Abstract. Aliberti G, Pulignano I, Schiappoli A, Minisola S, Romagnoli E, Proietta M (Università di Roma 'La Sapienza', Rome, Italy). Bone metabolism in ochronotic patients (Case report). J Intern Med 2003; 254: 296-300.We investigated skeletal involvement in five male and two female patients with ochronosis, aged 26-82 years. The main parameters of mineral metabolism, together with biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and formation (serum bone isoenzyme of alkaline phosphatase and serum osteocalcin) were evaluated. In the same subjects lumbar spine and femoral bone mineral density (BMD) were also measured by dual energy X-ray absorptiometry. All patients but the younger 26-year-old patient had lower than normal bone mass at femoral neck and total hip, showing marked osteopenia in three cases and osteoporosis in the remaining three cases. However, at lumbar spine BMD measurement provided spuriously overestimated results, because of intervertebral disc calcification and osteophyte formation. As far as biochemical markers of bone turnover are concerned, the most relevant finding was the increased N-telopeptides of type I collagen urinary excretion. Our results suggest that ochronosis may be associated with increased bone resorption rate leading to an accelerated bone loss. A role of the homogentisic acid polymer deposit in bone matrix and cells, possibly with osteocyte damage and interference in collagen metabolism, might be hypothesized.

In ochronotic patients, abnormalities in bone metabolism leading to increased bone loss have been reported. Therefore, we attempted antiresorptive therapy to (almost) partially reverse bone loss in four out of five osteopenic or osteoporotic ochronotic patients, two men and two women, aged 56-82 years. Each patient was treated with a 70-mg tablet of alendronate weekly and 1,000 mg/day of elemental calcium, such as gluconolactate or carbonate, throughout 24 months. Before starting therapy, and after 1 and 2 years of treatment, the bone mineral density (BMD) at the femoral subregions and at the lumbar spine was measured (in grams per square centimeter and as a T score) by dual energy X-ray absorptiometry. A 50-year-old osteopenic ochronotic man refusing the treatment underwent the same checks. The BMD was measured in all patients on the same densitometer by the same operator. The results showed a progressive decrease of the femoral subregion BMD measurements both in the bisphosphonate-treated patients and in the untreated patient. In particular, the percentage differences with respect to the basal values of the total femur BMD measurements ranged from -0.52 to -6.72% in the first year and from -5.29 to -9.05% in the second year. The lumbar spine BMD measurements provided spuriously overestimated results. Moreover, two treated patients and the untreated patient experienced fragility fractures of the femur. The study showed that osteoporosis and fragility fractures are prominent manifestations in the natural history of ochronosis. Matrix microdamage, osteocyte viability, and collagen cross-linking impairment, due to homogentisic acid and to its polymer, might be the processes involved. For this reason, the bisphosphonate therapy was ineffective.

Although numerous studies concern fibrinogen (FBG) associations, the relationship between platelet (PLT) count and FBG plasma levels has yet to be completely investigated. The present study concerns the association between FBG plasma levels and PLT count in 5891 patients (2831 men and 3060 women) attending our outpatients' laboratory. Of these, a subgroup of 4116 patients (1899 men and 2217 women) with normal values of the parameters investigated was selected. A group of 170 patients with coronary heart disease was also included. The parameters studied were FBG, PLT count, leukocyte count and age. Our results showed that, in the outpatient population, FBG was significantly correlated with the PLT count (P < 0.000001) and, as previously reported, with the leukocyte count and age. In the patients with coronary heart disease, there was a significant correlation between FBG and PLT count (P < 0.000001), to be considered very significant considering the limited number of patients, whereas no correlation with age or leukocyte count was found. The role of interleukin-6, both in FBG and PLT production, is well known and may explain the correlation between these two parameters. The association of FBG and PLT count has yet to be fully investigated in epidemiological studies, even though they play an important role as two of the major contributors to the pathogenesis and evolution of cardiovascular diseases.

Several studies have suggested that thrombopoiesis may occur in the lungs. To investigate the role of the lungs in platelet production, we measured automated platelet parameters in blood from the pulmonary artery and the radial artery (n=125) or aorta (n=26) in patients undergoing aorto-coronary bypass. No significant differences were found between pulmonary and radial arterial blood with regard to platelet count (192.132 +/- 46.250 vs. 192.004 +/- 46.294 x 10(9)/l), mean platelet volume (11.03 +/- 1.04 vs. 11.03 +/- 1.03 fl), plateletcrit (0.212 +/- 0.051 vs. 0.212 +/- 0.051 x 10(-2)), platelet distribution width (14.48 +/- 2.16 vs. 14.47 +/- 2.08 fl) and platelet-large cell ratio (0.350 +/- 0.076 vs. 0.351 +/- 0.078). Similar results were obtained in comparisons between pulmonary arterial and aortic blood. A coefficient of linear correlation of 0.98 was found between the pulmonary and radial arterial and aortic platelet counts. These findings suggest that the platelet population entering the lungs was the same as the platelet population leaving them. Our results do not therefore support the theory of pulmonary platelet production.

Automatized platelet parameters were evaluated in 23 unselected patients undergoing a bone marrow examination for diagnostic purposes, both in medullary and in peripheral blood, with the aim of investigating the biological significance of platelet volume heterogeneity. In the marrow blood the platelet count was 10.07 ± 21.25% (p < 0.05) lower and the platelet volume 7.93 ± 6.88% (p < 0.001) higher compared to peripheral venous blood: 275,173 ± 108,079 versus 296,652 ± 104,814/mm³ (p < 0.05) and 8.93 ± 1.46 versus 8.23 ± 1.57 f1 (p < 0.001), respectively. The same behavior was observed between the marrow and the arterial blood collected from 12 out of the 23 patients, while no significant difference was observed between arterial and venous blood. The differences observed might be attributable to a platelet population replacement under homeostatical regulation and seem to support the concept that the large platelets are younger elements.