The Traditional View of Skeleton in Male and Female

1
The Traditional View of Skeleton in Male and
Female

• Because estrogen (E) and testosteron (T) are the
  major sex steroids in women and men,
  respectively, E primarily regulated bone turnover
  in women and T played the analogous role in men.
• Other than under the circumstances of medical or
  surgical castration, men do not have the
  equivalent of a menopause and thus do not
  manifest a rapid phase of bone loss, although
  they clearly do undergo age-related bone loss.
• Because serum total T levels decline only
  marginally with age in men, it was assumed that
  men remain gonadally competent throughout their
  lives. As T is the major circulating sex steroid
  in men, the loss of T presumably caused the
  increased bone resorption and bone loss in
  castrated men.

2
Biosynthesis of Sex Steroids in Bone
Androst-5-ene-38, 17ß-diol sulphate
DHEA-S DHEA Androstenedione Estrone Estron
e sulfate
Steroid sulphatase
Androst-5-ene-38, 17ß-diol
17ß-HSDs
3ß-HSDs
5a-reductase 1 2
17ß-HSDs
Testosterone
DHT
Aromatase
17ß-HSDs
17ß-estradiol
Steroid sulphatase
17ß-estradiol sulphate
3
Smith EP, et al . Estrogen resistance caused by a
mutation in the estrogen-receptor gene in a man.
N Engl J Med 199433110561061

• The patient, aged 28 yr, was referred for genu
  valgum. He was tall (204 cm) and had incomplete
  epiphyseal closure, with a history of continued
  linear growth into adulthood despite otherwise
  normal pubertal development. He was normally
  masculinized and had bilateral axillary
  acanthosis nigricans.
• Serum estradiol and estrone concentrations were
  elevated, and serum testosterone concentrations
  were normal.
• Spine BMD (0.745 g/cm2) was 3.1 SD below the
  mean for age-matched normal women and more than
  2 SD below the mean for 15-yr-old boys (the
  patients bone age).
• This constellation of findings correctly
  suggested a syndrome of E resistance, which was
  confirmed by direct sequence analysis of his ER
  gene.

4
Bone Turnover Markers and BMD in a ER-negative
Male
1 Spine BMD was 3.1 SD below the mean for
age-matched normal women and more than 2 SD
below the mean for 15-yr-old boys (the patients
bone age). Modified from Smith EP, et al. N
Engl J Med 199433110561061,
5
A Dramatic Concept Shift of Sex Steroid
Regulation of the Male Skeleton

• Smith EP, et al. Estrogen resistance caused by a
  mutation in the estrogen-receptor gene in a man.
  NEJM 199433110561061
• Two aromatase-deficient males
• Bilezikian JP, et al. Increased bone mass as a
  result of estrogen therapy in a man with
  aromatase deficiency. NEJM 1998339599603
• Morishima A, et al. Aromatase deficiency in male
  and female siblings caused by a novel mutation
  and the physiological role of estrogens. JCEM
  1995 8036893698.
• Mouse knock-out models and studies in rats using
  an aromatase inhibitor.
• (Endocr Rev 199920358-417 Proc Natl Acad Sci
  USA 2000975474-5479. J Bone Miner Res
  2001161388-1398.)

6
Estrogen Is Important for Development of Male
Skeleton
Changes in BMD in an aromatase-deficient male
treated with E (0.3 mg/d of conjugated estrogens
initially, with a gradual increase to 0.75 mg/d).
Bilezikian JP, et al. N Engl J Med
1998339599603.
7
Sex Steroids and BMD in Women and Men (1)

• Khosla S, et al. Relationship of serum sex
  steroid levels to longitudinal changes in bone
  density in young versus elderly men. JCEM
  2001863555-3561.
• Slemenda CW, et al. Sex steroids and bone mass in
  older men positive associations with serum
  estrogens and negative associations with
  androgens. J Clin Invest 19971001755-1759.
• Greendale GA, et al. Endogenous sex steroids and
  bone mineral density in older women and men the
  Rancho Bernardo study. J Bone Miner Res
  1997121833-1843.
• Center JR, et al. Hormonal and biochemical
  parameters in the determination of osteoporosis
  in elderly men. JCEM 1999843626-3635.
• Ongphiphadhanakul B, et al. Serum oestradiol and
  oestrogen-receptor gene polymorphism are
  associated with bone mineral density
  independently of serum testosterone in normal
  males. Clin Endocrinol 1998 49803-809.

8
Sex Steroids and BMD in Women and Men (2)

• Amin S, et al. Association of hypogonadism and
  estradiol levels with bone mineral density in
  elderly men from the Framingham study. Ann Intern
  Med 2000133951-963.
• Szulc P, et al. Bioavailable estradiol may be an
  important determinant of osteoporosis in men the
  MINOS study. JCEM 200186192-199.
• Falahati-Nini A,et al. Relative contributions of
  testosterone and estrogen in regulating bone
  resorption and formation in normal elderly men. J
  Clin Invest 20001061553-1560..
• Van den Beld AW,et al. Measures of bioavailable
  serum testosterone and estradiol and their
  relationships with muscle strength, bone density,
  and body composition in elderly men. JCEM
  2000853276-3282

9
Serum SHBG levels as a function of age among an
age-stratified sample of 346 Rochester men (solid
lines, squares) and women (dashed lines, circles).
Khosla S.et al. JCEM 1998832266-2274.
10
Spearman correlation coefficients relating rates
of change in BMD at the radius and ulna to serum
sex steroid levels among a sample of Rochester,
Minnesota, men stratified by age
Elderly
Middle-aged
Young
1 P lt 0.05 2 P lt 0.01 3 P lt 0.001. Khosla
S.et al. J Clin Endocrinol Metab
20018635553561
11
Percentage changes in bone resorption markers (A)
and bone formation markers (B) in a group of 59
elderly men (mean age, 68 yr) made acutely
hypogonadal
Group A Aromatase
inhibitor Group B Estrogen (E) alone Group C
Testosterone (T) alone Group D both E and T
Change from baseline , P lt 0.05 , P lt
0.01 , P lt 0.001.
Falahati-Nini A, et al. J Clin Invest
200010615531560
12
MINOS study BMD in 596 men, aged 5185 yr, based
on quartiles of serum bioavailable E2 levels,
after adjustment for age and body weight. A,
Total hip BMD (F 5.14 P lt 0.002) B,
Distal forearm BMD (F 4.99 P 0.002)
C, Whole BMD content (F 3.15 P lt 0.03).
Szulc P. et al. J Clin Endocrinol Metab
200186192199.
13
Urinary NTx levels (A) and annualized rates of
change in mid-radius BMD (B) in a cohort of
elderly men (aged 6090 yr) as a function of
serum bioavailable E2 levels.
Khosla S.et al. J Clin Endocrinol Metab
20018635553561
14
Changes in lumbar spine BMD as a function of time
in an aromatase-deficient male treated with
progressively lower doses of transdermal E2
Rochira V, et al. J Clin Endocrinol Metab
20008518411845.
15
Baseline E2 levels vs. the change in urinary NTx
excretion (6 months, baseline) in
raloxifene-treated (A) and placebo-treated (B)
men.
Doran PM, et al. J Bone Miner Res
20011621182125.
16
Bioavailable E2 levels in 3 groups of Rochester
men and in post- and premenopausal Rochester
women
Young, ages 2239 yr Middle aged, 4059 yr
Elderly, 6090 yr
Khosla S.et al. J Clin Endocrinol Metab
20018635553561
17
Difference in Fracture and Bone Mass in Men and
Women

• Men suffer a substantial number of fractures
• Peak bone mass is on average 7 to 10 higher in
  men
• Men have larger bones than women do
• Superior bone quality, characterized by
  histomorphometric parameters such as fewer
  trabecular perforations, may also contribute to a
  reduced fracture risk independent of bone mass.
• Men do not have a clearly defined precipitous
  decline in sex hormones (or "andropause") and the
  consequent rapid bone loss that women experience
  during menopause.
• The relative importance of estrogens (compared
  with testosterone) in older men is increasingly
  recognized.
• Older men are less likely to fall than older women

18
Diagnosis of Osteoporosis in Men

• The major risk factors in men are corticosteroid
  use, alcohol abuse, and hypogonadism. Other risk
  factors for osteoporosis in men include renal or
  liver disease, cancer (particularly myeloma), and
  gastrointestinal disorders.
• Osteoporosis in men is typically diagnosed in 1
  of 2 waysafter a low-trauma fracture, or less
  often, by the presence of an abnormally low BMD.
• Low BMD in menstrongly predicts future fractures
  as it does in women.
• The sex- and ethnicity-matched normative data
  should be used in practice, and a T-score
  cutpoint of -2.5 is considered appropriate to
  initiate therapy.
• Some guidelines recommend screening BMD
  measurements in men over age 70

19
Treatment of Osteoporosis in Men

• Testosterone replacement should be used in the
  setting of clear-cut hypogonadism.
• On the basis of large studies that have
  demonstrated both efficacy and safety in men,
  bisphosphonates are an appropriate treatment for
  many men with osteoporosis.
• Subcutaneous parathyroid hormone, which is
  expected to be approved for clinical use in the
  United States in the near future, is an exciting
  possibility for some men with advanced
  osteoporosis.

20
References

• Smith EP, Boyd J, Frank GR, Takahashi H, Cohen
  RM, Specker B, Williams TC, Lubahn DB, Korach KS.
  Estrogen resistance caused by a mutation in the
  estrogen-receptor gene in a man. N Engl J Med
  19943311056-1061 .
• Khosla S, Melton III LJ, Atkinson EJ, O'Fallon
  WM. Relationship of serum sex steroid levels to
  longitudinal changes in bone density in young
  versus elderly men. J Clin Endocrinol Metab
  2001863555-3561.
• Khosla S, Melton LJ III, Riggs BL. Clinical
  review 144 Estrogen and the male skeleton. J
  Clin Endocrinol Metab. 2002871443-1450.
• Benjamin Z. Leder, Karen M. LeBlanc, David A.
  Schoenfeld, Richard Eastell and Joel S.
  Finkelstein . Differential Effects of Androgens
  and Estrogens on Bone Turnover in Normal Men. J
  Clin Endocrinol Metab 200388204-10.