The cellular basis of the normal bone remodeling sequence in the human adult is discussed in relation to a cycle of five stages--quiescence, activation, resorption, reversal, formation, and return to quiescence. Normally, 80% or more of free bone surfaces are quiescent with respect to remodeling. The structure of the quiescent surface comprises 5 layers; listed in order out toward the bone marrow these are: the lamina limitans (the electron dense outer edge of the mineralized bone matrix), unmineralized connective tissue that may be confused with osteoid by light microscopy, flattened lining cells of osteoblast lineage separated by narrow gaps, more unmineralized connective tissue, and finally either the squamous sac cells of red marrow or the cytoplasm of fat cells of yellow marrow. Activation requires the recruitment of new osteoclasts derived from precursor cells of the mononuclear phagocyte system (and so ultimately from the hematopoietic stem cell), a method for precursor cells to penetrate the cellular and connective tissue barrier of the quiescent surface, and so gain access to the bone mineral, and mechanisms for their attraction and binding to the mineralized surface, possibly in response to chemotactic signals released from bone matrix or mineral. Each of these three steps is probably mediated in some way by lining cells. Resorption is carried out by osteoclasts, most of which are multinucleated. The mean life span of individual nuclei is about 12.5 days; the additional nuclei needed to sustain resorption may be derived from local as well as blood-bone precursors, but nothing is known of their fate.(ABSTRACT TRUNCATED AT 250 WORDS)

We studied the natural history of primary hyperparathyroidism in patients in whom the disease was discovered fortuitously by multichannel biochemical screening and who were selected for conservative management because they were asymptomatic, had no renal stone disease or radiographic osteitis fibrosa, and had serum calcium values below 3.00 mmol/L, serum creatinine levels below 133 mumol/L, and forearm bone density not more than 2.5 SD below the mean expected for age, sex, and race. One hundred and seventy-four patients meeting these criteria were encountered during a 10-yr period, of whom 80 (mean age, 61 yr) had adequate follow-up; they did not differ significantly in any initial characteristic from the remaining 94 patients. These 80 patients were followed for 1-11 yr (mean, 46 months; median, 38 months), during which there was no change, mean or individual, in any index of PTH secretion or any of its biochemical effects and no decline in forearm bone density apart from that expected from increased age. There were 4 deaths from causes unrelated to hyperparathyroidism, and the overall death rate was not increased. The data suggest that no change occurred in either the number of parathyroid cells or secretory set-point, the 2 principal determinants of basal PTH secretion. This implies a biphasic course, with a short period of disease progression followed by a long period of disease stability. Our data support the decision to withhold surgical intervention in such patients, but to establish this as the correct policy for all asymptomatic patients will require a controlled clinical trial.

My purpose in this article is to restore the histologic appraisal of renal bone disease to the mainstream of bone and mineral metabolism from which it has been separated for many years. Historically, both the two major components were found in varying degrees in most patients, although one or other of them often predominated. For more than 15 years bone biopsy has been used almost exclusively to classify individual patients into hyperparathyroid, osteomalacic, mixed and adynamic categories according to rigid non-overlapping criteria, and remarkably few histologic data have been reported. All metabolic bone diseases result from disordered bone remodeling, the physiologic mechanism for replacing bone that has become too old to carry out its mechanical or metabolic functions. Bone remodeling is not directly concerned with the regulation of plasma calcium, which reflects the level of equilibration at quiescent bone surfaces between systemic and bone extracellular fluid set by parathyroid hormone. The separation of remodeling from homeostasis explains the concurrence of increased turnover and decreased plasma calcium in chronic renal failure; it is the homeostatic system, rather than the remodeling system, which is resistant to parathyroid hormone. The effect of mild hyperparathyroidism is a nonspecific increase in bone turnover, of which the best index is the bone formation rate measured by double tetracycline labeling expressed per unit of bone surface. Increased turnover is always accompanied by increased reversible mineral deficit. In prolonged hyperparathyroidism there is also accelerated irreversible bone loss manifested mainly as thinning of cortical bone, detectable in chronic renal failure before any symptoms, due to increased resorption depth on the endocortical surface. In severe hyperparathyroidism resorbed bone is replaced, not by a lesser quantity of normal bone, but by a mixture of vascular fibrous tissue and woven bone, referred to as osteitis fibrosa. In osteomalacia there is increased accumulation of osteoid, due not to increased turnover, but to prolongation of mineralization lag time, which in conjunction with increased thickness, surface and volume of osteoid is diagnostic. Converting histomorphometric data into category assignment discards most of the useful information, which can be retained by two-dimensional representation of severity. For the hyperparathyroid dimension, bone formation rate measured by double tetracycline labeling expressed per unit of bone surface is the most useful although not ideal. For the osteomalacic dimension a mineralization index was constructed that is unaffected by age or race. In patients with osteitis fibrosa, bone formation rate per unit of bone surface and mineralization index were inversely correlated. For the third dimension a structure/formation index was constructed which increases with age in healthy women and shows weak inverse correlation with bone formation rate. The structure/formation index is lower than normal in patients with osteitis fibrosa, and s...