- Email: [email protected]
HEALTH SYSTEMS RESEARCH
546
of dantrolene was based on some similarities between the NMS and malignant hyperthermia, for which dantrolene is a specific therapy. Indeed, small oral doses of dantrolene (100 mg/day) in the NMS rapidly reduced the muscle rigidity, body temperature, oxygen consumption, and circulating creatine kinase activity.5 Caroff and others’8 lately reported that a muscle biopsy specimen from a patient with the NMS responded to pharmacological testing in a manner similar to that observed in malignant-hyperthermiasusceptible patients, raising the possibility of an important link between the two syndromes.’8 There are, however, fundamental differences between the NMS and malignant hyperthermia. The clinical course of the NMS with its prolonged onset, mildi fever, only moderately increased creatine kinase activity, and few associated metabolic changes is completely different from that of malignant hyperthermia. Neuromuscular blockade with either curare or pancuronium in the NMS produces a flaccid paralysis of the muscles, l,l9 whereas in established malignant hyperthermia these drugs have no effect on the musculature. This indicates an important difference in the aetiology of the muscular rigidity in the two syndromes-central (presynaptic) in origin in the NMS and peripheral (postsynaptic) in malignant hyperthermia. Furthermore, there is a report of a patient with the NMS who came to no harm when anaesthetised (anaesthetic agents not stated) for surgical treatment of a fractured neck of femur. 13 Uneventful repeated anaesthesia after recovery from the NMS has also been described.2° The similarities between the NMS and malignant hyperthermia on invitro testing of muscle suggest a common pathway for thermogenesis in muscle rather than a common underlying defect. It is salutary to recall that dantrolene was introduced for the treatment of muscle spasticity secondary to cerebral dysfunction, and lowers body temperature whenever muscle activity is
HEALTH SYSTEMS RESEARCH
use
.
excessive.21 Prevention of the NMS will not be possible until the factor(s) responsible for the sudden increase in sensitivity to the neuroleptic drugs, and thus the initiation of the syndrome, have been defined. Prompt recognition of the NMS is essential for successful treatment and medical staff treating psychiatric patients should be alert to the possibility. (The rarity of reported cases in the UK may simply reflect a lack of awareness.) The NMS should be regarded as an acute medical emergency and the patients should be managed in an intensive therapy unit with facilities for treatment of cardiovascular, respiratory, and renal disorders as well as the hyperthermia. At present, the most useful drug therapy seems to be dantrolene (either intravenously or orally) in combination with bromo-
criptine or levodopa/carbidopa. 18.
Caroff S, Rosenberg H, Gerber JC. Neuroleptic malignant syndrome and malignant hyperthermia. Lancet 1983; i: 244. HH, McCormick WF, Reinarz JA. Neuroleptic malignant syndrome. Arch Neural 1980; 37: 462-63. Lostra F, Linkowski P, Mendlewicz J. General anaesthesia after neuroleptic malignant syndrome. Biol Psychiatry 1983, 18: 243-47. Lydiatt JS, Hill GE. Treatment of heat stroke with dantrolene. JAMA 1981; 246:
19. Morris 20. 21.
41-42.
’
IN autumn, 1982, the World Health Organisation convened a study group on research for the reorientation of national health systems; the group’s report is now available.1 It conveys sound counsel to countries with underdeveloped health services and with the will and the resources to improve them. The group accepted at the outset that defining what is and what is not health systems research is a thorny exercise and consensus is not to be hoped for. A main reason is that, in the report’s own words, "health status is influenced by activities in many other sectors, so that in the broadest sense ’health-related expenditures’ might include nearly the whole national income of a country". The endless vista of research wide enough to guide the spending ofanational income needs fencing in. Health systems research as defined in the report analyses the structure, functions, and performance of existing health systems; it studies with special interest, and indeed aims to predict, the outcome of any changes made in a health system. Its questions should be framed by policy-makers and researcher in collaboration, so that they can navigate safely between complacency and irrelevance. It needs diverse skills,
including medicine, sociology, economics, statistics, political science, and the special variety øf cunning specified in the report: "The health systems research worker must learn how
resistance, and this often requires mobilising countervailing forces from other social groups among the people". Since it aims to improve the delivery of health care, to overcome
competent health systems research claims encouragement as its right, and the report advises the World Health Organisation to encourage it in all countries. The findings of health systems research, like findings on bacterial resistance, may not keep well during export from one country to another, and
the local product is preferable if it can be had. Findings may decay unused, or be suppressed where they originated.
Democracy, inherently resistant to change, may not be the most promising soil in which health systems research can reach effective practical fruition. Paternalistic dictatorship, with the usual sanctions on those who abuse their powers, may offer more prospects (perhaps this is part of the promise of the Griffiths report on the British National Health
Service). The study group’s
report does not attempt to show how much health systems research proves fertile and how much falls on stony ground. It is in a sense a tract for the converted, who are already working in health systems research and have a vested interest, and for the Organisation itself, which is favourably disposed; the sceptic may not be won over, and may suspect that the practical value of health systems research is being taken too much for granted. Argument will inevitably be inconclusive while the territory remains unsurely defmed. The report’s definition of health systems research consists in a careful description of the useful approaches that can be made. They are by no means separate from each other and from the approaches of other varieties of research. The definition thus amounts to- a Venn diagram where the health systems research circles can happily overlap each other, and overlap the circles of other research too. Finance is the issue that converts this intellectual exercise into a confrontation: who is to pay for what, and which side is armed with the more potent definition? In Britain health services research, rather than health systems research, is the term in use, and whether the two are synonyms is a nice point. The Department of Health and Social Security, and in Scotland the Scottish Home and 1. World Health
Organisation. Research for the reorientation of national health systems. Rep Ser no. 694, 1983.
WHO Tech
547
Health Department, administer and pay for the bulk ofhealth services research. But the Medical Research Council has accepted since 1980 a responsibility to increase its own annual expenditure on health services research by up to 2 million (at 1980 prices) by 1985-86, and reckons2that it is ahead of schedule. To assist in definition and evaluation a Medical Research Council Health Services Research Panel now exists. An accepted definition of the research should underlie these financial arrangements, so that a conscientious cataloguer can confirm that the arrangements are being honoured. Confident definitions are not lacking, but concordance is. Some attribute prime importance to the aim of the research; the motive is the message, and one hopes that research workers do know their own motives. Other definitions include the cynically practical: "Health services research is such research as counts towards fulfilling the Medical Research Council’s undertaking". In the relations between the Health Departments and the Medical Research Council the dividing wall between biomedical and health services research is thus of obvious administrative importance, and history tends to perforate it: nuclear magnetic resonance began as physical science, and is now also2 partly biomedical and partly health services research; bargaining decides the share of each, and it is darkly suggested that the decision is more a matter of taste than of
logic. Too much can be made of the logical predicaments of administrators. There is one important distinction here, and it is not the distinction between health services research (or health systems research) and other research. It is the difference between good research and bad research. Good health systems research deserves support, and the World Health Organisation’s report helps to depict and to promote it.
FLUORIDE AND THE TREATMENT OF OSTEOPOROSIS EVER since osteosclerosis was recognised as a complication of chronic exposure to excessive fluoride, attention has focused on its possible therapeutic role in osteoporosis. Bone fluorosis is characterised by an increase in the radiological density of the axial skeleton. Initially, there is coarsening of the trabecular pattern of lumbar vertebrae, followed by blurring and fusion of trabeculae, and finally the bone assumes the marble-white appearance of osteosclerosis. The predominant effect of fluoride on the skeleton is to stimulate osteoblasts.3,4Osteoid is laid down, and unless calcium supplements are provided, osteomalacia develops.3,44 The osteogenic effect of fluoride contrasts with that of oestrogen and calcium,6 which maintain bone mass by retarding resorption rather than stimulating accretion. Fluoride also stimulates positive calcium balance,’ and is incorporated into the crystalline structure of bone as
fluoroapatite.8 2. Medical Research Council. Annual Report 1982-83. London: MRC, 1983. 3. Jowsey J, Schenk RK, Reutter RW. Some results of the effect of fluoride on bone tissue
in
osteoporosis. J Clin Endocrinol 1968; 28: 869-79. Riggs BL, Kelly PJ, Hoffman DL. Effect of combined therapy with sodium fluoride, vitamin D and calcium in osteoporosis. Am J Med 1972; 53: 43-49. 5. Riggs BL, Jowsey J, Goldsmith RS, Kelly PJ, Hoffman DL, Arnaud CD. Short- and long-term effects of estrogen and synthetic anabolic hormone in postmenopausal osteoporosis. J Clin Invest 1972; 51: 1659-63. 6. Recker RR, Saville PD, Heaney RP. Effect of estrogen and calcium carbonate on bone loss in postmenopausal women. Ann Intern Med 1977; 87: 649-55. 7. Rich G, Ensinck J, Ivanovich P. The effects of sodium fluoride on calcium metabolism of subjects with metabolic bone disease. J Clin Invest 1964; 43: 545-56. 8. Zipkin I, Posner AS, Eanes ED. The effect offluoride on the x-ray diffraction pattern of the apatite of human bone. Biochim Biophys Acta 1962; 59: 255-58. 4. Jowsey J,
Long-term exposure to excessive fluoride causes crippling fluorosis as a result of encroachment of new bone on nerves, and the development of spinal ankylosis. The aim of fluoride treatment in osteoporosis is to improve bone strength by inducing subclinical fluorosis. The strength of bone is determined both by bone mass and by the architecture of the trabecular scaffolding. In fluorosis, the trabecular pattern and crystalline structure of bone is abnormal. Hydroxyapatite crystals in healthy skeleton run parallel to the axis of the collagen fibres in which they are deposited, whereas fluoroapatite crystals are aligned perpendicular to the collagen fibre. The crystals are also larger than hydroxyapatite and the arrangement of atoms in the crystal is less regular. In man, the consequences of these changes are uncertain, but short-term animal experiments indicate that fluoridic bone has either normally or reduced strength." In addition, axial trabecular bone gain is not matched by similar changes in cortical bone. Studies in fluoride-treated osteoporotic patients indicate a loss of radial and metacarpal cortical bone, l2,13and it is possible that treatment, will strengthen vertebrae (which are composed of predominantly trabecular bone), while weakening the cortex-rich tubular bones of the appendicular skeleton. Carefully conducted controlled trials are essential to assess the value of any treatment in osteoporosis.l4 Two controlled trials of fluoride treatment have shown no reduction in fracture rates, l5,l6 and. one of these studies reported an increased fracture rate in fluoride-treated patients.l5 In neither trial was calcium supplementation provided with the fluoride, and this might have influenced the results. Fluoride has a narrow therapeutic index. At the recommended daily dose of 60 to 75 mg, sodium fluoride causes side-effects in one-third to one-half of patients. Rheumatic symptoms are and include sinovitis, plantar fasciitis, bone and pain, arthralgia. Epigastric pain, nausea, and vomiting occur, but are less troublesome if the fluoride is taken with meals. Despite concern about the quality of fluoride-treated bone and the apparent lack of clinical effect when used alone, some optimism can be derived from an uncontrolled study reported from the Mayo Clinic. l7 A considerable reduction in the vertebral fracture rate was apparent in osteoporotic patients treated with various combinations of calcium and fluoride, and an even more striking effect was seen when oestrogen was added to the combination. The study was neither blind nor randomised, and has been criticised. 18 However, the strategy of treating osteoporosis by stimulating osteogenesis with fluoride, and retarding resorption with calcium and oestrogen, is rational and worthy of further investigation, and a National Institutes of Health sponsored trial is underway.l9 most common,
9. Posner AS. Relationship between diet and bone mineral ultrastructure. Fed Proc 1967; 26: 1717-22. 10. Henrikson PA, Lutwak L, Krook L, et al. Fluoride and nutritional osteoporosis: physicochemical data on bones from an experimental study. J Nutr 1970; 100: 631-42.
Simkin A, Guggenheim K. Effects of fluoride on metabolism and mechanical properties of rat bone. Am J Physiol 1972; 223: 46-50. 12. Dambacher MA, Lauffenberger Th, Lammble B, Haas HG. In: Courvoisier B, Donath A, eds. Fluoride and bones. Bern: Hans Huber, 1978: 238-41. 13. Riggs BL, Hodgson SF, Hoffman DL, Kelly PJ, Johnson KA, Tawes D. Treatment of primary osteoporosis with fluoride and calcium. JAMA 1980; 243: 446-49. 14. Kanis JA, Caulin F, Russell RGG. Problems in the design of clinical trials in osteoporosis. In: Dixon A St J, Russell RCG, Stamp TCB, eds. Osteoporosis a multidisciplinary problem. London: Academic Press, 1983: 205-21. 15. Inkovaara J, Heikinheimo R, Jarvineri K, et al. Prophylactic fluoride treatment and aged bones. Br Med J 1975; iii: 73-75. 16. Harley JB, Schilling A, Glidewell O. Ineffectiveness of fluoride therapy in multiple myeloma. N Engl J Med 1972; 286: 1283-88. 17. Riggs BL, Seeman E, Hodgson SF, Taves DR, O’Fallon WM. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal 1982; 306: 446-50. osteoporosis. N Engl Med J 18. Hogg D. Fluoride/calcium in osteoporosis. N Engl J Med 1982; 307: 441. 19. Riggs BL, Hodgson SF, O’Fallon WM. Fluoride/calcium in osteoporosis. N Engl J Med 1982; 307: 442.
11. Wolinsky I,
of dantrolene was based on some similarities between the NMS and malignant hyperthermia, for which dantrolene is a specific therapy. Indeed, small oral doses of dantrolene (100 mg/day) in the NMS rapidly reduced the muscle rigidity, body temperature, oxygen consumption, and circulating creatine kinase activity.5 Caroff and others’8 lately reported that a muscle biopsy specimen from a patient with the NMS responded to pharmacological testing in a manner similar to that observed in malignant-hyperthermiasusceptible patients, raising the possibility of an important link between the two syndromes.’8 There are, however, fundamental differences between the NMS and malignant hyperthermia. The clinical course of the NMS with its prolonged onset, mildi fever, only moderately increased creatine kinase activity, and few associated metabolic changes is completely different from that of malignant hyperthermia. Neuromuscular blockade with either curare or pancuronium in the NMS produces a flaccid paralysis of the muscles, l,l9 whereas in established malignant hyperthermia these drugs have no effect on the musculature. This indicates an important difference in the aetiology of the muscular rigidity in the two syndromes-central (presynaptic) in origin in the NMS and peripheral (postsynaptic) in malignant hyperthermia. Furthermore, there is a report of a patient with the NMS who came to no harm when anaesthetised (anaesthetic agents not stated) for surgical treatment of a fractured neck of femur. 13 Uneventful repeated anaesthesia after recovery from the NMS has also been described.2° The similarities between the NMS and malignant hyperthermia on invitro testing of muscle suggest a common pathway for thermogenesis in muscle rather than a common underlying defect. It is salutary to recall that dantrolene was introduced for the treatment of muscle spasticity secondary to cerebral dysfunction, and lowers body temperature whenever muscle activity is
HEALTH SYSTEMS RESEARCH
use
.
excessive.21 Prevention of the NMS will not be possible until the factor(s) responsible for the sudden increase in sensitivity to the neuroleptic drugs, and thus the initiation of the syndrome, have been defined. Prompt recognition of the NMS is essential for successful treatment and medical staff treating psychiatric patients should be alert to the possibility. (The rarity of reported cases in the UK may simply reflect a lack of awareness.) The NMS should be regarded as an acute medical emergency and the patients should be managed in an intensive therapy unit with facilities for treatment of cardiovascular, respiratory, and renal disorders as well as the hyperthermia. At present, the most useful drug therapy seems to be dantrolene (either intravenously or orally) in combination with bromo-
criptine or levodopa/carbidopa. 18.
Caroff S, Rosenberg H, Gerber JC. Neuroleptic malignant syndrome and malignant hyperthermia. Lancet 1983; i: 244. HH, McCormick WF, Reinarz JA. Neuroleptic malignant syndrome. Arch Neural 1980; 37: 462-63. Lostra F, Linkowski P, Mendlewicz J. General anaesthesia after neuroleptic malignant syndrome. Biol Psychiatry 1983, 18: 243-47. Lydiatt JS, Hill GE. Treatment of heat stroke with dantrolene. JAMA 1981; 246:
19. Morris 20. 21.
41-42.
’
IN autumn, 1982, the World Health Organisation convened a study group on research for the reorientation of national health systems; the group’s report is now available.1 It conveys sound counsel to countries with underdeveloped health services and with the will and the resources to improve them. The group accepted at the outset that defining what is and what is not health systems research is a thorny exercise and consensus is not to be hoped for. A main reason is that, in the report’s own words, "health status is influenced by activities in many other sectors, so that in the broadest sense ’health-related expenditures’ might include nearly the whole national income of a country". The endless vista of research wide enough to guide the spending ofanational income needs fencing in. Health systems research as defined in the report analyses the structure, functions, and performance of existing health systems; it studies with special interest, and indeed aims to predict, the outcome of any changes made in a health system. Its questions should be framed by policy-makers and researcher in collaboration, so that they can navigate safely between complacency and irrelevance. It needs diverse skills,
including medicine, sociology, economics, statistics, political science, and the special variety øf cunning specified in the report: "The health systems research worker must learn how
resistance, and this often requires mobilising countervailing forces from other social groups among the people". Since it aims to improve the delivery of health care, to overcome
competent health systems research claims encouragement as its right, and the report advises the World Health Organisation to encourage it in all countries. The findings of health systems research, like findings on bacterial resistance, may not keep well during export from one country to another, and
the local product is preferable if it can be had. Findings may decay unused, or be suppressed where they originated.
Democracy, inherently resistant to change, may not be the most promising soil in which health systems research can reach effective practical fruition. Paternalistic dictatorship, with the usual sanctions on those who abuse their powers, may offer more prospects (perhaps this is part of the promise of the Griffiths report on the British National Health
Service). The study group’s
report does not attempt to show how much health systems research proves fertile and how much falls on stony ground. It is in a sense a tract for the converted, who are already working in health systems research and have a vested interest, and for the Organisation itself, which is favourably disposed; the sceptic may not be won over, and may suspect that the practical value of health systems research is being taken too much for granted. Argument will inevitably be inconclusive while the territory remains unsurely defmed. The report’s definition of health systems research consists in a careful description of the useful approaches that can be made. They are by no means separate from each other and from the approaches of other varieties of research. The definition thus amounts to- a Venn diagram where the health systems research circles can happily overlap each other, and overlap the circles of other research too. Finance is the issue that converts this intellectual exercise into a confrontation: who is to pay for what, and which side is armed with the more potent definition? In Britain health services research, rather than health systems research, is the term in use, and whether the two are synonyms is a nice point. The Department of Health and Social Security, and in Scotland the Scottish Home and 1. World Health
Organisation. Research for the reorientation of national health systems. Rep Ser no. 694, 1983.
WHO Tech
547
Health Department, administer and pay for the bulk ofhealth services research. But the Medical Research Council has accepted since 1980 a responsibility to increase its own annual expenditure on health services research by up to 2 million (at 1980 prices) by 1985-86, and reckons2that it is ahead of schedule. To assist in definition and evaluation a Medical Research Council Health Services Research Panel now exists. An accepted definition of the research should underlie these financial arrangements, so that a conscientious cataloguer can confirm that the arrangements are being honoured. Confident definitions are not lacking, but concordance is. Some attribute prime importance to the aim of the research; the motive is the message, and one hopes that research workers do know their own motives. Other definitions include the cynically practical: "Health services research is such research as counts towards fulfilling the Medical Research Council’s undertaking". In the relations between the Health Departments and the Medical Research Council the dividing wall between biomedical and health services research is thus of obvious administrative importance, and history tends to perforate it: nuclear magnetic resonance began as physical science, and is now also2 partly biomedical and partly health services research; bargaining decides the share of each, and it is darkly suggested that the decision is more a matter of taste than of
logic. Too much can be made of the logical predicaments of administrators. There is one important distinction here, and it is not the distinction between health services research (or health systems research) and other research. It is the difference between good research and bad research. Good health systems research deserves support, and the World Health Organisation’s report helps to depict and to promote it.
FLUORIDE AND THE TREATMENT OF OSTEOPOROSIS EVER since osteosclerosis was recognised as a complication of chronic exposure to excessive fluoride, attention has focused on its possible therapeutic role in osteoporosis. Bone fluorosis is characterised by an increase in the radiological density of the axial skeleton. Initially, there is coarsening of the trabecular pattern of lumbar vertebrae, followed by blurring and fusion of trabeculae, and finally the bone assumes the marble-white appearance of osteosclerosis. The predominant effect of fluoride on the skeleton is to stimulate osteoblasts.3,4Osteoid is laid down, and unless calcium supplements are provided, osteomalacia develops.3,44 The osteogenic effect of fluoride contrasts with that of oestrogen and calcium,6 which maintain bone mass by retarding resorption rather than stimulating accretion. Fluoride also stimulates positive calcium balance,’ and is incorporated into the crystalline structure of bone as
fluoroapatite.8 2. Medical Research Council. Annual Report 1982-83. London: MRC, 1983. 3. Jowsey J, Schenk RK, Reutter RW. Some results of the effect of fluoride on bone tissue
in
osteoporosis. J Clin Endocrinol 1968; 28: 869-79. Riggs BL, Kelly PJ, Hoffman DL. Effect of combined therapy with sodium fluoride, vitamin D and calcium in osteoporosis. Am J Med 1972; 53: 43-49. 5. Riggs BL, Jowsey J, Goldsmith RS, Kelly PJ, Hoffman DL, Arnaud CD. Short- and long-term effects of estrogen and synthetic anabolic hormone in postmenopausal osteoporosis. J Clin Invest 1972; 51: 1659-63. 6. Recker RR, Saville PD, Heaney RP. Effect of estrogen and calcium carbonate on bone loss in postmenopausal women. Ann Intern Med 1977; 87: 649-55. 7. Rich G, Ensinck J, Ivanovich P. The effects of sodium fluoride on calcium metabolism of subjects with metabolic bone disease. J Clin Invest 1964; 43: 545-56. 8. Zipkin I, Posner AS, Eanes ED. The effect offluoride on the x-ray diffraction pattern of the apatite of human bone. Biochim Biophys Acta 1962; 59: 255-58. 4. Jowsey J,
Long-term exposure to excessive fluoride causes crippling fluorosis as a result of encroachment of new bone on nerves, and the development of spinal ankylosis. The aim of fluoride treatment in osteoporosis is to improve bone strength by inducing subclinical fluorosis. The strength of bone is determined both by bone mass and by the architecture of the trabecular scaffolding. In fluorosis, the trabecular pattern and crystalline structure of bone is abnormal. Hydroxyapatite crystals in healthy skeleton run parallel to the axis of the collagen fibres in which they are deposited, whereas fluoroapatite crystals are aligned perpendicular to the collagen fibre. The crystals are also larger than hydroxyapatite and the arrangement of atoms in the crystal is less regular. In man, the consequences of these changes are uncertain, but short-term animal experiments indicate that fluoridic bone has either normally or reduced strength." In addition, axial trabecular bone gain is not matched by similar changes in cortical bone. Studies in fluoride-treated osteoporotic patients indicate a loss of radial and metacarpal cortical bone, l2,13and it is possible that treatment, will strengthen vertebrae (which are composed of predominantly trabecular bone), while weakening the cortex-rich tubular bones of the appendicular skeleton. Carefully conducted controlled trials are essential to assess the value of any treatment in osteoporosis.l4 Two controlled trials of fluoride treatment have shown no reduction in fracture rates, l5,l6 and. one of these studies reported an increased fracture rate in fluoride-treated patients.l5 In neither trial was calcium supplementation provided with the fluoride, and this might have influenced the results. Fluoride has a narrow therapeutic index. At the recommended daily dose of 60 to 75 mg, sodium fluoride causes side-effects in one-third to one-half of patients. Rheumatic symptoms are and include sinovitis, plantar fasciitis, bone and pain, arthralgia. Epigastric pain, nausea, and vomiting occur, but are less troublesome if the fluoride is taken with meals. Despite concern about the quality of fluoride-treated bone and the apparent lack of clinical effect when used alone, some optimism can be derived from an uncontrolled study reported from the Mayo Clinic. l7 A considerable reduction in the vertebral fracture rate was apparent in osteoporotic patients treated with various combinations of calcium and fluoride, and an even more striking effect was seen when oestrogen was added to the combination. The study was neither blind nor randomised, and has been criticised. 18 However, the strategy of treating osteoporosis by stimulating osteogenesis with fluoride, and retarding resorption with calcium and oestrogen, is rational and worthy of further investigation, and a National Institutes of Health sponsored trial is underway.l9 most common,
9. Posner AS. Relationship between diet and bone mineral ultrastructure. Fed Proc 1967; 26: 1717-22. 10. Henrikson PA, Lutwak L, Krook L, et al. Fluoride and nutritional osteoporosis: physicochemical data on bones from an experimental study. J Nutr 1970; 100: 631-42.
Simkin A, Guggenheim K. Effects of fluoride on metabolism and mechanical properties of rat bone. Am J Physiol 1972; 223: 46-50. 12. Dambacher MA, Lauffenberger Th, Lammble B, Haas HG. In: Courvoisier B, Donath A, eds. Fluoride and bones. Bern: Hans Huber, 1978: 238-41. 13. Riggs BL, Hodgson SF, Hoffman DL, Kelly PJ, Johnson KA, Tawes D. Treatment of primary osteoporosis with fluoride and calcium. JAMA 1980; 243: 446-49. 14. Kanis JA, Caulin F, Russell RGG. Problems in the design of clinical trials in osteoporosis. In: Dixon A St J, Russell RCG, Stamp TCB, eds. Osteoporosis a multidisciplinary problem. London: Academic Press, 1983: 205-21. 15. Inkovaara J, Heikinheimo R, Jarvineri K, et al. Prophylactic fluoride treatment and aged bones. Br Med J 1975; iii: 73-75. 16. Harley JB, Schilling A, Glidewell O. Ineffectiveness of fluoride therapy in multiple myeloma. N Engl J Med 1972; 286: 1283-88. 17. Riggs BL, Seeman E, Hodgson SF, Taves DR, O’Fallon WM. Effect of the fluoride/calcium regimen on vertebral fracture occurrence in postmenopausal 1982; 306: 446-50. osteoporosis. N Engl Med J 18. Hogg D. Fluoride/calcium in osteoporosis. N Engl J Med 1982; 307: 441. 19. Riggs BL, Hodgson SF, O’Fallon WM. Fluoride/calcium in osteoporosis. N Engl J Med 1982; 307: 442.
11. Wolinsky I,