Drugs 18: 484-492 ( 1979) 00 12-6667{79{ 12oo- 048 4{ $02.25{0 C ADIS Press Aus t ralasia Ply LId. AI right s reserved.
Treatment of Postmenopausal Osteoporosis BE.C .Nordin M RC Mineral Met abolism Unit . The General Infirmary. Leeds
S ummary
Bone loss can be prevented by standard oestrogen replacement therapy and delayed by the adminislrat ion 0/ calcium supplements_ The most suitable patients to treat are those with a raised urinary hydroxyproline or other evidence 0/ rapid bone loss . Patients aged below 65 years with established osteoporosis, and in whom oestrogens are nOI contraindicated, will derive some benefi t /rom oestrogen therapy. In /hose with malabsorption 0/ calcium. vitamin D may be added 10 oestrogen therapy in a dose nO/exceeding 10,000 units daily or allerna/ive!y , small doses 0/ one 0/ the vitamin D melaboliles. e.g. l aOHD, (al/aro/ddo/) IIllf daily . or / .25(OH~D, (caldlriol) 0.5 1llf daily . In patients aged over 65 years. supplementary calcium (not less than /Ooomg daily) is recommended.
Osteoporosis is a metabolic bone disease characterised by a reduction in the amount of bony tissue relative to the volume of anatomical bone. It may be
generalised or localised and it may affect cortical or trabecular bone, or both. It may be primary, i.e. not associated with any obvious predisposing condition, or it may be associated with disorders which are known to produce accelerated bone loss such as hyperthyroidism, hyperparathyroidism or hyperadrenocorticism. However, whether it is generalised or localised, primary or secondary, it is more common in postmenopausal women than any other age or sex group . This article will deal with the pathogenesis and management of postmenopausal osteoporosis.
I. Diagnosis of Osteoporosis and its Significance In all populations so far studied, loss or bone starts at the menopause, continues at a rate of about 0.5 to 1.0 % of the skeleton per annum to the end of life, and affects both cortical bone {about 80 % of the skeleton by weight> and trabecular bone {about 20 % of the skeleton by weight>. However, whereas most of the trabecular bone loss normally occurs in the first 10 years after the menopause. the cortical bone loss continues in a linear fashion indefinitely by a process of endosteal resorption which produces a widening of the medullary space in the long bones.
Trealment of Posl menopauslll OSleoporosis
485
1.1 Measurement of Cortical and Trabecular Bone Loss Cortical loss can be conveniently monitored at the midpoint of the second metacarpal of the right hand on good quality radiographs; medullary and total width are measured with needle calipers and cortical and total cross-sectional areas calculated on the assu mption that the bone is tubular. The mean cortical area /total area ratio (CA ITA) in premenopausal women is 0.86 and this falls to 0.60 by age 85 (fig. I). (The male value falls much less: from 0.82 to 0.74). Trabecular bone status is less easily monitored but can be determined in iliac crest bone biopsies where
•
the mean volume ratio falls from 24 96 in young women to about 1696 by age 65 and very little thereafter. (The corresponding fall in men is from about 2296 to about 18 96 ). Thus. cortical bone loss is slow but continuous; trabecular bone loss is faster initially but tends to be self-limiting (fig. n 1.2 Increased Fracture Risk As this bone loss proceeds. there is a rise in the incidence of certain fractures. notably those of the vertebrae. distal forearm and femoral neck (fig. 2). One way of looking at this is to say that fracture rates rise with age because the percentage of the population below the young lower normal limit is itself rising with age and the number of individuals at risk for these fractures is, therefore. increasing. The wrist and spine fracture incidences tend to reflect trabecular bone status since they rise to age 65 and very little thereafter, whereas the femoral neck fracture incidence rises steeply from 65 to the end of life and seems to reflect the loss of cortical bone (flg. 3).
1.3 Differential Diagnosis of Cortical and Trabecular Osteoporosis
The above data are compatible with the concept that fracture risk rises when bone mass taus below a ~ o certain threshold; further analysis shows that this > ~--.- ....... threshold is the lower limit for young normal >0...... women. It is, therefore. appropriate to define cortical ~ 20 ~, ''''b... osteoporosis as a condition in which cortical bone '-o-'- "..._ .C? - -----------._._-----..... mass falls below the lower limit of young normal adults, and trabecular osteoporosis as being present ,o,!-:-_--,':-_.....,....__'-when trabecular bone mass falls below the corres20 00 00 '0 ponding lower young normal limit. The former diagbL...J nosis may be made on a plain hand radiograph and Fig. I. a) Mea n metacarplll cortical area /tota l area ratios the latter on an iliac crest bone biopsy. but in cliniCl!! (CA/ TAI as a function of age in women . The dot ted ~nes practice it may generally be assumed that a postreprese nt the young norma l range. menopausal woman who has suffered a lower forebl Mean iliac crest volume /volume ratios (aa percentages) arm fracture, or particularly a vertebral crush fracin normal women aa a functiol'l of age . The do lt ed linea repreture, is suffering from trabecular osteoporosis, while sent the young normal range . 30
---- _.-_.-
.,.
--
-
TrN lrnenl 0 1 PoslmenopausalOsteoporo$il
250
20(
' 86
tains the plasma calcium concentration at the expense of the skeleton. whereas oestrogen dertciency leads to osteoporosis because bone is more sensitive to resorption by these agents when oestrogen concentrations ar e low than when they are high. The increase in bone resorption which follows the menopause results from th is increased sensitivity of bone to th ese resorbing agents and it can be mon itored. bo th within and between individuals. by the postmenopausal rise in resting ur inary calcium and hydroxyproline levels (fig. 4).
3 . Prevent ion of Postmenopau sa l Bone Loss
3.1 Effect ot Oesuogens and Calcium Supplements The raised fasting urinary calcium and hydroxyproline. which reflect the increased bone resorption in postmenopausal women. can be resto red to premeno-
F/V_ 2. Age specifIC frKI.., ..tft$ 01 lhe pro• .mal l_ and doslal..-ous in women.
an elderl y woman who has sustained a femoral neck. fracture is suffering from cortical osteoporosis. Measurements on a hand radiograph and / or an iliac crest biopsy are required when it is considered necessary or desirable to recognise the presence of osteoporosis be/ ore fracture has occurred.
2. Pathogenesis ofPostmenopausal Bone Loss In experi mental animals. osteoporosis can be produced by oophorecto my. calcium derlciency or a combination of the two. A ll the available data suggest that calcium de rtciency leads to osteoporosis because parathyroid hormone ( Pn-I) and Ia .2S-dihydro xyvita min 0 ) ( 1 .2 S(O Hb D~ mediatod bone resorption main-
... F/V. 3. The percenr.ge of women at dofferent egn ..tooM rne~CAITAra_andillKCtest~t~ra_
lal below thf young
~
Iimrt as a funetionol egot.
487
Treat men t of Postmenopau sal Osteoporo sis
pausal levels with any of the currently available oestrogen preparations in the doses normally used for the control of menopausaJ symptoms. These doses are: conjugated oestrogens (Premarin') O.625mg daily, oestradiol valerate 2mg daily, ethinyloestradiol I SJlg daily, piperazine oestrone sulphate I'Harmog en'I Jmg daily or the standard 'Menophase' pack (fig. 5). These agents seem to act by blocking the bone resorbing action of PTH and 1,25 (OH'PJ' but the cellular and molecular bas is for this mechanism are unknown and no oestrogen receptor has been identified in bone cells. A significant though lesser reduction in urinary hydroxyproline can also be achieved by administering calcium supplements in a dose of 1000 to 1500mg daily (fig. 6), which act by suppressing parathyroid horm one and 1,25(OH)IDj secretion. It is, therefore, not surprising that postmenopausal bone loss can be
0.75' 0 0
0.50
•
Q
t:J
0.25
f
::r 0
""'~~ pauSlII
3.2 When is Prophy lactic Therapy Indicated? This is not to say that all postmenopausal women should necessarily receive horm one replacement therapy or even calcium supplements , There is a very significant correlation between urinary hydroxyproline and bone loss which suggests that a hydroxyproline / creatinine ratio over about 0.012 is associated with rapid bone loss, which is likely to predispose to fracture. It might be argued, therefore, that proph ylactic oestrogen and for calcium therapy should be directed at those postmenopausal women with urinary hydroxyprolinefcreatinine ratios above this critical limit (fig. 4).
--
0.030
0 0 0 0
1
= t
Pcetmerepeusa t
-0
0
; .-t--._.-t-.0 0
prevented by the administration of oestrogens or calcium supplements (fig. 7).
0
0.020
-o< '"
._._.-.-._._. f:. 0 00
0.0 10
-
""'~~
pauSllI
Postmeno· pIIusal
Fig. 4. Faating cak::ium/ creatinne retios (Ca / Cr) and hydrollyproline/ creatinine ratios IOHPr/ Crl in normal prtI . and 1XJ$l. menopa use l women. Note that proportionately lTIOfe post- tha n premenopausal women hall'll Ca/Cr ratios above 0.30 and hy. drOllyproine/crelti nine ratios above 0.012.
488
Treatment of Post me rlOP
Treatment of Postmenopausal Osteoporosis BE.C .Nordin M RC Mineral Met abolism Unit . The General Infirmary. Leeds
S ummary
Bone loss can be prevented by standard oestrogen replacement therapy and delayed by the adminislrat ion 0/ calcium supplements_ The most suitable patients to treat are those with a raised urinary hydroxyproline or other evidence 0/ rapid bone loss . Patients aged below 65 years with established osteoporosis, and in whom oestrogens are nOI contraindicated, will derive some benefi t /rom oestrogen therapy. In /hose with malabsorption 0/ calcium. vitamin D may be added 10 oestrogen therapy in a dose nO/exceeding 10,000 units daily or allerna/ive!y , small doses 0/ one 0/ the vitamin D melaboliles. e.g. l aOHD, (al/aro/ddo/) IIllf daily . or / .25(OH~D, (caldlriol) 0.5 1llf daily . In patients aged over 65 years. supplementary calcium (not less than /Ooomg daily) is recommended.
Osteoporosis is a metabolic bone disease characterised by a reduction in the amount of bony tissue relative to the volume of anatomical bone. It may be
generalised or localised and it may affect cortical or trabecular bone, or both. It may be primary, i.e. not associated with any obvious predisposing condition, or it may be associated with disorders which are known to produce accelerated bone loss such as hyperthyroidism, hyperparathyroidism or hyperadrenocorticism. However, whether it is generalised or localised, primary or secondary, it is more common in postmenopausal women than any other age or sex group . This article will deal with the pathogenesis and management of postmenopausal osteoporosis.
I. Diagnosis of Osteoporosis and its Significance In all populations so far studied, loss or bone starts at the menopause, continues at a rate of about 0.5 to 1.0 % of the skeleton per annum to the end of life, and affects both cortical bone {about 80 % of the skeleton by weight> and trabecular bone {about 20 % of the skeleton by weight>. However, whereas most of the trabecular bone loss normally occurs in the first 10 years after the menopause. the cortical bone loss continues in a linear fashion indefinitely by a process of endosteal resorption which produces a widening of the medullary space in the long bones.
Trealment of Posl menopauslll OSleoporosis
485
1.1 Measurement of Cortical and Trabecular Bone Loss Cortical loss can be conveniently monitored at the midpoint of the second metacarpal of the right hand on good quality radiographs; medullary and total width are measured with needle calipers and cortical and total cross-sectional areas calculated on the assu mption that the bone is tubular. The mean cortical area /total area ratio (CA ITA) in premenopausal women is 0.86 and this falls to 0.60 by age 85 (fig. I). (The male value falls much less: from 0.82 to 0.74). Trabecular bone status is less easily monitored but can be determined in iliac crest bone biopsies where
•
the mean volume ratio falls from 24 96 in young women to about 1696 by age 65 and very little thereafter. (The corresponding fall in men is from about 2296 to about 18 96 ). Thus. cortical bone loss is slow but continuous; trabecular bone loss is faster initially but tends to be self-limiting (fig. n 1.2 Increased Fracture Risk As this bone loss proceeds. there is a rise in the incidence of certain fractures. notably those of the vertebrae. distal forearm and femoral neck (fig. 2). One way of looking at this is to say that fracture rates rise with age because the percentage of the population below the young lower normal limit is itself rising with age and the number of individuals at risk for these fractures is, therefore. increasing. The wrist and spine fracture incidences tend to reflect trabecular bone status since they rise to age 65 and very little thereafter, whereas the femoral neck fracture incidence rises steeply from 65 to the end of life and seems to reflect the loss of cortical bone (flg. 3).
1.3 Differential Diagnosis of Cortical and Trabecular Osteoporosis
The above data are compatible with the concept that fracture risk rises when bone mass taus below a ~ o certain threshold; further analysis shows that this > ~--.- ....... threshold is the lower limit for young normal >0...... women. It is, therefore. appropriate to define cortical ~ 20 ~, ''''b... osteoporosis as a condition in which cortical bone '-o-'- "..._ .C? - -----------._._-----..... mass falls below the lower limit of young normal adults, and trabecular osteoporosis as being present ,o,!-:-_--,':-_.....,....__'-when trabecular bone mass falls below the corres20 00 00 '0 ponding lower young normal limit. The former diagbL...J nosis may be made on a plain hand radiograph and Fig. I. a) Mea n metacarplll cortical area /tota l area ratios the latter on an iliac crest bone biopsy. but in cliniCl!! (CA/ TAI as a function of age in women . The dot ted ~nes practice it may generally be assumed that a postreprese nt the young norma l range. menopausal woman who has suffered a lower forebl Mean iliac crest volume /volume ratios (aa percentages) arm fracture, or particularly a vertebral crush fracin normal women aa a functiol'l of age . The do lt ed linea repreture, is suffering from trabecular osteoporosis, while sent the young normal range . 30
---- _.-_.-
.,.
--
-
TrN lrnenl 0 1 PoslmenopausalOsteoporo$il
250
20(
' 86
tains the plasma calcium concentration at the expense of the skeleton. whereas oestrogen dertciency leads to osteoporosis because bone is more sensitive to resorption by these agents when oestrogen concentrations ar e low than when they are high. The increase in bone resorption which follows the menopause results from th is increased sensitivity of bone to th ese resorbing agents and it can be mon itored. bo th within and between individuals. by the postmenopausal rise in resting ur inary calcium and hydroxyproline levels (fig. 4).
3 . Prevent ion of Postmenopau sa l Bone Loss
3.1 Effect ot Oesuogens and Calcium Supplements The raised fasting urinary calcium and hydroxyproline. which reflect the increased bone resorption in postmenopausal women. can be resto red to premeno-
F/V_ 2. Age specifIC frKI.., ..tft$ 01 lhe pro• .mal l_ and doslal..-ous in women.
an elderl y woman who has sustained a femoral neck. fracture is suffering from cortical osteoporosis. Measurements on a hand radiograph and / or an iliac crest biopsy are required when it is considered necessary or desirable to recognise the presence of osteoporosis be/ ore fracture has occurred.
2. Pathogenesis ofPostmenopausal Bone Loss In experi mental animals. osteoporosis can be produced by oophorecto my. calcium derlciency or a combination of the two. A ll the available data suggest that calcium de rtciency leads to osteoporosis because parathyroid hormone ( Pn-I) and Ia .2S-dihydro xyvita min 0 ) ( 1 .2 S(O Hb D~ mediatod bone resorption main-
... F/V. 3. The percenr.ge of women at dofferent egn ..tooM rne~CAITAra_andillKCtest~t~ra_
lal below thf young
~
Iimrt as a funetionol egot.
487
Treat men t of Postmenopau sal Osteoporo sis
pausal levels with any of the currently available oestrogen preparations in the doses normally used for the control of menopausaJ symptoms. These doses are: conjugated oestrogens (Premarin') O.625mg daily, oestradiol valerate 2mg daily, ethinyloestradiol I SJlg daily, piperazine oestrone sulphate I'Harmog en'I Jmg daily or the standard 'Menophase' pack (fig. 5). These agents seem to act by blocking the bone resorbing action of PTH and 1,25 (OH'PJ' but the cellular and molecular bas is for this mechanism are unknown and no oestrogen receptor has been identified in bone cells. A significant though lesser reduction in urinary hydroxyproline can also be achieved by administering calcium supplements in a dose of 1000 to 1500mg daily (fig. 6), which act by suppressing parathyroid horm one and 1,25(OH)IDj secretion. It is, therefore, not surprising that postmenopausal bone loss can be
0.75' 0 0
0.50
•
Q
t:J
0.25
f
::r 0
""'~~ pauSlII
3.2 When is Prophy lactic Therapy Indicated? This is not to say that all postmenopausal women should necessarily receive horm one replacement therapy or even calcium supplements , There is a very significant correlation between urinary hydroxyproline and bone loss which suggests that a hydroxyproline / creatinine ratio over about 0.012 is associated with rapid bone loss, which is likely to predispose to fracture. It might be argued, therefore, that proph ylactic oestrogen and for calcium therapy should be directed at those postmenopausal women with urinary hydroxyprolinefcreatinine ratios above this critical limit (fig. 4).
--
0.030
0 0 0 0
1
= t
Pcetmerepeusa t
-0
0
; .-t--._.-t-.0 0
prevented by the administration of oestrogens or calcium supplements (fig. 7).
0
0.020
-o< '"
._._.-.-._._. f:. 0 00
0.0 10
-
""'~~
pauSllI
Postmeno· pIIusal
Fig. 4. Faating cak::ium/ creatinne retios (Ca / Cr) and hydrollyproline/ creatinine ratios IOHPr/ Crl in normal prtI . and 1XJ$l. menopa use l women. Note that proportionately lTIOfe post- tha n premenopausal women hall'll Ca/Cr ratios above 0.30 and hy. drOllyproine/crelti nine ratios above 0.012.
488
Treatment of Post me rlOP
