Pituitary Diseases and Bone

In igfbp-4-null female mice, cortical area fraction and cortical thickness at the femur midshaft are significantly reduced.

“Significant reductions were also observed in cortical area fraction and cortical thickness at the femur midshaft.”

• cites [155] Maridas, 2017, IGFBP-4 regulates adult skeletal growth in a sex-specific manner, J Endocrinol sourceSupported

In this study baseline TBS was normal.

“However, in this study baseline TBS was normal.”

• cites [449] Allo Miguel, 2016, Seven years of follow up of trabecular bone score, bone mineral density, body composition and quality of life in adults with growth hormone deficiency treated with rhGH replacement in a single center, Ther Adv Endocrinol Metab sourceSupported

Questionnaires and databases cannot correctly identify vertebral fractures.

“likely reflecting the impossibility of questionnaires and databases to correctly identify VFs ().”

Increased bone formation seen in vivo is likely due to coupling of bone formation to bone resorption, which is absent in in vitro conditions.

“Increased bone formation seen in vivo was likely due to the coupling of bone formation to bone resorption, which was absent in in vitro conditions.”

Despite the stimulating effects of GH and IGF-I on renal activation of vitamin D, hypovitaminosis D has been consistently reported in patients with acromegaly.

“Despite the stimulating effects of GH and IGF-I on renal activation of vitamin D (), hypovitaminosis D has been consistently reported in patients with acromegaly (, ), and there is also evidence suggesting lower peripheral bioavailability of vitamin D in this clinical setting as an effect of an increase in vitamin D binding protein (, ).”

The effects of PTH on the RANKL-OPG axis may explain the differential effect of short versus prolonged exposure to PTH on the balance of its anabolic and catabolic actions.

“These effects on the RANKL-OPG axis may explain the differential effect of short vs prolonged exposure to PTH with respect to the balance of its anabolic and catabolic actions.”

Current experimental observations suggest that most of the effects of GH on bone are mediated by IGF-I.

“In summary, the current experimental observations suggest that most of the effects of GH on bone are mediated by IGF-I.”

There is growing evidence that pituitary hormones may bypass traditional endocrine organs to exert direct effects on the skeleton.

“However, there has been growing evidence to suggest that pituitary hormones may bypass traditional endocrine organs to exert remarkable direct effects on the skeleton.”

In several clinical studies, serum TSH values in the reference range were associated with BMD and fractures.

“In several clinical studies, serum TSH values in the reference range were associated with BMD and fractures.”

Dual-energy X-ray absorptiometry measurement of bone mineral density does not provide information on bone quality, which depends on bone macrostructure, microstructure, mineralization, microdamage, and collagen status.

“In fact, DXA measurement of BMD does not provide information on bone quality, which depends on bone macrostructure, microstructure, mineralization, microdamage, and collagen status.”

Vertebral fractures possibly contribute to kyphosis of patients with acromegaly.

“possibly contributing to kyphosis of patients with acromegaly, a feature clearly present in the first patients reported by Pierre-Marie ().”

GH excess influences PTH pulsatility with prolongation of pulse half-duration and increase in pulse mass.

“Moreover, GH excess was shown to influence PTH pulsatility with prolongation of pulse half-duration and increase in pulse mass ().”

In patients with acromegaly, vertebral fractures were shown to be slightly more frequent in males as compared with females.

“VFs were shown to be slightly more frequent in males as compared with females (Fig. ).”

In a retrospective longitudinal study, Battista et al. reported incident vertebral fractures in more than a third of acromegaly patients with hypogonadism regardless of activity of disease.

“In a retrospective longitudinal study, Battista et al. () reported incident VFs in more than a third of acromegaly patients with hypogonadism regardless of activity of disease.”

Using HR-pQCT, Madeira et al. reported significant associations between several parameters of bone microstructure and either gonadal or activity of disease in 82 patients with acromegaly.

“Using HR-pQCT, Madeira et al. () reported significant associations between several parameters of bone microstructure (i.e., BV/TV, Tb.N, and mean trabecular separation) and either gonadal or activity of disease in  patients with acromegaly ( males,  females).”

Such an association was shown to be independent of thyroid hormone values.

“Such an association was shown to be independent of thyroid hormone values.”

• cites [270] Mazziotti, 2010, Serum TSH values and risk of vertebral fractures in euthyroid post-menopausal women with low bone mineral density, Bone sourceNot checked — no full text of the source

IGF-I is the mediator of most effects of GH on peripheral tissues.

“IGF-I is the mediator of most effects of GH on peripheral tissues.”

Retrospective studies did not show an increased clinical fracture risk in acromegaly.

“Retrospective studies did not show an increased clinical fracture risk in acromegaly (, ), likely reflecting the impossibility of questionnaires and databases to correctly identify VFs ().”

DXA measurements of BMD in acromegaly may be affected by pitfalls related to the abnormalities of bone structure caused by GH hypersecretion.

“DXA measurements of BMD in acromegaly may be affected by some pitfalls related to the abnormalities of bone structure caused by GH hypersecretion.”

Patients with acromegaly have increased bone turnover, as determined by changes in biochemical markers, calcium kinetics, and bone histomorphometry.

“Patients with acromegaly have increased bone turnover, as determined by changes in biochemical markers, calcium kinetics, and bone histomorphometry ().”

A high prevalence and incidence of vertebral fractures is related to increased bone turnover and deterioration of bone structure.

“In the last few years, it has clearly emerged that a high prevalence and incidence of VFs is related to increased bone turnover and deterioration of bone structure, although evidence that acromegaly may cause impairment in bone quality was already provided by Ueland et al. () in : they reported loss of trabecular connections and low trabecular bone biomechanical competence in iliac crest bi”

Experimental models provide evidence that the direct skeletal effects of FSH may be influenced by gonadal function because severe hypoestrogenemia would invariably prevent full osteoprotection by FSH inhibition.

“However, the experimental models also provided evidence that the direct skeletal effects of FSH may be influenced by the gonadal function because severe hypoestrogenemia would invariably prevent full osteoprotection by FSH inhibition.”

Bone loss has been sporadically reported in hyperthyroid patients with TSH-secreting adenoma (TSH-oma), despite normal or even high TSH values.

“Likewise, bone loss has been sporadically reported in hyperthyroid patients with TSH-secreting adenoma (TSH-oma), despite normal or even high TSH values”

Pituitary diseases generally affect bone quality more than bone quantity.

“pituitary diseases generally affect bone quality more than bone quantity”

• cites [1] Mazziotti, 2015, Pituitary diseases and bone, Endocrinol Metab Clin North Am sourceNot checked — no full text of the source

There is evidence that TSH may have direct effects on skeletal remodeling in humans, such as previously demonstrated in experimental animals.

“There is evidence that TSH may have direct effects on skeletal remodeling in humans, such as previously demonstrated in experimental animals.”

That more than 50% of patients with fractures were shown to have either multiple or severe vertebral fractures suggests that vertebral fractures may be associated with an unfavorable functional outcome.

“However, that .% of patients with fractures were shown to have either multiple or severe VFs () suggests that VFs may be associated with an unfavorable functional outcome (), such as demonstrated in other clinical settings (-).”

Experimental data suggest that FSH stimulates osteoclastogenesis and bone resorption.

“In summary, experimental data suggest that FSH stimulates osteoclastogenesis and bone resorption.”

Some clinical studies evaluating skeletal endpoints in patients with prolactinoma suggest that PRL may have a direct effect on bone in humans, such as demonstrated in experimental models.

“However, some clinical studies evaluating the skeletal endpoints in patients with prolactinoma seem to suggest that PRL may have a direct effect on bone in humans, such as demonstrated in experimental models”

Pituitary hormones may directly modulate bone remodeling and metabolism.

“Neuroendocrinology of bone is a new area of research based on the evidence that pituitary hormones may directly modulate bone remodeling and metabolism.”

Our group reported vertebral fractures in 23 out of 40 male patients with acromegaly (median age 47 years).

“Three years later, our group also reported VFs in  out of  male patients with acromegaly (median age  years) ().”

Differences between lumbar spine and femoral neck BMD may be influenced by the activity of acromegaly, reflecting the different effects of GH excess on trabecular and cortical bone.

“Moreover, the differences between lumbar spine and femoral neck BMD may be also influenced by the activity of acromegaly, reflecting the different effects of GH excess on trabecular and cortical bone ().”

In studies evaluating both processes of bone remodeling, the differences in bone resorption were higher than those observed for bone formation.

“In studies evaluating both processes of bone remodeling, the differences in bone resorption were higher than those observed for bone formation (, , , , , ), supporting the concept that bone loss occurs in acromegaly as an effect of uncoupled bone turnover ().”

In cross-sectional studies of acromegaly, the rate of fractures was found to be relatively increased in hypogonadal as compared with eugonadal patients.

“Moreover, in five cross-sectional studies including  patients with acromegaly ( patients with hypogonadism,  with active disease), as already reported in other forms of secondary osteoporosis (), the rate of fractures was found to be relatively increased in hypogonadal as compared with eugonadal patients (, , , , ).”

Fractures were multiple in more than two-thirds of women with fractures.

“Fractures were multiple in more than twothirds of women with fractures.”

There is evidence suggesting lower peripheral bioavailability of vitamin D in acromegaly as an effect of an increase in vitamin D binding protein.

“there is also evidence suggesting lower peripheral bioavailability of vitamin D in this clinical setting as an effect of an increase in vitamin D binding protein (, ).”

Joint degenerative disorders, characterized by osteophyte formation and facet joint hypertrophy, may lead to an overestimation of BMD measured at the lumbar spine in acromegaly.

“Joint degenerative disorders, characterized by osteophyte formation and facet joint hypertrophy, may lead to an overestimation of BMD measured at the lumbar spine ().”

Loss of sex steroids increases bone turnover at the trabecular level, which is predominant in the spine.

“consistent with the concept that loss of sex steroids increases bone turnover at the trabecular level, which is predominant in the spine.”

Bone loss occurs in acromegaly as an effect of uncoupled bone turnover.

“supporting the concept that bone loss occurs in acromegaly as an effect of uncoupled bone turnover ().”

Many limitations of areal dual-energy X-ray absorptiometry measurement can be overcome by performing high-resolution peripheral quantitative CT at the distal radius and tibia.

“Many of the limitations of areal DXA measurement can be overcome by performing high-resolution peripheral quantitative CT (HR-pQCT) at the distal radius and tibia.”

No direct effects of PRL on osteoclasts have been demonstrated.

“No direct effects of PRL on osteoclasts were demonstrated.”

A recent retrospective study reported a higher incidence of vertebral fractures in patients with active acromegaly regardless of the therapeutic approach.

“This study reported a higher incidence of VFs in patients with active disease regardless of the therapeutic approach ().”

In hypogonadal patients with acromegaly, BMD was low at the lumbar spine and to a lesser extent at the femoral neck.

“Indeed, when the analysis was performed in hypogonadal patients (, , , -), BMD was low at the lumbar spine and to a lesser extent at the femoral neck (), consistent with the concept that loss of sex steroids increases bone turnover at the trabecular level, which is predominant in the spine.”

Ueland et al. reported loss of trabecular connections and low trabecular bone biomechanical competence in iliac crest biopsies of 13 acromegaly patients with active acromegaly.

“they reported loss of trabecular connections and low trabecular bone biomechanical competence in iliac crest biopsies of  acromegaly patients ( males and  females) with active acromegaly.”

Hypercalciuria may be considered, at least in part, as a marker of skeletal fragility.

“Therefore, hypercalciuria may be considered, at least in part, as a marker of skeletal fragility.”

The biochemical skeletal phenotype in endogenous hypercortisolism may be characterized by uncoupled low bone formation and slightly increased bone resorption.

“However, the biochemical skeletal phenotype may be characterized by uncoupled low bone formation and slightly increased bone resorption (-).”

In ACTH-independent hypercortisolism, abnormalities of bone microstructure are predictive of incident vertebral fractures.

“in ACTH-independent hypercortisolism abnormalities of bone microstructure were shown to be predictive of incident VFs ().”

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In a prospective study, acromegaly patients experiencing incident vertebral fractures had significant reduction in femoral neck BMD during follow-up.

“patients experiencing incident VFs were shown to have significant reduction in BMD at femoral neck during follow-up ().”

• cites Not matched

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In Cushing's disease, lumbar spine BMD is an important predictor of fractures in untreated and treated patients.

“lumbar spine BMD was shown to be an important predictor of fractures in untreated () and treated CD ().”

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• cites Not matched

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Two recent cross-sectional studies reported high prevalence of radiological vertebral fractures in women and men with PRL-oma.

“Two recent cross-sectional studies reported high prevalence of radiological VFs in women and men with PRL-oma (, ).”

When acromegaly is controlled, no significant difference in incident vertebral fractures is observed between pegvisomant and SRLs.

“When acromegaly was controlled, no significant difference in incident VFs was observed between pegvisomant and SRLs ().”

• cites ()Not matched

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Fractures are threefold more frequent in patients with persistently active acromegaly as compared with those in whom acromegaly is controlled by treatment.

“the fractures are threefold more frequent in patients with persistently active disease as compared with those in whom acromegaly is controlled by the treatment (-, , ).”

• cites -Not matched

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Twenty-two percent of premenopausal women with PRL-oma showed a pathological z score with more severe bone loss at lumbar spine as compared with femoral DXA sites.

“Twenty-two percent of premenopausal women with PRL-oma showed a pathological z score (i.e., a z score #2.SD) with more severe bone loss at lumbar spine as compared with femoral DXA sites ().”

In PRL-oma, the association between lower lumbar spine BMD and fractures is lost after adjustment for duration of disease.

“although such an association was lost after adjustment for duration of disease ().”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Pasireotide normalizes urinary cortisol values in 17% to 20% of patients with Cushing's disease.

“Pasireotide normalized urinary cortisol values in % to % of patients with CD (, ).”

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Prevalent vertebral fractures are a marker of skeletal fragility predisposing patients to develop other fractures, even when mild in severity.

“prevalent VFs, which are a marker of skeletal fragility () predisposing patients to develop other fractures (), even when VFs are mild in severity ().”

• cites Not matched

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The concept that prevalent vertebral fractures predispose to other fractures has been confirmed in pituitary diseases by prospective studies in acromegaly or GHD.

“This concept has been confirmed even in the specific setting of pituitary diseases by few prospective studies performed in patients with acromegaly (, ) or GHD ().”

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Several other studies reported a significant association between BMD values and hypogonadism in patients with PRL-oma.

“In contrast, several other studies reported a significant association between BMD values and hypogonadism in patients with PRL-oma (, , -).”

Silva et al. reported deterioration in trabecular microstructure of the radius in 16 eugonadal males with acromegaly.

“This concept was recently reinforced by Silva et al. (), who reported deterioration in trabecular microstructure of the radius in  eugonadal males with acromegaly.”

PRL excess per se may cause skeletal fragility regardless of gonadal status.

“These findings suggested that PRL excess per se may cause skeletal fragility regardless of gonadal status, although the cross-sectional design did not allow defining exactly when VFs developed in relationship with menopausal status ().”

The cross-sectional design did not allow defining exactly when vertebral fractures developed in relationship with menopausal status.

“although the cross-sectional design did not allow defining exactly when VFs developed in relationship with menopausal status ().”

Pasireotide LAR normalizes GH and IGF-I values in 20% of patients not responding to first-generation SRLs.

“Pasireotide LAR is a multireceptortargeted SRL that was shown to normalize GH and IGF-I values in % of patients not responding to first-generation SRLs ().”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Fractionated radiotherapy and stereotactic radiosurgery have comparable efficacy and safety.

“The two approaches were shown to have comparable efficacy and safety ()”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Patients with pituitary diseases without prevalent vertebral fractures and without densitometric osteoporosis may still develop fragility fractures.

“Patients affected by pituitary diseases, without prevalent VFs and densitometric diagnosis of osteoporosis, may still develop fragility fractures.”

In endogenous hypercortisolism, the early and transient phase of high bone turnover is not usually evident because the diagnosis of disease is often delayed with respect to onset of hypercortisolism.

“Differently from exogenous glucocorticoid excess (), in endogenous hypercortisolism the early and transient phase of high bone turnover is not usually evident because the diagnosis of disease is often delayed with respect to onset of hypercortisolism ().”

In patients with persisting active acromegaly, DXA measurement of BMD is of limited reliability in predicting fractures.

“DXA measurement of BMD is of limited reliability in predicting fractures when patients have persisting active disease.”

First-generation somatostatin receptor ligands (octreotide LAR and lanreotide autogel) are the first-line medical therapy of acromegaly either when surgery fails to control GH/IGF-I hypersecretion or as first-line therapy in patients with a low probability of surgical cure.

“First-generation somatostatin receptor ligands (SRLs), octreotide long-acting repeatable (LAR) and lanreotide autogel, are the first-line medical therapy of acromegaly either when surgery fails to control GH/ IGF-I hypersecretion or as first-line therapy in patients with a low probability of surgical cure (, , ).”

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In acromegaly, vertebral fractures often occur in the presence of normal or even high BMD.

“VFs often occur in the presence of normal or even high BMD”

The Prolactin Epidemiology, Audit and Research Study did not find a significant increase in fractures in patients with PRL-oma.

“Using the International Classification of Diseases codes, the Prolactin Epidemiology, Audit and Research Study did not find a significant increase in fractures in patients with PRL-oma, suggesting that this complication could be underestimated in real-life clinical practice ().”

In cross-sectional and prospective studies, biochemical control of acromegaly is associated with a decrease in serum levels of biochemical markers of bone turnover.

“In cross-sectional and prospective studies, biochemical control of acromegaly was associated with a decrease in serum levels of biochemical markers of bone turnover (, , , , , , ).”

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When DXA BMD shows either a decrease or an absolute value in the osteoporosis range, the risk of fractures is high.

“when DXA measurements of BMD report either a decrease of BMD values or an absolute BMD value in the range of osteoporosis, the risk of fractures is high.”

Structural properties of trabecular and cortical bone may be persistently deteriorated after reversal of GH hypersecretion.

“structural properties of trabecular and cortical bone may be persistently deteriorated after reversal of GH hypersecretion”

In Cushing's disease, nearly a third of patients experience long-term failure of surgery and require additional second-line treatment.

“In CD, nearly a third of patients experience in the long-term a failure of surgery and require an additional second-line treatment ().”

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In Cushing's disease, a remarkable number of patients may fracture in the presence of low-normal or even normal BMD values.

“a remarkable number of patients with CD may fracture in the presence of low-normal or even normal BMD values (-, ).”

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Compromised bone microstructure in acromegaly may occur regardless of gonadal status.

“supporting the hypothesis that compromised bone microstructure in acromegaly may occur regardless of gonadal status ().”

In untreated GHD, vertebral fractures occur also in a significant percentage of patients with normal BMD.

“VFs occurred also in a significant percentage of patients with normal BMD ().”

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Normal or low-normal BMD does not exclude that patients may develop fractures.

“the finding of normal or low-normal BMD does not exclude that patients may develop fractures.”

In active acromegaly, untreated hypogonadism and diabetes mellitus do not significantly impact the risk of vertebral fractures.

“both the clinical conditions did not significantly impact the risk of VFs when acromegaly was active”

Normalization of IGF-I values occurs in 60% to 80% of acromegaly patients treated with pegvisomant.

“Normalization of IGF-I values occurs in % to % of acromegaly patients treated with pegvisomant (, ).”

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Vestergaard et al. reported a 60% increase in risk of clinical fractures in PRL-oma before the diagnosis of disease as compared with controls.

“In contrast, Vestergaard et al. () reported a % increase in risk of clinical fractures in PRL-oma before the diagnosis of disease as compared with controls.”

SRLs and pegvisomant may have pleiotropic effects on peripheral targets of acromegaly with potential improvement of clinical endpoints regardless of the achievement of strict biochemical control of disease.

“There is evidence that SRLs and pegvisomant may have pleiotropic effects on peripheral targets of acromegaly with potential improvement of clinical endpoints regardless of the achievement of a strict biochemical control of disease (, , ).”

• cites (, , )Not matched

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Men and women with PRL-oma were equally affected by bone loss.

“Men and women with PRL-oma were equally affected by bone loss (, ).”

The association between pegvisomant and incident vertebral fractures is lost after adjustment for activity of acromegaly.

“Additionally, the association between pegvisomant and incident VFs was lost after adjustment for activity of acromegaly ().”

• cites ()Not matched

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In acromegaly, vertebral fractures are associated with impaired trabecular and cortical microstructure evaluated by HR-pQCT or bone histomorphometry.

“most of the data were derived from patients with acromegaly in whom VFs were associated with impaired trabecular and cortical microstructure evaluated by either HR-pQCT () or bone histomorphometry ().”

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In patients with PRL-oma, treatment with dopamine agonists is accompanied by normalization of serum markers of bone turnover in relationship to normalization of PRL values and restoration of gonadal function.

“In patients with PRL-oma, treatment with dopamine agonists was accompanied by normalization of serum markers of bone turnover in relationship to normalization of PRL values and restoration of gonadal function (, ).”

• cites (, )Not matched

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In a prospective analysis of GHD, incidence of vertebral fractures is significantly correlated with change in lumbar spine BMD T scores and z scores during the study period.

“When the analysis was performed prospectively, the incidence of VFs was significantly correlated with change in lumbar spine BMD T scores and z scores during the study period ().”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Biochemical control of acromegaly can be improved by increasing the SRL dose and frequency over conventional regimens.

“the biochemical control of acromegaly can be improved by increasing the SRL dose (, ) and frequency () over the conventional regimens.”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In Cushing's disease, when BMD values are in the osteoporosis range, the prevalence of vertebral fractures is higher.

“when BMD values were in the range of osteoporosis, the prevalence of VFs in CD was shown to be higher (, )”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In PRL-oma, patients with fractures have lower lumbar spine BMD than those without fractures.

“Patients with fractures with PRL-oma showed lower lumbar spine BMD as compared with patients without fractures (, )”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Even in males, PRL excess may influence fracture risk independent of gonadal status.

“Again, these findings suggest that even in males PRL excess may influence fracture risk independent of gonadal status.”

Duration of active disease is the most important determinant of vertebral fractures in acromegaly.

“Duration of active disease is the most important determinant of VFs in acromegaly ()”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Accelerated bone turnover is expected in patients exposed to PRL excess.

“Accelerated bone turnover is expected in patients exposed to PRL excess (), although biochemical data from clinical studies have been variable, with only few studies reporting an increase in serum levels of markers of bone formation and resorption (, ).”

Introduction of pegvisomant in the medical therapy of acromegaly, alone or in combination with SRLs, is accompanied by a significant decrease in the incidence of vertebral fractures, in close relationship with biochemical control of acromegaly.

“In a recent longitudinal study, the introduction of pegvisomant in the medical therapy of acromegaly (either alone or in combination with SRLs) was accompanied by a significant decrease in the incidence of VFs, in close relationship with biochemical control of acromegaly ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Some patients with controlled acromegaly still maintain high fracture risk, specifically in the presence of untreated hypogonadism and diabetes mellitus.

“some patients with controlled acromegaly still maintained high fracture risk, specifically in the presence of untreated hypogonadism (, ) and diabetes mellitus ()”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Reduction of BMD was more severe in childhood-onset hyperprolactinemic patients than in those who developed the disease in adulthood.

“In fact, reduction of BMD was more severe in childhood-onset hyperprolactinaemic patients than in those who developed the disease in adulthood (, ).”

The risk of vertebral fractures persists high in patients with controlled acromegaly and pre-existing (prevalent) vertebral fractures.

“the risk of VFs persisted high in patients with controlled acromegaly and pre-existing (i.e., prevalent) VFs (, ).”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

SRLs can induce tumor shrinkage in more than 50% of treated acromegaly patients.

“SRLs can induce tumor shrinkage in .% of treated patients (, )”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In PRL-oma, trabecular bone was damaged earlier than cortical bone.

“suggesting that trabecular bone was damaged earlier than cortical bone (, , ).”

The negative skeletal effects of abnormal glucose metabolism and lack of sex steroids may be overcome by those produced by chronically increased GH and IGF-I levels.

“suggesting that the negative skeletal effects of abnormal glucose metabolism and lack of sex steroids may be overcome by those produced by chronically increased GH and IGF-I levels.”

The prevalence of osteoporosis as assessed by DXA in Cushing disease has been reported to be 28% to 50%, in close relationship with activity of disease as assessed by measurement of urinary cortisol values.

“The prevalence of osteoporosis as assessed by DXA has been reported to be % to % (-), in close relationship with activity of disease as assessed by measurement of urinary cortisol values (, ).”

The mean spinal bone density in hyperprolactinemic amenorrheic women was significantly lower than that in eumenorrheic hyperprolactinemic women.

“The mean spinal bone density in the hyperprolactinemic amenorrheic women was significantly lower than that in eumenorrheic hyperprolactinemic women ().”

In acromegaly, bone quality is impaired as an effect of GH hypersecretion.

“supporting the concept that bone quality is impaired as an effect of GH hypersecretion”

In Cushing's disease, vertebral and nonvertebral fractures are not associated with trabecular and cortical bone microstructure as measured by HR-pQCT.

“vertebral and nonvertebral fractures in CD were not associated with trabecular and cortical bone microstructure as measured by HR-pQCT ().”

• cites Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In acromegaly, vertebral fractures are always a hallmark of skeletal fragility.

“confirming that in acromegaly, such as in other forms of osteoporosis (, ), VFs are always a hallmark of skeletal fragility.”

Repeated measurements of BMD may provide some information about ongoing risk of vertebral fractures.

“repeated measurements of BMD may provide some information about the ongoing risk of VFs.”

The underlying pituitary disease may alter the effects of rhGH on bone mass.

“The underlying pituitary disease may alter the effects of rhGH on bone mass.”

Vestergaard et al. showed a 14% decrease of annual rate of clinical fractures after diagnosis of PRL-oma.

“Vestergaard et al. () showed a % decrease of annual rate of clinical fractures after diagnosis of PRL-oma, suggesting a positive impact of treatment on fracture risk.”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The effect of rhGH on biochemical markers of bone turnover is dose-dependent.

“The effect of rhGH on biochemical markers of bone turnover is dosedependent (, , , ) but not influenced by the modality of administration (i.e., continuous vs daily administration, and daily vs administration three times a week) (, ).”

• cites (, , , )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In prospective and retrospective studies of 10 to 15 years, femoral neck BMD peaked at 5 to 7 years and returned to baseline at 10 to 15 years.

“In prospective and retrospective studies of  to  years in duration, lumbar spine BMD continued to increase for up to  years but subsequently plateaued (, , ), whereas femoral neck BMD peaked at  to  years and returned to baseline at  to  years (, ).”

• cites (, )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In a meta-analysis including 31 studies with 1340 patients (902 treated for >12 months), Barake et al. found a significant increase in lumbar spine and femoral neck BMD when treatment was >12 months (18 to 180 months).

“In a recent meta-analysis including  studies with  patients ( treated for .months), Barake et al. () found a significant increase in lumbar spine and femoral neck BMD when treatment was .months ( to  months).”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The earlier recovery of BMD after cure of CD in children compared with adults likely reflects rapid growth and increased bone turnover in the first decades of life.

“The recovery of BMD after the cure of CD seems to occur earlier in children as compared with adults, likely reflecting both the rapid growth and the increase of bone turnover in the first decades of life (, ).”

rhGH causes an increase in serum and urinary calcium after 3 to 6 months.

“rhGH causes an increase in serum and urinary calcium after  to  months, an effect caused by calcium mobilization from the skeleton, an increase in intestinal calcium absorption, and in the renal reabsorption of calcium due to increased sensitivity to PTH (-).”

• cites (-)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Underlying genetic differences may play a role in fracture risk of GHD patients.

“Underlying genetic differences may play a role in fracture risk of GHD patients.”

In PRL-oma, improvement of BMD is associated more with recovery from hypogonadism than with suppression of PRL levels.

“In general, the improvement of BMD was associated with the recovery from hypogonadism, more than to the suppression of PRL levels (-, , , , ).”

• cites (-, , , , )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The high incidence of bone-related events makes clinical trials of fracture preventive strategies possible in pituitary disease populations.

“Even considering the relative rarity of pituitary diseases, the high incidence of bone-related events makes such studies possible in those populations, despite the need for multicenter trials with long follow-up.”

Changes in bone turnover after correction of hypercortisolism are expected to be associated with an increase in BMD.

“These changes in bone turnover are expected to be associated with an increase in BMD, although the densitometric outcomes after treatment of hypercortisolism were shown to be variable, with some patients recovering normal BMD (, ) and others showing persistently abnormal BMD for several years after the cure of CD (, -).”

The study design of Holmer et al. limited the possibility of separately evaluating the effects of untreated and treated GHD on fracture incidence, because the person-years risk before starting rhGH therapy was too low for a reliable interpretation of GHD-specific fracture risk.

“The study design limited the possibility of separately evaluating the effects of untreated and treated GHD on fracture incidence, because the person-years risk before starting rhGH therapy was too low for a reliable interpretation of GHD-specific fracture risk.”

• cites [441] Holmer, 2007, Fracture incidence in GH-deficient patients on complete hormone replacement including GH, J Bone Miner Res sourceNot checked — no full text of the source

Antiresorptive agents, specifically alendronate, may be used to prevent bone loss during the first months of rhGH therapy in GHD patients.

“These findings suggest that antiresorptive agents, specifically alendronate, may be used to prevent bone loss during the first months of rhGH therapy in GHD patients.”

Persistently pathological BMD is reported in children several years after cure of CD.

“However, persistently pathological BMD was reported in children several years after cure of CD (, ).”

• cites (, )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

No studies have been performed so far to test the efficacy and safety of antiosteoporotic drugs in acromegaly.

“Despite the growing body of knowledge about bone fragility in acromegaly, no studies have been performed so far to test the efficacy and safety of antiosteoporotic drugs in this clinical setting.”

The heterogeneity in glucocorticoid replacement is increased by the absence of reliable biochemical or clinical markers of adequacy of glucocorticoid replacement.

“This is increased by the absence of reliable biochemical or clinical markers of adequacy of glucocorticoid replacement.”

Fat tissue has a role in the pathophysiology of bone recovery after remission of CD.

“Interestingly, improvement in lumbar spine BMD after the cure of hypercortisolism was predicted by a decrease in body mass index during the follow-up period (), suggesting a role for fat tissue in the pathophysiology of bone recovery after remission of CD ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

After 6 years of follow-up, risk of VFs was sevenfold higher in untreated as compared with treated GHD.

“After 6 years of follow-up, risk of VFs was sevenfold higher in untreated as compared with treated GHD.”

• cites [450] Mazziotti, 2016, Incidence of morphometric vertebral fractures in adult patients with growth hormone deficiency, Endocrine sourceNot checked — no full text of the source

Monitoring of skeletal health in pituitary diseases cannot be evidence based.

“Because no specific guidelines have been so far published on this topic, the monitoring of skeletal health in pituitary diseases cannot be evidence based.”

When long-acting glucocorticoids are used, one daily dose of approximately 5 mg prednisone and 0.5 mg dexamethasone is sufficient to replace cortisol insufficiency.

“When long-acting glucocorticoids are used, one daily dose of ~ mg of prednisone and . mg of dexamethasone is sufficient to replace cortisol insufficiency (, ).”

• cites (, )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

At these doses, L-T4 may cause skeletal fragility, especially when GHD is replaced.

“However at these doses, L-T may cause skeletal fragility, especially when GHD is replaced”

Patients with hypopituitarism under treatment with rhGH and estrogens may need higher glucocorticoid dose compared with patients in whom GHD and hypogonadism are not replaced, owing to inhibitory effects of GH on peripheral activation of cortisone in cortisol and decrease of cortisol bioavailability induced by estrogens.

“Patients with hypopituitarism under treatment with rhGH and estrogens may need higher glucocorticoid dose as compared with patients in whom GHD and hypogonadism are not replaced, owing to the inhibitory effects of GH on peripheral activation of cortisone in cortisol () and the decrease of cortisol bioavailability induced by estrogens ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Long-term use of rhGH does not preclude a beneficial effect of antiresorptive agents in GHD patients with osteoporosis.

“Moreover, there is also evidence that the long-term use of rhGH does not preclude a beneficial effect of antiresorptive agents in GHD patients with osteoporosis.”

The effect of rhGH on biochemical markers of bone turnover is not influenced by modality of administration (continuous vs daily, daily vs three times a week).

“The effect of rhGH on biochemical markers of bone turnover is dosedependent (, , , ) but not influenced by the modality of administration (i.e., continuous vs daily administration, and daily vs administration three times a week) (, ).”

• cites (, )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Randomized placebo-controlled trials of 18 to 24 months showed mixed results with either improvements or no effects on lumbar spine BMD.

“Randomized placebo-controlled trials of  to  months showed mixed results with either improvements or no effects on lumbar spine BMD (, ).”

• cites (, )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Longer prospective and nonrandomized studies reported more favorable effects of rhGH therapy on BMD.

“Longer prospective and nonrandomized studies reported more favorable effects of rhGH therapy on BMD (, , ).”

• cites (, , )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Patients with previous fractures are predisposed to develop new fractures after treatment of CD.

“Of note, patients with previous fractures were predisposed to develop new fractures after treatment of CD (), confirming that fractures are a hallmark of skeletal fragility in CD such as observed in other pituitary diseases (, ).”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

In prospective and retrospective studies of 10 to 15 years, lumbar spine BMD continued to increase for up to 10 years but subsequently plateaued.

“In prospective and retrospective studies of  to  years in duration, lumbar spine BMD continued to increase for up to  years but subsequently plateaued (, , ), whereas femoral neck BMD peaked at  to  years and returned to baseline at  to  years (, ).”

• cites (, , )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Male patients under treatment of PRL-oma show higher prevalence of vertebral fractures compared with age-matched control subjects.

“In fact, male patients under treatment of PRL-oma showed still higher prevalence of VFs as compared with age-matched control subjects ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The early effects of rhGH on bone turnover may explain why randomized placebo controlled trials of less than a year in duration showed either no significant change in BMD or some decline.

“The early effects of rhGH on bone turnover may explain why randomized placebo controlled trials of less than a year in duration showed either no significant change in BMD or some decline (, , , , , , -).”

• cites (, , , , , , -)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Early treatment of CD may have a favorable impact on fracture risk.

“The close association between fragility fractures and severity of hypercortisolism () and duration of disease () suggests that an early treatment of CD may have a favorable impact on fracture risk ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Combining studies that evaluated radiological vertebral fractures, treatment with dopamine agonist is accompanied by a significant decrease in fracture risk (OR, 0.25; 95% CI, 0.11 to 0.59).

“Combining the studies that evaluated radiological VFs, treatment with dopamine agonist was accompanied by a significant decrease in fracture risk (OR, .; % CI, . to .) ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

rhGH replacement therapy may not fully restore bone health in GHD patients previously exposed to GH excess, especially when treatment of GHD is started late after diagnosis of disease and patients had already developed fractures before replacement therapy.

“This finding suggests that rhGH replacement therapy may not fully restore bone health in GHD patients previously exposed to GH excess, especially when treatment of GHD is started late after diagnosis of disease and patients had already developed fractures before replacement therapy.”

No specific guidelines have been published on monitoring skeletal health in pituitary diseases.

“Because no specific guidelines have been so far published on this topic, the monitoring of skeletal health in pituitary diseases cannot be evidence based.”

The increase in DKK-1 in response to rhGH is consistent with the concept that bone formation is blunted during the first months of treatment.

“Interestingly, a recent study reported an increase in circulating and cortical bone matrix protein levels of the Wnt signaling antagonist DKK- in response to  to  months of treatment with rhGH, consistent with the concept that bone formation is blunted during the first months of treatment ().”

A recent study reported an increase in circulating and cortical bone matrix protein levels of the Wnt signaling antagonist DKK-1 in response to 9 to 12 months of treatment with rhGH.

“Interestingly, a recent study reported an increase in circulating and cortical bone matrix protein levels of the Wnt signaling antagonist DKK- in response to  to  months of treatment with rhGH, consistent with the concept that bone formation is blunted during the first months of treatment ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Effects of dopamine agonists on fracture risk in PRL-oma are largely unknown because only three cross-sectional studies have investigated fracture prevalence in relation to PRL-oma treatment.

“The effects of dopamine agonists on fracture risk are largely unknown, because only three crosssectional studies have investigated the prevalence of fractures in relationship to treatment of PRL-oma (, , ) (Table ).”

• cites (, , )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Early actions of rhGH on skeletal tissue induce activation of multiple bone remodeling units with consequent expansion of remodeling space and transient removal of bone during resorption before new bone is formed.

“The early actions of rhGH on skeletal tissue induce activation of multiple bone remodeling units with consequent expansion of remodeling space and transient removal of bone during resorption before new bone is formed (, ).”

• cites (, )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The 14% decrease in annual rate of clinical fractures after PRL-oma diagnosis suggests a positive impact of treatment on fracture risk.

“Vestergaard et al. () showed a % decrease of annual rate of clinical fractures after diagnosis of PRL-oma, suggesting a positive impact of treatment on fracture risk.”

Improvement in lumbar spine BMD after cure of hypercortisolism is predicted by a decrease in body mass index during follow-up.

“Interestingly, improvement in lumbar spine BMD after the cure of hypercortisolism was predicted by a decrease in body mass index during the follow-up period (), suggesting a role for fat tissue in the pathophysiology of bone recovery after remission of CD ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Replacement therapy with rhGH leads to an increase in bone turnover, as determined by changes in biochemical markers of bone resorption and bone formation.

“Replacement therapy with rhGH leads to an increase in bone turnover, as determined by changes in biochemical markers of bone resorption and bone formation ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Hydrocortisone has a short half-life of approximately 90 minutes.

“Hydrocortisone has a short half-life (~ minutes) (), and multiple dosing is recommended to try mimicking physiological conditions.”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

rhGH may normalize the circadian rhythm of PTH secretion.

“rhGH may normalize the circadian rhythm of PTH secretion ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

There is significant heterogeneity in type, dose, frequency, and timing of glucocorticoid replacement of adrenal insufficiency in real-life clinical practice.

“There is a significant heterogeneity in the type, dose, frequency, and timing of glucocorticoid replacement of adrenal insufficiency in real-life clinical practice ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

The decrease in BMD at the distal and total radius after cure of hypercortisolism is explained by a possible redistribution of bone minerals from the peripheral to axial skeleton.

“Interestingly, BMD decreased at the distal and total radius in the first  to  years after the cure of hypercortisolism, and this finding was explained by a possible redistribution of bone minerals from the peripheral to axial skeleton ().”

Some patients with cured pituitary disease may maintain high risk of fractures.

“However, some patients with cured pituitary disease may maintain high risk of fractures, providing the rationale to use boneactive drugs in this specific clinical setting”

The effect of rhGH on bone formation is sustained for prolonged periods of time.

“The effect on bone formation is sustained for prolonged periods of time (, , -).”

• cites (, , -)Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

BMD decreases at the distal and total radius in the first 3 to 4 years after cure of hypercortisolism.

“Interestingly, BMD decreased at the distal and total radius in the first  to  years after the cure of hypercortisolism, and this finding was explained by a possible redistribution of bone minerals from the peripheral to axial skeleton ().”

• cites ()Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

Biochemical control of acromegaly, PRL-oma, and CD is associated with a significant decrease in risk of fractures, especially when effective treatment is undertaken early after diagnosis.

“In summary, the biochemical control of acromegaly, PRL-oma, and CD was shown to be associated with a significant decrease in the risk of fractures, especially when an effective treatment was undertaken early after diagnosis of disease.”

Recovery of BMD after cure of CD seems to occur earlier in children compared with adults.

“The recovery of BMD after the cure of CD seems to occur earlier in children as compared with adults, likely reflecting both the rapid growth and the increase of bone turnover in the first decades of life (, ).”

• cites (, )Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.