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The Classic: The Metabolic Effects of Steroid Hormones in Osteoporosis

  • Symposium: Bone Quality: From Bench to Bedside
  • The Classic
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Clinical Orthopaedics and Related Research®

Abstract

This Classic Article is a reprint of the original work by E.C. Reifenstein Jr. and F. Albright, The Metabolic Effects of Steroid Hormones in Osteoporosis. An accompanying biographical sketch of F. Albright is available at DOI 10.1007/s11999-011-1831-0. The Classic Article is ©1946 and is reprinted with permission from The American Society for Clinical Investigation from Reifenstein EC, Albright F. The metabolic effects of steroid hormones in osteoporosis. J Clin Invest. 1947;26:24–56.

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Notes

  1. These observations were carried out by Dr. Nathan B. Talbot with his method [10]. The normal range is 0.10 to 0.35 mgm. per 24 hours.

  2. The level fell from 200-300 units per day to less than 6 units per day. Normal range of FSH excretion is 6 to 50 mouse units per day [11].

  3. Conjugated equine estrogens (Premarin [Ayerst, Mc-Kenna and Harrison]).

References

  1. Albright, F., Bloomberg, E., and Smith, P. H., Post-menopausal osteoporosis. Tr. Assoc. Am. Physicians, 1940, 55, 298.

    CAS  Google Scholar 

  2. Albright, F., Parson, W., and Bloomberg, E., Cushing’s syndrome interpreted as hyperadrenocorticism leading to hypergluconeogenesis; results of treatment with testosterone propionate. J. Clin. Endocrinol., 1941, 1, 375.

    Article  CAS  Google Scholar 

  3. Albright, F., Smith, P. H., and Richardson, A. M., Post-menopausal osteoporosis: its clinical features. J. A. M. A., 1941, 116, 2465.

    Google Scholar 

  4. Reifenstein, E. C, Jr., and Albright, F., Paget’s disease: its pathologic physiology and the importance of this in the complications arising from fracture and immobilization. New Eng. J. Med., 1944, 231, 343.

    Article  Google Scholar 

  5. Albright, F., Burnett, C. H., Cope, O., and Parson, W., Acute atrophy of bone (osteoporosis) simulating hyperparathyroidism. J. Clin. Endocrinol., 1941, 1, 711.

    Article  CAS  Google Scholar 

  6. Albright, F., Cushing’s syndrome. Its pathological physiology, its relationship to the adrenogenital syndrome, and its connection with the problem of the reaction of the body to injurious agents (“alarm reaction” of Selye). The Harvey Lecture Series, 1942–1943, 38, 123.

  7. Selye, H., The alarm reaction. Cyclopedia Med. Surg, and Spec., F. A. Davis Company, Philadelphia, 1940, 15. Also, Selye, H., The general adaptation syndrome and the diseases of adaptation. J. Clin. Endocrinol., 1946, 6, 117.

    Google Scholar 

  8. Reifenstein, E. C., Jr., Kinsell, L. W., and Albright, F., Observations on the use of the serum phosphorus level as an index of pituitary growth hormone activity; the effect of estrogen therapy in acromegaly. Endocrinol., 1946, 39, 71. Also Conference on Metabolic Aspects of Convalescence Including Bone and Wound Healing. Trans. of 12th Meeting, February 4–5, 1946, p. 97; distributed by Josiah Macy, Jr. Foundation, New York.

  9. Reifenstein, E. C., Jr., Albright, F., and Wells, S. L., The accumulation, interpretation, and presentation of data pertaining to metabolic balances, notably those of calcium, phosphorus, and nitrogen. J. Clin. Endocrinol., 1945, 5, 367.

    Article  Google Scholar 

  10. Talbot, N. B., Saltzman, A. H., Wixom, R. L., and Wolfe, J. K., The colorimetric assay of urinary corticosteroid-like substances. J. Biol. Chem., 1945, 160, 535.

    PubMed  CAS  Google Scholar 

  11. Klinefelter, H. F., Jr., Albright, F., and Griswold, G. C., Experience with a quantitative test for normal or decreased amounts of follicle stimulating hormone in the urine in endocrinological diagnosis. J. Clin. Endocrinol., 1943, 3, 529.

    Article  CAS  Google Scholar 

  12. Abels, J. C., and Dobriner, K., Conference on Metabolic Aspects of Convalescence Including Bone and Wound Healing, Transactions of Seventh Meeting, June 9–10, 1944, p. 122; distributed by Josiah Macy, Jr. Foundation, New York.

  13. Farquharson, R. F., Salter, W. T., Tibbets, D. M., and Aub, J. C., Studies of calcium and phosphorus metabolism. XII. The effect of the ingestion of acid-producing substances. J. Clin. Invest, 1931, 10, 221.

    Article  PubMed  CAS  Google Scholar 

  14. Howard, J. E., Parson, W., and Bigham, R. S., Jr., Studies on fracture convalescence. III. The urinary excretion of calcium and phosphorus. Bull. Johns Hopkins Hosp., 1945, 77, 291.

    PubMed  CAS  Google Scholar 

  15. Forbes, A. P., Donaldson, E. C., Reifenstein, E. C., Jr., and Albright, F., The effect of trauma and disease on the urinary 17-ketosteroid excretion in man. J. Gin. Endocrinol. To be published.

  16. Browne, J. S. L., Conference on Metabolic Aspects of Convalescence Including Bone and Wound Healing, Transactions of the Fifth Meeting, October 8–9, 1943, p. 91; distributed by Josiah Macy, Jr. Foundation, New York.

  17. Shorr, E., Bernheim, A. R., and Taussky, H., The relation of urinary citric acid excretion to the menstrual cycle and the steroidal reproductive hormones. Science, 1942, 95, 606.

    Article  PubMed  CAS  Google Scholar 

  18. Reifenstein, E. C., Jr., and Albright, F., Conferences on Metabolic Aspects of Convalescence Including Bone and Wound Healing, Transactions of the Fifth Meeting, October 8–9, 1943, p. 79; distributed by Josiah Macy, Jr. Foundation, New York.

  19. Fremont-Smith, M., Graham, R. M., Janzen, L. T., and Meigs, J. V., The vaginal smear in the diagnosis of uterine cancer. J. Clin. Endocrinol., 1945, 5, 40.

    Article  Google Scholar 

  20. Fraser, R. W., Forbes, A. P., Albright, F., Sulko-witch, H., and Reifenstein, E. C., Jr., Colorimetric assay of 17-ketosteroids in urine; a survey of the use of this test in endocrine investigation, diagnosis, and therapy. J. Clin. Endocrinol., 1941, 1, 234.

    Article  CAS  Google Scholar 

  21. Reifenstein, E. C., Jr., Albright, F., Parson, W., and Bloomberg, E., The effect of estradiol benzoate, of testosterone propionate, and of combinations of both on post-menopausal osteoporosis and senile osteoporosis. Endocrinol., 1942, 30, S1024.

    Google Scholar 

  22. Reifenstein, E. C, Jr., and Albright, F., Conferences on Metabolic Aspects of Convalescence Including Bone and Wound Healing, Transactions of First Meeting, September 11–12, 1942, p. 37; Transactions of Second Meeting, December 11–12, 1942, p. 69 and 96; and Transactions of Fourth Meeting, June 11–12, 1943, p. 77; distributed by Josiah Macy, Jr. Foundation, New York.

  23. Reifenstein, E. C., Jr., and Albright, F., Conferences on Metabolic Aspects of Convalescence Including Bone and Wound Healing, Transactions of Third Meeting, March 12–13, 1943, p. 63; and Transactions of Fourth Meeting, June 11–12, 1943, p. 77; distributed by Josiah Macy, Jr. Foundation, New York.

  24. Reifenstein, E. C., Jr., and Albright, F., Conferences on Metabolic Aspects of Convalescence Including Bone and Wound Healing, Transactions of Fourth Meeting, June 11–12, 1943, p. 77; distributed by Josiah Macy, Jr. Foundation, New York.

  25. Reifenstein, E. C., Jr., Forbes, A. P., Albright, F., Donaldson, E., and Carroll, E., Effect of methyl testosterone on urinary 17-ketosteroids of adrenal origin. J. Clin. Invest., 1945, 24, 416.

    Article  PubMed  CAS  Google Scholar 

  26. Albright, F., and MacMahon, H. E., Clinical Pathological Conference. Bull. New Eng. Med. Center, 1941, 3, 35.

    Google Scholar 

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Acknowledgments

The authors are grateful to Drs. Max Gilbert and Erwin Schwenk of the Schering Corporation, Bloomfield, New Jersey, for generous supplies of estradiol benzoate (Progynon-B), estradiol dipropionate (Progynon-DP), testosterone propionate (Oreton), methyl testosterone (Oreton-M), progesterone (Proluton), anhydro-hydroxy-progesterone (Pranone), dehydroisoandrosterone acetate, pregnenolone, and other steroids. The authors are indebted to Drs. Charles H. Burnett, Russell W. Fraser, Anne Pappinheimer Forbes, Laurence W. Kinsell, Harry F. Klinefelter, Jr., William Parson, Patricia H. Smith, and Hirsh W. Sulkowitch for professional assistance; and to Esther Bloomberg, Dorothy F. Bryant, Evelyn Caroll, Lowell D. Cox, Eleanor F. Dempsey, Elizabeth C. Donaldson, Grace C. Griswold, Marion MacAulay, Robin M. Suby, Shirley L. Wells, and Priscilla White for technical assistance.

Author information

Authors and Affiliations

  1. Medical Service of the Massachusetts General Hospital, Boston, USA

    Edward C. Reifenstein Jr. MD & Fuller Albright MD

  2. Department of Medicine , Harvard Medical School, Boston, MA, USA

    Edward C. Reifenstein Jr. MD & Fuller Albright MD

Authors
  1. Edward C. Reifenstein Jr. MD
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  2. Fuller Albright MD
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Corresponding author

Correspondence to Fuller Albright MD.

Additional information

The expense of these studies was defrayed by grants from the Josiah Macy, Jr. Foundation, from the Rockefeller Foundation, and from the National Research Council (Committee for Research in the Problems of Sex). A bed supported by the Mallinckrodt Chemical Company on the Metabolic Ward was used for part of these studies.

Presented in part at the twenty-sixth annual meeting of the Association for the Study of Internal Secretions, Atlantic City, New Jersey, June 8, 1942, in connection with a symposium on “Relation of Endocrines to Skeletal Development”; an outline of this presentation may be found in: Reifenstein, E. C., Jr.; Albright, F.; Parson, W.; and Bloomberg, E.: The effect of estradiol benzoate and of testosterone propionate and of combinations of both on post-menopausal osteoporosis and senile osteoporosis, Endocrinology, 30: S1024 (1942). Also presented in part at the first annual meeting of the American Federation for Clinical Research, Minneapolis, Minn., April 20, 1942. Preliminary reports of part of these data may be found in: Albright, F.; Reifenstein, E. C., Jr.; and Forbes, A. P.: Conferences on the Metabolic Aspects of Convalescence (Including Bone and Wound Healing), Transactions of the First Meeting, Sept. 11–12, 1942, pages 5–7, 37–38; Transactions of the Second Meeting, December 11–12, 1942, pages 69, 96–98; Transactions of the Third Meeting, March 12–13, 1943, pages 63–65; and Transactions of the Fourth Meeting, June 11–12, 1943, pages 77–85. Transactions distributed by the Josiah Macy, Jr. Foundation, New York, N. Y.

The work described in this paper was done in part under a contract, recommended by the Committee on Medical Research, between the Office of Scientific Research and Development and the Massachusetts General Hospital.

Richard A. Brand MD (✉) Clinical Orthopaedics and Related Research, 1600 Spruce Street, Philadelphia, PA 19103, USA e-mail: dick.brand@clinorthop.org

Appendix

Appendix

Case histories

Case 1. F. F. (M.G.H. 156453), a 42-year-old woman, had a bilateral oophorectomy at the age of 41 for endometriosis; following the operation she had “nocturnal seizures,” the exact nature of which was not determined. During the following year there was a gradual onset of back pain with increasing dorsal kyphosis and a loss of energy. On admission one year after operation, the patient was in good physical condition except for the deformities of her spine; her blood pressure was 130/80. X-rays revealed typical codfish deformity of many of the dorsal and lumbar vertebrae, a collapse of some vertebrae, and anterior wedging of others. Laboratory studies: serum calcium 10.5 mgm. per cent, serum phosphorus 4.2 mgm. per cent, serum alkaline phosphatase 3.6 Bodansky units, serum total protein 7.3 grams per cent, normal glucose tolerance test, some hypoglycemia unresponsiveness in an insulin tolerance test, basal metabolic rate of minus 6, follicle-stimulating hormone test positive for 25 mouse units per 100 ml., and 17-keto-steroid excretion of 4.3 mgm. per 24 hours. This case was mentioned in previous communications ([1] [Case 1], [3] [Case 37], [20] [Case 82], [21]).

Case 2. E. P. (M.G.H. 203540), a 60-year-old patient, had a physiological menopause at 53. Thirteen months before admission she fell down 6 steps and fractured her first lumbar vertebra; she was kept in bed 5 months for this injury, and then allowed up with a brace. Eight months before admission the 9th dorsal vertebra collapsed. Except for back and chest pain, the patient had no complaints, and was in good general health upon admission. Her blood pressure was 120/90. X-ray examination revealed the fractures of the first lumbar and the 9th dorsal vertebrae, marked osteoporosis of the spine and pelvis, but not of the skull, and gall stones. Laboratory studies: serum calcium 10.1 mgm. per cent; serum phosphorus 3.5 mgm. per cent; serum alkaline phosphatase 3.7 Bodansky units; serum total protein 7.6 grams per cent; no Bence-Jones protein in the urine. This case was mentioned in previous communications ([1] [Case 2], [3] [Case 13], [20] [Case 85], [21]).

Case 3. A. M. R. (M.G.H. 29358), a 60-year-old physician, developed menopause at 45 following radium treatment of submucous fibroids. Four years before admission she experienced pain in the back while trying to raise a window, and in the ensuing 4 years developed several fractures of vertebrae and progressive deformity of the spine. Physical examination on admission revealed the deformity of the spine and otherwise no abnormalities. Her blood pressure was 148/90. X-ray examination showed deformities of several thoracic and the first lumbar vertebrae, and osteoporosis of the bones of the spine and pelvis but not of the skull. Laboratory studies: serum calcium 10.1 mgm. per cent; serum phosphorus 3.0 mgm. per cent; serum phosphatase 3.7 Bodansky units; serum total protein 6.3 grams per cent. This case has been mentioned in previous communications ([1] [Case 3], [3] [Case 32], [20] [Case 84], [21]).

Case 4. R. W. (M.G.H. 319940), a 56-year-old woman, had a cholecystectomy at 26, and thyroidectomy for thyrotoxicosis at 46. At 48, an artificial menopause was induced with radium for metropathia hemorrhagica. Three years before admission the patient strained her back opening a heavy window, and thereafter had several episodes of sharp pain in the back when lifting. Physical examination showed a nervous woman with a tremor of her head, and considerable deformity of her back. Her blood pressure was 115/75. X-ray examination revealed extensive osteoporosis with multiple fractured vertebrae; bones of skull were approximately normal in density. Laboratory studies: no abnormalities of the urine, stools, or blood cells; urine calcium 2 to 4 plus by the Sulkowitch test; serum calcium 10.6 mgm. per cent; serum phosphorus 3.1 mgm. per cent; serum alkaline phosphatase 3.7 Bodansky units; serum chloride 93.2 m.eq. per 1.; serum carbon dioxide combining power 28.1 m.eq. per 1.; non-protein nitrogen level 26 mgm. per cent; and total protein 7.8 grams per cent with an albumin/globulin ratio of 1.7. Electrocardiographic tracing was normal; follicle-stimulating hormone excretion in the urine was high (consistent with the menopause). This case has been mentioned in a previous communication [21].

Case 5. S. B. (M.G.H. 430664), a 58-year-old woman, had at the age of 28 a bilateral oophorectomy with a hysterectomy for pelvic lacerations following childbirth. For some years she had occasional hot flashes and attacks of palpitation and nervousness. At the age of 50 she began to notice weakness and the gradual onset of skeletal deformities involving the skull, shoulder girdle, lower ribs, pelvis, and bones of the legs. At 54 she had acute tonsillitis, and then a tonsillectomy. At 57 she had pneumonia, and after 3 weeks in bed, increased weakness and pain in her tibiae. About this time she used braces on her legs because of difficulty in walking. Shortly afterward she developed low-back pain on weight-bearing.

On admission, the patient was undernourished and deformed with atrophic skin and muscles, dorsal kyphosis and right cervical-dorsal scoliosis, enlarged parietal bosses, bowing of the femora and tibiae, and collapse of the lumbar spine so that the ribs touched the wings of the iliae. The chest was distorted; veins of the neck were distended; corpulmonale was present; blood pressure was 156/80.

X-rays of the skull, shoulder girdle, lower ribs, pelvis, femora, tibiae, and entire thoracic and lumbar spine except for the upper three dorsal vertebrae showed Paget’s disease; in addition there were marked generalized decreased density of bones and typical codfish deformity of many vertebrae. There were pulmonary fibrosis, cardiac enlargement and displacement, and tortuosity of the aorta. Laboratory studies: serum calcium 10.5 mgm. per cent, serum phosphorus 4.2 mgm. per cent, serum alkaline phosphatase 34.3 Bodansky units, serum total protein 7.3 grams per cent, serum non-protein nitrogen 31 mgm. per cent, serum sodium 140.0 m.eq. per 1., serum potassium 4.7 m.eq. per 1., serum chloride 101 m.eq. per 1., serum carbon dioxide content 34.2 m.eq. per 1., follicle-stimulating hormone test positive for 192 mouse units per 24 hours, and 17-ketosteroid excretion of 2.6 mgm. per 24 hours. The venous pressure was 65 mm. of water; the vital capacity was 1,200 ml.

Case 6. M. H. (M.G.H. 278511), a male of 72 years, developed pain in the back after a minor injury 1 year before admission (1-1-41). The symptoms persisted in spite of local therapy, and he was referred to the hospital. The only abnormal findings on physical examination were a thin skin and deformities of the spine; his blood pressure was 140/80. X-ray examination of the spine showed marked decrease in density of the vertebrae with a codfish deformity of some, and wedging or collapse of others. Laboratory studies: serum calcium 10.0 mgm. per cent; serum phosphorus 3.1 mgm. per cent; serum alkaline phosphatase 4.2 Bodansky units; serum total protein 7.0 grams per cent; non-protein nitrogen 18 mgm. per cent; urinary 17-ketosteroid excretion 7.2 and 6.9 mgm. per 24 hours; follicle-stimulating hormone excretion in the urine normal; gastric acidity normal. The normal level of the follicle-stimulating hormone excretion is evidence against the idea of the osteoporosis having been due to the “male menopause.” This case has been mentioned in previous communications [6, 9, 21].

Case 7. E. S. (M.G.H. 360207), a female of 35 years, had poliomyelitis at the age of 9 involving the left leg alone, and since the age of 14 had worn a 6-pound brace on the left leg. She had always been very active. For the 10 years prior to study she had had metatarsal pain in the right foot, and for 3 years had turned her right ankle frequently. She was admitted for a triple arthrodesis and muscle transplant to strengthen the right ankle. The menstrual history was normal. From the point of view of the experiment the patient can be considered a normal adult female in every respect, except for the residuals of the poliomyelitis of the left leg; her blood pressure was 120/80. Laboratory studies: serum calcium 9.8 mgm. per cent; serum phosphorus 3.5 mgm. per cent; serum alkaline phosphatase 2.4 Bodansky units; and serum total protein 4.7 grams per cent; urinary 17-ketosteroid excretion 7.6 mgm. per 24 hours. This case has been mentioned briefly elsewhere [22].

Case 8. H. D. (M.G.H. 382395), a male fireman of 50 years, fell 3 stories and suffered fractures of ribs, pelvis, right tibia and right fibula, and multiple contusions and abrasions. The patient was in shock on admission, but responded promptly to a blood transfusion. On physical examination he was found to be a well-preserved man without organic disease; blood pressure was 110/60. A Kirschner wire was inserted through the os calcis and a Zimmer bow applied. During the next 2 weeks the fractures were reduced by traction and by several manipulations tinder anesthesia. The patient was transferred to the metabolic ward where studies were begun 44 days after the accident. Laboratory studies: serum calcium 10.7 mgm. per cent; serum phosphorus 3.3 mgm. per cent; serum alkaline phosphatase 2.7 Bodansky units; serum total protein 6.7 grams per cent This case has been mentioned briefly elsewhere [23].

Case 9. C. M. (M.G.H. 348774), a male of 24 years, sustained a fracture of the pelvis and of the right femur in an automobile accident 9 months before study. The femur failed to unite properly and, although the patient was active and able to walk about with a cane, he had unusual motion and instability in his right femur because of the poor union. He was readmitted for bone grafting. Physical examination revealed a young adult male who was normal in all respects except for the incomplete union of his right femur; his blood pressure was 105/60. Laboratory studies: serum calcium 10.3 mgm. per cent; serum phosphorus 4.5 mgm. per cent; serum alkaline phosphatase 2.9 Bodansky units, and serum total protein 6.0 grams per cent. This case has been mentioned briefly elsewhere [24].

Case 10. B. V. (M.G.H. 74372), a female of 25 years, with Cushing’s syndrome of 5 years duration. The case history of this patient has been published elsewhere ([2] [Case 1]). This case has been mentioned also in other previous communications ([6, 9, 20] [Case 37]).

Case 11. R. B. (M.G.H. 3397), a female of 50 years, with Cushing’s syndrome of 5 years duration. The case history of this patient has been published elsewhere ([2] [Case 2]). This case has been mentioned also in other previous communications ([6, 9, 20] [Case 36], [25] [Case 2]).

Case 12. B .A. (M.G.H. 234190), a female of 43 years, with Cushing’s syndrome of 6 years duration. A complete case history with autopsy findings is reported elsewhere [26]. This case has also been mentioned in previous communications ([2] [Case 3], [20] [Case 38]).

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Reifenstein, E.C., Albright, F. The Classic: The Metabolic Effects of Steroid Hormones in Osteoporosis. Clin Orthop Relat Res 469, 2096–2127 (2011). https://doi.org/10.1007/s11999-011-1832-z

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