M.W.J. Davie

Guidelines on the management of Paget's disease of bone

Paget’s disease is a chronic focal abnormality of bone turnover. Although there remains considerable controversy regarding its etiology, several different methods of treatment have now become available. In this review, a working party derived from members of the Bone and Tooth Society and the National Association for the Relief of Paget’s Disease, has examined the evidence currently available regarding the diagnosis and treatment of Paget’s disease in order to develop guidelines to assist in the management of this condition. In assessing the evidence available we have adopted the guidelines prepared by the U.S. Agency for Health Care Policy and Research), including:

Screening for vertebral osteoporosis using individual risk factors. The Multicentre Vertebral Fracture Study Group.

Osteoporosis is a major cause of ill health in postmenopausal women. Several risk factors for osteoporosis have been identified, and they have been widely recommended as a means of identifying subgroups of postmenopausal women who might benefit from prophylaxis and therapy. Evidence to support this use of risk factors is currently lacking, however. We have constructed and evaluated a profile of putative risk factors as a means of identifying women attending general practitioners who have sustained vertebral fractures. The overall prevalence of vertebral fractures in the 1012 women (mean age 64.4 years) studied was 7.8%. Women who had sustained vertebral fractures in this population were significantly (p<0.05) older and shorter than those without fractures. They reported a significantly (p<0.05) earlier menopause, lower parity and a greater prevalence of hyperthyroidism. However, the best screening instrument devised was not sufficiently predictive to warrant widespread use.

Isoforms of Bone Alkaline Phosphatase: Characterization and Origin in Human Trabecular and Cortical Bone

Alkaline phosphatase (ALP) is a glycoprotein and functions as an ectoenzyme attached to the cell membrane by a hydrophobic glycosyl‐phosphatidylinositol (GPI) anchor. Three bone ALP (BALP) isoforms in human serum were separated and quantitated by high‐performance liquid chromatography. B/I, a minor fraction, is composed on average of bone (70%) and intestinal (30%) ALP, and two major isoforms, B1 and B2. Treatment with GPI‐specific phospholipase C (GPI‐PLC) did not influence the activities or retention times for B1 and B2, indicating that the biochemical differences between B1 and B2 are likely to be due to different glycosylation patterns. The B/I fraction in serum, on average 4% of total ALP, was found to be composed of B1 and B2 isoforms, each with an intact hydrophobic GPI cell membrane anchor. We investigated the origin of these three BALP isoforms and osteocalcin in human femora from five healthy individuals (four males), mean age 51 years, obtained from a tissue bank. Bone was sampled from three sites: cortical bone, trabecular bone from the diaphysis, and trabecular bone from the greater trochanter. Trabecular bone, from both sites, had higher BALP activities compared with cortical bone. Conversely, the osteocalcin content of cortical bone was more than 3‐fold greater than that of trabecular bone. Cortical bone had approximately 2‐fold higher activity of B1 compared with B2, whereas trabecular bone had ∼2‐fold higher activity of B2 compared with B1. We observed a previously undescribed BALP isoform (B1x) in all bone samples. B1x was also observed in sera from some patients (60%) with severe renal insufficiency and on chronic dialysis therapy (n = 20). The isoforms of BALP may provide information relating to bone metabolism within specific bone compartments.

Vertebral deformity, bone mineral density, back pain and height loss in unscreened women over 50 years

Bone mineral density (BMD) was measured in the lumbar spine using dual-energy X-ray absorptiometry in 222 unscreened women (aged 50–82 years), and information on back pain and historic loss of standing height was obtained at interview. Vertebral morphometry was performed on lateral spinal radiographs. The shape of the vertebral body was quantified using appropriate vertebral shape indices (VSIs), and vertebral deformities were identified using thresholds defined in terms of the means (M) and standard deviations (SD) of these VSIs for the whole group. Severity of deformity was defined as either grade 1 (M+2SDM+4SD). Subjects with grade 1 vertebral deformities were older than subjects without such deformities, but did not have a reduced age-related Z-score of BMD. Grade 2 wedge and concave deformities were associated with a reduced age-relatedZ-score of BMD, suggesting that the aetiology of such deformities is closest to conventional concepts of ‘osteoporotic fracture’. Grade 3 deformities were associated with neither increased age nor decreased BMD. Stature decreased in these subjects with age. Subjects reporting historic height loss had a higher mean number of wedge deformities. Subjects with back pain did not have a higher incidence of vertebral deformity than subjects without, confirming that many deformities were asymtomatic. Neither back pain nor historic loss of height were found to be associated with low spinal BMD.

Sarcoma arising in Paget's disease of bone: Declining incidence and increasing age at presentation

BACKGROUND Pagets disease is presenting at older ages, with a trend to monostotic disease, associated with lower serum total alkaline phosphatase (serum total ALP) levels. Sarcomatous transformation is a rare complication, which only half a century ago had a median age of presentation of less than 60 years. We have investigated whether sarcomatous change exhibits increasing age at presentation, whether the trend to monostotic Pagets disease exists, whether male predominance in sarcoma still continues and explored factors that might affect survival. METHODS Notes of all patients from the Royal Orthopaedic Hospital, Birmingham primary malignant bone tumour registry were reviewed and all cases of Pagetic sarcoma since 1975 extracted. In addition to basic demographic data, mode of presentation, skeletal involvement by Pagets disease, history of treatment, presence of pulmonary metastases, serum total ALP levels and survival were obtained. RESULTS Unequivocal Pagetic sarcoma was identified in 32 patients (23 M, 9 F). Age at presentation was 73.8 years with no sex difference and with known pre-existing Pagets disease in 42%. Only 15% had received any specific Pagets disease treatment. Serum total ALP was not invariably markedly elevated (compared with non-sarcomatous disease) and was related to the number of skeletal sites, but not to the sarcoma histological subtype. Pagets disease was monostotic in 46%. Pagetic sarcoma fell from 23% to 8% of primary bone sarcoma referrals in patients aged over 50 years between the decades 1986-1995 and 1996-2005. Median survival remained poor at 0.66 years. Survival of greater than 2 years occurred in 4 patients, one of whom with a low grade Pagetic sarcoma being alive at 12 years follow up. CONCLUSIONS The proportion of Pagets disease patients with sarcoma has fallen steadily since Pagets original report and is now about 0.3%, the decline predating availability of effective therapy. Sarcoma is not necessarily associated with very high serum total ALP. It is present amongst polyostotic cases in the expected proportion suggesting that more widespread skeletal involvement by Pagets disease is not a significant risk factor for malignant transformation. Sarcoma is presenting later concurrent with the advancing age of non-malignant disease, but male predominance continues. Pagetic sarcoma is now rare, continues to have a poor prognosis and is often the presenting feature of the disease.

Single infusion of zoledronate in Paget’s disease of bone: a placebo-controlled, dose-ranging study

1 Hope Hospital, Salford, UK 2 Department of Clinical Chemistry, Royal Liverpool University Hospitals, Liverpool, UK 3 Nottingham City Hospital, Nottingham, UK 4 Rush Presbyterian–St. Luke’s Medical Center, Chicago, IL, USA 5 University of Arizona Health Sciences Center, Tucson, AZ, USA 6 John Wayne Cancer Institute, Santa Monica, CA, USA 7 Robert Jones and Agnes Hunt Hospital, Oswestry, Shropshire, UK 8 Osteoporosis Unit, Nuclear Medicine Department, Guy’s Hospital, London, UK 9 University of Massachusetts Medical School, Worcester, MA, USA 10 State University of New York Health Science Center, Syracuse, NY, USA 11 Duke University Medical Center and VA Medical Center, Durham, NC, USA 12 University of Manchester, Manchester, UK 13 Clinical Research, Novartis Pharmaceuticals, East Hanover, NJ, USA 14 Columbia University College of Physicians and Surgeons, New York, NY, USA

Regional Differences in Mechanical and Material Properties of Femoral Head Cancellous Bone in Health and Osteoarthritis

AbstractOsteoarthritis (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 Youngs modulus (EC) and yield strength (sy), 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 (rA), EC, and sy 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 rA were weaker in OA bone cores (r2 = 0.66 and r2 = 0.59) than in normals (r2 = 0.86 and r2 = 0.77, respectively). Likewise, sy and both BMDv and rA were weaker in OA (r2 = 0.74 and r2 = 0.70) than in normals (r2 = 0.83 and r2 = 0.77, respectively). For the same value of density measure, EC and sy 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.

Osteoclast recruitment in mice is stimulated by (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate

SummaryThough some evidence suggests that bisphosphonates (BPs) act directly on osteoclasts to inhibit bone resorption, other evidence suggests that they inhibit the development of the osteoclast. We found an increase in osteoclast recruitment in 2-day-old mice given (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD). A threefold increase in 5-bromo-2′-deoxyuridine (BrdU)-labeled osteoclast nuclei was observed on mouse parietal bones 3 days after APD injection. This suggests that inhibition of osteoclast development is not an action of APD in mice of this age. The mechanism of the increased recruitment was investigated. As osteoclast progenitors were not detected on parietal bonesin vitro, we looked for an increase in circulating monocytes to account for the recruitment. No such increase was found, but when51Cr-labeled bone marrow was injected intraperitoneally into mice given APD there was an increase in accumulation of51Cr in calvaria and in femur and tibia over controls. This increase did not occur when51Cr-labeled erythrocytes or free51Cr was injected. We conclude that APD causes increased recruitment of osteoclast precursors by increasing the avidity of bone for hematopoietically derived cells.

Vertebral morphometry in women aged 50-81 years.

Vertebral dimensions and vertebral shape indices (VSI) were investigated in T4-L4 in 926 females aged 50-81 years. The most consistent finding was the increase of inferior antero-posterior dimension with age. Wedging and concavity also increased with age but the changes were not significant at all vertebral levels. The value of VSIs also varied with level. Thus a particular degree of VSI, considered normal at one level or at one age, would be outside the reference range at a different level or age group. The number of subjects identified as osteoporotic by skewness (5.4%) or in excess of three standard deviations from the mean (6.5%) was much lower than in recent reports from North America. The number of subjects contributing to a skewed distribution increased with age from 0.5% at 55-59 years to 10.0% at 75-79 years. Change with age in the antero-posterior dimension could increase load-bearing area in older subjects, but the decline in bone density will be increased as a declining bone mineral content occupies a larger volume.

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.