The role of vitamin D in bone health
- Vitamin D is essential for musculoskeletal health as it promotes calcium absorption from the bowel, enables mineralisation of newly formed osteoid tissue in bone and plays an important role in muscle function. The main manifestation of vitamin D deficiency is osteomalacia in adults and rickets in children, which are generally associated with increased risk at plasma 25-hydroxyvitamin D (25(OH)D) concentrations below 20–25 nmol/L. Less severe vitamin D deficiency, sometimes termed vitamin D insufficiency, may lead to secondary hyperparathyroidism, bone loss, muscle weakness, falls and fragility fractures in older people.
The Royal Osteoporosis Society (ROS) propose that the following pragmatic vitamin D thresholds are adopted by UK Clinicians in respect to bone health:
- plasma 25(OH)D <25 nmol/L is deficient
- plasma 25(OH)D of 25–50 nmol/L may be inadequate in some people
- plasma 25(OH)D >50 nmol/L is sufficient for almost the whole population.
How should we assess vitamin D status?
- Measurement of plasma 25(OH)D is the best way of estimating vitamin D status
- Measurement of 25(OH)D is a better indicator of vitamin D stores, whether obtained from sunlight (ultraviolet [UV] exposure) or dietary sources.
Biochemical assessment of vitamin D status
- The main methods available to estimate 25(OH)D are immunoassay, high-performance liquid chromatography (HPLC) attached to fluorescence or mass spectrometry (MS) detection (tandem MS)
- The assay should have the ability to recognise all forms of 25(OH)D (D2 or D3) equally. In practice, this means that it should use either HPLC or, more likely, tandem MS. None of the immunoassays offer the ability to recognise all forms of 25(OH)D.
Who should be tested for vitamin D deficiency?
Patients with bone diseases (a) that may be improved with vitamin D treatment or (b) where correcting vitamin D deficiency prior to specific treatment would be appropriate
- There is good evidence that correcting vitamin D is essential in osteomalacia, but it is also likely to be beneficial in osteoporosis. There are other bone diseases where correcting vitamin D deficiency before drug treatment is recommended, such as when treating Paget’s disease with a bisphosphonate
- Correction of vitamin D deficiency is also required before starting osteoporosis treatment with a potent antiresorptive agent (zoledronate or denosumab or teriparatide), to avoid the development of hypocalcaemia. Nevertheless, in most cases routine 25(OH)D testing is unnecessary in patients with osteoporosis or fragility fracture, where a decision has been made to co-prescribe vitamin D supplementation with an oral antiresorptive treatment.
Patients with musculoskeletal symptoms that could be attributed to vitamin D deficiency
- Symptoms of vitamin D deficiency are unfortunately vague and it can be difficult to ascertain whether a low plasma 25(OH)D level is causal or a surrogate marker (for example, of poor nutrition or a lack of activity). Nonetheless, if patients are suspected of having symptoms caused by osteomalacia, or have chronic widespread pain with other features of osteomalacia (for example, proximal muscle weakness), consider measuring plasma 25(OH)D as part of their clinical and laboratory evaluation.
Asymptomatic individuals at higher risk of vitamin D deficiency
- Do not routinely test 25(OH)D levels in these groups.
Department of Health and Social Care guidance
Adult groups at risk of vitamin D deficiency:
older people, aged 65 years and over
people who have low exposure to the sun, for example those who cover their skin for cultural reasons, who are housebound or who are confined indoors for long periods
people who have darker skin, for example people of African, African-Carribbean or South Asian origin, because their bodies are not able to make as much vitamin D.
people aged 65 years and over and people who are not exposed to much sun should also take a daily supplement containing 10 μg (400 IU) of vitamin D.
Asymptomatic healthy individuals
- Universal screening of asymptomatic populations is not recommended.
Who will benefit from treatment?
- It is advised that in those patients where 25(OH)D is tested (discussed in the previous section: ‘Who should be assessed for vitamin D deficiency?’) the results be acted upon as follows:
- plasma 25(OH)D <25 nmol/L: treatment recommended
- plasma 25(OH)D 25–50 nmol/L: treatment is recommended in patients with the following:
- fragility fracture, documented osteoporosis or high fracture risk
- treatment with antiresorptive medication for bone disease
- symptoms suggestive of vitamin D deficiency
- increased risk of developing vitamin D deficiency in the future because of reduced exposure to sunlight, religious/cultural dress code, dark skin, etc.
- raised parathyroid horrmone
- medication with antiepileptic drugs or oral glucocorticoids
- plasma 25(OH)D >50 nmol/L: provide reassurance and give advice on maintaining adequate vitamin D levels through safe sunlight exposure and diet.
How should vitamin D deficiency be treated?
- Treatment regimens must be acceptable to both non-expert primary care physicians and to patients. Key aims for treating vitamin D deficiency in patients with bone disease:
- use adequate doses to ensure correction of vitamin D deficiency (ideally >50 nmol/L)
- reverse the clinical consequences of vitamin D deficiency in a timely manner
- avoid toxicity.
Vitamin D3 or vitamin D2?
- Based on the current medical consensus as well as problems related to the measurement of 25(OH)D2, vitamin D3 is recommended as the vitamin D preparation of choice for the treatment of vitamin D deficiency.
Oral or intramuscular administration?
- Parenteral vitamin D is not the firstline recommendation within the treatment guidance, primarily due to significant inter-individual variability in absorption
- Oral administration of vitamin D is recommended.
Fixed or titrated dosing strategy?
- The concentration of 25(OH)D varies not only according to external factors such as exposure to sunlight (UVB) and diet but also by patient characteristics, including genetic factors as well as body composition. These patient characteristics may also influence the subsequent pharmacokinetics and pharmacodynamics of vitamin D supplementation
- Recommend treatment based on fixed-loading doses and maintenance therapy.
Lower daily dose or high intermittent dose?
- Where correction of vitamin D deficiency is less urgent and when co-prescribing vitamin D supplements with an oral antiresorptive agent, maintenance therapy may be started without the use of loading doses
- Where rapid correction of vitamin D deficiency is required, such as in patients with symptomatic disease or about to start treatment with a potent antiresorptive agent (zoledronate or denosumab or teriparatide), the recommended treatment regimen is based on fixed loading doses followed by regular maintenance therapy.
1. Loading regimens for treatment of deficiency up to a total of approximately 300,000 IU given either as weekly or daily split doses. The exact regimen will depend on the local availability of vitamin D preparations but will include:
- 50,000 IU (tablets, capsules or liquid) given weekly for 6 weeks (300,000 IU)
- 40,000 IU given weekly for 7 weeks (280,000 IU)
- 1000 IU tablets, four a day for 10 weeks (280,000 IU)
- 800 IU capsules, five a day given for 10 weeks (280,000 IU)
- This list is not exhaustive
- The following should be borne in mind:
- advise that calcium/vitamin D combinations not be used as sources of vitamin D for the above regimens, given the resulting high dosing of calcium
2. Maintenance regimens should generally be started one month after loading with doses equivalent to 800 to 2000 IU daily (up to a maximum of 4000 IU daily), given either daily or intermittently at a higher equivalent dose. The strategies below have been demonstrated not to work or to have a high risk of being ineffective or causing toxicity, and are therefore not to be recommended:
- annual depot vitamin D therapy either by intramuscular injection or orally
- use of activated vitamin D preparations (calcitriol and alfacalcidol).
- Considering optimisation of bone health and the public health agenda, it is important to promote the relevance of adequate dietary calcium intake and consider use of ‘calcium calculators’ to help patients and primary-care clinicians (for example, www.rheum.med.ed.ac.uk/calcium-calculator.php).
- It is well known that vitamin D treatment, particularly combined with calcium supplementation, can unmask previously undiagnosed primary hyperparathyroidism. It is important that the clinician is aware of this. Although the dosing regimen is unlikely to result in toxicity, it ought to be recognised that certain groups may be at increased risk of this or adverse side effects and they ought to be monitored. This is usually done by measuring adjusted plasma calcium levels
- As more patients are treated, it is likely that patients with increased sensitivity to vitamin D therapy because of genetic abnormalities in vitamin D metabolism, co-morbidities such as CKD, granuloma-forming diseases or hyperparathyroidism will be identified and require lower subsequent dosing. Monitoring is an integral component of the proposed treatment algorithms as the requirements for repeat testing may be different according to the approaches used
- There is limited evidence for when to monitor response to therapy, but the aims are to:
1. detect those who remain deficient after loading
2. detect those who become deficient during maintenance
3. detect those patients in whom vitamin D therapy uncovers sub-clinical primary hyperparathyroidism.
Assessment of improvement in 25(OH)D status on replacement therapy
- Routine monitoring of plasma 25(OH)D is unnecessary but may be appropriate in patients with symptomatic vitamin D deficiency or in situations where malabsorption or poor compliance with medication is suspected or in patients taking antiresorptive therapy who have extremely low levels at baseline assessment.
- Repeat testing of 25(OH)D may be indicated prior to sequential doses of potent antiresorptives
- Based on the pharmacokinetics of 25(OH)D, assessment of adjusted plasma calcium levels within 1 month after the administration of the last loading dose are recommended to be undertaken to detect those with primary hyperparathyroidism. The presence of hypercalcaemia ought to lead to cessation of further vitamin D supplementation prior to investigation of the hypercalcaemia
- Adjusted plasma calcium is recommended to be checked one month after completing the loading regimen or after starting lower dose vitamin D supplementation in case primary hyperparathyroidism has been unmasked.
Vitamin D toxicity
- Overt vitamin D toxicity manifests itself through chronic hypercalcaemia (elevated plasma calcium)
- Less severe symptoms of vitamin D toxicity include prolonged hypercalciuria, which is a potential risk for renal stones.
Upper limit of intake
- The Food and Nutrition Board of the Institute of Medicine (IOM) concluded that vitamin D below 10,000 IU per day is not usually associated with toxicity, whereas doses equal to or above 50,000 IU per day for several weeks or months are frequently associated with toxicity. The IOM set the Upper limit (UL) for long-term intake at 4000 IU (100 μg) per day.
- There is evidence that higher levels of vitamin D2 can be tolerated compared to vitamin D3
- Patients with granulomatous disease are at risk of hypercalcaemia
- Toxicity has been reported during vitamin D treatment of tuberculosis and in patients with active sarcoidosis with lower dosages than those that are associated with toxicity in healthy people. It is advised that specialist advice be sought before starting these patients on vitamin D therapy.
Hypercalciuria and renal stones
- There is no strong evidence that correcting vitamin D deficiency with vitamin D alone will increase the risk of renal stones on healthy people. Patients with active or a history of nephrolithiasis are recommended to be managed on a case by case basis.
High bolus dosing of vitamin D and falls and fractures
- Based on the current evidence, there seems to be no rationale to recommend bolus doses in the majority of patients, unless urgent correction of vitamin D status is required. These patients are recommended to be monitored and be under medical supervision. For the majority of patients, as there are no convincing benefits that are likely to outweigh potential risks, lower dose schemes are recommended.
The Royal Osteoporosis Society
Vitamin D and bone health: a practical clinical guideline for patient management. December 2018.
Date published: June 2013.
Last updated: February 2019.
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