“VITAMIN D LEVELS IN PATIENTS WITH FRACTURES AROUND THE HIP....A HOSPITAL BASED STUDY”

Dr. Qazi Waris Manzoor 1 , Dr. Misbah Mehraj 2 and Dr. Tabish Tahir Kirmani 1 . 1. M. S. Orthopaedics, GMC Srinagar. 2. M. S. Orthopaedics, GMC Jammu. ...................................................................................................................... Manuscript Info Abstract ......................... ........................................................................ Manuscript History


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16 days, and 100% of treated patients achieved plasma levels above the desired threshold of 75 nmol/L. Results: Virtually all patients with a hip fracture have low vitamin D plasma levels ; substitution with 50,000 IU oral cholecalciferol daily for 7 days increases vitamin D plasma levels rapidly, safely and consistently. Conclusions: The study confirms that the vast majority of patients with hip fracture are vitamin D deficient and require supplements. The current target for 25-hydroxyvitamin D serum concentration in secondary fracture prevention is 75 nmol/L. The current study also demonstrates that, in patients with a normal corrected calcium level (< 2.60 mmol/L),rapid high dose substitution with 50,000 IU of vitamin D3 can normalize circulating serum vitamin D levels quickly and safely.

Introduction:-
Hip fractures are a major cause of morbidity and mortality in the elderly, and are associated with chronic pain, reduced mobility, disability, and an increasing degree of dependence (24). These low-energy injuries are costly to treat and have a significant physical and social impact. An estimated worldwide incidence of hip fractures in the year 2000 was 1.6 million (23). This number is projected to rise up to 2.6 million by 2025, and to more than 4.5 million by 2050 (17). Most hip fractures in the elderly can be related to the development of osteoporosis, a progressive, systemic skeletal disorder characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture (28). It has been shown that identification and management of patients at risk can significantly reduce the risk of a further fracture through modification of life style, adequate treatment of osteoporosis, and a falls prevention program (13,27). In the last decades, the development of effective therapies (e.g. bisphosphonates, RANK ligand inhibitors, selective estrogen receptor modulators (SERMs) and strontium ranelate) has extended the spectrum of osteoporosis treatment. Most current osteoporosis guidelines assume that patients who receive treatment for secondary prevention of osteoporotic fragility fractures have an adequate calcium intake and are vitamin D replete. Adequate levels of calcium and vitamin D are needed to ensure optimum effects of the treatments for osteoporosis and are recommended in the data sheets of all the commonly used drugs. Vitamin D status is best evaluated by measuring the circulating 25hydroxyvitamin D concentration in the serum. Although controversy surrounds the definition of low vitamin D status, there is general acceptance that the optimal circulating 25-hydroxyvitamin D level should be 75 nmol/L or above (3). A threshold for optimal 25-hydroxyvitamin D and hip Bone Mineral Density (BMD) has been established from 13,432 individuals of NHANES III (Third National Health and Nutrition Examination Survey), including both younger (20-49 years) and older (≥ 50 years) individuals with different ethnic racial background (7). This study shows that high serum 25-hydroxyvitamin D levels are associated with higher BMD throughout the reference range of 22.5-94 nmol/L in all subgroups. In younger whites and younger Mexican Americans, higher 25-hydroxyvitamin D was associated with higher BMD even beyond 100 nmol/L. A meta-analysis (9) of 12 double-blind RCTs for nonvertebral fractures (n = 42,279) and eight RCTs for hip fractures (n = 40,886) found that the efficacy of vitamin D in preventing fractures is dose dependent and increases significantly with a higher achieved level of 25hydroxyvitamin D in the treatment group, starting at 75 nmol/L (6,9). However, serum 25-hydroxyvitamin D levels above 220 nmol/L have been associated with hypercalcemia and other signs of toxicity (15,34). Bone remodeling is a balance between bone formation by osteoblasts and bone resorption by osteoclasts and mononuclear cells. It involves several hormones . Indeed, low calcium levels increase parathyroid hormone (PTH) production by the parathyroid glands. This stimulates calcium release from the bones and increases the reabsorption of calcium in the distal renal tubule cells. PTH also stimulates the renal production of biologically active vitamin D, which in turn increases calcium absorption from the gut. All these actions increase the calcium level in plasma. High calcium levels on the other hand stimulate the thyroid gland to produce and release calcitonin, which inhibits bone resorption by blocking PTH receptors on the osteoclasts, decreases calcium reabsorption in the kidney, and decreases calcium 422 absorption from the gut. Thus reducing plasma calcium levels. Vitamin D deficiency may be characterized biochemically by the presence of secondary hyperparathyroidism, which can also contribute to the bone loss in osteopenic patients. Secondary hyperparathyroidism is a physiological response to hypocalcaemia associated with vitamin D deficiency, and treatment with vitamin D will normalize the elevated PTH levels without significantly elevating the serum calcium level. It is important to distinguish secondary hyperparathyroidism from primary hyperparathyroidism due to a parathyroid adenoma, hyperplasia, or malignancy, in which excessive PTH secretion leads to bone resorption and high calcium levels in the plasma. In primary hyperparathyroidism substitution with vitamin D will not normalize PTH levels, and a potentially dangerous hypercalcemia may ensue. In the general population, particularly in the elderly, vitamin D levels are commonly reduced as a result of low dietary intake, decreased sun exposure, decreased intrinsic vitamin D production, and decreased vitamin D receptor activity. There is some evidence that vitamin D deficiency is also becoming widespread in younger patients (33). Other authors have also measured vitamin D levels in patients with a hip fracture, and demonstrated that levels are consistently low. In this study, we noted the levels of circulating 25-hydroxyvitamin D in a consecutive series of 381 patients sustaining a hip fracture (phase I, retrospective), and evaluated the effect of rapid substitution therapy with high dose oral vitamin D3 (cholecalciferol) (phase II : 3 days, and phase III : 7 days, both prospective). From these data, guidelines were developed for the management of low vitamin D levels in patients with a hip fracture.

Materials And Methods:-
Phase I (retrospective) : circulating 25-hydroxy-vitamin D and serum calcium levels were recorded from the files of 381 consecutive patients admitted with 387 hip fractures between May 2015 and November 2016 at Government hospital for Bone and Joint surgery, Barzulla, Kashmir, India. All patients were included. Vitamin D analysis was performed on serum using a direct competitive chemiluminescence immunoassay. Levels above 75 nmol/L were defined as sufficient, between 25-75 nmol/L as insufficient, and below 25 nmol/L as deficient. Calcium and corrected calcium (= calcium level based on the serum albumin level) analyses were also performed, using spectrophotometry. Phase II and phase III (both prospective) focused on rapid substitution therapy, respectively during 3 and 7 days. Inclusion criteria : all patients presenting with a hip fracture, with corrected calcium below 2.60 mmol/L (to avoid hypercalcemia), who agreed with a written informed consent. Exclusion criteria : patients with corrected calcium above 2.60 mmol/L, because treatment could potentially lead to dangerously high calcium levels ; they were assessed biochemically for primary hyperparathyroidism. Prior intake of a low dose of vitamin D and a calcium supplement was not an exclusion criterion. Patients with cognitive impairment resulting in non-compliance with therapy, and patients with a significantly reduced life expectancy (ASA grade 5) or significant renal impairment (GFR < 30 mL/min/1.73m2) were also excluded. Clinical side effects of hypercalcemia and hypervitaminosis D, such as nausea, vomiting, constipation, thirst and polyuria were recorded. Phase II (prospective) : rapid substitution therapy with 50,000 IU oral vitamin D3 (cholecalciferol) daily for 3 days was started in 14 consecutive patients with a hip fracture (November 2016). Phase III (prospective) : rapid substitution therapy with 50,000 IU oral vitamin D3 (cholecalciferol) daily for 7 days was started in 54 consecutive patients with a hip fracture, between November 2016 and March 2017. Initially 60 patients had been considered, but 6 were excluded (2 non-compliant, 2 absent repeat sample, 2 initial corrected calcium above 2.60 mmol/L).Both patient groups (phase II and phase III) had similar demographic characteristics, and did not differ in terms of age-related comorbidities, drug intake or dwelling status. Repeat vitamin D and calcium measurements were performed between 7 and 42 days after the start of substitution therapy. After completion of the study all patients were recommended to take a low dose vitamin D and calcium supplement for life : calcium carbonate (1500 mg) and vitamin D3 (400 IU). . Compliance with treatment was 100%. A paired t-test was performed to determine if supplementation was effective. The mean serum 25-hydroxyvitamin D level before 423 substitution was 29.6 nmol/L, the mean calcium level 2.12 mmol/L, and the corrected calcium level 2.43 mmol/L. Repeat measurements after a mean of 14 days (range, 7-23 days) demonstrated a significant increase in circulating 25-hydroxyvitamin D levels to +/-81.4 nmol/L (p < 0.0001). This represents a near threefold increase in circulating vitamin D. However 29% of these patients failed to increase their vitamin D levels above the desired threshold of 75 nmol/L. Mean calcium and corrected calcium values also increased significantly (p < 0.0001), but in nearly all cases remained within their normal limits of 2.2-2.6 mmol/L. No clinical or biochemical side effects or complications were noted. Phase III : 60 patients were initially eligible to receive 50,000 IU oral cholecalciferol for 7 days, but 6 were excluded (2 non-compliant, 2 absent repeat sample, 2 initial corrected calcium above 2.60 mmol/L). Hence 54 patients were included. Mean age was 83 years (range, 40-100 years). A paired t-test was performed to determine if supplementation was effective. The mean 25-hydroxyvitamin D level before substitution was 31.4 nmol/L, the mean calcium level was 2.19 mmol/L, and the mean corrected calcium level 2.47 mmol/L. Repeat measurements after a mean of 16 days (range, 7-42 days) demonstrated a significant increase in circulating 25-hydroxyvitamin D levels to +/ 131.1 nmol/L (p < 0.0001). This represents a fourfold increase in circulating vitamin D. All patients achieved levels above the desired threshold of 75 nmol/L. Calcium levels increased significantly (p < 0.0001), as well as the corrected calcium levels (p = 0.0002). No clinical or biochemical side effects or complications were noted. Significant increase in circulating 25-hydroxyvitamin D levels and normalizing of calcium levels 14 days (range, 7-23 days) after start of substitution ; 29% of patients do not reach desired threshold of 75 nmol/L. Group 2 (phase III ; n = 54) : substitution with 50,000 IU oral vitamin D3 (cholecalciferol) daily for 7 days. Significant increase in circulating 25-hydroxyvitamin D levels and normalizing of calcium levels 16 days (range, 7-42 days) after start of substitution. All patients achieve the desired vitamin D threshold of 75 nmol/L.

Discussion:-
Vitamin D is responsible for the absorption of calcium from the intestine, and may have other bone-protective effects independent of those on calcium metabolism (14,32). In addition, vitamin D plays an important role in muscular function : higher levels of vitamin D are associated with increased muscular strength and balance, reducing the risk of falls and subsequent fractures (5,12). In several double blind randomized controlled trials, vitamin D supplementation increased muscle strength and balance, and reduced the risk of falling (4,8,10,29,30). A study by Glerup et al (16) suggests that vitamin D deficiency may cause muscular impairment even before adverse effects on bone occur.

Hip fracture correlated with vitamin D deficiency:-
This study clearly confirms that the vast majority of patients with hip fracture are vitamin D deficient and require supplements. The current target for 25-hydroxyvitamin D serum concentration in secondary fracture prevention is 75 nmol/L. The fact that the majority of the patients taking low dose supplements were also found to be vitamin D 424 deficient raises the question as to whether the current dose recommended for supplementation is adequate. This question has also been raised by others (2,19). According to studies in younger adults, intakes of as high as 4,000-10,000 IU are safe (18,35). Furthermore, other studies indicate that individuals with a low starting level may need a high dose of vitamin D to achieve desirable vitamin D levels (18,20).

Vitamin D3 preferable to vitamin D2:-
The aim of the current study was to examine the effect of rapid vitamin D substitution with vitamin D3 (cholecalciferol). Pappaionnou et al (26) studied in 2011 the effect of a loading dose of vitamin D2 (ergocalciferol) and found no long-term advantage over daily supplementation (26). However, it has been shown that, although both vitamin D2 and D3 produce similar rises in serum 25-hydroxyvitamin D concentration over 3 days, levels decline much more rapidly in subjects treated with D2 (1). This may possibly reflect lower affinity of vitamin D2 for vitamin D binding protein in the circulation, leading to more rapid clearance. As such, use of supplements containing vitamin D3, rather than vitamin D2, is generally recommended (22). The current study demonstrates that, in patients with a normal corrected calcium level (< 2.60 mmol/L),rapid high dose substitution with 50,000 IU of vitamin D3 can normalize circulating serum vitamin D levels quickly and safely. This is important because all drugs used in the management of osteoporosis require normal vitamin D levels before they are started. However, the authors suspect that the majority of patients started on such treatment do not have their vitamin D levels checked systematically and are almost all deficient. This was certainly the case in the authors' institution before they undertook this study. This means that rapid substitution with high doses vitamin D3 makes sense after hip fractures. Interestingly, also calcium levels increase from an abnormal low value to within the normal range.

Vitamin D protects against falls and non-vertebral fractures:-
In addition, the fact that fall prevention and non-vertebral fracture prevention increased significantly with higher achieved 25-hydroxyvitamin D levels in two meta-analyses (8) of double-blind RCTs, is in itself a good reason to normalize vitamin D as soon as possible after admission with a fracture. Fall prevention was effective with 25hydroxyvitamin D levels of 60 nmol/L up to 95 nmol/L, while 75-112 nmol/L were required for non-vertebral fracture prevention (9,25). Whether higher levels of vitamin D give even more protection against falls and fracture is not known, but has been postulated (6).

Limitations:-
Phase II and III : patients were not randomized, but were treated sequentially. Both phase II and phase III groups were relatively small (14 and 54 patients), but the dramatic rise in vitamin D levels(p < 0.0001) makes the likelihood of the effects being fortuitous improbable. More research is needed to establish if the effect of a short course of high dose oral vitamin D3 substitution is maintained if followed by long term low dose therapy or if an occasional booster is required. Of more concern is the possibility that a patient with primary hyperparathyroidism might get high dose vitamin D supplementation causing severe hypercalcemia and the complications thereof. For this reason only patients with uncompromised renal function (GFR > 30 mL/min/1.73 m2) and a calcemic < 2.60 mmol/L received such a large dose. Patients who do not fit these criteria should be treated with much more caution. An algorithm for the management of all patients is shown. The authors' current practice for patients who present with a corrected calcium of 2.60-2.80 mmol/L is to measure the PTH level and renal function, and start a weekly dose of 50,000 units vitamin D3 and regular calcium monitoring. In the majority of cases initial high PTH levels are due to secondary hyperparathyroidism and at six weeks their repeat PTH level and calcium levels will have returned to normal. They can then receive additional vitamin D supplementation as required before remaining on a lifelong low dose vitamin D3 and calcium regime. Patients who present with corrected calcium of > 2.80 mmol/L and patients with corrected calcium between 2.60-2.80 mmol/L, whose PTH does not fall after a week of rapid vitamin D substitution, are referred to an endocrinologist for further investigation.

Conclusion:-
The benefits of maintaining adequate vitamin D levels in hip fracture patients have been established and the very low cost of the treatment makes it highly cost effective. The very low levels of vitamin D in this patient group took us by surprise, and further studies to evaluate levels in younger populations are clearly indicated. There have been recent reports of the re-emergence of vitamin D deficient related rickets in children in the, and it has been postulated that the national obsession with preventing sunburn because of the risk of skin cancer in later life, coupled with less time spent outdoors by the majority of the population, has had the unintended consequence of creating an entire population which is vitamin D deficient (21). The authors believe that the management of many other types of 425 osteoporotic fractures faces similar challenges with regard to vitamin D supplementation, although this needs to be explored. Investigating this should be a major public health priority, particularly because treatment would be easy and inexpensive.