Vitamin D deficiency, supplementation and testing: have we got it right in New Zealand?
View Article PDF
Severe prolonged vitamin D deficiency can cause rickets in children or osteomalacia in adults. Both are easily prevented by sunshine exposure and prevented or treated with vitamin D supplementation. Beyond these uncontroversial issues, vitamin D supplementation remains surprisingly topical. In the media, it is often portrayed enthusiastically as a cure for a wide range of illnesses,[[1,2]] whereas in scientific literature it is a subject of much debate.[[3–6]] For example, definitions of vitamin D deficiency range from 25-hydroxyvitamin D (25OHD) <25nmol/L to <100nmol/L,[[7–10]] even though the prevalence of biochemical osteomalacia is very low when 25OHD is <25nmol/L.[[11]]
New Zealand guidance on vitamin D supplementation and testing has been consistent for many years: supplementation is not recommended for the general population, but it can be considered for individuals from groups at risk of vitamin D deficiency.[[12]] At-risk groups are identified in this guidance: people with deeply pigmented skin, especially those who wear full-body coverage clothing; people who actively avoid sun exposure; people with low mobility who are frail or housebound; people in southern regions who spend a limited amount of time outdoors; and people with certain medical disorders (eg, kidney failure, malabsorption syndromes).[[12]] It is recognised that, because vitamin D testing costs considerably more (~$30 for gold standard LC-MS/MS assay costs alone) than vitamin D supplementation ($0.25/monthly tablet), supplementation for high-risk individuals should be undertaken without testing. Measurement of 25OHD, the accepted test for assessing vitamin D status, is only indicated for investigation of clinically suspected and symptomatic severe vitamin D deficiency, some biochemical abnormalities (eg, hypocalcaemia and hypophosphataemia) and certain metabolic bone disorders.[[12]]
Despite the unchanged guidance, vitamin D supplementation has been rising. We sought to quantify changes in prescriptions for vitamin D (chemical ID: 1187, name: colecalciferol) in recent years, and whether there have been any corresponding changes in the prevalence of the consequences of severe vitamin D deficiency, rickets and osteomalacia or changes in testing for 25OHD. We have also compared 25OHD results from 2009–2019 with previously published results from 2002–2003. We then considered whether the temporal patterns identified have implications for current vitamin D guidance.
Methods
We obtained data on prescriptions for colecalciferol in New Zealand from between 2003 to 2019 and data on hospitalisations with ICD-10 discharge codes for osteomalacia (M83), rickets (E55.0) and vitamin D deficiency (E55) for 2000–2018 from Stats NZ. We obtained deidentified data from Testsafe, the Auckland regional biochemistry database that includes results from community and hospital patients, for all measurements of 25OHD between 1 January 2009 and 31 December 2019.[[11]] Several different 25OHD assays in different laboratories were used during this time-period, including the Diasorin radioimmunoassay, Diasorin Liaison and immunoassays on the Roche, Siemens and Abbot platforms. However, the overwhelming majority of tests during this period were done at one laboratory, Labplus, largely using the Roche assay. In 2012, Auckland District Health Board (ADHB) introduced restrictions on 25OHD requests at Labplus because of rising numbers of requests and costs.[[13]] These restrictions included requests being limited to certain specialists; to individuals from high risk groups for rickets/osteomalacia; for investigation of rickets/osteomalacia; for disorders of calcium and phosphate metabolism, osteoporosis or other metabolic bone disease; to patients with chronic renal failure and renal transplant recipients; and to children. Tests requested for other reasons were declined.
We compared the results from 2009–2019 with earlier results from Labplus between 1 January 2002 and 30 September 2003. At that time, Labplus was the only laboratory in the Auckland region measuring 25OHD, and all measurements during this period used the Diasorin radioimmunoassay.[[14]]
Descriptive data (eg, frequencies, proportions, means and standard deviations (SDs)) are presented. For the analyses presenting summary 25OHD data by the time of the year, sine curves were fitted to model the seasonal variation (25OHD=a+b*sin(2Π/365*day of year)+c*cos(2Π/365*day of year)). All analyses were conducted with the R software package (R 3.5.1, 2019, R Foundation for Statistical Computing, Vienna, Austria).
Results
Figure 1A shows that the number of colecalciferol prescriptions increased from about 6,000 per month in early 2003 to about 107,000 per month by late 2019. Translated to yearly values, there was a 14-fold increase in annual prescriptions, from 86,295 in 2003 to 1,215,507 in 2019. Assuming an average cost of $1 per prescription for colecalciferol, this equates to an increase in the cost of supplementation from <$100,000 per year to >$1.2 million per year, and this ignores the cost to the patient of any prescription charges (currently $5 per prescription for individuals >13 years without other exemptions) and costs from doctor and pharmacy visits to obtain the prescription.
Figure 1B shows the annual prevalence of hospital admissions in New Zealand for rickets, osteomalacia and unspecified vitamin D deficiency. The total number of admissions per year for these three conditions ranged between 10 and 20 with no obvious change in the number of admissions per year for any condition over time.
Figure 1: (A) The number of prescriptions per month for vitamin D in New Zealand. (B) The number of hospital admissions per year for osteomalacia, rickets and unspecified vitamin D deficiency.
Figure 2 shows the rates of 25OHD measurements in the Auckland region between 2009 and 2019, along with the distribution of 25OHD results during this period. Two striking features in Figure 2 are the decrease in 25OHD concentrations in 2010 and the decrease in tests after 2012. In November 2009, there was a re-standardisation of the Roche assay used by Labplus, which led to results that were about 20% lower than previously. This explains the dramatic decrease in mean 25OHD in 2010. In 2012, ADHB introduced restrictions on 25OHD requests, which led to about a five-fold decrease in the number of tests per year. Despite the introduction of these restrictions, mean 25OHD remained stable after 2012, at approximately 70nmol/L each year (Figure 2C). Likewise, after 2012 the proportion of individuals with 25OHD <25nmol/L was low and stable (range 7.5%–12.5%); only approximately one third of individuals had 25OHD <50nmol/L (range 30%–35%); and 40%–50% had 25OHD >75nmol/L (Figure 2D).
Figure 2: (A) The distribution of 25-hydroxyvitamin D (25OHD) results between 2009 and 2019. The black bars indicate results that were below the lower limit or above the higher limit of detection. (B) The number of 25OHD tests by year. (C) The mean (SD) 25OHD by year. (D) The proportion of 25OHD <25, <50 or <75nmol/L by year.
The mean (55nmol/L) and median (53nmol/L) 25OHD were lower, and the proportions of individuals with 25OHD <50nmol/L and <75nmol/L were larger, in the earlier (2002–2003) compared to the later time-period (Figure 3). Similarly, the proportion with 25OHD <25nmol/L was higher in the earlier time-period. Figure 4 shows some loss of seasonal variation of 25OHD during the winter months in the later time-period. In 2002–2003, the mean 25OHD throughout the year closely followed a sine curve (Figure 4C), and, as expected, the proportions of 25OHD <25nmol/L and 25–50nmol/L were lower in summer and higher in winter, whereas the proportions of 25OHD 50–75nmol/L and >75nmol/L were higher in summer and lower in winter (Figure 4D). In contrast, in 2009–2019 there was little variation in mean 25OHD during the winter, spring and early summer months (Figure 4A): in weeks 1–4 (January) and 26–52 (end of June till December), the weekly mean 25OHD was between 57nmol/L and 65nmol/L. Reflecting the different seasonal variations during these weeks between the two time-periods, the variance of weekly mean 25OHD during these time-periods was smaller in 2009–2019 (4.4nmol/L) than in 2002–2003 (29nmol/L, P<0.001, F test). Likewise, there was less seasonal variation in the monthly proportions of individuals in each subgroup defined by 25OHD compared to the 2002–2003 period. In particular, there was very little variation in these proportions between July and January (Figure 4B).
Figure 3: The distribution of 25-hydroxyvitamin D (25OHD) results between 2002 and 2003.
Figure 4: (A) Mean (SD) 25-hydroxyvitamin D (25OHD) results by week of the year (January 1 = week 1) between 2009 and 2019 together with a sine curve line of best fit (dashed line). For comparison, the mean (SD) results from 2002–2003 (Figure 4C) are superimposed (open circles). (C) As for Figure 4A, but results from 2002–2003. (B) The proportions of measurements in each month for 2009–2019 grouped by 25OHD result (<25, 25–50, 50–75 or ≥75nmol/L). (D) The proportions of measurements in each month for 2002–2003 grouped by 25OHD result (<25, 25–50, 50–75 or ≥75nmol/L).
Discussion
Despite no change in guidance, vitamin D supplementation in New Zealand has increased dramatically over the last two decades and now exceeds 1.2 million prescriptions each year. Even with this very large increase, there is no evidence that the prevalence of the consequences of severe vitamin D deficiency, rickets and osteomalacia have changed over time. Fewer than 20 hospital admissions per year occur for these conditions or unspecified vitamin D deficiency. Between the two different time-periods (2002–2003 and 2009–2019), 25OHD concentrations increased; the proportions of measurements with 25OHD >50nmol/L and >75nmol/L grew and the proportions with 25OHD <25nmol/L shrank; and seasonal variation in 25OHD, particularly during the winter months, diminished. It seems most likely that the differences between the two time-periods are largely due to the increase in vitamin D supplementation from the first to second time-period. Since 2009, vitamin D measurements have mostly identified individuals without low vitamin D status: 40%–50% of 25OHD measurements were >75nmol/L, 65%–70% were >50nmol/L and only about 10% were <25nmol/L. Particularly noteworthy is that, even after restrictions for measuring 25OHD were introduced, the distribution of 25OHD results changed only a little, and there were no subsequent changes in proportions of results with 25OHD <25nmol/L.
Collectively, these findings suggest that the supplementation of vitamin D in New Zealand needs to change. Although vitamin D supplements are inexpensive to prescribe to an individual, their widespread use creates substantial costs for the health system and individual patients, and there is no clear clinical benefit from this expenditure. Adding to this concern is that, despite widespread supplementation, osteomalacia and rickets persist at a low prevalence, and vitamin D testing is still not targeting individuals at high risk of vitamin D deficiency.
Rickets and osteomalacia caused by vitamin D deficiency are both preventable. About two thirds of cases of osteomalacia in Auckland occur in the community setting,[[11]] suggesting that there may be still about 10 cases per year of osteomalacia in New Zealand, despite widespread supplementation. Two publications have reported data on rickets due to vitamin D deficiency in New Zealand. In 1998, 18 children <5y with rickets due to vitamin D deficiency and 25OHD measurements <25nmol/L were identified in Auckland from hospital notes.[[15]] Although not explicitly stated, given the severity of their symptoms, all these cases likely had hospital care. A survey of New Zealand paediatricians between 2010 and 2013 identified 58 cases of rickets over 36 months in children <15 years.[[16]] Again, the number of hospitalisations was not reported, but based on the reported symptoms, it is likely the majority had hospital care. The approximate corresponding number of cases of rickets in this time-period, given the hospital discharge data, was 15, which suggests that the total number of cases of rickets in New Zealand is likely to be about four times the numbers generated from discharge coding. This suggests an ongoing rate of approximately 20 cases each year. The occurrence of 30 cases per year of these two preventable illnesses, despite annual vitamin D prescriptions increasing and exceeding 1.2 million in 2019, supports the view that different approaches to those currently being undertaken are required. Examples would include education programmes for high-risk groups, targeted supplementation programmes or food fortification.[[17]]
Vitamin D supplementation is widespread, even though the risk of rickets and osteomalacia is very low (and not being eradicated). So why are New Zealand practitioners increasingly prescribing vitamin D supplements? In the recent past, vitamin D has been promoted for the prevention of falls[[18]] and, in combination with calcium supplementation, for the prevention of fractures.[[19]] However, recent clinical trials have not found evidence that vitamin D (without calcium supplements) improves bone density[[4,20]] or prevents falls and fractures[[4]] or other extra-skeletal conditions[[3,21–24]] in populations with vitamin D insufficiency or sufficiency. Calcium supplementation is no longer recommended for fracture prevention because the risks outweigh the benefits.[[25–28]] This has led to changes in recommendations, such that vitamin D is no longer recommended for the prevention of falls or fractures.[[28,29]] If this guidance were followed and supplementation given only to individuals at high risk of osteomalacia or rickets or with specific medical indications,[[12]] it is likely that supplementation rates would decrease markedly without any harm arising, thereby producing a substantial saving to the health system.
There are several lines of evidence from randomised controlled clinical trials that allow the strong conclusion to be drawn that vitamin D supplementation of cohorts with baseline 25OHD >25nmol/L does not improve health outcomes. Firstly, meta-analyses of 81 trials show no effect from vitamin D on falls, total or hip fracture or bone density, and the majority of trials have been conducted in cohorts with baseline 25OHD between 25nmol/L and 50nmol/L (57%) or >50nmol/L (42%).[[4]] Secondly, in trials that report subgroup analyses by individual baseline 25OHD, vitamin D had no effect on falls, fractures or bone density in subgroups with lower baseline 25OHD, or no difference in effect from the subgroup with higher 25OHD.[[4]] Thirdly, when trials are grouped by their mean baseline 25OHD, there is no difference in effect from vitamin D between subgroups with lower and higher baseline 25OHD and/or no effect from vitamin D on falls, fractures or bone density in the subgroup with lower 25OHD.[[4]] Fourthly, there is no consistent evidence of non-musculoskeletal effects from vitamin D.[[3,21–24]] For the situation where cohorts have baseline 25OHD <25nmol/L, few trials have been carried out: before 2016, only 12 such trials had been reported with clinical endpoints, and eight of these had neutral outcomes.[[30]] Thus, for such populations there is insufficient evidence to draw conclusions regarding the effects of vitamin D supplementation, but individuals at high risk of osteomalacia or rickets should receive vitamin D supplements, as these conditions are readily preventable.
Vitamin D testing decreased by about 75% in Auckland following the introduction of specific restrictions by the testing laboratory. However, even with those restrictions, 25OHD tests still largely identify vitamin D sufficient individuals, with consistently only 8%–12% of test results being <25nmol/L. This suggests that further restrictions could be safely introduced to encourage appropriate testing of individuals at high risk of vitamin D deficiency. As vitamin D supplementation is no longer routinely recommended in the management of osteoporosis, that criterion should be removed from testing indications.
A similar study undertaken in the United Kingdom also found increasing rates of vitamin D supplementation and testing, but still no decline in rates of hospital admissions for osteomalacia, rickets and undefined vitamin D deficiency.[[17]] To our knowledge, studies from other countries that address all these issues have not been reported.
An important limitation to these analyses is the change in population. The population of New Zealand increased in size by about 25% between 2003 and 2019. This change was not factored in any analyses. However, the size of the increase in prescriptions (14-fold) is much greater than the increase in population (1.25-fold), and the relatively few hospital admissions each year related to osteomalacia, rickets and unspecified vitamin D deficiency means that even random fluctuations of one or two cases a year are similar to or greater than the predicted effect of the increasing population size.
In summary, vitamin D supplementation is widespread and increasing steadily, but the conditions it is targeting, osteomalacia and rickets, persist at low rates. Likewise, vitamin D testing is frequently being undertaken in individuals at low risk of vitamin D deficiency. Taken together, this suggests that there is unnecessary testing and overtreatment and that vitamin D guidance and practice in New Zealand needs to change.
Summary
Abstract
Aim
Severe prolonged vitamin D deficiency can cause rickets or osteomalacia. Both can be prevented by sunshine exposure or vitamin D supplementation. Although New Zealand guidance does not recommend vitamin D supplementation for the general population, it can be considered for individuals at risk of vitamin D deficiency. Routine measurement of 25-hydroxyvitamin D (25OHD) is also considered unnecessary.
Method
We investigated the rates of vitamin D supplementation, rickets and osteomalacia in New Zealand, and of 25OHD results in Auckland, over the last two decades.
Results
Vitamin D prescriptions increased 14-fold, from 86,295/year to 1,215,507/year, between 2003 and 2019, with medication costs alone in 2019 being >$1 million. Despite these changes, the annual prevalence of hospital admissions for rickets, osteomalacia and unspecified vitamin D deficiency remained low and stable (10–20/year). 25OHD concentrations increased between 2002 and 2003 and between 2009 and 2019, and in the later time-period, 25OHD tests mainly identified individuals without vitamin D deficiency (40–50% >75nmol/L, 65–70% >50nmol/L and only 7–12.5% <25nmol/L).
Conclusion
Osteomalacia and rickets persist at low rates despite widespread, increasingly costly vitamin D supplementation and testing, which largely identifies individuals without vitamin D deficiency. These results suggest that vitamin D guidance and practice in New Zealand should change.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1) WebMD [Internet]. Vitamin D: Vital Role in Your Health; [cited 2019 Nov 1]. Available from: https://www.webmd.com/food-recipes/features/vitamin-d-vital-role-in-your-health#1
2) Guardian [Internet]. Top UK scientist urges people to take vitamin D supplements; [cited 2019 Nov 1]. Available from: https://www.theguardian.com/society/2019/may/26/top-uk-scientist-urges-people-to-take-vitamin-d-supplements
3) Bolland MJ, Avenell A, Grey A. Should adults take vitamin D supplements to prevent disease? BMJ. 2016;355:i6201.
4) Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol. 2018;6:847-58.
5) Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019;40:1109-51.
6) Giustina A, Adler RA, Binkley N, Bouillon R, Ebeling PR, Lazaretti-Castro M, et al. Controversies in Vitamin D: Summary Statement From an International Conference. J Clin Endocrinol Metab. 2019;104:234-40.
7) 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.
8) Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int. 2005;16:713-6.
9) Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18-28.
10) Scientific Advisory Committee on Nutrition (SACN). Vitamin D and Health. London: TSO; 2016.
11) Bolland MJ, Avenell A, Grey A. Prevalence of biochemical osteomalacia in adults undergoing vitamin D testing. Clin Endocrinol (Oxf). 2021;95:74-83.
12) Ministry of Health and Cancer Society of New Zealand. Consensus Statement on Vitamin D and Sun Exposure in New Zealand. Wellington: Ministry of Health; 2012.
13) Bolland MJ, Grey A, Davidson JS, Cundy T, Reid IR. Should measurement of vitamin D and treatment of vitamin D insufficiency be routine in New Zealand? N Z Med J. 2012;125:83-91.
14) Bolland MJ, Chiu WW, Davidson JS, Grey A, Bacon C, Gamble GD, et al. The effects of seasonal variation of 25-hydroxyvitamin D on diagnosis of vitamin D insufficiency. N Z Med J. 2008;121:63-74.
15) Blok BH, Grant CC, McNeil AR, Reid IR. Characteristics of children with florid vitamin D deficient rickets in the Auckland region in 1998. N Z Med J. 2000;113:374-6.
16) Wheeler BJ, Dickson NP, Houghton LA, Ward LM, Taylor BJ. Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study. Aust N Z J Public Health. 2015;39:380-3.
17) Bolland MJ, Avenell A, Smith K, Witham MD, Grey A. Vitamin D supplementation and testing in the UK: costly but ineffective? BMJ. 2021;372:n484.
18) Michael YL, Whitlock EP, Lin JS, Fu R, O'Connor EA, Gold R. Primary care-relevant interventions to prevent falling in older adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;153:815-25.
19) 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:CD000227.
20) Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet. 2014;383:146-55.
21) Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2:76-89.
22) 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;2:307-20.
23) Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.
24) Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017;5:986-1004.
25) Bolland MJ, Avenell A, Baron JA, Grey A, Maclennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.
26) Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.
27) Bolland MJ, Leung W, Tai V, Bastin S, Gamble GD, Grey A, et al. Calcium intake and risk of fracture: systematic review. BMJ. 2015;351:h4580.
28) U. S. Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, et al. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319:1592-9.
29) U. S. Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, et al. Interventions to Prevent Falls in Community-Dwelling Older Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319:1696-704.
30) Bolland MJ, Grey A, Avenell A. Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation. BMC Med Res Methodol. 2018;18:101.
For the PDF of this article,
contact nzmj@nzma.org.nz
Vitamin D deficiency, supplementation and testing: have we got it right in New Zealand?
View Article PDF
Severe prolonged vitamin D deficiency can cause rickets in children or osteomalacia in adults. Both are easily prevented by sunshine exposure and prevented or treated with vitamin D supplementation. Beyond these uncontroversial issues, vitamin D supplementation remains surprisingly topical. In the media, it is often portrayed enthusiastically as a cure for a wide range of illnesses,[[1,2]] whereas in scientific literature it is a subject of much debate.[[3–6]] For example, definitions of vitamin D deficiency range from 25-hydroxyvitamin D (25OHD) <25nmol/L to <100nmol/L,[[7–10]] even though the prevalence of biochemical osteomalacia is very low when 25OHD is <25nmol/L.[[11]]
New Zealand guidance on vitamin D supplementation and testing has been consistent for many years: supplementation is not recommended for the general population, but it can be considered for individuals from groups at risk of vitamin D deficiency.[[12]] At-risk groups are identified in this guidance: people with deeply pigmented skin, especially those who wear full-body coverage clothing; people who actively avoid sun exposure; people with low mobility who are frail or housebound; people in southern regions who spend a limited amount of time outdoors; and people with certain medical disorders (eg, kidney failure, malabsorption syndromes).[[12]] It is recognised that, because vitamin D testing costs considerably more (~$30 for gold standard LC-MS/MS assay costs alone) than vitamin D supplementation ($0.25/monthly tablet), supplementation for high-risk individuals should be undertaken without testing. Measurement of 25OHD, the accepted test for assessing vitamin D status, is only indicated for investigation of clinically suspected and symptomatic severe vitamin D deficiency, some biochemical abnormalities (eg, hypocalcaemia and hypophosphataemia) and certain metabolic bone disorders.[[12]]
Despite the unchanged guidance, vitamin D supplementation has been rising. We sought to quantify changes in prescriptions for vitamin D (chemical ID: 1187, name: colecalciferol) in recent years, and whether there have been any corresponding changes in the prevalence of the consequences of severe vitamin D deficiency, rickets and osteomalacia or changes in testing for 25OHD. We have also compared 25OHD results from 2009–2019 with previously published results from 2002–2003. We then considered whether the temporal patterns identified have implications for current vitamin D guidance.
Methods
We obtained data on prescriptions for colecalciferol in New Zealand from between 2003 to 2019 and data on hospitalisations with ICD-10 discharge codes for osteomalacia (M83), rickets (E55.0) and vitamin D deficiency (E55) for 2000–2018 from Stats NZ. We obtained deidentified data from Testsafe, the Auckland regional biochemistry database that includes results from community and hospital patients, for all measurements of 25OHD between 1 January 2009 and 31 December 2019.[[11]] Several different 25OHD assays in different laboratories were used during this time-period, including the Diasorin radioimmunoassay, Diasorin Liaison and immunoassays on the Roche, Siemens and Abbot platforms. However, the overwhelming majority of tests during this period were done at one laboratory, Labplus, largely using the Roche assay. In 2012, Auckland District Health Board (ADHB) introduced restrictions on 25OHD requests at Labplus because of rising numbers of requests and costs.[[13]] These restrictions included requests being limited to certain specialists; to individuals from high risk groups for rickets/osteomalacia; for investigation of rickets/osteomalacia; for disorders of calcium and phosphate metabolism, osteoporosis or other metabolic bone disease; to patients with chronic renal failure and renal transplant recipients; and to children. Tests requested for other reasons were declined.
We compared the results from 2009–2019 with earlier results from Labplus between 1 January 2002 and 30 September 2003. At that time, Labplus was the only laboratory in the Auckland region measuring 25OHD, and all measurements during this period used the Diasorin radioimmunoassay.[[14]]
Descriptive data (eg, frequencies, proportions, means and standard deviations (SDs)) are presented. For the analyses presenting summary 25OHD data by the time of the year, sine curves were fitted to model the seasonal variation (25OHD=a+b*sin(2Π/365*day of year)+c*cos(2Π/365*day of year)). All analyses were conducted with the R software package (R 3.5.1, 2019, R Foundation for Statistical Computing, Vienna, Austria).
Results
Figure 1A shows that the number of colecalciferol prescriptions increased from about 6,000 per month in early 2003 to about 107,000 per month by late 2019. Translated to yearly values, there was a 14-fold increase in annual prescriptions, from 86,295 in 2003 to 1,215,507 in 2019. Assuming an average cost of $1 per prescription for colecalciferol, this equates to an increase in the cost of supplementation from <$100,000 per year to >$1.2 million per year, and this ignores the cost to the patient of any prescription charges (currently $5 per prescription for individuals >13 years without other exemptions) and costs from doctor and pharmacy visits to obtain the prescription.
Figure 1B shows the annual prevalence of hospital admissions in New Zealand for rickets, osteomalacia and unspecified vitamin D deficiency. The total number of admissions per year for these three conditions ranged between 10 and 20 with no obvious change in the number of admissions per year for any condition over time.
Figure 1: (A) The number of prescriptions per month for vitamin D in New Zealand. (B) The number of hospital admissions per year for osteomalacia, rickets and unspecified vitamin D deficiency.
Figure 2 shows the rates of 25OHD measurements in the Auckland region between 2009 and 2019, along with the distribution of 25OHD results during this period. Two striking features in Figure 2 are the decrease in 25OHD concentrations in 2010 and the decrease in tests after 2012. In November 2009, there was a re-standardisation of the Roche assay used by Labplus, which led to results that were about 20% lower than previously. This explains the dramatic decrease in mean 25OHD in 2010. In 2012, ADHB introduced restrictions on 25OHD requests, which led to about a five-fold decrease in the number of tests per year. Despite the introduction of these restrictions, mean 25OHD remained stable after 2012, at approximately 70nmol/L each year (Figure 2C). Likewise, after 2012 the proportion of individuals with 25OHD <25nmol/L was low and stable (range 7.5%–12.5%); only approximately one third of individuals had 25OHD <50nmol/L (range 30%–35%); and 40%–50% had 25OHD >75nmol/L (Figure 2D).
Figure 2: (A) The distribution of 25-hydroxyvitamin D (25OHD) results between 2009 and 2019. The black bars indicate results that were below the lower limit or above the higher limit of detection. (B) The number of 25OHD tests by year. (C) The mean (SD) 25OHD by year. (D) The proportion of 25OHD <25, <50 or <75nmol/L by year.
The mean (55nmol/L) and median (53nmol/L) 25OHD were lower, and the proportions of individuals with 25OHD <50nmol/L and <75nmol/L were larger, in the earlier (2002–2003) compared to the later time-period (Figure 3). Similarly, the proportion with 25OHD <25nmol/L was higher in the earlier time-period. Figure 4 shows some loss of seasonal variation of 25OHD during the winter months in the later time-period. In 2002–2003, the mean 25OHD throughout the year closely followed a sine curve (Figure 4C), and, as expected, the proportions of 25OHD <25nmol/L and 25–50nmol/L were lower in summer and higher in winter, whereas the proportions of 25OHD 50–75nmol/L and >75nmol/L were higher in summer and lower in winter (Figure 4D). In contrast, in 2009–2019 there was little variation in mean 25OHD during the winter, spring and early summer months (Figure 4A): in weeks 1–4 (January) and 26–52 (end of June till December), the weekly mean 25OHD was between 57nmol/L and 65nmol/L. Reflecting the different seasonal variations during these weeks between the two time-periods, the variance of weekly mean 25OHD during these time-periods was smaller in 2009–2019 (4.4nmol/L) than in 2002–2003 (29nmol/L, P<0.001, F test). Likewise, there was less seasonal variation in the monthly proportions of individuals in each subgroup defined by 25OHD compared to the 2002–2003 period. In particular, there was very little variation in these proportions between July and January (Figure 4B).
Figure 3: The distribution of 25-hydroxyvitamin D (25OHD) results between 2002 and 2003.
Figure 4: (A) Mean (SD) 25-hydroxyvitamin D (25OHD) results by week of the year (January 1 = week 1) between 2009 and 2019 together with a sine curve line of best fit (dashed line). For comparison, the mean (SD) results from 2002–2003 (Figure 4C) are superimposed (open circles). (C) As for Figure 4A, but results from 2002–2003. (B) The proportions of measurements in each month for 2009–2019 grouped by 25OHD result (<25, 25–50, 50–75 or ≥75nmol/L). (D) The proportions of measurements in each month for 2002–2003 grouped by 25OHD result (<25, 25–50, 50–75 or ≥75nmol/L).
Discussion
Despite no change in guidance, vitamin D supplementation in New Zealand has increased dramatically over the last two decades and now exceeds 1.2 million prescriptions each year. Even with this very large increase, there is no evidence that the prevalence of the consequences of severe vitamin D deficiency, rickets and osteomalacia have changed over time. Fewer than 20 hospital admissions per year occur for these conditions or unspecified vitamin D deficiency. Between the two different time-periods (2002–2003 and 2009–2019), 25OHD concentrations increased; the proportions of measurements with 25OHD >50nmol/L and >75nmol/L grew and the proportions with 25OHD <25nmol/L shrank; and seasonal variation in 25OHD, particularly during the winter months, diminished. It seems most likely that the differences between the two time-periods are largely due to the increase in vitamin D supplementation from the first to second time-period. Since 2009, vitamin D measurements have mostly identified individuals without low vitamin D status: 40%–50% of 25OHD measurements were >75nmol/L, 65%–70% were >50nmol/L and only about 10% were <25nmol/L. Particularly noteworthy is that, even after restrictions for measuring 25OHD were introduced, the distribution of 25OHD results changed only a little, and there were no subsequent changes in proportions of results with 25OHD <25nmol/L.
Collectively, these findings suggest that the supplementation of vitamin D in New Zealand needs to change. Although vitamin D supplements are inexpensive to prescribe to an individual, their widespread use creates substantial costs for the health system and individual patients, and there is no clear clinical benefit from this expenditure. Adding to this concern is that, despite widespread supplementation, osteomalacia and rickets persist at a low prevalence, and vitamin D testing is still not targeting individuals at high risk of vitamin D deficiency.
Rickets and osteomalacia caused by vitamin D deficiency are both preventable. About two thirds of cases of osteomalacia in Auckland occur in the community setting,[[11]] suggesting that there may be still about 10 cases per year of osteomalacia in New Zealand, despite widespread supplementation. Two publications have reported data on rickets due to vitamin D deficiency in New Zealand. In 1998, 18 children <5y with rickets due to vitamin D deficiency and 25OHD measurements <25nmol/L were identified in Auckland from hospital notes.[[15]] Although not explicitly stated, given the severity of their symptoms, all these cases likely had hospital care. A survey of New Zealand paediatricians between 2010 and 2013 identified 58 cases of rickets over 36 months in children <15 years.[[16]] Again, the number of hospitalisations was not reported, but based on the reported symptoms, it is likely the majority had hospital care. The approximate corresponding number of cases of rickets in this time-period, given the hospital discharge data, was 15, which suggests that the total number of cases of rickets in New Zealand is likely to be about four times the numbers generated from discharge coding. This suggests an ongoing rate of approximately 20 cases each year. The occurrence of 30 cases per year of these two preventable illnesses, despite annual vitamin D prescriptions increasing and exceeding 1.2 million in 2019, supports the view that different approaches to those currently being undertaken are required. Examples would include education programmes for high-risk groups, targeted supplementation programmes or food fortification.[[17]]
Vitamin D supplementation is widespread, even though the risk of rickets and osteomalacia is very low (and not being eradicated). So why are New Zealand practitioners increasingly prescribing vitamin D supplements? In the recent past, vitamin D has been promoted for the prevention of falls[[18]] and, in combination with calcium supplementation, for the prevention of fractures.[[19]] However, recent clinical trials have not found evidence that vitamin D (without calcium supplements) improves bone density[[4,20]] or prevents falls and fractures[[4]] or other extra-skeletal conditions[[3,21–24]] in populations with vitamin D insufficiency or sufficiency. Calcium supplementation is no longer recommended for fracture prevention because the risks outweigh the benefits.[[25–28]] This has led to changes in recommendations, such that vitamin D is no longer recommended for the prevention of falls or fractures.[[28,29]] If this guidance were followed and supplementation given only to individuals at high risk of osteomalacia or rickets or with specific medical indications,[[12]] it is likely that supplementation rates would decrease markedly without any harm arising, thereby producing a substantial saving to the health system.
There are several lines of evidence from randomised controlled clinical trials that allow the strong conclusion to be drawn that vitamin D supplementation of cohorts with baseline 25OHD >25nmol/L does not improve health outcomes. Firstly, meta-analyses of 81 trials show no effect from vitamin D on falls, total or hip fracture or bone density, and the majority of trials have been conducted in cohorts with baseline 25OHD between 25nmol/L and 50nmol/L (57%) or >50nmol/L (42%).[[4]] Secondly, in trials that report subgroup analyses by individual baseline 25OHD, vitamin D had no effect on falls, fractures or bone density in subgroups with lower baseline 25OHD, or no difference in effect from the subgroup with higher 25OHD.[[4]] Thirdly, when trials are grouped by their mean baseline 25OHD, there is no difference in effect from vitamin D between subgroups with lower and higher baseline 25OHD and/or no effect from vitamin D on falls, fractures or bone density in the subgroup with lower 25OHD.[[4]] Fourthly, there is no consistent evidence of non-musculoskeletal effects from vitamin D.[[3,21–24]] For the situation where cohorts have baseline 25OHD <25nmol/L, few trials have been carried out: before 2016, only 12 such trials had been reported with clinical endpoints, and eight of these had neutral outcomes.[[30]] Thus, for such populations there is insufficient evidence to draw conclusions regarding the effects of vitamin D supplementation, but individuals at high risk of osteomalacia or rickets should receive vitamin D supplements, as these conditions are readily preventable.
Vitamin D testing decreased by about 75% in Auckland following the introduction of specific restrictions by the testing laboratory. However, even with those restrictions, 25OHD tests still largely identify vitamin D sufficient individuals, with consistently only 8%–12% of test results being <25nmol/L. This suggests that further restrictions could be safely introduced to encourage appropriate testing of individuals at high risk of vitamin D deficiency. As vitamin D supplementation is no longer routinely recommended in the management of osteoporosis, that criterion should be removed from testing indications.
A similar study undertaken in the United Kingdom also found increasing rates of vitamin D supplementation and testing, but still no decline in rates of hospital admissions for osteomalacia, rickets and undefined vitamin D deficiency.[[17]] To our knowledge, studies from other countries that address all these issues have not been reported.
An important limitation to these analyses is the change in population. The population of New Zealand increased in size by about 25% between 2003 and 2019. This change was not factored in any analyses. However, the size of the increase in prescriptions (14-fold) is much greater than the increase in population (1.25-fold), and the relatively few hospital admissions each year related to osteomalacia, rickets and unspecified vitamin D deficiency means that even random fluctuations of one or two cases a year are similar to or greater than the predicted effect of the increasing population size.
In summary, vitamin D supplementation is widespread and increasing steadily, but the conditions it is targeting, osteomalacia and rickets, persist at low rates. Likewise, vitamin D testing is frequently being undertaken in individuals at low risk of vitamin D deficiency. Taken together, this suggests that there is unnecessary testing and overtreatment and that vitamin D guidance and practice in New Zealand needs to change.
Summary
Abstract
Aim
Severe prolonged vitamin D deficiency can cause rickets or osteomalacia. Both can be prevented by sunshine exposure or vitamin D supplementation. Although New Zealand guidance does not recommend vitamin D supplementation for the general population, it can be considered for individuals at risk of vitamin D deficiency. Routine measurement of 25-hydroxyvitamin D (25OHD) is also considered unnecessary.
Method
We investigated the rates of vitamin D supplementation, rickets and osteomalacia in New Zealand, and of 25OHD results in Auckland, over the last two decades.
Results
Vitamin D prescriptions increased 14-fold, from 86,295/year to 1,215,507/year, between 2003 and 2019, with medication costs alone in 2019 being >$1 million. Despite these changes, the annual prevalence of hospital admissions for rickets, osteomalacia and unspecified vitamin D deficiency remained low and stable (10–20/year). 25OHD concentrations increased between 2002 and 2003 and between 2009 and 2019, and in the later time-period, 25OHD tests mainly identified individuals without vitamin D deficiency (40–50% >75nmol/L, 65–70% >50nmol/L and only 7–12.5% <25nmol/L).
Conclusion
Osteomalacia and rickets persist at low rates despite widespread, increasingly costly vitamin D supplementation and testing, which largely identifies individuals without vitamin D deficiency. These results suggest that vitamin D guidance and practice in New Zealand should change.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1) WebMD [Internet]. Vitamin D: Vital Role in Your Health; [cited 2019 Nov 1]. Available from: https://www.webmd.com/food-recipes/features/vitamin-d-vital-role-in-your-health#1
2) Guardian [Internet]. Top UK scientist urges people to take vitamin D supplements; [cited 2019 Nov 1]. Available from: https://www.theguardian.com/society/2019/may/26/top-uk-scientist-urges-people-to-take-vitamin-d-supplements
3) Bolland MJ, Avenell A, Grey A. Should adults take vitamin D supplements to prevent disease? BMJ. 2016;355:i6201.
4) Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol. 2018;6:847-58.
5) Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019;40:1109-51.
6) Giustina A, Adler RA, Binkley N, Bouillon R, Ebeling PR, Lazaretti-Castro M, et al. Controversies in Vitamin D: Summary Statement From an International Conference. J Clin Endocrinol Metab. 2019;104:234-40.
7) 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.
8) Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int. 2005;16:713-6.
9) Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18-28.
10) Scientific Advisory Committee on Nutrition (SACN). Vitamin D and Health. London: TSO; 2016.
11) Bolland MJ, Avenell A, Grey A. Prevalence of biochemical osteomalacia in adults undergoing vitamin D testing. Clin Endocrinol (Oxf). 2021;95:74-83.
12) Ministry of Health and Cancer Society of New Zealand. Consensus Statement on Vitamin D and Sun Exposure in New Zealand. Wellington: Ministry of Health; 2012.
13) Bolland MJ, Grey A, Davidson JS, Cundy T, Reid IR. Should measurement of vitamin D and treatment of vitamin D insufficiency be routine in New Zealand? N Z Med J. 2012;125:83-91.
14) Bolland MJ, Chiu WW, Davidson JS, Grey A, Bacon C, Gamble GD, et al. The effects of seasonal variation of 25-hydroxyvitamin D on diagnosis of vitamin D insufficiency. N Z Med J. 2008;121:63-74.
15) Blok BH, Grant CC, McNeil AR, Reid IR. Characteristics of children with florid vitamin D deficient rickets in the Auckland region in 1998. N Z Med J. 2000;113:374-6.
16) Wheeler BJ, Dickson NP, Houghton LA, Ward LM, Taylor BJ. Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study. Aust N Z J Public Health. 2015;39:380-3.
17) Bolland MJ, Avenell A, Smith K, Witham MD, Grey A. Vitamin D supplementation and testing in the UK: costly but ineffective? BMJ. 2021;372:n484.
18) Michael YL, Whitlock EP, Lin JS, Fu R, O'Connor EA, Gold R. Primary care-relevant interventions to prevent falling in older adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;153:815-25.
19) 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:CD000227.
20) Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet. 2014;383:146-55.
21) Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2:76-89.
22) 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;2:307-20.
23) Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.
24) Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017;5:986-1004.
25) Bolland MJ, Avenell A, Baron JA, Grey A, Maclennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.
26) Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.
27) Bolland MJ, Leung W, Tai V, Bastin S, Gamble GD, Grey A, et al. Calcium intake and risk of fracture: systematic review. BMJ. 2015;351:h4580.
28) U. S. Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, et al. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319:1592-9.
29) U. S. Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, et al. Interventions to Prevent Falls in Community-Dwelling Older Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319:1696-704.
30) Bolland MJ, Grey A, Avenell A. Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation. BMC Med Res Methodol. 2018;18:101.
For the PDF of this article,
contact nzmj@nzma.org.nz
Vitamin D deficiency, supplementation and testing: have we got it right in New Zealand?
View Article PDF
Severe prolonged vitamin D deficiency can cause rickets in children or osteomalacia in adults. Both are easily prevented by sunshine exposure and prevented or treated with vitamin D supplementation. Beyond these uncontroversial issues, vitamin D supplementation remains surprisingly topical. In the media, it is often portrayed enthusiastically as a cure for a wide range of illnesses,[[1,2]] whereas in scientific literature it is a subject of much debate.[[3–6]] For example, definitions of vitamin D deficiency range from 25-hydroxyvitamin D (25OHD) <25nmol/L to <100nmol/L,[[7–10]] even though the prevalence of biochemical osteomalacia is very low when 25OHD is <25nmol/L.[[11]]
New Zealand guidance on vitamin D supplementation and testing has been consistent for many years: supplementation is not recommended for the general population, but it can be considered for individuals from groups at risk of vitamin D deficiency.[[12]] At-risk groups are identified in this guidance: people with deeply pigmented skin, especially those who wear full-body coverage clothing; people who actively avoid sun exposure; people with low mobility who are frail or housebound; people in southern regions who spend a limited amount of time outdoors; and people with certain medical disorders (eg, kidney failure, malabsorption syndromes).[[12]] It is recognised that, because vitamin D testing costs considerably more (~$30 for gold standard LC-MS/MS assay costs alone) than vitamin D supplementation ($0.25/monthly tablet), supplementation for high-risk individuals should be undertaken without testing. Measurement of 25OHD, the accepted test for assessing vitamin D status, is only indicated for investigation of clinically suspected and symptomatic severe vitamin D deficiency, some biochemical abnormalities (eg, hypocalcaemia and hypophosphataemia) and certain metabolic bone disorders.[[12]]
Despite the unchanged guidance, vitamin D supplementation has been rising. We sought to quantify changes in prescriptions for vitamin D (chemical ID: 1187, name: colecalciferol) in recent years, and whether there have been any corresponding changes in the prevalence of the consequences of severe vitamin D deficiency, rickets and osteomalacia or changes in testing for 25OHD. We have also compared 25OHD results from 2009–2019 with previously published results from 2002–2003. We then considered whether the temporal patterns identified have implications for current vitamin D guidance.
Methods
We obtained data on prescriptions for colecalciferol in New Zealand from between 2003 to 2019 and data on hospitalisations with ICD-10 discharge codes for osteomalacia (M83), rickets (E55.0) and vitamin D deficiency (E55) for 2000–2018 from Stats NZ. We obtained deidentified data from Testsafe, the Auckland regional biochemistry database that includes results from community and hospital patients, for all measurements of 25OHD between 1 January 2009 and 31 December 2019.[[11]] Several different 25OHD assays in different laboratories were used during this time-period, including the Diasorin radioimmunoassay, Diasorin Liaison and immunoassays on the Roche, Siemens and Abbot platforms. However, the overwhelming majority of tests during this period were done at one laboratory, Labplus, largely using the Roche assay. In 2012, Auckland District Health Board (ADHB) introduced restrictions on 25OHD requests at Labplus because of rising numbers of requests and costs.[[13]] These restrictions included requests being limited to certain specialists; to individuals from high risk groups for rickets/osteomalacia; for investigation of rickets/osteomalacia; for disorders of calcium and phosphate metabolism, osteoporosis or other metabolic bone disease; to patients with chronic renal failure and renal transplant recipients; and to children. Tests requested for other reasons were declined.
We compared the results from 2009–2019 with earlier results from Labplus between 1 January 2002 and 30 September 2003. At that time, Labplus was the only laboratory in the Auckland region measuring 25OHD, and all measurements during this period used the Diasorin radioimmunoassay.[[14]]
Descriptive data (eg, frequencies, proportions, means and standard deviations (SDs)) are presented. For the analyses presenting summary 25OHD data by the time of the year, sine curves were fitted to model the seasonal variation (25OHD=a+b*sin(2Π/365*day of year)+c*cos(2Π/365*day of year)). All analyses were conducted with the R software package (R 3.5.1, 2019, R Foundation for Statistical Computing, Vienna, Austria).
Results
Figure 1A shows that the number of colecalciferol prescriptions increased from about 6,000 per month in early 2003 to about 107,000 per month by late 2019. Translated to yearly values, there was a 14-fold increase in annual prescriptions, from 86,295 in 2003 to 1,215,507 in 2019. Assuming an average cost of $1 per prescription for colecalciferol, this equates to an increase in the cost of supplementation from <$100,000 per year to >$1.2 million per year, and this ignores the cost to the patient of any prescription charges (currently $5 per prescription for individuals >13 years without other exemptions) and costs from doctor and pharmacy visits to obtain the prescription.
Figure 1B shows the annual prevalence of hospital admissions in New Zealand for rickets, osteomalacia and unspecified vitamin D deficiency. The total number of admissions per year for these three conditions ranged between 10 and 20 with no obvious change in the number of admissions per year for any condition over time.
Figure 1: (A) The number of prescriptions per month for vitamin D in New Zealand. (B) The number of hospital admissions per year for osteomalacia, rickets and unspecified vitamin D deficiency.
Figure 2 shows the rates of 25OHD measurements in the Auckland region between 2009 and 2019, along with the distribution of 25OHD results during this period. Two striking features in Figure 2 are the decrease in 25OHD concentrations in 2010 and the decrease in tests after 2012. In November 2009, there was a re-standardisation of the Roche assay used by Labplus, which led to results that were about 20% lower than previously. This explains the dramatic decrease in mean 25OHD in 2010. In 2012, ADHB introduced restrictions on 25OHD requests, which led to about a five-fold decrease in the number of tests per year. Despite the introduction of these restrictions, mean 25OHD remained stable after 2012, at approximately 70nmol/L each year (Figure 2C). Likewise, after 2012 the proportion of individuals with 25OHD <25nmol/L was low and stable (range 7.5%–12.5%); only approximately one third of individuals had 25OHD <50nmol/L (range 30%–35%); and 40%–50% had 25OHD >75nmol/L (Figure 2D).
Figure 2: (A) The distribution of 25-hydroxyvitamin D (25OHD) results between 2009 and 2019. The black bars indicate results that were below the lower limit or above the higher limit of detection. (B) The number of 25OHD tests by year. (C) The mean (SD) 25OHD by year. (D) The proportion of 25OHD <25, <50 or <75nmol/L by year.
The mean (55nmol/L) and median (53nmol/L) 25OHD were lower, and the proportions of individuals with 25OHD <50nmol/L and <75nmol/L were larger, in the earlier (2002–2003) compared to the later time-period (Figure 3). Similarly, the proportion with 25OHD <25nmol/L was higher in the earlier time-period. Figure 4 shows some loss of seasonal variation of 25OHD during the winter months in the later time-period. In 2002–2003, the mean 25OHD throughout the year closely followed a sine curve (Figure 4C), and, as expected, the proportions of 25OHD <25nmol/L and 25–50nmol/L were lower in summer and higher in winter, whereas the proportions of 25OHD 50–75nmol/L and >75nmol/L were higher in summer and lower in winter (Figure 4D). In contrast, in 2009–2019 there was little variation in mean 25OHD during the winter, spring and early summer months (Figure 4A): in weeks 1–4 (January) and 26–52 (end of June till December), the weekly mean 25OHD was between 57nmol/L and 65nmol/L. Reflecting the different seasonal variations during these weeks between the two time-periods, the variance of weekly mean 25OHD during these time-periods was smaller in 2009–2019 (4.4nmol/L) than in 2002–2003 (29nmol/L, P<0.001, F test). Likewise, there was less seasonal variation in the monthly proportions of individuals in each subgroup defined by 25OHD compared to the 2002–2003 period. In particular, there was very little variation in these proportions between July and January (Figure 4B).
Figure 3: The distribution of 25-hydroxyvitamin D (25OHD) results between 2002 and 2003.
Figure 4: (A) Mean (SD) 25-hydroxyvitamin D (25OHD) results by week of the year (January 1 = week 1) between 2009 and 2019 together with a sine curve line of best fit (dashed line). For comparison, the mean (SD) results from 2002–2003 (Figure 4C) are superimposed (open circles). (C) As for Figure 4A, but results from 2002–2003. (B) The proportions of measurements in each month for 2009–2019 grouped by 25OHD result (<25, 25–50, 50–75 or ≥75nmol/L). (D) The proportions of measurements in each month for 2002–2003 grouped by 25OHD result (<25, 25–50, 50–75 or ≥75nmol/L).
Discussion
Despite no change in guidance, vitamin D supplementation in New Zealand has increased dramatically over the last two decades and now exceeds 1.2 million prescriptions each year. Even with this very large increase, there is no evidence that the prevalence of the consequences of severe vitamin D deficiency, rickets and osteomalacia have changed over time. Fewer than 20 hospital admissions per year occur for these conditions or unspecified vitamin D deficiency. Between the two different time-periods (2002–2003 and 2009–2019), 25OHD concentrations increased; the proportions of measurements with 25OHD >50nmol/L and >75nmol/L grew and the proportions with 25OHD <25nmol/L shrank; and seasonal variation in 25OHD, particularly during the winter months, diminished. It seems most likely that the differences between the two time-periods are largely due to the increase in vitamin D supplementation from the first to second time-period. Since 2009, vitamin D measurements have mostly identified individuals without low vitamin D status: 40%–50% of 25OHD measurements were >75nmol/L, 65%–70% were >50nmol/L and only about 10% were <25nmol/L. Particularly noteworthy is that, even after restrictions for measuring 25OHD were introduced, the distribution of 25OHD results changed only a little, and there were no subsequent changes in proportions of results with 25OHD <25nmol/L.
Collectively, these findings suggest that the supplementation of vitamin D in New Zealand needs to change. Although vitamin D supplements are inexpensive to prescribe to an individual, their widespread use creates substantial costs for the health system and individual patients, and there is no clear clinical benefit from this expenditure. Adding to this concern is that, despite widespread supplementation, osteomalacia and rickets persist at a low prevalence, and vitamin D testing is still not targeting individuals at high risk of vitamin D deficiency.
Rickets and osteomalacia caused by vitamin D deficiency are both preventable. About two thirds of cases of osteomalacia in Auckland occur in the community setting,[[11]] suggesting that there may be still about 10 cases per year of osteomalacia in New Zealand, despite widespread supplementation. Two publications have reported data on rickets due to vitamin D deficiency in New Zealand. In 1998, 18 children <5y with rickets due to vitamin D deficiency and 25OHD measurements <25nmol/L were identified in Auckland from hospital notes.[[15]] Although not explicitly stated, given the severity of their symptoms, all these cases likely had hospital care. A survey of New Zealand paediatricians between 2010 and 2013 identified 58 cases of rickets over 36 months in children <15 years.[[16]] Again, the number of hospitalisations was not reported, but based on the reported symptoms, it is likely the majority had hospital care. The approximate corresponding number of cases of rickets in this time-period, given the hospital discharge data, was 15, which suggests that the total number of cases of rickets in New Zealand is likely to be about four times the numbers generated from discharge coding. This suggests an ongoing rate of approximately 20 cases each year. The occurrence of 30 cases per year of these two preventable illnesses, despite annual vitamin D prescriptions increasing and exceeding 1.2 million in 2019, supports the view that different approaches to those currently being undertaken are required. Examples would include education programmes for high-risk groups, targeted supplementation programmes or food fortification.[[17]]
Vitamin D supplementation is widespread, even though the risk of rickets and osteomalacia is very low (and not being eradicated). So why are New Zealand practitioners increasingly prescribing vitamin D supplements? In the recent past, vitamin D has been promoted for the prevention of falls[[18]] and, in combination with calcium supplementation, for the prevention of fractures.[[19]] However, recent clinical trials have not found evidence that vitamin D (without calcium supplements) improves bone density[[4,20]] or prevents falls and fractures[[4]] or other extra-skeletal conditions[[3,21–24]] in populations with vitamin D insufficiency or sufficiency. Calcium supplementation is no longer recommended for fracture prevention because the risks outweigh the benefits.[[25–28]] This has led to changes in recommendations, such that vitamin D is no longer recommended for the prevention of falls or fractures.[[28,29]] If this guidance were followed and supplementation given only to individuals at high risk of osteomalacia or rickets or with specific medical indications,[[12]] it is likely that supplementation rates would decrease markedly without any harm arising, thereby producing a substantial saving to the health system.
There are several lines of evidence from randomised controlled clinical trials that allow the strong conclusion to be drawn that vitamin D supplementation of cohorts with baseline 25OHD >25nmol/L does not improve health outcomes. Firstly, meta-analyses of 81 trials show no effect from vitamin D on falls, total or hip fracture or bone density, and the majority of trials have been conducted in cohorts with baseline 25OHD between 25nmol/L and 50nmol/L (57%) or >50nmol/L (42%).[[4]] Secondly, in trials that report subgroup analyses by individual baseline 25OHD, vitamin D had no effect on falls, fractures or bone density in subgroups with lower baseline 25OHD, or no difference in effect from the subgroup with higher 25OHD.[[4]] Thirdly, when trials are grouped by their mean baseline 25OHD, there is no difference in effect from vitamin D between subgroups with lower and higher baseline 25OHD and/or no effect from vitamin D on falls, fractures or bone density in the subgroup with lower 25OHD.[[4]] Fourthly, there is no consistent evidence of non-musculoskeletal effects from vitamin D.[[3,21–24]] For the situation where cohorts have baseline 25OHD <25nmol/L, few trials have been carried out: before 2016, only 12 such trials had been reported with clinical endpoints, and eight of these had neutral outcomes.[[30]] Thus, for such populations there is insufficient evidence to draw conclusions regarding the effects of vitamin D supplementation, but individuals at high risk of osteomalacia or rickets should receive vitamin D supplements, as these conditions are readily preventable.
Vitamin D testing decreased by about 75% in Auckland following the introduction of specific restrictions by the testing laboratory. However, even with those restrictions, 25OHD tests still largely identify vitamin D sufficient individuals, with consistently only 8%–12% of test results being <25nmol/L. This suggests that further restrictions could be safely introduced to encourage appropriate testing of individuals at high risk of vitamin D deficiency. As vitamin D supplementation is no longer routinely recommended in the management of osteoporosis, that criterion should be removed from testing indications.
A similar study undertaken in the United Kingdom also found increasing rates of vitamin D supplementation and testing, but still no decline in rates of hospital admissions for osteomalacia, rickets and undefined vitamin D deficiency.[[17]] To our knowledge, studies from other countries that address all these issues have not been reported.
An important limitation to these analyses is the change in population. The population of New Zealand increased in size by about 25% between 2003 and 2019. This change was not factored in any analyses. However, the size of the increase in prescriptions (14-fold) is much greater than the increase in population (1.25-fold), and the relatively few hospital admissions each year related to osteomalacia, rickets and unspecified vitamin D deficiency means that even random fluctuations of one or two cases a year are similar to or greater than the predicted effect of the increasing population size.
In summary, vitamin D supplementation is widespread and increasing steadily, but the conditions it is targeting, osteomalacia and rickets, persist at low rates. Likewise, vitamin D testing is frequently being undertaken in individuals at low risk of vitamin D deficiency. Taken together, this suggests that there is unnecessary testing and overtreatment and that vitamin D guidance and practice in New Zealand needs to change.
Summary
Abstract
Aim
Severe prolonged vitamin D deficiency can cause rickets or osteomalacia. Both can be prevented by sunshine exposure or vitamin D supplementation. Although New Zealand guidance does not recommend vitamin D supplementation for the general population, it can be considered for individuals at risk of vitamin D deficiency. Routine measurement of 25-hydroxyvitamin D (25OHD) is also considered unnecessary.
Method
We investigated the rates of vitamin D supplementation, rickets and osteomalacia in New Zealand, and of 25OHD results in Auckland, over the last two decades.
Results
Vitamin D prescriptions increased 14-fold, from 86,295/year to 1,215,507/year, between 2003 and 2019, with medication costs alone in 2019 being >$1 million. Despite these changes, the annual prevalence of hospital admissions for rickets, osteomalacia and unspecified vitamin D deficiency remained low and stable (10–20/year). 25OHD concentrations increased between 2002 and 2003 and between 2009 and 2019, and in the later time-period, 25OHD tests mainly identified individuals without vitamin D deficiency (40–50% >75nmol/L, 65–70% >50nmol/L and only 7–12.5% <25nmol/L).
Conclusion
Osteomalacia and rickets persist at low rates despite widespread, increasingly costly vitamin D supplementation and testing, which largely identifies individuals without vitamin D deficiency. These results suggest that vitamin D guidance and practice in New Zealand should change.
Author Information
Acknowledgements
Correspondence
Correspondence Email
Competing Interests
1) WebMD [Internet]. Vitamin D: Vital Role in Your Health; [cited 2019 Nov 1]. Available from: https://www.webmd.com/food-recipes/features/vitamin-d-vital-role-in-your-health#1
2) Guardian [Internet]. Top UK scientist urges people to take vitamin D supplements; [cited 2019 Nov 1]. Available from: https://www.theguardian.com/society/2019/may/26/top-uk-scientist-urges-people-to-take-vitamin-d-supplements
3) Bolland MJ, Avenell A, Grey A. Should adults take vitamin D supplements to prevent disease? BMJ. 2016;355:i6201.
4) Bolland MJ, Grey A, Avenell A. Effects of vitamin D supplementation on musculoskeletal health: a systematic review, meta-analysis, and trial sequential analysis. Lancet Diabetes Endocrinol. 2018;6:847-58.
5) Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, et al. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev. 2019;40:1109-51.
6) Giustina A, Adler RA, Binkley N, Bouillon R, Ebeling PR, Lazaretti-Castro M, et al. Controversies in Vitamin D: Summary Statement From an International Conference. J Clin Endocrinol Metab. 2019;104:234-40.
7) 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.
8) Dawson-Hughes B, Heaney RP, Holick MF, Lips P, Meunier PJ, Vieth R. Estimates of optimal vitamin D status. Osteoporos Int. 2005;16:713-6.
9) Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006;84:18-28.
10) Scientific Advisory Committee on Nutrition (SACN). Vitamin D and Health. London: TSO; 2016.
11) Bolland MJ, Avenell A, Grey A. Prevalence of biochemical osteomalacia in adults undergoing vitamin D testing. Clin Endocrinol (Oxf). 2021;95:74-83.
12) Ministry of Health and Cancer Society of New Zealand. Consensus Statement on Vitamin D and Sun Exposure in New Zealand. Wellington: Ministry of Health; 2012.
13) Bolland MJ, Grey A, Davidson JS, Cundy T, Reid IR. Should measurement of vitamin D and treatment of vitamin D insufficiency be routine in New Zealand? N Z Med J. 2012;125:83-91.
14) Bolland MJ, Chiu WW, Davidson JS, Grey A, Bacon C, Gamble GD, et al. The effects of seasonal variation of 25-hydroxyvitamin D on diagnosis of vitamin D insufficiency. N Z Med J. 2008;121:63-74.
15) Blok BH, Grant CC, McNeil AR, Reid IR. Characteristics of children with florid vitamin D deficient rickets in the Auckland region in 1998. N Z Med J. 2000;113:374-6.
16) Wheeler BJ, Dickson NP, Houghton LA, Ward LM, Taylor BJ. Incidence and characteristics of vitamin D deficiency rickets in New Zealand children: a New Zealand Paediatric Surveillance Unit study. Aust N Z J Public Health. 2015;39:380-3.
17) Bolland MJ, Avenell A, Smith K, Witham MD, Grey A. Vitamin D supplementation and testing in the UK: costly but ineffective? BMJ. 2021;372:n484.
18) Michael YL, Whitlock EP, Lin JS, Fu R, O'Connor EA, Gold R. Primary care-relevant interventions to prevent falling in older adults: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2010;153:815-25.
19) 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:CD000227.
20) Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet. 2014;383:146-55.
21) Autier P, Boniol M, Pizot C, Mullie P. Vitamin D status and ill health: a systematic review. Lancet Diabetes Endocrinol. 2014;2:76-89.
22) 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;2:307-20.
23) Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JP. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ. 2014;348:g2035.
24) Autier P, Mullie P, Macacu A, Dragomir M, Boniol M, Coppens K, et al. Effect of vitamin D supplementation on non-skeletal disorders: a systematic review of meta-analyses and randomised trials. Lancet Diabetes Endocrinol. 2017;5:986-1004.
25) Bolland MJ, Avenell A, Baron JA, Grey A, Maclennan GS, Gamble GD, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.
26) Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.
27) Bolland MJ, Leung W, Tai V, Bastin S, Gamble GD, Grey A, et al. Calcium intake and risk of fracture: systematic review. BMJ. 2015;351:h4580.
28) U. S. Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, et al. Vitamin D, Calcium, or Combined Supplementation for the Primary Prevention of Fractures in Community-Dwelling Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319:1592-9.
29) U. S. Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Barry MJ, Caughey AB, et al. Interventions to Prevent Falls in Community-Dwelling Older Adults: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319:1696-704.
30) Bolland MJ, Grey A, Avenell A. Assessment of research waste part 2: wrong study populations- an exemplar of baseline vitamin D status of participants in trials of vitamin D supplementation. BMC Med Res Methodol. 2018;18:101.
Contact diana@nzma.org.nz
for the PDF of this article
Vitamin D deficiency, supplementation and testing: have we got it right in New Zealand?
Severe prolonged vitamin D deficiency can cause rickets in children or osteomalacia in adults. Both are easily prevented by sunshine exposure and prevented or treated with vitamin D supplementation.
Subscriber Content
The full contents of this pages only available to subscribers.
Login, subscribe or email nzmj@nzma.org.nz to purchase this article.
