265
Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women
66 early postmenopausal women were randomised to 28-day cycles of either transdermal hormone
replacement therapy—continuous oestradiol 17-beta 0·05 mg daily, with norethisterone acetate 0·25 mg daily for 14 of each 28 days—or oral therapy—continuous
conjugated
equine
oestrogens 0·625 mg daily, with dl-norgestrel 0·15 mg daily for 12 of each 28 days. An untreated reference group of 30 women were studied concurrently. Bone density was measured in the lumbar spine and proximal femur by dual photon absorptiometry at 6-month intervals for 18 months. Skeletal turnover was assessed by serum measurements of calcium, phosphate, and alkaline phosphatase, and by urine estimations of hydroxyproline/creatinine and calcium/creatinine excretion. In both treatment groups by comparison with the untreated group, bone density increased in the vertebrae and proximal femur and biochemical measurements indicated a significant reduction in bone turnover.
Introduction Hormone replacement therapy (HRT), with oestrogen alone or in combination with progestagen, prevents the postmenopausal bone loss1-4 that underlies the development of osteoporotic fractures. Oestrogen was initially given by the oral route; now that transdermal preparations have been developed it is important to establish whether this route is as effective as oral therapy for preservation of bone density. Irrespective of the type of treatment, in most studies bone density has been measured in the peripheral skeleton; only a few studies have documented vertebral measurements. None of the studies has prospectively investigated the effects of HRT on bone density in the femoral neck, yet this is the most important site of osteoporotic fracture in terms of morbidity, mortality, and cost.5 We have previously reported that combined replacement therapy can be given with adhesive skin patches, and that this treatment prevents endometrial hyperstimulation.6 We now report the effects of such therapy on bone density in both lumbar spine and proximal femur. We have compared transdermal therapy with conventional oral therapy and with no treatment in healthy women soon after the menopause.
Patients and methods Patients 96 apparently healthy postmenopausal caucasian women were recruited. All were between 6 months and 7 years after natural
menopause or, in the 26 women who had had a hysterectomy with the conservation of at least one ovary, from the onset of typical symptoms of oestrogen deficiency. 66 symptomatic women who had requested HRT were randomly allocated to either transdermal or oral HRT. 30 women who had not requested oestrogens were recruited concurrently to serve as a reference group because we
granted ethical committee permission to randomise placebo group for a long-term study. None of the women was taking any drugs known to affect bone metabolism, all were within 20% of ideal body weight, and postmenopausal status was confirmed in each case by gonadotropin measurement. Women with excessive cigarette consumption (> 10/day) or excessive alcohol consumption (> 300 g/week) were excluded. Patients were recruited from the two centres and all attended the Wynn Institute were not
women to a
for Metabolic Research at 6-month intervals for 18 months. Informed written consent was obtained in each case, and the study was approved by the ethical committees of both centres. Drugs. Both transdermal and oral HRT were given in 28-day cycles. Oestrogen was given continuously and progestagen for 14 and 12 days, respectively, in each cycle. Transdermal therapeutic systems (TTS) were used to administer oestradiol and norethisterone acetate. 33 women applied one oestradiol-TTS (’Estraderm TTS 50’, Ciba-Geigy, Basel, Switzerland) delivering 0-05 mg oestradiol 17-beta daily for the first 2 weeks of the cycle, and then one norethisterone acetate/oestradiol-TTS (’NET Aj - TTS’, Ciba-Geigy) for the second 2 weeks of the cycle. A combined NET A/E2- TTS delivered about 0 05 mg of oestradiol 17-beta and 02-03 mg of NETA daily.6 All the patches were applied to the skin below the waist and were changed twice a week on fixed days. 33 women received oral therapy, consisting of conjugated equine oestrogens 0-625 mg/day continuously, with added dl-norgestrel 0- 15 mg/day for the last 12 days of each 28-day cycle. These hormones were supplied in a calendar pack (’Prempak
C’, Wyeth-Ayerst, Maidenhead, UK). Methods
Height, weight, cigarette use, and alcohol consumption were recorded at the beginning of the study. Thyroid disease was excluded by measurement of serum thyrotropin, and parathyroid disease and osteomalacia were excluded by measurements of serum parathyroid hormone and 25-hydroxyvitamin D levels, respectively. Routine haematological and biochemical tests were done to exclude other conditions such as hepatic and renal disorders. Dietary calcium intake was assessed by recording consumption of dairy produce, and physical exercise participation by interview and questionnaire. At each visit, after a 12-hour fast, venous blood samples were taken for measurement of serum calcium, albumin, phosphate, and
ADDRESSES: Wynn Institute for Metabolic Research, London, UK (J. C. Stevenson, MRCP, M. P. Cust, MRCOG, K. F. Gangar, MRCOG, T. C. Hillard, MRCOG, B. L. Lees, BSc), and Department of Obstetrics and Gynaecology, King’s College School of Medicine and Dentistry, London, UK (M. P. Cust, K. F. Gangar, T. C. Hillard, M. I. Whitehead, FRCOG). Correspondence to Dr Stevenson, Wynn Institute for Metabolic Research, 21 Wellington Road, London NW8 9SQ, UK.
266
TABLE I-BASELINE DEMOGRAPHIC DATA I
I
TABLE )H—CHANGES IN BONE DENSITY
(MEDIAN
AND
RANGE)
I
*Median and range; other values are mean and SD, or percentages as mdicated. tp < 0 05 vs oral group; tp < 0-05 vs both treatment groups
alkaline phosphatase (ALP) by autoanalyser. Serum calcium results corrected for serum albumin. A fasting urine sample was obtained for measurement of calcium and creatinine by autoanalyser, and for measurement of hydroxyproline by resincatalysed hydrolysis.7 Urine results were expressed as calcium/ creatinine (Ca/cre) and hydroxyproline/creatinine (OHPr/cre) ratios. Bone density measurements were carried out by dual photon absorptiometry with a Lunar DP3 (Lunar Radiation Corporation, Madison, Wisconsin) which incorporated a 153Gd source and used 8 mm detector collimation.8 Precision in vivo was determined by were
conducting 2-7 serial measurements in 26 healthy volunteers (6 males, median age 30 years, range 28-38; 20 females, median age 32 years, range 22-60) over the duration of the study. Bone density was measured in the first four lumbar vertebrae, and the values were expressed in g/cm2. Bone density was also measured in the femoral neck, Ward’s triangle, and the trochanteric region. The isotope
changed twice during the study. timepoints were unsatisfactory owing to technical difficulties, usually patient movement. For longitudinal comparisons, the same combinations of vertebral body densities were used throughout, and the mean value of the second, source was
A few
measurements at some
i
*p
Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women
66 early postmenopausal women were randomised to 28-day cycles of either transdermal hormone
replacement therapy—continuous oestradiol 17-beta 0·05 mg daily, with norethisterone acetate 0·25 mg daily for 14 of each 28 days—or oral therapy—continuous
conjugated
equine
oestrogens 0·625 mg daily, with dl-norgestrel 0·15 mg daily for 12 of each 28 days. An untreated reference group of 30 women were studied concurrently. Bone density was measured in the lumbar spine and proximal femur by dual photon absorptiometry at 6-month intervals for 18 months. Skeletal turnover was assessed by serum measurements of calcium, phosphate, and alkaline phosphatase, and by urine estimations of hydroxyproline/creatinine and calcium/creatinine excretion. In both treatment groups by comparison with the untreated group, bone density increased in the vertebrae and proximal femur and biochemical measurements indicated a significant reduction in bone turnover.
Introduction Hormone replacement therapy (HRT), with oestrogen alone or in combination with progestagen, prevents the postmenopausal bone loss1-4 that underlies the development of osteoporotic fractures. Oestrogen was initially given by the oral route; now that transdermal preparations have been developed it is important to establish whether this route is as effective as oral therapy for preservation of bone density. Irrespective of the type of treatment, in most studies bone density has been measured in the peripheral skeleton; only a few studies have documented vertebral measurements. None of the studies has prospectively investigated the effects of HRT on bone density in the femoral neck, yet this is the most important site of osteoporotic fracture in terms of morbidity, mortality, and cost.5 We have previously reported that combined replacement therapy can be given with adhesive skin patches, and that this treatment prevents endometrial hyperstimulation.6 We now report the effects of such therapy on bone density in both lumbar spine and proximal femur. We have compared transdermal therapy with conventional oral therapy and with no treatment in healthy women soon after the menopause.
Patients and methods Patients 96 apparently healthy postmenopausal caucasian women were recruited. All were between 6 months and 7 years after natural
menopause or, in the 26 women who had had a hysterectomy with the conservation of at least one ovary, from the onset of typical symptoms of oestrogen deficiency. 66 symptomatic women who had requested HRT were randomly allocated to either transdermal or oral HRT. 30 women who had not requested oestrogens were recruited concurrently to serve as a reference group because we
granted ethical committee permission to randomise placebo group for a long-term study. None of the women was taking any drugs known to affect bone metabolism, all were within 20% of ideal body weight, and postmenopausal status was confirmed in each case by gonadotropin measurement. Women with excessive cigarette consumption (> 10/day) or excessive alcohol consumption (> 300 g/week) were excluded. Patients were recruited from the two centres and all attended the Wynn Institute were not
women to a
for Metabolic Research at 6-month intervals for 18 months. Informed written consent was obtained in each case, and the study was approved by the ethical committees of both centres. Drugs. Both transdermal and oral HRT were given in 28-day cycles. Oestrogen was given continuously and progestagen for 14 and 12 days, respectively, in each cycle. Transdermal therapeutic systems (TTS) were used to administer oestradiol and norethisterone acetate. 33 women applied one oestradiol-TTS (’Estraderm TTS 50’, Ciba-Geigy, Basel, Switzerland) delivering 0-05 mg oestradiol 17-beta daily for the first 2 weeks of the cycle, and then one norethisterone acetate/oestradiol-TTS (’NET Aj - TTS’, Ciba-Geigy) for the second 2 weeks of the cycle. A combined NET A/E2- TTS delivered about 0 05 mg of oestradiol 17-beta and 02-03 mg of NETA daily.6 All the patches were applied to the skin below the waist and were changed twice a week on fixed days. 33 women received oral therapy, consisting of conjugated equine oestrogens 0-625 mg/day continuously, with added dl-norgestrel 0- 15 mg/day for the last 12 days of each 28-day cycle. These hormones were supplied in a calendar pack (’Prempak
C’, Wyeth-Ayerst, Maidenhead, UK). Methods
Height, weight, cigarette use, and alcohol consumption were recorded at the beginning of the study. Thyroid disease was excluded by measurement of serum thyrotropin, and parathyroid disease and osteomalacia were excluded by measurements of serum parathyroid hormone and 25-hydroxyvitamin D levels, respectively. Routine haematological and biochemical tests were done to exclude other conditions such as hepatic and renal disorders. Dietary calcium intake was assessed by recording consumption of dairy produce, and physical exercise participation by interview and questionnaire. At each visit, after a 12-hour fast, venous blood samples were taken for measurement of serum calcium, albumin, phosphate, and
ADDRESSES: Wynn Institute for Metabolic Research, London, UK (J. C. Stevenson, MRCP, M. P. Cust, MRCOG, K. F. Gangar, MRCOG, T. C. Hillard, MRCOG, B. L. Lees, BSc), and Department of Obstetrics and Gynaecology, King’s College School of Medicine and Dentistry, London, UK (M. P. Cust, K. F. Gangar, T. C. Hillard, M. I. Whitehead, FRCOG). Correspondence to Dr Stevenson, Wynn Institute for Metabolic Research, 21 Wellington Road, London NW8 9SQ, UK.
266
TABLE I-BASELINE DEMOGRAPHIC DATA I
I
TABLE )H—CHANGES IN BONE DENSITY
(MEDIAN
AND
RANGE)
I
*Median and range; other values are mean and SD, or percentages as mdicated. tp < 0 05 vs oral group; tp < 0-05 vs both treatment groups
alkaline phosphatase (ALP) by autoanalyser. Serum calcium results corrected for serum albumin. A fasting urine sample was obtained for measurement of calcium and creatinine by autoanalyser, and for measurement of hydroxyproline by resincatalysed hydrolysis.7 Urine results were expressed as calcium/ creatinine (Ca/cre) and hydroxyproline/creatinine (OHPr/cre) ratios. Bone density measurements were carried out by dual photon absorptiometry with a Lunar DP3 (Lunar Radiation Corporation, Madison, Wisconsin) which incorporated a 153Gd source and used 8 mm detector collimation.8 Precision in vivo was determined by were
conducting 2-7 serial measurements in 26 healthy volunteers (6 males, median age 30 years, range 28-38; 20 females, median age 32 years, range 22-60) over the duration of the study. Bone density was measured in the first four lumbar vertebrae, and the values were expressed in g/cm2. Bone density was also measured in the femoral neck, Ward’s triangle, and the trochanteric region. The isotope
changed twice during the study. timepoints were unsatisfactory owing to technical difficulties, usually patient movement. For longitudinal comparisons, the same combinations of vertebral body densities were used throughout, and the mean value of the second, source was
A few
measurements at some
i
*p
