Rickets before the discovery of vitamin D.

The story of rickets leading to the discovery of vitamin D is an extraordinary tale, spread over many centuries and involving some remarkable characters with much speculation and a few mysteries, before reaching an exciting climax. It would be wrong to credit a single person as discovering rickets or being the first to describe its features, for reasons that will be set out here. Yet the emergence of the term 'rickets' is as important as the discovery of vitamin D itself and the possible causes of its deficiency.

Dual photon absorptiometry for bone mineral measurements using a gamma camera.

A gamma camera was equipped with a special collimator and arm assembly for bone mineral measurements with dual photon absorptiometry (DPA). The system was evaluated in vitro and in vivo and compared both with a rectilinear DPA and a dual energy X-ray (DEXA) system. All 3 systems showed a linear response in measurements of 4 vials, containing different amounts of hydroxyapatite.

Palliative pamidronate treatment in patients with bone metastases from breast cancer.

Purpose: An open, randomized study was performed to assess the effects of supportive pamidronate treatment on morbidity from bone metastases in breast cancer patients.

Patients And Methods: Eighty-one pamidronate patients and 80 control patients were monitored for a median of 18 and 21 months, respectively, for events of skeletal morbidity and the radiologic course of metastatic bone disease. The oral pamidronate dose was 600 mg/d (high dose [HD]) during the earliest study years, then changed to 300 mg/d (low dose [LD]) because of gastrointestinal toxicity.

Improved treatment of Paget's disease with dimethylaminohydroxypropylidene bisphosphonate.

A group of 89 patients with Paget's disease of bone were treated with different intravenous or oral doses of the nitrogen-containing bisphosphonate dimethylaminohydroxypropylidene bisphosphonate (dimethyl-APD). Biochemical remission was obtained in 82% of treatments, and in the rest a clear response was found. Oral dimethyl-APD was well tolerated, and a dose of 200 mg/day for 10 days was sufficient to induce remission in the majority of patients.

The effect of tissue type plasminogen activator (tPA) on osteoclastic resorption in embryonic mouse long bone explants: a possible role for the growth factor domain of tPA.

Osteoblasts produce proteolytic enzymes and their production is regulated by osteotropic agents. It has been suggested that these proteases play a role in bone resorption by removing the superficial collagenous layer from the bone matrix and indirectly inducing migration of osteoclast precursors towards the bone matrix. We examined the effect of the plasminogen activator tPA on osteoclastic resorption using 17-day-old mouse embryonic long bone explants representing different stages of osteoclast development, that is, radii containing already mature osteoclasts and metacarpals containing no mature osteoclasts but only osteoclast precursors/progenitors which are still confined to the periosteum.

The use of bisphosphonates in the treatment of osteoporosis.

The efficacy of bisphosphonates in the treatment of conditions characterized by increased osteoclastic bone resorption has been established. Recent evidence indicates that these compounds are also effective in the treatment of patients with osteoporosis. Two main protocols have been tried.

Modulation of PTH-stimulated osteoclastic resorption by bisphosphonates in fetal mouse bone explants.

We examined the effects of the bisphosphonates Cl2MDP, APD, and Me2APD on osteoclastic resorption in the absence and presence of PTH using fetal mouse osteoclast-free bone explants cocultured with fetal liver as a source of osteoclast precursors. Results revealed qualitative and quantitative differences among the bisphosphonates tested. With Cl2MDP and APD fractional inhibition of resorption (measured as 45Ca release) in the presence of PTH was proportional to that obtained in its absence.

Regulation of the production of plasminogen activators by bone resorption enhancing and inhibiting factors in three types of osteoblast-like cells.

Production of proteolytic enzymes by osteoblasts is considered to be important for the initiation of osteoclastic bone resorption. We examined the production of tissue-type (tPA) and urokinase-type plasminogen activator (uPA) activity by three types of osteoblast-like cells (normal rat osteoblasts, rat and human osteosarcoma cells) using a quantitative spectrophotometric assay and a qualitative gel overlay technique. All 3 types of cells released both types of PA-activity into the medium, but normal rat osteoblasts released uPA probably in an inactive form.

Automated comparison of dual-photon absorptiometric studies of the lumbar spine.

An automated image comparison procedure was developed to optimize the precision of bone mineral density measurements by dual-photon absorptiometry. Changed acquisition conditions cause differences between two images to be compared. Alignment of one image with respect to the other is performed by a transformation that involves a rotation, a horizontal or vertical shift, and a correction for the soft tissue level.

Automatic region of interest determination in dual photon absorptiometry of the lumbar spine.

In a heuristic approach, the authors developed an algorithm for automatic region-of-interest (ROI) determination in bone mineral density (BMD) measurements of the lumbar spine. First, the algorithm detects the boundaries of the spine utilizing simple smoothing and gradient operators followed by a dynamic programming technique. Second, it selects L2, L3, and L4 from the spine by examining the BMD values along lines that are orthogonal to the local direction of the spine.

The effect of supportive pamidronate treatment on aspects of quality of life of patients with advanced breast cancer.

Selective aspects of quality of life during supportive pamidronate (APD) treatment were assessed in breast cancer patients with osteolytic metastases. 144 patients were randomised to a pamidronate group (n = 76) or a control group (n = 68). A questionnaire measuring mobility impairment, bone pain, fatigue and gastrointestinal toxicity was administered at 3-monthly intervals.

Limited precision of lumbar spine dual-photon absorptiometry by variations in the soft-tissue background.

The estimation error due to variations in soft-tissue baseline in lumbar bone mineral content (BMC) measured by dual-photon absorptiometry (DPA) was calculated with a new method of automatic baseline subtraction. In water phantom measurements, the s.d.

Modulation of the production of a parathyroid hormone-like protein in human squamous carcinoma cell lines by interaction with fibroblasts.

Normal human keratinocytes as well as human squamous cell carcinomas produce a parathyroid hormone-like protein (PLP). However, PLP production by these cells is not a constant phenomenon. Since nothing is known about factors which regulate the production of PLP, in vitro studies were performed with normal keratinocytes and squamous carcinoma cell lines in order to establish conditions under which PLP production may vary.

Crystal agglomeration is a major element in calcium oxalate urinary stone formation.

The effects of urines from 36 healthy subjects and 86 calcium oxalate renal stone formers on calcium oxalate monohydrate crystallization kinetics were studied using a seeded crystal growth method in which the solubility, the growth and the agglomeration of the crystals are measured as three separate and system-independent parameters. The urines of healthy subjects were found to increase the solubility and to strongly inhibit the growth and the agglomeration of calcium oxalate monohydrate crystals. The urines of stone formers had a similar effect on the solubility, but a significantly lower ability to inhibit the crystal growth and the crystal agglomeration.

Application of an in vitro model and a clinical protocol in the assessment of the potency of a new bisphosphonate.

The development of new bisphosphonates for clinical use requires congruence between the results of basic and clinical investigations. We have previously shown that this can be achieved with the use of an in vitro coculture mouse metacarpal resorption system sensitive to the activation of osteoclast precursors together with a clinical protocol in which the rate of decrease in urinary hydroxyproline excess with bisphosphonate treatment is assessed in patients with Paget's disease. In these studies bisphosphonates of known potencies were used.

Parathyroid hormone (PTH) and PTH-like protein (PLP) stimulate interleukin-6 production by osteogenic cells: a possible role of interleukin-6 in osteoclastogenesis.

Osteogenic cells mediate PTH-stimulated osteoclastic bone resorption by a yet unidentified mechanism. We show that primairy rat osteoblast-like cells and the clonal osteogenic sarcoma cell line UMR-106 produce interleukin-6 (IL-6) and that bPTH(1-84) and synthetic hPLP(1-34) stimulate this production dose-dependently. With both peptides a close relation between IL-6 and cyclic-AMP production was found, though for PTH concentrations higher than 2.

Maintained improvement in calcium balance and bone mineral content in patients with osteoporosis treated with the bisphosphonate APD.

The effects of the (3-amino-1-hydroxypropylidene)-1,1-bisphosphonate (APD) in osteoporosis were investigated in a series of open studies. Seven patients received a high dose of 600 mg/day of APD orally and showed an increase in calcium balance of 5.5 mmol/day (P less than 0.

The reproducibility of single photon absorptiometry in a clinical setting.

The reproducibility of single photon absorptiometry (SPA) results for detection of changes in bone mineral content (BMC) was evaluated in a clinical setting. During a period of 18 months with 4 different sources, the calibration scans of an aluminium standard had a variation of less than 1% unless the activity of the 125I source was low. The calibration procedure was performed weekly and this was sufficient to correct for drift of the system.

Precision of dual photon absorptiometry measurements: comparison of three different methods of selection of the region of interest.

To determine the short-term reproducibility of bone mass calculations with dual photon absorptiometry of the lumbar spine (L2-L4), duplicate measurements in healthy subjects were used. Three different methods for selection of region of interest were compared: a rectangular region with variable height and width, an irregular region to be drawn freely by the operator and the standard calculation software supplied with the bone densitometer. Contributions of changes in size and location of the region of interest on calculated bone mineral mass were also investigated.

Effect of long-term bisphosphonate treatment on morbidity due to bone metastases in breast cancer patients.

The effect of long-term bisphosphonate (APD) treatment on the morbidity from bone metastases in breast cancer patients was studied in a controlled clinical trial. 131 patients were randomized between treatment with APD (300 mg/day orally) or control. Systemic treatment for breast cancer was left to the discretion of the physician.

Modulation of calcium oxalate monohydrate crystallization kinetics in vitro.

The effects of several low and high molecular weight (mol wt) compounds on the kinetics of calcium oxalate crystallization were examined using a seeded crystal growth method in which the solubility, the growth and the agglomeration of calcium oxalate crystals were measured as three separate and system-independent parameters. Citrate, magnesium, phosphate, pyrophosphate, chondroitinsulphate, pentosanpolysulphate and heparin were tested in a wide range of concentrations. The solubility of calcium oxalate crystals was increased only by citrate and magnesium.

Migration and phenotypic transformation of osteoclast precursors into mature osteoclasts: the effect of a bisphosphonate.

Osteoclast-devoid bone explants were cultured together with embryonic liver as a source of osteoclast precursors, but separated from each other by a filter. Cells migrated through the filter toward the calcified matrix and acquired the characteristics of mature, tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts upon contact with the bone explant. Migration and attachment could be visualized separately.

Bone scintigraphy and radiology in Paget's disease of bone: a review.

Since effective treatment of Paget's disease is now feasible, knowledge of the possibilities of diagnostic imaging, especially the changes in these images induced by treatment, has become essential. Some forms of treatment may lead to radiographic improvement, indicating that the macroscopic bone texture is changing; radiological imaging, however, is painstaking and liable to technical errors. Different information is derived from the bone scintigram, which is a good monitor of the local bone metabolism and often a sensitive means of identifying lesions.