Treatment of postmenopausal osteoporosis

BMJ 2005; 330 doi: http://dx.doi.org/10.1136/bmj.330.7496.859 (Published 14 April 2005)
Cite this as: BMJ 2005;330:859

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6 May 2005

According to the book “Orthopaedics by Samuel L.Turek” 4th edition, volume 1,page 256,a negative calcium balance requires a daily iv calcium gluconate for two weeks to produce a temporary hypercalcemia which suppresses parathyroid function & stimulates thyrocalcitonin release which slows bone resorption & hence retains calcium. Many general practitioners in India use IV calcium gluconate for the treatment of osteoporosis. Can someone throw some light on this issue?

Competing interests: None declared

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milind m deshpande, consultant orthosurgeon

hubli,India,580031

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6 May 2005

The short answer appears to be NO. The long answer would take too much space but the medium answer states that ITMNS is effective ("it's the micronutrients, stupid"). Notably universal magnesium undersupply, followed by Zinc and the whole gamut of trace minerals.

These would be amply supplied by the adoption of a diet that kept our ancestors healthy.

For those who have forgotten what this consists of, it means plenty of animal proteins and fats, cholesterol, fewer cereal grains and vegetable oils (exception being olive and non genetically modified canola oils) and about 21 plus eggs per person per week.

Looking for micronutrients? You've found them.

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Dr. Herbert H. Nehrlich, Private Practice

Bribie Island, Australia 4507

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5 May 2005

is there any role of intravenous calcium gluconate in the management of osteoporosis?

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milind m deshpande, consultant orthosurgeon

hubli,india,580031

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4 May 2005

I read with the greatest attention the comments made to my editorial by Dr Taylor, Fowler and Grant. Dr Taylor, most likely, misunderstood the general sense of my message when he concludes that I am really coming down to suggesting either a bisphosphonate or oral calcium and vitamin D as prophylaxis against osteoporosis. While I agree that calcium and vitamin D should be a primary prophylaxis against osteoporosis, bisphosphonates are definitely not the only therapeutic option to be offered to patients with low bone mineral density or osteoporosis (1). For instance, raloxifene and strontium ranelate were shown to reduce vertebral fractures in women with osteopenia (bone mineral density T-score between -1 and -2.5) or osteoporosis while the latter also decreases hip fractures in elderly subject with low bone density. These are first-line prophylactic options and their use should not be limited to patients who cannot tolerate the upper GI side effects of bisphosphonates. When it comes to the administration of vitamin D, Dr Taylor properly recalls that several investigations were conducted to assess the efficacy of intermittent vitamin D on bone mineral density or fracture rates. These studies yielded rather conflicting results. Annual intramuscular injections of ergocalciferol (150.000 – 300.000 IU), given to subjects from both genders, aged more than 85 years who were living in their own home or to subjects aged 75-84 years and living in homes for aged people, reduced the rate of new fractures but only in females and at the upper limb and the ribs compared to controls (2). The same investigators, later reported that bone mineral density in the distal forearm and femoral neck did not differ between residents of nursing homes who had received an annual injection of 150 000 IU ergocalciferol during the previous 2-7 years (mean 5.1 years) and aged-, weight- and height-matched control subjects who had subnormal 25 hydroxyvitamin D level (3). In the paper quoted by Dr Taylor, supplementation with 100.000 IU oral cholecalciferol, every 4 months for 5 years, resulted in a significant reduction in the risk of any first fracture and first hip, wrist or forearm, or vertebral fracture in subjects from both genders, aged 65-85 years living in the general community (4). Part of the anti-fracture efficacy of vitamin D could be explained by an improvement in musculoskeletal function, decreasing the propensity of elderly subjects to fall (5). In this perspective, an interesting alternative to plain vitamin D would be the use of alfacalcidol, the one-alphahydroxylated metabolite of vitamin D which has been recently shown to significantly decrease the risk of falls associated with low creatinine clearance in elderly people (6). In recently published meta-analyses, active metabolites of vitamin D (D-hormones) were shown to exert a significant positive anti-fracture efficacy on overall vertebral and non-vertebral fractures (7). This preventive efficacy against spinal and nonspinal fractures appears more marked for alfacalcidol and calcitriol compared to native vitamin D (8). We subsequently agree with Dr Taylor that intermittent oral or intramuscular injections of vitamin D or use of active metabolites of vitamin D can be interesting options for the prophylaxis of osteoporosis.

We first have to apologize to Dr Fowler for not mentioning, in our editorial, the role of physical exercise and physical activity in the prophylaxis and management of osteoporosis. Due to space constraints, we focused our review on the pharmacological management of the disease. There is a concurrent body of evidence showing that exercise intervention augments bone mineral accrual in children and adolescents (9), reduces the risk of osteoporosis on delays the physiological decrease of bone mineral density in adults (10) or prevent the risk of falls in elderly subjects (11). We fully agree with Dr Taylor that maintaining physical activity (not only into old age) improves bone quality but also positively impacts on muscle coordination and balance, which are main determinants of the propensity to fall of elderly people (12).

More than 15 years ago, we reported decreased serum levels of manganese (13) and magnesium (14) in patients with postmenopausal osteoporosis. While several reports, elegantly quoted by Dr Grant have suggested that deficiencies in nutrients or trace elements might be involved in the pathogenesis of osteoporosis, no intervention studies, so far, have brought an unequivocal demonstration of the anti-fracture efficacy of copper, zinc, magnesium or manganese supplementation. We agree with Dr Grant that the exact balance between risks and benefits of HRT still needs to be better defined. Our perception, however, was that the exhaustive discussion of the putative mechanisms action through which HRT could be deleterious on the skeleton and other body systems went far beyond the scope of our editorial.

We would like to thank this opportunity to sincerely thank Dr Taylor, Fowler and Grant for their relevant comments.

Jean-Yves REGINSTER

References:

1. J.-Y. REGINSTER. The high prevalence of inadequate serum vitamin D levels and implications for bone health. Curr Med Res Opin 2005;21:579-85.

2. R.J. HEIKINHEIMO, J.A. INKOVAARA, E.J. HARJU, M.V. HAAVISTO, R.H. KAARELA, J.M. KATAJA, A.M.L. KOKKO, L. A. KOLHO and S.A. RAJALA. Annual injection of vitamin D and fractures of aged bones. Calcif Tissue Int 1992;51:105-10.

3. R.J. HEIKINHEIMO, H. SIEVANEN, P. JANTTI, P.L. MAKI-JOKELA, S. RAJALA, I. VUORI. Vitamin D treatment and bone mineral density in the aged. Maturitas 1996;23:77-80.

4. D.P. TRIVEDI, R. DOLL, K.T. KHAW. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003;326:1-6.

5. H.A. BISCHOFF, H.B. STAHELIN, W. DICK, R. AKOS, M. KNECHT, C. SALIS, M. NEBIKER, R. THEILER, M. PFEIFER, B. BEGEROW, R.A. LEW, M. CONZELMANN. Effects of vitamin D and calcium supplementation on falls: A randomized controlled trial. J Bone Miner Res 2003;18: 343-51.

6. L. DUKAS, E. SCHACHT, Z. MAZOR, H.B. STAHELIN. Treatment with alfacalcidol in elderly people significantly decreases the high risk of falls associated with a low creatinine clearance of <_65 xmlns:_200516="urn:x-prefix:_200516" ml="ml" min.="min." osteoporos="osteoporos" int="int" _200516:_198-203.="_200516:_198-203." p="p"/> 7. F. RICHY, O. ETHGEN, O. BRUYERE, J.Y. REGINSTER. Efficacy of alphacalcidol and calcitriol in primary and corticosteroid-induced osteoporosis: a meta-analysis of their effects on bone mineral density and fracture rate. Osteoporos Int 2004;15:301-10.

8. F. RICHY, E. SCHACHT, O. BRUYERE, O. ETHGEN, M. GOURLAY, J.Y. REGINSTER. Vitamin D analogs versus native vitamin D in preventing bone loss and osteoporosis-related fractures: a comparative meta-analysis. Calcif Tissue Int 2005; accepted in print.

9. K.J. MacKELVIE, H.A. McKAY, K.M. KHAN, P.R.E. CROCKER. A school- based exercise intervention augments bone mineral accrual in early pubertal girls. J Pediatr 2001;139:501-8.

10. E. ERNST. Exercise for female osteoporosis. A systematic review of randomised clinical trials. Sports Med 1998;25:359-68.

11. A.J. CAMPBELL, M.C. ROBERTSON, M.M. GARDNER, R.N. NORTON, M.W. TILYARD, D.M. BUCHNER. Randomised controlled trial of a general practice programme of home based to prevent falls in elderly women. BMJ 1997;315:1065-9.

12. J.Y. REGINSTER, C. GOSSET, G. REGINSTER-HANEUSE. Falls among the elderly: a community problem. Arch Public Health 1996;54:363-72.

13. J.Y. REGINSTER, L.G. STRAUSE, P. SALTMAN, P. FRANCHIMONT. Trace elements and postmenopausal osteoporosis: a preliminary report of decreased serum manganese. Med Science Res 1998;16:337-8.

14. J.Y. REGINSTER, L. STRAUSE, R. DEROISY, M.P. LECRAT, P. SALTMAN, P. FRANCHIMONT. Preliminary report of decreased serum magnesium in postmenopausal osteoporosis. Magnesium 1989;8:106-9.

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Jean-Yves Reginster, director

Bone and Cartilage Metabolism Research Unit, CHU Centre-Ville, 4020 Liège, Belgium

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I would caution everyone treating osteoporosis to monitor their treatment since dangerous drug induced adverse effects could occur, like hypercalcemia, renal stones, gastritis, exacerbation of post menopausal symptoms, deep vein thrombosis & rarely malignancies.

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milind m deshpande, consultant orthosurgeon

hubli,india,580031

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Jean-Yves Reginster writes that besides all these pharmacological agents, calcium and vitamin D should be a first line strategy for the management of osteoporosis—unless an individual's dietary assessment shows a satisfactory intake.1

Contrary to popular belief the available published evidence suggests that osteoporosis is not primarily due to deficiencies of either calcium or oestrogen but is related to deficiencies of key nutrients.2 Low serum serum bone alkaline phosphatase (ALP) activity (a measure of poor bone formation), relates to reduced zinc, magnesium and manganese concentrations. ALP activity improves when these nutrients are supplemented, both in vitro and in vivo.2

Among women with confirmed or suspected osteoporosis, those taking hormone replacement therapy (HRT) had abnormally high serum copper levels and decreased ALP activity compared with non-users with osteoporosis. HRT takers also had significantly lower white cell zinc, lower red cell magnesium and lower serum bone ALP concentrations, and significantly higher mean serum phosphate levels, than other women with osteoporosis. Hormone takers also tended to have lower serum manganese, tartrate- resistant acid phosphatase (a measure of bone resorption), and vitamin C levels, and higher urinary excretion of zinc and hydroxyproline. Taking exogenous steroid sex hormones is associated with a reduction in essential bone nutrients and reduced bone formation.2 International incidence data show that fractures among women aged 35-65 years have increased dramatically in hormone prescribing countries, and this may be mediated by reduction in essential nutrients for bone formation.3

Dr Kitty Little, the author of Bone Behaviour, wrote that observations on osteoporosis from the sixth century onwards have shown that stress is the main causative factor.3 This has been confirmed by animal experiments, using rabbits, with stress simulated by the administration of cortisone. For normal health, the hormonal anticatabolic/catabolic ratio should remain on the anticatabolic side. Stress, emotional or otherwise, can tip the balance over to the catabolic side. In the presence of progestational compounds (in the pill or hormone replacement therapy), much lower levels of stress are needed. The main types of osteoporosis are disuse, with a lower blood flow through bone, steroid-induced and thrombus-induced osteoporosis. When the anticatabolic/catabolic ratio tips to the catabolic side, cell membranes become more rigid. Osteogenic precursor cells coalesce to form osteoclasts, which remove bone. Memory cells are affected, and also those responsible for the absorption of food from the gut. Increased catabolic levels also lead to the production of abnormal megakaryocytes. These produce sticky platelets that immediately coalesce to form thrombi. Many can block blood vessels in cortical bone, killing the osteocytes. Later the dead bone is removed by phagocytic cells. Other thrombi are deposited elsewhere in the body, including the coronary arteries. In these ways, hormone replacement therapy may cause osteoporosis, thrombi, heart attacks and senility, rather than preventing them.3

It is likely that the changes in vascularity and clotting caused by HRT have given clinicians a misleadingly false impression of favourable increases in bone density. The WHI study underestimated adverse effects like fractures by not comparing current HRT users with never users of hormones.

1 Reginster J-Y. Treatment of postmenopausal osteoporosis. BMJ 2005; 330:859-860 (16 April), doi:10.1136/bmj.330.7496.859

2 McLaren-Howard J, Grant ECG, Davies S. Hormone Replacement Therapy and Osteoporosis: Bone Enzymes and Nutrient Imbalances. J Nutr Environ Med 1998; 8: 129-138.

3 Little K. Progestogens: Thrombosis and Osteoporosis. J Nutr Environ Med 1998: 1998; 8: 139-152.

Competing interests: None declared

Competing interests: None declared

Ellen C G Grant, physician and medical gynaecologist

Kingston-upon-Thames, KT2 7JU, UK

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Treatment of postmenopausal osteoporosis

I was surprised to see a review ¹ of the treatment of osteoporosis that made no reference to exercise, which is both the most important factor in its causation and the chief cause of its morbidity.

Thirty five years ago, Chalmers and Ho² presented demographic evidence that osteoporotic fractures of the femoral neck were inversely related to the level of physical activity. Osteoporosis is therefore a disorder of civilization.

Although osteoporosis predisposes to age-related fractures, the essential cause of these fractures is loss of balance and falling, This was shown by Aitken in 1984 ³ who found that those who suffered fractures of the femoral neck had the same bone density as controls.

Maintaining physical activity into old age, not only conserves bone strength; more importantly it improves muscle co-ordination and balance, which are crucially important in preventing falls. So we must not let our current enthusiasm for drug treatment of osteoporosis divert us from promoting exercise programmes which are much more important because they are effective in preventing falls.4

Alan W Fowler

1. Reginster J-Y. Treatment of postmenopausal osteoporosis. BMJ 2005;330:859-60

2. Chalmers J, Ho KC. Geographical variations in senile osteoporosis. J.Bone Jt. Surg. 1970;52B:667-675

3. Aitken JM. Relevance of osteoporosis in women with fractures of the femoral neck. BMJ 1984;288:597-601

4. Kai MC, Anderson M, Lau EM. Exercise interventions; defusing the world’s osteoporosis time bomb. Canad. Med. Ass. J. 2002;167:S1-S35

Competing interests: None declared

Competing interests: None declared

Alan W Fowler, Retired orthopaedic surgeon

Home CF31 1QJ

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21 April 2005

Dr Reginster really comes down to suggesting either a bisphosphonate or oral calcium and Vitamin D as prophylaxis against osteoporosis.

In practice a small but significant proportion of people cannot tolerate the upper GI side effects of the bisphosphonate nor the daily grind and taste of the oral calcium and Vitamin D.

Others have recommended intermittent im Vitamin D (Ref below) a few years ago. Has anyone got more experience of this?

BMJ 2003;326:469 ( 1 March )Trivedi et al.

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David Taylor, GP

Birmingham B31 2HS

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