The fear I expressed in my editorial for the second issue of 2019 of the Journal has unfortunately turned out to be well founded, given that there have been no occasions for an exchange with Health Board officials with regard to a cost-benefit analysis of vitamin D supplementation and for bringing operators in the health field up to date on the best ways of using it. Now, in my opinion, we run the risk that many patients will lack proper access to vitamin D treatment. As you know, faced with the exorbitant – and admittedly unjustifiable – costs for vitamin D in Italy, the national drug administration (AIFA) has indeed recently taken measures to limit prescriptions paid by the national health service (SSN) for some vitamin D-based drugs (cholecalciferol, cholecalciferol in capsules, cholecalciferol /calcium salts) for the “prevention and treatment of vitamin D deficiency in adults” (note 96, see this and future issues).
The contents of the note acknowledge the importance of vitamin D supplementation in the case of deficiency, particularly for musculoskeletal health. Yet its statements, I believe, are prone to unsure if not ambiguous interpretations, which could give rise to numerous doubts, in spite of clarifications subsequently issued by the AIFA for health workers and citizens.
The implementation of this measure will certainly reduce the costs borne by the SSN for vitamin D supplementation. Yet the Health Board will not be able to attribute these savings to an improved suitability of its use: to my mind, the note lends itself to restrictive interpretations which may negatively affect patients who should have the right to use and benefit from supplementation. Costs for the SSN may actually increase, in terms of diagnosis and above all for lack of prevention.
In my opinion, the critical parts of note 96 are as follows:
While recognizing that vitamin D deficiency may be asymptomatic (point 3, vitamin D chart – for citizens), its measurement is recommended only for persons with symptoms, those clearly affected by severe deficiency and above all patients with serious hypovitaminosis D complications such as osteomalacia. This recommendation seems to contradict one of the principles of the AIFA, which has always been concerned with encouraging prevention of diseases rather than the use of drugs for their treatment. Another statement, found in the measurement guidelines in Attachment 1 to the note, is likewise open to ambiguous interpretation in clinical practice: this says that determining 25(OH)D levels is not necessarily recommended in all possible risk categories. Yet does this mean that a doctor may choose to ignore those risk conditions, or, as I understand it, that in that case measuring vitamin D levels is superfluous and wasteful because it is in any case recommended for purposes of prevention?
Symptoms that can be attributed to hypovitaminosis D (asthenia, myalgia, diffused or localized pain, bone soreness, lumbosacral, pelvic or lower limb pain, sensory impairment, muscle weakness mainly in the quadriceps and glutes with difficulty standing up and sitting down, unsteady gait, susceptibility to falls, etc.) are varied and nonspecific. More often than not, these symptoms are attributable not to hypovitaminosis D but to many other conditions, some of which are more severe. Should we not believe that such a scenario might disorient doctors, leading them to overprescribe ineffective and costly doses of 25(OH)D? Should we not further imagine that unrealistic expectations will thereby be created regarding the symptomatic benefits of vitamin D supplementation, including in conditions in which a possible associated deficiency does not play a pathogenetic role?
The note recommends measuring 25(OH)D levels in persons with secondary hyperparathyroidism by means of a dose of parathormone (PTH), which leading international guidelines do not recommend, as it is notoriously subject to great analytic and biological variability, costly (€22) and physiopathologically altered in most elderly patients. In addition, it is known that most individuals with vitamin D deficiency do not have above average PTH concentrations.
The note also recommends measuring vitamin D levels in individuals affected by osteoporosis due to any cause or osteopathic diagnosed diseases that require mineralizing therapy, for which correction of hypovitaminosis should be propaedeutic for the beginning of therapy. And what about patients already undergoing therapy? And, further, why administer doses of 25(OH)D, given that even if these are above 20 ng/mL supplementation is recommended for recognized bone pathologies (as shown in the algorithm of Attachment 1)? It seems to me that the current text of the note does not clearly state what can be legitimately assumed from application of the algorithm, namely, that in all conditions of osteoporosis or of verified osteopathic diseases, including in those candidate to a mineralizing therapy, vitamin D supplementation is nonetheless recommended (as stated in note 79) and therefore reimbursed. In addition, in clinical practice, whether before or at the start of a mineralizing therapy, supplementation with higher or more generous doses of vitamin D is called for, such that measuring 25(OH)D levels is not in most cases indispensable in the clinical management of patients.
Given that exposure to sunlight – as has been rightly recognized – represents the principal mechanism of vitamin D production (80%), how is it that among the risk conditions for hypovitaminosis D the most frequent ones are not given? These are conditions resulting from circumstances that necessitate reduced exposure to sunlight (for example, for reasons of work, disability, cultural prohibitions or side effects linked to UVB exposure), or from those linked to an inability to produce adequate quantities of vitamin D in spite of sun exposure, such as often occurs in the elderly. It does not seem proper to limit discussion of this point to a mere acknowledgement of the risk conditions generated by long-term therapy with drugs that interfere with vitamin D metabolism or of those diseases which can result in poor absorption.
In my Region, testing for 25(OH)D levels in a single patient costs €17. Using cheaper pharmaceutical formulations, I can treat three patients with vitamin D for a year for this amount. Given that note 97 encourages the widespread and general usage of vitamin D – not to mention the frequent cases in which it demands it – do we not run the risk of shifting expense from prescription to diagnosis?
The note states that doses higher than 40 ng/ml may be associated with additional risks, among which – as is specified in the relevant clarifications – that of neoplasms. This claim is based on several reports, upon which doubt has been cast by the very source cited in the note, and which other studies have contradicted. As far as I know, so far EU regulatory agencies have not issued any alerts on the risk of oncological pathologies. In any case, exceeding the limit of 40 ng/mL can easily be caused by following commonly recommended dosages … or even by a nice sunny day. At present, this limit therefore appears to be unnecessarily alarmist, which among other things may result in doctors and patients further requesting repeated and useless tests for measuring 25(OH)D levels for fear of having exceeded them. It is known that before running the risk of the most certain side effect of vitamin D supplementation, hypercalcemia, over 100 ng/mL must be taken. In light of our current knowledge, I believe that in any case it would be more appropriate to warn of possible side effects with levels above 50 ng/mL, as stated in many guidelines.
The minimum threshold of 20 ng/mL of 25(OH)D is deemed sufficient in the general population, though not for some particular risk conditions: in the elderly, in patients with secondary hyperparathyroidism or in those in mineralized therapy for osteoporosis, as is in part recognized on the basis of scientific evidence in point 5 of AIFA clarifications for health workers. Some authoritative scientific societies, which are not mentioned in the background section of the note, maintain that in such conditions 25(OH)D levels above 30 ng/mL provide greater guarantees.
The note recommends interrupting corrective treatment once symptoms of the deficiency have disappeared, except in the case that they should resurface. But if they persist, perhaps because the conditions that expose patients to the risk of hypovitaminosis D cannot be modified, must I wait until my patient becomes ill again before treating him or her at the SSN’s expense? What has happened to the appreciation for the benefits of prevention and in that sense respect for SPC recommendations for cholecalciferol?
All notes issued by the AIFA essentially aim to define the criteria for the reimbursement of drugs for optimal therapeutic suitability. As note 79 reminds us, prescriptions should nonetheless be written following the recommendations and warnings of the information sheets for each drug. Not only is this principle not repeated in note 96, it is even, I believe, sometimes not even respected. A possible consequence of this neglect is that it could encourage, for example, the use of some known medications even if these present side effects or are not recommended. Furthermore, Attachment 1 provides indications for the use of specific doses and not for all uses authorized by the SPC. In addition, certain studies indicate that the doses recommended in the note are insufficient for certain types of patients.
The note (in particular Attachment 1) recommends the need for specialist evaluation for certain conditions, such as kidney failure (I assume, by the way, that the incorrect unit of measure used for its definition is due to a typographical error); yet if fails to indicate whether there are criteria for vitamin D reimbursement in these conditions.
With regard now to the statement in the background section about the extra skeletal effects of vitamin D, according to which results of randomized clinical trials (RCTs) with high numbers of participants have not confirmed the hypothesis of benefits resulting from supplementation and have in particular identified areas of documented ineffectiveness in oncology and cardiology: it seems that the authors of this statement have not considered that currently available RCTs were largely conducted on non-deficient subjects and are therefore not able to exclude possible benefits in conditions of deficiency (as one could rationally expect and as has in fact been observed in some sub analyses).
And on the subject of recognized immunological effects: in this issue we feature an update from a well-known institute in Genoa on the role of vitamin D in rheumatological diseases. The authors conclude that even if the complexity of rheumatological and autoimmune diseases as well as several methodological limits of published studies significantly circumscribe the possibility of making generalizations as to the therapeutic potential of cholecalciferol in these pathologies, preliminary data from these studies, together with the safety and low cost of cholecalciferol, strongly support its use in patients affected by these diseases, considering the potential and relevant clinical benefits.
What do you think?
I hope you enjoy reading this issue.