Treatment with vitamin A analogues such as isotretinoin and acitretin does not increase fracture risk, according to findings from a nationwide Danish case-control study.
Of all fractures sustained in a single year, no form of systemic or topical vitamin A analogues was associated with fracture risk at any skeletal site, said Dr. Peter Vestergaard and his associates at Aarhus (Denmark) University Hospital.
Previous research has yielded conflicting results. Some studies have found that high-dose therapy is related to an increased risk of fracture and adverse bone changes, including hyperostosis, hypercalcemia, impaired bone turnover, and decreased bone mineral density, while other studies have found no such association.
The results of this large population-based study show that “even very large daily doses of 14 mg of vitamin A analogues (equivalent to 14,000 micrograms of retinol equivalents per day) were not associated with an increased risk of fractures. It thus seems that vitamin A analogues are safe in terms of fractures, even at very high doses,” Dr. Vestergaard and his colleagues wrote (Arch. Dermatol. 2010;146:478-82).
They used data from 124,655 cases of fracture that occurred in 2000 and 373,962 control cases matched for age and sex. The data were adjusted to account for the severity of the underlying disease requiring treatment with vitamin A analogues, as well as for the concomitant use of drugs known to affect fracture risk, such as corticosteroids and antiepileptic agents.
There was no association between any form of vitamin A analogue and fracture risk at any site. Moreover, no trend was found between increasing dose or increasing duration of treatment and any fracture risk, the investigators reported.
There also was no association with fracture risk when the use of individual vitamin A analogues was analyzed.
“Even though some studies have reported a decreased BMD with high doses of vitamin A as retinol in dietary intake or as supplements, the decrease may not have been of such magnitude that it altered bone biomechanical competence,” Dr. Vestergaard and his associates noted.
In an editorial accompanying the report, Dr. John J. DiGiovanna of Brown University, Providence, noted that these results are particularly reassuring because the investigators examined “a large population of humans treated under real therapeutic conditions” and because the end point (fracture) was clinically important.
The main weakness of the study was that it could not completely account for potentially confounding factors such as smoking habits, body mass index, vitamin D status, and sun exposure, he wrote (Arch. Dermatol. 2010; 146:551-3).
“While it is reassuring to see this evidence of retinoid drug safety in relation to bone demineralization in a large population, the treatment of patients must rely on personalized prescription. Sound measures for good skeletal health, including adequate nutrition (especially vitamin D and calcium, etc.) and healthy physical activity, should be encouraged.
“Monitoring may be indicated for individuals with a family or personal history of osteoporosis, advanced age, and exposure to agents known to cause demineralization, and possibly those requiring long-term or high-dose retinoid drug therapy,” Dr. DiGiovanna added.
This study was supported by the Danish Medical Research Council. Dr. Vestergaard reported receiving support from Servier, Bayer Pharmaceuticals, Eli Lilly and Company, Novartis, and Sanofi-Aventis. Dr. DiGiovanna reported receiving support from Basilea, Hoffman La Roche, Allergan, and Cipher Pharmaceuticals.