Dehydroepiandrosterone (DHEA): A Role in Bone Health?
By Saurin Mehta, MD, and Sharon L. Kolasinski, MD, FACP, FACR
Dr. Mehta is a first-year fellow in the Division of Rheumatology, and Dr. Kolasinski is Associate Professor of Clinical Medicine, Director of the Fellowship Program in Rheumatology and Chief of the Clinical Service in the Division of Rheumatology at the University of Pennsylvania, in Philadelphia; they report no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study.
Dehydroepiandrosterone (DHEA) and its sulfated form (DHEAS) are the most abundant circulating steroid hormones in humans, produced in large quantities by the adrenal glands and subsequently converted into androgens and estrogens via enzymatic pathways in peripheral tissues. In recent years, DHEA has received much media attention due to data suggesting roles in mood regulation, sexual function, insulin sensitivity, cardiovascular disease, and cognitive changes with aging. Another question that has been posed is the effect of DHEA on bone metabolism.
With claims of increasing bone mineral density (BMD) and reducing osteoporosis, DHEA has become a popular, albeit poorly understood, dietary supplement. This article reviews some of the current literature available on the effect of DHEA on BMD and explores whether this supplement has any therapeutic role in treatment or prevention of osteoporosis.
DHEA and DHEAS are derived from 17-OH pregnenolone in the steroid synthesis pathway, produced primarily in the zona reticularis of the adrenal gland. They are the most prevalent circulating hormones in humans. Neither one possesses significant androgenic activity, but both can be converted to potent sex steroids. DHEA is the more active form, and its metabolite, DHEAS, is the product of enzymatic action by 3b-hydroxysteroid sulfotransferase in the peripheral tissues.1 DHEA levels peak by age 20-24 in men and age 15-19 in women, and then steadily decline so that by age 70, serum levels are less than 20% of peak ranges.2 The hormone levels vary significantly between individuals based on numerous other factors including race, sex, body mass index, nutritional status, alcohol and tobacco intake, and medications.3
Most data on exogenously administered DHEA have focused on oral formulations, though transdermal and intravenous forms have also been studied. Oral DHEA has a very low potency and bioavailability, but is converted to DHEAS by intestinal cells and subsequently acts as a pool from which the body can synthesize more DHEA, according to animal studies.4
DHEA has a short half-life of 1-3 hours, but DHEAS is more tightly bound to albumin and has a slower rate of clearance. This gives DHEAS a longer half-life of 10-20 hours and also helps maintain more constant serum levels.1 DHEAS can be found in a 300- to 500-fold greater serum concentration than DHEA.5 Transdermal patches made of various polymers have been developed, offering close to 100% bioavailability of DHEA in a more continuous and controlled delivery system (data from rat studies6).
Mechanism of Action
The direct mechanism of action of DHEA on bone is not fully known. Though many of its actions are via the downstream sex steroids that are derived from it, the search continues for other receptors that may mediate additional effects of the hormone.1
Regarding DHEA's effects on bone metabolism, several molecular mechanisms have been postulated. An in vitro study by Scheven and colleagues examined the effect of DHEA and its sulfated form on human osteoblast proliferation and differentiation.7 The investigators found that neither hormone exerted a direct, independent, significant effect on osteoblastic cells as measured by alkaline phosphate activity or osteocalcin production, but such effects were observed in a synergistic fashion when the cells were co-stimulated with 1,25 (OH)2 D3 through a mechanism that remains un-explained.7 Another in vitro study found that DHEA could indirectly inhibit bone resorption of osteoclasts by increasing osteoprotegerin (OPG) production and decreasing RANKL production in osteoblasts. RANK/RANKL interaction is needed for differentiation of osteoclasts, so increased OPG expression in osteoblasts leads to less binding between RANK on the surface of osteoclasts and RANKL expressed on osteoblasts.8
Prior work on endogenous sex steroids and BMD has been inconsistent in finding correlations between DHEA levels and BMD at various measured sites.9,10 Spector and colleagues sought to test whether DHEA and other sex hormones could serve as markers of BMD and, hence, be useful tests to detect those postmenopausal patients at risk for osteoporosis.9 They found that DHEAS correlated weakly with spinal BMD, but not with femoral BMD. Moreover, no association was observed between any other sex hormone and BMD. In another similar study by Nordin and colleagues, 307 untreated postmenopausal women had forearm BMD measured at the beginning and the end of the five-year study period.10 The investigators found that serum DHEAS levels measured at the outset of the study did not correlate to rate of change in BMD.
A larger epidemiologic trial was a retrospective cohort study of 991 older men and women done in Rancho Bernardo, CA.11 The study aimed to find any possible correlation between blood levels of various endogenous sex steroids between 1984 and 1987 and subsequent BMD from 1988 to 1991. Patients who were taking corticosteroids or exogenous sex steroids at the time of steroid level measurement were excluded from the trial. The sex steroids measured were total estradiol, total testosterone, dihydrotestosterone, estrone, DHEA, and DHEAS. BMD was measured at the distal radius, midshaft radius, lumbar spine, and total hip. The primary outcome measurement was BMD of each measured site by sex steroid level, adjusted for age, body mass index, cigarette or alcohol use, thiazide diuretic or thyroid hormone use, former estrogen use, and leisure exercise. Results of the study found the strongest link between bioavailable estradiol and BMD. DHEA was associated with a small, but statistically significant, increase in BMD of the forearm, spine, and hip, but only in women (unadjusted BMD increase 0.0200-0.0233).
A recent randomized controlled trial conducted by Jankowski and colleagues examined the effects of orally administered DHEA on BMD and body composition in older adults that had low endogenous DHEAS levels.12 Seventy women and 70 men aged 60-88 were randomized to either oral DHEA 50 mg/d or placebo for a 12-month period. The measured variables were BMD, fat mass, and fat-free mass before and after intervention. The investigators found that compared to placebo, the DHEA group experienced an increase in BMD across regions of the hip equally for men and women (increase of 1.0% at total hip, 1.2% at trochanter, and 1.2% at shaft), and at the lumbar spine (2.2%) in women alone. Multiple prior studies focusing on a male population had found no alteration in bone turnover markers and no increase in BMD in healthy middle-aged to elderly men consuming doses of DHEA high enough to cause a substantial increase in serum DHEA.13,14
In some patients who are taking corticosteroids, DHEA supplementation may halt bone loss. Van Vollenhoven and colleagues conducted a small, double-blind, randomized placebo-controlled trial studying the effects of DHEA on patients with severe systemic lupus erythematosus (SLE).15 Severe lupus was defined as patients with nephritis, serositis, or hematological manifestations (autoimmune hemolytic anemia or thrombocytopenia). Twenty-one patients were given either DHEA 200 mg/d or placebo for six months, followed by a six-month open-label period. The patients were maintained on their prednisone doses (approximately 40-50 mg/d) as well as any immunosuppressive medications they may have been taking. The primary outcome measure was objective evidence of improvement in the nephritis, serositis, or hematologic phenomena. Secondary outcome measures included improvement in the systemic lupus erythematosus disease activity index score or the systemic lupus activity measure score, as well as global assessments by patients and physicians, steroid dosage, and health assessment questionnaires. Both primary and secondary outcomes were achieved in more of the patients taking DHEA than placebo.
This same study included an additional measure: a comparison of BMD. BMD was measured in all patients at baseline and at six months, and in 16 patients at 12 months. The DHEA group had no significant change in BMD at the lumbosacral spine, while the placebo group had a small but statistically significant reduction (0.05 g/cm2) in bone density at six months (P < 0.05), but no further reduction at 12 months. No significant difference in BMD was seen at the femoral neck, and during the open-label period, BMD was stable in both groups.
In another lupus study, 60 women (mean age 42.6 years) with quiescent SLE were randomized to either 200 mg/d of DHEA or placebo for 12 months.16 Dual-energy X-ray absorptiometry scores were measured at baseline and after the study period. The average prednisone dose between the two groups was 5.6 mg/d. The results of a subgroup analysis in the study showed no impact of DHEA supplementation on BMD of premenopausal patients with quiescent SLE; however, there was a small but significant increase in BMD at the lumbar spine in postmenopausal patients with quiescent SLE who where not already receiving estrogens or bisphosphonates (1.80% vs. -2.32% in the placebo group).
The most recent trial studied effects of DHEA on BMD, physical performance, body composition, glucose tolerance, and quality of life in a two-year double-blind, randomized, placebo-controlled trial involving 87 elderly men with low levels of DHEAS and bioavailable testosterone and 57 elderly women with low levels of DHEAS.17 The study was conducted on a generally healthy elderly population; patients who had any clinically relevant illnesses that could have an effect on outcome measures were excluded. In the male group, 29 received DHEA, 27 received testosterone, and 31 received placebo. In the female group, 27 received DHEA and 30 received placebo. The investigators found that restoring DHEA levels to those considered high normal for young people yielded statistically significant, but very little, improvement in BMD of the femoral neck for men (median difference 0.02 g/cm2) and at the distal radius in elderly women (median difference 0.02 g/cm2) compared to baseline BMD measurements at the beginning of the study. Elderly men who received testosterone had similarly slight increases in BMD at the femoral neck (median difference 0.03 g/cm2). No other measured sites (lumbar spine, total hip, or distal radius) showed any statistically significant improvement in BMD with DHEA treatment. No beneficial effect was seen in the treatment group regarding the remainder of the outcome measures.
Overall, DHEA is reasonably well tolerated. Many of the side effects are those that are expected with supplemental androgenic steroids. The reported side effects, many of which are obtained from studies in SLE patients, were acne, hirsutism, dyslipidemia (particularly low HDL-cholesterol), mild transaminase elevation, abdominal pain, insomnia, headache, weight gain, asthenia, prostate enlargement, metrorrhagia, breast tenderness, and rash.18 In the recent trial by Nair et al, there was no significant increase in adverse events in patients given DHEA when compared to placebo.17 From these trials, it appears that adverse effects of DHEA are dose-related, with the highest occurrence at doses of 100-200 mg/d.
Contraindications and Precautions
Given that DHEA is metabolized to potent androgens and estrogens, its use is potentially hazardous in patients with a history of hormone-dependent tumors (breast, prostate, endometrium) and should therefore be avoided. A rodent model revealed an increased incidence of hepatocellular carcinoma, but with suprapharmacological doses of DHEA.19 No such effect has been observed in humans.
Patients with other hormone-dependent conditions such as benign prostatic hypertrophy, endometriosis, and uterine fibroids should also use caution before taking DHEA. Women who are pregnant or nursing should avoid DHEA. Because serum DHEA levels do not drop significantly until after the third decade of life, DHEA supplementation is not commonly advised for younger people.
Various doses of DHEA have been studied for various potential uses. It has most commonly been given in doses ranging from 25 mg/d to 200 mg/d. Although DHEA has a short half-life, its rapid conversion to DHEAS makes once daily dosing possible. Of the studies showing the most beneficial effect on bone health, oral doses were generally in the 50 mg/d to 75 mg/d range.12,14,20 However, higher doses of up to 200 mg/d were used in some studies with SLE patients.15,16,18
Because DHEA is considered a nutritional supplement and not a prescription drug, it is exempt from rigorous testing by governing agencies to ensure that various preparations meet appropriate quality standards regarding content, dosage, and safety. As a result, DHEA purchased from one manufacturer may not yield the same results as those purchased from another manufacturer, and the experienced side effects may not be identical. A study by Genelabs examined 16 different DHEA products for variations in content, as measured by high-performance liquid chromatography. Only seven of 16 products were found to have DHEA content in accordance with typical product specifications (90-110% of the label claim).21 One product was found to have no DHEA, and two others had only trace amounts detectable.
DHEA is a generally well-tolerated hormonal supplement that acts via mechanisms that are not yet fully understood to treat a multitude of medical conditions. Its use in increasing BMD has been the focus of many studies that have had mixed results to date. The populations that seem most likely to benefit are older women and those who have low baseline serum DHEA levels. However, any increases in BMD have proven to be quite small, and modest in comparison to those seen with more standard therapy such as bisphosphonates. Further, there are no data to show that lower levels of DHEA have a direct impact on fractures or that DHEA replacement alone can reduce fracture risk.
DHEA use is not recommended as a primary means to increase BMD. Increase in BMD may be observed if DHEA is recommended as part of a treatment regimen for other diseases, but this increase may not be clinically significant. Furthermore, DHEA is not recommended in patients who have a history of hormone-sensitive tumor.
1. Dhatariya KK, Nair KS. Dehydroepiandrosterone: Is there a role for replacement? Mayo Clin Proc 2003;78:1257-1273.
2. Orentreich N, et al. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984;59:551-555.
3. Olech E, Merrill JT. DHEA supplementation: The claims in perspective. Cleve Clin J Med 2005;72:965-966, 968, 970-971.
4. Longcope C, Tast J. Dehydroepiandrosterone metabolism in the female rhesus monkey: Oral versus intravenous administration. Steroids 1996;61:7-10.
5. Ebeling P, Koivisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994;343:1479-1481.
6. Labrie C, et al. High bioavailability of dehydroepi-androsterone administered percutaneously in the rat. J Endocrinol 1996;150(Suppl):S107-S118.
7. Scheven BA, Milne JS. Dehydroepiandrosterone (DHEA) and DHEA-S interact with 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) to stimulate human osteoblastic cell differentiation. Life Sci 1998;62:59-68.
8. Wang Y, et al. Dehydroepiandrosterone inhibited the bone resorption through the upregulation of OPG/RANKL. Cell Mol Immunol 2006;3:41-45.
9. Spector TD, et al. The relationship between sex steroids and bone mineral content in women soon after the menopause. Clin Endocrinol (Oxf) 1991;34:37-41.
10. Nordin B, et al. A 5-year longitudinal study of forearm bone mass in 307 postmenopausal women. J Bone Miner Res 1993;8:1427-1432.
11. Greendale GA, et al. Endogenous sex steroids and bone mineral density in older women and men: The Rancho Bernardo Study. J Bone Miner Res 1997;12:1833-1843.
12. Jankowski CM, et al. Effects of dehydroepiandro-sterone replacement on bone mineral density in older adults: A randomized, controlled trial. J Clin Endocrinol Metab 2006;91:2986-2993. Epub 2006 May 30.
13. Kahn AJ, et al. Dehydroepiandrosterone supplementation and bone turnover in middle-aged to elderly men. J Clin Endocrinol Metab 2002;87:1544-1549. Erratum in: J Clin Endocrinol Metab 2003;88:41-48.
14. Baulieu EE, et al. Dehydroepiandrosterone (DHEA), DHEA sulfate, and aging: Contribution of the DHEAge Study to a sociobiomedical issue. Proc Natl Acad Sci U S A 2000;97:4279-4284.
15. van Vollenhoven RF, et al. A double-blind, placebo-controlled, clinical trial of dehydroepiandrosterone in severe systemic lupus erythematosus. Lupus 1999;8:181-187.
16. Hartkamp A, et al. The effect of dehydroepiandro-sterone on lumbar spine bone mineral density in patients with quiescent systemic lupus erythematosus. Arthritis Rheum 2004;50:3591-3595.
17. Nair KS, et al. DHEA in elderly women and DHEA or testosterone in elderly men. N Engl J Med 2006;355:1647-1659.
18. Petri M, et al. Effects of prasterone on corticosteroid requirements of women with systemic lupus erythematosus: A double-blind, randomized, placebo-controlled trial. Arthritis Rheum 2002;46:1820-1829.
19. Prough RA, et al. Regulation of cytochromes P450 by DHEA and its anticarcinogenic action. Ann N Y Acad Sci 1995;774:187-199.
20. Villareal DT, et al. Effects of DHEA replacement on bone mineral density and body composition in elderly women and men. Clin Endocrinol (Oxf) 2000;53:561-568.
21. Parasrampuria J, et al. Quality control of dehydroepiandrosterone dietary supplement products. JAMA 1998;280:1565.