Primary hyperparathyroidism: effect of parathyroidectomy on regional bone mineral density in Danish patients: a three-year follow-up study

Changes in skeletal remodeling (biochemical bone markers) and regional bone mineral density (spine, hip, and forearm bone mineral density [BMD]) were observed for 3 years in 20 patients (15 women and 5 men; age 54 +/- 11 years, range 29-69 years) after successful surgery for primary hyperparathyroidism (PHPT). Fifteen PHPT patients were compared with 15 normal controls who were exactly matched with respect to age, gender, and menopausal status (10 women and 5 men; age 53 +/- 12 years, range 29-65 years [PHPT] and 29-66 years [controls]). All bone markers (serum osteocalcin, bone alkaline phosphatase, and type I collagen telopeptide [ICTP], and urinary hydroxyproline and NTx/creatinine ratio) declined significantly and reached normal levels within 6 months. No major changes took place during the remaining 2.5 years, apart from urine hydroxyproline, which disclosed a small peak around 12 months with a further decline towards study end (p < 0.05). Bone mineral density increased significantly in all regions (p < 0.001). At all locations, except the intertrochanteric region of the hip, the increase continued from 6 months until study end (p < 0.05). The increase in BMD was unequally distributed among regions (p < 0.001). The increase at the proximal forearm was less than in the spine (p < 0.05), the trochanteric region of the hip (p < 0.05), and the distal forearm (p < 0.05). No difference in BMD increase was observed between men, and pre- and postmenopausal women. Compared with the matched control group, PHPT patients had significantly lower BMD at baseline in the proximal (p < 0.02) and distal (p < 0.05) forearm. Furthermore, during the 3-year follow-up period, the PHPT patients showed a significant increase in BMD compared with controls in the spine (p < 0.005), the trochanteric and intertrochanteric regions of the hip (p < 0.005 and p < 0.05, respectively), and the distal forearm (p < 0.005). In conclusion, bone remodeling is normalized within the first 6 months after successful parathyroid surgery, with no major changes during the following 2.5 years. Bone mineral density increases at both cancellous and cortical sites, but in predominantly cortical bone, the recovery in BMD is less than in cancellous bone-rich areas.     

Parathyroidectomy improves bone geometry and microarchitecture in female patients with primary hyperparathyroidism: a one-year prospective controlled study using high-resolution peripheral quantitative computed tomography

Following parathyroidectomy (PTX), bone mineral density (BMD) increases in patients with primary hyperparathyroidism (PHPT), yet information is scarce concerning changes in bone structure and strength following normalization of parathyroid hormone levels postsurgery. In this 1‐year prospective controlled study, high‐resolution peripheral quantitative computed tomography (HR‐pQCT) was used to evaluate changes in bone geometry, volumetric BMD (vBMD), microarchitecture, and estimated strength in female patients with PHPT before and 1 year after PTX, compared to healthy controls. Twenty‐seven women successfully treated with PTX (median age 62 years; range, 44–75 years) and 31 controls (median age 63 years; range, 40–76 years) recruited by random sampling from the general population were studied using HR‐pQCT of the distal radius and tibia as well as with dual‐energy X‐ray absorptiometry (DXA) of the forearm, spine, and hip. The two groups were comparable with respect to age, height, weight, and menopausal status. In both radius and tibia, cortical (Ct.) vBMD and Ct. thickness increased or were maintained in patients and decreased in controls (p < 0.01). Radius cancellous bone architecture was improved in patients through increased trabecular number and decreased trabecular spacing compared with changes in controls (p < 0.05). No significant cancellous bone changes were observed in tibia. Estimated bone failure load by finite element modeling increased in patients in radius but declined in controls (p < 0.001). Similar, albeit borderline significant changes in estimated failure load were found in tibia (p = 0.06). This study showed that females with PHPT had improvements in cortical bone geometry and increases in cortical and trabecular vBMD in both radius and tibia along with improvements in cancellous bone architecture and estimated strength in radius 1 year after PTX, reversing or attenuating age‐related changes observed in controls. © 2012 American Society for Bone and Mineral Research.     

Effects of separate and combined therapy with growth hormone and parathyroid hormone on lumbar vertebral bone in aged ovariectomized osteopenic rats

Previous studies have demonstrated that growth hormone (GH) has a marked anabolic effect on cortical bone, and parathyroid hormone (PTH) has been shown to increase cancellous bone markedly and cortical bone to some extent in ovariectomized (ovx) rats. Combined therapies mostly focused on combining a bone anabolic agent with an antiresorptive agent. The following study was carried out to examine the efficacy of combined therapy with GH and PTH, two bone anabolic agents in rebuilding bone after loss due to ovariectomy in lumbar vertebrae, which contain both cortical and cancellous bones. Twelve-month-old female F344 rats were divided into five groups: sham + solvent vehicle, ovx + solvent vehicle, ovx + GH (2.5 mg/kg/day), ovx + PTH (80 microg/kg/day), and ovx + GH (2.5 mg/kg/day) + PTH (80 microg/kg/day). After surgery, animals were left for 4 months to become osteopenic before the beginning of therapy. Hormone administrations were given 5 days per week for 2 months and the animals were killed. The L3 vertebra was removed and examined by pQCT densitometry and by histomorphometry. Compared with age-matched, sham-operated controls, there was a 21% decrease in total bone mineral content (BMC) (p < 0.0001), 17.0% decrease in total bone mineral density (BMD) (p < 0.0001), 25.4% decrease in cortical BMC (p < 0.001), 3.1% decrease in cortical BMD (p < 0.05), 50.5% decrease in cancellous BMC (p < 0.01), 47.3% decrease in cancellous BMD (p < 0.01), and 14.5% decrease in cancellous bone volume (BV/TV) (p < 0.05) in the vehicle-treated ovx rats. Compared with age-matched, vehicle-treated ovx controls, GH, PTH, and GH + PTH increased total BMC by 22.8% (p < 0.001), 32.4% (p < 0.0001), and 72.7% (p < 0.0001), respectively; total BMD by 9.7% (p > 0.05), 22.6% (p < 0.001), and 38.8% (p < 0.0001), respectively; cortical BMC by 28.8% (p < 0.01), 50.8% (p < 0.0001), and 98.4% (p < 0.0001), respectively; and cortical BMD by 4.5% (p < 0.01), 2.9% (p < 0.05), and 6.3% (p < 0.0001), respectively. PTH and GH + PTH significantly increased cancellous BMC by 95.3% (p < 0.01) and 255.8% (p < 0.0001), respectively; cancellous BMD by 77.6% (p < 0.05) and 181% (p < 0.0001), respectively; cancellous BV/TV by 38.6% (p < 0.0001) and 55.9% (p < 0.0001), respectively; and trabecular thickness by 48% (p < 0.0001) and 68.3% (p < 0.0001), respectively. Note that GH by itself had no significant effect on vertebral cancellous BMC, cancellous BMD, and cancellous BV/TV. In conclusion, the effect of PTH was mostly more marked than that of GH. GH acted mainly by increasing cortical bone with less effect on cancellous bone, while PTH acted by increasing both cortical and cancellous bones. Combined therapy with GH and PTH was more effective in rebuilding bone after ovariectomy than either therapy alone. The effects of combined therapy with GH and PTH were additive in vertebral bone in the aged osteopenic rats.     

The aged male rat as a model for human osteoporosis: Evaluation by nondestructive measurements and biomechanical testing

Summary Effects of androgen deficiency and androgen replacement on bone density, as measured with dual-energy X-ray absorptiometry (DXA) and single photon absorptiometry (SPA), cortical ratio (cortical thickness/outside bone diameter x 100), and biomechanical properties were evaluated in 14-month-old (1 month after orchiectomy (orch) or sham-operation) and in 17-month-old (4 months after orch or sham) male rats. Whole femoral bone mineral content (BMC) and density (BMD) measured with DXA were not significantly decreased 1 month after orch. Whole femoral BMC and BMD were 10% and 8% lower in 4 months after orch (P < 0.01 andP < 0.001, respectively). This decrease was prevented by testosterone replacement. There was an excellent correlation (R = 0.99) between whole femoral BMC and femoral ash weight. Selective scanning of cortical and cancellous sites of the femur showed that both cancellous and cortical BMC and BMD were significantly decreased 4 months after orch. SPA of the right tibia confirmed a 7% decrease in cancellous BMC and BMD 4 months after orch (preventable by testosterone) but not in cortical BMD and BMC. Femoral cortical ratio decreased with age (47 ± 2 in 14-month-old and 40 ± 2 in 17-month-old sham rats versus 63 ± 1 in 6-month-old male rats) due to a continuously enlarging femoral shaft. Androgen deficiency resulted in an even greater decrease of the cortical ratio 4 months after orch (36 ± 2 in 17-month-old orch rats) that was again prevented by testosterone (47 ± 3). These changes in femoral cortical, cancellous density, and cortical ratio did not affect biomechanical properties of the femur as evaluated by torsion testing. The lack of an effect on bone biomechanics was most likely due to the protection afforded by an increased femoral shaft diameter. We conclude that 4 months after orch, aged male orch rats had a lower femoral cortical and cancellous density and a lower cortical ratio without decrease of biomechanical properties of the femoral shaft. Testosterone replacement was effective not only in preventing the decrease of cancellous and cortical density but also in preventing the age-related thinning of the femoral cortex.     

Male rodent model of age-related bone loss in men

Osteoporosis is a common occurrence in aging men. There is currently no appropriate animal model for studying age-related bone loss in men. To determine whether male Sprague-Dawley (SD) rats experience bone loss with aging and whether this rodent model is appropriate for studying age-related bone loss in men, SD rats aged 1-27 months were examined at the L-4 vertebra, the left femoral neck, and the left proximal tibia using peripheral quantitative computed tomography (pQCT) densitometry. In the L-4 vertebra of the male SD rats, cortical bone mineral content (BMC), cortical bone mineral density (BMD), and cortical bone thickness (Ct.Th) increased to a maximum at about 4 months of age and then plateaued. Vertebral cortical BMC began to decrease after about 13 months and vertebral Ct.Th began to decrease after about 9 months. By 27 months of age, vertebral cortical BMC decreased by 26.1% (p < 0.0001) and vertebral Ct.Th decreased by 31% (p < 0.0001). Vertebral cancellous BMC and vertebral cancellous BMD increased to a maximum at about 3 months of age and then declined progressively with aging after a short plateau. From 3 to 27 months of age, vertebral cancellous BMC and vertebral cancellous BMD had decreased linearly by 35.4% (p < 0.0001) and 49.4% (p < 0.0001), respectively. Both vertebral periosteal and vertebral endocortical perimeters of the L-4 vertebra of the rats increased with aging. From 9 to 27 months of age, the percent increase of vertebral endocortical perimeter (19.8%, p < 0.0001) was higher than that of vertebral periosteal perimeter (7.4%, p < 0.0001). This process was associated with a decrease with aging in vertebral Ct.Th. In addition, cancellous bone in the femoral neck and the proximal tibia began to be lost at 9 months of age and, by 27 months of age, cancellous BMC and cancellous BMD decreased by 59.7% (p < 0.0001) and 58.4% (p < 0.0001), respectively, in the femoral neck and by 72.2% (p < 0.0001) and 71.4% (p < 0.0001), respectively, in the proximal tibia. To gain further insight into the effects of aging on cancellous bone in the L-4 vertebra, histomorphometry was done on the L-4 vertebral body of animals aged 3, 6, 9, 18, and 24 months after pQCT densitometry. From 3 months of age and thereafter, cancellous bone volume (BV/TV) decreased progressively and, by 24 months, there was a decrease of 35.7% (p < 0.0001). In the L-4 vertebra, single- and double-labeled surfaces, mineral apposition rate (MAR), and bone formation rate (BFR/BS) decreased with aging. In conclusion, age-related bone loss in male SD rats started mostly from 9 months of age when bone growth had been completed. Aging male SD rats experience bone loss comparable to that seen in men. Thus, male SD rats represent an appropriate animal model of age-related bone loss in men. We recommend using male SD rats that are 9 months old as the starting age for age-related bone loss. We also suggest using the L-4 vertebra and femoral neck as the clinically relevant bone sites for determining the cause of the loss of bone, and how and whether therapeutic agents could modulate age-related bone loss in men.     

Recombinant human parathyroid hormone (1-34) [teriparatide] improves both cortical and cancellous bone structure.

Histomorphometry and microCT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume. INTRODUCTION: We studied the ability of teriparatide (rDNA origin) injection [rhPTH(1-34), TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data. METHODS: Fifty-one paired iliac crest bone biopsy specimens (placebo [n = 19], 20 microg teriparatide [n = 18], and 40 microg teriparatide [n = 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (microCT). Data for both teriparatide treatment groups were pooled for analysis. RESULTS AND CONCLUSIONS: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, -24%; p = 0.001) and reduced marrow star volume (teriparatide, -16%; placebo, 112%; p = 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, -12%; placebo, 7%; p = 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, - 14%; p = 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p = 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.     

Primary hyperparathyroidism: whole-body bone mineral density in surgically treated Danish patients: a three-year follow-up study

Whole-body bone mineral density (BMD) and body composition were measured before surgery in 25 patients (20 women and 5 men, aged 53 +/- 13 years, range 26-73 years) with mild to moderate primary hyperparathyroidism (PHPT) and compared with 25 controls exactly matched with respect to age, gender, and menopausal status. Fifteen pairs of matched patients and controls were reexamined 3 years later (5 men and 10 women, aged 53 +/- 12 years in both groups). In the untreated PHPT patients, whole-body BMD was 95.4% +/- 10.5% (SD) of control BMD (p < 0.05). Body weight and height, body mass index, whole-body fat mass, and lean body mass did not differ significantly between the groups. Relative to values in matched controls, whole-body bone mineral content (BMC) and BMD increased by 4.4% and 3.0%, respectively, in PHPT patients (p < 0.005) during the 3-year follow-up. Neither whole-body BMC nor BMD differed between patients and controls after the 3-year follow-up. A positive correlation was observed between initial serum calcium levels and the 3-year increase in whole-body BMD (r(s) = 0.645, p < 0.01). Baseline serum osteocalcin, serum pyridinoline crosslinked telopeptide of Type I collagen and several histomorphometric indices of trabecular bone turnover (eroded and labeled surfaces, bone formation rate, and activation frequency) also correlated positively with the subsequent increase in whole-body BMD. Six patients disclosed transient postoperative secondary hyperparathyroidism, probably due to hungry bones. Four of these patients completed 3 years of follow-up and had higher increases in whole-body BMD than the remaining normo-parathyroid patients (7.9% +/- 4.5%, range 4.3-14.3% versus 1.9% +/- 2.1%, p < 0.01). It is concluded that Danish patients with mild to moderate PHPT only reveal small reductions in whole-body mineral density. Furthermore, within 3 years after parathyroid surgery, most of the lost bone mineral is regained even in patients with initial high bone turnover. Finally, PHPT in these patients is not associated with substantial changes in body compositions.     

The Treatment of Patients with ARF and MOSF: A Framework for a Discussion on Ethical Issues

The human nephrotic syndrome (NS) is accompanied by important alterations of mineral and bone metabolism. The purpose of the present study was to examine bone metabolism in rats with experimental NS and normal creatinine clearance, and to evaluate the reversibility of this alteration. NS was induced by three injections of puromycin aminonucleoside (PAN) on days 0, 21, and 35 (10, 5, and 5 mg/100 g body weight, respectively). The biochemical markers of bone formation (osteocalcin and alkaline phosphatase) and bone resorption (hydroxyproline and pyridinoline), bone mineral content (BMC), and bone mineral density (BMD), determined by dual-energy x-ray absorptiometry (DEXA), were studied on days 0, 7, 14, 28, 42, 56, 84, and 112. Proteinuria was present throughout the study. Hypoproteinemia was seen on days 7, 28, 42, and 56, returning to control values on days 84 and 112. In serum, osteocalcin (OC) concentration increased (p < 0.001), and alkaline phosphatase (ALP) decreased (p = 0.002). In urine, hydroxyproline increased (p < 0.001), but urinary pyridinoline was not different from the control group throughout the study. Increased serum parathyroid hormone concentration and decreased levels of 25-hydroxy and 1,25-dihydroxyvitamin D were found from day 7. During the intense proteinuria, bone resorption predominates and decreased BMC and BMD ensues in PAN-nephrotic rats. PAN-nephrotic rats showed low BMC and BMD compared to control group (p < 0.001). At the end of the study, when proteinuria persisted but total serum protein returned to control values, the biochemical bone markers, BMC, and BMD returned to normal. In conclusion, PAN-nephrotic rats had reversible bone alterations that were related to the magnitude of proteinuria and the concentration of total serum protein.     

Continuous parathyroid hormone and estrogen administration increases vertebral cancellous bone volume and cortical width in the estrogen-deficient rat.

Generally, it is believed that intermittent administration of parathyroid hormone (PTH) has an anabolic effect on the skeleton, whereas continuous administration is catabolic. However, there is evidence that continuous exposure to PTH may have an anabolic effect, for example, in patients with mild primary hyperparathyroidism (PHPT). The possibility of delivering PTH continuously may have important implications for the treatment of osteoporosis. Furthermore, estrogen treatment may be useful in the medical management of PHPT. Therefore, we examined the skeletal effects of continuous administration of PTH, with or without estrogen, in the estrogen-deficient rat with established osteopenia. Forty 7-month-old SD rats were divided into four ovariectomy (OVX) groups and one sham-operated group. Eight weeks post-OVX, three groups received subcutaneous implants of Alzet mini pumps loaded with PTH(1-34) (30 microg/kg per day), 17beta-estradiol (10 microg/kg per day) pellet, or both PTH and 17beta-estradiol separately for 4 weeks. OVX and sham control groups were given the mini pumps loaded with vehicle. Two doses of calcein (10 mg/kg) were given subcutaneously to all rats 2 days and 8 days before death. Histomorphometry was performed on cancellous and cortical bone of the fourth lumbar vertebra. At 3 months, post-OVX rats displayed bone loss with high bone turnover. Estrogen reversed OVX-mediated high turnover without restoring cancellous bone volume (BV/TV). PTH infusion further increased bone turnover and partially restored BV/TV. However, PTH infusion increased cortical porosity. Estrogen inhibited PTH-mediated cancellous bone resorption and substantially increased BV/TV above sham control. The combined treatment was associated with a significant increase in peritrabecular fibrosis and woven bone formation. The combined treatment of PTH infusion and estrogen replacement enhanced cortical width but estrogen did not prevent the PTH-induced cortical tunneling. We conclude that continuous administration of PTH and estrogen increases cortical porosity but has substantial beneficial effects on vertebral cancellous bone volume and cortical width in OVX rats.     

Significance of time-course changes of serum bone markers after parathyroidectomy in patients with uraemic hyperparathyroidism.

BACKGROUND: The increase of bone mineral density in cortical bone after parathyroidectomy is smaller than that in cancellous bone. Changes of serum bone markers reflect those of bone metabolism both in cortical and cancellous bone after parathyroidectomy. The present study was undertaken to investigate changes of histomorphometric parameters of cortical and cancellous bone together and their correlation with those of serum bone markers. METHODS: Iliac bone biopsy was performed before and 1 week after parathyroidectomy in Group I (n = 13), and before and 4 and 12 weeks after in Group II (n = 11). Moreover, changes of histomorphometric parameters of the endocortical, intracortical and periosteal surfaces as well as in cancellous bone were monitored. Serum levels of intact parathyroid hormone and bone markers were measured simultaneously. Results. In cancellous bone, osteoclast surface (Oc.S/BS) decreased to 0% within 4 weeks after parathyroidectomy, while osteoblast surface (Ob.S/BS) transiently increased at 1 week, followed by a reduction at 4 weeks to levels below the pre-surgical level. In cortical bone, Oc.S/BS was not reduced to 0%, while a significant and temporary increase of Ob.S/BS was observed only on the endocortical and intracortical surfaces at 4 weeks, but not at 1 week. Serum bone resorption markers did not completely disappear and significant and sustained increases of bone formation markers were observed until 4 weeks after parathyroidectomy. CONCLUSIONS: Changes of bone formation markers lagged behind those of histomorphometric parameters in cancellous bone because changes of cortical bone were observed later and were incomplete compared with those of cancellous bone.     

Comparative effects of orchidectomy and sciatic neurectomy on cortical and cancellous bone in young growing rats

 The purpose of the present study was to compare the effects of orchidectomy and sciatic neurectomy on cortical and cancellous bone in male rats. Fifty male Sprague-Dawley rats, 6 weeks of age, were randomized into five groups, with ten rats in each group: baseline control, age-matched intact control, orchidectomy (ORX), unilateral sciatic neurectomy (NX), and ORX + NX. After 8 weeks of feeding, the tibial shaft and proximal tibia were processed for cortical and cancellous bone histomorphometric analyses, respectively. ORX-induced reductions in maturation-related cortical and cancellous bone gains were attributable to decreased periosteal bone gain and increased trabecular bone resorption, respectively. NX- and ORX + NX-induced reductions in maturation-related cortical bone gain were attributable to decreased periosteal bone formation and increased endocortical bone turnover, while NX- and ORX + NX -induced reductions in maturation-related cancellous bone gain were attributable to increased bone resorption and decreased bone formation. NX more markedly reduced maturation-related cortical and cancellous bone gains than did ORX, and the ORX-induced reductions in maturation-related cortical and cancellous bone gains were more pronounced when combined with NX. The present study demonstrated differences in changes in cortical and cancellous bone following ORX and NX in young rats. The importance of mechanical loading, with or without testosterone deficiency, is emphasized in cortical and cancellous bone growth. Received: October 5, 2002 / Accepted: January 20, 2003 RID="*" ID="*" Offprint requests to: J. Iwamoto     

Bone density, strength, and formation in adult cathepsin K (-/-) mice

Cathepsin K (CatK) is a cysteine protease expressed predominantly in osteoclasts, that plays a prominent role in degrading Type I collagen. Growing CatK null mice have osteopetrosis associated with a reduced ability to degrade bone matrix. Bone strength and histomorphometric endpoints in young adult CatK null mice aged more than 10 weeks have not been studied. The purpose of this paper is to describe bone mass, strength, resorption, and formation in young adult CatK null mice. In male and female wild-type (WT), heterozygous, and homozygous CatK null mice (total N=50) aged 19 weeks, in-life double fluorochrome labeling was performed. Right femurs and lumbar vertebral bodies 1-3 (LV) were evaluated by dual-energy X-ray absorptiometry (DXA) for bone mineral content (BMC) and bone mineral density (BMD). The trabecular region of the femur and the cortical region of the tibia were evaluated by histomorphometry. The left femur and sixth lumbar vertebral body were tested biomechanically. CatK (-/-) mice show higher BMD at the central and distal femur. Central femur ultimate load was positively influenced by genotype, and was positively correlated with both cortical area and BMC. Lumbar vertebral body ultimate load was also positively correlated to BMC. Genotype did not influence the relationship of ultimate load to BMC in either the central femur or vertebral body. CatK (-/-) mice had less lamellar cortical bone than WT mice. Higher bone volume, trabecular thickness, and trabecular number were observed at the distal femur in CatK (-/-) mice. Smaller marrow cavities were also present at the central femur of CatK (-/-) mice. CatK (-/-) mice exhibited greater trabecular mineralizing surface, associated with normal volume-based formation of trabecular bone. Adult CatK (-/-) mice have higher bone mass in both cortical and cancellous regions than WT mice. Though no direct measures of bone resorption rate were made, the higher cortical bone quantity is associated with a smaller marrow cavity and increased retention of non-lamellar bone, signs of decreased endocortical resorption. The relationship of bone strength to BMC does not differ with genotype, indicating the presence of bone tissue of normal quality in the absence of CatK.     

Primary hyperparathyroidism: short-term changes in bone remodeling and bone mineral density following parathyroidectomy.

Changes in bone remodeling and bone mineral density were observed during a period of 6 months after surgery in 24 patients with primary hyperparathyroidism (20 women and 4 men; age 54+/-12 years, range 26-69 years). All bone markers declined significantly within the 6 month follow-up period, but the time course for changes in renal N-terminal telopeptide of type 1 collagen (NTx) excretion differed from those of the other markers by a steep and significant reduction (p < 0.05) after less than 1 month. During the 6 month period, bone mineral density (BMD) increased significantly at all sites measured (p < 0.05) apart from the femoral neck and the proximal and midforearm. The greatest increase of 4.2% was observed in the trochanteric region (p < 0.001). The increase in BMD in spine, trochanteric, and intertrochanteric regions of the hip correlated inversely with baseline forearm BMD values (p < 0.05). Baseline bone markers (serum alkaline phosphatase [AP], serum bone AP, serum pyridinoline crosslinked telopeptide of type 1 collagen, urinary hydroxyproline, urinary osteocalcin), as well as baseline histomorphometric indices of bone turnover (eroded and labeled surface, bone formation rate, activation frequency, and cortical porosity) were positively correlated with changes in spinal BMD over 6 months (p < 0.05). It was concluded that, within 6 months after parathyroidectomy, patients with primary hyperparathyroidism obtain normalization of bone remodeling and a substantial increase in bone mineral density in regions rich in cancellous bone but no significant changes in regions with predominantly cortical bone.     

Age-related changes in bone mineral content and density in intact male F344 rats.

This study was undertaken to determine whether age-related bone loss occurs in intact male F344 rats. Bone loss was assessed in male F344 rats aged 3 to 27 months by scanning different bones using peripheral quantitative computed tomography (pQCT) densitometry. Cancellous and cortical bones were analyzed at the vertebra, proximal tibial metaphysis (PTM), and the neck of the femur. Cortical bone was also analyzed at the tibial and femoral diaphysis and at the tibio-fibula junction. In the vertebra, cancellous bone mineral content (Cn. BMC) did not change significantly with age. Cancellous bone mineral density (Cn. BMD) gradually decreased from 9 months onwards; and at 27 months of age, there was a 29% (p < 0.0001) decrease, when compared with 9-month-old animals. No significant change was observed in cortical bone mineral content (Ct. BMC) and cortical bone mineral density (Ct. BMD) with age. In the PTM, bone loss started to occur after 18 months of age. At 27 months of age, Cn. BMC decreased by 58% (p < 0.0001) and Cn. BMD also decreased by 58% (p < 0.0001). Ct. BMC decreased by 28% (p < 0.0001) in 27-month-old animals, whereas Ct. BMD was not affected by aging. At the tibio-fibula junction, Ct. BMC and Ct. BMD decreased after 18 months of age. At 27 months, Ct. BMC and Ct. BMD had decreased by 8% (p < 0.001) and 3% (p < 0.0001), respectively. Ct. BMC in the tibial diaphysis did not change significantly with age, whereas Ct. BMD decreased by 1% (p < 0.05) at 27 months. In the neck of the femur, Cn. BMC increased up to 24 months of age. Cn. BMD increased up to 18 months of age and decreased by 9% (p < 0.05) at 24 months and 11% (p < 0.001) at 27 months of age when compared with 18-month-old animals. Ct. BMC and Ct. BMD increased with age. In conclusion, although some components of the PTM decreased appreciably with age, in this study, most of the bone parameters analyzed either increased or did not change significantly with age. We conclude that unlike male Sprague Dawley rats, male F344 rats appear not to be a good model for studying age-related bone loss as occurs in aging men.     

Bisphosphonate kinetics in patients undergoing continuous ambulatory peritoneal dialysis: relations to dynamic bone histomorphometry, osteocalcin and parathyroid hormone.

In the evaluation of renal osteodystrophy bone biopsy is often performed. However, a reliable noninvasive test could be very useful, and recently the estimation of osseous tracer uptake as an index of bone formation has been introduced-the bone bisphosphonate clearance (BBC). The aim of the present investigation therefore was to compare BBC with parameters of bone histology, serum levels of osteocalcin, alkaline phosphatase, and parathyroid hormone in patients (n = 8) undergoing continuous ambulatory peritoneal dialysis (CAPD). No significant correlations were found between BBC values and the bone histomorphometrical variables measured. A positive correlation was seen between serum osteocalcin and resorption and active resorption surface (p < 0.05), as well as tetracycline-labelled surface, bone formation rate, surfaces, volume and tissue referents, respectively (p < 0.01). Furthermore, levels of alkaline phosphatase showed significant correlations to mineral appositional rate, tetracycline-labelled surface and bone formation rate, volume referent (p < 0.05). Values of parathyroid hormone were significantly correlated to resorption surface (p < 0.02), active resorption surface, mineral appositional rate and mineralization lag time (p < 0.05). In conclusion, BBC was of no use in patients treated with CAPD as a noninvasive test for evaluation of bone histomorphometry. However, osteocalcin correlated best with resorption and bone dynamics indices. Levels of alkaline phosphatase and parathyroid hormone were of a more limited value.     

Bone mineral and stiffness loss at the distal femur and proximal tibia in acute spinal cord injury

Summary

Computed tomography and finite element modeling were used to assess bone mineral and stiffness loss at the knee following acute spinal cord injury (SCI). Marked bone mineral loss was observed from a combination of trabecular and endocortical resorption. Reductions in stiffness were 2-fold greater than reductions in integral bone mineral.

Introduction

SCI is associated with a rapid loss of bone mineral and an increased rate of fragility fracture. The large majority of these fractures occur around regions of the knee. Our purpose was to quantify changes to bone mineral, geometry, strength indices, and stiffness at the distal femur and proximal tibia in acute SCI.

Methods

Quantitative computed tomography (QCT) and patient-specific finite element analysis were performed on 13 subjects with acute SCI at serial time points separated by a mean of 3.5 months (range 2.6–4.8 months). Changes in bone mineral content (BMC) and volumetric bone mineral density (vBMD) were quantified for integral, trabecular, and cortical bone at epiphyseal, metaphyseal, and diaphyseal regions of the distal femur and proximal tibia. Changes in bone volumes, cross-sectional areas, strength indices and stiffness were also determined.

Results

Bone mineral loss was similar in magnitude at the distal femur and proximal tibia. Reductions were most pronounced at epiphyseal regions, ranging from 3.0 % to 3.6 % per month for integral BMC (p?<?0.001) and from 2.8 % to 3.4 % per month (p?<?0.001) for integral vBMC. Trabecular BMC decreased by 3.1–4.4 %/month (p?<?0.001) and trabecular vBMD by 2.7–4.7 %/month (p?<?0.001). A 3.8–5.4 %/month reduction was observed for cortical BMC (p?<?0.001); the reduction in cortical vBMD was noticeably lower (0.6–0.8 %/month; p?≤?0.01). The cortical bone loss occurred primarily through endosteal resorption, and reductions in strength indices and stiffness were some 2-fold greater than reductions in integral bone mineral.

Conclusions

These findings highlight the need for therapeutic interventions targeting both trabecular and endocortical bone mineral preservation in acute SCI.     

Structural and histomorphometric studies of iliac crest trabecular and cortical bone in autosomal dominant osteopetrosis: a study of two radiological types

Cylindrical iliac crest biopsies were obtained from 16 patients with autosomal dominant osteopetrosis after intravital double labeling with tetracycline, and compared with normal age- and sex-matched controls. Ten patients had the radiological type I (5 women, 5 men, aged 17-62 years, mean 42) characterized by diffuse, symmetrical osteosclerosis and enlarged thickness of the cranial vault. Six patients had type II (2 women, 4 men, aged 22-44 years, mean 36), where "Rugger Jersey Spine" and endobone are characteristic findings. Structural studies of cortical and trabecular bone were performed, and trabecular bone resorption and formation rates were studied using dynamic histomorphometry. The total biopsy length (C. Wi) were increased in type I (p less than 0.05), and unchanged in type II. Both types showed increased cortical width (Ct. Wi) (p less than 0.01 and p less than 0.05, respectively), and decreased fractional width of cancellous bone (Cn.Wi/C.Wi) (p less than 0.01 and p less than 0.05). The fractional trabecular bone volume (BV/TV) and trabecular thickness (Tb. Th) were both significantly increased in type I (p less than 0.05), while resorptive and formative indices of trabecular bone remodeling were normal. No difference was found in trabecular bone balance, which was slightly positive in both patients and controls. In type II osteopetrosis the eroded surfaces (OS/BS) were significantly increased (p less than 0.01), as was the total resorptive period RP) (p less than 0.05). The resorption depth (R.D.) was normal, while the resorption rate (MRR) was insignificantly decreased. Many big multinucleated osteoclasts were seen in this type suggesting defective resorptive function.(ABSTRACT TRUNCATED AT 250 WORDS)     

Structural and cellular changes during bone growth in healthy children

Normal postnatal bone growth is essential for the health of adults as well as children but has never been studied histologically in human subjects. Accordingly, we analyzed iliac bone histomorphometric data from 58 healthy white subjects, aged 1.5-23 years, 33 females and 25 males, of whom 48 had undergone double tetracycline labeling. The results were compared with similar data from 109 healthy white women, aged 20-76 years, including both young adult reference ranges and regressions on age. There was a significant increase with age in core width, with corresponding increases in both cortical width and cancellous width. In cancellous bone there were increases in bone volume and trabecular thickness, but not trabecular number, wall thickness, interstitial thickness, and inferred erosion depth. Mineral apposition rates declined on the periosteal envelope and on all subdivisions of the endosteal envelope. Because of the concomitant increase in wall thickness, active osteoblast lifespan increased substantially. Bone formation rate was almost eight times higher on the outer than on the inner periosteum, and more than four times higher on the inner than on the outer endocortical surface. On the cancellous surface, bone formation rate and activation frequency declined in accordance with a fifth order polynomial that matched previously published biochemical indices of bone turnover. The analysis suggested the following conclusions: (1) Between 2 and 20 years the ilium grows in width by periosteal apposition (3.8 mm) and endocortical resorption (3.2 mm) on the outer cortex, and net periosteal resorption (0.4 mm) and net endocortical formation (1.0 mm) on the inner cortex. (2) Cortical width increases from 0.52 mm at age 2 years to 1.14 mm by age 20 years. To attain adult values there must be further endocortical apposition of 0.25 mm by age 30 years, at a time when cancellous bone mass is declining. (3) Lateral modeling drift of the outer cortex enlarges the marrow cavity; the new trabeculae filling this space arise from unresorbed cortical bone and represent cortical cancelization; (4) Lateral modeling drift of the inner cortex encroaches on the marrow cavity; some trabeculae are incorporated into the expanding cortex by compaction. (5) The net addition of 37 microm of new bone on each side of a trabecular plate results from a <5% difference between wall thickness and erosion depth and between bone formation and bone resorption rates; these small differences on the same surface are characteristic of bone remodeling. (6) Because the amount of bone added by each cycle of remodeling is so small, the rate of bone remodeling during growth must be high to accomplish the necessary trabecular hypertrophy.     

Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites.

In a population-based, cross-sectional study, we assessed age- and sex-specific changes in bone structure by QCT. Over life, the cross-sectional area of the vertebrae and proximal femur increased by approximately 15% in both sexes, whereas vBMD at these sites decreased by 39-55% and 34-46%, respectively, with greater decreases in women than in men. INTRODUCTION: The changes in bone structure and density with aging that lead to fragility fractures are still unclear. MATERIALS AND METHODS: In an age- and sex-stratified population sample of 373 women and 323 men (age, 20-97 years), we assessed bone geometry and volumetric BMD (vBMD) by QCT at the lumbar spine, femoral neck, distal radius, and distal tibia. RESULTS: In young adulthood, men had 35-42% larger bone areas than women (p < 0.001), consistent with their larger body size. Bone area increased equally over life in both sexes by approximately 15% (p < 0.001) at central sites and by approximately 16% and slightly more in men at peripheral sites. Decreases in trabecular vBMD began before midlife and continued throughout life (p < 0.001), whereas cortical vBMD decreases began in midlife. Average decreases in trabecular vBMD were greater in women (-55%) than in men (-46%, p < 0.001) at central sites, but were similar (-24% and -26%, respectively) at peripheral sites. With aging, cortical area decreased slightly, and the cortex was displaced outwardly by periosteal and endocortical bone remodeling. Cortical vBMD decreased over life more in women ( approximately 25%) than in men (approximately 18%, p < 0.001), consistent with menopausal-induced increases in bone turnover and bone porosity. CONCLUSIONS: Age-related changes in bone are complex. Some are beneficial to bone strength, such as periosteal apposition with outward cortical displacement. Others are deleterious, such as increased subendocortical resorption, increased cortical porosity, and, especially, large decreases in trabecular vBMD that may be the most important cause of increased skeletal fragility in the elderly. Our findings further suggest that the greater age-related decreases in trabecular and cortical vBMD and perhaps also their smaller bone size may explain, in large part, why fragility fractures are more common in elderly women than in elderly men.     

Effect of parathyroidectomy versus risedronate on volumetric bone mineral density and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism

The objective of the study was to evaluate the effect of parathyroidectomy (PTX) versus 35 mg once-weekly (ow) risedronate administration on volumetric bone mineral density (vBMD) and bone geometry at the tibia in postmenopausal women with primary hyperparathyroidism (PHPT). Our open-label prospective observational study included 32 postmenopausal women with PHPT as the study group: 16 underwent PTX and 16 were treated with 35 mg ow risedronate for 2 years. We assessed areal BMD (aBMD) by DXA, and vBMD and bone mineral content (BMC) (cortical and trabecular area) by peripheral quantitative computed tomography (pQCT) at the tibia at baseline and at 2 years. Risedronate did not result in any significant change on vBMD and structural pQCT indices. PTX resulted in significant increase in trabecular (trab) BMC (6.44 %) and vBMD (4.64 %), with percent increase being significantly higher than risedronate (p < 0.05). At cortical sites, there was no significant change following PTX. However, the percent change in cortical (cort) vBMD was higher following PTX versus risedronate (0.39 % vs. ?0.26 %, p < 0.05). In conclusion, in postmenopausal women with PHPT, PTX is superior to ow risedronate, in terms of improvement of trabecular mineralization and vBMD at the tibia, whereas the effect at cortical sites is less pronounced.