Vitamin D Supplements Could Have Potential as XLH Therapy, Mouse Study Shows

Vitamin D dietary supplements can promote bone mineralization without changing phosphate levels or causing calcium to rise to unhealthy levels and form solid deposits in the kidneys.

That finding, from a study in a mouse model of X‐linked hypophosphatemia (XLH), suggests that vitamin D supplements, when used alone or in combination with phosphate supplements, should be explored as a potential therapy for XLH, researchers said.

The study, “Vitamin D supplementation improves bone mineralisation independent of dietary phosphate in male X-linked hypophosphatemic (Hyp) mice,” was published in the journal Bone and was conducted by researchers at the University of South Australia and their collaborators.

XLH is a rare genetic disorder characterized by the excessive production of fibroblast growth factor 23 (FGF23), an enzyme responsible for controlling phosphate reabsorption in the kidneys.

When present in abnormally high levels, FGF23 prevents the kidneys from reabsorbing phosphate and block the production of active vitamin D. This leads to chronic hypophosphatemia — low levels of phosphate in the blood — as well as softening and weakening of bone tissues.

The standard treatment for XLH in children is a combination of oral phosphate supplements and active vitamin D compounds, such as calcitriol. However, these treatments sometimes lead to side effects, including abnormally high levels of calcium in the blood (hypercalcemia) and formation of calcium deposits in soft tissues.

“Thus, further efforts are required to establish effective and safe strategies to prevent under-mineralized bone without causing the significant side effects that can arise with active vitamin D,” the researchers wrote.

To investigate if vitamin D supplements could improve bone mineralization without causing such side effects, the scientists explored the effects of dietary regimens containing different levels of vitamin D in a mouse model of XLH (Hyp mice).

In their experiments, they used young male mice that were fed one of four diets until they reached 12 weeks of age.

In the normal (control) diet group, mice were fed with food that contained 1,000  international units of vitamin D per kilogram (IU/kg) and 0.35% of phosphate. In the group receiving vitamin D supplemented diet, the animals were fed with food that contained the same amount of phosphate as the control group, but was supplemented with vitamin D (20,000  IU/kg).

Animals in the other two groups were fed either with a diet that was  supplemented only with phosphate (1.25% phosphate, 1,000 IU/kg vitamin D), or with a vitamin D and phosphate double supplemented diet — 1.25% phosphate, 20,000 IU/kg vitamin D.

Compared to animals fed with the normal diet, those receiving the vitamin D supplemented regimen had much higher levels of vitamin D in the blood — 72.8 vs. 33.9 nanomole per liter (nmol/L).

Also, the investigators found that bone mineral density was 15% higher in mice fed with the vitamin D supplemented diet, compared with controls. Importantly, increases in bone mineral density and vitamin D in these animals were not accompanied by changes in calcium or phosphate levels.

They also found that compared to control animals, mice given phosphate supplementation had longer and thicker bones. However, the addition of phosphate to a diet that was already supplemented with vitamin D did not further enhance its effects on bone mineralization.

Yet, mice fed with double supplemented diet were those with the highest levels of vitamin D in the blood (118.8 nmol/L).

In addition, the increases in bone mineral density observed in mice fed with the vitamin D supplemented diet were associated with a reduction in osteoid (unmineralized bone) volume, along with a tendency for low levels of parathyroid hormone, which controls blood calcium levels.

According to the researchers, these observations suggested that bone turnover — the balance between the formation and breakdown of bone tissue — was reduced in these mice.

“In conclusion, the contribution of high dietary vitamin D3 to improve bone mineralization in male Hyp mice, without changes to circulating levels of phosphate, without causing hypercalcemia, and without causing nephrocalcinosis [kidney calcification], demonstrates that vitamin D supplementation, with or without phosphate administration, could be explored further as potential therapy for XLH,” they wrote.