Botulinum Toxin for Pain Relief in Cancer Patients: A Systematic Review of Randomized Controlled Trials.

Cancer pain is one of the most disabling symptoms complained by cancer patients, with a crucial impact on physical and psychological well-being. Botulinum neurotoxins (BoNTs) type A and B have emerged as potential interventions for chronic pain; however, their role in these patients is still debated. Thus, this systematic review of randomized controlled trials aimed at assessing the effects of BoNT treatment for cancer pain to guide physicians in an evidence-based approach integrating BoNT in cancer care. Out of 5824 records, 10 RCTs satisfied our eligibility criteria and were included in the present work for a total of 413 subjects with several cancer types (breast, head and neck, esophageal, and thoracic/gastric cancers). While some studies demonstrated significant pain reduction and improved quality of life post-BoNT-A injections, outcomes across different cancer types were inconclusive. Additionally, several effects were observed in functioning, dysphagia, salivary outcomes, esophageal strictures, gastric emptying, and expansions. This review emphasizes the need for further standardized research to conclusively establish the efficacy of BoNT in comprehensive cancer pain management.

Role of vitamin D for orthodontic tooth movement, external apical root resorption, and bone biomarker expression and remodeling: A systematic review.

Objective: : This systematic review aimed to evaluate the correlation between vitamin D levels and the rate of tooth movement, external apical root resorption, bone biomarker expression, and bone remodeling. Methods: : Three databases (PubMed, Scopus, and Web of Science) were systematically searched from inception until 14th March 2023 to identify studies investigating the correlation between orthodontic tooth movement and vitamin D in animals and humans. The quality assessment was made in accordance with the Joanna Briggs Institute Critical Appraisal Checklist. Results: : Overall, 519 records were identified, and 19 were selected for the qualitative synthesis. Eleven studies investigated the effect of local administration (injections in the periodontal ligament, to the gingiva distal to the teeth, or submucosae palatal area) and systemic administration (oral supplementation) of vitamin D on tooth movement, external apical root movement, pro-inflammatory cytokines, and bone remodeling factors. The remaining eight studies investigated the correlation between serum vitamin D levels and salivary vitamin D levels on bone turnover markers and tooth movement. Conclusions: : The findings of this systematic review support that vitamin D3 local injections might increase the rate of tooth movement via the receptor activator of the nuclear factor-kB/osteoprotegerin axis. However, the non-uniform study designs and the different protocols and outcome methods make it challenging to draw reliable conclusions.

Role of Prehabilitation and Rehabilitation on Functional Recovery and Quality of Life in Thyroid Cancer Patients: A Comprehensive Review.

BACKGROUND: This narrative review aims to provide a comprehensive overview of the current prehabilitation and rehabilitation strategies for thyroid cancer survivors to optimize functional outcomes and enhance their quality of life. METHODS: The review follows the SANRA quality criteria and includes an extensive literature search conducted in PubMed/Medline, Web of Science, and Scopus. RESULTS: The review emphasizes the role of a comprehensive rehabilitation approach in targeting the different domains that generate disability in thyroid cancer patients. In this context, physical activity, range of motion exercises, myofascial release, joint mobilization, and postural exercises are crucial for improving functional outcomes and reducing treatment-related discomfort and disability. Moreover, tailored rehabilitative management addressing dysphonia and dysphagia might have a positive impact on the quality of life of these patients. Despite these considerations, several barriers still affect the implementation of a multimodal rehabilitative approach in common clinical practice. Thus, sustainable and effective strategies like digital innovation and patient-centered approaches are strongly needed in order to implement the rehabilitative treatment framework of these subjects. CONCLUSIONS: This narrative review provides valuable insights into the current prehabilitation and rehabilitation strategies to treat thyroid cancer survivors, addressing physical, psychological, and vocational needs to optimize functional outcomes and enhance their quality of life.

Tolerability, Safety and Efficacy of a Specific Rehabilitation Treatment Protocol for Axillary Web Syndrome: An Observational Retrospective Study.

Axillary web syndrome (AWS) is a highly prevalent surgical complication affecting BC survivors. It presents as a subcutaneous cording that limits the upper limb range of motion (ROM) and causes pain. Its etiology is still debated, and its treatment is not well defined. Therefore, we aimed to investigate the safety, tolerability and efficacy of our specific AWS rehabilitative treatment protocol. We conducted an observational retrospective study on a cohort of 92 AWS patients referred to the oncological outpatient service of a university hospital. We collected data from medical records before (T0) and after (T1) the treatment. The studied protocol was composed of 60-min sessions, carried out 3 times/week by specialized physiotherapists, until the clinical resolution of AWS. We found that a mean of 8.74 ± 2.12 rehabilitative sessions were needed, and only one patient stopped early. At T1, shoulder ROM was complete in both abduction and flexion in 98% of patients; AWS was no longer detectable in 64% of them, and pain significantly decreased compared to T0. In conclusion, our protocol proved to be safe, well-tolerated and seemed to be effective in treating AWS.

Osteosarcopenia in Patients with Chronic Obstructive Pulmonary Diseases: Which Pathophysiologic Implications for Rehabilitation?

Chronic obstructive pulmonary disease (COPD) is a burdensome condition affecting a growing number of people worldwide, frequently related to major comorbidities and functional impairment. In these patients, several factors might have a role in promoting both bone and muscle loss, including systemic inflammation, corticosteroid therapies, sedentary behaviours, deconditioning, malnutrition, smoking habits, and alcohol consumption. On the other hand, bone and muscle tissues share several linkages from functional, embryological, and biochemical points of view. Osteosarcopenia has been recently defined by the coexistence of osteoporosis and sarcopenia, but the precise mechanisms underpinning osteosarcopenia in patients with COPD are still unknown. In this scenario, a deeper understanding of the molecular basis of osteosarcopenia might guide clinicians in a personalized approach integrating skeletal muscle health with the pulmonary rehabilitation framework in COPD. Taken together, our results summarized the currently available evidence about the multilevel interactions between osteosarcopenia and COPD to pave the way for a comprehensive approach targeting the most common risk factors of these pathological conditions. Further studies are needed to clarify the role of modern clinical strategies and telemedicine solutions to optimize healthcare delivery in patients with COPD, including osteopenia, osteoporosis, and sarcopenia screening in these subjects.

Impact of nutraceuticals and dietary supplements on mitochondria modifications in healthy aging: a systematic review of randomized controlled trials.

BACKGROUND: To date, the mitochondrial function has been related to several pathways involved in the cellular aging process. Dietary supplements might have reciprocal and multilevel interactions with mitochondria network; however, no systematic review assessed the role of different nutraceuticals in mitochondria modification of healthy older adults. AIM: To assess the effects of different dietary supplements on mitochondria modifications in older adults. METHODS: On February 22, 2022, PubMed, Scopus, Web of Science, and Cochrane were systematically searched from inception for randomized controlled trials (RCTs). According to PICO model, we considered healthy older adults as participants, nutraceutical treatment as intervention, any treatment as comparator, mitochondrial modifications as outcome. Jadad scale was used for the quality assessment. RESULTS: Altogether, 8489 records were identified and screened until 6 studies were included. A total of 201 healthy older adults were included in the systematic review (mean age ranged from 67.0 ± 1.0 years to 76.0 ± 5.6 years). The dietary supplements assessed were sodium nitrite, N-3 polyunsaturated fatty acids, hydrogen-rich water, nicotinamide riboside, urolithin A, and whey protein powder. Positive effects were reported in terms of mitochondrial oxidative and antioxidant capacity, volume, bioenergetic capacity, and mitochondrial transcriptome based on the nutritional supplements. The quality assessment underlined that all the studies included were of good quality. DISCUSSION: Although dietary supplements might provide positive effects on mitochondria modifications, few studies are currently available in this field. CONCLUSION: Further studies are needed to better elucidate the reciprocal and multilevel interactions between nutraceuticals, mitochondria, and environmental stressors in healthy older adults.

Oral Health in Breast Cancer Women with Vitamin D Deficiency: A Machine Learning Study.

Breast cancer (BC) survivors treated with aromatase inhibitors (AIs) commonly show several pathological issues, including poor oral health, bone health impairment, and vitamin D deficiency. However, to date, oral health issues in BC survivors treated with AIs have been poorly investigated and their relationship with vitamin D deficiency are far from being understood. This study aimed to evaluate the correlation between oral health and vitamin D status in BC survivors undergoing treatment with AIs through a machine learning approach. In this cross-sectional study, we included post-menopausal BC women with vitamin D deficiency undergoing AIs therapy. The outcome measures were the following: oral health indexes as the Decayed, Missing, and Filled Permanent Teeth Index (DMFT); serum levels of 25(OH)D3; Bone Mineral Density (BMD); and the diagnosis of osteoporosis. We included 41 post-menopausal BC women, mean aged 66.10 ± 8.47 years, with mean serum levels of vitamin D of 14.63 ± 6.62 ng/mL. Furthermore, 56.10% of patients had a diagnosis of osteoporosis and 36.59% were osteopenic. DMFT was significantly related to smoking (p-value = 0.005) and dental floss use (p-value = 0.001). There was a significant correlation between DMFT and vitamin D levels (Pearson's r: -0.73; p-value = 0.001). The regression machine learning model showed that vitamin D status and the use of dental floss were the most relevant variables in terms of correlation with DMFT. In conclusion, vitamin D deficiency, inadequate use of dental floss, and smoking had a negative impact on oral health in BC women. Thus, vitamin D deficiency screening and supplementation and a prompt oral rehabilitation plan should be suggested and implemented in the complex treatment framework of BC survivors undergoing treatment with AIs.

Surgical Treatment and Rehabilitation Strategies for Upper and Lower Extremity Lymphedema: A Comprehensive Review.

Lymphedema is a chronic disabling condition affecting a growing number of patients worldwide. Although lymphedema is not life-threatening, several reports underlined detrimental consequences in terms of distress, pain, functional impairment, and infections with a relevant decrease in quality of life. Currently, there is no cure, and the therapeutic management of this condition aims at slowing down the disease progression and preventing secondary complications. Early diagnosis is paramount to enhance the effects of rehabilitation or surgical treatments. On the other hand, a multidisciplinary treatment should be truly integrated, the combination of microsurgical and reductive procedures should be considered a valid strategy to manage extremity lymphedema, and rehabilitation should be considered the cornerstone of the multidisciplinary treatment not only for patients not suitable for surgical interventions but also before and after surgical procedures. Therefore, a specialized management of Plastic Reconstructive Surgeons and Physical and Rehabilitative Medicine physicians should be mandatory to address patients' needs and optimize the treatment of this disabling and detrimental condition. Therefore, the aim of this review was to characterize the comprehensive management of lymphedema, providing a broad overview of the potential therapy available in the current literature to optimize the comprehensive management of lymphedema and minimize complications.

Oxygen-Ozone Therapy for Reducing Pro-Inflammatory Cytokines Serum Levels in Musculoskeletal and Temporomandibular Disorders: A Comprehensive Review.

To date, the application of oxygen-ozone (O2O3) therapy has significantly increased in the common clinical practice in several pathological conditions. However, beyond the favorable clinical effects, the biochemical effects of O2O3 are still far from being understood. This comprehensive review aimed at investigating the state of the art about the effects of O2O3 therapy on pro-inflammatory cytokines serum levels as a modulator of oxidative stress in patients with musculoskeletal and temporomandibular disorders (TMD). The efficacy of O2O3 therapy could be related to the moderate oxidative stress modulation produced by the interaction of ozone with biological components. More in detail, O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune overactivation. In this context, most musculoskeletal and temporomandibular disorders (TMD) share these two pathophysiological processes. Despite the paucity of in vivo studies, this comprehensive review suggests that O2O3 therapy might reduce serum levels of interleukin 6 in patients with TMD, low back pain, knee osteoarthritis and rheumatic diseases with a concrete and measurable interaction with the inflammatory pathway. However, to date, further studies are needed to clarify the effects of this promising therapy on inflammatory mediators and their clinical implications.

Information Survey on the Use of Complementary and Alternative Medicine.

Background and Objectives: Complementary and alternative medicines (CAMs) are generally considered non-scientific and poor effective therapies. Nevertheless, CAMs are extensively used in common clinical practice in Western countries. We decided to promote a Delphi consensus to intercept the opinion of Italian physicians on CAM use in clinical practice. Materials and Methods: We run a Delphi-based consensus, interviewing anonymously 97 physicians. Of these, only 78 participate to the questionnaire. Results: Consensus about agreement and disagreement have been reached in several topics, including indication, as well as safety issues concerning CAMs. Conclusions: The use of CAMs in clinical practice still lacks evidence. Experts agree about the possibility to safely use CAMs in combination with conventional medicines to treat non-critical medical conditions.

Role of Physical Exercise and Nutraceuticals in Modulating Molecular Pathways of Osteoarthritis.

Osteoarthritis (OA) is a painful and disabling disease that affects millions of patients. Its etiology is largely unknown, but it is most likely multifactorial. OA pathogenesis involves the catabolism of the cartilage extracellular matrix and is supported by inflammatory and oxidative signaling pathways and marked epigenetic changes. To delay OA progression, a wide range of exercise programs and naturally derived compounds have been suggested. This literature review aims to analyze the main signaling pathways and the evidence about the synergistic effects of these two interventions to counter OA. The converging nutrigenomic and physiogenomic intervention could slow down and reduce the complex pathological features of OA. This review provides a comprehensive picture of a possible signaling approach for targeting OA molecular pathways, initiation, and progression.

Rethinking the clinical management of volumetric muscle loss in patients with spinal cord injury: Synergy among nutritional supplementation, pharmacotherapy, and rehabilitation.

Spinal cord injury (SCI) is a condition defining the damage of the spinal cord that leads to musculoskeletal sequelae, including volumetric muscle loss (VML) in a significant proportion of patients. VML occurring after SCI is responsible for delayed recovery, with detrimental consequences in terms of functional outcomes and additional alterations of the muscle tissue. The treatment of muscle alterations in these patients usually relies on nutritional supplementation. However, rehabilitation therapy has a well-recognized role in improving muscle mass and function, even in subjects affected by SCI. Furthermore, novel medical therapies have been recently investigated, with positive results. In this scoping review, we portray the state-of-the-art treatment of muscle modifications after SCI, focusing on the multidisciplinary and multidimensional management of these patients.

Oxygen-Ozone Therapy in the Rehabilitation Field: State of the Art on Mechanisms of Action, Safety and Effectiveness in Patients with Musculoskeletal Disorders.

In recent years, the interest in oxygen-ozone (O2O3) therapy application has considerably increased in the field of rehabilitation. Despite its widespread use in common clinical practice, the biochemical effects of O2O3 are still far from being understood, although its chemical properties seem to play a pivotal role in exerting its positive effects on different pathological conditions. Indeed, the effectiveness of O2O3 therapy might be partly due to the moderate oxidative stress produced by O3 interactions with biological components. O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune over-activation, and most musculoskeletal disorders share these pathophysiological processes. The present comprehensive review depicts the state-of-the-art on the mechanisms of action, safety and effectiveness of O2O3 therapy in the complex scenario of the management of musculoskeletal disorders. Taken together, our findings suggest that O2O3 therapy seems to reduce pain and improve functioning in patients affected by low back pain and knee osteoarthritis, as reported by several studies in the literature. However, to date, further studies are warranted to clearly investigate the therapeutic effects of this promising therapy on other musculoskeletal disorders in the field of rehabilitation.

Efficacy of Antiresorptive Drugs on Bone Mineral Density in Post-Menopausal Women With Early Breast Cancer Receiving Adjuvant Aromatase Inhibitors: A Systematic Review of Randomized Controlled Trials.

BACKGROUND: Cancer treatment-induced bone loss (CTIBL) is a frequent complication of breast cancer therapies affecting both disability and health-related quality of life (HRQoL). To date, there is still a lack of consensus about the most effective approach that would improve bone health and HRQoL. Therefore, the aim of this systematic review of randomized controlled trials (RCTs) was to summarize the evidence on the effects of antiresorptive drugs on CTIBL in patients with early breast cancer. METHODS: PubMed, Scopus, and Web of Science databases were systematically searched up to April 30, 2021 to identify RCTs satisfying the following PICO model: P) Participants: postmenopausal women with early breast cancer receiving adjuvant aromatase inhibitors (AI), age >18 years; I) Intervention: antiresorptive drugs (i.e. bisphosphonates and/or denosumab); C) Comparator: any comparator; O) Outcome: bone mineral density (BMD) modifications. Moreover, a quality assessment was performed according to the Jadad scale. RESULTS: Out of the initial 2415 records, 21 papers (15 studies) were included in the data synthesis. According to the Jadad scale, 6 studies obtained a score of 5, 1 study obtained a score of 4, 13 studies obtained a score of 3, and 1 study with score 1. Although both bisphosphonates and denosumab showed to increase BMD, only denosumab showed significant advantages on fractures. CONCLUSIONS: Bone health management in patients with early breast cancer receiving adjuvant AIs remains challenging, and the optimal therapeutic approach is not standardized. Further studies are needed to investigate CTIBL, focusing on both the need for antiresorptive drugs and their duration based on individual patients' characteristics. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero, identifier CRD42021267107.

Long-term effects of intra-articular oxygen-ozone therapy versus hyaluronic acid in older people affected by knee osteoarthritis: A randomized single-blind extension study.

BACKGROUND: There is little evidence on intra-articular (IA) treatment in knee osteoarthritis (KOA) and there is a lack of long-term follow-up studies. OBJECTIVE: To assess the long-term effectiveness and safety of IA oxygen-ozone (O2O3) and hyaluronic acid (HA) in terms of functioning in KOA patients over a 31-week period. METHODS: Patients aged ⩾ 60 years with KOA were randomly allocated to receive 4 IA knee injections (1/week) of O2O3 or HA (T0-T3) and a follow-up visit 4 weeks after the fourth injection (T4). In this extension study we assessed VAS and safety in patients with Visual Analogue Scale (VAS) ⩾ 4 at the at 6-month follow-up visit (T5), undergoing a second treatment cycle (T5-T8) and 1-month follow-up visit (T9). RESULTS: Forty-two patients (aged 70.5 ± 5.8 years) were randomly allocated to O2O3 (n= 22) or HA group (n= 20). Twenty-three underwent another IA cycle: 12 (54.6%) in the O2O3 group and 11 (55.0%) in the HA group. Both groups showed significant reduction in VAS (p< 0.013) compared to baseline during both cycles. At follow-up visits (T4 and T9), VAS was significantly lower in the HA group (p< 0.013). There were no differences in adverse events occurrence between groups. CONCLUSIONS: IA O2O3 might be comparable to HA in terms of effectiveness and safety in reducing pain in KOA patients, although at both follow-up visits (T4 and T9) VAS was significantly lower in the HA group.

Myostatin as a potential biomarker to monitor sarcopenia in hip fracture patients undergoing a multidisciplinary rehabilitation and nutritional treatment: a preliminary study.

Hip fractures are the most common osteoporotic fractures related to disability in older adults, requiring surgery and a subsequent rehabilitation treatment. Sarcopenia is currently considered as a predictive of worse outcome in hip fracture patients and myostatin has been recently proposed a potential biomarker of this condition. Twenty hip fracture patients after total hip replacement (mean aged 75.9 ± 2.4 years) were randomly divided into two groups of ten subjects (groups A and B). Both groups performed a rehabilitation program (5 sessions of 40 min/week for 2 weeks, followed by home-based exercise protocol). Group A received also 2-month amino acid supplementation. Serum myostatin levels significantly decreased after 2 months in both group A (p = 0.01) and group B (p = 0.03) in sarcopenic patients only in group A (p = 0.04). These results suggest that myostatin might be considered a promising biomarker of sarcopenia in hip fracture older adults' patients undergoing rehabilitation and amino acid supplementation.

Electrical stimulation of antagonist muscles after botulinum toxin type A for post-stroke spastic equinus foot. A randomized single-blind pilot study.

BACKGROUND: Botulinum toxin type A (BoNT-A) injection is an effective treatment for lower-limb spasticity and should be offered as first-line treatment for focal manifestations. Although its possible role has been hypothesized, the efficacy of electrical stimulation (ES) of antagonists of the injected muscles for improving clinical outcome after BoNT-A injection remains to be established. OBJECTIVES: This randomized single-blind pilot study aimed to investigate the efficacy of ES of antagonist muscles as adjunct treatment after BoNT-A injection to plantar flexor muscles in hemiplegic patients with spastic equinus foot. METHODS: After BoNT-A injection at triceps surae, patients were randomly allocated to 2 groups: group 1, single ES session on injected muscles plus 5 sessions of ES on antagonist muscles, and group 2, single ES session on injected muscles alone. Both groups underwent daily physical therapy for 60min for 2 weeks (5 days/week). Assessments were performed before treatment (T0) and at 10 days (T1), 20 days (T2), and 90 days (T3) after treatment. Our primary outcome was gait velocity at a comfortable speed at T2 (10-m walk test [10MWT]). The following were secondary outcomes: triceps surae spasticity (Modified Ashworth Scale), ankle passive range of motion (pROM), strength of tibialis anterior muscle, and 2-min walk test (2MWT). RESULTS: The 30 patients enrolled were randomly allocated to the 2 groups: 15 in group 1 and 15 in group 2. At T1, T2 and T3, both groups showed a significant reduction in muscle tone and an increase in ankle pROM (P<0.05). At T2 and T3, both groups showed a significant increase in 10MWT and 2MWT. The groups did not significantly differ in tibialis anterior strength or primary or secondary outcome measures. CONCLUSIONS: ES of antagonist muscles does not improve clinical outcomes in the post-stroke spastic equinus foot after BoNT-A injection.

Effects of essential amino acid supplementation and rehabilitation on functioning in hip fracture patients: a pilot randomized controlled trial.

BACKGROUND: Physical exercise and nutrition seem to have a key role in the management of hip fracture patients. AIM: To evaluate the impact of a 2-month rehabilitative protocol combined with dietetic counseling, with or without essential amino acid supplementation, on functioning in hip fracture patients. METHODS: In this pilot randomized controlled study, we recruited patients aged more than 65 years, at 3 months after hip fracture. We randomly assigned the participants into two groups (A and B). Both groups performed a physical exercise rehabilitative programme (five sessions of 40 min/week for 2 weeks, followed by a home-based exercise protocol) and received a dietetic counseling; only group A was supplemented with two sachets of 4 g/day of essential amino acids (Aminotrofic®). We evaluated at baseline and after 2 months of intervention (T1): hand grip strength, Timed Up and Go, and Iowa Level of Assistance scale (ILOA). RESULTS: The 32 hip fracture patients (mean aged 79.03 ± 7.80 years) were allocated into two groups: group A (n = 16) and group B (n = 16). All the participants showed significant differences in all outcomes at T1 (p < 0.017). Sarcopenic patients in group A (n = 10) showed statistically significant differences in all the primary outcomes at T1 (p < 0.017), whereas sarcopenic patients in group B (n = 13) showed a significant reduction of ILOA only. In non-sarcopenic patients, we found no differences at T1 in all outcome measures. DISCUSSION: Hip fractures are a complex multifactorial condition of the elderly that determines devastating effects on functioning and independence. CONCLUSION: A multidisciplinary rehabilitative and nutritional intervention seems to be effective on functioning in hip fracture patients, in particular sarcopenic ones.

Multimodal Analgesia in Total Knee Arthroplasty: A Randomized, Double-Blind, Controlled Trial on Additional Efficacy of Periarticular Anesthesia.

Pain management is a main determinant of functional recovery after total knee arthroplasty (TKA). We performed a randomized, controlled, double blind study to evaluate additive efficacy of periarticular anesthesia in patients undergoing TKA in reducing post-operative pain, operated limb edema and improving post-operative mobility. Patients were randomly assigned to study or control group; all subjects received the same analgesic protocol; before wound closure, the study group received also a periarticular anesthesia (ropivacaine 1% 20 mL). The results show no statistical differences in any of the variable evaluated. Our data suggest that additive periarticular anesthetic protocol with ropivacaine 1% 20 mL is not superior to oral and intravenous analgesia alone in patients undergoing TKA, regarding post-operative pain control, operated limb edema reduction and post-operative mobility improvement.

Different vitamin D substrate-product relationship after oral vitamin D supplementation in familial benign hypercalcemia, primary hyperparathyroidism, and healthy controls.

CONTEXT: In healthy subjects and in patients with primary hyperparathyroidism (PH), the administration of a low dose of 25(OH)D (25 µg/day) increases the serum levels of both 25(OH)D and 1,25(OH)(2)D. It is unknown whether this relationship is present in patients affected by familial benign hypocalciuric hypercalcemia (FBH). OBJECTIVE: To evaluate the different vitamin D substrate-product relationship after oral vitamin D supplementation in familial benign hypercalcemia, PH, and healthy controls. DESIGN: We evaluated the main physiological regulators of 1α-hydroxylase and the substrate-product relationship of 25(OH)D and 1,25(OH)(2)D in 20 patients with PH, 25 with FBH, and 122 healthy sex- and age-matched controls before and after administration of 25(OH)D for 2 weeks. RESULTS: 25(OH)D increased significantly in all subjects, whereas 1,25(OH)(2)D serum levels increased significantly in PH patients and healthy controls but not in patients with FBH. Therefore, a significant positive substrate-product relationship of 25(OH)D-1,25(OH)(2)D was found in PH and healthy controls, but not in FBH. Monomeric calcitonin (hCT-M) was significantly lower at baseline and after 25(OH)D supplementation in the FBH group compared with the other two groups. CONCLUSIONS: The lack of 1,25(OH)(2)D increase in FBH may be due to a direct inhibitory effect on 1α-hydroxylase of hypercalcemia per se, increased metabolic clearance of 1,25(OH)(2)D, or a decreased stimulus of 1α-hydroxylase related to persistently low levels of hCT.