Positive Bone Balance Research Articles

Effects of a one-year administration of phosphate and intermittent calcitonin on bone-forming and bone-resorbing cells in involutional osteoporosis: A histomorphometric study

The bone histomorphometric effects of intermittent phosphate and calcitonin therapy during 1 year were analyzed in 15 involutional osteoporotic patients. Phosphate was administered continuously (1.5 g/day) and calcitonin was injected during 5 days every third week (50 IU/day). The bone cell response was analyzed in two separate groups, according to the amount of trabecular bone present in the iliac bone biopsy: patients with trabecular bone volume (TBV) beyond the histomorphometric spontaneous fracture threshold (0.16 mm3/mm3) (group 1; 11 patients) and patients with TBV above this threshold (group 2; 4 patients). In group 1, the treatment significantly increased TBV from 0.113±0.025 to 0.156±0.046 mm3/mm3 by thickening the existing trabeculae rather than by creating new trabeculae; stimulation of bone formation rate (+50%) and significant reduction in active trabecular resorption surfaces (from 0.021±0.013 to 0.010±0.006 mm2/mm2;P<.05) may have led to positive bone balance. In group 2, TBV was not changed because of the treatment's relative inefficiency for reducing the bone-resorbing cell activity, leading to likely persistent negative bone balance. Cortical thickness did not change in either group. This study confirms the positive effectiveness of continuous treatment with phosphate and intermittent calcitonin during 1 year on bone balance in involutional osteoporosis with low amount of bone. The lack of response in patients with normal amount of bone must be verified before raising the hypothesis of different bone cell activity and before anticipating the therapeutic response according to local bone mass besides bone remodeling status in osteoporosis.

Effects of a one-year administration of phosphate and intermittent calcitonin on bone-forming and bone-resorbing cells in involutional osteoporosis: a histomorphometric study.

The bone histomorphometric effects of intermittent phosphate and calcitonin therapy during 1 year were analyzed in 15 involutional osteoporotic patients. Phosphate was administered continuously (1.5 g/day) and calcitonin was injected during 5 days every third week (50 IU/day). The bone cell response was analyzed in two separate groups, according to the amount of trabecular bone present in the iliac bone biopsy: patients with trabecular bone volume (TBV) beyond the histomorphometric spontaneous fracture threshold (0.16 mm3/mm3) (group 1; 11 patients) and patients with TBV above this threshold (group 2; 4 patients). In group 1, the treatment significantly increased TBV from 0.113 +/- 0.025 to 0.156 +/- 0.046 mm3/mm3 by thickening the existing trabeculae rather than by creating new trabeculae; stimulation of bone formation rate (+ 50%) and significant reduction in active trabecular resorption surfaces (from 0.021 +/- 0.013 to 0.010 +/- 0.006 mm2/mm2; P less than .05) may have led to positive bone balance. In group 2, TBV was not changed because of the treatment's relative inefficiency for reducing the bone-resorbing cell activity, leading to likely persistent negative bone balance. Cortical thickness did not change in either group. This study confirms the positive effectiveness of continuous treatment with phosphate and intermittent calcitonin during 1 year on bone balance in involutional osteoporosis with low amount of bone. The lack of response in patients with normal amount of bone must be verified before raising the hypothesis of different bone cell activity and before anticipating the therapeutic response according to local bone mass besides bone remodeling status in osteoporosis.

Results of a stimulatory therapy of low bone metabolism in osteoporosis with (1-38)hPTH and diphosphonate EHDP. Protocol of study I, osteoporosis trial Hannover.

In contrast to prevention, the therapy of manifest osteoporosis remains a clinically significant problem. So far all therapeutic attempts have yielded unsatisfying results. For this reason we have tried to achieve a positive bone balance by sequential stimulation and inhibition of the osseous metabolism. The therapy consisted of six 14-day courses with 400 units (1-38)hPTH per day and, in addition, starting with the 2nd week of PTH therapy, EHDP 5 mg per kg body weight per day for a total of 2 weeks. Already the initial therapeutic course resulted in a stimulation of decreased bone metabolism which could be documented by an increase in the calcium-47 accretion rate (six patients). An increase of the alkaline phosphatase could be noted (four patients); this, however, did not correlate with the calcium accretion. A positive calcium balance could, nonetheless, only be attained in four of eight patients within this period, while neither the alkaline phosphatase nor the kinetics would allow a prediction of this effect. Changes of the balance coincided with equal changes in the net calcium absorption. The urinary calcium excretion increased temporarily during the therapeutic phase. We were not able to detect an influence on the vitamin D metabolites. Histomorphometric studies did not demonstrate an increase in bone mass in the iliac creast after six therapeutic courses. Nevertheless, progressive deformations of vertebral bodies did not occur. We conclude that already after 2 weeks this therapeutic concept can lead to a stimulation of bone metabolism.

Induction of de novo bone formation in the beagle. A novel effect of aluminum.

To define the primary effects of aluminum on bone in the mammalian species, we examined the dose/time-dependent actions of aluminum in normal beagles. Administration of low dose aluminum (0.75 mg/kg) significantly elevated the serum aluminum (151.7 +/- 19.9 micrograms/liter) compared with that in controls (4.2 +/- 1.35 micrograms/liter) but did not alter the calcium, creatinine, or parathyroid hormone. After 8 wk of therapy, bone biopsies displayed reduced bone resorption (2.6 +/- 0.63 vs. 4.5 +/- 0.39%) and osteoblast covered bone surfaces (2.02 +/- 0.51 vs. 7.64 +/- 1.86%), which was indicative of low turnover. In contrast, prolonged treatment resulted in increased bone volume and trabecular number (38.9 +/- 1.35 vs. 25.2 +/- 2.56% and 3.56 +/- 0.23 vs. 2.88 +/- 0.11/mm) which was consistent with uncoupled bone formation. Administration of higher doses of aluminum (1.20 mg/kg) increased the serum aluminum further (1242.3 +/- 259.8 micrograms/liter) but did not affect calcium, creatinine, or parathyroid hormone. However, after 8 wk of treatment, bone biopsies displayed changes similar to those after long-term, low-dose therapy. In this regard, an increased trabecular number (3.41 +/- 0.18/mm) and bone volume (36.5 +/- 2.38%) again provided evidence of uncoupled bone formation. In contrast, in this instance poorly mineralized woven bone contributed to the enhanced bone volume. High-dose treatment for 16 wk further enhanced bone volume (50.4 +/- 4.61%) and trabecular number (3.90 +/- 0.5/mm). These observations illustrate that aluminum may stimulate uncoupled bone formation and induce a positive bone balance. This enhancement of bone histogenesis contrasts with the effects of pharmacologic agents that alter the function of existing bone remodeling units.

Kinetics of trabecular bone resorption and formation in hypothyroidism: Evidence for a positive balance per remodeling cycle

Using a recently described model for reconstruction of the entire remodeling sequence in trabecular bone after tetracycline double labeling, bone remodeling was investigated in 18 hypothyroid female patients and 11 age- and sex-matched controls. In the hypothyroid group, the final resorption depth was reduced to 42 μm vs 53 μm in the control group ( P < 0.01). The total resorption period was increased to 76 days vs 32 days in the control group ( P < 0.001), and the resorption rate was lowered to 0.8 μm/ day vs 2.1 μm/day in the control group ( P < 0.001). The function period for preosteoblast-like cells was 22 days compared to 14 days in normals ( P < 0.05). The total bone formation period was prolonged to 620 days in the hypothyroid group compared to 151 days in the control group ( P < 0.001), and the matrix and mineral appositional rates were lowered to 0.7 and 0.5 μm 3/μm 2 per day compared to 1.8 ( P < 0.001) and 1.4 ( P < 0.001) μm 3/ μm 2 per day, respectively. The mineralization lag time in the hypothyroid group was 48 days vs 25 days in the control group ( P < 0.001), and at the start of bone formation this difference was even more pronounced (63 and 16 days, respectively, P < 0.001). The mean completed wall thickness was increased in the hypothyroid group to 59.5 μm compared to 54 μm in the control group ( P < 0.001). This, combined with the decrease in amount of bone removed during resorption, creates a significant positive balance ( P < 0.001) between resorption and formation per remodeling cycle of +16 μm. No difference in trabecular bone volume could, however, be demonstrated between the two groups. The number of new remodeling cycles initiated per day at any site on the trabecular bone surface was 4 × 10 −4 day −1 in the hypothyroid group and 14.5 × 10 −4 day −1 in controls ( P < 0.001). The data presented in this paper demonstrate that hypothyroidism decreases recruitment, maturation, and activity of bone cells, leading to decreased bone resorption and bone formation per unit time. The end result is a reduction in final resorption depth and an increase in the thickness of bone laid down, leading to a positive bone balance. Due to the decreased birth rate of remodeling cycles, however, a significant increase in trabecular bone volume could not be demonstrated during the time span over which these patients were studied.

Vitamin D, hydroxyapatite, and calcium gluconate in treatment of cortical bone thinning in postmenopausal women with primary biliary cirrhosis

Women with primary biliary cirrhosis malabsorb calcium, phosphate and vitamin D, and develop accelerated cortical bone thinning. We have assessed the value of parenteral vitamin D, oral hydroxyapatite (HA), and calcium gluconate (CG) in the treatment of cortical bone thinning in primary biliary cirrhosis. Sixty-four postmenopausal women with primary biliary cirrhosis were assigned randomly into three groups: one group receiving no mineral supplements (control), one group receiving HA, and one group receiving CG. All patients received parenteral vitamin D2 (100,000 IU monthly). Eleven patients withdrew from the study and 10 withdrew due to poor compliance (six HA, four CG). Over a 14-month follow-up period, none of the groups showed a significant change in serum calcium or inorganic phosphate levels. Pre- and posttreatment hand radiographs were used to assess changes in metacarpal cortical thickness using the technique of caliper radiogrammetry. Cortical bone loss occurred in the control group (p < 0.01). The HA group showed a significant gain in cortical bone thickness (p < 0.01), while no significant change occurred in the CG group. This study indicates that vitamin D2 does not halt metacarpal cortical bone thinning in primary biliary cirrhosis. The addition of CG prevents bone thinning, and HA promotes positive cortical bone balance.

Physiology and Pathology of Bone Remodeling: Cellular Basis of Bone Structure in Health and in Osteoporosis

Physiology and Pathology of Bone Remodeling: Cellular Basis of Bone Structure in Health and in Osteoporosis

Coherence Treatment of Osteoporoses

SUMMARY No agent yet found when given continuously to the intact, temporally incoherent adult human skeleton can store in it progressively increasing amounts of bone. BMU theory plus clinical observation suggest that such failure derives from approximately equal effects of such agents on both resorptive and formative activity, partly by affecting the naturally coupled activities of already existing osteoclast and osteoblast populations in BMU and partly by affecting BMU activation. However, the BMU theory also suggests that special sequences of therapeutic manipulations can create a positive bone balance in repeatable increments. One such proposal, called the ADFR sequence, involves first briefly pulsing BMU activation. The resorptive and formative activities created by that pulse will occur in step but at predictably different times, that is, they become temporally coherent. Depressing the coherent resorption with a suitable agent during its lifetime, then freeing the skeleton of treatment during the following coherent osteoblastic activity should cause BMU to deposit normal amounts of new bone in smaller than normal holes, resulting in a net surplus or increment. Repeating the sequence should add further increments. Other manipulations of coherent bone cell populations could remove bone or simply alter its turnover speed, as desired. Thus, special sequences of simple pharmacologic actions that have no useful ultimate effects upon global bone balance when delivered continuously and alone to the incoherent skeleton could create a simple new kind of therapy in the coherent skeleton. The concept of manipulating deliberately induced coherent states for therapeutic purposes should generalize to the treatment of many other tissues, cells, and organs that have the requisite properties. Accepting the encouragement provided by early human and animal trials of the idea, time will tell whether it will join numerous disappointing predecessors reviewed elsewhere in this issue or if it will indeed mark a turn away from them toward a more fruitful approach to treatment and prevention.

The action of the main therapeutic regimes on paget's disease of bone, with a note on the effect of vitamin d deficiency

AbstractThe effect of vitamin D deficiency was studied in 3 patients with Paget's disease of bone. The biochemical parameters of bone turnover strikingly increased, while the pagetic bone became radiolucent. This occurred whether the nonpagetic bones were osteomalacic or not. All the observed changes were reversed upon correction of the deficiency. The effects of mithramycin and calcitonin on the biochemical parameters of bone turnover were compared sequentially in three cases. No treatment proved definitely superior in this regard. The effectiveness of calcitonin to induce a positive focal bone balance in osteolytic Paget's disease was studied radiologically and compared to the effects of the diphosphonate EHDP, and to the combined therapy of EHDP and calcitonin. Calcitonin showed a constructive action in 100% of the cases. EHDP, administered at low dosages (7.0 mg/kg/24 hr during a period of 7.4 months) did not demonstrate a uniformly constructive action in any patient. Radiolucent lesions appeared in 56%, “dissociated” effects (both a constructive and a destructive action) were seen in 33%, and no effect in 11% of the cases. Combined therapy was intermediate in its action between calcitonin and EHDP. After discontinuation of combined therapy, an EHDP‐like effect was often apparent.

PATHOGENESIS AND NATURAL COURSE OF PRIMARY OSTEOPOROSIS

A new concept of the pathogenesis and natural course of osteoporosis is described, based on histomorphometric evaluation of iliac crest bone biopsies of 108 patients with untreated primary osteoporosis. It is suggested that primary osteoporosis spontaneously runs a three-phase course: during the initial period of negative bone balance, bone mass falls below the normal range; during the second phase bone mass remains consistently below age-related normal values; in the third phase restitution of osteoporosis is introduced by a positive bone balance. It is suggested that only about a quarter of patients with a skeletal mass below the age-related normal range have true primary osteoporosis; the remaining three-quarters may have secondary forms of osteoporosis where the underlying disease responsible for the bone loss had been missed before the osteoporosis was diagnosed.

Treatment of Osteoporoses by Manipulation of Coherent Bone Cell Populations

Up to and including the year 1979, no agent, combination of agents or other treatment has been found which, when given continuously to the intact incoherent adult human skeleton, can store in it clinically useful amounts of bone in a way which can continue with continued treatment. BMU theory suggests that failure derives from a depression by such treatments of both resorptive and formative activity, partly by depressing the naturally coupled activities of already existing 'clast and 'blast populations, and partly by reducing BMU activation. However BMU theory also suggests that selected agents given in special sequences can create a positive bone balance in repeatable increments. One such proposal, called the ADFR sequence, involves generating a pulse of increased BMU activations. The resorptive and formative activities created by that pulse will occur at predictably different periods of time, that is, they will prove coherent. By depressing the coherent resorption with a suitable agent during its lifetime, and then freeing the skeleton of treatment during the following coherent osteoblastic activity one stores an increment of new bone, because the ADF sequence causes remodeling BMU to deposit normal amounts of new bone in smaller than normal holes. The sequence is repeated as often as needed to add further increments. Other manipulations of coherent bone cell populations could remove bone or simply alter its turnover speed, as desired. Thus special sequences of simple pharmacologic actions, which have no useful ultimate effects upon global bone balance when delivered continuously and alone to the incoherent skeleton, create a simple new kind of therapy which should (and did) exert dramatic (and probably repeatably incrementable) effects in the coherent skeleton. The concept of manipulating deliberately induced coherent skeletal states for therapeutic purposes would not appear to depend for its success upon any one or 2 or even 3 special drugs.

Osteomalacic New Bone Formation during Chemotherapy of Acute Granulocytic Leukemia

The development of a rapid rate of regeneration of osteomalacic bone in a patient treated for acute granulocytic leukemia has been demonstrated for the first time. This positive bone balance was most intense at the time of maximal depletion of leukemic tissue. The authors postulate that new formation of osteomalcic bone is due to inability to maintain the rate of calcification parallel to that of bone formation. A similar abnormality occurs in egg-laying birds, in rapidly growing children on a diet suboptimal in vitamin D who have rickets, and in some patients with osteoblastic metastases.

The Direction of Transverse Drift of Actively Forming Osteons in Human Rib Cortex

In this paper the direction of transverse drift of those actively forming osteons which show drift was quantitated with respect to: (1) per cent drifting toward the marrow cavity, (2) per cent drifting toward periosteum, and (3) per cent drifting intermediately. It was found that approximately 71 per cent of all drifting osteons drift toward the marrow cavity. This value was not related to age or sex. On the basis of these results it was postulated that some agent in the marrow cavity favors a negative cortical endosteal bone balance, that some agent at the periosteal surface favors a positive periosteal bone balance, or that both factors are involved.