A. Michael Parfitt

Trabecular bone architecture in the pathogenesis and prevention of fracture

Rapid loss of trabecular bone (as after menopause) occurs by complete removal of some structural elements, leaving those that remain more widely separated and less well connected. The most likely cellular mechanism is an increase in the number of resorption cavities deep enough to lead to focal perforation of trabecular plates, either as a non-specific consequence of increased remodeling activation, or as a specific consequence (direct or indirect) of estrogen deficiency. Disruption of the connections between structural elements produces a disproportionate loss of strength, for which the increased thickness of the remaining trabeculae can only partly compensate. Consequently, the most biomechanically significant component of trabecular bone loss occurs rapidly and irreversibly. This emphasizes the importance of prevention, but no treatment except estrogen replacement is of proven efficacy in preventing estrogen-dependent bone loss. For adequate repair of structural damage after it has been allowed to occur, adding bone to existing surfaces may be insufficient, and it may be necessary to devise some means of forming new bone directly in the bone marrow cavity in order to re-establish normal connectivity.

The actions of parathyroid hormone on bone: Relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease

Kinetic and morphologic studies in patients with parathyroid disease, and a wide variety of studies in experimental animals indicate that one major effect of PTH is to increase the proliferation of osteoprogenitor cells into osteoclasts and so to increase bone turnover. PTH stimulates bone cells by increasing cell membrane permeability to calcium and consequently increasing calcium influx and by activating membrane-bound adenyl-cyclase. It is likely that the former event precedes the latter and that calcium is the second messenger and cyclic AMP the third messenger. PTH increases the production by bone cells of lactate, citric and carbonic acids, lysosomal enzymes, collagenase, and hyaluronic acid, some or all of which are concerned in the mechanism of bone resorption. With the exception of lactate which probably comes mainly from osteocytes, the increase in metabolic activity is largely due to the increase in the number of osteoclasts. There is also ultrastructural, biochemical, and biophysical evidence that PTH stimulates existing osteoclasts, but this most likely represents the transformation of inactive cells into an active state, and is a transient and nonsustainable effect. As yet, there is no evidence that either increased osteoprogenitor cell proliferation or increased osteoclast activity is mediated by adenyl-cyclase activation. PTH also acts on the deep osteocyte to cause rapid mobilization of calcium from the zone of hypomineralized metabolically active perilacunar bone. This effect is mediated by adenyl-cyclase activation and is preceded by a slight fall in plasma calcium probably due to the movement of calcium into bone cells. The function of this rapid hypercalcemic response to PTH is correct errors in the prevailing steady-state level of plasma calcium...

The actions of parathyroid hormone on bone: Relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone diseases: Part II of IV parts: PTH and bone cells: Bone turnover and plasma calcium regulation

Kinetic and morphologic studies in patients with parathyroid disease, and a wide variety of studies in experimental animals indicate that one major effect of PTH is to increase the proliferation of osteoprogenitor cells into osteoclasts and so to increase bone turnover. PTH stimulates bone cells by increasing cell membrane permeability to calcium and consequently increasing calcium influx and by activating membrane-bound adenyl-cyclase. It is likely that the former event precedes the latter and that calcium is the second messenger and cyclic AMP the third messenger. PTH increases the production by bone cells of lactate, citric and carbonic acids, lysosomal enzymes, collagenase, and hyaluronic acid, some or all of which are concerned in the mechanism of bone resorption. With the exception of lactate which probably comes mainly from osteocytes, the increase in metabolic activity is largely due to the increase in the number of osteoclasts. There is also ultrastructural, biochemical, and biophysical evidence that PTH stimulates existing osteoclasts, but this most likely represents the transformation of inactive cells into an active state, and is a transient and nonsustainable effect. As yet, there is no evidence that either increased osteoprogenitor cell proliferation or increased osteoclast activity is mediated by adenyl-cyclase activation. PTH also acts on the deep osteocyte to cause rapid mobilization of calcium from the zone of hypomineralized metabolically active perilacunar bone. This effect is mediated by adenyl-cyclase activation and is preceded by a slight fall in plasma calcium probably due to the movement of calcium into bone cells. The function of this rapid hypercalcemic response to PTH is correct errors in the prevailing steady-state level of plasma calcium...

Bone age, mineral density, and fatigue damage

SummaryThe most plausible purpose for bone remodeling is to prevent excessive aging of bone, which can cause osteocyte death and increase susceptibility to fatigue microdamage. The age of any particular volume of bone depends on two factors: the probability of remodeling beginning on the nearest bone surface, which is given by the local activation frequency; and the probability of a particular remodeling event penetrating to a specified distance from the surface. These two probabilities can be combined in a mathematical model. According to the model, within about 40 μm from the surface, the rate of surface remodeling is the main determinant of bone age, but beyond 40 μm, the distance from the surface becomes progressively more important. Beyond 75 μm, the bone is essentially isolated from surface remodeling. Application of the model to subjects with and without vertebral fracture indicated that the proportion of iliac cancellous bone with a mean age greater than 20 years was less than 20% in all the control subjects without fracture, but was more than 20% in about one-third of the patients with fracture. Bone age is a major determinant of the degree of mineralization, so that osteoporotic patients with prolonged bone age should have bone of higher true mineral density. Accordingly, mineral density distribution was determined by scanning electron microscopy with backscattered electron imaging, calibrated in terms of atomic number. In osteoporotic patients, the mean atomic number was lower, the proportion of bone with high values was lower, and the proportion of bone with low values was higher than in control subjects, the opposite of what would be predicted by the bone age model just described. These data, together with our failure, to date, to detect osteocyte death and fatigue microdamage in iliac cancellous bone in patients with osteoporosis, cast doubt on the role of low bone turnover and increased bone age in the pathogenesis of vertebral fracture. Although conclusive data are still lacking, bone age, osteocyte death, and fatigue failure are more likely relevant to the pathogenesis of hip fracture. Nevertheless, enhanced bone conservation as a result of modest therapeutic inhibition of remodeling activation more than offsets the hypothetical risk of increasing bone age.

Disordered calcium and phosphorus metabolism during maintenance hemodialysis: Correlation of clinical, roentgenographic and biochemical changes

Abstract The incidence and progression of renal osteodystrophy and soft tissue calcification in sixteen patients undergoing maintenance hemodialysis (MHD) for eight to thirty-eight months at Mount Sinai Hospital, Los Angeles, were determined by clinical and roentgenographic observation. The most common symptom was pruritus, which occurred in every patient. Ocular, periarticular or arterial calcification, usually asymptomatic, appeared or worsened during MHD in at least thirteen patients. Roentgenographic signs of hyperparathyroidism were present in nine of ten patients who underwent dialysis for more than one year, and appeared or progressed during dialysis in at least five. Stress fractures and reduction in bone density occurred in three patients. The mean serum levels immediately before and after dialysis were calcium 9.16 and 10.28 mg/100 ml, inorganic phosphate 7.94 and 3.85 mg/100 ml, blood urea nitrogen 87.5 and 25.7 mg/100 ml, and creatinine 12.97 and 5.08 mg/100 ml. The increment in serum calcium during dialysis was partly due to the high calcium level of the dialysate (6.87 ± 0.58 mg/100 ml), but there was considerable variation between patients which was only partly explained by individual differences in the correction of hyperphosphatemia and uremia. Although some patients showed a fall in predialysis serum phosphate levels in the first few months, high levels eventually developed in all; this constituted the most striking difference between the present series and that reported from Fulham Hospital, London, in which the incidence of osteodystrophy and soft tissue calcification was much lower. This difference resulted partly from insufficient ingestion of phosphate-binding antacids and inadequate control of dietary phosphate intake, but it may also have reflected a more severe disorder of parathyroid cell proliferation (mitotic autonomy) in uremic patients in Los Angeles than in London.

Use of bisphosphonates in the prevention of bone loss and fractures

The bisphosphonates, formerly diphosphonates, are a class of synthetic analogues of pyrophosphate, with a phosphate-calcium-phosphate (PCP) instead of a phosphate-oxygen-phosphate (POP) backbone, which renders them resistant to hydrolysis [l]. They are poorly absorbed and bind avidly to bone mineral and are either retained in mineralized tissue or excreted in the urine. Many members of the class have been synthesized and tested in animals, and some have been used in human subjects. All bisphosphonates are capable of inhibiting bone mineralization and bone resorption [l], but with more recent compounds, the relative potency has shifted in favor of inhibition of resorption; the ambiguity of this term will be explained later. The mechanisms of action are poorly understood, and the profile of mechanisms is probably different for each member of the class [Z]. Bisphosphonates are retained in bone by at least two mechanisms. Like other bone-seeking substances, they are irreversibly trapped at sites of new bone formation, a property that has permitted their use as bone-scanning agents. With prolonged administration, all bone adjacent to the cancellous surface will eventually contain the drug to an average depth of approximately 50 pm and at a concentration that depends on the average blood level. A steady state will be attained when resorbed bone contains as much bisphosphonate as the new bone formed in its place. The time taken to attain this steady state will depend upon the prevailing rate of remodeling activation and whether the drug is given continuously or intermittently. The drug will also be reversibly bound to the most superficial layer of mineral that is accessible to exchange with the extracellular fluid. When administration is halted, the surface-bound drug will diffuse out of bone back into the circulation, in accordance with adsorptionidesorption kinetics [3], and most of the surface-bound bisphosphonate will have left the bone within a week. There is evidence for binding to some constituent of bone matrix [4], and small