Skeletal Health in Pituitary and Neuroendocrine Diseases: Prevention and Treatments of Bone Fragility

Abstract

Bone loss is common in patients affected by pituitary and neuroendocrine disorders as both hormone excess and hormone deficiency can affect bone structure. There is increasing evidence that pituitary hormones directly influence bone cells turnover by bypassing endocrine organs. Osteopenia, osteoporosis, and vertebral fractures often result from these skeletal changes; however, diagnosing and managing bone frailty in pituitary and neuroendocrine disorders is still challenging because of the unpredictable outcomes in terms of fracture risk, even after the improvement of pituitary dysfunction, and the limited evidence for the use of bone-active drugs in these pathologies. The use of vitamin D supplements for fracture prevention is still debated in these secondary forms of bone frailty, although some studies have shown similar benefits to those derived in the general population. This review offers an overview on the characteristics of bone fragility in different pituitary and neuroendocrine diseases, and focuses on the prevention and treatment of skeletal disorders with bone-active drugs and vitamin D formulations currently available in this setting.

1. Introduction

Through direct and indirect effects on bone cells, pituitary hormones are involved in maintaining skeletal health and may bypass endocrine organs [1,2]. Bone loss is common in patients with pituitary and neuroendocrine disorders, and both excesses and deficiency of pituitary hormones, such as adrenocorticotropic hormone (ACTH), growth hormone (GH), thyroid-stimulating hormone (TSH), gonadotropins (FSH and LH), and prolactin (PRL), can affect bone structure. Skeletal changes, mediated by peripheral hormones such as insulin-like growth factor 1 (IGF-I), cortisol, free triiodothyronine (fT3) and free thyroxine (fT4), estradiol, and testosterone, can manifest as osteopenia, osteoporosis, and fractures. In many pituitary disorders, vertebral fractures (VFs) are a hallmark of secondary osteoporosis [1], strongly associated with decreased survival and quality of life (QoL), depending on the degree of pituitary dysfunction and disease duration [2]. Diagnosing and managing bone frailty in pituitary and neuroendocrine disorders is still challenging because of the difficulties reported in clinically characterizing skeletal fragility in this context due to the unpredictable outcome of fracture risk even after improvements in pituitary dysfunction, the unreliable information provided by dual-energy X-ray absorptiometry (DXA), and the limited evidence for the use of bone-active drugs in these pathologies. Therefore, in most pituitary and neuroendocrine disorders, morphometric X-ray absorptiometry is currently the main method for assessing vertebral morphology [3]. The high-resolution peripheral quantitative computed tomography (HR-pQCT), a three-dimensional non-invasive imaging technique that scans the extremities and can evaluate volumetric bone density and the microarchitecture of cortical bone, has been proposed as a complementary tool to assess bone fragility risk in secondary osteoporosis but, due to its high costs, it is currently mainly used for research purposes [4,5]. Other diagnostic techniques, such as the measurement of the trabecular bone score (TBS) using the two-dimensional lumbar spine DXA image, or the bone material strength index (BMSi) using the OsteoProbe, can be valuable alternatives and complementary methods for identifying bone deterioration [2]. The treatment of skeletal fragility in pituitary and neuroendocrine disorders involves using bone-active drugs that are already approved for treating other types of osteoporosis. These include anabolic treatments (e.g., teriparatide, abaloparatide, romosozumab) and catabolic treatments (e.g., bisphosphonates, denosumab). These therapies have been shown to be effective in the improvement of bone density and the prevention of bone fractures [6]. On the other hand, there is still debate about vitamin D (VD) supplementation in this specific setting. Although the protective effect of VD supplementation on fracture risk has been demonstrated in some specific populations with hypovitaminosis D (i.e., elderly, postmenopausal, glucocorticoid-induced osteoporosis), few studies have investigated the preventive role of supplementation with VD in different formulations and metabolites (i.e., cholecalciferol, alfa-calcidiol, calcitriol) on fracture risk in pituitary and neuroendocrine secondary osteoporosis. This review will focus on the characteristics, prevention, and treatment of skeletal fragility in patients with pituitary and neuroendocrine disorders, also offering an overview of bone-active drugs and vitamin D formulations currently available.

2. Methods

The literature search was performed in April 2025. We explored MEDLINE (PubMed database), using the following keywords: (osteoporosis OR osteopenia OR fractures) AND (pituitary diseases OR neuroendocrine diseases) AND (bone OR skeletal fragility) AND (vitamin D OR bone-active drugs). The papers met the following inclusion criteria: (1) written in English; (2) published before 1 June 2025; (3) original studies and case reports concerning the characteristics, prevention, and treatment of osteoporosis in pituitary and neuroendocrine diseases. We selected and analyzed pertinent articles and we focused on information regarding the management of skeletal fragility occurring in patients affected by pituitary and neuroendocrine disorders. This review was conducted in accordance with the 2020 PRISMA guidelines for systematic reviews [7]. While the PRISMA guidelines are primarily intended for systematic reviews, we chose to follow them to enhance the transparency and rigor of our literature search and selection process. However, we acknowledge that our work does not fulfill all the methodological requirements of a systematic review. In particular, we did not pre-register a review protocol, conduct a formal risk of bias assessment, or perform a meta-analysis. Rather, our aim was to conduct a structured and critical narrative review that identifies key themes and trends in the literature. For this reason, we refer to our work as a “review,” as this term more accurately represents the scope and intent of our manuscript, which still adhered to high methodological standards where applicable.

3. Skeletal Health in Pituitary and Neuroendocrine Diseases: Osteopenia, Osteoporosis, and Fractures

The impairment of bone structure and strength, as well as bone loss, may appear as a consequence of hormonal hypersecretion caused by pituitary neuroendocrine tumors, such as in Cushing disease (CD); in acromegaly; in PRL-secreting tumors, namely, prolactinomas; and TSH-secreting tumors. Additionally, it can occur in cases of hyposecretion, such as GH deficiency (GHD), hypogonadotropic hypogonadism (HH), or in general hypopituitarism, which may be consequent to different neuroendocrine diseases, such as hypophysitis, pituitary metastasis, craniopharyngioma, Langerhans cell histiocytosis, and pituitary germinoma. In each case, an alteration of the bone structure occurs, which causes a loss of bone mass and skeletal fragility, which can manifest in the form of osteopenia, osteoporosis, and vertebral fractures.

3.1. Osteopenia

Osteopenia is a bone disorder characterized by reduced bone mass and the microarchitectural deterioration of the skeleton. This is defined as a T-score between −1 and −2.5 SD in the postmenopausal women and in men of 50 years older. In younger subjects, a Z-score of 2.0 or lower is used to define a BMD below the expected range for age [8]. Several studies have shown that osteopenia is a common feature of pituitary and neuroendocrine diseases.

In hypercortisolism, bone fragility is one of the most serious complications, irrespective of exogenous or endogenous origin, and it often manifests in the form of osteopenia. CD remains the most frequent cause of endogenous cortisol hypersecretion and the grade of impairment of bone health mainly depends on the time of exposure and excessive levels of serum cortisol [9]. Bone deterioration has been described in 64–100% of patients with endogenous hypercortisolism: osteopenia occurs approximately in 40–78%, osteoporosis occurs in 22–57%, and skeletal fractures occur in 11–76% of CD patients [10]. Patients with CD may experience less severe bone loss than patients with adrenal hypercortisolism because of the protective role of adrenal androgens, which have a greater presence in CD as a consequence of ACTH stimulation [11,12]. Moreover, the possible addition of testosterone deficiency may negatively affect the bone structure, meaning men with endogenous hypercortisolism are more likely to suffer from osteoporosis and vertebral fractures than women [13]. Conversely to postmenopausal osteoporosis or hyperparathyroidism, hypercortisolism mainly disturbs bone formation processes, through the inhibition of osteoblast differentiation and the inactivation of the Wnt/β-catenin signaling pathway [2]. Prior to this phase, an initial increase in bone resorption is mediated by the predomination of the receptor activator of nuclear factor-κB ligand (RANKL), produced by osteoblasts and osteocytes [14]. A study evaluated BMD in 77 patients affected by Cushing’s syndrome (CS), and osteopenia was observed in 82% of cases, with low Z-score levels in both the lumbar spine (−1.07 SD), and in the femoral neck (−0.81 SD) [15].

Osteopenia is also a frequent manifestation of skeletal fragility in acromegaly and GHD. This is due to an excess in the first case and a deficiency of GH in the other case. Some studies on animal models and humans have attempted to elucidate the mechanisms at the base of the altered bone structure when the GH/insulin growth factor 1 (IGF-I) axis is impaired. A study on mice with mutations of the GH-releasing hormone receptor (GHRH-R), the GH receptor (GHR), or liver-specific IGF-I invariably showed a decreased cortical bone volume, but preserved trabecular bone [16], reduced periosteal bone formation, and thus osteopenia [17]. Mice with altered IGF-I synthesis displayed an altered number of functional osteoclasts [18] or osteoblasts [19], underlining the fundamental role of IGF-I in normal bone cell genesis (Table 1). Another study on mice carrying deletions of the signaling molecules IRS-1 and -2 showed the occurrence of osteopenia [20,21], confirming the physiological function of IGF-I in maintaining skeletal homeostasis. The role of insulin growth-factor binding protein 3 (IGFBP-3), a main element of the IGF complex, has been underlined in some studies, showing that its concentrations are GH-dependent [22], and its constitutive activation may cause growth retardation and osteopenia [23].

GHD can be a congenital condition, usually presenting during childhood, or an acquired condition, manifesting later in life. Childhood-onset GHD generally results in short stature and growth retardation, while adult-onset GHD in reduces energy levels, impairs cardiac function, causes metabolic abnormalities, and impairs bone structure. A lower BMD, compared to the peak bone mass of a young adult population, has been identified in adolescents with GHD, who generally discontinue GH treatment at the completion of linear growth. Given the early increment of bone remodeling indices, which may persist for up to 5 years, the importance of GH replacement therapy has been discussed in adult-onset GHD patients [24]. In fact, in adult patients, BMD values and the degree of bone loss seem to be influenced by the early onset of GH deficiency [25,26,27], particular t if it occurs before 30 years of age, and correlates with the severity of the disease [28,29,30,31,32], presenting more severe osteopenia from healthy controls. Beckers et al. analyzed the changes in body composition in 21 GHD adults after treatment with recombined GH for a wide time range from 9 to 78 months. After 12 months, DEXA displayed a bone mass and density gain, in particular in the axial skeleton [33]. Also, Gómez et al. aimed to assess the effects of long-term GH therapy on bone metabolism and BMD in adult subjects with GHD. In total, 20 patients were included in this randomized study; these were divided into 2 groups. One group received replacement therapy from the beginning of the study; the other group started GH treatment after 6 months. Similarly to the other studies, the GHD patients had low BMD values but, after prolonged GH replacement therapy, they showed an increase in BMD and Z-score values, which remained stable even after 12 months of GH treatment withdrawal [34]. Thus, the protective effect of GH replacement therapy against the onset of bone fragility disorders has been suggested.

Acromegaly osteoarthropathy is an emerging complication that increases disability and decreases QoL. Skeletal fragility is prevalent in 30–60% in acromegaly patients. Most patients display osteopenia, especially if the disease is not fully controlled [2]. Specific analysis was performed on the hip joints of acromegalic patients treated by total hip arthroplasty, showing diffused osteopenia and a subverted bone structure due to the presence of medial osteophytes, moderate chronic lymphoplasmacytic synovitis, and the irregular pitting of the subchondral bone. This indicates the peculiar bone picture of acromegaly arthropathy [35].

The PRL’s excess may induce the development of osteopenia, osteoporosis and fragility fractures [36,37] through an increase in the serum PRL levels that can impact on bone cells and calcium metabolism, a direct mechanism, or through the hypogonadism effect induced by PRL excess, an indirect mechanism [38]. In patients affected by PRL-secreting tumors, there does not appear to be a gender difference in the incidence of bone loss [39,40]. According to some studies, approximately 80% percent of male patients with prolactinoma were affected by osteopenia or osteoporosis at the lumbar spine, while only 30% showed a low BMD at the femoral neck. These data may suggest the earlier impairment of the trabecular bone than the cortical bone [41,42].

Partial or complete hypopituitarism, a condition characterized by the deficiency of one or more hormones, can occur in pituitary and neuroendocrine diseases due to the destruction of the gland, the mass effect, and surgery. According to several studies, hypopituitarism has been associated with osteopenia. Ragnarsson et al. performed a cross-sectional study on 365 patients with hypopituitarism on treatment with glucocorticoid replacement therapy (GRT) (average hydrocortisone equivalent dose of approximately 20 mg per day), and demonstrated the independent association of GRT with reduced BMD and a higher prevalence of osteopenia [43]. Another study was also conducted on women affected by hypopituitarism, demonstrating that androgen levels, markedly reduced in these patients, and lean body mass may be relevant BMD determinants in this setting [44]. As already mentioned, hypopituitarism is a condition that may occur in patients who undergo surgery in the sella turcica region for pituitary tumors or parasellar lesions. A study was conducted by Okinaga et al. on 35 postoperative patients after the surgical removal of pituitary tumors, craniopharyngiomas, Ratke’s cleft cysts, and pituitary abscess to assess BMD values before starting any treatment with bone-active drugs or hormonal replacement therapy. An increased risk of osteopenia was found in these patients, especially in those operated for craniopharyngiomas, regardless of age at diagnosis or at surgery [45]. Sheehan’s syndrome (SS) is a well-characterized cause of hypopituitarism. It is a rare disorder that classically happens after delivery due to significant blood loss. Also, in this case, a study including 35 patients with SS showed reduced values of tibial cortical BMD, even if they were adequately replaced for respective hormone deficiencies [46]. These results corroborate two previous studies aimed at assessing BMD in patients with SS, which similarly detected a low bone mineral mass [47,48]. Agarwal et al. conducted an open-label, prospective, cross-sectional study on 19 subjects with SS, showing a significantly lower BMD compared to controls in the lumbar spine, hip and femoral neck, with an improvement only seen in lumbar spine BMD after the replacement of estradiol and supplementation with calcium and cholecalciferol [49].

Bone health results are usually also altered in HH, characterized by a gonadotropin deficiency, with a higher risk of osteopenia and, consequently, osteoporosis [50,51,52,53,54,55,56,57]. A retrospective study on 138 women with idiopathic HH indicated that most of them had osteopenia and low bone age [58]. Finkelstein et al. assessed the impact of testosterone deficiency on skeletal health in 23 men with isolated gonadotropin-releasing hormone deficiency, finding that osteopenia was severe in men with both immature and mature bone ages, and cortical BMD was at least 2 SD below normal in 16 of them [59]. The long-term effects of testosterone replacement therapy in congenital HH were investigated by Antonio et al. The results of this retrospective observational study demonstrated a stable BMD at femoral and lumbar sites; however, it remained in the osteopenic/osteoporotic range, and there were only limited osteoanabolic effects from the supplemental therapy [60]. Similar results were found in a further study that analyzed a cohort of 51 patients affected by HH (congenital or due to Kallmann syndrome) who were treated with testosterone and/or combined gonadotropins. Reductions in cortical and trabecular BMD, as well as cortical thickness at the tibia and the radius, were revealed. Moreover, precocious treatment conferred a significant advantage for trabecular bone volume, highlighting the importance of an early start for treatment [61]. Varimo et al. also corroborated these data [62]. Another retrospective observational study investigated the effects of testosterone replacement therapy on BMD in postoperative hypogonadal patients with pituitary tumors. After a prolonged follow-up period of 56 months on average, significant beneficial effects were observed on lumbar BMD, but with minimum changes in femur neck BMD or total femur BMD [63]. In conclusion, although osteopenia is a very common feature in pituitary and neuroendocrine patients, most studies have shown that adequate replacement may protect bone structures from changes due to hormone deficiency.

3.2. Osteoporosis

Osteoporosis is a skeletal disorder leading to bone fragility and fracture predisposition and a relevant cause of morbidity and mortality. It is defined by a T-score less than or equal to −2.5 SD at the hip or spine, according to the World Health Organization criteria based on comparisons of patient’s BMD with the average for young adults, accompanied by adjustments for race and gender. The measurement of bone mineral density (BMD) at lumbar spine, total hip, and femoral neck by dual-energy X-ray absorptiometry (DXA) is currently the mainstay of osteoporosis diagnosis. These densitometric definitions are applicable only for postmenopausal women and men aged equal to or older than 50 years; conversely, a Z-score, that is the number of standard deviations from age-matched controls, of 2.0 or lower is used for younger subjects to define BMD, as clarified before [8]. Osteoporosis can be classified in primary or secondary forms, whether caused by an underlying disease or medication. Pituitary and neuroendocrine disorders are a relevant and increasing cause of secondary osteoporosis. It should not be underestimated because treatment response may be limited if the underlying disorder is unrecognized [64].

In CD, hypercortisolism is an important determinant of osteoporosis that can manifest asymptomatically and constitute the first clinical feature of the disease. Osteoporosis in CD has a complicated multifactorial pathogenesis, determining low bone turnover and bone formation suppression. Endogenous hypercortisolism significantly impacts bone structure, causing deterioration that persists after hypercortisolism ceases. Patients with CD typically exhibit no long-term improvement in BMD values or histomorphometric examination [65]. However, in the majority of patients with pituitary pathologies (e.g., acromegaly, CD, GHD), the assessment of osteoporosis using BMD values alone appears to be partially dependable. For this reason, there are only a few limited studies in this area due to the unreliability of the measurement and the complexity of the structural bone damage, and other tools have been used to address this issue. Through the measurement of lumbar spine TBS, Hong et al. revealed lower values of 6% in acromegaly patients, without, however, detecting any significant difference in BMD [66]. Another study, involving 48 patients with active acromegaly naïve to any treatment, discovered TBS values were partially degraded [67].

Osteoporosis is a distinctive feature of HH and, in contrast to other pituitary disorders, some studies have been carried out on this condition using BMD values. A retrospective study found the significantly high occurrence of both osteopenia (30%) and osteoporosis (54%) in HH [68]. In addition to osteopenia, several studies evaluated the impact of replacement therapies on bone health. A study on BMD in 21 subjects with isolated GnRH deficiency investigated the effects of gonadal steroid replacement on bone density in osteoporosis by examining two different groups of men: one with open and one with fused epiphyses. An increase in cortical bone density during the treatment of these men with idiopathic HH was found, particularly in those skeletally immature [69], confirming the results of a previous study of the same group [59]. Subsequent studies corroborated that young hypogonadal men with maturation abnormalities may present low BMD (p < 0.009 for the lumbar spine and p < 0.006 for the femoral neck) [70]. De Rosa et al. evaluated BMD and bone markers in a cohort of 12 patients with idiopathic HH after prolonged treatment with testosterone enanthate (250 mg i.m. every 3 weeks). Half of them were affected by osteoporosis and the remaining portion were affected by osteopenia. Compared to controls, BMD of the spine was significantly lower, while bone markers were increased [71]. The role of testosterone has also been evaluated in a randomized and prospective study that included 32 men with severe deficiencies of GH and testosterone due to panhypopituitarism. Although results did not show an improvement in BMD measured in the distal tibia, testosterone alone seemed to determine the structural increase in trabecular bone [72].

As with HH, hyperprolactinemia significantly impacts on skeletal health, often presenting in the form of osteoporosis. High levels of serum prolactin contribute to the stimulation of bone resorption and the suppression of bone resorption [73]. A study on animal models showed that prolactin may exert a direct inhibitory impact on the functioning of osteoblasts (Table 1) [74]. Prolactin seems to be involved in the upregulation of osteoclastogenic modulators, suggesting a possible direct effect on osteoclasts [75,76]. A study conducted by Schlechte et al. measured BMD in women with hyperprolactinemia, finding 25% lower values than in healthy women, while women who underwent successful transsphenoidal pituitary surgery for prolactin-secreting pituitary tumors, with regular menstrual cycles, had a slightly higher spinal bone mineral content than women with amenorrhea, but this was still lower compared to healthy women [77]. Bone structure in fertile female patients with hyperprolactinemia caused by pituitary tumors resulted in impaired in some studies, with decreases of 17% in cortical bone density [78] and 15–30% in trabecular bone density [79,80].

The presented data indicate that it may be beneficial to focus on the early detection of signs of skeletal health impairment in case of either homonal excess or deficiency. This suggests that it may be appropriate to perform bone frailty screening in pituitary and neuroendocrine pathologies.

Table 1. An overview of studies on skeletal health in pituitary and neuroendocrine diseases in animal models or cell models, summarizing the mechanistic pathways and the main outcomes.

Authors	Year of Publication	Disease Model	Animal/Cell Models	Mechanistic Pathways	Main Results
Sjögren et al. [17]	2002	GHD	Mice transgenic model (IGF-I-/-)	liver-specific IGF-I inactivation on skeletal growth and adult bone metabolism	Reduced periosteal bone formation, and adult axial skeletal growth, osteopenia.
Ogata et al. [19]	2000	GHD	Mice transgenic Model IRS-1(-/-)	deletions of the signaling molecules IRS-1 and -2	Impaired osteoblast proliferation, differentiation, and support of osteoclastogenesis, resulting in low-turnover osteopenia.
Bataille-Simoneau et al. [74]	1996	Hyperprolactinemia	Human osteosarcoma cell lines (MG-63 and Saos-2)	PRL-R transcript enhanced in cultured cells	Prolactin may exert a direct inhibitory impact on the functioning of osteoblasts.

Table 1. An overview of studies on skeletal health in pituitary and neuroendocrine diseases in animal models or cell models, summarizing the mechanistic pathways and the main outcomes.

Authors	Year of Publication	Disease Model	Animal/Cell Models	Mechanistic Pathways	Main Results
Sjögren et al. [17]	2002	GHD	Mice transgenic model (IGF-I-/-)	liver-specific IGF-I inactivation on skeletal growth and adult bone metabolism	Reduced periosteal bone formation, and adult axial skeletal growth, osteopenia.
Ogata et al. [19]	2000	GHD	Mice transgenic Model IRS-1(-/-)	deletions of the signaling molecules IRS-1 and -2	Impaired osteoblast proliferation, differentiation, and support of osteoclastogenesis, resulting in low-turnover osteopenia.
Bataille-Simoneau et al. [74]	1996	Hyperprolactinemia	Human osteosarcoma cell lines (MG-63 and Saos-2)	PRL-R transcript enhanced in cultured cells	Prolactin may exert a direct inhibitory impact on the functioning of osteoblasts.

3.3. Vertebral Fractures

The evaluation of VFs is a valuable tool for assessing bone health status in patients with secondary osteoporosis who are affected by pituitary and neuroendocrine disorders [81,82]. As these disorders are characterized by predominant deterioration in bone quality, some patients may experience the occurrence of fractures, even in the presence of normal BMD. Consequently, as conventional methods of BMD assessment results are often faulty for the prediction of fracture risk, the detection of VFs plays an essential role as a predictor of further fractures [83]. This is in addition to their potential clinical impact on the overall morbidity of the patient [84] and QoL [85].

In recent decades, several studies have been performed to assess the incidence of VFs in active and controlled acromegaly. Bone turnover is increased in active acromegaly, resulting in impaired bone microstructure, and so reduced BMD levels, according to the duration of the disease. The first study performed on this topic detected the occurrence of incident VFs (I-VFs) in 42% of patients with acromegaly during a 3-year follow-up, with a close correlation with the duration of active disease and baseline disease status [86]. More recently, a study demonstrated a high prevalence of radiological VFs (33.7%) in patients with a recent diagnosis of acromegaly by evaluating 92 patients before transsphenoidal surgery and comparing them to controls (p = 0.001) without secondary forms of osteoporosis and pituitary disorders [87]. The high presence of VFs in acromegaly has been linked to the deterioration of bone structure following the increase in bone turnover. A study on iliac crest biopsies in 13 acromegaly patients with active acromegaly showed a remarkable loss of trabecular connections [88]. A cohort study of 82 patients with acromegaly identified associations between certain parameters of bone microstructure and both gonadal and disease activity. The subanalysis of eugonadal acromegalic patients revealed that most trabecular measurements at the distal radius and distal tibia were compromised [89]. These data were corroborated by a further study that detected the impairment of radius trabecular microstructure in 16 eugonadal males with acromegaly [90], whereby the abnormalities of bone microstructure in acromegaly may occur regardless of gonadal status. On the other hand, in a longitudinal study, I-VFs were reported in approximately one-third of acromegaly patients with hypogonadism, aside from the activity of disease [91], while in another study hypogonadism seemed to influence the development of fractures only in patients with controlled acromegaly [92]. However, the bone alterations in acromegaly involve also cortical bone structure in terms of increased porosity [91,93,94] and impaired cortical strength [95]. A longitudinal cohort study aimed to compare hip cortical bone alterations in patients with acromegaly (56 subjects) and clinically nonfunctioning pituitary adenomas (47 subjects) at baseline and 1 year after pituitary surgery, finding a marked decline in cortical bone thickness in acromegaly patients [96]. A 2-year prospective study was conducted on 70 acromegaly patients, showing that cortical BMD value appeared to be the most sensitive and specific predictor of incident VFs, and suggesting that cortical bone is involved in fracture development despite the control of the disease [97]. A prospective longitudinal study on patients with biochemically controlled acromegaly showed a progression of VFs in the long term in 20% of patients, even without osteoporosis or osteopenia, underlining how abnormal bone quality may persist after remission of disease [92]. Another longitudinal, prospective, follow-up study was conducted on long-term, well-controlled acromegalic patients. A cohort of 31 patients with acromegaly in remission for equal to or more than 2 years was included, and spine X-rays from T4 to L4 using the Genant score were performed at baseline after 2.6 years and 9.1 years. Despite the achievement of a longstanding remission, prevalence and progression of VFs were high [98]. A Danish nationwide cohort study including 1777 patients with acromegaly and 8885 age- and sex-matched controls found an increased fracture risk in acromegaly patients, which was time-dependent [99]. A retrospective study evaluated I-VFs in patients with active acromegaly under treatment with different medications, reporting a higher incidence in those with an active state of the disease, despite the therapeutic approach [100]. The influence of acromegaly treatment on the occurrence of VFs has not been totally clarified yet. A reduced risk of VFs was found in patients treated with first-generation SRL in combination with pegvisomant, in parallel with disease control [100,101], whereas the superior protective role of pasireotide compared to pegvisomant against VF risk was revealed in another study, suggesting a possible direct osteometabolic effect or one via GH inhibition [102]. A prospective study on 58 patients with acromegaly evaluated the presence of spinal fractures and deformities, sagittal imbalances, and spinopelvic compensatory mechanisms using panoramic spine radiographs, detecting an increased number of vertebral fractures and a high prevalence of spinal deformities related to sagittal imbalance, reaching a prevalence of fractures of 13.8%. Fractures were mostly identified in the thoracic spine, with mild and anterior wedge compressions. Increased numbers of vertebral fractures and a high prevalence of spinal deformities related to sagittal imbalance were detected [103]. Finally, in recent years, studies on the role of the polymorphism of the GH receptor (GHR), characterized by the deletion of exon-3 and higher sensitivity to GH, underlined a correlation with higher prevalence of VFs, possibly as a consequence of the amplified negative effects of GH excess on the skeleton of acromegaly patients [104]. Moreover, GHR polymorphisms may guide second-line therapies to prevent acromegaly skeletal fragility [105,106]. Specifically, in a cohort of patients with acromegaly, it was found that all patients who experienced VFs during the treatment with Pegvisomant carried the full-length GHR isoform, while all patients which experienced VFs during the treatment with Pasireotide LAR carried the GHR isoform with the deletion of exon 3 [105,106]. Additionally, the reduction in circulating GH levels has been associated with an increased risk of VFs. Mazziotti et al. found that the occurrence of VFs was associated with BMD in patients with untreated GHD, but similarly to patients affected by GH excess, VFs may occur also in a significant portion of patients with normal BMD [107]. A further prospective study showed a correlation between the incidence of VFs with changes in lumbar spine BMD T-score and Z-score during the study period [106]. Moreover, a nationwide surveillance study in severe GHD adults was conducted by extracting data from the Dutch national registry of growth hormone treatment in adults to investigate potential influencing factors for fracture risk. Patients under treatment for equal to or more than 30 days of GH replacement therapy with previous NFPA (783 subjects), CD (180 subjects) and acromegaly (65 subjects) were included in this study. During follow-up, after 6 years of GH replacement therapy, I-VFs occurred in 3.8% of all patients. In comparison with patients with a history of NFPA, only patients with a history of acromegaly had an increased risk of fracture [108].

The incidence of fragility fractures in CD has been reported to be up to 50%. Diagnosis of endogenous hypercortisolism is often delayed, and VFs, including multiple VFs, may be the first sign of the disease [109]. In CD, Bone microarchitecture is usually impaired, so DXA alone is not a sufficient tool for bone health assessment [110], which also requires morphometric vertebral assessment upon diagnostic completion [111]. Cortisol excess primarily impairs the trabecular bone, leading to an increased risk of osteoporotic fractures, in particular of the spine. According to the Danish Cohort Study, endogenous hypercortisolism may increase the risk of fractures within the 3 years prior to diagnosis and treatment, with this risk decreasing with a longer follow-up duration [112]. A retrospective cross-sectional study was conducted on 135 patients diagnosed with CS, including 108 patients with CD and 27 patients with adrenocortical adenoma, as well as 107 healthy controls. Lateral vertebral radiograms and BMD values were obtained using DXA, and I-VFs were detected in 75.3% patients. At baseline, patients were affected by osteoporosis and osteopenia in 16.2% and 40.7% of cases, respectively. Interestingly, all patients present with thoracic VFs and 50.7% of the patients had lumbar fractures, and, unsurprisingly, a relevant segment of patients (40.7%) experienced VFs despite having normal BMD values. The fact that VF frequency was higher in CS patients further underlines how harmful the impact of hypercortisolism is on bone health [113]. According to a recent study, vertebral adiposity may also be considered a predictor of skeletal fragility in osteoporosis, being secondary to hypercortisolism, and the measurement of spine bone marrow fat may be useful in diagnostic work-ups for the evaluation of fracture risk in CS [114].

Untreated hyperprolactinemia and persistent amenorrhea have been associated with a decrease in BMD caused by estrogen deficiency and VF occurrence [41]. In a case–control study, a higher rate of radiographic VFs was found in women with prolactin-secreting pituitary tumors compared to healthy women [115], with no restoration to normal BMD values, even after successful treatment. In a subsequent study on 32 male prolactinoma patients, the same group found morphometric VFs in 37.5% of cases, a five-fold higher rate compared to age-matched controls [116]. According to a meta-analysis, both men and women with higher levels of prolactin due to pituitary tumors had significantly lower VF rates regardless of their gonadal function, if treated for hyperprolactinemia with dopamine agonists, compared to those not treated [117]. The reduced prevalence of VFs and improvement in BMD levels in patients treated for PRL-secreting pituitary tumors may be explained by the better bone quality, connected to decreased PRL, and the restored sex steroid secretion [118].

Finally, only one retrospective study evaluated the prevalence of radiological VFs in 22 patients affected by TSH-oma, compared to 44 patients with nonfunctioning pituitary adenoma (NFPA) as controls. A significantly higher prevalence of VFs was found in TSH-oma vs. NFPA (59.1% vs. 22.7%; p = 0.003), which was also associated with older age (p = 0.007) and higher serum free T4 values (p = 0.02). Moreover, all patients not treated with somatostatin receptor ligands (SRLs) presented VFs, compared with treated patients who presented fractures in 25% of cases (p = 0.001) [119].

Table 2. An overview of studies on skeletal health in pituitary and neuroendocrine diseases, summarizing their main characteristics and outcomes.

Authors	Year of Publication	Disease Model	Research Type	Number of Subjects	Main Results
Van der Eerden et al. [15]	2007	Cushing’s disease	Clinical Trial	77	82% of patients had osteopenia at one or both sites (T score lower than −1 SD or Z-score levels in lumbar spine −1.07 SD and in the femoral neck −0.81 SD), including 31% with osteoporosis (T score −2.5 SD or lower).
Beckers et al. [33]	2001	GHD	Clinical Trial	21	After 12 months of GH replacement therapy, patients experienced bone mass and density gain, in particular in the axial skeleton.
Gómez et al. [34]	2000	GHD	Clinical trial	20	The included patients had baseline low BMD values and, after prolonged GH replacement therapy, showed an increase in BMD and Z-score values that remained stable even after 12 months of GH treatment withdrawal.
Johanson et al. [35]	1983	Acromegaly	Retrospective, observational	11	Patients with acromegaly showed diffused osteopenia and subverted bone structures.
Naliato et al. [40]	2005	Hyperprolactinemia	Prospective, cross-sectional study	30	80% percent of male patients with prolactinoma were affected by osteopenia or osteoporosis at lumbar spine, while only 30% showed a low BMD at the femoral neck, suggesting the early impairment of the trabecular bone than the cortical bone.
Ragnarsson et al. [43]	2012	Hypopituitarism	Prospective, cross-sectional study	365	An independent association of glucorticoid replacement therapy with reduced BMD and higher prevalence of osteopenia was observed.
Miller et al. [44]	2002	Hypopituitarism	Clinical trial	16	In women with hypopituitarism a strong correlation between androgen levels, lean body mass and BMD was found.
Okinaga et al. [45]	2005	Postoperative patients after surgical removal of pituitary tumors, craniopharyngiomas, Ratke’s cleft cysts, and pituitary abscess	Retrospective, observational	15	An increased risk of osteopenia was found, especially in patients operated on for craniopharyngiomas, regardless of age at diagnosis or at surgery.
Das et al. [46]	2024	Sheehan’s syndrome	Retrospective, observational	35	Reduced values of tibial cortical BMD were observed, even if adequately replaced for respective hormone deficiencies.
Agarwal et al. [49]	2019	Sheehan’s syndrome	Prospective, cross-sectional study	19	Significantly lower BMD values were observed compared to controls in the lumbar spine, hip and femoral neck, with an improvement only in lumbar spine BMD after the replacement of estradiol and supplementation with calcium and cholecalciferol.
Tang et al. [58]	2017	Hypogonadotropic hypogonadism	Retrospective, observational	138	The median Z scores at the lumbar spine and femur were –1.20  ±  0.87 and –1.70  ±  1.06, respectively, indicating that osteopenia was relatively common and that the BMD values increased significantly after treatment for hypogonadism.
Finkelstein et al. [59]	1987	Hypogonadotropic hypogonadism	Retrospective, observational	23	Osteopenia was severe in men with both immature and mature bone ages, and cortical BMD was at least 2 SD below normal in more than half of patients.
Antonio et al. [60]	2019	Hypogonadotropic hypogonadism	Retrospective observational	25	Stable on femoral and lumbar sites were observed BMD values, remaining in osteopenic/osteoporotic range, with only limited osteoanabolic effects given from the supplemental therapy.
Ostertag et al. [61]	2021	Hypogonadotropic hypogonadism	Retrospective observational	51	Reduced BMD and cortical bone thickness were observed in patients with hypogonadism.
Varimo et al. [62]	2021	Hypogonadotropic hypogonadism	Prospective, cross-sectional	16	Reduced cortical and trabecular BMD, as well as cortical thickness at the tibia and the radius, were revealed in patients with hypogonadism.
Lee et al. [63]	2014	Hypogonadotropic hypogonadism	Retrospective observational	21	Significant beneficial effects on lumbar BMD, with minimum changes in femur neck BMD or total femur BMD were observed.
Hong et al. [66]	2016	Acromegaly	Retrospective observational	33	Lower values of TBS were found in 6% of this cohort.
Godang et al. [67]	2016	Acromegaly	Retrospective observational	48	Active acromegaly naïve to any treatment presented, with TBS values partially degraded.
Finkelstein et al. [69]	1989	Hypogonadotropic hypogonadism	Retrospective observational	21	An increase was found in cortical bone density during the treatment of men with idiopathic HH, particularly in those who were skeletally immature.
De Rosa et al. [71]	2001	Hypogonadotropic hypogonadism	Retrospective observational	12	BMD of the spine was significantly lower, while bone markers were increased; half of patients were affected by osteoporosis and the remaining part by osteopenia.
Schlechte et al. [77]	1987	Hyperprolactinemia	Retrospective observational	24	BMD values were 25% lower in women with hyperprolactinemia than in healthy women, while women who underwent successful transsphenoidal pituitary surgery for prolactin-secreting pituitary tumors, with regular menstrual cycles, had a slightly higher spinal bone mineral content than women with amenorrhea, but this was still lower compared to healthy women.
Frara et al. [87]	2022	Acromegaly	Retrospective observational	92	A significantly higher prevalence of VFs (33.7%) in patients with acromegaly with recent diagnosis was found.
Ueland et al. [88]	2002	Acromegaly	Retrospective, observational	13	Reduced trabecular biomechanical competence and apparent density were measured in iliac crest biopsies.
Madeira et al. [89]	2013	Acromegaly	Retrospective, observational	82	Active disease appeared to have a negative influence on trabecular bone, but not on cortical bone, as assessed by high-resolution peripheral quantitative computed tomography.
Silva et al. [90]	2017	Acromegaly, GHD	Prospective, cross-sectional	48	At the radius, patients with acromegaly had greater cortical area cortical thickness cortical pore volume and cortical porosity. At the tibia, patients with acromegaly had lower trabecular bone density.
Godang et al. [96]	2019	Acromegaly	Retrospective, observational	56	A marked decline in cortical bone thickness was found 1 year after pituitary surgery compared to clinically nonfunctioning pituitary adenomas.
Kužma et al. [97]	2021	Acromegaly	Prospective, longitudinal	70	Cortical BMD value appeared to be the most sensitive and specific predictor of incident VFs.
Pelsma et al. [98]	2020	Acromegaly	Prospective, longitudinal	31	Despite the achievement of a longstanding remission, prevalence and progression of VFs were high in this cohort.
de Azevedo Oliveira et al. [103]	2019	Acromegaly	Prospective	58	Increased number of vertebral fractures and high prevalence of spinal deformities related to sagittal imbalance, reaching a prevalence of fractures of 13.8%. Fractures were identified mostly in the thoracic spine, with mild and anterior wedge compressions. Increased number of vertebral fractures and high prevalence of spinal deformities related to sagittal imbalance were detected.
Apaydın et al. [113]	2021	Cushing’s disease	Retrospective	135	VF frequency was higher in CS patients. Most of the patients with VFs had multiple fractures. Although low lumbar BMD was associated with VF, patients with CS with normal bone densitometry could experience VF.
Mazziotti et al. [116]	2011	Hyperprolactinemia	Retrospective	32	In this cohort of male prolactinoma patient, morphometric VFs were found in 37.5%, a five-fold higher rate compared to age-matched controls.
Frara et al. [119]	2018	TSH-omas	Retrospective, observational	22	A significantly higher prevalence of VFs in TSH-omas vs. nonfunctioning pituitary adenomas (59.1% vs. 22.7%) was found, also associated with older age and higher serum fT4 values. All not treated patients with somatostatin receptor ligands presented VFs, compared with treated patients who presented fractures in 25% of cases

offers a schematic summary of presented studies on skeletal health in pituitary and neuroendocrine diseases, showing their main characteristics and outcomes.

4. Treatment with Bone-Active Drugs in Pituitary and Neuroendocrine Disorders

Evidence shows that a significant proportion of patients with pituitary and neuroendocrine disorders do not regain their pre-disease skeletal health, even after receiving adequate hormone replacement. These patients are at increased risk of bone fragility, particularly during active disease, and this provides the rationale for the use of bone-active drugs in this specific setting. As in the general population, osteoporosis in patients with pituitary and neuroendocrine diseases is treated with a variety of currently available drugs with different mechanisms of action and efficacy (Figure 1). Bone-active drugs are categorized in anabolic treatments, which activate bone synthesis by the osteoblasts, and catabolic treatments, which instead inhibit excessive bone degradation by osteoclasts. The most used catabolic treatments are bisphosphonates, namely alendronate, ibandronate, risedronate, and zoledronate, selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, and monoclonal receptor activators of nuclear factor-κB ligand (RANKL) antibodies, such as denosumab [2]. Parathyroid hormones, such as teriparatide and abaloparatide, and monoclonal sclerostin antibodies, namely the recently marketed romosozumab, are the most used anabolic treatments. Novel and tailored approaches include the combination of anabolic and catabolic treatments [120]. No evidence-based indications are available in this clinical setting, even if bone fragility in these patients constitutes a remarkable problem. Despite the increased knowledge about bone fragility in pituitary and neuroendocrine diseases, very few studies have been performed to test the safety and efficacy of bone-active drugs for osteoporosis.

Bisphosphonates are the most commonly prescribed bone-active drugs. They are currently approved for the treatment of postmenopausal, elderly, and glucocorticoid-induced osteoporosis in patients exposed to estrogen and androgen-deprivation treatment and patients with Paget disease of bone, bone metastases, multiple myeloma, malignant hypercalcemia, and osteogenesis imperfecta. Bisphosphonates act as anti-resorptive drugs, promoting osteoclast apoptosis, and have become the primary treatment for managing osteoclast-mediated bone resorption. A very limited number of studies have been performed to evaluate treatment of bone-active drugs on skeletal fragility in pituitary and neuroendocrine disorders. Only one study focused on the effects of alendronate in CD. A small cohort of patients with active (10 subjects) and inactive (11 subjects) disease was considered during a 12-month follow-up [121]. Treatment with alendronate, in combination with ketoconazole in the active disease group, induced a significant increase in lumbar spine and femoral neck BMD. Although it has been suggested the possibility that bisphosphonates may delay the restoration of bone remodeling after resolution of hypercortisolism in CD cured patients, treatment with anti-resorptive drugs should be appropriate in patients with persistently active CD to prevent further skeletal deterioration and VF occurrence. Successful treatment with alendronate (10 mg/die for two years), in addition to the estroprogestogen therapy, was reported in a woman affected by hypogonadotropic and hypothyrotropic partial hypopituitarism. Authors observed the recovery of bone mass with a BMD improvement of 16% compared to initial values and put forward the hypothesis of a synergic mechanism between the estrogen and the alendronate [122]. A prospective study evaluated the efficacy of pamidronate in GHD patients regarding the prevention of bone resorption in the first months of GH replacement therapy. After 6 months of treatment, a reduced decline in BMD and bone turnover was encountered [123]. A study with the longer observation of 18 GHD patients, treated with 3 years of stable replacement therapy, performed made by Biermasz et al. [124]. They assessed the effects of alendronate combined with GH treatment during 12-month treatment, noticing a relevant decrease in bone turnover markers and an increase in lumbar spine BMD. The further evaluation performed after 3 years of treatment showed a later increase in lumbar spine BMD and also femoral neck BMD, and a decrease in VF occurrence. White et al. performed a study on alendronate in combination with GH replacement therapy in 14 GHD patients. Interestingly, an increase in renal phosphate reabsorption and an improvement in renal PTH sensitivity were revealed, inducing a significant decrease in bone resorption [125], similar to the results of the previous study. In active acromegaly, the rationale of the usage of inhibitors of osteoclastogenesis and bone resorption lies in counteracting the overstimulating effects of GH and IGF-I excess on bone remodeling [2]. Only one retrospective study was conducted on this topic, showing that patients with active acromegaly benefit from any form of anti-osteoporosis treatment (anti-resorptive with bisphosphonates or denosumab and anabolic with teriparatide), with a preventive effect on VF incidence [126]. Finally, a study on patients affected by Arginine Vasopressin Deficiency (AVP-D), formerly known as central diabetes insipidus (DI), demonstrated the effect of short-term treatment with alendronate for 6 months on BMD values at the lumbar spine, which was significantly improved in treated patients compared to controls with documented osteopenia or osteoporosis [127].

SERMs are anti-resorptive drugs approved for the treatment of postmenopausal osteoporosis, but since the introduction of bisphosphonates and denosumab, they have become the least used treatment, specifically against osteoporosis. In some pituitary diseases, such as acromegaly, the usage of SERMs can have a rationale based on bone resorption and their concomitant inhibitory effects on IGF-I production [128], while they could not be appropriate for GHD for the same reason. However, SERM usage in clinical practice is very limited now.

Denosumab is a human monoclonal antibody of the IgG2 immunoglobulin isotype. It is able to bind RANKL, with high affinity and specificity, and may induce the reversible inhibition of osteoclastogenesis and bone resorption [129]. Denosumab is currently approved for the treatment of the same form of osteoporosis of bisphosphonates, but it is generally administered as a second-line treatment or in particular cases in which bisphosphonates cannot be utilized [2]. There is a lack of data on treatment with denosumab in osteoporosis secondary to pituitary and neuroendocrine diseases. Given the antiresorptive mechanism of action of denosumab, its use could be suggested in patients with secondary osteoporosis characterized by high bone turnover, similarly to the usage of bisphosphonates. Denosumab has been proven to reverse the effects of hypercortisolism on bone structure impairment. Considering its rapidly reversible effect after discontinuation, some authors suggested the potential short-term usage of this drug when curative surgery is expected [130]. Furthermore, the compliance to 6-month single-administration therapy in these patients who often have complex multi-medical therapy could improve the total benefits for bone health.

Teriparatide is the 1–34 active fragment of PTH. It stimulates osteoblastogenesis and bone formation and it is usually administered once daily. Teriparatide is currently approved for the treatment of osteoporosis patients at high risk of fractures and for glucocorticoid-induced osteoporosis [2]. The pathophysiological role of reduced bone formation caused by hypercortisolism may provide a rationale for the use of teriparatide [131]. Its use in pituitary pathologies, especially in cases of tumors, is much debated. Nevertheless, when the pituitary disease is well-controlled, but a progression of skeletal fragility is observed and does not benefit from antiresorptive therapy, an anabolic option can be carefully considered, strictly monitoring the progress of both the pituitary and skeletal disease. Nevertheless, evidence for the safety and efficacy of teriparatide in patients with pituitary disorders is still lacking.

Romosozumab is a recently approved humanized monoclonal antibody sclerostin inhibitor. It can only be used to treat osteoporosis in postmenopausal women at high risk of fracture or if other available osteoporosis therapies have failed [132]. It is the first anabolic drug that increases bone formation and decreases bone resorption, and it has a combined action. These factors constitute the novelty of romosozumab. Sclerostin is an osteocyte-derived secreted glycoprotein that is able to bind low-density lipoprotein receptor proteins (LRP) 5 and 6. This action prevents the activation of the Wnt/β-catenin pathway, which normally stimulates osteoblasts. Thus, the ubiquitinated ß-catenin is degraded and blocks nuclear import. It results in the inhibition of osteogenic function and in decreased bone formation [133]. Sclerostin also increases the RANKL production and decreases the osteoprotegerin (OPG) production in osteoblasts and pre-osteoblasts and activates the osteoclasts. Romosozumab is able to neutralize sclerostin’s ability to bind to the LRP5 and LRP6 receptor proteins, allowing the Wnt/β-catenin pathway to work, promoting osteogenesis, and in parallel inhibiting bone resorption [134]. Some recent studies showed that acromegaly patients, especially during active disease [135], have high sclerostin levels, and these may contribute to increased VF risk [136,137,138,139]. Prolactin was also shown to reduce the expression OPG in osteoblasts, while increasing RANKL levels [140]. However, no studies are available on the administration of romosozumab in pituitary and neuroendocrine diseases. Because of its mechanism of sclerostin inhibition, it would be interesting to observe any preventive effects of romosozumab in acromegaly patients, assuming sufficient cardiac health and prolactin-secreting pituitary tumors. According to a study on a cohort of hypogonadal men, a direct correlation exists between testosterone levels and sclerostin, so authors suggested sclerostin as a therapeutic target for osteoporosis treatment in this setting [141]. On the contrary, studies performed on CD showed decreased sclerostin levels in patients with chronic endogenous hypercortisolism and increased levels after treatment [142,143,144], for which the treatment of osteoporosis with romosozumab should not be effective.

5. Preventive Vitamin D Supplementation with Different Formulations in Skeletal Fragility of Pituitary and Neuroendocrine Diseases

VD supplementation can be administered in several formulations, both oral and intramuscular, in different dosage units, with variable administration intervals, which can be tailored based on a single patient’s preference [145].

Cholecalciferol (VD3) is the most commonly used preparation for VD supplementation [145]. It is a prohormone and corresponds to the inactive form of VD. It can be acquired endogenously, in the skin after exposure to sunshine, or exogenously, with some foods. It is indicated for use as a dietary supplement and it is available in oral liquid solutions, oral drops, hard and soft capsules, orodispersible films, coated tablets, chewable tablets, and intramuscular vials [146].

Calcidiol (25 dihydroxyvitamin D or V25OH-D) is the metabolite produced by the first hydroxylation in the liver. It is a minor dietary component acquired along with cholecalciferol. The serum V25OH-D response is approximately fourfold greater per microgram of calcidiol versus per microgram of cholecalciferol. Currently, its use is reserved for patients with liver disease, obesity, intestinal malabsorption, and secondary hyperparathyroidism associated with chronic kidney disease. It is available as oral drops, soft capsules, and extended-release capsules [145].

Calcitriol (1-25 dihydroxyvitamin D or V1-25OH-D) is the active form of VD and the metabolite produced by the second hydroxylation, mainly in the kidneys, even if hydroxylation can also occur in other tissues. Patients with advanced chronic kidney disease may require supplementation with V1-25OH-D, but this must be performed with careful monitoring to avoid the risk of hypercalcaemia. The supplement is available in soft capsules [145].

In the general population, supplementation with cholecalciferol seemed to not be effective in the prevention of frailty fractures, on the contrary to special populations at high risk of hypovitaminosis D, such as subjects with elderly, postmenopausal, and glucocorticoid-induced osteoporosis [146,147]. Some meta-analyses on the effect of vitamin D supplementation on bone density have shown no clinically significant benefit from the treatment [148,149], but selection biases are identifiable, including normal levels of VD at baseline, the usage of different doses of cholecalciferol and combined calcium and VD supplementation, and the duration of follow-up [148]. Nevertheless, more recent studies have demonstrated that individuals with baseline V25OH-D levels < 30 nmol/L have ongoing bone loss at a rate of 1% per year when treated with placebo, which could be prevented by VD supplementation [150,151,152,153,154]. The antifracture efficacy of VD supplementation significantly increased for both non-vertebral fractures and hip fractures in a meta-analysis of 12 double-blinded trials, with reduced fracture rates, respectively, of 20% and 18% after the administration of VD3 482–770 IU/daily [155], even if only subjects aged 65 years or older were included in this study [156].

There is a paucity of available studies on VD supplementation in pituitary and neuroendocrine disorders. Only two studies in acromegaly [157,158], two in CD [159,160], and only one in GHD [158] investigated the response to a bolus of cholecalciferol, even if only one had for the endpoint the evaluation of skeletal fragility [160]. In these studies, the only formulation used for research purposes was the oral solution, with an amount of IU that ranged from 100,000 to 300,000 [157,158,159,160] (

Table 3. Bone mineral density (BMD), bone turnover, risk of osteopenia, osteoporosis, vertebral fractures and hypovitaminosis D in pituitary diseases.

Pituitary Diseases	Bone Mineral Density (BMD)	Bone Turnover	Risk of Osteopenia, Osteoporosis and Vertebral Fractures	Risk of Hypovitaminosis D
Acromegaly	Moderate Decrease [35,83,84,85,86,87,88,89]	Moderate Increase [66,88]	Moderate Increase [96,97,98,99,100,101,102,103]	Mild Increase [157,158]
Cushing’s Disease	Mild Decrease [15,109,110,111,112,113,114,115]	Mild Decrease [113,114,115,143]	Relevant Increase [109,110,111,112,113,114]	Mild Increase [159,160]
Hyperprolactinemia	Moderate Decrease [78,79]	Mild Increase [40,73,74]	Moderate Increase [115,116,117,118]	Mild Increase [152]
Hypogonadism	Moderate Decrease [69,70,71]	Moderate Increase [62,70,72]	Relevant Increase [58,59,60,61,62,63,64]	Relevant Increase [152]
GH deficiency	Mild Decrease [33,34]	Mild Decrease [17,19]	Moderate Increase [107,108]	Mild Increase [152]
Hypopituitarism	Mild Decrease [43,44]	Mild Decrease [46,72]	Moderate Increase [112,122]	Mild Increase [152]

). However, there is a total lack in the literature on calcidiol and calcitriol studies in pituitary and neuroendocrine disorders. Moreover, more studies on the preventive role of cholecalciferol on bone fragility are necessary for all pituitary and neuroendocrine diseases.

6. Limitations, Future Direction and Conclusions

Despite several studies being conducted on bone fragility in pituitary and neuroendocrine disorders, there are some limitations that should be addressed. A significant proportion of the clinical studies are observational studies, characterized by small sample sizes. Moreover, a number of studies have been performed without control groups and with a tendency to be confined to single-center experiences. These limitations compromise the statistical power and external validity of the research. Furthermore, the assessment of bone health frequently relies solely on BMD measurements (via DEXA), without the consistent evaluation of bone quality or fracture risk using more advanced tools such as TBS or HR-pQCT. Moreover, while the findings of several animal studies have proven to be mechanistically insightful, the employment of genetically modified models may not accurately replicate the complexity of human endocrine disorders. However, data concerning long-term outcomes, particularly the persistence or reversibility of bone damage subsequent to hormonal correction, remains scarce. It is recommended that future research efforts concentrate on the execution of multicenter and prospective studies, encompassing larger and more diverse populations. These studies should be meticulously designed to evaluate fracture incidence and long-term skeletal outcomes. In addition, it would be useful to employ advanced imaging techniques (e.g., TBS, HR-pQCT) in conjunction with conventional BMD assessments to more accurately assess bone quality.

Furthermore, bone fragility in patients with pituitary and neuroendocrine disorders is treated with a variety of currently available medications, similar to those used in the general population. The results of the presented studies suggest that pituitary disorders with high bone turnover, such as acromegaly and CD, and low bone turnover, such as GHD, benefit from bisphosphonate or denosumab treatment. With appropriate attention to patient selection and monitoring, the usage of romosozumab could be reserved for specific cases. Supplementation with VD in patients with pituitary and neuroendocrine diseases may have preventive effects on bone fractures, both in cases of hormone excess and deficiency, although the mechanisms are not yet fully understood due to the limited number of studies available, differences in populations, doses, and the types of VD formulations used in different trials (Figure 1).

Figure 1. Osteopenia, osteoporosis and vertebral fractures may be the result of direct and indirect effects on bone cells of pituitary hormones that can bypass other endocrine organs. Skeletal changes induced by pituitary and neuroendocrine diseases should be treated with bone-active drugs and vitamin D supplementation [145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165].

Figure 1. Osteopenia, osteoporosis and vertebral fractures may be the result of direct and indirect effects on bone cells of pituitary hormones that can bypass other endocrine organs. Skeletal changes induced by pituitary and neuroendocrine diseases should be treated with bone-active drugs and vitamin D supplementation [145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165].

Subsequent trials should endeavor to establish the most effective VD regimens and elucidate more specifically their skeletal consequences within the framework of hormonal excess or deficiency. Collectively, these areas represent still significant knowledge gaps, necessitating further research and analysis. The resolution of these issues will enhance the personalization of bone health strategies in patients with pituitary and neuroendocrine disorders, thereby supporting the evidence-based use of bone-active therapies and VD supplementation in this complex clinical setting.