Vitamin D: When? How Much? Targets?

28 ENDO 2015 • MEET-THE-PROFESSOR CLINICAL CASE MANAGEMENT Vitamin D: When? How Much? Targets? M11 Presented, March 5– 8, 2015 Paul Lips, MD, PhD...
2 downloads 3 Views 192KB Size
28

ENDO 2015



MEET-THE-PROFESSOR CLINICAL CASE MANAGEMENT

Vitamin D: When? How Much? Targets? M11 Presented, March 5– 8, 2015

Paul Lips, MD, PhD. Department of Internal Medicine, Endocrine Section, VU University Medical Center, Amsterdam, The Netherlands, E-mail: [email protected]

consensus exists on the optimal doses to treat and prevent vitamin D deficiency, as higher target 25(OH)D levels, eg, 30 instead of 20 ng/mL, require much higher doses because the increase in serum 25(OH)D following vitamin D supplementation is nonlinear. Another consequence of higher target levels is that a much larger segment of the population has to be treated.

SIGNIFICANCE OF THE CLINICAL PROBLEM

LEARNING OBJECTIVES

Vitamin D deficiency is very common in risk groups such as children, adolescents, older persons, especially when institutionalized, pregnant women, and nonwestern immigrants. Vitamin D status is usually defined according to the 25-hydroxyvitamin D [25(OH)D] concentration. Vitamin D deficiency is defined as serum 25(OH)D of ⬍10 ng/mL (25 nmol/L). When serum 25(OH)D is between 10 and 20 ng/mL (25-50 nmol/L), this is called vitamin D insufficiency. Vitamin D deficiency and insufficiency also cause secondary hyperparathyroidism, increased bone turnover, and bone loss (1). Vitamin D deficiency, when severe, may cause mineralization defects in the bone, leading to rickets and osteomalacia. Vitamin D deficiency is also associated with muscle weakness and falls. Mineralization defects, bone loss, and falls may all contribute to the occurrence of osteoporotic fractures in older persons (2). Supplementation with vitamin D and calcium can decrease the incidence of fractures (3, 4). In the past few decades, epidemiological studies have shown that poor vitamin D status is often associated with many chronic diseases, eg, cardiovascular disease, diabetes type 2, autoimmune diseases such as multiple sclerosis (MS) and diabetes mellitus type 1, infectious diseases, such as tuberculosis (TB), depression, and cancer (5). Laboratory studies have demonstrated plausible pathways for these relationships. Although these associations often are strong, the proof for causal relationships should come from randomized placebo-controlled clinical trials, and the results of these have not been convincing (6, 7). Within the next 5 years, results of at least 6 controlled megatrials with vitamin D doses around 2000 IU/d are awaited.

Which segments of the normal population should be treated? • Which risk groups should be treated? • Skeletal vs extraskeletal outcomes? • How should vitamin D deficiency be diagnosed? ⴰ Laboratory method ⴰ Seasonal variation

BARRIERS TO OPTIMAL PRACTICE There is no consensus on the target serum 25(OH)D level for treatment and prevention. Whereas the Institute of Medicine has defined the target at ⬎20 ng/mL (50 nmol/L) (8), a task group of the Endocrine Society has set the desirable level at 30 ng/mL (75 nmol/L) (9). Opinions also differ regarding the evidence that has been provided by clinical studies on relationships between vitamin D deficiency and extraskeletal outcomes, including many chronic diseases. Variations between laboratories also form a barrier for optimal diagnosis, although programs now try to decrease interlaboratory variation (10). No

• Which daily doses can be recommended? Are weekly or monthly doses equivalent? ⴰ What is the advantage of loading doses? ⴰ Special cases, requiring different approach. ⴰ Risks of overdosing, intoxication. • Treatment targets

STRATEGIES FOR DIAGNOSIS AND MANAGEMENT (TREATMENT, PREVENTION) Diagnosis Vitamin D deficiency may be suspected in risk groups. When serum 25(OH)D is measured, one should be aware of the laboratory method. The gold standard is liquid chromatography followed by tandem mass spectrometry, but classic radioimmunoassays can also give accurate results. The laboratory should participate in a quality control (QC) program (10). When one is diagnosing vitamin D deficiency or insufficiency, the season is important. The seasonal variation in adults is about 8 to 10 ng/mL (20-25 nmol/L) (11). A serum 25(OH)D of 12 ng/mL in February has a very different meaning than a similar value at the end of August (12). A low value at the end of summer means severe vitamin D deficiency in winter, whereas a similar value in winter may indicate an adequate level in summer. Severe (clinical) vitamin D deficiency may also be associated with hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase levels. Clinical vitamin D deficiency only occurs with very low serum 25(OH)D, ⬍8 ng/mL (13), but it is remarkable that such low levels often exist without any complaints by the patient. In case of osteomalacia, bone mineral density (BMD) may be decreased. This may become apparent when BMD shows a large increase upon treatment with vitamin D and calcium. The gold standard for the diagnosis of osteomalacia is a transiliac bone biopsy that is processed without prior decalcification (14). However, this is

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 January 2017. at 13:06 For personal use only. No other uses without permission. . All rights reserved.

ENDO 2015

only indicated when rare causes, such as hypophosphatemic osteomalacia or osteomalacia associated with chronic kidney disease, are suspected. The most common causes of vitamin D deficiency are low sunshine exposure or less effective exposure due to skin pigmentation or covering of the skin because of religious or cultural reasons. In addition, vitamin D intake can be low when fatty fish is avoided, and fortified foods, eg, milk, are not available (15). Poor absorption of vitamin D can occur in the case of gastrointestinal (GI) disorders such as celiac disease, inflammatory bowel disease, or GI bypass surgery in obese persons. Management A dose finding trial was done in residents of a residence for elderly individuals and a nursing home. With a dose of vitamin D3 of 400 IU/d, serum 25(OH)D increased from about 10 ng/mL to a mean of 25 ng/mL, and with 800 IU/d serum 25(OH)D increased to a mean value of ⬎30 ng/mL (Figure 1). In this study, nonresponders were not observed, and the lowest serum 25(OH)D was 16 ng/mL after supplementation (16). The difference in the increase in serum 25(OH)D between 400 and 800 IU/d was relatively small, showing that the dose response

FIGURE 1: Mean (ⴞSD) serum 25(OH)D concentrations during a 1-year vitamin D3 supplementation study in a nursing home (top panel) and a residence for elderly individuals (bottom panel). (Adapted from Lips et al [16]).



BONE

29

is nonlinear. Another trial in nursing home residents with equivalent doses of 600 IU/d, 4200 IU/wk, or 18 000 IU/mo showed that daily and weekly doses had similar efficacy with 89% of the treated persons having serum 25(OH)D of ⬎20 ng/mL (50 nmol/L) after 4 months (17). Although nursing home residents usually get very little sunshine exposure and may have a low dietary vitamin D intake, adults usually get some sunshine and have a vitamin D intake between 100 and 200 IU/d. In any case, serum 25(OH)D tends to be 8 to 10 ng/mL (20-25 nmol/L) higher in summer than in winter, making vitamin D supplementation more obvious in winter. In case of vitamin D insufficiency [serum 25(OH)D between 10 and 20 ng/mL], supplementation with low doses of vitamin D3 will be sufficient, eg, 600 to 800 IU/d. These doses are quite similar to the recommended daily allowance (RDA) according to the Institute of Medicine (8). This RDA is based on negligible sunshine exposure (Table 1). The doses recommended by the task group of the Endocrine Society are considerably higher, because the target serum 25(OH)D level is higher (30 ng/mL). This considerable increase in the dose with the higher target is needed because the increase in serum 25(OH)D levels off with higher doses instead of increasing linearly. This was shown in a careful doseresponse study with increasing doses of vitamin D3 from 400 to 4800 IU/d (18). This study also confirmed that the serum 25(OH)D level of 20 ng/mL (50 nmol/L) can be reached in 97.5% of the population with 600 to 800 IU/d. Obese persons have lower serum 25(OH)D levels, probably due to a larger extracellular pool size. Some clinicians recommend loading doses in case of (severe) vitamin D deficiency, eg, 50 000 IU/wk for 4 weeks followed by 50 000 IU/mo. However, the lower the baseline serum 25(OH)D, the faster is the increase in serum 25(OH)D (18). Most clinicians will give a somewhat higher dose in the case of severe vitamin D deficiency (eg, double dose). However, evidence for a faster cure of clinical vitamin D deficiency with higher doses is not available. Special situations include celiac disease, inflammatory bowel disease, resections of the small intestine, or gastric bypass surgery. In these situations, higher doses and regular checking of serum 25(OH)D are necessary. High doses of vitamin D3 associated with levels of serum 25(OH)D of ⬎50 ng/mL (125 nmol/L) may carry some risks as was shown in an Australian clinical trial where 500 000 IU was given once per year (19). This resulted in more falls and fractures in the vitamin D group than in the placebo group. Very high doses of vitamin D and especially highly concentrated solutions of vitamin D (eg, 50 000 IU/mL) carry the risk of vitamin D intoxication, because of prescription or intake errors. Vitamin D intoxication is associated with nausea, thirst, polyuria, hypercalcemia, and renal functional impairment. This can be treated with rehydration and prednisone, but prevention is better.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 January 2017. at 13:06 For personal use only. No other uses without permission. . All rights reserved.

30

ENDO 2015



MEET-THE-PROFESSOR CLINICAL CASE MANAGEMENT

TABLE 1: RDAs, Requirements, and Upper Limit of Intake According to the Institute of Medicine and the Endocrine Society IOM Age Children, 1–8 y Children, 9–18 y Adults, 19–70 y Adults, ⬎70 y Pregnancy, 19–50 y Lactation, 19–50 y

Endocrine Society

RDA, IU/ d

UL, IU/ d

Requirement, IU/d

UL, IU/ d

600 600 600 800 600

2500 4000 4000 4000 4000

600–1000 600–1000 1500–2000 1500–2000 1500–2000

4000 4000 10 000 10 000 10 000

600

4000

1500–2000

10 000

Abbveviations: IOM, Institute of Medicine; RDA, recommended dietary allowance; UL, upper limit.

MAIN CONCLUSIONS Vitamin D deficiency and insufficiency are common in risk groups such as children, adolescents, pregnant women, older persons, and nonwestern immigrants. It causes secondary hyperparathyroidism and bone loss and, when severe, mineralization defects and osteomalacia. It is also associated with muscle weakness and falls. It contributes to fractures. Fractures may be prevented with vitamin D and calcium supplementation. There is no consensus on adequate serum 25(OH)D, either ⬎20 or ⬎30 ng/mL. These target levels correspond to different recommendations and supplementation doses. Low-dose vitamin D supplementation (600-800 IU/d) is sufficient to increase serum 25(OH)D to ⬎20 ng/mL in 95% of the population. In case of severe clinical vitamin D deficiency, higher initial doses may be prescribed, as well as in the case of absorption problems such as small bowel disorders or surgery. Whereas vitamin D is not very toxic, highly concentrated solutions (eg, 50 000 IU/mL) carry the risk of vitamin D intoxication due to prescription or intake errors.

CASES WITH QUESTIONS Case 1 A 62-year-old woman visits the clinic in February to rule out osteoporosis after having had a distal radius fracture. Her history is unremarkable, but her mother had had a hip fracture at age 79 years. Lumbar spine BMD measurement revealed a T-score of ⫺1.9. Laboratory investigation was unremarkable except for a serum 25(OH)D of 14 ng/mL (35 nmol/L). It is decided to treat her with vitamin D3. Question: What is the appropriate dose? 1. 400-800 IU/d 2. 2000 IU/d 3. 4000 IU/d 4. 50 000 IU/wk for the first month and then 50 000 IU/mo

Case 2 A 79-year-old male has had a fracture of the second lumbar vertebra after a fall on a wet pavement in mid-August. It is a second-degree fracture (25% anterior height loss), and he is slowly recovering. His history is unremarkable except for immobility due to knee problems. His dairy intake is adequate. BMD of the lumbar spine showed a T-score of ⫺2. Laboratory investigation did not reveal a secondary cause for osteoporosis, but serum 25(OH)D was 16 ng/mL (40 nmol/L). Besides bisphosphonates, he receives a prescription for vitamin D3. Question: What is the appropriate dose? 1. 800 IU/d 2. 4000 IU/d 3. 10 000 IU/d 4. 50 000 IU/wk for the first month and then 50 000 IU/mo Case 3 A 38-year-old man was brought to the emergency room with extreme muscle weakness, diffuse musculoskeletal pain, and cramps. He had been bedridden during the last weeks. On physical examination, he was in a poor nutritional state with a body weight of 40 kg. The pain was localized around his shoulders and pelvis. The proximal muscle weakness was extreme. The Trousseau sign was positive. Laboratory data revealed calcium of 1.20 mmol/L (4.8 mg/dL), phosphate of 0.76 mmol/L, albumin of 35 g/L, alkaline phosphatase of 210 U/L, ␥-glutamyl transferase (GGT) of 10 U/L, creatinine of 34 ␮mol/L, creatine kinase (CK) of 1574 U/L. The 24-urine calcium was 0.5 mmol/24 h. BMD of the lumbar spine was 0.46 g/cm2 with a T-score of ⫺6.1. Total hip BMD was 0.43 g/cm2 with a T-score of ⫺4.0.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 January 2017. at 13:06 For personal use only. No other uses without permission. . All rights reserved.

ENDO 2015

Question: What is the diagnosis? 1. Vitamin D deficiency, secondary hyperparathyroidism, and bone loss 2. Osteoporosis 3. Osteomalacia 4. Hypoparathyroidism Question: What is the appropriate management? 1. High-dose vitamin D 2. Bisphosphonates 3. High-dose vitamin D and calcium 4. Calcitriol and calcium Case 4 An 81-year-old woman was thirsty and had frequent micturition for a few months. She complained of nausea and had to vomit sometimes. Her appetite was poor. Her history also revealed depression in the past, atrial fibrillation (AF), myocardial infarction (MI), diabetes type 2, pyelonephritis, and vitamin D deficiency. Medications she was taking were tolbutamide, metoprolol, olanzapine, acenocoumarol, and vitamin D3 (50 000 IU/mo). On physical examination, her pulse was 50/min, and she had a systolic murmur III/VI and some ankle edema. Laboratory examination showed a serum creatinine of 254 ␮mol/L, calcium of 3.27 mmol/L (reference value, 2.15-2.60 mmol/L), phosphate of 1.38 mmol/L, alkaline phosphatase of 95 U/L, and PTH of 4.2 pmol/L (normal). Skeletal radiographs and ultrasound of the abdomen did not reveal a cause for the hypercalcemia. Question: What is the next diagnostic step? 1. Skeletal scintigraphy 2. Measure serum 1,25-dihydroxyvitamin D [1,25(OH)2D] 3. Measure serum 25(OH)D 4. Measure serum PTHrP

DISCUSSION OF CASES AND ANSWERS Case 1 This woman with vitamin D insufficiency in winter will have a serum 25(OH)D of ⬎20 ng/mL in summer unless she completely avoids sunshine. Therefore, a low dose of vitamin D3 of 400 IU/d will be sufficient to raise her serum 25(OH)D to ⬎20 ng/mL all year long. Even vitamin D supplementation only from October until March might be sufficient. However, there is no objection to supplement her with 600 to 800 IU/d. Case 2 This man aged 79 years has vitamin D insufficiency in summer. He will be deficient in winter with serum 25(OH)D of



BONE

31

about 8 ng/mL (20 nmol/L). This man needs vitamin D supplementation all year long. At this moment in summer, there is no need for high doses, as the 25(OH)D level is not in the deficiency range. With a vitamin D3 dose of 800 IU/d, he will be soon in the range of vitamin D adequacy with a serum 25(OH)D of ⬎20 ng/mL (50 nmol/L). If serum 25(OH)D would have been 8 ng/mL in any season, the patient would have been vitamin D deficient. Even in that case, a vitamin D3 dose of 800 IU/d would do its work fairly quickly, because the initial increase is steep especially when baseline serum 25(OH)D is low. Loading doses, eg, 10 000 IU/d or 50 000 IU/wk, will lead to a faster cure of vitamin D deficiency, but the advantage regarding clinical signs or consequences has not been proven. Case 3 This man with severe hypocalcemia, a normal serum phosphate, and high alkaline phosphatase does not have hypoparathyroidism. In that case, serum phosphate would have been high, and alkaline phosphatase would have been normal or low. The very low BMD is compatible with the diagnosis of osteoporosis, but the biochemistry results are not. The hypocalcemia is caused by very low calcium absorption from the gut associated with very severe vitamin D deficiency, leading to osteomalacia and secondary hyperparathyroidism. The high alkaline phosphatase points to a mineralization defect, ie, osteomalacia. Serum 25(OH)D and serum 1,25(OH)2D both were below the detection limit (4 ng/mL and 4 pg/mL, respectively). This patient had been eating only bread and avocados for the last 2 years. He did not have much sunshine exposure. His dietary calcium intake was very low, which had contributed to his poor clinical condition. He received tablets, containing 500 mg of calcium and 800 IU of vitamin D3, 4 tablets daily. His recovery was very fast: he could be remobilized within a week. After 3 weeks, he was walking slowly, and serum calcium was 2.16 mmol/L, and serum 25(OH)D was 24 ng/mL (59 nmol/L). After 1 year, his BMD T-score for the lumbar spine had increased to ⫹1.1 and the T-score for the hip increased to ⫺0.9. Case 4 At the age of this woman, 81 years, the most common causes of hypercalcemia would be malignancy and primary hyperparathyroidism. The latter was excluded by the PTH measurement, and the former was not immediately evident. Skeletal scintigraphy could exclude bone metastasis, and an elevated PTHrP could point to humoral hypercalcemia of malignancy. Hypercalcemia with an increased serum 1,25(OH)2D is observed with sarcoidosis, malignant lymphoma, and granulomatous diseases. In this patient, who already used a concentrated vitamin D solution, one should think of a prescription error or intake error. The patient should have taken 50 000 IU/mo, but she had taken 50 000 IU/d for 3 months. Serum 25(OH)D was 230 ng/mL (575 nmol/L) and serum 1,25(OH)2D was normal (46

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 January 2017. at 13:06 For personal use only. No other uses without permission. . All rights reserved.

32

ENDO 2015



MEET-THE-PROFESSOR CLINICAL CASE MANAGEMENT

pg/mL, 114 pmol/L). The diagnosis was vitamin D intoxication. Vitamin D was discontinued. The patient was rehydrated and treated with prednisone (20 mg daily). Serum calcium normalized within 10 days. Hypercalcemia is encountered more often because concentrated vitamin D medication is used more often. We saw two participants in an epidemiological study with very high serum 25(OH)D. The message is: do not use these high doses when not clearly needed.

REFERENCES 1. Lips P. Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications. Endocr Rev. 2001;22:477-501. 2. Lips P, van Schoor NM. The effect of vitamin D on bone and osteoporosis. Best Pract Res Clin Endocrinol Metab. 2011;25:585-591. 3. Avenell A, Gillespie WJ, Gillespie LD, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2009;2:CD000227. 4. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med. 2012;367:40-49. 5. Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2:76-89. 6. Bouillon R, Van Schoor NM, Gielen E, et al. Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. J Clin Endocrinol Metab. 2013:98(8):E1283–E1304. 7. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014;2:307-320. 8. Ross AC, Manson JE, Abrams SA, et al. The 2011 Report on dietary reference intakes for calcium and vitamin D from the Institute of Medi-

9.

10.

11.

12.

13.

14.

15. 16.

17.

18.

19.

cine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96:53-58. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96:1911-1930. Cashman KD, Kiely M, Kinsella M, et al. Evaluation of vitamin D standardization program protocols for standardizing serum 25-hydroxyvitamin D data: a case study of the program’s potential for national nutrition and health surveys. Am J Clin Nutr. 2013;97:1235-1242. van Schoor NM, Knol DL, Deeg DJ, Peters FP, Heijboer AC, Lips P. Longitudinal changes and seasonal variations in serum 25-hydroxyvitamin D levels in different age groups: results of the Longitudinal Aging Study Amsterdam. Osteoporos Int. 2014;25(5):1483-1491. Sohl E, Heymans MW, de Jongh RT, et al. Prediction of vitamin D deficiency by simple patient characteristics. Am J Clin Nutr. 2014;99(5):1089-1095. Need AG, O’Loughlin PD, Morris HA, Coates PS, Horowitz M, Nordin BE. Vitamin D metabolites and calcium absorption in severe vitamin D deficiency. J Bone Miner Res. 2008;23:1859-1863. Lips P, van Schoor NM, Bravenboer N. Vitamin D-related disorders. In: Rosen CJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 8th ed. Hoboken, NJ: Wiley-Blackwell; 2013:613-623. Lips P, van Schoor NM, de Jongh RT. Diet, sun, and lifestyle as determinants of vitamin D status. Ann NY Acad Sci. 2014;1317:92-98. Lips P, Wiersinga A, van Ginkel FC, et al. The effect of vitamin D supplementation on vitamin D status and parathyroid function in elderly subjects. J Clin Endocrinol Metab. 1988;67:644-650. Chel V, Wijnhoven HA, Smit JH, Ooms M, Lips P. Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents. Osteoporos Int. 2008;19(5):663-671. Gallagher JC, Sai A, Templin T II, Smith L. Dose response to vitamin D supplementation in postmenopausal women; a randomized trial. Ann Intern Med. 2012;156:425-437. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815-1822.

The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 18 January 2017. at 13:06 For personal use only. No other uses without permission. . All rights reserved.