The role of vitamin D in maintaining bone health in older people

Abstract

This review summarises aspects of vitamin D metabolism, the consequences of vitamin D deficiency, and the impact of vitamin D supplementation on musculoskeletal health in older age. With age, changes in vitamin D exposure, cutaneous vitamin D synthesis and behavioural factors (including physical activity, diet and sun exposure) are compounded by changes in calcium and vitamin D pathophysiology with altered calcium absorption, decreased 25-OH vitamin D [25(OH)D] hydroxylation, lower renal fractional calcium reabsorption and a rise in parathyroid hormone. Hypovitaminosis D is common and associated with a risk of osteomalacia, particularly in older adults, where rates of vitamin D deficiency range from 10–66%, depending on the threshold of circulating 25(OH)D used, population studied and season. The relationship between vitamin D status and osteoporosis is less clear. While circulating 25(OH)D has a linear relationship with bone mineral density (BMD) in some epidemiological studies, this is not consistent across all racial groups. The results of randomized controlled trials of vitamin D supplementation on BMD are also inconsistent, and some studies may be less relevant to the older population, as, for example, half of participants in the most robust meta-analysis were aged under 60 years. The impact on BMD of treating vitamin D deficiency (and osteomalacia) is also rarely considered in such intervention studies. When considering osteoporosis, fracture risk is our main concern, but vitamin D therapy has no consistent fracture-prevention effect, except in studies where calcium is coprescribed (particularly in frail populations living in care homes). As a J-shaped effect on falls and fracture risk is becoming evident with vitamin D interventions, we should target those at greatest risk who may benefit from vitamin D supplementation to decrease falls and fractures, although the optimum dose is still unclear.

Vitamin D metabolism and ageing

Advancing age brings about socioeconomic, lifestyle and biological changes. In terms of endogenous synthesis of vitamin D, the dermal capacity to produce the vitamin in persons aged 65 years has been estimated to be about 25% of that in persons aged 20–30 years exposed to the same amount of sunlight. ¹ , ² This reduction cannot be explained by the decrease in mass of the epidermis with ageing, but rather seems to be related to the reduction in the concentration of skin 7-dehydrocholesterol. Other indirect factors that reduce exposure to sunlight in older adults include the wearing of more concealing clothing, ³ an increased use of sunscreen lotion, ⁴ and reduced sun exposure, arising from less physical activity and time outdoors. ⁵ Calcium is absorbed from the bowel by an active vitamin D-dependent transport mechanism and by passive diffusion. The active transport mechanism plays an important role in calcium homeostasis, as calcium absorbed is inversely related to dietary intake. ⁶ Fractional calcium absorption therefore increases when dietary calcium intake is reduced. ⁷ However, calcium absorption decreases with age, ⁸ due to: a reduction in serum 25(OH)D, ⁹ impaired hydroxylation of 25(OH)D to 1,25(OH)₂D with declining renal function, ¹⁰ resistance to the action of vitamin D metabolites on the bowel mucosa ¹¹ and (at least in women) low circulating oestrogen concentrations. ¹² Oral vitamin D supplementation improves serum 25(OH)D concentrations and calcium absorption in older women, although this is attenuated by renal impairment, suggesting that both a lower level of substrate serum 25(OH)D and impaired hydroxylation of 25(OH)D to 1,25(OH)₂D contribute to a decrease in calcium absorption with age.

Lower dietary calcium intake is associated with increased calcium absorption, but this relationship is less marked in older people, ⁶ probably due to reduced 1,25(OH)₂D production and resistance to the actions of vitamin D metabolites on the bowel, since studies have shown an attenuated response in calcium absorption to increases in 1,25(OH)₂D in older women. ¹¹ Although the decline in calcium absorption with advancing age is probably multifactorial in origin, the effects of vitamin D supplementation suggest that vitamin D deficiency is the major cause of malabsorption of calcium in older people. ¹⁰ The relationship between serum 25(OH)D and fractional absorption extends to 25(OH)D concentrations above 100 nmol/l, ¹⁰ , ¹³ leading some experts to advocate that these concentrations are necessary for optimal bone health. However, while a recent randomized controlled trial showed higher calcium absorption at a serum 25(OH)D of 75 nmol/l than at 50 nmol/l, the magnitude of the difference was small. ¹³ Renal function is another important factor, as its declines with age and is associated with a decrease in serum 1,25(OH)₂D concentration ¹⁴ and an attenuation of the effect of vitamin D supplementation on calcium absorption. As glomerular filtration rate (GFR) falls below 50 ml/min, serum 1,25(OH)₂D is reduced as fractional absorption of calcium lowers ¹⁰ and an increased serum parathyroid hormone (PTH) is observed. An inverse relationship between serum 25(OH)D and PTH has been observed across all adult age groups, but PTH is higher in older people than young adults for any given serum 25(OH)D concentration. ¹⁵

Osteomalacia and the global prevalence of vitamin D deficiency in older adults

Recommended circulating levels of 25(OH)D in adult life are commonly set against the clinical risk of developing osteomalacia, although falls and fracture risk are important considerations, while links to the pathogenesis of osteoporosis are less clear. The gold standard diagnostic test for mineralization disorder associated with vitamin D deficiency (vitamin D deficiency osteomalacia) is bone histomorphometry after tetracycline labelling to identify mineralization defect with increased osteoid thickness and reduced numbers of calcification fronts. However, population-based studies, using this invasive technique, are impractical. One study used bone histomorphometry in postmortem specimens in Germany, reporting that abnormal bone mineralization was only seen in a proportion of subjects whose circulating 25(OH)D was greater than 75 nmol/l. ¹⁶ However, the study has been criticized because it used postmortem samples without tetracycline labelling, so generalizability is compromised and causes for abnormal histomorphometric other than vitamin D deficiency were not explored, while the use of postmortem data to make dietary recommendations seems bizarre. ¹⁷ This theme has been addressed comprehensively in the North American Institute of Medicine (IOM) review of dietary reference intakes for vitamin D and calcium, ¹⁸ which considered Priemel’s study, and concluded that osteomalacia may be reported at serum 25(OH)D levels less than 30 nmol/l but rarely observed at 25(OH)D levels greater than 50 nmol/l.

A number of studies have reported 25(OH)D concentrations among representative populations of older adults across the globe, with most data on Europe, followed by North America and Asia, although there are few data for South America or Africa. ¹⁹ Cross-sectional studies predominate and year-round 25(OH)D concentrations are only available in some studies. Comparisons of the prevalence of hypovitaminosis D between studies is compounded by differences in circulating 25(OH)D concentrations used to define vitamin D status and differences in performance between assays of 25(OH)D. ²⁰ However, available information has been synthesized into an interactive web page by the International Osteoporosis Foundation (IOF), where individual national results are available, based on available study data. ²¹ Variation in calcium intakes complicates the interpretation, as there remains a risk of osteomalacia (or at least childhood rickets), which is observed in populations with relatively high circulating 25(OH)D, but poor dietary calcium intakes. ²² Data from three multicentred, standardized studies show that between 17% and 58% of older Europeans are vitamin D deficient [serum 25(OH)D less than 30 nmol/l].^23–25 In the UK, in men and women aged over 64 years, approximately 10% of free-living and 40% of institutionalized adults have plasma 25(OH)D concentrations less than 25 nmol/l throughout the year. ²⁶ Data on the vitamin D status of very old adults (aged over 80 years) are scarce. Among 775 participants in the baseline phase of the Newcastle 85+ cohort study, median serum 25(OH)D concentrations ranged from 27 nmol/l during spring to 45 nmol/l in summer ²⁷ and the prevalence of vitamin D deficiency (using the IOM cutoff point of less than 30 nmol/l ¹⁸ ) also varied with season: highest in spring (51%) and lowest in autumn (23%). In a Belgian study, of adults aged over 79 years, 20% had serum 25(OH)D concentrations less than 25 nmol/l and 66% less than 50 nmol/l ²⁸ and in another recent clinical study, including 1894 individuals aged over 79 years recruited to a osteoporosis treatment study from nine European countries, ²⁹ the mean serum 25(OH)D concentration was 53.3 nmol/l, with considerable geographical variation: from Belgian participants with a mean 25(OH)D concentration of 45.7 nmol/l to Spanish participants with the highest mean concentration at 81.7 nmol/l. ²⁹ British participants in this study had a mean 25(OH)D concentration of 61.8 nmol/l with 22% of the participants having 25(OH)D concentrations < 50 nmol/l. While no information on season was available, vitamin D-containing supplements were taken by a third of British participants, which confirms evidence from other studies that vitamin D supplementation has a significant effect on circulating 25(OH)D in older adults. ³⁰

Vitamin D and osteoporosis

Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. ³¹ While a considerable proportion of the interindividual variation in bone mineral density (BMD) is genetically determined, lifestyle factors, including nutrition and exercise, are well established modifiable factors influencing bone mass. Low BMD is associated with an increased risk of osteoporotic fracture and maintaining higher BMD in older adults can reduce the fracture risk, which may be achieved by pharmacological and dietary intervention, including the use of calcium and vitamin D supplementation. ³²

Interventions with vitamin D supplementation

There is epidemiological evidence that higher serum 25(OH)D levels are associated with a greater BMD in both young and old populations, with a linear relationship maintained up to a serum 25(OH)D level of approximately 75 nmol/l. However, this association is not as robust in black or Hispanic populations in North America. ³³ A number of placebo-controlled intervention trials have examined the effect of vitamin D supplementation on BMD, but a recent meta-analysis concluded there was very little evidence that vitamin D improved bone mass. No consistent relationship between vitamin D supplementation and increased BMD was found across anatomical sites, although there was some evidence of significant benefit at the femoral neck and some evidence of less consistent benefit at other sites studied. ³⁴ In interpreting this important systematic review and meta-analysis in the context of older people’s health, we should be aware that the mean age of participants was 59 years with almost a quarter aged under 50 years; a number of studies recruited specific ethnic groups, including African–Americans, Bangladeshi women and Pakistani immigrants, and two studies solely recruited overweight populations. A range of supplement doses was used (from the equivalent of 300 IU/day to more than 7,000 IU/day); the baseline 25(OH)D level (where measured) and dietary calcium intakes varied considerably. In contrast, one placebo-controlled study of women aged over 65 years in Aberdeen, not included in the meta-analysis by Reid and colleagues, showed that a daily dose of 1000 IU (but not 400 IU) vitamin D₃ attenuated the decline in BMD over 12 months at the total hip site. ³⁵ In the treatment of osteomalacia, BMD can increase considerably (by 70% or more), although the evidence is based on relatively small case series in groups with profound vitamin D deficiency, ³⁶ and it has been suggested that the effect of vitamin D supplementation seen in some studies is due to the prevalence of hypovitaminosis D and the treatment of mineralization disorder in associated osteomalacia, rather than an effect of supplement on the prevention of osteoporosis. ³⁷

Beyond changes in BMD, the important clinical outcome of interest must be osteoporotic fracture risk reduction. It has been suggested that vitamin D supplementation in doses of at least 800–1000 IU daily are required to decrease the incidence of both falls and fractures in older women, whereas lower doses are ineffective.^38–40 In contrast, the IOM review of dietary reference intakes for vitamin D and calcium, ¹⁸ the DIPART (vitamin D Individual Patient Analysis of Randomized Trials) Group, ⁴¹ and Cochrane review ⁴² found no evidence that vitamin D supplementation can prevent fractures. However, with coprescription of calcium, hip fracture risk is reduced, as are total fractures, ⁴¹ and nonvertebral fractures, ¹⁸ , ⁴² particularly in those living in institutions (care homes or sheltered housing).

Dose of supplement has already been mentioned as a determinant of effect and the interval between doses is another potentially important factor. Intermittent high-dose oral vitamin D₃ supplementation (100,000 IU every 4 months) was associated with a 33% reduction in risk for hip, wrist or vertebral fracture. ⁴³ Whereas another study using 300,000 IU of vitamin D₂ given intramuscularly to care home residents for 10 months had no effect on hip fracture incidence. ⁴⁴ Another study, giving 300,000 IU of vitamin D₂ yearly for 3 years, found no evidence of effect on overall fracture risk, but an unexpected increase in hip fractures by 49%, with wide 95% confidence intervals (2% to 118%, p = 0.04). ⁴⁵ More recently, a study using a yearly oral dose of 500,000 IU vitamin D intended to prevent fractures in a group of women aged over 70 years was surprisingly associated with an increased risk of both fractures (15% greater, p = 0.047) and falls (15% greater, p = 0.03), the latter particularly increased (by 31%) during the first 3 months after dose administration. ⁴⁶ Most recently, a study looking at monthly bolus dosing using three regimens (60,000 IU D₃ versus 24,000 IU plus 300 µg calcifediol versus 24,000 IU D₃) observed significantly more falls in the 60,000 IU and the 24,000 IU plus calcifediol groups compared with the 24,000 IU group. The study was too small to evaluate differences in fracture risk. ⁴⁷

The mechanisms underlying the apparent J-shaped curve of fall and fracture risk associated with vitamin D dose and dosing interval remain unclear. Unfortunately, the majority of clinical trials have not measured the effects of vitamin D supplementation on plasma 25(OH)D concentration, although this may be a better predictor of benefit. ³⁹ It would therefore be useful to know more about the baseline vitamin D status, the dose effect on 25(OH)D levels and the relationship of calcium intakes at baseline and during supplementation to help interpret their effects on falls and fracture risk in the populations which have been studied.

Vitamin D and muscle

Muscle weakness has long been recognized as a component of rickets (in children) and osteomalacia, and deterioration in both muscle strength and muscle mass (sarcopenia) with age are potential components of age-associated decline in musculoskeletal health. Direct effects of vitamin D and its metabolites on neuromuscular function have been postulated. However, the existence and significance of vitamin D receptors (VDR) in muscle is controversial, with debate about the possible impact of 1,25(OH)₂-vitamin D on muscle VDR expression in humans. ⁴⁸ Lower circulating 25(OH)D levels are associated with a reduction in muscle mass and increasing levels of frailty and may contribute to the mechanisms contributing to an increase in risk of falls and fractures. ⁴⁹ , ⁵⁰ However, we need to be cautious in interpreting epidemiological evidence. One recent randomized controlled trial in older, frail, vitamin D-insufficient women found that high-dose vitamin D supplementation could increase intramyonuclear VDR concentration by 30% with increased muscle fibre size by 10%. ⁵¹ However, studies aimed at showing that vitamin D supplementation can improve muscle mass or muscle strength are less convincing. In a meta-analysis of short-term trials looking at a range of supplementation strategies in just 310 adults aged 18–40, increased upper and lower limb strength was observed. ⁵² However, in another study of vitamin D supplementation which incorporated 17 randomized controlled trials involving 5072 participants, in the majority aged over 60 years, an increase in proximal muscle strength was only found in adults with vitamin D deficiency at baseline. ⁵³

In clinical practice, improving muscle strength in older people has an intuitive benefit with regard to fall prevention, but the relationship is likely to be complex. An overlap between frailty, sarcopenia and osteoporosis with ageing has been recognized and distilled into the concept of ‘osteosarcopenic obesity’, with affected individuals at increased risk of falls and fractures. ⁵⁴ Targeting all three domains of this syndrome may help to develop strategies in fall and fracture prevention, with vitamin D deficiency potentially having impacts on all three via improved insulin sensitivity, muscle strength and bone mass. However, it is early days for this hypothesis and robust clinical evidence from randomized controlled trials are required!

We conclude that there is convincing evidence of vitamin D deficiency in the older population of many countries. There is a clear risk to musculoskeletal health from osteomalacia and hyperparathyroidism with muscle weakness (myopathy) and osteoporosis. The risk factors in older age for frailty, sarcopenia, osteomalacia and osteoporosis cluster, and the population at risk of falls and fractures can be identified. The treatment of vitamin D deficiency is clearly effective in patients with severe osteomalacia; falls prevention is also supported by evidence, but the role of vitamin D in osteoporosis treatment and fracture prevention is less clear. Moreover, there is increasing concern about the optimal dose of vitamin D to be given to prevent adverse outcomes and some evidence is gathering that high, intermittent dosing may actually be harmful, resulting in an increased risk of falls and possibly fractures.