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PubMed2004

Gamma interferon (IFN-gamma) and IFN-gamma-inducing cytokines interleukin-12 (IL-12) and IL-18 do not augment infection-stimulated bone resorption in vivo.

Periapical granulomas are induced by bacterial infection of the dental pulp and result in destruction of the surrounding alveolar bone. In previous studies we have reported that the bone resorption in this model is primarily mediated by macrophage-expressed interleukin-1 (IL-1). The expression and activity of IL-1 is in turn modulated by a network of Th1 and Th2 regulatory cytokines. In the present study, the functional roles of the Th1 cytokine gamma interferon (IFN-gamma) and IFN-gamma-inducing cytokines IL-12 and IL-18 were determined in a murine model of periapical bone destruction. IL-12-/-, IL-18-/-, and IFN-gamma-/- mice were subjected to surgical pulp exposure and infection with a mixture of four endodontic pathogens, and bone destruction was determined by microcomputed tomography on day 21. The results indicated that all IL-12-/-, IL-18-/-, and IFN-gamma-/- mice had similar infection-stimulated bone resorption in vivo as wild-type control mice. Mice infused with recombinant IL-12 also had resorption similar to controls. IFN-gamma-/- mice exhibited significant elevations in IL-6, IL-10, IL-12, and tumor necrosis factor alpha in lesions compared to wild-type mice, but these modulations had no net effect on IL-1alpha levels. Recombinant IL-12, IL-18, and IFN-gamma individually failed to consistently modulate macrophage IL-1alpha production in vitro. We conclude that, at least individually, endogenous IL-12, IL-18, and IFN-gamma do not have a significant effect on the pathogenesis of infection-stimulated bone resorption in vivo, suggesting possible functional redundancy in proinflammatory pathways.

Animals↗
PubMed1998

Detection of an inhibiting activity for osteoclast bone resorption from human prostatic cancer cells.

An inhibiting activity for isolated osteoclasts and bone resorption was demonstrated in culture supernatants from androgen-independent, but not androgen-dependent, human prostatic cancer cell lines. It causes a dose-dependent osteoclast inhibition as quantified with a bone resorbing pit formation assay. The constitutively released activity was determined to be protein (>50 kDa) distinct from some of the known cytokines in bone resorption. The activity does not affect osteoclast morphology and viability. Time-lapse video microscopy revealed an osteoclast motility increase, disrupting their anchorage to the bone and resorbing processes. The association of the activity with androgen-independent cancer cells that disrupt bone remodeling is discussed.

Androgens↗
PubMed1997

Quantitation of biochemical markers of bone resorption following strontium-89-chloride therapy for metastatic prostatic carcinoma.

UNLABELLED: The urinary production of pyridinium collagen cross-links, pyridinoline (PYD) and deoxypyridinoline (DPD), has been correlated to increased bone resorption in patients with neoplasms. This study investigated the production of these compounds in patients with metastatic prostate carcinoma who received palliative treatment that did and did not include 89Sr-chloride therapy. METHODS: Urinary production of PYD and DPD was measured by high-performance liquid chromatography and natural flucrescence detection methods. The urine from several age-matched groups of patients was examined for these compounds including healthy controls (n = 20), patients with early-stage (Stage A-B) prostate carcinoma (n = 8), patients with metastatic prostate carcinoma treated with conventional analgesic and radiotherapeutic palliation (n = 20), patients with metastatic disease who underwent 89Sr-chloride therapy (n = 20) and patients with mild Paget's disease (n = 5). Patients were also monitored for urinary PYD and DPD production for a 6-mo interval after a palliative intervention. RESULTS: Elevated PYD and DPD (p < 0.05) concentrations were measured in patients with metastatic and nonmetastatic prostate cancer and Paget's disease. The urinary production of these compounds remained unchanged for 6 mo after 89Sr-chloride therapy for symptomatic osseous metastases. However, the patients who did not undergo 89Sr-chloride therapy exhibited a two-fold increase in PYD and a four-fold increase in DPD above controls during the interval. CONCLUSION: PYD and DPD are sensitive and specific bone resorption markers which demonstrate a slowing of bone resorption after palliative 89Sr-chloride therapy in patients with bone metastases.

Aged↗
PubMed1980

Prostaglandins as mediators of bone resorption in renal and breast tumours.

Amounts of prostaglandin E and prostaglandin F have been measured by radioimmunoassay in extracts of renal cortical carcinoma and benign and malignant breast tumours after solvent extraction and column chromatography. 2. Substantial amounts of prostaglandin E were found in extracts of benign and malignant breast tumours and in renal tumours. Much lower amounts of prostaglandin F were present in all tumour types. 3. Co-cultivation of tumour explants with mouse calvaria led to significant bone resorption in 10 of 13 renal carcinomas, three of eight malignant breast tumours, and two of nine benign breast tumours. Tumours associated with bone resorption had higher concentrations of prostaglandin E in culture media at the end of incubation than did non-resorbers. 4. Indomethacin (14 mumol/1) greatly reduced bone resorption in the presence of the tumour, but this was not always complete, particularly with breast tumours. Indomethacin had no effect on prostaglandin-induced bone resorption. Theophylline (2.2 mmol/1) significantly increased prostaglandin E production and resorption by an effect on the tumour. 5. It is concluded that prostaglandins may be important in mediating the effects of renal cortical carcinoma and possibly breast cancer on bone destruction. A non-prostaglandin mechanism may also contribute to bone destruction by breast carcinoma.

Animals↗
PubMed1992

Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia.

Osteoclastic activity is increased in tumor-associated hypercalcemia, which, thus, constitutes an excellent opportunity to assess new markers of the bone resorption rate. We have measured the fasting urinary excretion of the pyridinium cross-links pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) in 36 hypercalcemic cancer patients (mean +/- SD, 3.2 +/- 0.4 mmol/L for total serum Ca and 1.66 +/- 0.24 mmol/L for Ca2+). Thirty-two of them were reevaluated after treatment with iv bisphosphonates. Urinary Pyr and D-Pyr levels were higher than those in healthy controls (130 +/- 62 vs. 40 +/- 19 nmol/mmol creatinine for Pyr and 20 +/- 15 vs. 6 +/- 3 nmol/mmol creatinine for D-Pyr; P less than 0.001 for both). This represented a mean 3.3-fold increase over the normal mean compared to 5.8- and 3.4-fold increases for fasting urinary Ca and hydroxyproline, respectively. Individual values were elevated in 83% and 75% of the cases for Pyr and D-Pyr compared to 97% and 83% for urinary Ca and hydroxyproline, respectively. The levels of Pyr and D-Pyr tended to be higher in patients with head and neck tumors than in patients with breast cancer. Urinary Pyr and D-Pyr correlated with each other (r = 0.72; P less than 0.001) and were highly correlated with hydroxyproline (r = 0.68 and 0.83, respectively; P less than 0.001 for both), but poorly correlated with urinary Ca (r = 0.21; P = NS and r = 0.42; P = 0.01, respectively), suggesting that these markers reflect different events of bone resorption. Similarly, after bisphosphonate therapy, urinary Pyr and D-Pyr levels fell by 31% and 50%, respectively, compared to 38% for hydroxyproline and 76% for urinary Ca. There was a significant correlation between posttreatment D-Pyr and serum Ca levels (r = 0.43; P less than 0.05). In summary, we found that the urinary excretion of Pyr and D-Pyr was markedly increased in hypercalcemic cancer patients and was adequately lowered by bisphosphonate therapy. The urinary excretion of the pyridinium cross-links, especially D-Pyr, should be helpful to specifically quantitate bone matrix resorption and monitor the inhibition of bone resorption in cancer patients receiving antiosteolytic drugs.

Amino Acids↗
PubMed1999

Studies on disease-modifying antirheumatic drugs. III. Bone resorption inhibitory effects of ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate (TAK-603) and related compounds.

In the course of our studies aimed at obtaining new drugs for treatment of bone and joint diseases, chemical modification of the potent bone resorption inhibitors justicidins, was performed and various naphthalene lactones, quinoline lactones and quinoline derivatives bearing an azole moiety at the side chain were prepared. Their inhibitory effects on bone resorption were evaluated by Raisz's method, and several compounds, including ethyl 4-(3,4-dimethoxyphenyl)-6,7-dimethoxy-2-(1,2,4-triazol-1-ylmeth yl)quinoline -3-carboxylate (6c, TAK-603), were found to have activities comparable with or superior to the justicidins. The 4-(3-isopropoxy-4-methoxy)-phenyl derivative (6d), in particular, displayed a marked increase in potency. TAK-603 and compound 6d were very effective in preventing osteoclast formation and bone resorption by mature osteoclasts. Further, TAK-603 was shown to be effective in preventing bone loss in ovariectomized mice.

Animals↗
PubMed1981

Bone resorption and prostaglandin production by mouse calvaria in vitro: response to exogenous prostaglandins and their precursor fatty acids.

Mouse calvaria were maintained in organ culture for 96 h and endogenous prostaglandin production and active bone resorption (45Ca release) measured. After a lag phase of 12 h, active resorption increased over the 96 h period. The amounts of prostaglandins released into the culture medium (measured by radioimmunoassay) were highest in the first 24 h of culture. Unless these were removed by preculturing for 24 h, or suppressed by indomethacin, no response to exogenous PGE2, or prostaglandin precursors could be demonstrated. Bone resorption was stimulated after preculture by both PGE2 and PGF2 alpha in a dose-dependent manner (10-8M-10-5M), with PGE2 being the more potent. Collagen synthesis was unaffected by PGF2 alpha, whereas PGE2 (10-5M) had an inhibitory effect. Eicosatrienoic acid did not stimulate bone resorption at lower concentrations (10-7M-1-5M), but was inhibitory at 10-4M. Arachidonic acid also inhibited resorption at 10-4m, but at lower concentrations (10-7M-10-5M) increased active resorption. This was concomitant with a rise in PGE2 and PGF2 alpha levels, PGE2 production being significantly higher than PGF2 alpha. The effects of PGE2 (10-8M) and PGF2 alpha (10-8M) appeared additive; there was no evidence of synergistic or antagonistic effects when varying ratios of PGE2: PGF2 alpha were employed.

Animals↗
PubMed1983

Direct measurements of basal bone resorption in microphthalmic mice in vivo.

Microphthalmic mice and their normal littermates were prelabeled extensively in utero with 3H-tetracycline and 3H-proline, or with 45Ca alone. The loss of 3H-tetracycline and 3H-collagen from whole femur was measured from birth to 24 days of age at weekly intervals to determine bone resorption of mineral and matrix in vivo. The ratio of blood 45Ca specific activity to that of bone (blood/bone ratio) was used to reflect the interrelationship between bone, blood, and dietary calcium, as well as bone resorption. There was little, if any, loss of 3H-tetracycline and 3H-collagen from bones of the microphthalmic mutants whereas there was a marked and continuous loss (67 and 51%, respectively) from bones of the normal littermates due to normal bone modeling. Blood/bone ratio was much lower in the mutants (42-70%) compared with the normals, suggesting that blood calcium is maintained by diet. These data provide direct evidence that basal bone resorption in growing microphthalmic mice was almost completely inhibited.

Animals↗
PubMed1993

Local bone injections of LPS and M-CSF increase bone resorption by different pathways in vivo in rats.

We investigated the local in vivo action of lipopolysaccharide (LPS), a potent monocyte activator, and of macrophage colony-stimulating factor (M-CSF), a hemopoietic growth factor influencing monocyte differentiation, on bone resorption in normal female 8-wk-old rats. LPS (2 injections of 0.5 microgram), M-CSF (2 injections of either 12.5, 25, 100, or 500 ng), or vehicle was injected into bone marrow space through a thin catheter implanted, under hydrochloride anesthesia, in the distal end of the right femur. Histomorphometry was performed after staining of the tartrate-resistant acid phosphatase (TRAP). The number of osteoclasts and of TRAP-positive marrow cells (considered as osteoclast precursors) were counted in the secondary spongiosa. LPS caused a 3-fold increase in osteoclast surface, a 4.5-fold increase in the number of osteoclasts, but no change in the number of TRAP-positive marrow cells. M-CSF induced a striking dose-dependent biphasic effect on the number of TRAP-positive marrow cells and on bone resorption (no change with the lowest or with the highest concentrations, although the two intermediate doses significantly increased resorption surfaces and the number of osteoclasts). Our results demonstrate a local in vivo effect of LPS and of M-CSF on bone resorption and suggest that these substances act at different stages of osteoclast development and function.

Acid Phosphatase↗
PubMed1998

Prostaglandin-independent stimulation of bone resorption in mouse calvariae and in isolated rat osteoclasts by thyroid hormones (T4, and T3).

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), were found to enhance both neonatal mouse calvarial bone resorption and pit formation on bovine slices by isolated rat osteoclasts. Dosage-dependent release of 45Ca from mouse calvarial bones was observed after 120 hr of culture with 10(-6)-10(-8) MT4 and 10(-6)-10(-10) M T3. Maximum treatment/control ratios of 45Ca release were recorded for 10(-7) M T4 and 10(-8) MT3. Inhibition of 45Ca release stimulated by 10(-8) M T3 was observed in the presence of 30 nM salmon calcitonin at 48 hr and 120 hr of culture with no indication of "escape" by T3-treated bones. In contrast, stimulation of 45Ca release from mouse calvarial bones by 10(-7) MT4 and 10(-8) MT3 was not inhibited by 10(-6) M indomethacin. Formation of PGE2 and PGI2 (evaluated by measuring 6-keto-PGF1alpha) by mouse calvariae was also not increased by 10(-8) MT3 after 120 hr of culture. Furthermore, no increases in cAMP formation were observed in calvarial bone cultures after either 10 min or 24 hr of exposure to 10(-8) MT3. However, significant inhibition of 45Ca release stimulated by 10(-8) M T3 was found at 120 hr in the presence of 10(-3) M hydroxyurea. When isolated rat osteoclasts were cultured in the presence of 10(-7) MT3, a 1.4-fold stimulation of pit number was observed. Pit formation was not affected by addition of 10(-6) M indomethacin to either the control or T3-treated cultures. These data suggest that the stimulation of bone resorption in neonatal mouse calvariae and activation of isolated rat osteoclasts by the thyroid hormones is not related to either prostaglandin or cAMP formation. In mouse calvariae, the effect on bone resorption of the thyroid hormones is dependent on increased cellular replication, perhaps of osteoclast precursors, or other bone cells involved in the resorptive process.

6-Ketoprostaglandin F1 alpha↗
PubMed2004

Lowering dietary protein to U.S. Recommended dietary allowance levels reduces urinary calcium excretion and bone resorption in young women.

High-protein diets increase calciuria. No previous studies have examined the ad libitum U.S. diet's effect on calciuria or bone resorption.Thirty-nine healthy, premenopausal women consuming ad libitum diets [mean, 1.1 g/kg protein, 819 mg (20.5 mmol) Ca, 1152 mg (37 mmol) P, 129 mmol Na] were switched to isocaloric diets containing the U.S. recommended dietary allowance (RDA) of protein (0.8 g/kg) and similar amounts of calcium, phosphorus, and sodium. Bone resorption and related endpoints were assessed before and 1 wk after the switch. As dietary protein changed from ad libitum to RDA levels, mean urine nitrogen decreased 26% (2.4 g/d; P < 0.001) and mean blood urea nitrogen decreased 15% (1.9 mg/dl; P < 0.001). Mean urine pH increased from 6.3 to 6.8 (P < 0.001), and net renal acid excretion (NRAE = urine ammonium plus titratable acids minus bicarbonate) decreased 68% (21.4 mEq/d; P < 0.001). Mean urinary calcium decreased 32% [42 mg (1 mmol)/d; P < 0.001], and bone resorption urine N-telopeptides) decreased 17% (74 micromol bovine collagen equivalents/d; P < 0.001). Mean serum calcium, PTH, and 1,25 dihydroxy vitamin D remained unchanged. In this 2-wk study, decreasing dietary protein from ad libitum to RDA levels decreased NRAE, calciuria and estimates of bone resorption, suggesting that decreased U.S. protein consumption might reduce bone loss. Inasmuch as other dietary modifications, such as increasing vegetable and fruit intake, can result in sustained reductions in NRAE without reducing protein intake, the advisability of reducing protein intake for skeletal protection from acid attack requires further investigation.

Acids↗
PubMed2001

Acid attack and cathepsin K in bone resorption around total hip replacement prosthesis.

Normal bone remodeling and pathological bone destruction have been considered to be osteoclast-driven. Osteoclasts are able to attach to bare bone surface and produce an acidic subcellular space. This leads to acid dissolution of hydroxyapatite, allowing cathepsin K to degrade the organic type I collagen-rich osteoid matrix under the acidic condition prevailing in Howship lacunae. Using a sting pH electrode, the interface membrane around a loosened total hip replacement prosthesis was found to be acidic. Confocal laser scanning disclosed irregular demineralization of the bone surface in contact with the acidic interface. Cathepsin K, an acidic collagenolytic enzyme, was found in interface tissue macrophages/giant cells and pseudosynovial fluid. Tissue extracts contained high levels of cathepsin K messenger RNA (mRNA) and protein. These observations suggest the presence of an acid- and cathepsin K-driven pathological mechanism of bone resorption, mediated not by osteoclasts in subosteoclastic space, but rather by the uncontrolled activity of macrophages in extracellular space.

Acids↗
PubMed1990

Effects of vitamin D-binding protein on bone resorption stimulated by 1,25 dihydroxyvitamin D3.

Vitamin D and its metabolites are tightly bound to the serum vitamin D-binding protein (DBP) and only the free hormone is considered to be physiologically active. On the other hand, DBP could interact with cell membranes and even favor its intracellular entry. The present study was undertaken to examine the effects of DBP on bone resorption stimulated by 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. Forelimb bones from 19-day-old fetal rats were cultured for 5 days in the presence of purified human or rat serum albumin (hSAP or rSAP) and 1,25(OH)2D3, with or without human or rat DBP (hDBP or rDBP). Bone resorption was assessed by measuring the release of previously incorporated 45Ca. We found that the resorptive response to 1,25(OH)2D3 was minimally altered by hDBP (5 microM). The minimal effects of hDBP on 1,25(OH)2D3 activity on rat bones might be explained by a 6-fold lower affinity of hDBP (1.1 x 10(7) M-1) than rDBP (5.9 x 10(7) M-1) for 1,25(OH)2D3 or by species differences in cellular recognition of DBP. In a homologous rat system, however, rDBP at low (0.5 microM) or physiological (5 microM) concentration significantly decreased 1,25(OH)2D3-induced bone resorption. These data therefore support the hypothesis that free rather than DBP-bound 1,25(OH)2D3 is physiologically important.

Animals↗
PubMed2004

Relationship between bone resorption and adrenal sex steroids and their derivatives in oophorectomized women.

OBJECTIVE: To clarify the role of adrenal sex steroids and their derivatives on bone resorption in oophorectomized women. DESIGN: Cross-sectional study. SETTING: Department of Obstetrics and Gynecology, Graduate School of Medical Sciences, Kyushu University. SUBJECT(S): Forty-eight women who were within one year of bilateral oophorectomy were recruited for this study. INTERVENTION(S): None of the subjects were treated with the drugs affecting bone metabolism. MAIN OUTCOME MEASURE(S): Urinary deoxypyridinoline (Dpyr) as marker of bone resorption and serum DHEAS, androstenedione (A-dione), testosterone (T) and estrone (E1) levels as adrenal sex steroids and their derivatives. RESULT(S): There was an inverse correlation between urinary Dpyr and serum concentrations of E1, DHEAS, or A-dione. There was no significant relationship between urinary Dpyr and T. CONCLUSION(S): These results suggest that adrenal steroids and their derivatives may influence the bone resorption in oophorectomized women.

Adult↗
PubMed1986

Osteoporosis and mandibular bone resorption in the Sprague Dawley rat.

Mandibular bone resorption in normal and osteoporotic rats was measured using standard scintillation techniques for tritiated tetracycline (H3-TC). Thirty-four Sprague-Dawley rats were labeled with H3-TC at 4-9 weeks of age. Ten animals were then sacrificed for baseline radioactivity levels, while 12 experimental animals were given a high protein, low calcium diet, and 12 control animals were given a normal calcium diet. Osteoporotic and normal diets were instituted for 90 days. The results show a significant reduction in the quantity of bone in the experimental group (P less than .05) as compared to the control group. In addition, serum samples collected were found to contain significantly elevated (P less than .01) alkaline phosphatase level in the experimental group when compared to the control group.

Alkaline Phosphatase↗
PubMed2001

Bone resorption in post-menopausal women with normal and low BMD assessed with biochemical markers specific for telopeptide derived degradation products of collagen type I.

Biochemical markers of bone resorption can be used clinically to predict the risk of osteoporosis-related fractures (prognostic tool) and to assess the response of an osteoporotic patient to an antiresorptive therapy (monitoring tool). Our aim was to assess the ability of four currently marketed biochemical markers of bone resorption, based on the measurement of degradation products from collage type I telopeptides to monitor the elevated resorption associated with menopause. Women (846) were stratified for menopause, age, and bone mineral density and the following markers were measured: urinary cross-linked N-telopeptides of type I collagen (NTx), the levels of breakdown products of type I collagen C-telopeptides in serum (S-CTx), and in urine, by ELISA (U-CTx-E), and RIA (U-CTx-R). Furthermore, the ratio (alpha/beta) between the alphaL form of CTx measured in the CTx RIA and the betaL form measured in the ELISA was calculated. The mean difference was calculated for each marker in women with osteopenia (Op) or osteoporosis (PMO) (WHO definition) compared with healthy premenopausal (Pre) women and postmenopausal (N Post) women with normal bone mass. Serum CTx showed the highest elevation in post- compared with premenopausal women. All marker values were significantly higher in Op and PMO subjects compared with both Pre and to N Post women. Compared with premenopausal values, the largest elevation in both Op and PMO women was observed for serum CTx. Compared with N Post, urine NTx showed the highest increase in OP subjects. The alpha/beta CTx ratio was elevated in post- compared with Pre women, but there was no difference in the ratio among N Post, Op, or PMO women. In conclusion, postmenopausal women showed elevated turnover with all bone resorption markers, but with substantial individual variation in resorption levels. Furthermore, the turnover process in postmenopausal women appears to be quantitatively different from the premenopausal stage, apparent as altered alpha/beta CTx ratios.

Adult↗
PubMed1992

Bone resorption by cells isolated from rheumatoid synovium.

Cellular mechanisms accounting for the osteolysis of rheumatoid erosions are poorly understood. Cells were isolated and characterised from the synovium of 16 patients with rheumatoid arthritis (RA) and four patients with osteoarthritis and their ability to resorb bone was assessed using a scanning electron microscope bone resorption assay. Macrophages were the major cell type isolated from the synovium of patients with RA. These produced extensive roughening of the bone surface without resorption pit formation. This low grade type of bone resorption was not affected by systemic (calcitonin, parathyroid hormone, 1,25-dihydroxyvitamin D3) or local (interleukin 1, prostaglandin E2) factors influencing bone resorption. Macrophage mediated bone resorption differs qualitatively and quantitatively from that of osteoclasts but is likely to play an important part in the development of marginal erosions in RA.

Adult↗
PubMedDate not supplied

Inhibition of bone resorption by difluoromethylene diphosphonate in organ culture.

A newly synthesized diphosphonate, difluoromethylene diphosphonate (F2MDP), was studied for its effects on bone resorption, as measured by the release of previously incorporated 45Ca. F2MDP (10 microM to 1000 microM) effectively inhibited both unstimulated and parathyroid hormone-stimulated resorption, and the amount of 45Ca release decreased with time. Dichloromethylene diphosphonate (Cl2MDP) and ethane-1-hydroxyl-1, 1-diphosphonate (EHDP) inhibited resorption to similar extents with two exceptions: At concentrations of 10 microM and 100 microM, F2MDP was more effective than EHDP and less effective than Cl2MDP. No greater inhibition was observed when bones had been stimulated with PTH prior to the addition of F2MDP. In addition, bones treated with F2MDP only during the first half of the incubation period exhibited reductions in the amount of 45Ca released during the second half similar to that observed when F2MDP was continuously in the medium, indicating a prolonged effect. Morphologic alterations of osteoclasts suggestive of cell degeneration were observed in F2MDP-treated bones, which were similar to those observed in bones treated with Cl2MDP and EHDP. Due to the presence of fluorine, F2MDP may be useful as an experimental tool to investigate the mode of action of all diphosphonates, in addition to its possible use as a therapeutic agent for diseases of increased bone resorption.

Animals↗