Markers of Bone Turnover To be useful, measured indices of bone turnover should be specific, sensitive, minimally invasive, and relatively simple and cheap to quantify. Bone formation indices have been possible to measure for some years. Osteocalcin is synthesised exclusively by osteoblasts and odontoblasts and of newly synthesised osteocalcin some enters the circulation. Levels are readily measured by radio immunoassay and correlate with histomorphometrically determined rates of bone formation in osteoporosis. Bone specific alkaline phosphatase is measured by the ELISA technique and is the exclusive product of the osteoblast. The dichotomy that occurs when measuring both BAP and osteocalcin may imply that they reflect different aspects of osteoblast function. Bone resorption indices have been measured much less satisfactorily and evaluation histomorphometrically of bone resorption is also inaccurate. However, the collagen cross links deoxypyridinoline (Dpyd) measured in urine is correlated with bone turnover in patients with vertebral osteoporosis. It is elevated in: post menopausal women (and falls to pre-menopausal levels within months of commencement of HRT) thyroid hormone excess/primary hyperparathyroidism and Pagets disease. These markers can be used to predict bone loss in individual patients (given as % loss p.a.). When incorporated into an algorithm which includes initial bone mass, these bone markers may be able to identify individuals at high risk of osteoporosis (Christiansen et al 1987). Bone densitometry has provided a major impetus to research and should lead to major changes in the management of osteoporosis. DEXA is the most recent development in bone density measurement and has superior performance compared to other methods previously used. It is accessible widely, has high precision and resolution with fast scanning times and lower irradiation exposure: it is reasonable to limit the information given to the use of this equipment in the diagnosis and management of osteoporosis. Some salient points: prudence dictates that densitometry should not be performed when there is a possibility of pregnancy; at the level of precision (1% or better for the lumbar spine) if a patient's two serial bone density measurements differ by 3% there is a 95% confidence that the change is real. Thus if a patient's management is likely to be influenced by a finding of a 3% per annum rate of change of bone density, then repeated measurements one year apart would be appropriate; there is a continuing lack of funding by most government health authorities and/or non availability of reimbursement by most health insurers; measuring bone mineral content (g) which arrives at a measurement of BMD g/cm2 gives no information about the bone architecture or the cause of bone loss, therefore causes of osteopenia other than osteoporosis need to be considered and excluded in the clinical context; consider major medical causes of osteoporosis which may require specific management and other causes of fracture (with or without radiographic evidence of osteoporosis. Strategies in Prevention In essence, prevention needs to be promoted both at individual and community levels by minimising modifiable risk factors. Some risk factors operate in childhood and adolescence (to impair the optimal development of peak bone mass) while many factors have been documented to exacerbate bone loss later in life. Hormone Replacement Therapy It has been estimated that long term use of HRT reduces the risk of osteoporotic fractures by 50%. It therefore remains the gold standard for prevention of post-menopausal bone loss - primarily by preventing bony resorption. There is also evidence that elderly women who take HRT have a lower incidence of injurious falls. This may be explained by the reduced rate of decline in central processing speed as found in oestrogen users over about seventy years of age (the mechanism by which oestrogen exerts this effect may be through its effects on cerebral blood flow and through its expression in neurotrophic factors that facilitate the normal repair of damaged neurones). Provera appears to confer little additional benefit with respect to bone mass when used with HRT. On the other hand, norethisterone has been shown to increase bone mass, either when used alone or when combined with HRT. Calcium intake There is substantial evidence that dietary calcium intake is below recommended levels in many females in their adolescent years and for much of their years beyond. In this group, gains from a high calcium intake are real but they may not be large. Women within five years of the menopause lose bone at similar rates regardless of calcium supplementation. Late post menopausal women whose dietary calcium intakes are low will benefit from calcium supplements (citrate) by having bone loss arrested. Therefore it seems prudent to advise adherence to the recommended daily allowances at various ages and to advise that calcium supplementation should not be regarded as protective against post menopausal bone loss. Recommended daily allowance of calcium in post menopausal women is in excess of 1000 mg. Physical activity Physical activity has been associated with a positive influence on bone mass but further randomised intervention studies are still needed. However, Notelovitz et al in 1991 showed that following a surgical menopause the addition of weight training to oestrogen replacement was associated with an 8% increase in spinal bone density within one year compared to HRT alone which maintained bone density. Moderation needs to be emphasised particularly in females as bone loss due to menstrual disturbance in training females is well documented. Modifiable risk factors intake of alcohol above two standard drinks per day should be discouraged due to direct inhibition of osteoblast function; the adverse effects of smoking on bone are mediated by changes in oestrogen metabolism (decreased endogenous production and increased metabolic clearance); caffeine consumption is not deleterious if calcium intake is adequate to balance the increased urinary calcium excretion (similarly diets high in sodium and protein have been implicated in promoting urinary calcium loss); prevention of falling by avoidance of hazards avoidance of drugs which impair balance improved quadriceps strength Treatment of Established Post Menopausal Osteoporosis Treatment in established post menopausal osteoporisis should be more vigorous. Emphasis on preventative measures and a sensible level of physical activity may help. In the event of fracture, immobilisation should be as brief as possible with adequate analgesia and rehabilitative support offered. The post menopausal woman who has fragility fractures should be investigated to exclude other causes of osteoporosis such as hyperthyroidism or hyperparathyroidism. Agents to treat established osteoporosis are those that inhibit bone resorption or stimulate bone formation. Hormone Replacement Therapy Oestrogens prevent bone loss at the spine and proximal femur up to age 75 and may slightly increase bone mass even in older patients. The minimum effective doses are shown in this table: Medication Dose Premarin 0.625 mg Progynova2.0 mg Ogen 2.0 mg Trisequens2.0 mg Estradermtwice weekly Oestradiol implant50-100 mg 6-18 monthly For women with an intact uterus a continuous low dose progestogen results in endometrial atrophy and eliminates periodic bleeding for most. The standard HRT progestogen appears to confer little additional benefit with respect to bone mass. On the other hand norethisterone has been shown to increase bone mass when used alone or when combined with HRT. Long term or even indefinite therapy may be necessary and this raises the following discussion. Oestrogen used for 15 years or more may be associated with a small increase in the relative risk of breast cancer, nevertheless such long term recipients also have a lower risk of heart disease and have fewer falls! In those women with a history of, or predisposition to, hypertension, or thromboembolic disease, the use of transdermal patches may avoid the potential hazards. Here a therapy regime may be tailored to suit an elderly woman who would prefer to be amenorrhoeic and avoid troublesome mastalgia. This could consist of NETA 5mg daily, with the later addition of a small dose of oestrogen, the oestrogen can be slowly increased to the standard dose required to prevent bone loss; reducing the dose of NETA to 1 - 3 mg once amenorrhea has been achieved. Calcium In post menopausal women, calcium supplementation (1000 mg/day or more) may slightly decrease bone loss particularly in the age group 80 years and more. One glass of milk (250 mls), 35 gm of cheddar cheese, 200 gm of yoghurt and 200 gm of ice cream each provide 300 mg of calcium which is about one quarter of the recommended daily dietary intake. Calcitriol Calcitriol is a potent, physiologically active metabolite of vitamin D (which stimulates intestinal calcium absorption). It has been thought to inhibit bone resorption and perhaps to increase bone formation. One highly significant study (Tilyard et al, 1991) showed a reduction in vertebral fracture rates in the second and third year of therapy; but did not evaluate its effect on bone mineral density. Patients taking calcitriol require regular monitoring of plasma calcium levels and urinary calcium excretion. Its PBS authority listing requires the presence of at least one vertebral fracture for its prescription. Biphosphonates These are potent inhibitors of bone resorption. Two studies show that an intermittent regimen of two weeks of Etidronate (400 mg/day) followed by 11-13 weeks of calcium supplementation will slightly increase spinal bone mass and decrease the rate of new vertebral fractures during the first two years of treatment. Didronel (Proctor and Gamble) is not available on PBS for this indication in Australia at present. These agents are poorly absorbed (and therefore must be taken on an empty stomach) and may cause gastro-intestinal irritation. The main concern with their use is the occurrence of mineralisation defects with higher doses. However, newer biphosphonates that can inhibit bone resorption at much lower doses are currently under investigation. Calcitonin This small peptide hormone directly inhibits the activity of osteoclasts, decreasing bone resorption. It is not available in Australia for the treatment of symptomatic osteoporosis in older women, but is widely used in Europe partly because of its analgesic effect after a fracture. Studies have shown it to reduce vertebral bone loss but its effect on fracture rates is as yet unknown. It is expensive and requires parenteral administration. Anabolic steroids The mechanism by which anabolic steroids increase bone mass remains uncertain. These agents increase lean body mass and reduce fat mass. Changes in bone density are more consistent at peripheral sites than spinal sites and may be due to effects on soft tissue composition. Their use is limited by androgenic side effects including adverse lipid profiles. Further evaluation is required, including study of their effects on fracture rates. Fluoride Bone formation is stimulated by fluoride. Higher doses of fluoride may cause abnormal bone structure and increased spinal bone mass. On this basis clinical trials are needed to evaluate the doses and duration of treatment with fluoride and other factors before it is either abandoned or used routinely in the treatment of patients with osteoporosis. An ideal treatment for established disease is yet to emerge but several therapeutic options are now available and improved therapies will probably result from ongoing clinical trials. However, prevention strategies directed at the community and at high risk individuals hold the greater hope in controlling this major health problem. Gillian McConnell, Women's Health Matters, Lismore This page was last built on 19/01/03. It was originally posted on 12/4/98; 8:40:41 AM. Previous Index 1Preventable causes of congenital abnormalities Women's HealthIndex NextObstetric emergencies - Postpartum
