Osteochondromas in fibrodysplasia ossificans progressiva: a widespread trait with a streaking but overlooked appearance when arising at femoral bone end.

Metaphyseal bony outgrowths are a well-recognized feature of fibrodysplasia ossificans progressiva (FOP) phenotype, but its genuine frequency, topographic distribution, morphological aspect, and potential implications are not fully established. To better ascertain the frequency and characteristics of osteocartilaginous exostoses in FOP disease, we conducted a cross-sectional radiological study based on all the traceable cases identified in a previous comprehensive national research. Metaphyseal exostoses were present in all the 17 cases of FOP studied. Although most often arising from the distal femoral (where metaphyseal exostoses adopt a peculiar not yet reported appearance) and proximal tibial bones, we have found that they are not restricted to these areas, but rather can be seen scattered at a variety of other skeletal sites. Using nuclear magnetic resonance imaging, we show that these exophytic outgrowths are true osteochondromas. As a whole, these results are in agreement with data coming from the literature review. Our study confirms the presence of metaphyseal osteochondromas as a very frequent trait of FOP phenotype and an outstanding feature of its anomalous skeletal developmental component. In line with recent evidences, this might imply that dysregulation of BMP signaling, in addition to promoting exuberant heterotopic ossification, could induce aberrant chondrogenesis and osteochondroma formation. Unveiling the molecular links between these physiopathological pathways could help to illuminate the mechanisms that govern bone morphogenesis.

Childhood vasculitis hospitalizations in Spain, 1997-2011.

The aim of this study is to describe the childhood vasculitis hospital burden in Spain (1997-2011), considering type of disease, hospitalization rates and time trends. Data were obtained from the National Discharges Basic Minimum Data Set (National Patient Data Base). Inpatient events of children younger than 15 years of age were analyzed. Principal diagnosis of vasculitis were selected according Ninth Revision of the International Classification of Diseases: Takayasu arteritis, Polyarteritis nodosa, Kawasaki disease, Wegener`s granulomatosis, Churg-Strauss syndrome, and Henoch-Schönlein purpura. A total of 14518 children hospitalizations related to vasculitis were identified in Spain from 1997 to 2011. The average hospitalization rate for children was 13.33±1.71 per 100,000. Henoch-Schönlein purpura and Kawasaki disease were the most common type of vasculitis, hospitalization rates were 11.00 and 3.97 per 100,000 children, respectively. Other vasculitis hospitalizations are much rare in childhood. Average length of stay was 6.04 days and estimated cost per inpatient hospital care was 2,847€. Hospital case fatality rate was 0.05% for overall vasculitis. In conclusion, epidemiological data of childhood vasculitis are useful both to health decision-making and to identify research priorities.

Monostotic Paget's disease of the femur: a diagnostic challenge and an overlooked risk.

BACKGROUND: Although radiological diagnosis of Paget's disease of bone (PD) is usually straightforward, monostotic cases may potentially raise specific problems which lead to performing invasive procedures. Therefore, the purpose of this study is to ascertain whether or not monostotic femoral Paget's disease (MFPD) presentation poses particular diagnostic difficulties which prompt excessive use of excisional biopsies. METHODS: We retrospectively reviewed the medical records of 24 MFPD patients identified from a series of 412 patients; their clinical features were compared with those of the remaining 164 monostotic cases and the radiological images were systematically assessed. RESULTS: When compared with the remaining monostotic cases, MFPD patients were more prone to having normal alkaline phosphatase levels (31.8% vs. 16.4%; 0.08) and a significantly higher percentage of patients have PD symptoms (75% vs. 51%; 0.02) and complain of bone pain (73.9% vs. 40.8%; 0.003). Six (25%) MFPD patients evidenced a fracture over the pagetic lesion. This incidence is higher than that of the monostotic cases of other locations (8.4%; p=0.02). The existence of PD lesion was not recognised initially in 10 cases and an excisional bone biopsy was performed in 7 (29%). One patient subsequently experienced a fracture through the biopsy site and another two experienced worsening of their previous bone pain. CONCLUSION: The femur is a relatively common monostotic PD location which often causes diagnostic confusion, prompting a bone biopsy in many cases. Careful assessment of this lesion by X-ray examination may help attain an early appropriate diagnosis and avoidance of unnecessary surgical morbidity.

Fibrodysplasia ossificans progressiva in Spain: epidemiological, clinical, and genetic aspects.

We aimed to investigate the epidemiological determinants, clinical features, and genetic pattern of FOP in our country by evaluating the entire population of patients identified according to a combination of methods. To achieve this, 24 individuals were confirmed as FOP cases, 17 of whom were alive at the end of 2011 (point prevalence=0.36 × 10(-6)). The gender distribution (male/female ratio=13/11) and the concurrent range of ages (from 4 to 53 years; mean ± SD: 30.2 ± 13.8) are in agreement with similar reports. Twenty-one (87.5%) had characteristic congenital malformations of the big toe, and short thumbs were found in 65.2% of cases. In addition, other skeletal malformations such us fusion of the posterior elements of the cervical spine (89.0%), knee osteochondromas (71%), scoliosis (54.5%), and short and broad femoral neck (52.6%) were observed. All had developed mature ossicles of heterotopic bone in typical anatomic and temporal patterns, ranging in number from 1 to 17 (9.5 ± 3.9). Age at appearance of first ossifying lesion varied from 3 months to 15 years. Mean age at diagnosis was 7.3 ± 5.1 years and the average delay in reaching the correct diagnosis after the onset of heterotopic ossification was 2.7 years (range=0-12 years). Biopsy of the pre-osseous lesions was performed in 11 of 20 (55.0%), providing no useful information for the diagnosis of FOP. Seven of 18 (38.9%) reported some hearing loss, and 5 (27.8%) experienced diffuse thinning of the hair or were bald. No patient had relatives with a typical FOP clinical picture. Fourteen of the 16 cases which were genetically investigated displayed the single heterozygous mutation c.617G>A in exon 4 of the ACVR1 gene. One of the two patients who did not present with the canonical ACVR1 mutation showed a heterozygous mutation c.774G>C in exon 5 leading to the substitution of Arginine 258 with a serine. The other patient had a heterozygous c.774G>T substitution in exon 5 leading to the same amino acid change (p.Arg258Ser). These two patients had only nonspecific abnormalities of the great toe, lacked the typical anatomic and developmental pattern of heterotopic ossification, and shared a trend toward uncommon clinical features. These results provide new insight on the epidemiological and clinical traits of FOP, reinforcing the notion of its worldwide homogeneity. The molecular characterization of ACVR1 sequence variation will contribute to the understanding of the genetic profile of this devastating disease in different geographical areas.

Further evidence supporting a genetic background for Paget's disease of bone in Spain.

The aim of this paper is to investigate heritable factors that might be related to the recognised genetic susceptibility for developing Paget's disease of bone (PD). This was a hospital-based, case-control study of a systematically selected group of PD patients and a group of controls drawn from the same health setting. In these populations we assessed surname pattern, parental consanguinity and constitutional physical traits. In a separate case-control analysis, genetically-based features and pathological traits of interest for genetic inference in 43 demonstrated familial cases were then compared to those in 24 sporadic cases. Results showed coincidence of three or four surnames (Odds Ratio [OR] = 5.6; 95% CI = 1.7-18.5), degree of parental consanguinity (OR = 4.1; 95% CI = 2.1-1.8), and green or blue eye colour (OR = 1.5; 95% CI = 1.1-2.1) were significantly associated with PD. Comparison of proven familial and sporadic PD cases showed that the former had a stronger association with Monckeberg-type vascular calcifications (32% vs. 4%; p = 0.02), percentage of skeleton affected (13.1 vs. 9.0), and green and blue eye colour (82% vs. 25%; p = 0.006), with Monckeberg-type vascular calcifications being the main variable of interest (OR = 30.9; 95% CI = 12.75-347.00) in the multivariate analysis. In conclusion, heritable factors are crucial in the pathogenesis of PD and, in line with other data sources, might account for the ethnic predisposition observed in different countries.

Public health research on rare diseases.

Despite the low prevalence of Rare Diseases (RD), over 30 million EU citizens suffer from these conditions. This paper summarizes some aspects of these life-threatening chronic and debilitating diseases that usually require long term specialist care and costly formal and informal surveillance. Epidemiology does have an important role to play in the field of RD, since it provides appropriate methods and tools for assessing exposures and health outcomes. In this regard, the utility of registries, biobanks and population-based surveillance systems are discussed. The lack of effective diagnoses and treatments in RD patients often underlies their shortened life expectancy and quality of life. Due to the limited number of patients and the scarcity of relevant knowledge and expertise, coordination at European level is probably the best way of pooling the very limited resources available and provides a very high added-value. RD require the combined efforts of health and social care professionals, politicians, managers and researchers to increase the availability of effective disease management tools to improve care and to extend both life expectancy and Health Related Quality of Life.

Factores que determinan la duración de la respuesta al tratamiento con tiludronato en una cohorte de pacientes con enfermedad de Paget / Factors determining duration of response to tiludronate in a cohort of patients with Paget's disease

Fundamento: Investigar la influencia de los factores que determinan la duración de la respuesta al tiludronato en la enfermedad de Paget. Pacientes y métodos: Se ha seguido a intervalos regulares, desde abril de 1993 hasta mayo de 2003, a todos los pacientes (n = 26) incluidos en un ensayo clínico sobre eficacia y bioequivalencia del tiludronato en la enfermedad de Paget. Cada paciente tomó 400 mg/día por vía oral durante 90 ñ 6 días. Diecisiete (65 por ciento) eran varones y 9 (35 por ciento) mujeres, y la media de edad ñ desviación estándar (DE) era 60,3 ñ 9,8 años. La evolución de la probabilidad de recaída bioquímica se investigó mediante la prueba de Kaplan-Meier. Para determinar qué variables predicen mejor la duración de la respuesta, y en qué medida, se realizó análisis de modelos de riesgo proporcional (regresión de Cox).Resultados: Sólo uno de los 26 pacientes incluidos en el ensayo clínico presentó resistencia inicial al tratamiento con tiludronato. De los restantes, en 19 se normalizaron las cifras de fosfatasa alcalina y 6 tuvieron una respuesta superior al 50 por ciento de los valores basales, aunque no alcanzaron la remisión completa. Nueve de los 19 pacientes en que se normalizaron las cifras de fosfatasa alcalina han permanecido durante los 10 años de seguimiento libres de recaída, por lo que no han precisado de nuevos ciclos. Los 16 restantes han presentado recaída, y han recibido uno o varios ciclos posteriores, con una media ñ DE de 1,43 ñ 0,68 ciclos por paciente. No se observaron efectos secundarios importantes ni alteraciones analíticas relevantes que indicaran toxicidad en los 49 ciclos administrados. El tiempo medio hasta la primera recaída fue de 53,5 meses y de 36 meses hasta la segunda. El porcentaje máximo de reducción de fosfatasa alcalina (media ñ DE) tras el segundo ciclo fue del 55,3 ñ 12,9 por ciento. Los pacientes con recaída muestran una mayor extensión de las lesiones óseas (11,68 ñ 7,4 frente a 5,33 ñ 0,7; p = 0,003) y una fosfatasa alcalina más elevada (1.446 ñ 810 frente a 849 ñ 255; p = 0,01). La concentración basal de fosfatasa alcalina y las concentraciones mínima y máxima de tiludronato al mes de comenzar el tratamiento son las que predicen con mayor fiabilidad la probabilidad de recaída. Conclusiones: El tiludronato suprime de manera eficaz a largo plazo la actividad bioquímica de la enfermedad de Paget. La concentración mínima o valle de tiludronato en plasma es el mejor predictor de la duración de la respuesta (AU)

Identification of possible areas of high prevalence of Paget's disease of bone in Spain.

OBJECTIVE: In view of the fact that Paget's disease of bone (PD) tends to appear in so-called 'foci', a case-control study was undertaken with the dual aim of: 1) identifying areas having a higher likelihood of constituting PD 'foci'; and 2) detecting the geographic origin of 'PD-carrier' families. METHODS: Two data sets were analysed, one covering the place of birth of 231 cases and 436 controls, and the other covering the place of birth of cases, controls and their parents. Analysis was restricted to six Autonomous Regions accounting for 60% of Spain's towns and cities. To identify geographical areas of high prevalence we used the scan statistic. RESULTS: In the first analysis, 6 possible clusters were detected, corresponding to the districts of Avila (Avila), Lozoya-Somosierra (Madrid), Tierra de Campos(Palencia), the Guadalajara Range, South-west Madrid and Cuenca Hills. The second analysis confirmed the 6 groupings identified by the above procedure and, in addition, detected a further 8 possible clusters. Geographical proximity suggests that in some cases, rather than individual groupings, these may instead constitute larger foci. CONCLUSION: The results point to the possible existence of different PD foci, some coinciding with clusters that have already been reported, and others indicating familial origin in areas that had never previously received PD-specific attention.

Mujer con osteoporosis con dolor en región ilíaca / Woman with osteoporosis and pain in the iliac region

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¿Para qué sirve y cómo fracasa el remodelado óseo? / What is bone remodeling for and how does it fail?

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Is clinical expressiveness of Paget's disease of bone decreasing?

Recent data have suggested secular changes implying a current trend toward decreased clinical severity of Paget's disease of bone (PD). To test this hypothesis, we conducted a study comparing the characteristics of two groups of PD patients, as disclosed from a sample assessed systematically. The investigation was a hospital-based study of all cases followed up at our unit since 1980. Throughout the follow-up period, diagnosis was based on standard X-ray criteria and the same clinical assessment was applied. Group I (n = 124) represented patients born before 1926, whereas group II (n = 109) included those born after that year. A bone scan performed with 99mTc-EHDP was available for all patients. X-rays of the pelvis and spine, and views of any hot spot observed on the scintigraphy scans were reviewed. The skeletal extent of PD, based on bone scan uptake, was determined by using the index proposed by Coutris. Alkaline phosphatase and hydroxyproline excretion levels were determined in blood and urine, respectively. Baseline characteristics were recorded on a purpose-designed computerized database. The proportion of males (47% in group I vs. 65% in group II; p = 0.007) and the mean (+/-SD) age at diagnosis (69.0 +/- 8.15 vs. 54.3 +/-9.14; p < 0.001) differed significantly between groups. The year of birth showed a strong negative correlation with age at diagnosis (r = -0.83, p < 0.0001) and a weak, but significant, negative correlation with extent of bone lesion (r = -0.20; p = 0.002). Likewise, subjects born prior to 1926 showed a greater percentage of affected skeleton cases (9.6 plus minus 8.01 vs. 7.06 +/- 5.79; p = 0.001). Group I individuals who had pelvic and/or femoral bone lesions were more prone to suffer "pagetic coxopathy" (65% vs. 40%; p = 0.003) with "protrusio acetabuli" (32% vs. 17%; p = 0.01), and the percentage of patients showing radiographic Monckeberg-type vascular calcifications (36% vs. 14%; p = 0.0006) was higher than in those born after 1926. No other epidemiologically clinically, or biochemically relevant differences were seen in the crude analysis. Multivariate analysis identified extent of skeletal lesions (OR = 0.76; p = 0.01), age at diagnosis (OR = 0.79; p = 0.008), number of bones involved (OR = 1.53; p = 0.03), and occupation (p < 0.0001) as the predictive variables linked to year of birth. Our data are consistent with a temporal tendency toward a smaller number of bone lesions and a decreased percentage of instances of affected skeleton. An earlier age at recent diagnosis times and absence of any relevant clinical or biochemical differences seems more likely linked to recent changes in referral and sociological patterns.

Avances en el tratamiento de la osteoporosis al comienzo del nuevo milenio / Advances inthe treatment of osteoporosis at the beginning of the new millenium

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Evaluation of the role of RANK and OPG genes in Paget's disease of bone.

Paget's disease of bone (PDB) is one of the most common bone disorders in the western world. PDB is characterized by focal areas of increased osteoclastic bone resorption and bone formation, which leads to the formation of poorly structured bone. These abnormalities of bone turnover and structure predispose affected individuals to various complications including bone pain, deformity, pathological fracture, and an increased risk of osteosarcoma. One of the main mechanisms of osteoclast formation and activation involves the receptor activator of nuclear factor -kappaB (RANK)/RANK ligand (RANKL)/osteoprotegerin (OPG) pathway, where binding of RANKL to RANK results in the differentiation of osteoclast precursors. OPG, on the other hand, acts as an inhibitor of osteoclastogenesis by serving as a decoy receptor for RANKL. Recently, mutations in the RANK gene have been shown to cause familial expansile osteolysis, a rare bone disorder showing great similarity to PDB. We performed mutation analysis in the RANK and OPG genes in 28 PDB patients to investigate whether mutations in these genes could be responsible for PDB. Our data suggest that RANK is not directly involved in PDB in our set of patients, as no mutations in the RANK coding region could be identified and allele frequencies of RANK polymorphisms did not differ in PDB patients as compared with the random population. Also, in the OPG gene, we could not detect PDB-causing mutations. However, of the several polymorphisms identified, one (400 + 4 C/T in intron 2), showed a statistically significant increased frequency for the C allele in PDB patients, suggesting that individuals harboring this allele may be more susceptible for developing PDB.

Assessment of cardiac function by echocardiography in Paget's disease of bone.

OBJECTIVE: To identify the mechanisms which influence the development of cardiac insufficiency in Paget's disease of bone (PD). METHODS: In this hospital-based case-control study 23 consecutive, recently diagnosed and untreated PD patients were compared against 23 controls frequency-matched by sex, age and body index. All subjects underwent non-invasive assessment of cardiac function by two-dimensional Doppler echocardiography. Calcium, phosphate, and creatinine were determined in the serum and urine, along with alkaline phosphatase and hydroxyproline excretion, two biochemical parameters of PD activity. RESULTS: Peripheral vascular resistance proved lower (1604.9 +/- 390.1 vs 1801.2 +/- 421.0) and the stroke volume higher in PD patients (67.2 +/- 14.4 vs 56.0 +/- 8.6; p = 0.07) compared with controls. These differences were greater (1504.7 +/- 289.9 and 71.0 +/- 6.2) and attained statistical significance (p = 0.008) when the subgroup with more extensive skeletal disease only was considered. A moderate correlation was observed between hydroxyproline excretion and the E/A ratio (r = 0.45; p = 0.03), peripheral vascular resistance (r = -0.42; p = 0.04), and diastolic arterial pressure (r = -0.42; p = 0.04). The final model obtained via multivariate analysis identified both urinary hydroxyproline and age as predictive variables linked to peripheral vascular resistance. CONCLUSION: In the early phases of PD there is a trend towards a reduction in peripheral vascular resistance. If this persists, it may lead progressively to increased cardiac output, which is mainly influenced by the degree of turnover impairment and the age of the individual.

Tiludronate. A new treatment for an old ailment: Paget's disease of bone.

Tiludronate ([[(4-chlorophenyl)thio]-methylene]-bis-phosphonate, ClPsMBP, Skelid, Sanofi) is a powerful inhibitor of bone resorption which has been shown to be a highly effective and safe agent for the treatment of Paget's disease of bone. Preclinical studies in vitro and in vivo have demonstrated a dose-dependent inhibitory effect on bone resorption. Unlike other bisphosphonates, tiludronate does not seem to interfere with the differentiation of osteoclasts or with their access to bone mineral. Bone tolerance studies indicate that tiludronate has an excellent therapeutic window. Thus, at the doses which induce a substantial inhibition of bone resorption it neither causes an appreciable effect on mineralisation, nor impairs biomechanical bone resistance. New formulations of tiludronate (tablets) have a bioavailability of 6% (2-11%) when ingested under optimal conditions. The pharmacokinetic profile of tiludronate is linear. Approximately 50% of the absorbed dose is bound to bone and the rate of release from this site is limited by bone turnover. Several open uncontrolled, open randomised, and double-blind, placebo-controlled studies carried out in patients with active Paget's disease have demonstrated that tiludronate reduces bone pain and produces an intense and sustained biochemical response. 3-6 months after starting tiludronate therapy, serum alkaline phosphatase levels fall far more than 50% from baseline values, reaching normal values in a percentage of the cases ranging from 35-70%. At present, tiludronate, together with pamidronate and alendronate, appear to be the drugs of choice for first-line use in the management of relatively young patients at risk of having long-term complications, when long-lasting control of disease activity is required.

Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity.

Paget's disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis of the disease remains unclear. Previous genetic linkage studies have mapped the rare Paget's disease-like bone dysplasia familial expansile osteolysis (FEO) to chromosome 18q21-22, and recent work has shown evidence of linkage between this locus and Paget's disease in one family. Here we studied the relationship between the 18q21-22 locus and Paget's disease in eight large multiplex families from diverse ethnic backgrounds with inherited Paget's disease. Paget's disease was inherited as an autosomal dominant trait in all families, with high penetrance by the sixth decade. Analysis of seven highly polymorphic markers from chromosome 18q21-22 showed positive summated two-point log10 odds ratio (lodscores) of +2.97 with the marker D18S42 at a recombination fraction (theta) = 0.05, and of +2.95 with the marker D18S60 at theta = 0.00, values which are close to the cut-off of +3.0, which is generally accepted as evidence of linkage. Segregation analysis of the haplotypes and formal statistical analysis using the HOMOG program provided evidence for genetic heterogeneity, however, with evidence for linkage in five families and against linkage in the remaining three families (chi square 8.82; df = 2; p < 0.025). Multipoint linkage analysis in the five linked families showed lodscores of above +3.5 across the whole susceptibility region and a maximum summated lodscore of 3.89 at the marker D18S465. In the three nonlinked families, negative multipoint results were obtained for the whole region, with lodscores below -2.0 in one family, excluding this as a candidate locus for the disease. Our studies demonstrate the importance of hereditary factors in the pathogenesis of Paget's disease and confirm evidence of linkage between Paget's disease and chromosome 18q21-22 in some families. This raises the possibility that Paget's disease and FEO may share a common molecular basis, perhaps due to different mutations in the same gene or family of genes. Data from three families did not support evidence of linkage to 18q21-22 however, indicating that Paget's disease is genetically heterogeneous and suggests the presence of at least one additional locus which remains to be discovered.

[Factors that determine intensity of response to treatment with tiludronate in Paget's disease]. / Factores que determinan la intensidad de la respuesta al tratamiento con tiludronato en la enfermedad de Paget.

OBJECTIVE: To investigate the influence of both clinical and pharmacokinetic factors as determinants of response to tiludronate in Paget's bone disease (PBD). PATIENTS AND METHODS: Twenty six PBD patients with serum alkaline phosphatase (SAP) levels at least twice the normal upper limit were enrolled. The sample included 17 (65%) men and 9 (35%) women whose mean age (SD) was 60.3 (9.8) (range: 38-76). Each patient received 400 mg/day of tiludronate, per os, for 90 (6) days. The SAP variations were considered as the main parameter of response. Plasma concentrations of tiludronate were assayed using the HPLC method with UV detection; the maximum and minimum (Cmin) concentration, as well as the area under a concentration-time curve were calculated. Multivariate regression analysis was performed to assess the influence on tiludronate effect. RESULTS: Mean (SD) percent reduction of SAP from the initial values ranged from 30.5 (13.9) at the end of the first month of drug intake to a nadir of 76.1 (8.8) achieved 6 months after the treatment was stopped. Serum SAP activity fell to normal range in 7 (27%) patients at the end of the therapy period, in 17 (65%) three months later, and in 18 (69%) one year thereafter. One year after the treatment ended only one patient had evidence of relapse. Final multivariate regression model showed that the percent reduction of SAP increases by 11.9 percent points per Cmin tiludronate unit and by 0.006 points per basal SAP unit, and decreases by 0.52 per year of age. Out of 13 patients with bone pain, 9 (69%) experienced relief within the second and third months of treatment. No clinical or laboratory severe side effects were seen and only five patients (19%) had mild adverse events. CONCLUSIONS: These results confirm that tiludronate leads to a marked suppression of PDB clinical and biochemical activity. Cmin of tiludronate in plasma is the best predictor of biochemical response.

Cattle, pets, and Paget's disease of bone.

To identify animal-related factors associated with Paget's disease of bone (osteitis deformans), we conducted a case-control study in two geographical areas of Spain characterized by different socioeconomic profiles. The analysis presented here is based on 149 cases and 150 controls, frequency matched by sex, age, study area, and place of residence in youth (urban/rural). From a logistic regression analysis, we found that contact with bovine cattle [odds ratio (OR) = 2.14; 95% confidence interval (CI) = 1.16-3.94], consumption of meat traceable to sick livestock (OR = 2.70; 95% CI = 0.98-7.43), and frequent consumption during youth of brains (OR = 1.77; 95% CI = 1.05-2.98) and other viscera increased the risk for Paget's disease of bone. Contact with bovine cattle and consumption during youth of bovid viscera exhibited a dose-response effect as regards length of exposure and frequency of consumption, respectively. A life-style shared with dogs showed itself to be differentially linked to the disease in one study area. Overall, our results support the hypothesis that various animal species are carriers of etiologic agents of Paget's disease of bone.