[Skip to Content]
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.161.130.145. Please contact the publisher to request reinstatement.
[Skip to Content Landing]
Observation
August 1999

Bone Densities in Patients Receiving Isotretinoin for Cystic Acne

Author Affiliations

From the Departments of Dermatology (Drs Leachman and Milstone), Internal Medicine (Dr Insogna and Ms Ellison), and Diagnostic Imaging (Dr Katz), Yale University School of Medicine, and the Department of Dermatology, Veterans Affairs Medical Center Connecticut (Dr Milstone), New Haven. Dr Leachman is now with the Department of Dermatology, University of Utah School of Medicine, Salt Lake City.

Arch Dermatol. 1999;135(8):961-965. doi:10.1001/archderm.135.8.961
Abstract

Background  Few studies have been done of bone densities in humans receiving retinoids, despite a substantial amount of literature concerning retinoid-induced osteoporosis in animals. We prospectively measured bone density and calcium metabolism in young men (aged 17-25 years) receiving oral isotretinoin for cystic acne and in a group of healthy volunteers (aged 19-26 years).

Observations  Compared with that in healthy control subjects, mean bone density was lower at all sites (spine, femoral neck, and Ward triangle) and was considerably more variable at the spine in young men with cystic acne even before treatment. Bone density at the Ward triangle decreased a mean of 4.4% (P=.03) after 6 months of isotretinoin use (1 mg/kg of body weight). Four patients showed decreased density of more than 9% at the Ward triangle. The difference between the mean change in bone density in the patient group and in the control group was significant at the Ward triangle (P=.04) but not at the other sites. Measurements of calcium metabolism did not change over time in either group.

Conclusions  A loss of bone density occurring in the absence of measurable alterations of calcium metabolism is likely to be a direct effect of retinoids on bone. Further study of retinoid-induced osteoporosis in humans and of bone density in patients with cystic acne is needed.

RETINOIDS have an important and expanding role as therapeutic agents. Since the introduction of isotretinoin for the treatment of inherited disorders of keratinization1 and cystic acne2 more than 20 years ago, naturally occurring and synthetic retinoids have been used increasingly in the treatment of additional cutaneous diseases3 and in the prevention or treatment of malignant neoplasms.48

Although the benefit-risk ratio of the use of retinoids is generally excellent,9 vitamin A has profound and complex effects on bone growth and metabolism.10 Vitamin A toxic effects in humans and in animals include hypercalcemia,1114 cortical new bone formation,15 premature closure of epiphyses,16,17 and demineralization that can lead to fractures.10,17 Indeed, long bone fractures in animals was a key measure of toxic effects in the initial efficacy-toxicity screens designed to evaluate potentially useful synthetic retinoids.18 A recent study19 in women found that high dietary intake of retinol was associated with osteoporosis and an increased risk for hip fracture.

The reported musculoskeletal effects of synthetic retinoids in humans mimic those of hypervitaminosis A.20 They include pain, diffuse idiopathic skeletal hyperostosis,21 premature closure of epiphyses,22,23 and calcification of ligaments and tendons at bony insertions.24,25 "Lucent" bones have been described24,26 on radiographs, and a spontaneous vertebral fracture developed in 1 person receiving isotretinoin long term.27 Nonetheless, no relation between isotretinoin use and osteoporosis was identified in several recent studies.2830 To understand better the effects of synthetic retinoids on bone, we prospectively investigated bone density and calcium metabolism in young men who received isotretinoin for cystic acne.

PARTICIPANTS AND METHODS
STUDY DESIGN

Bone densities and indices of calcium metabolism were measured during a 6-month period in men receiving isotretinoin (1 mg/kg of body weight) for acne and in an age-matched untreated control group.

PARTICIPANTS

Subjects in the treatment group were referred from the dermatology faculty practice of Yale University School of Medicine, New Haven, Conn, or from local dermatologists for the treatment of cystic acne. Control subjects were recruited from local universities. Subjects were limited to men between the ages of 17 and 26 years to minimize age-related decreases in bone density and to avoid intrinsic differences in the response of men and women and the confounding effects of estrogen-containing oral contraceptives used by many women who take retinoids orally. Other exclusion criteria included a history of acne fulminans, the prior use of isotretinoin, the prior or current use of corticosteroids or diuretics, and a personal or family history of metabolic bone disease. The Human Investigation Committee of the Yale University School of Medicine approved this study. All participants gave written informed consent and were instructed not to make notable changes in their diets or to take supplemental vitamin A.

BONE DENSITY MEASUREMENTS

Bone densitometry was performed using absorptiometry (Hologic 1000 QDR; Hologic, Inc, Waltham, Mass) following the manufacturer's recommended protocols. The manufacturer uses the following measurements of precision for this machine: lumbar spine, 0.00806 g/cm2; femoral neck, 0.0104 g/cm2; and the Ward triangle, 0.0161 g/cm2. To ensure that there were no technical anomalies in the raw data and that the density readouts were correct, all scans were reanalyzed independently, in a blinded manner, by a company scientist.

METABOLIC MEASUREMENTS

Circulating levels of 25-hydroxyvitamin D were measured by a previously described31 competitive protein-binding assay using rat plasma as the source of vitamin D–binding protein. Circulating levels of 1,25-dihydroxyvitamin D were determined by a competitive protein-binding assay32 using calf thymus receptor protein for 1,25-dihydroxyvitamin D. The serum immunoreactive parathyroid hormone (PTH) concentration was measured using an antiserum to the midregion of human PTH. Bovine PTH (amino acids 37-84) labeled with iodine I 125 was used as a tracer with standards from a human PTH adenoma extract, as previously described.32 Urinary and plasma cyclic adenosine monophosphate (cAMP) levels were measured by radioimmunoassay,33 and nephrogenous cAMP was calculated using the measured plasma and urine values and serum creatinine concentrations. The renal tubular maximum for the absorption of phosphorus was normalized to the glomerular filtration rate.34 The oral calcium tolerance test was performed as previously reported35 following an overnight fast after subjects had been receiving a low-calcium diet for 10 days. Briefly, baseline blood and urine specimens were collected between 7 and 9 AM. At 9 AM, oral calcium, 1 g, was given, and blood and urine specimens were again collected between noon and 1 PM after an equilibration period from 9 to 11 AM. Total serum and urinary calcium values were determined by atomic absorption spectrometry (model 2380; Perkin-Elmer Corp, Norwalk, Conn). Serum and urinary phosphorous levels were determined by a colorimetric method adapted for the automated centrifugal analyzer (Gemini; Electro-Nucleonics Inc, Silver Springs, Md). Serum creatinine, electrolyte, triglyceride, cholesterol, aspartate and alanine aminotransferase, alkaline phosphatase, and bilirubin concentrations were measured by standard automated methods.

DATA ANALYSIS

Each parameter was analyzed using paired t tests. Differences in changes between groups were assessed using t tests, adjusted for unequal variances where necessary.

RESULTS

Seventeen of the 18 patients and 13 of the 14 control subjects were white. At the time of baseline measurements (expressed as mean±SD), the age of the men receiving isotretinoin was 19.7±2.3 years and that of the control group was 23.0±2.1 years; weight was 71.4±7.3 kg vs 73.2±7.7 kg, and height was 176.4±6.6 cm vs 173.9±7.6 cm. Heights and weights did not change significantly during the 6 months of the study. The interval between the baseline and the second calcium tolerance test was 195±26 days for the group receiving isotretinoin and 219±53 days for the control group.

Bone mineral density at the lumbar spine, femoral neck, and Ward triangle was measured at baseline and after 6 months. Initial bone densities were more variable at all sites in the patient group than in the control group (Figure 1). Two subjects receiving isotretinoin for the treatment of acne had densities at the spine that were more than 2 SDs below the reference means supplied by the manufacturer of the measuring device. Initial mean bone densities at all sites were lower in the patient group than in the control group (Table 1). In both groups, however, the mean densities were well within the age- and sex-matched reference ranges.

Figure 1.
Bone mineral densities were measured during a 6-month period in control subjects and in patients receiving isotretinoin for acne. Each line represents 1 patient: the baseline measurement is at the left end of the line, and the 6-month measurement is at the right end.

Bone mineral densities were measured during a 6-month period in control subjects and in patients receiving isotretinoin for acne. Each line represents 1 patient: the baseline measurement is at the left end of the line, and the 6-month measurement is at the right end.

Measurements of Bone Density and Calcium Metabolism*
Measurements of Bone Density and Calcium Metabolism*

During the 6 months of observation, bone density decreased at all sites in both groups, except for an increase at the lumbar spine in the group receiving isotretinoin (Figure 2). Patients receiving isotretinoin had a mean decrease in bone density at the Ward triangle of 4.4% (P=.03) and an increase at the lumbar spine of 1.1% (P=.02). The mean change of −4.4% at the Ward triangle in the patient group was significantly different (P=.04) from the −0.01% change at the Ward triangle in the control group (Table 1).

Figure 2.
The change in bone density at 3 sites during 6 months of observation is plotted for patients receiving isotretinoin for acne and for control subjects. The mean (±SEM) change for each group is shown to the right of individual changes.

The change in bone density at 3 sites during 6 months of observation is plotted for patients receiving isotretinoin for acne and for control subjects. The mean (±SEM) change for each group is shown to the right of individual changes.

Four of the 18 men treated with isotretinoin had a mean decrease in bone density at the Ward triangle of more than 9%. These 4 had 4 of the 5 lowest spine densities at the start of treatment. No significant differences in the other measurements of bone density or calcium metabolism characterized this group of 4 compared with the control group or the rest of the isotretinoin-treated men.

Serum and urine measurements of calcium metabolism were obtained at baseline and at 6 months, and selected values are shown in Table 1. Serum calcium, phosphorous, PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D concentrations were within the reference range at both times for every patient. A mean increase in the 25-hydroxyvitamin D levels in the patient group and a mean decrease in the urinary nephrogenous cAMP response to the calcium load in the control group were noted. These changes were not associated with significant differences in values between the patient and control groups.

An oral calcium tolerance test was used to demonstrate that men receiving isotretinoin absorbed oral calcium and had an appropriate rise in serum calcium levels and an appropriate fall in nephrogenous cAMP concentrations (Table 1). The response to the calcium tolerance test after 6 months of isotretinoin treatment was the same as the response at baseline. The response in the patient group was not significantly different from that in the control group.

COMMENT

The decrease in bone density at the Ward triangle in our patients who received isotretinoin should not be surprising. Research published during the past 70 years has demonstrated that the profound effects of retinoids on bone growth and mineralization are dependent on the dose and duration of treatment. Normal bone growth and development require adequate levels of vitamin A.36 Animals fed excess vitamin A or synthetic retinoids have accelerated bone remodeling10,37 that leads to poor bone growth, radiolucency, loss of mineral content,3840 and spontaneous fractures.18,41,42 Retinoids act directly on bone, causing demineralization of intact bones in vitro43,44 and the activation of isolated osteoblasts45 and osteoclasts.46 Retinoids act by binding to a family of nuclear receptors, and each receptor shows tissue-specific and developmentally regulated expression. In evaluating the risk-benefit ratios of retinoids that have therapeutic actions on skin, the finding47,48 that the retinoic acid γ receptor is predominantly expressed in skin, cartilage, and developing bone is likely to be important, although still cryptic.

Hypervitaminosis A causes bone demineralization and even fractures in humans, most of which have occurred in children.12,17 Yet, a number of considerations fostered the hope that these toxic effects of vitamin A on the skeleton might not be a problem in adults using synthetic retinoids such as isotretinoin. First, the synthetic retinoids available for clinical use were marketed because of their tissue-selective effects: compared with vitamin A, they have relatively strong effects on epithelial tissues and weak effects on bone.18 Second, it was hoped that skeletal toxic reactions might not be directly relevant to synthetic retinoid use in adult humans. Most of the experiments in animals have been done on growing rather than adult bones, and most of the toxic effects of vitamin A in humans have been observed in children.

Although several reports have suggested that isotretinoin use is associated with radiolucency of long bones24,26 and abnormal findings on bone scans,49 3 recent patient series2830 published following the initiation of our study were reassuring in their assessment of isotretinoin use in adults. None found deleterious effects of isotretinoin use on measurements of bone density.

Why are the results and conclusions of the bone density measurements in those 3 series different from ours? Kocijancic28 prospectively measured bone densities at a single location, the lumbar spine, in males receiving isotretinoin for acne. He attributed a small increase in density of the spine to an age-expected change at that site. We, too, saw a small increase in density of the spine and would add that mild isotretinoin-induced calcification of the anterior longitudinal spinal ligament, which has been reported50 in patients receiving isotretinoin for acne, might contribute to that increase. DiGiovanna et al29 took single measurements of bone density in patients who had received retinoids long term for inherited disorders of keratinization and compared them with those of age- and sex-matched "normals" provided by the manufacturer of the densitometer. The use of etretinate, but not of isotretinoin, was associated with low bone density at the Ward triangle compared with the reference values. Reservations about that report have been raised51 because of the heterogeneity of the patient population in underlying diagnosis, age, sex, and ancillary treatments and because some patients had diseases that predisposed them to elevations in PTH levels and abnormalities in calcium metabolism. In addition, long-term therapy with retinoids would have predisposed those patients to widespread ligamentous calcifications that could confound the density measurements. Margolis et al30 prospectively studied patients who received isotretinoin for acne. In contrast to our study, they identified no effect of isotretinoin on bone density. The Margolis study differed from our study in several respects: it lacked a control group; it used a variable and, on average, lower dose of isotretinoin (0.89 mg/kg); the treatment course lasted 20 weeks instead of 28 weeks; both men and women (many of whom were using oral contraceptives) were enrolled; and the patients' ages ranged from 19 to 35 years.

Our study, too, has flaws and raises questions. Larger samples might have added weight to the statistical differences and allowed a detection of changes in addition to the change at the Ward triangle. It is regrettable that we have no measures of bone turnover, such as osteocalcin or procollagen telopeptide levels. A randomized, prospective comparison of treated and untreated patients with cystic acne would have been better. We question, however, whether administering a mildly toxic medicine to healthy persons or withholding a uniquely effective treatment from young men with cystic acne is justified. Other impediments to prospective studies of retinoid effects on bones—such as the reluctance of insurers to pay for monitoring tests—have been discussed51; perhaps our identification of a potentially serious toxic effect now provides adequate justification for such a study.

Retinoid dosage and individual susceptibility may each be determinants of toxicity. Case reports and experimental studies11,12,40 generally point to the importance of dosage in provoking more serious toxic effects, such as hypercalcemia. Our inability to detect measurable changes in PTH levels or in calcium and vitamin D metabolism is consonant with other studies of comparable doses29 and suggests that subtle, direct effects of isotretinoin on bone cause the loss of bone density at the Ward triangle without causing hypercalcemia.

The baseline findings of generally low bone densities and great variability of spine density in the patients with acne were unexpected and deserve further study. That patients with acne fulminans have lytic lesions in bone, but patients with cystic acne apparently do not, is well known.52 In our series, the 4 persons showing the greatest decrease in bone density at the Ward triangle had 4 of the 5 lowest baseline densities at the spine. That observation suggests that some persons may be at increased risk for retinoid-induced osteoporosis at the Ward triangle and that they might be identifiable by pretreatment measurements of spine density. Villablanca et al53 have suggested that individual susceptibility may be a determinant of retinoid-induced toxic effects: peak serum concentrations of retinoid did not correlate with the degree of hypercalcemia after high doses of isotretinoin were given for neuroblastoma.

The important question raised by our study is the clinical significance of a mean 4% decrease in bone density at the Ward triangle in young men. In a dietary study of Scandinavian women,19 a high intake of vitamin A was associated with osteoporosis—most notably at the Ward triangle—and with an increased risk for hip fracture. Is progressive demineralization likely in persons who need long-term retinoid therapy for chemoprevention or for chronic, serious skin disease such as psoriasis or ichthyosis? Is the isotretinoin-induced osteoporosis at the Ward triangle reversible after short courses of retinoids? Are some persons predisposed or sensitized to the demineralizing effect of retinoids, and how can those persons be identified?

As the clinical uses for retinoids expand, it is important to determine whether retinoid-induced loss of bone density is reversible, whether it is progressive with longer courses of treatment, and whether the effect applies to all treatment populations and to all retinoids having a therapeutic action on skin. If the loss of bone density leads to more serious medical sequelae, such as fractures, can preventive measures, such as dietary supplements of calcium, vitamin D, or vitamin E,8 prevent retinoid-induced demineralization without increasing the risk of ligamentous calcifications or decreasing efficacy? Further studies are needed so that this unique and potent class of drugs can be used with the highest possible margin of safety.

Back to top
Article Information

Reprints: Leonard M. Milstone, MD, Department of Dermatology, Yale University School of Medicine, PO Box 208059, New Haven, CT 06520-8059 (e-mail: leonard.milstone@yale.edu).

Accepted for publication April 21, 1999.

This study was supported in part by grant ROO-0125 from the National Institutes of Health, Bethesda, Md, to the Yale University School of Medicine General Clinical Research Center, and by a grant from Hoffmann-La Roche Inc, Nutley, NJ.

Presented in abstract form at the 60th annual meeting of the Society for Investigative Dermatology, Chicago, Ill, May 5-9, 1999.

We thank Ellen B. Milstone, MD, Judit Stenn, MD, and Lisa C. Kugelman, MD, for referring participants and Mary Meighan, MD, and Ellen Markstein, MD, for clinical data collection. We are grateful to Thomas L. Kelly at Hologic, Inc, Waltham, Mass, for reviewing the bone density measurements and to Carolyn K. Wells, MPH, for statistical analysis.

References
1.
Peck  GLYoder  FW Treatment of lamellar ichthyosis and other keratinising dermatoses with an oral synthetic retinoid. Lancet. 1976;21172- 1174Article
2.
Peck  GLOlsen  TGYoder  FW  et al.  Prolonged remissions of cystic and conglobate acne with 13-cis-retinoic acid. N Engl J Med. 1979;300329- 333Article
3.
 edBernhard  JD The evolving role of retinoids in the management of cutaneous conditions. J Am Acad Dermatol. 1998;39 (suppl) 1- 122Article
4.
Kraemer  KHDiGiovanna  JJMoshell  ANTarone  REPeck  GL Prevention of skin cancer in xeroderma pigmentosum with the use of oral isotretinoin. N Engl J Med. 1988;3181633- 1637Article
5.
Hong  WKLippman  SMItri  LM  et al.  Prevention of second primary tumors with isotretinoin in squamous-cell carcinoma of the head and neck. N Engl J Med. 1990;323795- 801Article
6.
Muto  YMoriwaki  HNinomiya  M  et al.  Prevention of second primary tumors by an acyclic retinoid, polyprenoic acid, in patients with hepatocellular carcinoma: Hepatoma Prevention Study Group. N Engl J Med. 1996;3341561- 1567Article
7.
Tallman  MSAndersen  JWSchiffer  CA  et al.  All-trans-retinoic acid in acute promyelocytic leukemia [published correction appears in N Engl J Med. 1997;337:1639]. N Engl J Med. 1997;3371021- 1028Article
8.
Besa  ECAbrahm  JLBartholomew  MJHyzinski  MNowell  PC Treatment with 13-cis-retinoic acid in transfusion-dependent patients with myelodysplastic syndrome and decreased toxicity with addition of alpha-tocopherol. Am J Med. 1990;89739- 747Article
9.
 edKoren  G Retinoids in Clinical Practice: the Risk-Benefit Ratio.  New York, NY Marcell Dekker Inc1993;
10.
Wolbach  SB Vitamin-A deficiency and excess in relation to skeletal growth. J Bone Joint Surg. 1947;29171- 192
11.
Ragavan  VVSmith  JEBilezikian  JP Vitamin A toxicity and hypercalcemia. Am J Med Sci. 1982;283161- 164Article
12.
Frame  BJackson  CEReynolds  WAUmphrey  JE Hypercalcemia and skeletal effects in chronic hypervitaminosis A. Ann Intern Med. 1974;8044- 48Article
13.
Fisher  GSkillern  PG Hypercalcemia due to hypervitaminosis A. JAMA. 1974;2271413- 1414Article
14.
Katz  CMTzagournis  M Chronic adult hypervitaminosis A with hypercalcemia. Metabolism. 1972;211171- 1176Article
15.
Caffey  J Chronic poisoning due to excess of vitamin A. Pediatrics. 1950;5672- 687
16.
Pease  CN Focal retardation and arrestment of growth of bones due to vitamin A intoxication. JAMA. 1962;182980- 985Article
17.
Ruby  LKMital  MA Skeletal deformities following chronic hypervitaminosis A. J Bone Joint Surg. 1974;561283- 1287
18.
Bollag  W Therapeutic effects of an aromatic retinoic acid analog on chemically induced skin papillomas and carcinomas of mice. Eur J Cancer. 1974;10731- 737Article
19.
Melhus  HMichaëlsson  KKindmark  A  et al.  Excessive dietary intake of vitamin A is associated with reduced bone mineral density and increased risk for hip fracture. Ann Intern Med. 1998;129770- 778Article
20.
White  SIMacKie  RM Bone changes associated with oral retinoid therapy. Pharmacol Ther. 1989;40137- 144Article
21.
Pittsley  RAYoder  FW Retinoid hyperostosis: skeletal toxicity associated with long-term administration of 13-cis-retinoic acid for refractory ichthyosis. N Engl J Med. 1983;3081012- 1014Article
22.
Milstone  LMMcGuire  JAblow  RC Premature epiphyseal closure in a child receiving oral 13-cis-retinoic acid. J Am Acad Dermatol. 1982;7663- 666Article
23.
Prendiville  JBingham  EABurrows  D Premature epiphyseal closure: a complication of etretinate therapy in children. J Am Acad Dermatol. 1986;151259- 1262Article
24.
McGuire  JMilstone  LLawson  J Isotretinoin administration alters juvenile and adult bone. Sauret  JHed.Retinoids: New Trends in Research and Therapy. Basel, Switzerland S. Karger1985;419- 439
25.
DiGiovanna  JJHelfgott  RKGerber  LHPeck  GL Extraspinal tendon and ligament calcification associated with long-term therapy with etretinate. N Engl J Med. 1986;3151177- 1182Article
26.
Ruiz-Maldonado  RTamayo  L Retinoids in disorders of keratinization: their use in children. Dermatologica. 1987;175 (suppl 1) 125- 132
27.
Milstone  LMEllison  AFInsogna  KL Serum parathyroid hormone level is elevated in some patients with disorders of keratinization. Arch Dermatol. 1992;128926- 930Article
28.
Kocijancic  M 13-cis-Retinoic acid and bone density. Int J Dermatol. 1995;34733- 734Article
29.
DiGiovanna  JJSollitto  RBAbangan  DLSteinberg  SMReynolds  JC Osteoporosis is a toxic effect of long-term etretinate therapy. Arch Dermatol. 1995;1311263- 1267Article
30.
Margolis  DJAttie  MLeyden  JJ Effects of isotretinoin on bone mineralization during routine therapy with isotretinoin for acne vulgaris. Arch Dermatol. 1996;132769- 774Article
31.
Rosenthal  NInsogna  KLGoodsall  JWSmaldone  LWaldron  JAStewart  AF Elevations in circulating 1,25-dihydroxyvitamin D in three patients with lymphoma-associated hypercalcemia. J Clin Endocrinol Metab. 1985;6029- 33Article
32.
Insogna  KLMitnick  MEStewart  AFBurtis  WJMallette  LEBroadus  AE Sensitivity of the parathyroid hormone–1,25-dihydroxyvitamin D axis to variations in calcium intake in patients with primary hyperparathyroidism. N Engl J Med. 1985;1131126- 1130Article
33.
Broadus  AEMahaffey  JEBartter  FCNeer  RM Nephrogenous cyclic adenosine monophosphate as a parathyroid function test. J Clin Invest. 1977;60771- 783Article
34.
Bijvoet  OLM Kidney function in calcium and phosphate metabolism. Aviolo  LVKrane  SMeds.Metabolic Bone Disease. 1 Orlando, Fla Academic Press Inc1977;49- 140
35.
Broadus  AEDominguez  MBartter  FC Pathophysiological studies in idiopathic hypercalciuria: use of an oral calcium tolerance test to characterize distinctive hypercalciuric subgroups. J Clin Endocrinol Metab. 1978;47751- 760Article
36.
Wolbach  SBHowe  PR Tissue changes following deprivation of fat-soluble A vitamin. J Exp Med. 1925;42753- 777Article
37.
Clark  ISmith  MR Effects of hypervitaminosis A and D on skeletal metabolism. J Biol Chem. 1964;2391266- 1271
38.
Khogali  A Bone strength and calcium retention of rats in hypervitaminosis-A. Q J Exp Physiol. 1966;51120- 129
39.
Metz  ALWalser  MMOlson  WG The interaction of dietary vitamin A and vitamin D related to skeletal development in the turkey poult. J Nutr. 1985;115929- 935
40.
Trechsel  UStutzer  AFleisch  H Hypercalcemia induced with an arotinoid in thyroparathyroidectomized rats: new model to study bone resorption in vivo. J Clin Invest. 1987;801679- 1686Article
41.
Collaxo  JARodriguez  JS Hypervitaminosis A. Klin Wochenschr. 1933;121732- 1734Article
42.
Kamm  JJ Toxicology, carcinogenicity, and teratogenicity of some orally administered retinoids. J Am Acad Dermatol. 1982;6652- 659Article
43.
Fell  HBMellanby  E Effects of hypervitaminosis A on foetal mouse bones cultivated in vitro. BMJ. September2 1950;535- 539
44.
Reynolds  JJ Inhibition by calcitonin of bone resorption induced in vitro by vitamin A. Proc R Soc Lond B Biol Sci. 1968;17061- 69Article
45.
Ng  KWLivesey  SACollier  FGummer  PRMartin  TJ Effect of retinoids on the growth, ultrastructure, and cytoskeletal structures of malignant rat osteoblasts. Cancer Res. 1985;455106- 5113
46.
Oreffo  ROCTeti  ATriffitt  JTFrancis  MJOCarano  AZallone  AZ Effect of vitamin A on bone resorption: evidence for direct stimulation of isolated chicken osteoclasts by retinol and retinoic acid. J Bone Miner Res. 1988;3203- 210Article
47.
Zelent  AKrust  APetkovich  MKastner  PChambon  P Cloning of murine α and β retinoic acid receptors and a novel receptor γ predominantly expressed in skin. Nature. 1989;339714- 717Article
48.
Ruberte  EDolle  PKrust  AZelent  AMorriss-Kay  GChambon  P Specific spatial and temporal distribution of retinoic acid receptor gamma transcripts during mouse embryogenesis. Development. 1990;108213- 222
49.
Török  LGaluska  LKasa  MKadar  L Bone-scintigraphic examinations in patients treated with retinoids: a prospective study. Br J Dermatol. 1989;12031- 36Article
50.
Kilcoyne  RFCope  RCunningham  W  et al.  Minimal spinal hyperostosis with low-dose isotretinoin therapy. Invest Radiol. 1986;2141- 44Article
51.
Whitmore  SE Osteoporosis and long-term etretinate therapy [letter]. Arch Dermatol. 1996;132713Article
52.
Laasonen  LSKarvonen  SLReunala  TL Bone disease in adolescents with acne fulminans and cystic acne: radiologic and scintigraphic findings. AJR Am J Roentgenol. 1994;1621161- 1165Article
53.
Villablanca  JGKhan  AAAvramis  VIReynolds  CP Hypercalcemia: a dose-limiting toxicity associated with 13-cis-retinoic acid. Am J Pediatr Hematol Oncol. 1993;15410- 415
×