We declare that we have no competing interests.

Spyridon N Karras, Panagiotis Anagnostis, Olivier Beauchet, Dimitrios G Goulis, *Cedric Annweiler [email protected] Unit of Reproductive Endocrinology, First Department of Obstetrics and Gynecology, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece (SNK, PA, DGG); Department of Neuroscience, Angers University Hospital, 49933 Angers, France (OB, CA); and Robarts Research Institute, Department of Medical Biophysics, Schulich School of Medicine and Dentistry, University of Western Ontario, London, ON, Canada (CA) 1





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. Lawlor DA, Wills AK, Fraser A, Sayers A, Fraser WD, Tobias JH. Association of maternal vitamin D status during pregnancy with bonemineral content in offspring: a prospective cohort study. Lancet 2013; 381: 2176–83. Bischoff-Ferrari HA, Kiel DP, Dawson-Hughes B, et al. Dietary calcium and serum 25-hydroxyvitamin D status in relation to BMD among U.S. adults. J Bone Miner Res 2009; 24: 935–42. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a metaanalysis of randomized controlled trials. Arch Intern Med 2009; 169: 551–61. Anderson PH, Turner AG, Morris HA. Vitamin D actions to regulate calcium and skeletal homeostasis. Clin Biochem 2012; 45: 880–86.

could free up substantial resources that could be better used elsewhere in health care”.1 Vitamin D supplementation is not the core treatment in the prevention of osteoporosis, but a supportive one, essential to reduce the incidence of falls, which cause fractures.2,3 Levis and Theodore’s summary4 of the Agency for Healthcare Research and Quality systematic review report that vitamin D treatment reduced vertebral fractures among primary osteoporosis, and calcium and vitamin D decreased the risk of fracture in elderly women. Reid and colleagues pointed out in their analysis of 23 studies that in ten studies vitamin D supplementation was less than 800 IU per day, this dose might not be sufficient to make any difference in the bone mineral density. Also, six studies showed benefit of vitamin D supplementation. The authors have not taken into consideration the non-compliance of vitamin D intake by patients. The cost of a year’s supply of vitamin D is less than US$35 per patient in western countries and much less in Asian countries. Vitamin D might not increase bone mineral density in 100% of the patients but it reduces falls and thereby reduces the incidence of fractures—this should not be ignored. Without a large randomised controlled study with full compliance of vitamin D use showing no benefit, it is inaccurate to state that it is inappropriate to give vitamin D while vitamin D deficiency is rampant worldwide. Understanding the bias and limitations of the studies analysed is crucial if we do not want many physicians to stop prescribing vitamin D supplementation, which could have serious consequences. We declare that we have no competing interests.

*Mir Sadat-Ali, Haifa A Al-Turki [email protected]

We read with interest and dismay Ian Reid and colleagues’ study. 1 They state that “targeting of lowdose vitamin D supplements only to individuals who are likely to be deficient Vol 383 April 12, 2014

College of Medicine University of Dammam and King Fahd Hospital of the University, Al-Khobar 31952, Saudi Arabia 1

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.

2 3 4

Vieth R. The role of vitamin D in the prevention of osteoporosis. Ann Med 2005; 37: 278–85. Kozaki K. Fall risk and fracture. Aging and fall/ fracture. Clin Calcium 2013; 23: 653–60. Levis S, Theodore G. Summary of AHRQ’s comparative effectiveness review of treatment to prevent fractures in men and women with low bone density or osteoporosis: update of the 2007 report. J Manag Care Pharm 2012; 18: S1–15.

Saturn Stills/Science Photo Library

and detrimental effects on BMD, respectively. Therefore, we propose that potential effects of vitamin D supplements on BMD could have been missed. BMD increases with serum 25-hydroxyvitamin D concentration reaching a plateau at about 75–85 nmol/L.3,4 Beyond this threshold, it is difficult to observe increased bone formation despite increasing vitamin D activity within osteoblast cells through expression of vitamin D receptor transgene.5 The results of this metaanalysis1 urge for further randomised controlled trials investigating vitamin D supplementation in representative populations, in which hypovitaminosis D is common.

Authors’ reply Helen Macdonald and Terence Aspray’s data should be interpreted in the context of existing evidence, and their addition to our meta-analysis does not alter the results.1 We further note the minimal effect of vitamin D on bone mineral density (BMD) in the other two studies published since our meta-analysis. 2,3 These studies are consistent with the findings of our review, small effects on BMD at some sites are seen in patients with baseline concentrations of vitamin D below 40 nmol/L. We agree that those who are deficient will benefit most from supplementation, but better defining deficiency remains a priority. Studies in groups with hypovitaminosis D will aid this, as noted by Spiros Karras and colleagues, although we do not accept that correlations between vitamin D and BMD reflect causation, or that vitamin D acts directly on osteoblasts to increase bone formation, an issue discussed in our paper.1 There was no heterogeneity between the pooled results of trials using D2 or D3 at any skeletal site. With regards to Colin Dunstan’s comments, our data are differences between the vitamin D and placebo groups. Thus, a zero difference does not imply the absence of bone loss but the absence of a therapeutic effect of vitamin D. In response to Mir Sadat-Ali and Haifa Al-Turki’s comments, we reiterate that vitamin D supplementation should be targeted to those likely to be deficient, not that vitamin D supplementation should be abandoned. As discussed in our paper,1 there is little evidence for the anti-fracture efficacy of vitamin D monotherapy, evidence 1293


of falls prevention is inconsistent, and significant effects on other nonskeletal endpoints are unlikely.4 Our meta-analysis suggested that lower doses of vitamin D were more effective than higher doses on BMD, refuting the suggestion that more aggressive dosing might produce better outcomes. Non-compliance is an issue with any intervention, more so in clinical practice than in clinical trials. Thus, if vitamin D is ineffective in a trial context, it is even less likely to be effective in clinical practice. Our review suggests that vitamin concentrations higher than 40 nmol/L are adequate for bone health and, as a result, that vitamin D deficiency is rather less common than previously suggested. We declare that we have no competing interests.

*Ian R Reid, Mark J Bolland, Andrew Grey [email protected] Faculty of Medical and Health Sciences, University of Auckland, PB 92019, Auckland, New Zealand (IRR, MJB, AG); and Department of Endocrinology, Auckland District Health Board, Auckland, New Zealand (IRR) 1




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. Iuliano-Burns S, Ayton J, Hillam S, et al. Skeletal and hormonal responses to vitamin D supplementation during sunlight deprivation in Antarctic expeditioners. Osteoporos Int 2012; 23: 2461–67. Wamberg L, Pedersen SB, Richelsen B, Rejnmark L. The effect of high-dose vitamin D supplementation on calciotropic hormones and bone mineral density in obese subjects with low levels of circulating 25-hydroxyvitamin D: results from a randomized controlled study. Calcif Tissue Int 2013; 93: 69–77. 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; published online Jan 24. http://dx.doi. org/10.1016/S2213-8587(13)70212-2.

number of invasive cervical cancers detected in the human papillomavirus (HPV)-based screening group was slightly lower than in the cytologybased screening group only at the first screening round. This result suggests that HPV testing is not as effective as cytology in early detection of invasive cervical cancers;2 and this is plausible from both epidemiological and biological points of view. In western countries the incidence of invasive cervical cancers is very low; after the first round of screening, clearance of cervical intraepithelial neoplasia grade 3 (CIN3) following HPV testing is high, and the efficacy of early detection of invasive cancer by cytology is masked. The lesser sensitivity of HPV testing for invasive cervical cancers could be explained because invasive cervical cancers are shedding cells with major molecular rearrangement and the viral DNA load could be in some instances under the sensitivity of the test.3 Ronco and colleagues’ study infers two different roles for cytology and HPVbased testing: the first is best directed for the identification of precursors, the second is best for early diagnosis of cervical cancer and to a lesser extent to CIN3 detection. These two different performances should be acknowledged to choose cytology or HPV-based testing on the basis of disease prevalence and screening aims, cancer prevention, or early cancer diagnosis. The European Institute of Oncology receives fundings for the activity of MS from Sanofi Pasteur, GSK, Qiagen, Roche Molecular Systems, and Becton Dickinsons. SI declares that she has no competing interests.

Mario Sideri, *Sarah Igidbashian [email protected] Preventive Gynaecology Unit, European Institute of Oncology, 20141 Milano, Italy

HPV-based screening for prevention of invasive cervical cancer



We read with interest Guglielmo Ronco and colleagues’ Article (Feb 8, p 524).1 It is important to note that the 1294

Ronco G, Dillner J, Elfström KM, et al. International HPV screening working group. Efficacy of HPV-based screening for prevention of invasive cervical cancer: follow-up of four European randomised controlled trials. Lancet 2014; 383: 524–32. Zucchetto A, Ronco G, Giorgi Rossi P, et al. IMPATTO CERVICE Working Group. Screening patterns within organized programs and survival of Italian women with invasive cervical cancer. Prev Med 2013; 57: 220–26.


Sundström K, Ploner A, Dahlström LA, et al. Prospective study of HPV16 viral load and risk of in situ and invasive squamous cervical cancer. Cancer Epidemiol Biomarkers Prev 2013; 22: 150–58.

The landmark follow-up study by Guglielmo Ronco and colleagues 1 clearly demonstrates that high grade cervical intraepithelial neoplasia (CIN) is an excellent surrogate marker for invasive cervical cancer, strengthening the findings of the initial screening studies conducted in the four European countries (Sweden [Swedescreen], the Netherlands [POBASCAM], England [ARTISTIC], and Italy [NTCC]). Non-believers now lose another argument often used against prophylactic HPV vaccination programmes. Furthermore, the pooled analysis proves again that HPV testing is superior to regular cytologic screening, as has been repeatedly proven in multiple trials over the years. However, it is disappointing that even with HPV screening so many women still developed cervical cancer in both groups, especially the 19 patients diagnosed during the long-term follow-up raise concern. The rates in the Italian NTCC trial were much lower than in the other three trials. Can this be explained by a more stringent triage, a more careful follow-up of test-positive women, or because of other reasons? We feel the authors should really provide a more thorough analysis of all such breakthrough cases, including compliance issues, demographics, history, stage, proportion of adenocarcinomas, just to name a few potential key variables. While there is evidence that HPV testing is the best screening test, it appears that further improvement is needed. We must identify the best triage, including colposcopy and follow-up protocols to ensure that women who comply do not develop cervical cancer. Another important point is the fact that in some countries the first cohorts of HPV-vaccinated women are already in their thirties thus entering the Vol 383 April 12, 2014

Vitamin D supplements and bone mineral density - Authors' reply.

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