Transforming growth factor ␤ (TGF-␤) is thought to play an important role in bone metabolism, but its relationship to human bone turnover and bone mass has not been examined yet. In this study, we measured the concentration of TGF-␤ in 811 samples of male and female bone from four representative sites of the human skeleton and in the supernatants of 72 short-term human bone marrow cultures from the iliac crest. The concentrations of TGF-␤1 and TGF-␤2 in the bone matrix were positively correlated with histomorphometric indices of bone resorption and bone formation and with serum levels of osteocalcin and bone-specific alkaline phosphatase. We also observed a positive association between the release of TGF-␤ in the bone marrow cultures and serum osteocalcin. Changes in the rate of cancellous or cortical bone remodeling with age or menopause were accompanied by corresponding changes in skeletal TGF-␤. In contrast, there was no significant relationship between the concentration of TGF-␤ and bone volume at any skeletal site. In conclusion, our study supports the hypothesis that TGF-␤ plays an important role in human bone remodeling, but fails to demonstrate an association between the skeletal concentration of TGF-␤ and human bone mass. (J Bone Miner Res 1998;13:716-730)

Longitudinal growth; bone and growth zone histology; growth cartilage and bone mineralization (tetracycline technique); bone Ca content (neutron activation analysis); bone radiology; serum and urine chemistry; urinary cAMP and serum 25-OH-vitamin D₃ were studied in a long-term model of experimental uremia in the rat. Uremia was induced by two-stage subtotal nephrectomy with irradiation of the remaining parenchyma. Ccr in the experimental group was 113 ± 5.8 µl/min × 100 g (19.8% of controls) and serum creatinine 1.67 ± 0.04 mg% (5.1 × control value). Uremic animals were pair-fed with sham-operated controls. In the proximal tibia delayed transformation of cartilage into primary spongiosa with appearance of chondro-osteoid and delayed transformation of primary spongiosa into secondary spongiosa was observed (rickets). Increased amounts of osteoid were present although 25-OH-vitamin D₃-levels were high. There were only modest signs of secondary hyperparathyroidism (osteoclast counts; urinary cAMP). In spite of the presence of bone disease, longitudinal growth was not reduced in uremic animals as compared with pair-fed sham-operated animals, but was significantly reduced as compared with ad lib fed control animals. In contrast, weight gain was significantly diminished in uremic animals as compared with pair-fed sham-operated control animals. It is concluded that diminished intake of food is the major determinant of growth retardation in preterminal experimental renal failure.

Animal models are important tools to study the development of bone metastases and to evaluate strategies for their prevention and treatment. We here describe a new model in which tumour inoculation is achieved by injection of cancer cells into the femoral artery. This approach results in the development of multiple osteolytic lesions in the distal femora and proximal tibiae within 18 days after inoculation, with a success rate of 95-100% and no additional comorbidity. In untreated animals, osteolyses expanded continuously at a growth rate of 4.7-8.2 mm 2 /4 days, causing extensive destruction of resident bone structures by the tumour, significant loss of tibial bone density and a transient rise in urinary bone resorption markers. Continuous daily treatment with ibandronate (10 g/kg) inhibited further growth of fully established metastases and reduced the mean osteolytic growth rate to 0.03 mm 2 /4 days. In lesions <6 mm bisphosphonate treatment resulted in a negative growth rate (-0.33 to -0.81 mm 2 /4 days). When ibandronate was started 3 days prior to tumour cell inoculation, the development of osteolytic lesions was substantially reduced (take rate only 17%) and bone density and structure were mostly preserved. We conclude that the intra-arterial approach used in this new model of metastatic bone disease results in site-specific osteolytic lesions with high take rates, steady tumour growth and no additional morbidity. While serial bone marker assessments did not prove useful to monitor osteolytic growth, our studies provide in vivo evidence that ibandronate treatment induces tumour remission by reversal of tumour growth. © Bone metastases are frequent complications of many malignant tumours, particularly of breast, prostate and lung cancers. 1,2 Animal models are important tools to study the mechanisms involved in the development of metastatic bone disease and to evaluate in vivo strategies for its prevention and treatment. 3 Most current animal models utilise suspensions from malignant cell lines that are brought to the skeleton either via direct 4 -6 or indirect inoculation. With intracardial injections, 3,7-11 cells are inoculated at a relatively high tumour dose and, in most models, malignant dissemination occurs into both skeletal and visceral peripheries, resulting in varying degrees of animal comorbidity (e.g., cachexia, paraplegia). Direct inoculation of tumour cells into the bone marrow leads to site-specific osteolyses, but these models lack the processes associated with extravasation of tumour cells, while the injection itself causes bone damage that might result in nonspecific wound responses. [12][13][14][15] Furthermore, all currently characterised animal models of metastatic bone disease use either syngeneic tumours or human xenografts in small animals ( e.g., mice) or syngeneic tumours in larger animals (e.g., rats). While small-animal models are often restricted to end-point analyses or radiographic follow-up, studies in larger animals allow the longitudinal assessment of bone turnover by s...

We have developed a rat model of inflammation-mediated osteopenia. Generalized loss of trabecular bone occurs in the rat after sc injection of nonspecific irritants such as talcum (magnesium silicate) and cotton wool (Cellulose). Although it appears likely that a systemic mediator of bone resorption is responsible for these effects, the loss of bone was not due to increased PTH secretion, since it occurred in parathyroidectomized rats, nor due to excessive 1,25-dihydroxyvitamin-D3 production. In parathyroidectomized rats, this inflammation was associated with significant increase in serum calcium within 4-7 days independent of its cause. Identification and characterization of this mechanism may provide insight into the bone loss associated with chronic inflammatory diseases such as rheumatoid arthritis and periodontal disease.