Steven Conway. July, 2001. Osteoporosis [online]. Seacroft and St James's University Hospitals, Leeds, UK. Available from http://www.cysticfibrosismedicine.com
Introduction
Median survival with CF is now to the early thirties. Many of today's children can expect good quality life into late middle age with their median survival predicted to be over 40 years of age if their care is supervised from a CF centre (1). As we see the natural adult history of CF unfold, both carers and patients must deal with the longterm effects of this multisystem disease, with issues that were not seen as clinical problems when CF was only a disease of childhood. Osteoporosis is one such entity with major implications for patients' quality of life.
Osteoporosis is a complicated disease of the skeleton resulting in a deficiency of bone mass and a reduced bone density. Alterations to the bones' architectural structure make them more fragile and more likely to fracture. Mischler, in 1979, was the first to document reduced bone mineral density [BMD] in adults and children with CF (2). Over the last decade it has become a central issue in patient care, highlighted by the high incidence of fractures in adult patients, and the risks to patients after lung transplant when the daily corticosteroids used in immunosuppressive regimens will exacerbate any BMD deficits.
Background
Throughout life the skeleton is constantly remodelled by a co-ordinated programme of cellular activity that removes, renews and repairs damaged bone. About 10% of the adult skeleton is remodelled each year. Osteoclasts, stimulated by local factors such as microfractures and mechanical forces, resorb a specific amount of bone from the damaged areas creating microscopic pits on the bone surface, before undergoing a programmed cell death. Osteoblasts continue the repair process, filling in the pits with new osteoid. New minerealisation takes place over about the next five months. Disturbance of the fine control of this resorption/renewal process may result in osteopenia or osteoporosis.
The normal population achieves peak bone mass in the third decade. This is maintained by the balanced resorption/new bone formation process until bone mass inexorably declines after about 35 years of age. Whether any particular individual develops osteoporosis is influenced by their daily-life factors like smoking, diet, alcohol intake, weight bearing exercises, but also by inherited genetic factors. If sufficient calcium and other bone minerals are not accrued in the first three decades of life the maximum bone density achieved will be suboptimal and even the natural ageing process will place any such person at risk of osteoporosis whilst still a relatively young adult. Early bone mineral deficits cannot be made up. In any individual with CF the aetiology of osteoporosis is likely to be multifactorial.
Prevalence
Patients with end-stage lung disease show an almost universal reduction in BMD. Aris found a 57% prevalence of osteoporosis in this patient group (3). Donovan documented normal BMD in only 20% and a history of fracture in 41% (4). Seventy-five percent of patients on a lung tranplant waiting list had osteoporosis (5). Two studies of large unselected populations of adults with CF found osteopenia in over 40% and one third with osteoporosis (6,7).
Recent studies have compared adults and children with CF in good health and with no history of routine corticosteroid use to controls matched for body size as well as sex and age. The CF group showed no BMD deficiency (8,9). Osteoporosis may thus be restricted to patients with poor overall clinical status or chronic malnutrition, or to those on longterm corticosteroids. Optimism should be tempered, however, by the data of Henderson and Madsen which showed a 19% reduction in total body bone mineral in patients compared to controls, even though the former had only moderately reduced height and weight, (mean Z-scores = -0.7) (10). There is probably a large number of patients at risk of developing osteoporosis if preventive measures, routine screening and effective treatments are not introduced.
Techniques for measurement of BMD
Dual Energy X-ray Absorptiometry (DXA) scanning is widely available, safe, and takes less than five minutes. It measures areal density (gm/cm2) and therefore may underestimate BMD in short, narrow bones i.e. in the stunted patient with CF.
Conventional Quantitative Computerisesd Tomography [QCT] measures volumetric BMD (gm/cm3) but involves a higher radiation exposure. Peripheral QCT scans are used to measure forearm volumetric BMD and provide values for both cortical and trabecular bone.
Ultrasound techniques can be used but Broadband Ultrasound Attenuation at the calcaneum remains largely a research tool, and Amplitude Dependent Speed of Sound devices are not routinely available in the UK.
BMD results are reported as either T scores or Z scores. The former is the standard deviation [SD] of the measured BMD from the mean of a control population of young adults at their peak bone mass. The latter is the standard deviation of the measurement from the mean of an age and gender matched control group.
Osteopenia and osteoporosis respectively are usually defined as between one and 2.5 SD below the mean of a normal young adult population, or more than 2.5 SD below that mean.
Risk factors for BMD deficits in CF
Uncoupling of the bone remodelling process
Patients with CF have both decreased bone mineral accretion and an accelerated bone resorption rate.
Inadequate bone mineral accretion is an important factor (11). Absolute BMD may increase with age but, when expressed as a Z score, it declines relative to normal values at a rate of about 1SD every six to eight years, i.e. bone growth does not occur at a normal rate (12). Prepubertal, pubertal and young adult patients show increased bone resorption (raised urinary telopeptides) as well as reduced mineral accretion (low osteocalcin and carboxy-terminal propeptide of type I procollagen) (13).
Delayed puberty and hypogonadism
Adolescents with CF may still have delayed puberty despite the advances in nutritional care. This can hinder bone mineral accretion. Hypogonadism in older patients may accelerate bone loss.
Malabsorption
About 85% of patients have exocrine pancreatic insufficiency. Poor overall nutritional status has been repeatedly associated with reduced BMD. Despite routine daily vitamin D supplementation with at least 800 IU low blood vitamin D levels are common in CF (6,7). Vitamin D levels also sensitively reflect exposure to sunlight, being significantly lower in the winter months (14). Deficiency of fat soluble vitamin D alone predisposes to osteoporosis. Both fat malabsorption and vitamin D deficiency are risk factors for calcium malabsorption. Patients show suboptimal calcium absorption when challenged with a high calcium meal and higher serum parathyroid levels suggestive of a mild secondary hyperparathyroidism. These abnormalities are not fully redressed by pancreatic enzyme replacement therapy (15). The intrinsic absorptive ability of the intestine and its responsiveness to vitamin D may also be inefficient in CF (15).
Weight bearing activity
Although today most children can compete physically on equal terms with their peers, historically patients with CF have been relatively physically inactive. For maximal BMD development bones need the stimulus of muscle pulling forces and the mechanical loading of impact.
Corticosteroid therapy
Corticosteroids are often prescribed, e.g. in the treatment of allergic bronchopulmonary aspergillosis or reversible airways disease, as non-specific anti-inflammatory agents, or as immunosuppressives. An association between oral and inhaled corticosteroid use and reduced BMD at various sites has been documented (7).
Disease severity
Overall disease severity is the single most important factor determining BMD status in CF (6,7). The continuous catabolic state characteristic of the chronic lung infection results in a profusion of proinflammatory cytokines. Urinary telopeptide concentrations, indicative of bone breakdown, are significantly related to the latter and their soluble receptors and inversely related to FEV1 (16,17). Post-mortem L2/L3 vertebral bone biopsy specimens show markedly reduced BMD in both trabecular and cortical bone. Osteoblastic activity is decreased and osteoclastic activity increased (18). These data suggest that there is no primary abnormality of bone metabolism in CF, but an imbalance between bone formation and resorption consequent upon an ongoing catabolic state.
Treatment
Treatment aims can be divided into a) prevention and b) treatment of established disease.
Prevention
Inadequate bone mineral accretion in childhood followed by accelerated loss in adult life are probably the key aetiological factors. Attention should first be directed at optimising bone growth in childhood.
Children without CF showed improvement in BMD at the hip19 following the introduction of weight bearing exercises into the school programme. We should encourage children with CF to participate in regular weight bearing exercise. Doing this outdoors may also enhance vitamin D levels by increasing sunlight exposure. They should have frequent review by a CF specialist dietician and at least an annual comprehensive dietary assessment.
As most studies show a positive correlation between disease severity and reduced BMD, probably due to increased bone resorption as a consequence of the continuing infection/inflammatory state, all possible means to control respiratory infection should be employed, e.g. prompt treatment of any exacerbation, and consideration of maintenance treatment with nebulised antibiotics and pulmozyme. Corticosteroids should be used only when essential. This meticulous but essential attention to the minutiae of the treatment regimen is best supervised by a CF centre.
Treatment of osteopenia and osteoporosis
Calcium and vitamin D deficiency should be treated with appropriate supplements. Similarly primary or secondary gonadal hormone deficiency should be treated with oestrogen or testosterone.
In cases where BMD deficiency has no underlying cause other than the CF disease process itself, treatment with bisphosphonates has given promising early results. These drugs inhibit osteoclast induced bone resorption. Because of their sustained effects once weekly dosing regimens are possible. Their main immediate disadvantages are poor intestinal absorption, further reduced if they are taken with meals or drinks other than water, and their potential for causing gastrointestinal upset and oesophageal ulceration. Concerns remain over their use. Blocking bone resorption in patients who malabsorb may lower serum calcium. Their half-life in bone is over ten years and theoretically their use in children may produce longterm problems by inhibition of normal remodelling. An adequately powered randomised controlled trial is needed to cofirm efficacy and safety.
Intravenous pamidronate has been used successfully both pre- and post-lung transplant but may induce bone pain in patients not receiving corticosteroids (20,21). Oral bisphosphonates are cheaper and easier for both the patient and the CF unit. Significant benefits have been documented in a two year observational study (22).
Conclusion
Osteoporosis is common in adults with CF and although seemingly less prevalent in well children and teenagers, only longer surveillance of these patients will confirm that better nutrition and more efficient treatment of respiratory tract infection has had a longterm positive impact on their bone health.
Osteoporotic fractures can have severe consequences. Vertebral compression fractures can be very painful and structural changes in the chest wall can interfere with patients' breathing pattern. Fractures occurring even in the absence of accidental injury may complicate the postoperative course after lung transplant and impair patients' quality of life through resulting debility and pain. Because osteoporosis is a silent disease until such fractures occur, all patients should be screened by DXA scanning at least every two years from adolescence.
Treatment should be directed at maximising bone mineral accretion in childhood and preventing accelerated bone loss in adult life. This means optimising nutritional and respiratory health always, and assessing the best use of the bisphosphonates in clinical trials.
References
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