Current and investigational approaches for reversing established osteoporosis.

Osteoporosis is a disease of elderly women marked by low bone mass and increased risk of fracture. Though its prevalence can be reduced by timely estrogen replacement at menopause, many persons present with fragility fractures long after much bone has been lost. Osteoporotic subjects have low bone mass and poor structure but few or no metabolic abnormalities, such as ongoing bone loss, for treatment to normalize. The problem is to increase their bone mass and improve their bone structure. Today's major therapeutic approaches are summarized in Table 2. Ironically, they aim at stopping bone loss. Although preventing the skeleton of an osteoporotic person from growing weaker by stopping bone loss is better than allowing the process to continue, raising her to a significantly higher level of bone mass would be a better aim. Existing agents that stop bone loss by reducing turnover also increase bone mass mildly by filling the remodeling space. The result is a rise in bone mass during the first year or two of treatment to a new steady state 2% to 5% higher than baseline that persists throughout treatment. Fluoride increases spinal bone mass markedly. It decreases vertebral, but not hip fractures, but is associated with side effects and a nonresponse rate that makes pursuing other therapies attractive. Agents that upregulate bone mass through regulatory means have been tested in preclinical and a few clinical trials. PGE2 has been thoroughly tested preclinically. By studying PGE2, the field has learned that marked bone mass increases in the estrogen-deplete osteopenic skeleton are possible. The lack of bone specificity for PGE2 will probably limit its use to that of preclinical demonstration agent but leave open the possibility that less potent members of the prostaglandin family with better bone specificity might have promise as osteoporosis treatments. PTH or one of its analogues shows good promise for osteoporosis treatment. The wide availability of cheap PTH or proprietary analogues with similar activity will do much to speed its development. It increases bone formation and cancellous bone mass markedly. If PTH increases bone mass consistently in either large animal or human trials while causing only mild transient cortical bone mass declines, it can be a successful osteoporosis treatment agent. Bone growth factors appear to have much untapped potential for furthering the understanding of local control of bone processes and possibly for treating osteoporosis. Another possibility is biphasic therapy.(ABSTRACT TRUNCATED AT 400 WORDS)

Calibration and standardization of bone mineral densitometers.

Measurements of bone mineral density (BMD) by four 153Gd and two x-ray bone densitometers were compared utilizing spine phantoms that simulated the human lumbar spine. The six instruments provided BMD values that differed by as much as 16%, due to differences as large as 8% in bone mineral content and as large as 7% in bone area. Instrument calibration curves, determined by measuring thin, medium, and thick hydroxyapatite blocks, were linear (r = 0.99) but had different (p less than 0.0001) slopes and intercepts. Serial measurements of spine and total body phantoms were employed to evaluate the long-term stability of 153Gd bone densitometry. These measurements of spine phantom BMD increased 1.0-2.6% (p less than 0.0001) following a software change, and measurements of total body bone density increased 4-6% after 153Gd source replacement. The changes occurred at a time when serial measurements of cylindrical calibration standards were stable, indicating that such simple standards are unable to detect and correct for changes in instrumental response. We conclude that investigators, manufacturers, and government regulatory agencies must develop and implement the following: (1) effective calibration procedures that would assure comparability among instruments, and (2) appropriate quality control phantoms that would allow the confident interpretation of serial patient measurements.

Quantitative digital radiography versus dual photon absorptiometry of the lumbar spine.

Lumbar spine bone mineral density (BMD) was measured by quantitative digital radiography, a new dual energy x-ray technique, and by 153Gd dual photon absorptiometry (DPA) in 85 patients. Each patient was measured twice by the new method and once by DPA on the same day, with repositioning between measurements. Serial measurements were made on an hydroxyapatite spine phantom embedded in tissue-equivalent plastic to evaluate the long term reproducibility of each instrument. The spinal BMD measurements with the 2 techniques were linearly related and highly correlated (r = 0.98) over a range from severely osteopenic to high normal. This correlation was not affected by the age, weight, or BMD of the patient measured. Quantitative digital radiography's long-term reproducibility using the spine phantom was stable for 180 days (coefficient of variation, 0.23%); DPA values were 3 times as variable for 170 days (coefficient of variation 0.73%) and increased 1.0% (P less than 0.0001) after a software change. The short term reproducibility of quantitative digital radiography, estimated from paired patient measurements, was 2-fold better than reported values for DPA and was independent of the patient's age, weight, or BMD. Measurement time by quantitative digital radiography was 5-8 min, with a maximum radiation exposure of 3 mrem, significantly lower than the corresponding DPA values. Quantitative digital radiography's image resolution was superior to that of DPA, enabling it to measure more bones. These advantages along with the elimination of 153Gd source changes and Nuclear Regulatory Commission licensing requirements indicate that quantitative digital radiography is the superior method for spinal BMD measurements.

Changes in serum levels of type I and III procollagen extension peptides during infusion of human parathyroid hormone fragment (1-34).

Parathyroid hormone (PTH) inhibits collagen synthesis in vitro, in organ or cell culture and cell-free translation systems. We have designed studies to measure the effects of PTH on collagen synthesis in vivo in humans, utilizing measurements of the serum levels of procollagen extension peptides during and after infusion of synthetic human PTH (hPTH) fragment (1-34). Radioimmunoassays for the carboxy-terminal peptide of type I procollagen (pColl-C) and the amino-terminal peptide of type III procollagen (pColl-III-N) were used to measure acute changes in serum during and after hPTH(1-34). In all six osteoporotic subjects and two normal individuals, serum levels of pColl-I-C were decreased by 16 hr of infusion and returned towards normal 14 hr after the infusion was discontinued; serum levels of pColl-III-N did not change significantly during the infusion, but were increased at 14 hr after the infusion was discontinued. The PTH-induced decrease in levels of pColl-I-C correlated with an increase in blood levels of ionized calcium. In all but two subjects the serum levels of 1,25-dihydroxy vitamin D [1,25(OH)2D] were also increased during the period when serum levels of pColl-I-C were decreased. These results are compatible with the conclusion that infusion of PTH acutely inhibits type I (bone) collagen synthesis, but not type III collagen synthesis. These effects could be direct or indirect, related in part to PTH-induced increased 1-alpha-hydroxylation of 25-(OH) vitamin D and the resultant increased serum levels of 1,25(OH)2D.

Restoration of spinal bone in osteoporotic men by treatment with human parathyroid hormone (1-34) and 1,25-dihydroxyvitamin D.

Daily subcutaneous injection of a synthetic human parathyroid hormone fragment, combined with daily ingestion of 1,25(OH)2 vitamin D, significantly increased trabecular bone density in the spine (p less than .01), and improved intestinal calcium and phosphorus absorption and total body retention of dietary calcium and phosphorus in middle-aged men with idiopathic osteoporosis. The increases in spinal bone mineral were marked and progressive during a year of treatment. These results indicate that increasing intestinal absorption of dietary calcium while simultaneously stimulating new bone formation with small doses of parathyroid hormone can restore spinal bone in osteoporotic men.

Quantitative computed tomography for spinal density measurement. Factors affecting precision.

Quantitative computed tomography (QCT) was performed in duplicate on 84 patients to test the short-term precision of the technique. Statistical analysis of the data revealed that precision was not a function of spinal density. It appeared to be worse in osteopenic individuals only when expressed as a percentage. Precision was slightly better in male than in female patients. There is a 90% likelihood that a duplicate measurement will fall within 20 CT units of the first determination in female patients and within ten units in male patients.

Clinical evaluation of bone turnover by serum osteocalcin measurements in a hospital setting.

Serum levels of osteocalcin, the major noncollagenous bone protein, are elevated in patients with certain metabolic bone diseases, but the effects of other illnesses on serum osteocalcin levels are not known. We measured serum osteocalcin concentrations in 250 patients in a rehabilitation hospital who suffered from various illnesses. Mean serum osteocalcin levels were elevated in patients with 1) recent hip fracture who required open reduction and pin insertion (mean +/- SE, 19.0 +/- 3.2 ng/ml), 2) primary (22.0 +/- 4.9 ng/ml) or secondary hyperparathyroidism (51.6 +/- 9.9 ng/ml), 3) Paget's disease of bone (22.7 +/- 6.1 ng/ml), or 4) metastatic skeletal disease who had not received therapy (37.5 +/- 11.3). Mean serum osteocalcin levels were normal in patients who had received 1) a hip prosthesis for a recent fracture or for severe degenerative joint disease of the hip (6.4 +/- 0.9 ng/ml), 2) recent chemotherapy or irradiation for bone metastases (6.1 +/- 1.3 ng/ml), or 3) a variety of medical problems not related to bone disease (5.2 +/- 0.3 ng/ml). Serum osteocalcin and alkaline phosphatase values did not correlate. This study demonstrates that serum osteocalcin levels are normal in disorders not involving bone, can be used in a general-hospital setting, where concomitant illnesses are present, and may provide additional information for the clinical evaluation of metabolic bone disease.

Renal 1,25-dihydroxyvitamin D, phosphaturic, and cyclic-AMP responses to intravenous synthetic human parathyroid hormone-(1-34) administration in normal subjects.

The exogenous administration of bovine parathyroid hormone or parathyroid extract has been used to differentiate states of parathyroid hormone resistance and parathyroid gland secretory failure, and in recent years to test renal 1,25-dihydroxyvitamin D (1,25-(OH)2-D) secretion. We evaluated the effect of synthetic human parathyroid hormone (hPTH-(1-34] administration on the renal 1,25-(OH)2-D, phosphaturic and cyclic-AMP responses in eleven normal young adults. The intravenous administration of 200 units of hPTH-(1-34) over 10 min produced a 1.3-5.4 fold increase (P less than 0.01) in renal phosphate clearance and a 19-75 fold increase (P less than 0.0001) in urinary cyclic-AMP excretion. Serum 1,25-(OH)2-D levels showed a small and insignificant change at 2.5 h and a significant (P less than 0.05) but small (21 +/- 24 pmol/l) increase at 7 h after the first injection. In eight subjects a second injection of hPTH-(1-34) was given at 7 h. In these individuals serum 1,25-(OH)2-D levels at 24 h were 40 +/- 14 pmol/l (44%) higher than baseline (P less than 0.01), but were variable over the 24 h period. The present study shows that hPTH-(1-34) produces renal phosphaturic and cyclic-AMP responses in normals similar to those produced by bovine PTH preparations. However, the serum 1,25-(OH)2-D response to one or two intravenous injections of hPTH-(1-34) is small, variable, and inconsistent and, therefore, will not provide a consistent way of stimulating renal 1,25-(OH)2-D secretion.

The vitamin D endocrine system, calcium metabolism, and osteoporosis.

Although the nutritional aspects related to bone development and subsequent bone loss have been appreciated for many years, they are now being reemphasized in view of current information concerning the vitamin D endocrine system, the development of new assay procedures and more sensitive radiologic techniques to assess changes in bone mass, and the realization that clinical problems related to bone loss will increase as individuals live longer. The vitamin D endocrine system is complex, involving the skin, liver, and kidney for synthesis of the vitamin D metabolites and, primarily, the intestine and bone for biologic expression. Numerous factors and disorders affecting the skin, gastrointestinal tract, and kidney will adversely affect vitamin D metabolism. Vitamin D deficiency is common in elderly individuals, especially those who are chronically ill, house-bound, and poorly nourished. Subclinical vitamin D deficiency and osteomalacia may also be complicating problems in elderly patients with osteoporosis and hip fractures. At present the role of the vitamin D endocrine system in the pathogenesis and treatment of osteoporosis is unclear. There is little evidence that vitamin D or its metabolites are helpful in osteoporosis, except perhaps to heal osteomalacia which may be present. It is hoped that encouraging results will follow the use of more potent vitamin D metabolites, either alone or in combination with other agents. Calcium homeostasis is affected by numerous dietary factors (including protein, phosphorus, fiber, and lactose) and drugs (including alcohol, diuretics, and antacids), and calcium absorption in the intestine and the ability to adapt to low-calcium diets will decrease with advancing age. There are conflicting reports concerning the relation between low-calcium intake and osteoporosis, and about the role of calcium intake in the development and then maintenance of bone mass. There is little doubt that many older individuals ingest less calcium than is recommended, especially at a time when even more may be required to maintain bone mass. Several studies show that calcium supplementation producing a total calcium intake of 1,200-1,500 mg/day can slow the rate of bone loss. When the high doses of calcium are given along with vitamin D, periodic monitoring of blood and urine calcium is necessary to avoid hypercalcemia and hypercalciuria.

Gut-mediated hypercalcemia in rabbits bearing VX2 carcinoma: new mechanism for tumor-induced hypercalcemia.

The VX2 carcinoma-bearing rabbit is an animal model for tumor-induced hypercalcemia, thought to be due to increased bone destruction effected by prostaglandin E2. The present experiments suggest that the pathophysiology of the hypercalcemia differs from that previously proposed. Tumor was transplanted intramuscularly into 2.5- to 3-kg male New Zealand White rabbits, which were conditioned to a 1.5% calcium diet and treated with daily subcutaneous injections of dichloromethane diphosphonate (10 mg . kg-1 . day-1), a potent inhibitor of bone resorption, or 0.9% NaCl (2 ml . kg-1 . day -1). The diphosphonate had no significant effect on plasma Ca2+ in either group. After day 31, half the animals of each group were fed a calcium-free diet. This normalized the plasma Ca2+ in each VX2-bearing rabbit within 3 to 4 days but had little effect in control rabbits. In a second series of experiments, VX2-bearing rabbits maintained on standard rabbit chow were treated for 11 days with parenteral indomethacin (30--60 mg/day) or 0.9% NaCl. Although indomethacin normalized the markedly elevated urinary excretion of prostaglandin E2, both treatment groups became severely hypercalcemic. Dietary calcium restriction promptly restored to normal the plasma Ca2+ concentration. In a third series of experiments, rabbits were fed standard rabbit chow and treated with oral indomethacin (40 mg/day) while control-rabbits were pair fed in identical chow. Transplantation of VX2 tumor into both groups caused hypercalcemia. We conclude that the hypercalcemia produced by this tumor strain is indomethacin resistant and dependent on an increase in gastrointestinal calcium absorption, not on skeletal calcium mobilization.

Short-term effects of synthetic human parathyroid hormone-(1--34) administration on bone mineral metabolism in osteoporotic patients.

Since studies in animals and humans have shown that parathyroid hormone can stimulate bone formation and increase trabecular bone, and patients with primary and secondary hyperparathyroidism may exhibit osteosclerosis, we evaluated the effect of short-term administration of human parathyroid hormone, hPTH-(1--34), in patients with osteoporosis. Six patients with osteoporosis underwent detailed studies including blood and urinary measurements of calcium, phosphate, and magnesium; 47Ca kinetic studies; and 18-d balance studies before and during the short-term administration (3--4 wk) of a daily subcutaneous injection of hPTH fragment 1--34 given as 450 or 750 U/dose. The mean fasting plasma calcium values rose slightly after hPTH-(1--34) administration, primarily in the high-dose group. There was no difference in the mean fasting plasma inorganic phosphate levels. The mean daily urinary excretion of calcium and phosphate was significantly increased in patients given the higher dose. In patients given 750 U, net intestinal calcium absorption increased, phosphate absorption increased, calcium balance improved, and phosphate balance improved. In patients given 450 U, calcium balance and phosphate balance worsened. 47Ca kinetic studies showed a minimal increase in bone accretion rate, a decrease in the mean transit time of calcium in the exchangeable pools, and a decrease in the exchangeable-pool size. In all six patients there was an increased renal clearance of 47Ca as a result of hPTH-(1--34) administration. These studies indicate that low doses of parathyroid hormone may promote bone formation, whereas higher doses clearly have an adverse effect on the skeleton.

Deficient production of 1,25-dihydroxyvitamin D in elderly osteoporotic patients.

There is uncertainty about the adequacy of renal secretion of 1,25-dihydroxyvitamin D(1,25-(OH)2-D) in elderly patients with osteoporosis. To investigate this uncertainty, we stimulated secretion of 1,25-(OH)2-D with a 24-hour intravenous infusion of synthetic human parathyroid hormone fragment 1-34 and compared the results in normal young adults and elderly patients with untreated osteoporosis. Serum levels of 1,25-(OH)2-D were similar in both groups (49 +/- 10 and 42 +/- 9 pg per milliliter [116 +/- 24 and 99 +/- 21 pmol per liter]) before the infusion. However, during the 24-hour infusion, serum levels nearly doubled (P less than 0.01) in the normal volunteers but did not change significantly in the patients. Serum ionized calcium increased and serum inorganic phosphate decreased similarly in both groups during the infusion (P less than 0.05). Although the present study does not establish whether deficient 1,25-(OH)2-D secretory reserve is an effect of age or of osteoporosis, it is possible that such a deficiency will explain the inability of elderly osteoporotic patients to adapt to the low-calcium diets common in this age group. If so, this phenomenon may play a part in the pathogenesis of age-related osteoporosis.

Parathyroid hormone and 25-hydroxyvitamin D levels in glucocorticoid-treated patients.

Abnormalities in parathyroid hormone (PTH) secretion or vitamin D action or metabolism have been suggested as pathogenetic factors in the bone disease associated with chronic glucocorticoid therapy. We have found normal plasma PTH values in forty-eight adult asthmatic patients on chronic glucocorticoid therapy, twelve asthmatics treated without glucocorticoids and ten adults on short-term, high-dose glucocorticoid therapy for non-asthmatic illnesses. The mean serum 25-OHD level in the glucocorticoid-treated asthmatics was not significantly different from a disease control group of asthmatic patients not on glucocorticoids, but nine such patients had abnormally low 25-OHD levels. Our results indicate that in asthmatic patients on chronic glucocorticoid therapy: (1) PTH and 25-OHD values are usually normal regardless of dose or duration of therapy and (2) there is a subset of patients with low 25-OHD values which may reflect unusual sensitivity to glucocorticoids.