An unusual cause of spinal bone loss detected by DXA scanning.

Routine DXA scanning in a 68-year-old asymptomatic man undergoing long-term bisphosphonate treatment for osteogenesis imperfecta showed unexplained loss of bone mineral density in two lumbar vertebrae. Subsequent radiographs revealed a 14-cm abdominal aortic aneurysm eroding the vertebrae. The importance of reviewing all the vertebrae in DXA scans is emphasized, and reasons for the absence of symptoms suggested.

Health-related quality of life in patients with osteoporosis in the absence of vertebral fracture: a systematic review.

To review whether osteoporosis in the absence of vertebral fracture (VFX) affects health-related quality of life (HRQoL), a systematic search of the main literature databases for HRQoL in patients with osteoporosis without VFX was undertaken. This was undertaken. This identified 1,327 articles as potentially relevant to the review. After screening of abstracts and reviewing 168 articles in detail, 27 were considered relevant. HRQoL data were extracted and collated into tables and, where possible, were converted into normative scores and further analysed. Data relating to the associations between HRQoL and bone mineral density (BMD) were also collated. Of the 27 articles included, only 5 directly compared osteoporosis without VFX with a control group (BMD T-score > -1.0, without VFX). Extracted raw data from 21 articles demonstrated that patients with osteoporosis without VFX had clinically relevant reductions in role physical, general health, vitality, mental health domains and the mental component summary score, using SF36. Using Qualeffo-41, pain and physical function were worse in these patients. Also, HRQoL was related to upper femur, but not lumbar spine BMD. HRQoL data in patients with osteoporosis without VFX are limited and variable but suggest that HRQoL is adversely affected by osteoporosis in the absence of VFX. The association of lower BMD and worse HRQoL suggests that more attention should be paid to HRQoL in those without VFX. Future studies are needed to investigate HRQoL in patients with osteoporosis in the absence of fracture, controlling for co-morbidities and social and economic status.

Uptake of treatment for osteoporosis and compliance after bone density measurement in the community.

BACKGROUND: Management of osteoporosis is imperfect because patients may not start, persist or comply with treatment. This study was aimed to identify baseline variables associated with women failing to start, persist or comply with bisphosphonate treatment. METHODS: 254 women >50 years old were selected 5 years after having a bone densitometry (bone mineral density (BMD)) diagnosis of osteoporosis. At the outset, information about osteoporosis was sent to the general practitioner (GP). Women were not under pressure at the outset to start or comply, and they and their GP were unaware that follow-up studies would take place. Patient survival was identified from the National Health Service Strategic Tracing Service, prescription data from GP records and baseline data from the initial questionnaire. Persistence was defined as at least one prescription issued per year and compliance as having a medicine possession ratio of >or=80% for each of 5 years. RESULTS: 38% failed to start treatment. Failure was associated with higher BMD Z score and residence in a nursing/residential home. Half of those starting and alive at 5 years persisted with treatment, whereas only 23% achieved a medicine possession ratio of >or=80%. Persistence was associated with a lower comorbidity index and compliance with a lower BMD Z score and a fall before starting treatment. CONCLUSIONS: Treatment was low, especially in nursing/residential homes where known low treatment prevalence appears to be associated with non-initiation. The degree of depression of BMD (not just low BMD) was associated with better initiation and compliance. The association of falls with compliance suggests that fall clinics may be able to play a part in improving osteoporosis management.

DXA scanning in women over 50 years with distal forearm fracture shows osteoporosis is infrequent until age 65 years.

AIMS: Women with distal forearm fracture (DFF) may have low bone mineral density (BMD) and merit Dual Energy Xray (DXA) scanning. However patient age at fracture and the database for 'healthy' subjects may influence how many have osteoporosis and require DXA scans. Osteoporosis prevalence in DFF patients by age was investigated using local or nHanes III databases for BMD. METHODS: A total of 186 women over 50 years consecutively referred with DFF over 1 year were audited without exclusion criteria. BMD of L2-4 and femoral neck (Hologic QDR4500A) was measured and T- and Z-scores calculated from a local database or nHanes III. RESULTS: Of 90 patients aged 50-64 years, 21.1% had femoral neck T-score < -2.5 and 7.7% < -3.0 (local) and 8.8% and 4.4% respectively (nHanes III). Patients aged 65-74 years (n = 61) included 19.7% with T-score < -2.5 (nHanes III = 10%). 41.2% (nHanes III = 28.6%) of patients > 75 years had femoral neck osteoporosis. Including patients with spine T < -2.5 increased the proportion to 31.1% (50-64 years) and 34.4% (65-74 years) with no extra over 75 years. Weight predicted low BMD ineffectively (area under ROC = 70%). CONCLUSION: Osteoporosis is infrequent in women with DFF below 65 years. As fracture prevention treatment yields significant fracture reduction only in patients with T-score < -2.5, DXA scanning below 65 years is not justified. After 65 years scanning is justified at all ages, as even in the elderly patients osteoporosis is present in < 50% of patients with DFF. Using nHanes III limits the number of DFF patients warranting treatment. Low body weight is unreliable for identifying osteoporosis.

Effect of age and gender on the number and distribution of sites in Paget's disease of bone.

Paget's disease of bone (PDB) is reportedly declining in prevalence and severity, with increasing numbers of monostotic cases. Some accounts suggest that these findings are more evident in women, and that monostotic disease is unexpectedly frequent at certain sites. We have studied whether birth date or gender is associated with the number of sites affected and with the distribution of sites in monostotic disease and, by reviewing 100 follow-up 99Tc(m) methylene diphosphonate (MDP) scans, whether additional sites appear after initial diagnosis. Scintigraphic scans from 171 male (age 40-91 years) and 179 female (44-88 years) consecutive referrals with PDB were reviewed. Patients were analysed by referral date (1982-1992 and 1993-2001), and by their median date of birth (before (PRE21) and after (POST21) 1921). Mean age of pre-1993 patients was 69 years and 75 years for referrals after 1993. Younger patients had more monostotic disease (POST21 vs PRE21 subjects (47% vs 28%)), with a more marked trend in females (52% vs 25%), and POST21 females had fewer polyostotic sites than males (p<0.05), whereas the number in PRE21 males and females was similar. Monostotic females, but not males, showed an excess of tibial involvement. The spine was less involved in monostotic disease. Follow-up scans in 100 patients revealed no new sites. The incidence of monostotic disease has doubled over the last 30 years, but diminishing site involvement appears to be more marked in females. The lesser involvement at the axial sites in monostotic disease may lead to overestimation of the decline in PDB based on abdominal radiographs.

Muscle mass deficits are associated with bone mineral density in men with idiopathic vertebral fracture.

INTRODUCTION AND HYPOTHESIS: The causes of idiopathic vertebral fractures (IVF) in men are poorly understood. We hypothesised that in IVF, areal bone mineral density (aBMD) deficits would be associated with reduced muscle mass. METHODS: In this case-control study, 48 men (61.5 +/- 12.1 years old) presenting with symptomatic IVF were compared with 48 healthy controls matched for age (+/-5 years) and stature (+/-5 cm). The aBMD and soft-tissue body composition were determined by dual energy X-ray absorptiometry (DXA). Muscle mass was defined as the ratio of appendicular lean mass to the square of height (ALMI). Sex hormones, IGF-I and its binding protein IGFBP-3 were measured by immunoassay. RESULTS: ALMI was significantly lower in IVF patients (8.27 +/- 0.90 vs 8.65 +/- 0.88 kg/m(2), t = 2.193, df = 47, P = 0.033 by paired sample t-test). Hierarchical regression analysis revealed that for IVF patients, ALMI explained the greatest proportion of variance in BMD at the lumbar spine, femoral neck and total hip (R (2) (change) = 16.4-22.7%, P = 0.012-0.002) and only IGFBP-3 explained variance in ALMI (R (2) (change) = 19.9%, P = 0.006). CONCLUSIONS: In men with IVF, ALMI was reduced and associated with IGFBP-3. ALMI was identified as a novel factor that explained a greater proportion of variance in BMD than either fat mass or serum biochemistry.

Parafibromin mutations in hereditary hyperparathyroidism syndromes and parathyroid tumours.

OBJECTIVE: To investigate two patients with the hyperparathyroidism-jaw tumour (HPT-JT) syndrome and three patients with familial isolated hyperparathyroidism (FIHP), together with 31 parathyroid tumours (2 HPT-JT, 2 FIHP and 27 sporadic) for HRPT2 mutations. The HPT-JT syndrome and FIHP are autosomal dominant disorders that may be caused by abnormalities of the HRPT2 gene, located on chromosome 1q31.2. HRPT2 encodes a 531 amino acid protein, parafibromin, which interacts with human homologues of the yeast Paf1 complex. DESIGN: Leukocyte and tumor DNA was used with HRPT2-specific primers for polymerase chain reaction amplification of the 17 exons and their splice junctions, and the DNA sequences of the polymerase chain reaction products determined. RESULTS: Three heterozygous germline HRPT2 mutations, two in HPT-JT and one in FIHP patients, were identified. These consisted of one 1-bp duplication (745dup1bp), 1 nonsense (Arg234Stop) and 1 missense (Asp379Asn) mutation. One parathyroid tumour from an FIHP patient was demonstrated to harbour a germline deletion of 1 bp together with a somatic missense (Leu95Pro) mutation, consistent with a 'two-hit' model for hereditary cancer. The 27 sporadic benign parathyroid tumours did not harbour any HRPT2 somatic mutations. Six HRPT2 polymorphisms with allele frequencies ranging from 2% to 15% were detected. CONCLUSIONS: Our results have identified three novel HRPT2 mutations (two germline and one somatic). The Asp379Asn mutation is likely to disrupt interaction with the human homologue of the yeast Paf1 complex, and the demonstration of combined germline and somatic HRPT2 mutations in a parathyroid tumour provide further evidence for the tumour suppressor role of the HRPT2 gene.

Effects of dissociated glucocorticoids on OPG and RANKL in osteoblastic cells.

Glucocorticoids are effective anti-inflammatory and immunosuppressive agents, but their use is often associated with debilitating side effects such as glucocorticoid-induced osteoporosis. Newly developed glucocorticoid analogues such as the so-called dissociated glucocorticoids are potent immunosuppressants and have the potential for fewer side effects. The effects of these new analogues on osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) in osteoblastic cells have not been studied. OPG and RANKL are osteoblast-derived proteins pivotal to the regulation of bone mass. RANKL stimulates bone resorption by increasing osteoclast differentiation, activation and survival. OPG is the decoy receptor for RANKL and thus inhibits bone resorption. Here, we show that dexamethasone, prednisolone, deflazacort and the dissociated glucocorticoids, RU24858, RU40066, RU24782, AL438-F1 and ZK216348 significantly inhibit OPG production in two human osteoblastic cell lines (MG63 and hFOB). The potency for OPG inhibition was ligand and cell-type specific. In both cell types, dexamethasone and prednisolone were the most potent ligands inhibiting OPG production with IC(50)s of approximately 0.1 nM and 10 nM respectively. In MG63 cells, deflazacort and the RU compounds were the next most potent ligands followed by AL438-F1 and ZK216348. In hFOB cells, however, the RU compounds were the least potent ligands with an IC(50) 74 times higher than in MG63 cells. In contrast, the level of maximum inhibition or effectiveness of OPG inhibition did not vary between cell types but did vary according to the ligand. Dexamethasone, prednisolone, deflazacort and the RU compounds all inhibited OPG production by a maximum of approximately 70-80%, whereas AL438-F1 and ZK 216348 inhibited OPG production by a maximum of only 40-50% at 1 microM. All of the dissociated glucocorticoids and deflazacort were poor stimulators of RANKL gene expression stimulating by only approximately 1-3-fold compared to 7-fold by prednisolone. These data demonstrate that deflazacort and the dissociated glucocorticoids are weak stimulators of the RANKL:OPG ratio compared to prednisolone. Therefore, these compounds have the potential to cause less bone loss than that seen with prednisolone, though this was not investigated here.

A bio-assay for effectors of osteoclast differentiation in serum from patients with bone disease.

UNLABELLED: Osteoclast differentiation and activity, and hence bone loss, depend on two opposing cytokines. Receptor activator of NF-(kappa)B ligand (RANKL) produced by osteoblasts and T-cells stimulates, while osteoprotegerin inhibits. Both of these cytokines are found in serum. Our aim was to develop a functional assay for any factors present in human serum that can affect osteoclast differentiation and to assess whether any such factors vary in diseases in which bone loss occurs. METHODS: Using a culture model of osteoclast differentiation in the presence of macrophage colony stimulating factor and soluble RANKL, we have measured the effects of different human sera on osteoclast differentiation. The production of a marker enzyme for the osteoclast, tartrate-resistant acid phosphatase (TRAP), was used to follow osteoclast differentiation. RESULTS: In general, human serum stimulates osteoclast differentiation as indicated by TRAP activity, but in patients with low bone density this stimulation was attenuated. Sera from 40 female subjects with low bone mineral density showed significantly lower TRAP cell differentiation activity than sera from the healthy female controls. CONCLUSION: We describe a functional bio-assay for factors in human serum which can affect osteoclast differentiation. This assay may have application in monitoring the effects of therapy in bone disease.

Increased matrix concentrations of IGFBP-5 in cancellous bone in osteoarthritis.

BACKGROUND: In osteoarthritis cancellous bone adapts to meet altered mechanical loading. These changes may be mediated by insulin-like growth factors (IGF-I and IGF-II), but the matrix bound binding protein, IGFBP-5 has not been investigated. OBJECTIVES: To measure IGF-I, IGF-II, and IGFBP-5 in femoral head bone from non-OA controls and patients with OA, and to relate these to apparent density (rhoA) and elastic modulus (Ec). METHODS: rhoA, Ec, and IGF system components were measured in cancellous bone from superior and inferior regions of femoral heads from 31 patients with OA and 11 age selected controls. RESULTS: Ec and rhoA were greater (p<0.05) in the superior region of all femoral heads. In primary OA, rhoA was increased in the inferior region (p<0.05). IGFBP-5 was increased, about twofold, at superior and inferior regions in primary OA (1.60 and 1.54 ng/mg bone, respectively, both p<0.05) and in Paget's disease (2.44 and 1.75 ng/mg bone, both p<0.05) compared with controls (0.73 and 0.95 ng/mg bone). In controls, inverse correlations between IGFBP-5 and both rhoA and Ec at superior (rs = -0.64 and -0.73, both p<0.05) and inferior regions (rs = -0.72, p<0.05 and -0.24 (NS)) were seen, but these were lost in OA. CONCLUSIONS: IGFBP-5 may modulate cancellous bone formation by negative feedback. In end stage OA this is disrupted, but has little influence on material properties.

Radiological and biochemical resolution of nutritional rickets with calcium.

AIMS: To determine the response to oral calcium in Nigerian children with rickets. METHODS: In a teaching hospital in Western Nigeria, 26 children (13 boys, 13 girls, aged 2-5 years) with confirmed rickets received calcium lactate (2.7 g/day). RESULTS: Within one month of treatment leg pain was relieved and the children were more active. The mean x ray score improved from 3.3 at baseline to 1.7 at three months and 0.9 at six months (arbitrary scoring system, 0-6). Twelve cases were healed radiologically after six months, 11 others improved considerably, two showed no significant improvement, and a non-compliant patient was worse. There was progressive reversal of biochemical features. Median plasma alkaline phosphatase fell from 519 (range 178-1078) to 283 (209-443) IU/l (p = 0.04) in four months, while mean 1,25-dihydroxyvitamin D fell from 473 (251-1057) to 281 (155-481) pmol/l (p = 0.04), and mean plasma calcium increased from 2.26 (1.63-2.54) to 2.37 (2.06-2.54) mmol/l (p = 0.13). Parathyroid hormone fell from 5.3 (0.4-21.5) to 1.7 (0.45-7.4) pmol/l. Type I collagen carboxy terminal cross linked telopeptide was very high at baseline (20 (7.2-103) to 14 (11-24) micro g/l) (p = 0.03) and fell promptly to normal. CONCLUSION: Calcium supplementation alone effected healing of rickets in most of these Nigerian children and may provide sufficient treatment in this environment.

Oral corticosteroid prescribing in women over 50, use of fracture prevention therapy, and bone densitometry service.

OBJECTIVE: To identify the most common diseases and age of corticosteroid use in women over 50, dosage in last year, duration of oral corticosteroid use, prescription for fracture prevention (drug used), and referrals for bone densitometry. METHODS: General practice records from 41 practices in Shropshire identified 62,230 women aged >50 from a population of 80,082. Data on fractures, duration of corticosteroid use, dose in the study year (1 April 1997-31 March 1998), use of fracture prevention therapy and bone densitometry were sampled from one out of three records. RESULTS: 3.2% were prescribed corticosteroids; 633 patients investigated in detail aged 70.1 (SD 10.5) years, had been prescribed 1526 (SD 1727) mg prednisolone (median 1040 mg) for 3.31 (SD 3.20) years (median 2.0 years). Patients with asthma/lung disease, most common in the younger group, had the lowest annual corticosteroid use; patients with rheumatoid arthritis (RA), polymyalgia rheumatica/temporal arteritis (PMR/TA), who were more likely to be elderly, had the highest annual use. Between the age of 70 and 79 years patients with RA had significantly more hip fractures than the other groups, and corticosteroid prescribing was most common. Bisphosphonates or hormone replacement therapy were prescribed for 48% aged 50-59 years but only 32% at 70-79 years (p<0.01); patients with asthma and RA being less likely recipients (p<0.01). Referrals for bone densitometry had occurred in 20.2%,with 60.2% having osteoporosis. Referrals were more common in those taking corticosteroids for longer periods (p<0.01). CONCLUSIONS: The elderly had the most prescriptions for corticosteroid treatment but the fewest for effective fracture prevention therapy. Patients with RA, PMR/TA had the greatest corticosteroid dosage, for the longest time. Patients with RA sustained more hip fractures than other groups but were least likely to have effective fracture prevention therapy prescribed.

Regional differences in mechanical and material properties of femoral head cancellous bone in health and osteoarthritis.

Osteoarthritis (OA) is a debilitating condition common among the aging population. In this study we have determined mechanical and material properties of cancellous bone cores from two differently loaded regions of femoral heads obtained from healthy subjects and those with end-stage osteoarthritis. Densitometric properties were determined prior to compression testing for Young's modulus (EC) and yield strength (sigma(y)), after which bones were powdered for analysis of collagen and mineral content. In both OA and normal cancellous bone, volumetric bone mineral density (BMDv), apparent density (rhoA), E(C), and sigma(y) were systematically greater in the superior than in the inferior region (P<0.05). In the OA inferior region, median BMDv (0.434 g-cm(-3)) and rA (0.426 g-cm(-3)) were significantly greater than in normals (0.329 and 0.287 g-cm(-3), respectively, both P<0.05) reflecting an increased amount of tissue. The mineral:collagen ratio was decreased in OA, but this was only significant in the superior region (P<0.008). Relationships between EC and both BMDv and rho(A) were weaker in OA bone cores (r(2) = 0.66 and r(2) = 0.59) than in normals (r(2) = 0.86 and r(2) = 0.77, respectively). Likewise, sigma(y) and both BMDv and rho(A) were weaker in OA (r(2) = 0.74 and r(2) = 0.70) than in normals (r(2) = 0.83 and r(2) = 0.77, respectively). For the same value of density measure, EC and sigma(y) tended to be lower in OA bone when compared with normal bone. In conclusion, femoral head cancellous bone mass in end-stage osteoarthritis is increased but undermineralized, and is neither stiffer nor stronger than normal cancellous bone.

Low body size and elevated sex-hormone binding globulin distinguish men with idiopathic vertebral fracture.

Factors predisposing to vertebral fracture in men are less well defined compared with women. Most studies of osteoporosis in men have included patients with low bone mineral density (BMD), with or without vertebral fracture, or have included other fractures. To clarify these associations we investigated sex hormone levels, bone markers, and (indirectly) lean body mass (LBM) in 81 men with idiopathic vertebral fracture. Serum testosterone, estradiol, sex-hormone binding globulin (SHBG), 24-hr urinary creatinine (24-hr UCr), urinary free deoxypyridinoline (UfDPD) and serum type I procollagen carboxy-terminal propeptide, type I procollagen amino-terminal propeptide, type I collagen carboxy-terminal telopeptide, and osteocalcin were measured. SHBG was higher and 24-hr UCr lower in osteoporotic subjects. UfDPD was higher when corrected for 24-hr UCr. Serum bone turnover markers were not significantly increased, nor were serum sex hormones (and free hormone indices) significantly decreased in patients. SHBG levels were inversely related with lumbar spine and femoral neck BMD in both patients and control subjects. Free estradiol index was only correlated with BMD in men with osteoporosis. Body size is lower in men with established osteoporosis. The normal free hormone indices suggest that SHBG does not affect free hormone levels whereas the relationship between SHBG (but not sex hormones) and 24-hr UCr points to a relationship between SHBG and LBM. The association of high levels of SHBG with low levels of LBM may indicate an action via the known inverse relationship of SHBG with IGF-I, though any action through IGF-I probably occurred at an earlier age than that at which the patients presented. Estrogen has no relationship with BMD in normal men but may play a role in men with osteoporosis.