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Volume 2013 (2013), Article ID 471695, 12 pages
Vitamin D Status and Spine Surgery Outcomes
Nola Physical Therapy, 2 West 45th Street, Suite 208, New York, NY 10036, USA
Received 20 February 2013; Accepted 19 March 2013
Academic Editors: M. Kawakami, C.-H. Lee, and B. K. Weiner
Copyright © 2013 William J. Rodriguez and Jason Gromelski. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
There is a high prevalence of hypovitaminosis D in patients with back pain regardless of whether or not they require surgical intervention. Furthermore, the risk of hypovitaminosis D is not limited to individuals with traditional clinical risk factors. Vitamin D plays an essential role in bone formation, maintenance, and remodeling, as well as muscle function. Published data indicate that hypovitaminosis D could adversely affect bone formation and muscle function in multiple ways. The literature contains numerous reports of myopathy and/or musculoskeletal pain associated with hypovitaminosis D. In terms of spinal fusion outcomes, a patient may have a significant decrease in pain and the presence of de novo bone on an X-ray, yet their functional ability may remain severely limited. Hypovitaminosis D may be a contributing factor to the persistent postoperative pain experienced by these patients. Indeed, hypovitaminosis D is not asymptomatic, and symptoms can manifest themselves independent of the musculoskeletal pathological changes associated with conditions like osteomalacia. It appears that vitamin D status is routinely overlooked, and there is a need to raise awareness about its importance among all healthcare practitioners who treat spine patients.
A large portion of the United States population experiences low back pain, and an increasing number undergo spinal fusion each year. While many patients achieve a satisfactory outcome, there is a subpopulation that fails to achieve acceptable outcomes. These patients may have obvious causes for their outcomes (e.g., pseudarthrosis); however, there are those that are deemed fused yet continue to experience low back pain and other symptoms. Although many factors may be considered when a patient experiences a suboptimal outcome following spinal fusion surgery, serum vitamin D concentration is rarely considered even though most physicians acknowledge its importance in maintaining musculoskeletal health. In this review, we discuss the role of vitamin D in musculoskeletal health especially in relation to low back pain and outcomes of spinal fusion surgery. Our discussion includes the risk factors and prevalence rates of hypovitaminosis D as well as the literature published on vitamin D and spinal surgery. A key concept is the fact that hypovitaminosis D is not asymptomatic, and we delineate the mechanisms by which hypovitaminosis D can adversely affect spinal fusion outcomes.
2. Vitamin D
2.1. What Is Vitamin D?
The term vitamin D refers to a group of structurally related metabolites . Vitamin D is classified as a fat-soluble vitamin; however, it is not technically a vitamin because the body is capable of producing vitamin D3. Structurally, vitamin D is a secosteroid . Individuals obtain vitamin D either from dietary sources, supplementation, or cutaneous synthesis. Vitamin D is hydrophobic, and, therefore, upon entering plasma it is bound by vitamin D binding protein (DBP) . DBP transports vitamin D to the liver where hydroxylating enzymes catalyze the first of two hydroxylation reactions to form 25(OH)D (25-hydroxyvitamin D) . 25(OH)D is eventually transported to the kidney where a second hydroxyl group is added to form 1,25-dihydroxycholecalciferol (1,25-dihydroxyvitamin D or 1,25(OH)2D) . The kidney also is capable of producing over 30 other vitamin D metabolites .
2.2. Vitamin D Nomenclature
Unfortunately, the literature contains a wide array of vitamin D nomenclature for both vitamin D metabolites and vitamin D status, most of which either have no standardized recommendations for use or the common usage does not conform to those recommendations [1, 6]. Matters can be further confounded by the fact that definitions have changed over time and authors can be inconsistent; for example, two orthopedic studies submitted for publication the same year by the same group of authors inexplicably defined vitamin D sufficiency as 30 ng/mL in one publication and as 32 ng/mL in the other [7, 8]. It is beyond the scope of this review to discuss recommended nomenclature versus what is frequently utilized. However, in an attempt to avoid confusion, we have elected to use the terms most commonly found in the literature to describe both vitamin D metabolites and status [9–14].
2.3. Determining Vitamin D Status
The major circulating form of vitamin D, 25(OH)D, is the only metabolite universally recommended to determine the vitamin D status of an individual [6, 15–17]. The most commonly used assays to determine serum 25(OH)D concentrations are high-performance liquid chromatography (HPLC) and radioimmunoassay (RIA). Expert guidelines do not favor either technology; however, studies have demonstrated that HPLC is more sensitive and less variable than RIA when assaying 25(OH)D [6, 17]. Nevertheless, this does not alter the fact that hypovitaminosis D prevalence rates are high regardless of the technology used to assay 25(OH)D concentrations or the concentration used to define vitamin D sufficiency; in fact, Binkley et al. utilized both HPLC and RIA and determined that prevalence rates were substantial by either measurement .
2.4. Vitamin D Sufficiency
There is consensus that individuals with serum 25(OH)D concentrations less than 20 ng/mL are vitamin D deficient. However, there is disagreement over what 25(OH)D concentration is sufficient; the Institute of Medicine of the National Academies (IOM) recommends 20 ng/mL, while the majority of those specializing in vitamin D research, as well as expert guidelines, recommend concentrations greater than 30 ng/mL [6, 15, 18–22]. Some of the differences of opinion are due to individuals considering only the relationship between one factor and health outcome (e.g., 25(OH)D concentrations and parathyroid hormone levels). However, one must take into account all health outcomes when considering recommendations for sufficient 25(OH)D concentrations. Those specializing in vitamin D research have done this, and they determined that 25(OH)D concentrations should be greater than 30 ng/mL [6, 15, 19–22]. For the purposes of this review, vitamin D sufficiency is defined as a serum 25(OH)D concentration greater than 30 ng/mL ; hypovitaminosis D refers to any and all 25(OH)D concentrations below the level of sufficiency (i.e., <30 ng/mL) [9–11]. Finally, whenever possible, the actual 25(OH)D concentrations are provided to facilitate the understanding of what these terms represent.
2.5. Prevention and Treatment of Hypovitaminosis D
When considering prevention and treatment of hypovitaminosis D, one must take into account both recommended 25(OH)D concentrations and the recommended dietary allowance (RDA). In terms of the RDA, studies found that up to 46% of individuals meeting or exceeding the 1997–2009 RDA had insufficient 25(OH)D concentrations [16, 23–26]. Experts in the field of vitamin D research, therefore, stated that individuals required a vitamin D intake greater than the 1997 RDA in order to maintain sufficient 25(OH)D concentrations [15, 16, 24, 27–30].
In 2010, the IOM increased the RDA to 600 IU per day for those of 1–70 years of age and 800 IU for those over 70 years of age . Once again those that specialize in vitamin D research, expert guidelines, and published data suggest that this increased RDA still is likely inadequate to ensure that individuals maintain sufficient 25(OH)D concentrations [6, 15, 20, 31–33]. This is especially true for those at increased risk for hypovitaminosis D. However, as discussed below, the risk of hypovitaminosis D extends beyond traditionally defined categories to include the majority of the population. Individuals with hypovitaminosis D require a daily vitamin D intake greater than the RDA, and in fact, the RDA is for healthy individuals only [26, 34, 35]. The recommended treatment for hypovitaminosis D is an eight-week course of either 50,000 IU vitamin D once per week or 6000 IU daily, followed by maintenance therapy of 1500–2000 IU per day .
Furthermore, published studies suggest that even healthy adults require a daily vitamin D intake greater than the RDA of 600 IU in order to maintain sufficient 25(OH)D concentrations. For example, several studies suggest that an intake between 700 and 1000 IU per day is needed to maintain sufficient 25(OH)D concentrations [20, 31, 32]. Bischoff-Ferrari et al. suggested an intake of at least 1000 IU daily for all racial-ethnic groups; whereas Heaney estimated that individuals needed close to 2000 IU daily [15, 33]. Finally, the Endocrine Society guidelines state that individuals of 19–70 years of age require at least 600 IU of vitamin D daily and those over 70 years of age require at least 800 IU; however, they also state that all adults over 19 years of age may require at least 1500–2000 IU of vitamin D daily in order to maintain a serum 25(OH)D concentration consistently greater than 30 ng/mL .
2.6. Vitamin D Safety
Like any hormone, there is a healthy range for vitamin D levels; concentrations outside this range can lead to health problems. In terms of safety and 25(OH)D concentrations, the IOM recommends that concentrations of 50–60 ng/mL should be avoided . In terms of safety and daily vitamin D intake, both expert guidelines and the IOM set the tolerable upper limits (ULs) of vitamin D intake at 4000 IU per day for adults; this amount should not be exceeded without medical supervision [6, 18]. To summarize, most experts consider 600 IU of vitamin D daily to be the minimum intake, and that to maintain 25(OH)D concentrations of at least 30 ng/mL, an appropriate daily intake is 1500–2000 IU of vitamin D. It should be noted that even though the expert recommendations for both daily vitamin D intake and 25(OH)D concentrations exceed those of the IOM, both fall well within the IOM recommended safety standards.
3. Prevalence of Hypovitaminosis D
There is a high-prevalence rate of hypovitaminosis D among the general population. The National Health and Nutrition Examination Survey (NHANES) revealed an overall prevalence rate of approximately 30% using a serum 25(OH)D concentration of 20 ng/mL as a threshold; however, the prevalence rate would have been over 70% if a concentration of 32 ng/mL had been used as the threshold . Studies of healthy children and adolescents reported hypovitaminosis D prevalence rates of 73% (<32 ng/mL) and 45% (≤20 ng/mL), respectively [13, 37], while Binkley et al. found a prevalence rate of 51% (<30 ng/mL) among young adults . Thomas et al. studied general medical inpatients and reported a hypovitaminosis D prevalence rate of 57% . However, the threshold was a serum 25(OH)D concentration of less than or equal to 15 ng/mL; the authors stated that had they used a concentration of 30 ng/mL as the threshold, the prevalence rate would have been 93% .
Orthopedic patients also have high rates of hypovitaminosis D. Bogunovic et al. studied adults undergoing a variety of orthopedic procedures and found 43% had hypovitaminosis D (<32 ng/mL) . Unnanuntana et al. published both a prospective and a retrospective study of adult total hip arthroplasty (THA) patients and reported hypovitaminosis D prevalence rates of 46.6% (<30 ng/mL) and 39.5% (<32 ng/mL), respectively [7, 8]. Parry et al. conducted a study of pediatric orthopedic patients and found a hypovitaminosis D prevalence rate of 90% (<32 ng/mL); additionally 50% of all patients had 25(OH)D concentrations less than 20 ng/mL . Among female patients with hip fractures, LeBoff et al. found 96% had hypovitaminosis D (≤32 ng/mL) and 85% had 25(OH)D concentrations less than or equal to 20 ng/mL . Brinker et al. studied patients with nonunions and found a hypovitaminosis D prevalence rate of 57% (≤30 ng/mL) .
There is a paucity of vitamin D-related spine studies. Waikakul found that all nine patients in a group with failed back surgery syndrome had hypovitaminosis D (<30 ng/mL); other case reports of failed spine surgery found similar rates [42–45]. Kim et al. studied female spinal fusion patients and found all 31 had hypovitaminosis D (<30 ng/mL) preoperatively . The largest spinal fusion study to date (313 preoperative patients) revealed a hypovitaminosis D prevalence rate of 57% (<30 ng/mL); furthermore, 27% of patients had 25(OH)D concentrations less than 20 ng/mL . The prevalence of hypovitaminosis D is high among patients with chronic low back pain. One study of 360 chronic back pain patients reported the prevalence of severe vitamin D deficiency (<9 ng/mL) as 83% . Another study of chronic low back pain patients found 82% to have hypovitaminosis D (defined as a serum 25(OH)D concentration between 20 and 40 ng/mL, which is higher than the 30 ng/mL threshold most utilized); although they reported hypovitaminosis D in the control group, none of the controls had a serum 25(OH)D concentration less than 32 ng/mL .
There also appears to be a high prevalence of hypovitaminosis D among patients with chronic musculoskeletal pain. A study of patients with persistent musculoskeletal pain found a hypovitaminosis D prevalence rate of 93% (<20 ng/mL) , while another reported a prevalence rate of 58% (<20 ng/mL) . Therefore, one can conclude that the prevalence of hypovitaminosis D is incredibly high, whether considering the general population or a specific subset thereof; this holds true even if one uses the most conservative definitions of vitamin D sufficiency (i.e., the lowest 25(OH)D concentrations).
4. Risk Factors for Hypovitaminosis D
Those commonly agreed upon to be most at risk for hypovitaminosis D include the elderly, females, obese persons, individuals with dark skin pigmentation, and persons living in northern latitudes and/or that have limited sun exposure. However, multiple studies have demonstrated a high prevalence of hypovitaminosis D in populations that would not be deemed at risk.
Age is a risk factor for hypovitaminosis D because the elderly have a diminished physiological ability to synthesize vitamin D due to decreased amounts of a vitamin D precursor in their skin . Despite this risk factor, clinical studies have demonstrated that age is not a good predictor of 25(OH)D concentrations. Studies of orthopedic surgery and spinal fusion patients found high-prevalence rates of hypovitaminosis D among younger adult patients [7–9, 47]. One of these studies found that patients of 51–70 years of age were 35% less at risk for hypovitaminosis D compared with those of 18–50 years of age . Thomas et al. looked at a subgroup of medical inpatients with no known risk factors for hypovitaminosis D and found greater than 40% were vitamin D deficient even though the mean age of this subgroup was years . The prevalence of hypovitaminosis D among those in a pediatric residency program was 69% even though the mean age was years . Studies focusing on young adults, teens, and children also found prevalence rates of 42–90% [13, 37–39]. Therefore, considering published clinical data, one must conclude that although the elderly are at risk for hypovitaminosis D, the risk extends to individuals of all ages, and that age is not a good predictor of serum 25(OH)D status.
4.2. Skin Tone
Skin tone is a risk factor because melanin can absorb UVB radiation; it is estimated that vitamin D synthesis can be reduced by greater than 90% in very dark-skinned individuals . However, clinical studies have demonstrated a high prevalence of hypovitaminosis D among whites [8, 9, 14, 16, 40, 46, 47, 51]. Recent orthopedic and spine studies comprised mainly of white patients had hypovitaminosis D prevalence rates greater than 40% [8, 9, 47]. These are high rates for a population generally not considered to have an increased risk. One must conclude that even though dark-skinned individuals are at risk for hypovitaminosis D, the risk extends to light-skinned individuals as well (albeit for reasons other than skin pigmentation). Therefore, skin tone is not a good predictor of serum 25(OH)D status, and it would be unwise to assume that white patients are not at risk.
4.3. Sun Exposure, Seasonality, and Latitude
Those living in northern latitudes during winter and those with limited exposure to sunlight are known to be at risk for hypovitaminosis D . Even among those who have exposure to ideal sunlight, the amount of UVB radiation that reaches the skin varies. Clothing can exclude varying amounts of UVB radiation depending on the style and color, and sunscreen with an SPF as low as 8 can exclude up to 95% of UVB radiation [54, 55]. Binkley et al. found a high prevalence of hypovitaminosis D in individuals with substantial sun exposure even though 40% never utilized sunscreen, and the remainder were outside for at least 20 hours per week without sunscreen . Clinical studies also demonstrated high rates of hypovitaminosis D in lower latitudes, as well as during the summer [17, 39, 41, 56]. Although lack of, or limited, sun exposure certainly puts an individual at risk for hypovitaminosis D, sun exposure regardless of latitude, season, or length of exposure does not ensure an individual to have a sufficient 25(OH)D concentration [17, 39, 41, 56]. Therefore, these sun exposure variables are not good predictors of serum 25(OH)D status.
The female sex traditionally has been considered a risk factor for hypovitaminosis D. A few large studies confirm this association [36, 57]. However, some studies found no differences between sexes [14, 39]. Whereas, other studies found that the female sex was associated with a decrease in risk for hypovitaminosis D, and the male sex was identified as a risk factor [8, 9, 58]. In light of these apparently conflicting data, it would be unwise to assume that an individual is not at increased risk based on their sex.
4.5. Body Mass Index
Obesity is a risk factor for hypovitaminosis D. Multiple clinical studies confirm that there is an inverse correlation between body mass index (BMI) and 25(OH)D concentrations [8, 9, 13, 59–61]. Bogunovic et al. quantified the risk for orthopedic surgery patients; compared with patients of normal BMI, obese patients were twice as likely to have hypovitaminosis D . Furthermore, the odds of hypovitaminosis D increased by approximately 5% for every unit increase in BMI . However, clinical studies also reveal high rates of hypovitaminosis D among populations that are not obese . Therefore, although the obese are at elevated risk, one should not assume that a nonobese individual is not at risk.
4.6. Other Risk Factors
Any physiological condition and/or medication that alters intestinal absorption or vitamin D metabolism can increase the risk of hypovitaminosis D . Stoker et al. found prior cholecystectomy was a predictor of hypovitaminosis D in spinal fusion patients . Counterintuitively, metabolic bone disease may decrease the risk of hypovitaminosis D as was found in a study of orthopedic surgery patients . The authors concluded that this was likely the result of patient awareness of their condition and their being managed with vitamin D supplementation .
4.7. Predicting Hypovitaminosis D
Published data demonstrate that the risk of hypovitaminosis D is not limited to individuals with traditional clinical risk factors. It is also clear that standard clinical risk factors are poor predictors of hypovitaminosis D. Indeed, Thomas et al. concluded that, at best, they would have been able to identify only 68% of vitamin D deficient patients using risk factors alone . Additionally, in a subgroup of patients with no known risk factors for hypovitaminosis D, 42% were found to have a serum 25(OH)D concentration less than or equal to 15 ng/mL . Since it is difficult to predict hypovitaminosis D by the presence or absence of risk factors alone, the only way to accurately identify this condition is to determine the 25(OH)D concentration of an individual. Holick recommends testing patients once a year to determine their vitamin D status .
5. Musculoskeletal Roles of Vitamin D
Vitamin D has numerous and varied roles in the body, this is underscored by the fact that the vitamin D receptor (VDR) has been identified in several dozen diverse tissues and cells, including those not involved in calcium homeostasis . Two types of VDRs have been identified, and ligand binding to each type activates a distinct signal transduction pathway. The first type of receptor identified was a nuclear VDR (VDRnuc). The genomic responses that result from the activation of VDRnuc include transcriptional regulation of specific genes [65, 66]. The second type of receptor identified was a cell surface VDR (VDRmem). Activation of the VDRmem results in rapid local responses like the opening of voltage-gated calcium channels and transcaltachia—rapid stimulation of intestinal calcium absorption [67–69]. Studies of VDR knockout mice revealed muscular effects one might not expect like muscle fibers with smaller diameters and postural control abnormalities [70–72]. However, the best-known role of vitamin D is its role in calcium homeostasis; appropriate serum calcium concentrations are essential for many functions, including proper mineralization of the bone, muscle contraction, and transmission of nerve impulses. And studies of VDR knockout mice also revealed the metabolic and skeletal abnormalities one would expect like secondary hyperparathyroidism, hypocalcemia, osteomalacia, and growth retardation .
5.1. Vitamin D and Bone Tissue
Vitamin D deficiency can result in musculoskeletal pathological changes. The traditional understanding is that vitamin D deficiency eventually results in changes like hypocalcemia and secondary hyperparathyroidism. These changes can lead to the upregulation of osteoclastic activity resulting in resorption of mineral content from bone tissue; prolonged demineralization and the resulting weakening of bone tissue eventually upregulate osteoblastic activity. However, due to the inadequate calcium and phosphate concentrations, the newly formed osteoid is not sufficiently mineralized. Interestingly, recent data indicates that individuals may be vitamin D deficient and have increased bone turnover without having secondary hyperparathyroidism . Previous studies confirmed that hypovitaminosis D increases bone turnover and that individuals may have hypovitaminosis D without secondary hyperparathyroidism [10, 13, 17, 41, 74–76]. Therefore, vitamin D appears to play a direct role in bone formation, maintenance, and remodeling; indeed VDRs have been identified in both osteoblasts and osteoclasts [65, 77–79].
Data reveal that osteoblasts express both nuclear and membrane VDRs . Vitamin D treatment of osteoblasts leads to increased synthesis of bone matrix proteins as well as extracellular signals involved in angiogenesis like vascular endothelial growth factor [65, 80]. Vitamin D also causes a calcium influx into osteoblasts, and this influx is not required for the increased synthesis of bone matrix proteins . Additional data shows that vitamin D-VDR binding in osteoblasts regulates osteoclast formation . There appears to be conflicting data in the literature regarding the role of vitamin D and osteoclasts [78, 82]. However, closer examination of the literature reveals that vitamin D may affect osteoclastic activity in two separate ways. First, the most studied interaction, vitamin D can induce osteoclast formation [81, 82]. This occurs indirectly via vitamin D interaction with osteoblasts, which in turn interact with osteoclast precursor cells. Takeda et al. demonstrated that VDR knockout mice (VDR-null) could form osteoclasts . Osteoclasts were formed when osteoblasts and osteoclast precursors, both VDR-null, were cultured together and treated with either parathyroid hormone (PTH) or IL-1 . However, if osteoblasts and osteoclast precursor cells, both VDR-null, were cultured together and treated with vitamin D, osteoclasts were not formed . Finally, when VDR-expressing (wild-type) osteoblasts were cultured with VDR-null osteoclast precursors, osteoclast formation occurred with vitamin D treatment . Taken together these data show that osteoclast formation can be induced by multiple, independent signals (i.e., PTH and vitamin D), and that a VDR expressed by osteoblasts mediates vitamin D-induced formation of osteoclasts. There is a second, less studied role of vitamin D in regards to osteoclastic activity—the direct interaction of vitamin D with osteoclasts [77, 78]. Takasu et al. showed that vitamin D could decrease osteoclast formation and that a VDR expressed by osteoclast precursors mediates this activity . Therefore, it appears that vitamin D may regulate osteoclastic activity via two different mechanisms—indirectly (via osteoblasts) and directly. Osteoclastic activity is often thought of in a negative manner; this, however, is not the case unless it is uncoupled from osteoblastic activity and/or inappropriately high. In fact, osteoclastic activity is a necessary part of healthy bone formation and maintenance.
One thing is certain, whether via an indirect role (involving PTH), a direct role, or both, vitamin D plays an essential role in bone formation and maintenance. In vivo studies on the effect of vitamin D on fracture healing confirm this. Fu et al. investigated the effect of vitamin D on osteoporotic fracture healing in an ovariectomized rat model . Delayed healing occurred in the control group compared to the vitamin D-treated group at 6 and 16 weeks after fracture . This was demonstrated in each of several measures: radiographic (X-rays and micro-CT scans), biomechanical testing, and histological examination. At 6 weeks after fracture, the vitamin D-treated group had a greater amount of bony callus compared to the control group; the vitamin D group also had continuous callus and mature woven bone, whereas the control group had delayed endochondral ossification . Biomechanically, at 6 weeks, the ultimate load at failure and energy absorption were 96% and 95% higher in the vitamin D group, respectively . Histological examination at 16 weeks revealed remodeled mature bone at the fracture site in the vitamin D group, whereas the control group was still undergoing endochondral ossification; both biomechanical measures were higher in the vitamin D group at this time point as well . This in vivo study and others demonstrate that vitamin D treatment results in accelerated bone healing and maturation, as well as stronger bone tissue [84, 85]. A randomized placebo-controlled study of proximal humerus fracture healing in women revealed similar results . Unfortunately, the treatment group received both vitamin D and calcium; therefore, one must attribute the results to the combined effect. However, the data is in accordance with vitamin D only treatment in the previously discussed studies. At 6 weeks after fracture, the treatment group had a significantly higher increase in bone mineral density compared to the control group . Finally, hypovitaminosis D-delayed bone formation and healing may account for the findings of Brinker et al. in patients with nonunions .
In summary, published data indicate that hypovitaminosis D could adversely affect bone formation in multiple ways: (1) decreasing intestinal calcium absorption thereby limiting calcium availability for both mineralization of newly formed osteoid and cellular functions; (2) altering both the number and activity of osteoblasts and osteoclasts. Although PTH can play a role in each of these effects, vitamin D can affect both independent of PTH. Therefore, in terms of spinal surgery patients, hypovitaminosis D could result in delayed spinal fusion or pseudarthrosis, as well as impaired osseointegration of implanted spinal hardware.
5.2. Vitamin D and Muscle Function
Both types of VDRs have been identified in human skeletal muscle cells [87–89]. Vitamin D can directly affect skeletal muscle cells in multiple ways. It affects phosphate transport and phospholipid metabolism; in addition, calcium metabolism and transport is affected at both the genomic and nongenomic levels [90–94]. Vitamin D also promotes muscle cell proliferation, growth, and differentiation [72, 95–97]. Studies of myopathy associated with hypovitaminosis D began appearing in the 1960s and have continued to the present [43, 98–101]. This myopathy has been observed in patients with and without osteomalacia as well as with and without hyperparathyroidism [98, 99, 102–107]. The myopathy is described as muscular atrophy and weakness [98, 100, 101, 103, 105, 106]. Unfortunately, many review articles restrict their description of the muscle weakness to proximal muscle weakness, they often mention altered gait also. However, Mytton et al. reported that proximal muscle weakness and gait change occurred in less than 3% and 2% of patients with this myopathy, respectively . Others reported findings similar to Mytton et al. [10, 109]. Additionally, patients often complain of fatigue [14, 49, 102, 107, 108]. Vitamin D treatment has been shown to improve these symptoms [98, 100, 102, 107, 110–112].
In terms of clinical studies of vitamin D and muscle function, some apparently conflicting data have been published. There are reviews solely dedicated to vitamin D and skeletal muscle that address this issue . Nevertheless, both in vitro and in vivo studies demonstrate that vitamin D plays a direct role in normal muscular function. In fact, human studies have revealed the effect of vitamin D on muscle fibers. Vitamin D deficient adults have been shown to have type II muscle fiber atrophy, and vitamin D treatment increased both the amount and diameter of type II muscle fibers [110, 114]. Two areas are particularly relevant to the outcomes of spine surgery patients in regards to hypovitaminosis D and impaired muscle function: first, trunk stability because spine patients require core strength and stability, especially during the fusion process ; second, lower limb weakness because many spine patients have lower limb muscle atrophy. Prolonged weakness in these two areas may lead to extended use of assistance devices (e.g., back braces and canes) [99, 105, 106]. Furthermore, protracted core weakness also may place additional stress on implanted hardware and/or adjacent spinal segments.
5.3. Vitamin D and Musculoskeletal Pain
There are numerous reports of musculoskeletal pain associated with hypovitaminosis D [10, 14, 43–45, 48, 49, 102, 103, 107–109, 116–119]. This pain is described as both bone pain and muscular pain [14, 49, 108]. The bone pain is reported as both excluding the joints and including the joints [102, 107, 109]. Often, but not always, the musculoskeletal pain begins in the low back [107–109]. Vitamin D treatment has been shown to improve these symptoms [43–45, 48, 102, 107, 109, 117, 120]. Resolution of symptoms often occurs between three and seven months [102, 107, 109].
The mechanism often proposed to generate hypovitaminosis D-related musculoskeletal pain is that insufficiently mineralized osteoid absorbs fluid and swells; the expanded osteoid then exerts pressure on the periosteum and corresponding nociceptors, thus generating pain [14, 63, 119]. However, Tague et al. recently published neurological data which implicates a different mechanism . First, Tague and Smith identified VDRs on sensory neurons . Next, in a separate publication, they demonstrated that vitamin D deficiency produced muscle hypersensitivity and balance deficits in rats similar to those observed in humans . Vitamin D deficiency resulted in nociceptor hyperinnervation and hypersensitivity that was specific to skeletal muscle tissue; neither occurred in rat hindpaw skin . Interestingly, increased calcium intake exacerbated the adverse effects instead of ameliorating them . Their model was one of early vitamin D deficiency and not prolonged deficiency. Therefore, the pathological features of prolonged vitamin D deficiency were not observed, including altered bone morphology and muscle atrophy . From these data, they concluded that it is unlikely that musculoskeletal pain during early vitamin D deficiency is the result of either skeletal or muscle pathology, rather it is the result of an increased density of pain sensing nerves in muscle tissue . However, as previously discussed, musculoskeletal pathology is known to occur with prolonged hypovitaminosis D. It may be that both of these mechanisms (nociceptor hyperinnervation and musculoskeletal pathological changes like expanded osteoid) work either independently or concomitantly to generate pain in patients with hypovitaminosis D. Finally, in terms of clinical relevancy, both animal and human data show that insufficient 25(OH)D concentrations can produce symptoms in patients prior to and/or independent of the pathological changes that are thought of in connection with vitamin D deficiency [10, 102, 121]. Therefore, hypovitaminosis D is not asymptomatic.
6. Vitamin D and Spine Patients
6.1. Spine Studies
Unfortunately, there is a dearth of vitamin D-related spine data, and only four articles have data from 30 or more patients [10, 46–48]. The limited number of spine studies include both spinal surgery patients and those without surgical intervention [10, 42–48]. Two studies examined correlations between pain and 25(OH)D concentrations in patients with back pain. The first study reported that patients with chronic back pain had significantly lower 25(OH)D concentrations compared to a control group . The second, a study of preoperative spinal fusion patients, found that those with vitamin D deficiency had greater pain and higher disability scores . The symptoms described for spine patients with hypovitaminosis D are similar to those discussed in the sections on muscle function and musculoskeletal pain [10, 42–45, 47, 48]. Treatment with vitamin D has been shown to improve these symptoms [42–45, 48]. One study reported that 95% of all patients and 100% of patients with severe vitamin D deficiency had resolution of chronic low back pain three months following vitamin D treatment . Similar results have been reported for patients with chronic back pain and failed spinal fusion surgery [42, 44, 45].
Of the two spinal fusion studies with greater than 30 patients, one reported preoperative data only and the other pre- and postoperative data [46, 47]. As previously discussed, Stoker et al. reported an association between vitamin D deficiency and pain and disability scores, as well as a high prevalence of hypovitaminosis D in a study of 313 patients . The second article looked at 31 female spinal fusion patients and found all to have hypovitaminosis D preoperatively and 16% to be vitamin D sufficient 1-year postoperatively . Vitamin D treatment was not part of this study, as the premise was that patients’ 25(OH)D concentrations would increase postoperatively due to the increased mobility. However, the premise holds true only for those patients whose 25(OH)D concentration is limited by their level of mobility; increased mobility would most likely involve increased UVB exposure. However, as previously discussed, Binkley et al. demonstrated that abundant UVB exposure does not ensure vitamin D sufficiency . Therefore, even if all patients’ UVB exposure significantly increased postoperatively, only a portion would achieve sufficient 25(OH)D concentrations. And, the data revealed this, only 16% of patients had sufficient 25(OH)D concentrations after 1 year; the remaining 84% still had hypovitaminosis D and, therefore, were at risk for musculoskeletal symptoms like pain, myopathy, and delayed fusion or pseudarthrosis . A correlation between postoperative 25(OH)D concentration and Oswestry disability index (ODI) scores was observed . Unfortunately, 1-year postoperative fusion status data was not reported.
Even though there is limited spine data, several conclusions can be drawn. First, there is a high prevalence of hypovitaminosis D in patients with back pain regardless of whether or not they require surgical intervention. Second, spine patients with hypovitaminosis D display symptoms similar to other populations with hypovitaminosis D, and the correlation between pain and 25(OH)D concentration also holds true for spine patients. Third, in the absence of an intervention with vitamin D supplementation the majority of spine patients will not achieve sufficient 25(OH)D concentrations after a surgical intervention. Finally, patients with hypovitaminosis D may experience delayed fusion or pseudarthrosis and/or a return of persistent pain that requires revision surgery and/or vitamin D treatment [42–45].
6.2. Surgical Outcomes
Although not spinal fusion studies, two recent articles on THA and vitamin D status should be addressed [7, 8]. These studies looked at functional milestones in-hospital and at 6 weeks postoperatively [7, 8]. Neither study found an association between 25(OH)D concentration and functional outcomes. However, the functional outcomes were bare minimum measures and, therefore, would not likely reveal differences between vitamin D sufficient and insufficient patients. The main item these studies reveal is that there are different perspectives of functional outcomes and surgical success; although a patient may qualify as having a technically successful outcome by certain measures, their actual functional ability may be severely limited.
Often successful spinal fusion surgery is defined by the appearance of de novo bone tissue on plain radiographs. However, using X-rays (whether static or dynamic) to evaluate the status of a fusion site has severe limitations. First, surgical implants make evaluation difficult. Second, bone grafts (both natural and synthetic) can be mistaken for de novo bone formation [123, 124]. Spinal fusion studies demonstrate that sites deemed fused via X-rays actually contained large amounts of fibrous tissue when assessed via CT scan and/or histology [123–125]. Therefore, patients may be deemed fused without being fully fused. Additionally, successful spinal fusion surgery may be defined as a significant decrease in pain and disability scores (e.g., ODI and SF-36). Unfortunately, there is a subpopulation of spinal fusion patients that are considered technically successful in this regard yet are wholly unsuccessful in terms of their residual pain and disability. Although considered a success, these patients require ongoing treatment for their pain and may continue to have extensive limitations on their mobility and ability to sit, perform weight-bearing activities, and/or return to work. We think (based on the data discussed in this review) that hypovitaminosis D may be a major contributing factor to the symptoms experienced by these patients.
6.3. Vitamin D Status Is Overlooked
Published data reveals that physicians routinely neglect evaluating the vitamin D status of a patient. A study of patients with musculoskeletal pain for at least one year found that although greater than 90% had been medically evaluated for their chronic pain, none had been tested for hypovitaminosis D . Upon testing, the prevalence rate for this group was determined to be 93%; furthermore, five of the patients had undetectable 25(OH)D concentrations . Apparently many spine surgeons regularly overlook vitamin D status and underestimate its importance as well. One survey of orthopedic surgeons and neurosurgeons who treat spine conditions found that metabolic bone laboratories (vitamin D, PTH, and calcium) were utilized by 12% and 20% of spine surgeons as part of a workup for preoperative fusion and pseudarthrosis patients, respectively . Furthermore, 33% of those who do not routinely check metabolic bone laboratory tests stated that, “they did not think it would affect clinical management” . Interestingly, of those surveyed, 71% had completed a spine fellowship, and 32% were affiliated with an academic institution . Publications by those who have utilized vitamin D to treat patients with chronic pain due to failed spine surgery confirm that surgical intervention, pain management, and/or physical rehabilitation often are considered while vitamin D status is an afterthought at best [42–45]. Therefore, there is a need to raise awareness about the importance of vitamin D status among all healthcare practitioners who treat spine patients.
Given the high prevalence of hypovitaminosis D among the general population as well as spine patients and that it is difficult to predict its presence based on risk factors alone, all spine surgery patients should be screened as part of their preoperative workup. Postoperative spine patients that continue to experience musculoskeletal pain should be screened as well. Patients with hypovitaminosis D should be treated according to the Endocrine Society guidelines discussed above, especially since vitamin D treatment is safe and the cost burden low. Furthermore, hypovitaminosis D is not asymptomatic, and symptoms can manifest themselves independent of (or prior to) the musculoskeletal pathological changes associated with conditions like osteomalacia. Published data indicate that hypovitaminosis D could adversely affect bone formation and muscle function in multiple ways. For spinal fusion patients the consequences may include delayed fusion or pseudarthrosis, impaired osseointegration of implanted spinal hardware, prolonged core, and lower limb muscle weakness, and additional stress on implanted hardware and/or adjacent spinal segments. Any of these, as well as hypovitaminosis D-induced neurological changes, may contribute to a spinal fusion patient’s persistent postoperative pain; indeed, musculoskeletal pain is a hallmark of hypovitaminosis D. Therefore, it is imperative for spinal fusion patients to maintain sufficient serum 25(OH)D concentrations (i.e., >30 ng/mL). Finally, although hypovitaminosis D is associated with a multitude of adverse health outcomes, vitamin D is not a panacea but rather one critical factor in maintaining musculoskeletal health.
- P. Karlson, H. B. F. Dixon, B. L. Horecker et al., “International Union of Pure and Applied Chemistry and International Union of Biochemistry—nomenclature of vitamin D,” Pure and Applied Chemistry, vol. 54, no. 8, pp. 1511–1516, 1982.
- J. G. Haddad, L. Y. Matsuoka, B. W. Hollis, Y. Z. Hu, and J. Wortsman, “Human plasma transport of vitamin D after its endogenous synthesis,” Journal of Clinical Investigation, vol. 91, no. 6, pp. 2552–2555, 1993.
- G. Ponchon and H. F. DeLuca, “The role of the liver in the metabolism of vitamin D,” Journal of Clinical Investigation, vol. 48, no. 7, pp. 1273–1279, 1969.
- A. W. Norman, “Evidence for a new kidney-produced hormone, 1,25-dihydroxycholecalciferol, the proposed biologically active form of vitamin D,” American Journal of Clinical Nutrition, vol. 24, no. 11, pp. 1346–1351, 1971.
- R. Bouillon, W. H. Okamura, and A. W. Norman, “Structure-function relationships in the vitamin D endocrine system,” Endocrine Reviews, vol. 16, no. 2, pp. 200–256, 1995.
- M. F. Holick, N. C. Binkley, H. A. Bischoff-Ferrari et al., “Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline,” The Journal of Clinical Endocrinology & Metabolism, vol. 96, no. 7, pp. 1911–1930, 2011.
- A. Unnanuntana, B. J. Rebolledo, B. P. Gladnick et al., “Does vitamin D status affect the attainment of in-hospital functional milestones after total hip arthroplasty?” Journal of Arthroplasty, vol. 27, no. 3, pp. 482–489, 2012.
- A. Unnanuntana, A. Saleh, J. T. Nguyen et al., “Low vitamin D status does not adversely affect short-term functional outcome after total hip arthroplasty,” Journal of Arthroplasty, vol. 28, no. 2, pp. 315–322, 2013.
- L. Bogunovic, A. D. Kim, B. S. Beamer, J. Nguyen, and J. M. Lane, “Hypovitaminosis D in patients scheduled to undergo orthopaedic surgery: a single-center analysis,” Journal of Bone and Joint Surgery. American, vol. 92, no. 13, pp. 2300–2304, 2010.
- A. Lotfi, A. M. Abdel-Nasser, A. Hamdy, A. A. Omran, and M. A. El-Rehany, “Hypovitaminosis D in female patients with chronic low back pain,” Clinical Rheumatology, vol. 26, no. 11, pp. 1895–1901, 2007.
- G. E. Stoker, J. M. Buchowski, K. H. Bridwell, K. D. Riew, and L. P. Zebala, “Vitamin D status of adults undergoing surgical spinal fusion,” in Proceedings of the 26th Annual Meeting of the North American Spine Society, Chicago, Ill, USA, November 2011.
- H. A. Bischoff-Ferrari, Y. Zhang, D. P. Kiel, and D. T. Felson, “Positive association between serum 25-hydroxyvitamin D level and bone density in osteoarthritis,” Arthritis and Rheumatism, vol. 53, no. 6, pp. 821–826, 2005.
- C. M. Gordon, K. C. DePeter, H. A. Feldman, E. Grace, and S. J. Emans, “Prevalence of vitamin D deficiency among healthy adolescents,” Archives of Pediatrics and Adolescent Medicine, vol. 158, no. 6, pp. 531–537, 2004.
- G. A. Plotnikoff and J. M. Quigley, “Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain,” Mayo Clinic Proceedings, vol. 78, no. 12, pp. 1463–1470, 2003.
- H. A. Bischoff-Ferrari, E. Giovannucci, W. C. Willett, T. Dietrich, and B. Dawson-Hughes, “Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes,” American Journal of Clinical Nutrition, vol. 84, no. 1, pp. 18–28, 2006.
- M. K. Thomas, D. M. Lloyd-Jones, R. I. Thadhani et al., “Hypovitaminosis D in medical inpatients,” The New England Journal of Medicine, vol. 338, no. 12, pp. 777–783, 1998.
- N. Binkley, R. Novotny, D. Krueger et al., “Low vitamin D status despite abundant sun exposure,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 6, pp. 2130–2135, 2007.
- IOM, Institutue of Medicine Dietary Reference Intakes for Calcium and Vitamin D, National Academies Press, Washington, DC, USA, 2010.
- D. A. Hanley, A. Cranney, G. Jones et al., “Vitamin D in adult health and disease: a review and guideline statement from osteoporosis Canada,” CMAJ, vol. 182, no. 12, pp. E610–E618, 2010.
- B. Dawson-Hughes, R. P. Heaney, M. F. Holick, P. Lips, P. J. Meunier, and R. Vieth, “Estimates of optimal vitamin D status,” Osteoporosis International, vol. 16, no. 7, pp. 713–716, 2005.
- B. Dawson-Hughes, A. Mithal, J. P. Bonjour et al., “IOF position statement: vitamin D recommendations for older adults,” Osteoporosis International, vol. 21, no. 7, pp. 1151–1154, 2010.
- R. Vieth, “Why the minimum desirable serum 25-hydroxyvitamin D level should be 75 nmol/L (30 ng/ml),” Best Practice & Research Clinical Endocrinology & Metabolism, vol. 25, no. 4, pp. 681–691, 2011.
- S. S. Harris, B. Dawson-Hughes, and G. A. Perrone, “Plasma 25-hydroxyvitamin D responses of younger and older men to three weeks of supplementation with 1800 IU/day of vitamin D,” Journal of the American College of Nutrition, vol. 18, no. 5, pp. 470–474, 1999.
- R. Vieth, “Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety,” American Journal of Clinical Nutrition, vol. 69, no. 5, pp. 842–856, 1999.
- R. P. Heaney, K. M. Davies, T. C. Chen, M. F. Holick, and M. J. Barger-Lux, “Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol,” American Journal of Clinical Nutrition, vol. 77, no. 1, pp. 204–210, 2003.
- R. Vieth, D. E. Cole, G. A. Hawker, H. M. Trang, and L. A. Rubin, “Wintertime vitamin D insufficiency is common in young Canadian women, and their vitamin D intake does not prevent it,” European Journal of Clinical Nutrition, vol. 55, no. 12, pp. 1091–1097, 2001.
- H. Glerup, K. Mikkelsen, L. Poulsen et al., “Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited,” Journal of Internal Medicine, vol. 247, no. 2, pp. 260–268, 2000.
- R. P. Heaney, M. S. Dowell, C. A. Hale, and A. Bendich, “Calcium absorption varies within the reference range for serum 25-hydroxyvitamin D,” Journal of the American College of Nutrition, vol. 22, no. 2, pp. 142–146, 2003.
- R. Vieth, “Why the optimal requirement for vitamin D3 is probably much higher than what is officially recommended for adults,” Journal of Steroid Biochemistry and Molecular Biology, vol. 89-90, no. 1–5, pp. 575–579, 2004.
- B. W. Hollis, “Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D,” Journal of Nutrition, vol. 135, no. 2, pp. 317–322, 2005.
- V. Tangpricha, E. N. Pearce, T. C. Chen, and M. F. Holick, “Vitamin D insufficiency among free-living healthy young adults,” American Journal of Medicine, vol. 112, no. 8, pp. 659–662, 2002.
- M. J. Barger-Lux, R. P. Heaney, S. Dowell, T. C. Chen, and M. F. Holick, “Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men,” Osteoporosis International, vol. 8, no. 3, pp. 222–230, 1998.
- R. P. Heaney, “The vitamin D requirement in health and disease,” Journal of Steroid Biochemistry and Molecular Biology, vol. 97, no. 1-2, pp. 13–19, 2005.
- S. Datta, M. Alfaham, D. P. Davies et al., “Vitamin D deficiency in pregnant women from a non-European ethnic minority population—an interventional study,” BJOG, vol. 109, no. 8, pp. 905–908, 2002.
- M. Lehtonen-Veromaa, T. Möttönen, I. Nuotio, K. Irjala, and J. Viikari, “The effect of conventional vitamin D2 supplementation on serum 25(OH)D concentration is weak among peripubertal Finnish girls: a 3-y prospective study,” European Journal of Clinical Nutrition, vol. 56, no. 5, pp. 431–437, 2002.
- E. A. Yetley, “Assessing the vitamin D status of the US population,” American Journal of Clinical Nutrition, vol. 88, no. 2, pp. 558S–564S, 2008.
- S. A. Abrams, I. J. Griffin, K. M. Hawthorne, S. K. Gunn, C. M. Gundberg, and T. O. Carpenter, “Relationships among vitamin D levels, parathyroid hormone, and calcium absorption in young adolescents,” Journal of Clinical Endocrinology and Metabolism, vol. 90, no. 10, pp. 5576–5581, 2005.
- N. Binkley, R. Novotny, D. Krueger et al., “Low vitamin D status despite abundant sun exposure,” Journal of Clinical Endocrinology and Metabolism, vol. 92, no. 6, pp. 2130–2135, 2007.
- J. Parry, E. Sullivan, and A. C. Scott, “Vitamin D sufficiency screening in preoperative pediatric orthopaedic patients,” Journal of Pediatric Orthopaedics, vol. 31, no. 3, pp. 331–333, 2011.
- M. S. LeBoff, W. G. Hawkes, J. Glowacki, J. Yu-Yahiro, S. Hurwitz, and J. Magaziner, “Vitamin D-deficiency and post-fracture changes in lower extremity function and falls in women with hip fractures,” Osteoporosis International, vol. 19, no. 9, pp. 1283–1290, 2008.
- M. R. Brinker, D. P. O'Connor, Y. T. Monla, and T. P. Earthman, “Metabolic and endocrine abnormalities in patients with nonunions,” Journal of Orthopaedic Trauma, vol. 21, no. 8, pp. 557–570, 2007.
- W. E. Plehwe and R. P. L. Carey, “Spinal surgery and severe vitamin D deficiency,” Medical Journal of Australia, vol. 176, no. 9, pp. 438–439, 2002.
- S. G. Pneumaticos, C. P. Zafeiris, E. Chronopoulos, E. Kassi, and G. P. Lyritis, “Vitamin D deficiency resulting to a subsequent vertebral fracture after kyphoplasty,” Journal of Musculoskeletal Neuronal Interactions, vol. 11, no. 1, pp. 81–83, 2011.
- G. Schwalfenberg, “Improvement of chronic back pain or failed back surgery with vitamin D repletion: a case series,” Journal of the American Board of Family Medicine, vol. 22, no. 1, pp. 69–74, 2009.
- S. Waikakul, “Serum 25-hydroxy-calciferol level and failed back surgery syndrome,” The Journal of Orthopaedic Surgery, vol. 20, no. 1, pp. 18–22, 2012.
- T. H. Kim, J. Y. Yoon, B. H. Lee et al., “Changes in vitamin D status after surgery in female patients with lumbar spinal stenosis and its clinical significance,” Spine, vol. 37, no. 21, pp. E1326–E1330, 2012.
- G. E. Stoker, J. M. Buchowski, K. H. Bridwell, L. G. Lenke, K. D. Riew, and L. P. Zebala, “Preoperative vitamin D status of adults undergoing surgical spinal fusion,” Spine, vol. 38, no. 6, pp. 507–515, 2013.
- S. Al Faraj and K. Al Mutairi, “Vitamin D deficiency and chronic low back pain in Saudi Arabia,” Spine, vol. 28, no. 2, pp. 177–179, 2003.
- K. V. Knutsen, M. Brekke, S. Gjelstad, and P. Lagerløv, “Vitamin D status in patients with musculoskeletal pain, fatigue and headache: a cross-sectional descriptive study in a multi-ethnic general practice in Norway,” Scandinavian Journal of Primary Health Care, vol. 28, no. 3, pp. 166–171, 2010.
- J. MacLaughlin and M. F. Holick, “Aging decreases the capacity of human skin to produce vitamin D3,” Journal of Clinical Investigation, vol. 76, no. 4, pp. 1536–1538, 1985.
- A. S. Growdon, C. A. Camargo Jr., S. Clark, M. Hannon, and J. M. Mansbach, “Serum 25-hydroxyvitamin D levels among Boston trainee doctors in winter,” Nutrients, vol. 4, no. 3, pp. 197–207, 2012.
- T. L. Clemens, J. S. Adams, S. L. Henderson, and M. F. Holick, “Increased skin pigment reduces the capacity of skin to synthesise vitamin D3,” Lancet, vol. 1, no. 8263, pp. 74–76, 1982.
- A. R. Webb, L. Kline, and M. F. Holick, “Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin,” Journal of Clinical Endocrinology and Metabolism, vol. 67, no. 2, pp. 373–378, 1988.
- L. Y. Matsuoka, L. Ide, J. Wortsman, J. A. MacLaughlin, and M. F. Holick, “Sunscreens suppress cutaneous vitamin D3 synthesis,” Journal of Clinical Endocrinology and Metabolism, vol. 64, no. 6, pp. 1165–1168, 1987.
- L. Y. Matsuoka, J. Wortsman, M. J. Dannenberg, B. W. Hollis, Z. Lu, and M. F. Holick, “Clothing prevents ultraviolet-B radiation-dependent photosynthesis of vitamin D3,” Journal of Clinical Endocrinology and Metabolism, vol. 75, no. 4, pp. 1099–1103, 1992.
- G. El-Hajj Fuleihan, M. Nabulsi, M. Choucair et al., “Hypovitaminosis D in healthy schoolchildren,” Pediatrics, vol. 107, no. 4, p. E53, 2001.
- S. Saintonge, H. Bang, and L. M. Gerber, “Implications of a new definition of vitamin D deficiency in a multiracial US adolescent population: the National Health and Nutrition Examination Survey III,” Pediatrics, vol. 123, no. 3, pp. 797–803, 2009.
- G. Guardia, N. Parikh, T. Eskridge, E. Phillips, G. Divine, and D. S. Rao, “Prevalence of vitamin D depletion among subjects seeking advice on osteoporosis: a five-year cross-sectional study with public health implications,” Osteoporosis International, vol. 19, no. 1, pp. 13–19, 2008.
- S. Arunabh, S. Pollack, J. Yeh, and J. F. Aloia, “Body fat content and 25-hydroxyvitamin D levels in healthy women,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 1, pp. 157–161, 2003.
- G. E. Stoker, J. M. Buchowski, and M. E. Stoker, “Prior cholecystectomy as a predictor of preoperative vitamin D deficiency in adults undergoing spine surgery,” Archives of Surgery, vol. 147, no. 6, pp. 577–578, 2012.
- E. Kamycheva, R. M. Joakimsen, and R. Jorde, “Intakes of calcium and vitamin D predict body mass index in the population of Northern Norway,” Journal of Nutrition, vol. 133, no. 1, pp. 102–106, 2003.
- U. Grober and K. Kisters, “Influence of drugs on vitamin D and calcium metabolism,” Dermato-Endocrinology, vol. 4, no. 2, pp. 158–166, 2012.
- M. F. Holick, “Vitamin D deficiency: what a pain it is,” Mayo Clinic Proceedings, vol. 78, no. 12, pp. 1457–1459, 2003.
- S. S. Hannah and A. W. Norman, “1α,25(OH)2 vitamin D3-regulated expression of the eukaryotic genome,” Nutrition Reviews, vol. 52, no. 11, pp. 376–382, 1994.
- R. S. Khoury, J. Weber, and M. C. Farach-Carson, “Vitamin D metabolites modulate osteoblast activity by Ca+2 influx- independent genomic and Ca+2 influx-dependent nongenomic pathways,” Journal of Nutrition, vol. 125, no. 6, supplement, pp. 1699S–1703S, 1995.
- L. N. Drittanti, R. L. Boland, and A. R. de Boland, “Induction of specific proteins in cultured skeletal muscle cells by 1,25-dihydroxyvitamin D-3,” Biochimica et Biophysica Acta, vol. 1012, no. 1, pp. 16–23, 1989.
- I. Nemere and A. W. Norman, “Transcaltachia, vesicular calcium transport, and microtubule-associated calbindin-D(28K): emerging views of 1,25-dihydroxyvitamin D3-mediated intestinal calcium absorption,” Mineral and Electrolyte Metabolism, vol. 16, no. 2-3, pp. 109–114, 1990.
- I. Nemere, V. Leathers, and A. W. Norman, “1,25-dihydroxyvitamin D3-mediated intestinal calcium transport. Biochemical identification of lysosomes containing calcium and calcium-binding protein (Calbindin-D(28K)),” Journal of Biological Chemistry, vol. 261, no. 34, pp. 16106–16114, 1986.
- Z. Xiaoyu, B. Payal, O. Melissa, and L. P. Zanello, “1α,25(OH)2-vitamin D3 membrane-initiated calcium signaling modulates exocytosis and cell survival,” Journal of Steroid Biochemistry and Molecular Biology, vol. 103, no. 3–5, pp. 457–461, 2007.
- A. Minasyan, T. Keisala, J. Zou et al., “Vestibular dysfunction in vitamin D receptor mutant mice,” Journal of Steroid Biochemistry and Molecular Biology, vol. 114, no. 3–5, pp. 161–166, 2009.
- T. H. J. Burne, J. J. McGrath, D. W. Eyles, and A. Mackay-Sim, “Behavioural characterization of vitamin D receptor knockout mice,” Behavioural Brain Research, vol. 157, no. 2, pp. 299–308, 2005.
- I. Endo, D. Inoue, T. Mitsui et al., “Deletion of vitamin D receptor gene in mice results in abnormal skeletal muscle development with deregulated expression of myoregulatory transcription factors,” Endocrinology, vol. 144, no. 12, pp. 5138–5144, 2003.
- S. Ikegami, M. Kamimura, S. Uchiyama, and H. Kato, “Women with insufficient 25-hydroxyvitamin D without secondary hyperparathyroidism have altered bone turnover and greater incidence of vertebral fractures,” Journal of Orthopaedic Science, vol. 16, no. 5, pp. 573–580, 2011.
- O. Sahota, M. K. Mundey, P. San, I. M. Godber, N. Lawson, and D. J. Hosking, “The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis,” Bone, vol. 35, no. 1, pp. 312–319, 2004.
- O. Sahota, T. Masud, P. San, and D. J. Hosking, “Vitamin D insufficiency increases bone turnover markers and enhances bone loss at the hip in patients with established vertebral osteoporosis,” Clinical Endocrinology, vol. 51, no. 2, pp. 217–221, 1999.
- D. Jesudason, A. G. Need, M. Horowitz, P. D. O'Loughlin, H. A. Morris, and B. E. C. Nordin, “Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D insufficiency,” Bone, vol. 31, no. 5, pp. 626–630, 2002.
- M. Kogawa, D. M. Findlay, P. H. Anderson et al., “Osteoclastic metabolism of 25(OH)-vitamin D3: a potential mechanism for optimization of bone resorption,” Endocrinology, vol. 151, no. 10, pp. 4613–4625, 2010.
- H. Takasu, A. Sugita, Y. Uchiyama et al., “c-Fos protein as a target of anti-osteoclastogenic action of vitamin D, and synthesis of new analogs,” Journal of Clinical Investigation, vol. 116, no. 2, pp. 528–535, 2006.
- A. P. Mee, J. A. Hoyland, I. P. Braidman, A. J. Freemont, M. Davies, and E. B. Mawer, “Demonstration of vitamin D receptor transcripts in actively resorbing osteoclasts in bone sections,” Bone, vol. 18, no. 4, pp. 295–299, 1996.
- D. S. Wang, M. Miura, H. Demura, and K. Sato, “Anabolic effects of 1,25-dihydroxyvitamin D3 on osteoblasts are enhanced by vascular endothelial growth factor produced by osteoblasts and by growth factors produced by endothelial cells,” Endocrinology, vol. 138, no. 7, pp. 2953–2962, 1997.
- S. Takeda, T. Yoshizawa, Y. Nagai et al., “Stimulation of osteoclast formation by 1,25-dihydroxyvitamin D requires its binding to vitamin D receptor (VDR) in osteoblastic cells: studies using VDR knockout mice,” Endocrinology, vol. 140, no. 2, pp. 1005–1008, 1999.
- R. Masuyama, I. Stockmans, S. Torrekens et al., “Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts,” Journal of Clinical Investigation, vol. 116, no. 12, pp. 3150–3159, 2006.
- L. Fu, T. Tang, Y. Miao, Y. Hao, and K. Dai, “Effect of 1,25-dihydroxy vitamin D3 on fracture healing and bone remodeling in ovariectomized rat femora,” Bone, vol. 44, no. 5, pp. 893–898, 2009.
- P. F. Brumbaugh, D. P. Speer, and M. J. Pitt, “1α,25-dihydroxyvitamin D3. A metabolite of vitamin D that promotes bone repair,” American Journal of Pathology, vol. 106, no. 2, pp. 171–179, 1982.
- A. D. Delgado-Martinez, M. E. Martinez, M. T. Carrascal, M. Rodriguez-Avial, and L. Munuera, “Effect of 25-OH-vitamin D on fracture healing in elderly rats,” Journal of Orthopaedic Research, vol. 16, no. 6, pp. 650–653, 1998.
- A. M. Doetsch, J. Faber, N. Lynnerup, I. Wätjen, H. Bliddal, and B. Danneskiold-Samsøe, “The effect of calcium and vitamin D3 supplementation on the healing of the proximal humerus fracture: a randomized placebo-controlled study,” Calcified Tissue International, vol. 75, no. 3, pp. 183–188, 2004.
- R. U. Simpson, G. A. Thomas, and A. J. Arnold, “Identification of 1,25-dihydroxyvitamin D3 receptors and activities in muscle,” Journal of Biological Chemistry, vol. 260, no. 15, pp. 8882–8891, 1985.
- H. A. Bischoff, M. Borchers, F. Gudat et al., “In situ detection of 1,25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue,” Histochemical Journal, vol. 33, no. 1, pp. 19–24, 2001.
- E. M. Costa, H. M. Blau, and D. Feldman, “1,25-dihydroxyvitamin D3 receptors and hormonal responses in cloned human skeletal muscle cells,” Endocrinology, vol. 119, no. 5, pp. 2214–2220, 1986.
- G. Vazquez, A. R. de Boland, and R. Boland, “Stimulation of Ca2+ release-activated Ca2+ channels as a potential mechanism involved in non-genomic 1,25(OH)2-vitamin D3-induced Ca2+ entry in skeletal muscle cells,” Biochemical and Biophysical Research Communications, vol. 239, no. 2, pp. 562–565, 1997.
- A. R. de Boland, S. Gallego, and R. Boland, “Effects of vitamin D-3 on phosphate and calcium transport across and composition of skeletal muscle plasma cell membranes,” Biochimica et Biophysica Acta, vol. 733, no. 2, pp. 264–273, 1983.
- L. Drittanti, A. R. de Boland, and R. Boland, “Stimulation of calmodulin synthesis in proliferating myoblasts by 1,25-dihydroxy-vitamin D3,” Molecular and Cellular Endocrinology, vol. 74, no. 2, pp. 143–153, 1990.
- L. Drittanti, A. R. de Boland, and R. L. Boland, “Effects of 1,25-dihydroxyvitamin D-3 on phospholipid metabolism in chick myoblasts,” Biochimica et Biophysica Acta, vol. 962, no. 1, pp. 1–7, 1988.
- D. A. Capiati, G. Vazquez, M. T. Tellez Inon, and R. L. Boland, “Role of protein kinase C in 1,25(OH)2-vitamin D3 modulation of intracellular calcium during development of skeletal muscle cells in culture,” Journal of Cellular Biochemistry, vol. 77, no. 2, pp. 200–212, 2000.
- C. Buitrago, R. Boland, and A. R. de Boland, “The tyrosine kinase c-Src is required for 1,25(OH)2-vitamin D3 signalling to the nucleus in muscle cells,” Biochimica et Biophysica Acta, vol. 1541, no. 3, pp. 179–187, 2001.
- S. Morelli, C. Buitrago, G. Vazquez, A. R. de Boland, and R. Boland, “Involvement of tyrosine kinase activity in 1α,25(OH)2-vitamin D3 signal transduction in skeletal muscle cells,” Journal of Biological Chemistry, vol. 275, no. 46, pp. 36021–36028, 2000.
- C. G. Buitrago, N. S. Arango, and R. L. Boland, “1α, 25(OH)2D3-dependent modulation of Akt in proliferating and differentiating C2C12 skeletal muscle cells,” Journal of Cellular Biochemistry, vol. 113, no. 4, pp. 1170–1181, 2012.
- Y. Al-Said, H. Al-Rached, H. Al-Qahtani, and M. Jan, “Severe proximal myopathy with remarkable recovery after vitamin D treatment,” Canadian Journal of Neurological Sciences, vol. 36, no. 3, pp. 336–339, 2009.
- H. Glerup, K. Mikkelsen, L. Poulsen et al., “Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement,” Calcified Tissue International, vol. 66, no. 6, pp. 419–424, 2000.
- K. Ekbom, R. Hed, L. Kirstein, and K. E. Astroem, “Weakness of proximal limb muscles, probably due to myopathy after partial gastrectomy. Preliminary report,” Acta Medica Scandinavica, vol. 176, pp. 493–496, 1964.
- J. W. Prineas, A. S. Mason, and R. A. Henson, “Myopathy in metabolic bone disease,” British Medical Journal, vol. 1, no. 5441, pp. 1034–1036, 1965.
- D. N. Golding, “Muscle pain and wasting in osteomalacia,” Journal of the Royal Society of Medicine, vol. 78, no. 6, pp. 495–496, 1985.
- A. J. Reginato, G. F. Falasca, R. Pappu, B. McKnight, and A. Agha, “Musculoskeletal manifestations of osteomalacia: report of 26 cases and literature review,” Seminars in Arthritis and Rheumatism, vol. 28, no. 5, pp. 287–304, 1999.
- K. Ekbom, R. Hed, L. Kirstein, and K. E. Astroem, “Myopathy in metabolic bone disease,” British Medical Journal, vol. 1, no. 5451, pp. 1670–1671, 1965.
- J. K. Dhesi, L. M. Bearne, C. Moniz et al., “Neuromuscular and psychomotor function in elderly subjects who fall and the relationship with vitamin D status,” Journal of Bone and Mineral Research, vol. 17, no. 5, pp. 891–897, 2002.
- M. Visser, D. J. H. Deeg, and P. Lips, “Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the Longitudinal Aging Study Amsterdam,” Journal of Clinical Endocrinology and Metabolism, vol. 88, no. 12, pp. 5766–5772, 2003.
- J. F. J. B. Nellen, Y. M. Smulders, P. H. J. Frissen, E. H. Slaats, and J. Silberbusch, “Hypovitaminosis D in immigrant women: slow to be diagnosed,” British Medical Journal, vol. 312, no. 7030, pp. 570–572, 1996.
- J. Mytton, A. P. Frater, G. Oakley, E. Murphy, M. J. Barber, and S. Jahfar, “Vitamin D deficiency in multicultural primary care: a case series of 299 patients,” British Journal of General Practice, vol. 57, no. 540, pp. 577–579, 2007.
- G. de Torrenté de La Jara, A. Pécoud, and B. Favrat, “Female asylum seekers with musculoskeletal pain: the importance of diagnosis and treatment of hypovitaminosis D,” BMC Family Practice, vol. 7, article 4, 2006.
- O. H. Sorensen, B. Lund, B. Saltin et al., “Myopathy in bone loss of ageing: improvement by treatment with 1α-hydroxycholecalciferol and calcium,” Clinical Science, vol. 56, no. 2, pp. 157–161, 1979.
- H. A. Bischoff, H. B. Stähelin, W. Dick et al., “Effects of vitamin D and calcium supplementation on falls: a randomized controlled trial,” Journal of Bone and Mineral Research, vol. 18, no. 2, pp. 343–351, 2003.
- F. M. Gloth III, C. E. Smith, B. W. Hollis, and J. D. Tobin, “Functional improvement with vitamin D replenishment in a cohort of frail, vitamin D-deficient older people,” Journal of the American Geriatrics Society, vol. 43, no. 11, pp. 1269–1271, 1995.
- L. Ceglia, “Vitamin D and its role in skeletal muscle,” Current Opinion in Clinical Nutrition and Metabolic Care, vol. 12, no. 6, pp. 628–633, 2009.
- Y. Sato, J. Iwamoto, T. Kanoko, and K. Satoh, “Low-dose vitamin D prevents muscular atrophy and reduces falls and hip fractures in women after stroke: a randomized controlled trial,” Cerebrovascular Diseases, vol. 20, no. 3, pp. 187–192, 2005.
- M. Pfeifer, B. Begerow, H. W. Minne et al., “Vitamin D status, trunk muscle strength, body sway, falls, and fractures among 237 postmenopausal women with osteoporosis,” Experimental and Clinical Endocrinology and Diabetes, vol. 109, no. 2, pp. 87–92, 2001.
- M. Z. Erkal, J. Wilde, Y. Bilgin et al., “High prevalence of vitamin D deficiency, secondary hyperparathyroidism and generalized bone pain in Turkish immigrants in Germany: identification of risk factors,” Osteoporosis International, vol. 17, no. 8, pp. 1133–1140, 2006.
- W. Ahmed, N. Khan, C. J. Glueck et al., “Low serum 25 (OH) vitamin D levels (<32 ng/mL) are associated with reversible myositis-myalgia in statin-treated patients,” Translational Research, vol. 153, no. 1, pp. 11–16, 2009.
- A. W. M. Fok and T. P. Ng, “Osteomalacia: a case series of patients with atypical clinical orthopaedic presentations,” Hong Kong Medical Journal, vol. 16, no. 6, pp. 476–479, 2010.
- M. K. Turner, W. M. Hooten, J. E. Schmidt, J. L. Kerkvliet, C. O. Townsend, and B. K. Bruce, “Prevalence and clinical correlates of vitamin D inadequacy among patients with chronic pain,” Pain Medicine, vol. 9, no. 8, pp. 979–984, 2008.
- H. Badsha, M. Daher, and K. Ooi Kong, “Myalgias or non-specific muscle pain in Arab or Indo-Pakistani patients may indicate vitamin D deficiency,” Clinical Rheumatology, vol. 28, no. 8, pp. 971–973, 2009.
- S. E. Tague, G. L. Clarke, M. K. Winter, K. E. McCarson, D. E. Wright, and P. G. Smith, “Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation,” The Journal of Neuroscience, vol. 31, no. 39, pp. 13728–13738, 2011.
- S. E. Tague and P. G. Smith, “Vitamin D receptor and enzyme expression in dorsal root ganglia of adult female rats: modulation by ovarian hormones,” Journal of Chemical Neuroanatomy, vol. 41, no. 1, pp. 1–12, 2011.
- T. Akamaru, D. Suh, S. D. Boden, H. S. Kim, A. Minamide, and J. Louis-Ugbo, “Simple carrier matrix modifications can enhance delivery of recombinant human bone morphogenetic protein-2 for posterolateral spine fusion,” Spine, vol. 28, no. 5, pp. 429–434, 2003.
- T. Nakajima, H. Iizuka, S. Tsutsumi, M. Kayakabe, and K. Takagishi, “Evaluation of posterolateral spinal fusion using mesenchymal stem cells: differences with or without osteogenic differentiation,” Spine, vol. 32, no. 22, pp. 2432–2436, 2007.
- G. Cinotti, A. Corsi, B. Sacchetti, M. Riminucci, P. Bianco, and G. Giannicola, “Bone ingrowth and vascular supply in experimental spinal fusion with platelet-rich plasma,” Spine, vol. 38, no. 5, pp. 385–391, 2013.
- C. P. Dipaola, J. E. Bible, D. Biswas, M. Dipaola, J. N. Grauer, and G. R. Rechtine, “Survey of spine surgeons on attitudes regarding osteoporosis and osteomalacia screening and treatment for fractures, fusion surgery, and pseudoarthrosis,” Spine Journal, vol. 9, no. 7, pp. 537–544, 2009.