Int. J. Gynecol. Obstet., 1991,34: 253-256
253
International Federation of Gynecology and Obstetrics
Prevention of osteoporosis by medroxyprogesterone in postmenopausal women S.G. McNeeley
Jr., J.S. Schinfeld,
T.G.
Stovall,
acetate
F.W. Ling and B.H. Buxton
University of Tennessee College of Medicine, Lkpartment of Obstetrics and Gynecology and Department of Internal Medicine Memphis, Tennessee (USA) (Received April Uth, 1989) (Revised and accepted January 2Oth, 1990)
Abstract The effect of medroxyprogesterone acetate IO mg BID alone, conjugated estrogens alone or in a combination regimen for the prevention of osteoporosis was determined in 36 postmenopausal women using single photon densitometty. No significant differences in cortical or trabecular bone mass over time were detected in women between the three treatment groups, although a slight increase in bone mass was noted in women with the combined therapy. Medroxypogesterone acetate appears efficacious in preventing postmenopausal osteoporosis, and may be eqxcially useful in women with contraindications to estrogeti replacement therapy. Keywords: Osteoporosis; esterone; Postmenopausal.
Medroxyprog-
Introduction There are approximately 35 million postmenopausal women in the United States. These women are at increased risk for medical problems related directly to estrogen deficiency, and 75-85% will develop the signs and symptoms of estrogen deficiency including vasomotor hot flushes, urogenital atrophy and osteoporosis. 0020-7292/91/w3.s0 0 1991 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
Although unopposed estrogen is effective in treating menopausal symptoms and preventing osteoporosis, it has been associated with increased risk for endometrial carcinoma [ll-131. The addition of a progestogen to estrogen therapy reduces the risk of developing endometrial carcinoma [2]. Progestins, including medroxyprogesterone acetate, have been shown to have positive effects on bone metabolism manifested by the reduction of urinary ratios of calcium and hydroxyproline to creatinine, and other indices of bone resorption [l,S]. We report the effectiveness of estrogen plus medroxyprogesterone acetate, medroxyprogesterone acetate therapy alone as well as estrogen therapy, all in combination with calcium supplementation, in the prevention of osteoporosis as determined by single photon bone densitometry. Materials and methods Thirty-six women requesting treatment of postmenopausal complaints were enrolled in this study. A thorough history and physical examination was performed and written informed consent obtained as approved by the Institutional Review Board. All patients were counseled with respect to proper diet and exercise. Calcium supplementation of 500 -1000 mg daily was prescribed but doses were not randomized in this study. Patients in Clinicaland ClinicalResearch
254
McNeeley et al.
Group I (n = 13) received conjugated estrogen 0.625 mg daily and medroxyprogesterone acetate 10 mg for 15 days each month. Group 2 (n = 13) consisted of patients with contraindications to estrogen therapy or who declined estrogen therapy and received medroxyprogesterone acetate 10 mg twice daily. Patients in Group 3 (n = 10) had undergone surgical menopause and received unopposed estrogen 0.625 mg alone. An endometrial biopsy was performed on appropriate patients receiving estrogen. Physical examination was performed at 6-month intervals. Bone densitometry was performed prior to hormone therapy and every 3 months for a minimum of 18 months. Densitometry was performed using a Norland Cameron Bone Mineralizer. Measurements for cortical bone mass were obtained at the midshaft of the radium of the lesser used arm while trabecular mass was measured at 2.5 cm proximal to the distal end of the ulna. The net change in g/cm* of trabecular or cortical bone mass was determined after at least 1 year of therapy. Analysis of variance and the nonparametric Kruskal-Wallis test were used to determine significant differences between the treatment groups. Results The characteristics of the patient groups are noted in Table I. Patient’s receiving medTable I.
roxyprogesterone acetate alone were significantly older than patients in the other treatment groups (P < 0.005). Patients were similar with respect to height, weight, and risk factors for osteoporosis. The mean duration of menopause for patients receiving medroxyprogesterone was greater than 5 years; this was not significantly different from patients with estrogen alone or in combination with medroxyprogesterone acetate. No significant differences in change of bone mass over time when compared to duration of menopause was noted in patients receiving medroxyprogesterone acetate. The mean changes in bone mineral content for the three groups are noted in Fig. 1. There was no significant decrease in trabecular or cortical bone mass between the treatment groups, (P > 0.05) during the study period. Patients receiving estrogen and medroxyprogesterone acetate therapy experienced slight increases in both cortical (0.086 g/cm2) and trabecular (0.045 g/cm*) bone mass. Decreases of less than 0.015 g/cm* for both trabecular and cortical mass was detected in the medroxyprogesterone acetate group while estrogen treated patients experienced no change in cortical mass and a 0.014 g/cm* decline in trabecular mass. No endometrial atypia was detected in patients undergoing repeat endometrial biopsy. Failure to complete the study in five patients receiving medroxyprogesterone acetate ‘alone or in
Clinical characteristics of women on hormone therapy
Age (years, mean) Height (inches, mean) Weight (lb, mean) Family history of osteoporosis (no.) Tobacco use (no.) Duration of menopause (ye-, mean) ‘P< 0.005. Int JGynecol Obstet 34
Estrogen plus medroxyprogesterone acetate
Estrogen
Medroxyprogesterone acetate
41.3 f 8.2 69.1 + 2.4 155.14 f 14.6
44.3 + 7.6 68.5 f 2.2 156.1 f 12.8
54.8 + 4.1. 64.3 f 4.3 146.0 f 14.9
3 1 2.2
2 1 +
0.8
2.6 f
4 2 0.7
5.3 +
1.2
Osteoporosis and medroxyprogesterone acetate
Trabecular ?? .08
N;
.06
m
.04
i 5
.02
5
0
Estrogen Plus Medroxyprogesterone Acetate
Medroxyprogasterone Acetate
Estrogen
Fig. 1. Mean change of cortical and trabecular mass.
combination was due to weight gain and mastalgia (2), depression (2), and irregular undesired bleeding (1). Discussion Cessation of ovarian function characteristic of the menopause is associated with accelerated bone loss. Both estrogen deficiency and aging have been implicated in the pathogenesis of osteoporosis in postmenopausal women. Estrogen deficiency may be the predominant cause of bone loss during the first two decades after a natural menopause [8], related in part to calcium deficiency due to decreased intestinal absorption of calcium and mild hypercalciuria due to defective renal adaptation with hypoestrogenism. Estrogen therapy has been shown to be effective in the prevention of this accelerated bone loss [4,1 l-131. We now report that there is no significant difference in the changes of cortical or trabecular bone mass in postmenopausal women taking either estrogen plus medroxyprogesterone acetate or medroxyprogesterone acetate alone or daily estrogen when combined with dietary and exercise counseling and calcium supplementation. Our finding of a slight increase in bone mass in patients on estrogen replacement therapy is consistent with other reports [7]. Medroxyprogesterone acetate and the 19-
255
nortestosterone progestins have recently been shown to reduce urinary calcium excretion. Oral and depomedroxyprogesterone acetate reduce the urinary calcium/creatinine ratio and the hydroxyproline/creatinine ratio to levels similar to those seen in premenopausal women. Our study supports this biochemical data by reporting the preservation of bone mineral content as measured by bone densitometry. The mechanism of this effect is unclear but may include both an anabolic action of medroxyprogesterone acetate on bone metabolism and increased intestinal absorption of calcium or effects on calcitonin as reported with estrogen [9,10]. Similar effects have been reported with norethisterone [ 11. Reduction and aromatization of these progestins in the body is also a possible explanation of this effect. Single photon densitometry as used in this study is the most widely tested and available method of studying cortical and trabecular bone mass. Using techniques described, prediction of total skeletal calcium from the bone mineral content in a single patient incurs a minimum error of l-2070, or only 20 g of calcium. This predicted value is greatly increased when a well defined patient group is studied every 4-6 months over a period of 1 -2 years. If the radius is used for screening, it should realized that low radius bone mineral content indicates a high probability for concomitant low total skeletal calcium and low spinal bone mineral content; however, a normal value does not exclude spinal osteoporosis. Other techniques are available to study bone mineral content including radiography and CT scans. Photon densitometry is more widely available and allows studies of predominantly cortical and trabecular bone sites and thus total skeletal calcium. Contemporary hormone replacement therapy of the menopause includes daily estrogen and the addition of a progestin for lo-15 days each month, especially to prevent endometrial hyperplasia in women with their uteri in situ. For patients with contraindications to or side effects from estrogen therapy, Clinical and Clinical Research
256
McAWey et al.
medroxyprogesterone acetate may be an alternative choice due its demonstrated effectiveness in the prevention of osteoporosis over the l-2 year treatment period, as well as the symptomatic relief of postmenopausal vasomotor symptoms [6]. Acknowledgment
7
8
9
Supported in part by a grant in aid from the Upjohn Company. 10
References Abdalla HI, Hart DM, Lindsay R et al: Prevention of bone mineral loss in postmenopausal women by Norethisterone. Obstet Gynecol66: 789.1985. Hammond CB, Jelovsek FR. Lee KI et al: Effects of longterm estrogen replacement therapy: II. Neoplasia. Am J Obstet Gynecol IN: 537,1979. Hirvonen E, Malkonene M, Manninen V: Effects of different progestins on lipoproteins during postmenopausal replacement therapy. N Engl J Med 304: 560,198 1. Lobo RA, McCormick W, Sinxeu F et al: Depo-medroxyprogesterone acetate compared with conjugated estrogens for the treatment of postmenopausal women. Obstet Gynecol63: 1,1984. Mandel FP, Davidson BJ, Erlik Y et al: Effects of progestins on bone metabolism in postmenopausal women. J Reprod Med 27(Suppl): 511,1982. Morrison JC, Martin DC, Blair RA et al: The use of med-
Int J Gynecol Obstet 34
11
12
13
roxyprogesterone acetate for relief of climacteric symptoms. Am J Obstet Gynecol138: 99,198O. Nochtigall LE, Nochtigall RH, Nochtigall RD et al: Estrogen replacement therapy I: A lo-year prospective study in the relationship of osteoporosis. Obstet Gynecol 53: 277,1979. Richelson LS. Wahner HW, Melton LJ et al: Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 311: 1273.1984. Scali G, Coscelli C, Palmari V et al: Changes induced with the administration of thyrocalcitonin on serum Ca47 clearance curve in osteoporotics treated with medroxyprogesterone acetate. Giom Geront 18: 382, 1970. Tonelli M, Cucinotta D. Gnudi A et al: Intestinal absorption of radiocalcium in aged osteoporotic patients treated with medroxyprogesterone acetate. Giom Geront 18: 420, 1970. Walker AM, Jick H: Cancer of the corpus uteri: increasinp incidence in the U.S., 1970-1975. Am J Epidemiol 110: 47.1979. Weiss NS, Sxekely DR, Austin DF: Increasing incidence of endometrial cancer in the U.S. N Engl J Med 294: 1259,1976. Ziel HK, Finkle W: Increased incidence of endometrial carcinoma among users of conjugated estrogens. N Engl J Med293: 1167,1975.
Address for correspondence: S.G. McNeeley, Jr. Department of Obstetrks and Gyneeolo& untvemity of Mtcbtgaa Hospitals D2232 Medical Professional Butldtng Ann Arbor, MI 481094718, USA
253
International Federation of Gynecology and Obstetrics
Prevention of osteoporosis by medroxyprogesterone in postmenopausal women S.G. McNeeley
Jr., J.S. Schinfeld,
T.G.
Stovall,
acetate
F.W. Ling and B.H. Buxton
University of Tennessee College of Medicine, Lkpartment of Obstetrics and Gynecology and Department of Internal Medicine Memphis, Tennessee (USA) (Received April Uth, 1989) (Revised and accepted January 2Oth, 1990)
Abstract The effect of medroxyprogesterone acetate IO mg BID alone, conjugated estrogens alone or in a combination regimen for the prevention of osteoporosis was determined in 36 postmenopausal women using single photon densitometty. No significant differences in cortical or trabecular bone mass over time were detected in women between the three treatment groups, although a slight increase in bone mass was noted in women with the combined therapy. Medroxypogesterone acetate appears efficacious in preventing postmenopausal osteoporosis, and may be eqxcially useful in women with contraindications to estrogeti replacement therapy. Keywords: Osteoporosis; esterone; Postmenopausal.
Medroxyprog-
Introduction There are approximately 35 million postmenopausal women in the United States. These women are at increased risk for medical problems related directly to estrogen deficiency, and 75-85% will develop the signs and symptoms of estrogen deficiency including vasomotor hot flushes, urogenital atrophy and osteoporosis. 0020-7292/91/w3.s0 0 1991 International Federation of Gynecology and Obstetrics Published and Printed in Ireland
Although unopposed estrogen is effective in treating menopausal symptoms and preventing osteoporosis, it has been associated with increased risk for endometrial carcinoma [ll-131. The addition of a progestogen to estrogen therapy reduces the risk of developing endometrial carcinoma [2]. Progestins, including medroxyprogesterone acetate, have been shown to have positive effects on bone metabolism manifested by the reduction of urinary ratios of calcium and hydroxyproline to creatinine, and other indices of bone resorption [l,S]. We report the effectiveness of estrogen plus medroxyprogesterone acetate, medroxyprogesterone acetate therapy alone as well as estrogen therapy, all in combination with calcium supplementation, in the prevention of osteoporosis as determined by single photon bone densitometry. Materials and methods Thirty-six women requesting treatment of postmenopausal complaints were enrolled in this study. A thorough history and physical examination was performed and written informed consent obtained as approved by the Institutional Review Board. All patients were counseled with respect to proper diet and exercise. Calcium supplementation of 500 -1000 mg daily was prescribed but doses were not randomized in this study. Patients in Clinicaland ClinicalResearch
254
McNeeley et al.
Group I (n = 13) received conjugated estrogen 0.625 mg daily and medroxyprogesterone acetate 10 mg for 15 days each month. Group 2 (n = 13) consisted of patients with contraindications to estrogen therapy or who declined estrogen therapy and received medroxyprogesterone acetate 10 mg twice daily. Patients in Group 3 (n = 10) had undergone surgical menopause and received unopposed estrogen 0.625 mg alone. An endometrial biopsy was performed on appropriate patients receiving estrogen. Physical examination was performed at 6-month intervals. Bone densitometry was performed prior to hormone therapy and every 3 months for a minimum of 18 months. Densitometry was performed using a Norland Cameron Bone Mineralizer. Measurements for cortical bone mass were obtained at the midshaft of the radium of the lesser used arm while trabecular mass was measured at 2.5 cm proximal to the distal end of the ulna. The net change in g/cm* of trabecular or cortical bone mass was determined after at least 1 year of therapy. Analysis of variance and the nonparametric Kruskal-Wallis test were used to determine significant differences between the treatment groups. Results The characteristics of the patient groups are noted in Table I. Patient’s receiving medTable I.
roxyprogesterone acetate alone were significantly older than patients in the other treatment groups (P < 0.005). Patients were similar with respect to height, weight, and risk factors for osteoporosis. The mean duration of menopause for patients receiving medroxyprogesterone was greater than 5 years; this was not significantly different from patients with estrogen alone or in combination with medroxyprogesterone acetate. No significant differences in change of bone mass over time when compared to duration of menopause was noted in patients receiving medroxyprogesterone acetate. The mean changes in bone mineral content for the three groups are noted in Fig. 1. There was no significant decrease in trabecular or cortical bone mass between the treatment groups, (P > 0.05) during the study period. Patients receiving estrogen and medroxyprogesterone acetate therapy experienced slight increases in both cortical (0.086 g/cm2) and trabecular (0.045 g/cm*) bone mass. Decreases of less than 0.015 g/cm* for both trabecular and cortical mass was detected in the medroxyprogesterone acetate group while estrogen treated patients experienced no change in cortical mass and a 0.014 g/cm* decline in trabecular mass. No endometrial atypia was detected in patients undergoing repeat endometrial biopsy. Failure to complete the study in five patients receiving medroxyprogesterone acetate ‘alone or in
Clinical characteristics of women on hormone therapy
Age (years, mean) Height (inches, mean) Weight (lb, mean) Family history of osteoporosis (no.) Tobacco use (no.) Duration of menopause (ye-, mean) ‘P< 0.005. Int JGynecol Obstet 34
Estrogen plus medroxyprogesterone acetate
Estrogen
Medroxyprogesterone acetate
41.3 f 8.2 69.1 + 2.4 155.14 f 14.6
44.3 + 7.6 68.5 f 2.2 156.1 f 12.8
54.8 + 4.1. 64.3 f 4.3 146.0 f 14.9
3 1 2.2
2 1 +
0.8
2.6 f
4 2 0.7
5.3 +
1.2
Osteoporosis and medroxyprogesterone acetate
Trabecular ?? .08
N;
.06
m
.04
i 5
.02
5
0
Estrogen Plus Medroxyprogesterone Acetate
Medroxyprogasterone Acetate
Estrogen
Fig. 1. Mean change of cortical and trabecular mass.
combination was due to weight gain and mastalgia (2), depression (2), and irregular undesired bleeding (1). Discussion Cessation of ovarian function characteristic of the menopause is associated with accelerated bone loss. Both estrogen deficiency and aging have been implicated in the pathogenesis of osteoporosis in postmenopausal women. Estrogen deficiency may be the predominant cause of bone loss during the first two decades after a natural menopause [8], related in part to calcium deficiency due to decreased intestinal absorption of calcium and mild hypercalciuria due to defective renal adaptation with hypoestrogenism. Estrogen therapy has been shown to be effective in the prevention of this accelerated bone loss [4,1 l-131. We now report that there is no significant difference in the changes of cortical or trabecular bone mass in postmenopausal women taking either estrogen plus medroxyprogesterone acetate or medroxyprogesterone acetate alone or daily estrogen when combined with dietary and exercise counseling and calcium supplementation. Our finding of a slight increase in bone mass in patients on estrogen replacement therapy is consistent with other reports [7]. Medroxyprogesterone acetate and the 19-
255
nortestosterone progestins have recently been shown to reduce urinary calcium excretion. Oral and depomedroxyprogesterone acetate reduce the urinary calcium/creatinine ratio and the hydroxyproline/creatinine ratio to levels similar to those seen in premenopausal women. Our study supports this biochemical data by reporting the preservation of bone mineral content as measured by bone densitometry. The mechanism of this effect is unclear but may include both an anabolic action of medroxyprogesterone acetate on bone metabolism and increased intestinal absorption of calcium or effects on calcitonin as reported with estrogen [9,10]. Similar effects have been reported with norethisterone [ 11. Reduction and aromatization of these progestins in the body is also a possible explanation of this effect. Single photon densitometry as used in this study is the most widely tested and available method of studying cortical and trabecular bone mass. Using techniques described, prediction of total skeletal calcium from the bone mineral content in a single patient incurs a minimum error of l-2070, or only 20 g of calcium. This predicted value is greatly increased when a well defined patient group is studied every 4-6 months over a period of 1 -2 years. If the radius is used for screening, it should realized that low radius bone mineral content indicates a high probability for concomitant low total skeletal calcium and low spinal bone mineral content; however, a normal value does not exclude spinal osteoporosis. Other techniques are available to study bone mineral content including radiography and CT scans. Photon densitometry is more widely available and allows studies of predominantly cortical and trabecular bone sites and thus total skeletal calcium. Contemporary hormone replacement therapy of the menopause includes daily estrogen and the addition of a progestin for lo-15 days each month, especially to prevent endometrial hyperplasia in women with their uteri in situ. For patients with contraindications to or side effects from estrogen therapy, Clinical and Clinical Research
256
McAWey et al.
medroxyprogesterone acetate may be an alternative choice due its demonstrated effectiveness in the prevention of osteoporosis over the l-2 year treatment period, as well as the symptomatic relief of postmenopausal vasomotor symptoms [6]. Acknowledgment
7
8
9
Supported in part by a grant in aid from the Upjohn Company. 10
References Abdalla HI, Hart DM, Lindsay R et al: Prevention of bone mineral loss in postmenopausal women by Norethisterone. Obstet Gynecol66: 789.1985. Hammond CB, Jelovsek FR. Lee KI et al: Effects of longterm estrogen replacement therapy: II. Neoplasia. Am J Obstet Gynecol IN: 537,1979. Hirvonen E, Malkonene M, Manninen V: Effects of different progestins on lipoproteins during postmenopausal replacement therapy. N Engl J Med 304: 560,198 1. Lobo RA, McCormick W, Sinxeu F et al: Depo-medroxyprogesterone acetate compared with conjugated estrogens for the treatment of postmenopausal women. Obstet Gynecol63: 1,1984. Mandel FP, Davidson BJ, Erlik Y et al: Effects of progestins on bone metabolism in postmenopausal women. J Reprod Med 27(Suppl): 511,1982. Morrison JC, Martin DC, Blair RA et al: The use of med-
Int J Gynecol Obstet 34
11
12
13
roxyprogesterone acetate for relief of climacteric symptoms. Am J Obstet Gynecol138: 99,198O. Nochtigall LE, Nochtigall RH, Nochtigall RD et al: Estrogen replacement therapy I: A lo-year prospective study in the relationship of osteoporosis. Obstet Gynecol 53: 277,1979. Richelson LS. Wahner HW, Melton LJ et al: Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 311: 1273.1984. Scali G, Coscelli C, Palmari V et al: Changes induced with the administration of thyrocalcitonin on serum Ca47 clearance curve in osteoporotics treated with medroxyprogesterone acetate. Giom Geront 18: 382, 1970. Tonelli M, Cucinotta D. Gnudi A et al: Intestinal absorption of radiocalcium in aged osteoporotic patients treated with medroxyprogesterone acetate. Giom Geront 18: 420, 1970. Walker AM, Jick H: Cancer of the corpus uteri: increasinp incidence in the U.S., 1970-1975. Am J Epidemiol 110: 47.1979. Weiss NS, Sxekely DR, Austin DF: Increasing incidence of endometrial cancer in the U.S. N Engl J Med 294: 1259,1976. Ziel HK, Finkle W: Increased incidence of endometrial carcinoma among users of conjugated estrogens. N Engl J Med293: 1167,1975.
Address for correspondence: S.G. McNeeley, Jr. Department of Obstetrks and Gyneeolo& untvemity of Mtcbtgaa Hospitals D2232 Medical Professional Butldtng Ann Arbor, MI 481094718, USA
