1065
EDITORIALS destruction of bone microstructure,13 but it is still important to arrest further loss even in patients with is attended considerable established osteoporosis to reduce the risk of further Osteoporosis by morbidity, fractures. Calcitonin is effective in the prevention14 mortality, and financial cost.1 There are many causes of the disease, but postmenopausal osteoporosis is by and treatment15 of osteoporosis but has to be far the commonest. The development of osteoporosis administered by subcutaneous injection, which makes maximum amount of has two main components-the its widespread use impractical. When nasal spray bone tissue accrued (peak bone mass) and its preparations16,17 become generally available they will Peak bone in the axial loss. form a realistic treatment strategy. density subsequent the and is skeleton, including spine proximal femur, Bisphosphonates are another class of antithe end of linear attained early in adulthood (around resorptive agents. They are widely used in the skeletal growth); there may be a slight delay in the treatment of Paget’s disease, and are very successful in cortical bone of the peripheral skeleton. Peak bone the management of malignant hypercalcaemia. 18 mass or density is largely genetically determined?-9 These drugs, which can be administered orally, are Whilst factors such as physical activity and nutrition now being tried for the prevention and treatment of in childhood may also be important, in practice it is osteoporosis and appear to be effective.1920 Etidronate could be achieved that much by lifestyle disodium, a widely available bisphosphonate, has now unlikely modifications. Thus, treatment for osteoporosis is been studied in a double-blind, placebo-controlled trial in women with postmenopausal osteoporosis.21 usually aimed at prevention of bone loss. In women, little bone tissue is lost until ovarian function ceases at Cyclical etidronate was given orally in a dose of 400 the menopause, when there is pronounced loss from mg daily-2 weeks’ treatment was repeated every 3 all skeletal sites.3A6 The rate of loss eventually slows months over 3 years. Therapy resulted in a modest increase in vertebral bone density which, most but it continues intermittently into old age. The decline in bone density is associated with a continuous importantly, led to a significant reduction in new fractures compared with the control group. increase in fracture risk in sites where trabecular bone Histological studies did not show any evidence of predominates--eg, vertebrae, proximal femur, and distal forearm. The type of fall often determines impaired mineralisation. Etidronate is rather poorly absorbed by mouth and must therefore be given on an whether a fracture occurs in the hip or wrist. 10 Loss of bone density after the menopause results empty stomach; fasting must continue for another 2 hours to ensure adequate absorption. The drug has a from an imbalance between bone resorption and formation. The most successful therapies for long skeletal half-life, which could theoretically lead to increased amounts of "old" bone in the very long term have been those that are preventing osteoporosis Hormone bone because of reduced remodelling. Nevertheless, it replacement prevents anti-resorptive. in the longloss, and hence osteoporotic fracture, represents a new and effective therapeutic approach for osteoporosis. term.! There are many other benefits of this therapy’1 Another approach is to stimulate new bone and it is suitable for most women. However, the formation. Sodium fluoride is the best established addition of a progestagen (given for a minimum of 12 agent in this respect, and preliminary trials with this days each month) to the continuous oestrogen treatment is mandatory in women who have not had a drug have been encouraging. 2223 Fluoride causes a to endometrial sustained increase in bone density, but there are some hysterectomy prevent hyperplasia. This treatment usually results in a regular withdrawal important drawbacks to this therapy. Significant bleed, which becomes less well tolerated with proportions of patients either do not respond to the treatment or get side-effects, including increasing age. Some women-eg, those with hormone-sensitive tumours-are unable to receive gastrointestinal bleeding, lower limb pain, and the hormone replacement. Moreover, since the very suggestion of an increase in the incidence of femoral of hormone has not neck fracture.23,24 An early study from the Mayo long-term safety yet replacement been fully elucidated,l2 there is a need for other Clinic suggested that fluoride administration caused a effective therapies for the prevention and treatment of reduction in the incidence of vertebral fractures in osteoporosis. osteoporotic patients,25 but the treatment groups in Prevention of bone loss is most effective in the this study were not randomised and therefore not earliest stages of osteoporosis, before perforation and truly comparable. A 4-year prospective, controlled, removal of trabecular elements lead to irreversible randomised study has now been conducted by the
New treatments for
osteoporosis
1066
group.26 They showed an increase in bone density in both the spine and the proximal femur in
A Scottish lament
same
the fluoride-treated group but there was no reduction in spinal fracture incidence compared with the control group. Of even more concern, there were twice as many hip fractures in the fluoride group as in the control group. The dose of fluoride (average 75 mg daily) was higher than the 50 mg daily commonly used. However, the fact that bone density increased yet fracture incidence was not reduced might suggest that the quality of the bone produced was defective. If so, it is likely that any dose of fluoride that increases bone density will result in new bone of inferior quality and hence impaired mechanical strength. Use of fluoride for the treatment of osteoporosis cannot be generally recommended. 1. Stevenson JC, Whitehead MI. Postmenopausal osteoporosis. Br Med J 1982; 285: 585-88. 2. Riggs BL, Wahner HW, Seeman E, et al. Changes in bone mineral density of the proximal femur and spine with aging. J Clin Invest 1982; 70: 716-23. 3. Gallagher JC, Goldger D, Moy A. Total body calcium in normal women: effect of age and menopause status. J Bone Min Res 1987; 2: 491-96. 4. Hui SL, Slemenda CW, Johnston CC, Appledorn CR. Effects of age and menopause on vertebral bone density. Bone Min 1987; 2: 141-46 5. Gilsanz V, Gibbens DT, Carlson M, Boechet MI, Cann CE, Schulz EE. Peak trabecular vertebral density: a comparison of adolescent and adult females. Calcif Tissue Int 1988; 43: 260-62. 6. Stevenson JC, Lees B, Devenport M, Cust MP, Ganger KF. Determinants of bone density in normal women: risk factors for future osteoporosis? Br Med J 1989; 298: 924-28. 7. Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC. Genetic factors in determining bone mass. J Clin Invest 1973, 52: 2800-08. 8. Cohn SH, Abesamis C, Yasamura S, Aloia JF, Zanzi I, Ellis KJ. Comparative skeletal mass and radial bone mineral content in black and white women. Metabolism 1977; 26: 171-78. 9. Seeman E, Hopper JL, Bach LA, et al. Reduced bone mass in daughters of women with osteoporosis. N Engl J Med 1989; 320: 554-58. 10. Cummings SR, Nevitt MC, Browner WS, Genant HK, Arnaud C. Hip and wrist fractures are due to different types of falls, not different types of osteoporosis. J. Bone Min Res 1989; 4 (suppl): S170. 11. Whitehead MI. The climacteric. In: Studd JW, ed. Progress in obstetrics and gynaecology. Vol 5. Edinburgh: Churchill Livingstone, 1985 332-61. 12. Barrett-Connor E. Postmenopausal estrogen replacement and breast cancer. N Engl J Med 1989; 321: 319-20. 13. Dempster DW, Shane E, Herbert W, Lindsay R. A simple method for correlative light and scanning electron microscopy of human iliac crest bone biopsies: qualitative observations in normal and osteoporotic subjects. J Bone Mm Res 1986; 1: 15-21. 14. Maclntyre I, Stevenson JC, Whitehead MI, Wimalawansa SJ, Banks LM, Healy MJR. Calcitonin for prevention of postmenopausal bone loss. Lancet 1988; ii: 1481-83. 15. Gruber HE, Ivey JL, Baylink DJ, et al. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 1984, 33: 295-303 16. Reginster JY, Denis D, Albert A, et al. 1-year controlled randomised trial of prevention of early postmenopausal bone loss by intranasal calcitonin. Lancet 1987, ii: 1481-83. 17. Overgaard K, Rits BJ, Christiansen C, Podenphant J, Johansen JS. Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 1989; 30:435-42. 18. Stevenson JC. Current management of malignant hypercalcaemia. Drugs 1988; 36: 229-38. 19. Genant HK, Harris ST, Steiger P, Davey PF, Block JE The effect of etidronate therapy in postmenopausal osteoporotic women: preliminary results. In: Christiansen C, Johansen JS, Rlis BJ, eds. Osteoporosis 1987 Copenhagen: Osteopress ApS, 1987: 1177-81. 20. Hodsman AB. Effects of cyclical therapy for osteoporosis using an oral regimen of inorganic phosphate and sodium etidronate: a clinical and bone histomorphometric study. Bone Min 1989; 5: 201-12. 21. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent, cyclical endronate therapy on bone mass and fracture rate in postmenopausal osteoporosis. N Engl J Med 1990; 322: 1265-71. 22. Briancon D, Meunier PJ. Treatment of osteoporosis with fluoride, calcium and vitamin D. Orthop Clin North Am 1981; 12: 629-48. 23. Riggs BL, Melton LJ III. Treatment of osteoporosis with sodium fluonde: an appraisal. In: Peck WA, ed. Bone and mineral research. Annual 2. New York: Elsevier, 1984. 366-93. 24. Hedlund LR, Gallagher JC. Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. J Bone Min Res 1987; 2: 123-26. 25. Riggs BL, Seeman E, Hodgson SF, Taves DR, O’Fallon WM. Effect of the fluonde/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis: comparison with conventional therapy. N Engl J Med 1982; 306: 446-50. 26. Riggs BL, Hodgson SF, O’Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802-09.
For
over a
year the clinical laboratories in Greater
Glasgow Health Board, the largest Health Authority in the UK, have been in a state of turmoil and uncertainty as to their future. In the spring of 1989 Health Board officers instituted in-house strategic reviews for each of the main laboratory disciplines. Most of these exercises had been completed, or were nearing completion when, without consultation, heads of departments were visited by members of a management consultant team from Peat Marwick McLintock who announced that they were undertaking a laboratory review for the Health Board. They conducted fairly brief interviews with the departmental heads, handed over a questionnaire for completion, and departed. Requests made by individual departments for a sight of the preliminary reports on their own performance were ignored, despite original assurances that there would be consultation to check the accuracy of the information before these reports were submitted. At the end of June, 1989, an advertisement appeared in the Journal of the European Community requesting expressions of interest in tendering for the entire Laboratory Services of Greater Glasgow Health Board. No prior notice of such intent had been given. Whilst the chairman and the general manager subsequently apologised for this oversight, they nonetheless indicated that competitive tendering for laboratory services was on the Board’s agenda. The uncertainty created by the appearance of the advertisement caused several members of the scientific staff, often at a very senior level, to seek employment elsewhere. Some middle-grade medical staff are known to have withdrawn their applications for posts advertised, and apprehension was created among applicants for consultant posts. Peat Marwick McLintock reported to the Board officers in the summer of 1989, but copies of that report, despite requests, were not made available to the consultants who had provided the information on which it was based. Even more surprisingly, the report was not made available to Board members. In December, 1989, the Board approved a strategic review of the laboratory services for widespread consultation. This document was prepared by Board officers and is substantially based on the Peat Marwick McLintock report, which is known to have come out against privatisation as an option on several groundseg, difficulties of training junior staff, and of conducting research in private laboratories, increased costs of a service based on profit, the fact that approximately 30% of tests carried out in the private sector require to be referred to National Health Service laboratories, and the possibility of poorer quality control. Some years ago the Board specifically forbade the undertaking of private work by NHS laboratories. As a result, there are now three small independent laboratories, which serve the private
EDITORIALS destruction of bone microstructure,13 but it is still important to arrest further loss even in patients with is attended considerable established osteoporosis to reduce the risk of further Osteoporosis by morbidity, fractures. Calcitonin is effective in the prevention14 mortality, and financial cost.1 There are many causes of the disease, but postmenopausal osteoporosis is by and treatment15 of osteoporosis but has to be far the commonest. The development of osteoporosis administered by subcutaneous injection, which makes maximum amount of has two main components-the its widespread use impractical. When nasal spray bone tissue accrued (peak bone mass) and its preparations16,17 become generally available they will Peak bone in the axial loss. form a realistic treatment strategy. density subsequent the and is skeleton, including spine proximal femur, Bisphosphonates are another class of antithe end of linear attained early in adulthood (around resorptive agents. They are widely used in the skeletal growth); there may be a slight delay in the treatment of Paget’s disease, and are very successful in cortical bone of the peripheral skeleton. Peak bone the management of malignant hypercalcaemia. 18 mass or density is largely genetically determined?-9 These drugs, which can be administered orally, are Whilst factors such as physical activity and nutrition now being tried for the prevention and treatment of in childhood may also be important, in practice it is osteoporosis and appear to be effective.1920 Etidronate could be achieved that much by lifestyle disodium, a widely available bisphosphonate, has now unlikely modifications. Thus, treatment for osteoporosis is been studied in a double-blind, placebo-controlled trial in women with postmenopausal osteoporosis.21 usually aimed at prevention of bone loss. In women, little bone tissue is lost until ovarian function ceases at Cyclical etidronate was given orally in a dose of 400 the menopause, when there is pronounced loss from mg daily-2 weeks’ treatment was repeated every 3 all skeletal sites.3A6 The rate of loss eventually slows months over 3 years. Therapy resulted in a modest increase in vertebral bone density which, most but it continues intermittently into old age. The decline in bone density is associated with a continuous importantly, led to a significant reduction in new fractures compared with the control group. increase in fracture risk in sites where trabecular bone Histological studies did not show any evidence of predominates--eg, vertebrae, proximal femur, and distal forearm. The type of fall often determines impaired mineralisation. Etidronate is rather poorly absorbed by mouth and must therefore be given on an whether a fracture occurs in the hip or wrist. 10 Loss of bone density after the menopause results empty stomach; fasting must continue for another 2 hours to ensure adequate absorption. The drug has a from an imbalance between bone resorption and formation. The most successful therapies for long skeletal half-life, which could theoretically lead to increased amounts of "old" bone in the very long term have been those that are preventing osteoporosis Hormone bone because of reduced remodelling. Nevertheless, it replacement prevents anti-resorptive. in the longloss, and hence osteoporotic fracture, represents a new and effective therapeutic approach for osteoporosis. term.! There are many other benefits of this therapy’1 Another approach is to stimulate new bone and it is suitable for most women. However, the formation. Sodium fluoride is the best established addition of a progestagen (given for a minimum of 12 agent in this respect, and preliminary trials with this days each month) to the continuous oestrogen treatment is mandatory in women who have not had a drug have been encouraging. 2223 Fluoride causes a to endometrial sustained increase in bone density, but there are some hysterectomy prevent hyperplasia. This treatment usually results in a regular withdrawal important drawbacks to this therapy. Significant bleed, which becomes less well tolerated with proportions of patients either do not respond to the treatment or get side-effects, including increasing age. Some women-eg, those with hormone-sensitive tumours-are unable to receive gastrointestinal bleeding, lower limb pain, and the hormone replacement. Moreover, since the very suggestion of an increase in the incidence of femoral of hormone has not neck fracture.23,24 An early study from the Mayo long-term safety yet replacement been fully elucidated,l2 there is a need for other Clinic suggested that fluoride administration caused a effective therapies for the prevention and treatment of reduction in the incidence of vertebral fractures in osteoporosis. osteoporotic patients,25 but the treatment groups in Prevention of bone loss is most effective in the this study were not randomised and therefore not earliest stages of osteoporosis, before perforation and truly comparable. A 4-year prospective, controlled, removal of trabecular elements lead to irreversible randomised study has now been conducted by the
New treatments for
osteoporosis
1066
group.26 They showed an increase in bone density in both the spine and the proximal femur in
A Scottish lament
same
the fluoride-treated group but there was no reduction in spinal fracture incidence compared with the control group. Of even more concern, there were twice as many hip fractures in the fluoride group as in the control group. The dose of fluoride (average 75 mg daily) was higher than the 50 mg daily commonly used. However, the fact that bone density increased yet fracture incidence was not reduced might suggest that the quality of the bone produced was defective. If so, it is likely that any dose of fluoride that increases bone density will result in new bone of inferior quality and hence impaired mechanical strength. Use of fluoride for the treatment of osteoporosis cannot be generally recommended. 1. Stevenson JC, Whitehead MI. Postmenopausal osteoporosis. Br Med J 1982; 285: 585-88. 2. Riggs BL, Wahner HW, Seeman E, et al. Changes in bone mineral density of the proximal femur and spine with aging. J Clin Invest 1982; 70: 716-23. 3. Gallagher JC, Goldger D, Moy A. Total body calcium in normal women: effect of age and menopause status. J Bone Min Res 1987; 2: 491-96. 4. Hui SL, Slemenda CW, Johnston CC, Appledorn CR. Effects of age and menopause on vertebral bone density. Bone Min 1987; 2: 141-46 5. Gilsanz V, Gibbens DT, Carlson M, Boechet MI, Cann CE, Schulz EE. Peak trabecular vertebral density: a comparison of adolescent and adult females. Calcif Tissue Int 1988; 43: 260-62. 6. Stevenson JC, Lees B, Devenport M, Cust MP, Ganger KF. Determinants of bone density in normal women: risk factors for future osteoporosis? Br Med J 1989; 298: 924-28. 7. Smith DM, Nance WE, Kang KW, Christian JC, Johnston CC. Genetic factors in determining bone mass. J Clin Invest 1973, 52: 2800-08. 8. Cohn SH, Abesamis C, Yasamura S, Aloia JF, Zanzi I, Ellis KJ. Comparative skeletal mass and radial bone mineral content in black and white women. Metabolism 1977; 26: 171-78. 9. Seeman E, Hopper JL, Bach LA, et al. Reduced bone mass in daughters of women with osteoporosis. N Engl J Med 1989; 320: 554-58. 10. Cummings SR, Nevitt MC, Browner WS, Genant HK, Arnaud C. Hip and wrist fractures are due to different types of falls, not different types of osteoporosis. J. Bone Min Res 1989; 4 (suppl): S170. 11. Whitehead MI. The climacteric. In: Studd JW, ed. Progress in obstetrics and gynaecology. Vol 5. Edinburgh: Churchill Livingstone, 1985 332-61. 12. Barrett-Connor E. Postmenopausal estrogen replacement and breast cancer. N Engl J Med 1989; 321: 319-20. 13. Dempster DW, Shane E, Herbert W, Lindsay R. A simple method for correlative light and scanning electron microscopy of human iliac crest bone biopsies: qualitative observations in normal and osteoporotic subjects. J Bone Mm Res 1986; 1: 15-21. 14. Maclntyre I, Stevenson JC, Whitehead MI, Wimalawansa SJ, Banks LM, Healy MJR. Calcitonin for prevention of postmenopausal bone loss. Lancet 1988; ii: 1481-83. 15. Gruber HE, Ivey JL, Baylink DJ, et al. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 1984, 33: 295-303 16. Reginster JY, Denis D, Albert A, et al. 1-year controlled randomised trial of prevention of early postmenopausal bone loss by intranasal calcitonin. Lancet 1987, ii: 1481-83. 17. Overgaard K, Rits BJ, Christiansen C, Podenphant J, Johansen JS. Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 1989; 30:435-42. 18. Stevenson JC. Current management of malignant hypercalcaemia. Drugs 1988; 36: 229-38. 19. Genant HK, Harris ST, Steiger P, Davey PF, Block JE The effect of etidronate therapy in postmenopausal osteoporotic women: preliminary results. In: Christiansen C, Johansen JS, Rlis BJ, eds. Osteoporosis 1987 Copenhagen: Osteopress ApS, 1987: 1177-81. 20. Hodsman AB. Effects of cyclical therapy for osteoporosis using an oral regimen of inorganic phosphate and sodium etidronate: a clinical and bone histomorphometric study. Bone Min 1989; 5: 201-12. 21. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent, cyclical endronate therapy on bone mass and fracture rate in postmenopausal osteoporosis. N Engl J Med 1990; 322: 1265-71. 22. Briancon D, Meunier PJ. Treatment of osteoporosis with fluoride, calcium and vitamin D. Orthop Clin North Am 1981; 12: 629-48. 23. Riggs BL, Melton LJ III. Treatment of osteoporosis with sodium fluonde: an appraisal. In: Peck WA, ed. Bone and mineral research. Annual 2. New York: Elsevier, 1984. 366-93. 24. Hedlund LR, Gallagher JC. Increased incidence of hip fracture in osteoporotic women treated with sodium fluoride. J Bone Min Res 1987; 2: 123-26. 25. Riggs BL, Seeman E, Hodgson SF, Taves DR, O’Fallon WM. Effect of the fluonde/calcium regimen on vertebral fracture occurrence in postmenopausal osteoporosis: comparison with conventional therapy. N Engl J Med 1982; 306: 446-50. 26. Riggs BL, Hodgson SF, O’Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802-09.
For
over a
year the clinical laboratories in Greater
Glasgow Health Board, the largest Health Authority in the UK, have been in a state of turmoil and uncertainty as to their future. In the spring of 1989 Health Board officers instituted in-house strategic reviews for each of the main laboratory disciplines. Most of these exercises had been completed, or were nearing completion when, without consultation, heads of departments were visited by members of a management consultant team from Peat Marwick McLintock who announced that they were undertaking a laboratory review for the Health Board. They conducted fairly brief interviews with the departmental heads, handed over a questionnaire for completion, and departed. Requests made by individual departments for a sight of the preliminary reports on their own performance were ignored, despite original assurances that there would be consultation to check the accuracy of the information before these reports were submitted. At the end of June, 1989, an advertisement appeared in the Journal of the European Community requesting expressions of interest in tendering for the entire Laboratory Services of Greater Glasgow Health Board. No prior notice of such intent had been given. Whilst the chairman and the general manager subsequently apologised for this oversight, they nonetheless indicated that competitive tendering for laboratory services was on the Board’s agenda. The uncertainty created by the appearance of the advertisement caused several members of the scientific staff, often at a very senior level, to seek employment elsewhere. Some middle-grade medical staff are known to have withdrawn their applications for posts advertised, and apprehension was created among applicants for consultant posts. Peat Marwick McLintock reported to the Board officers in the summer of 1989, but copies of that report, despite requests, were not made available to the consultants who had provided the information on which it was based. Even more surprisingly, the report was not made available to Board members. In December, 1989, the Board approved a strategic review of the laboratory services for widespread consultation. This document was prepared by Board officers and is substantially based on the Peat Marwick McLintock report, which is known to have come out against privatisation as an option on several groundseg, difficulties of training junior staff, and of conducting research in private laboratories, increased costs of a service based on profit, the fact that approximately 30% of tests carried out in the private sector require to be referred to National Health Service laboratories, and the possibility of poorer quality control. Some years ago the Board specifically forbade the undertaking of private work by NHS laboratories. As a result, there are now three small independent laboratories, which serve the private
