Effects of Isotretinoin (Accutane) on Bone Health
Isotretinoin at standard acne doses (approximately 1 mg/kg/day for 16-20 weeks) does not cause clinically significant bone mineral density loss or skeletal abnormalities in the vast majority of patients, though rare cases of bone changes warrant awareness in specific high-risk populations. 1, 2
Bone Mineral Density Effects
Standard Acne Treatment (Short-Term, Standard Dose)
A prospective study of 217 adolescent patients (ages 12-17) treated with isotretinoin at approximately 1 mg/kg/day for 16-20 weeks showed no clinically significant mean change in bone mineral density at the lumbar spine (+1.4%) or total hip (-0.26%). 2
In this adolescent study, 92% of patients had no significant decreases or had increases in lumbar spine BMD (adjusted for body mass index), and 89% had no significant decreases or had increases in total hip BMD. 2
A separate cohort study of 20 adults receiving isotretinoin for severe acne found no changes in bone mineralization of the lumbar spine or hip after 20 weeks of treatment. 3
Another study examining 120 patients treated with 0.5 mg/kg/day isotretinoin found only 12% showed minor radiographic changes (spinal or calcaneal hyperostoses), none of which were clinically significant, and 8% of matched controls showed similar changes. 4
Potential Concerns with Long-Term or High-Dose Use
The FDA label warns that effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown, and there is evidence that long-term, high-dose, or multiple courses may have more effect than a single course. 1
One study of young men (ages 17-25) with cystic acne showed a mean 4.4% decrease in bone density at Ward's triangle after 6 months of isotretinoin at 1 mg/kg, with four patients showing decreases greater than 9%. 5
In an open-label extension study of 10 adolescent patients who started a second course of isotretinoin 4 months after the first course, two patients showed decreases in mean lumbar spine BMD up to 3.25%. 1
Skeletal Hyperostosis and Calcification
Risk Profile by Indication and Dose
Hyperostosis is primarily associated with high-dose, long-term retinoid therapy for disorders of keratinization (mean dose 2.24 mg/kg/day), not standard acne treatment. 1
The British Association of Dermatologists reports that long-term (2-4 years) treatment with etretinate (a related retinoid) was associated with extraspinal tendon and ligament calcification at ankles, pelvis, and knees, though no correlation with dose or duration was established. 6
Diffuse idiopathic skeletal hyperostosis (DISH)-like involvement has been reported as a rare side effect of systemic retinoids, characterized by degenerative spondylosis, vertebral arthritis, and syndesmophytes. 6
In the prospective study of 217 adolescent acne patients treated for 16-20 weeks at approximately 1 mg/kg/day, hyperostosis was not observed in any patient. 2
Clinical Significance
The American Academy of Dermatology/National Psoriasis Foundation guidelines note that diffuse idiopathic hyperostosis is a rarely reported adverse effect that can be severe and debilitating in some cases. 6
Minimal skeletal hyperostosis and calcification of ligaments and tendons have been observed by x-ray in prospective studies of nodular acne patients treated with a single course at recommended doses, though clinical significance remains unclear. 1
Premature Epiphyseal Closure in Children
The FDA label includes spontaneous reports of premature epiphyseal closure in acne patients receiving recommended doses of isotretinoin, though this is rare. 1
The British Association of Dermatologists reports occasional cases of premature epiphyseal closure in children on long-term etretinate, noting that very high dose exposure in one case led to osteopenia and fractures in bones that fused prematurely. 6
A prospective follow-up of 42 children treated over 11 years did not reveal abnormalities that would significantly impede starting or continuing therapy, and effects on growth were not seen in an additional 18 children. 6
The American Academy of Dermatology/National Psoriasis Foundation guidelines state that systematic retinoids may rarely cause premature epiphyseal growth plate closure in young patients. 6
Osteoporosis Risk
Whether isotretinoin causes osteoporosis is controversial; the risk appears highest in patients receiving long-term, high-dose retinoids. 6
The FDA label states that although an effect of isotretinoin on bone loss is not established, physicians should use caution when prescribing to patients with genetic predisposition for age-related osteoporosis, history of childhood osteoporosis conditions, osteomalacia, or other bone metabolism disorders. 1
A study of long-term acitretin therapy (median 3.6 years) found no association between daily dose, total dose, or duration of treatment and risk of osteopenia or osteoporosis. 7
Fracture Risk
Spontaneous reports of osteoporosis, osteopenia, bone fractures, and delayed healing of bone fractures have been seen in the isotretinoin population, though causality has not been established. 1
The FDA label warns that patients may be at increased risk when participating in sports with repetitive impact where risks of spondylolisthesis with and without pars fractures and hip growth plate injuries are known. 1
There are spontaneous reports of fractures and/or delayed healing in patients while on therapy or following cessation while involved in high-impact activities, though causality to isotretinoin has not been established. 1
Monitoring Recommendations
Routine Radiographic Surveillance
The British Association of Dermatologists consensus states that routine radiographic assessments are not required for long-term acitretin therapy, as the evidence does not support this practice which exposes subjects to unnecessary radiation. 6
Targeted X-rays for atypical musculoskeletal pain may be informative. 6
High-Risk Populations Requiring Caution
Patients with genetic predisposition for age-related osteoporosis should be prescribed isotretinoin with caution. 1
Patients with history of childhood osteoporosis conditions, osteomalacia, or other bone metabolism disorders require careful consideration. 1
Patients diagnosed with anorexia nervosa warrant caution. 1
Those on chronic drug therapy causing drug-induced osteoporosis/osteomalacia or affecting vitamin D metabolism (systemic corticosteroids, anticonvulsants) require heightened vigilance. 1
Clinical Decision-Making Algorithm
For standard acne treatment (single course, 16-20 weeks, ~1 mg/kg/day):
- Proceed with treatment in otherwise healthy patients without special bone monitoring. 2, 3
- Counsel patients about rare skeletal risks but emphasize that clinically significant bone effects are uncommon at standard doses. 1, 2
For patients requiring multiple courses or long-term therapy:
- Consider bone density assessment before initiating additional courses, particularly in adolescents or those with risk factors. 1
- Ensure isotretinoin is given at recommended doses for no longer than recommended duration. 1
For pediatric patients on long-term therapy:
- Clinically monitor for abnormalities of growth parameters and bone development if severe condition warrants long-term use. 6
- Appropriate daily dose in children under 12 years is 0.5 mg/kg, occasionally increased to 1 mg/kg. 6
For patients with musculoskeletal symptoms:
- Obtain targeted imaging for atypical musculoskeletal pain rather than routine surveillance. 6
- Discontinue therapy if severe or debilitating skeletal changes develop. 6
Important Caveats
The skeletal effects of multiple isotretinoin treatment courses for acne are unknown, as hyperostosis may require a longer time frame to appear. 1
Longer term effects beyond single-course therapy have not been adequately studied. 1
Bone density measurements in young patients may be confounded by normal growth and development, making interpretation challenging. 2
Patients with cystic acne may have lower baseline bone density compared to healthy controls even before treatment, suggesting a possible disease-related effect. 5