 1998; El Maghraoui et al., 2012). Vertebral fractures have direct and indirect effects on quality of life with increased morbidity and mortality (Lyles et al., 1993). Several studies revealed a high rate of hypovitaminosis D in postmenopausal women with osteoporotic vertebral fractures (El Maghraoui et al., 2012; Sakuma et al., 2011). A recent study showed a possible role of vitamin D levels in the occurrence of postkyphoplasty-recurrent vertebral compression fractures in elderly patients undergoing kyphoplasty due to osteoporotic fractures (Zafeiris et al., 2012).
In one of our recent studies, we identified a 89% prevalence of hypovitaminosis D in patients with vertebral fractures. By comparison, a well-matched group of patients with back pain in the absence of fracture who were seen in the same geographical locale (Mainz, Germany, 50 degrees northern latitude) and around the same time of year had a hypovitaminosis D prevalence of 60%. The majority of patients presenting with back pain had low vitamin D levels, regardless of whether or not fractures were present (Maier et al., 2015b). Our results suggest that patients who present with a vertebral fragility fracture are significantly more likely to be vitamin D insufficient or even deficient in comparison to patients without vertebral fractures. These results are in line with the findings of former studies, revealing that higher serum concentrations of vitamin D contribute to healthy bone metabolism and prevent osteoporosis as well as osteoporotic fractures (Bischoff-Ferrari et al., 2006).
Several studies examined the association between fractures in postmenopausal women and low vitamin D levels. Nakamura et al. showed in their 6-year cohort study of 773 community-dwelling elderly Japanese women that patients with sufficient vitamin D concentrations (>71 nmol/L) had a 58% lower risk of developing osteoporotic fractures than those with insufficient serum vitamin D concentrations. They concluded that optimal serum levels of vitamin D could reduce fracture risk (Nakamura et al., 2011). Gerdhem et al. (2005) were able to show that women with serum vitamin D concentrations below 20 ng/mL were twice as likely to sustain osteoporotic fractures compared to women with vitamin D concentrations above this threshold. In 415 elderly Brazilian women assessed with vertebral fragility fracture, vitamin D insufficiency was found to be one of the most important influencing factors (Lopes et al., 2009). El Maghraoui et al. enrolled 178 menopausal Moroccan women in their cohort study to determine serum vitamin D status and assess the association of bone mineral density and vertebral fractures. A widespread rate of vitamin D insufficiency (85% of tested patients) and deficiency (52%) was found. Furthermore, hypovitaminosis D was identified as an independent risk factor for vertebral fractures in postmenopausal women (El Maghraoui et al., 2012).
There is a certain discrepancy in literature regarding the association of gender with vitamin D levels and osteoporosis. Some studies indicate that females have a higher risk to be vitamin D deficient than men (Cooper et al., 1992), but other data identified male sex as a risk factor (Guardia et al., 2008). This conflicting literature indicates that gender may not necessarily be of importance for vitamin D deficiency, which is supported by our data. Both males and females need to be monitored for hypovitaminosis D because both groups are at high risk.
We have shown a mean vitamin D level of 17.1 ng/mL among 1083 patients 70 and older (Maier et al., 2015a). Data on such old geriatric and orthopedic patients is scarce, but they all support a widespread rate of hypovitaminosis D in the elderly (Drinka, 1996). This is an alarming fact, knowing that the official recommendation by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis is a minimum serum 25-OH-D level of 30 ng/mL in fragile elderly subjects at an elevated risk of falls and fractures (Rizzoli et al., 2013). Bischoff-Ferrari et al. (2004) showed a 22% reduction in falls of patients taking vitamin D supplements. Gerdhem et al. (2005) evaluated 986 postmenopausal women and showed a twofold increased fracture risk for patients with 25-OH-D levels below 20 ng/mL compared to patients with higher serum vitamin D levels. Moreover, a contributing role of vitamin D deficiency in the occurrence of simultaneous fractures has recently been described in a study of 472 elderly hip fracture patients (Di Monaco et al., 2011).
Besides its regulatory function in bone metabolism, vitamin D has been found by several studies to exert a growing number of nonskeletal effects. In particular, hypovitaminosis D has been linked to a higher risk of cardiovascular diseases, type 2 diabetes, and even mental illness (Giovannucci et al., 2008; Mattila et al., 2007; Menkes et al., 2012). Furthermore, vitamin D also regulates innate and adaptive immune functions by activating macrophages, dendritic cells, and lymphocytes (Hewison, 2010). Hypovitaminosis D has been shown to increase the risk of respiratory tract infection and periprosthetic joint infection, and a recent clinical trial demonstrated that vitamin D supplementation decreases the risk of influenza A infection (Ginde et al., 2009; Maier et al., 2014; Urashima et al., 2010). Dobnig et al. (2008) showed in their prospective cohort study of 3258 patients that patients with deficient vitamin D levels were twice as likely to die over a 7-year follow-up than patients with normal serum 25-OH-D levels. Vitamin D levels below 17.8 ng/mL were shown to increase the risk of death by 26% of all mortalities in the general population. Matthews et al. showed an inverse relation with the length of hospital stay and vitamin D levels in surgical patients admitted to the intensive care unit. With more than 250 patients evaluated, the mean length of stay for patients with severe vitamin D deficiency (<13 ng/mL) was 13.33 days compared to 5.17 days for patients with vitamin D levels above 27 ng/mL (Matthews et al., 2012). The length of stay of 253 patients of a geriatric acute care unit was inversely associated with low vitamin D levels. Helard et al. (2013) reported that patients with vitamin D levels below 50 nmol/L were hospitalized 3 days longer on average than patients with vitamin D levels above 50 nmol/L. Thus, vitamin D not only is important to bone health but also plays an important role in immunomodulation, the regulation of inflammation and cytokines, cell proliferation, cell differentiation, apoptosis, angiogenesis, muscle strength, and muscle contraction.