OP is a systemic skeletal illness marked by low bone mass, micro-architectural degeneration of bone tissue, bone fragility, and an increase in fracture risk (especially of vertebrae, femur, humerus, wrist and ankle bones) due to even minimal trauma (7). The epidemiological impact is very high: nowadays it is believed that in Italy around 5 million elderly people are affected by OP and a greater increase in its incidence is expected in the next future, since the proportion of the Italian community of over 65 years is going to rise by 25% in the next 20 years. Osteoporotic fractures raise the relative risk of mortality, particularly for femur fractures: it is 5-8 times greater in the first 3 months after the occurrence, decreases in the next 2 years, but stays high even after a 10-year follow-up. Furthermore, 50% of women with hip fractures had a significant loss in self-sufficiency which involves long-term institutionalization in about 20% of cases. The economic burden of such a widespread pathology is therefore very high (8, 9). The World Health Organization operationally defines OP as the presence of a bone mineral density (BMD) of 2.5 SDs under the average of young white adult women (1). OP is classed as ‘primary’ when it is not caused by medical conditions, and secondary’ when it arises as a result of particular, well-defined clinical diseases or drug use (10).

Under physiological conditions, skeletal homeostasis is guaranteed by an appropriate ratio between formation and resorption of bone tissue. Skeletal homeostasis is maintained under physiological settings by a balance of bone production and bone resorption. This adjustment is altered in pathological circumstances in favor of osteoclast-mediated bone resorption (5).

This bone regeneration cycle decoupling is exactly what happens in elderly people: the decreased osteoblast activity determine a longer time required to fill resorption cavities and there is a low-grade systemic inflammation, especially involving pro-inflammatory cytokines [tumor necrosis factor-alpha (TNF-alpha), IL-1, and IL-6)] which determine an increase in the amount and functioning of osteoclasts. As a result, in older persons there is an overall decline in bone with time. A negative calcium balance resulting from decreased dietary intake, reduced absorption and the compromise of kidney function, reduces the activation of VD and the calcium absorption from the gut (11). Osteoclasts indeed must resorb calcium in order to fill this void (4). Estrogen deficiency is of course another critical factor responsible for the increased bone resorption both in men and women. For either sex, bone loss occurs right after attaining maximal bone mass; nevertheless, this process accelerates after menopause in women and after the age of 70 in men (12). Estrogens are well known for regulating the synthesis of bone. They have a bone-protective role by limiting bone resorption and sustaining bone formation (13). As a result, estrogen deprivation causes OP, which is associated with an increase in bone resorption due to a boost in the number and activity of osteoclasts, as well as osteocyte death. A growing body of information suggests that OP related with estrogen loss of estrogen is also due to the increase in oxidative stress and changes in immune system homeostasis and inflammatory pathways, which are accentuated by the aging process. Specific T-cell subsets, such as T helper cells, can be activated, supporting the production of IL-17, Receptor activator of nuclear factor-Kappa B Ligand (RANKL), IL-1, TNF, and IL-6. These factors are able to stimulate osteoclast maturation and activity by preventing the differentiation of osteoblast, increasing apoptotic osteocytes, and raising RANKL expression and the RANKL/Osteoprotegerin (OPG)-ratio (14).

OP is asymptomatic for the majority of its clinical history; approximately one-third of fracture occurrences are silent, while the remainder present in pain. Osteoporotic fractures are fragility fractures, meaning they occur spontaneously or as a result of little trauma. In order of frequency, the most commonly affected sites are vertebra, femur, major non-vertebral/non-femoral fractures (pelvis, radial tip, proximal tibia, humerus, 3 or more ribs, etc.), minor fractures followed by pain. Vertebral compression fractures (VCFs) are the hallmark clinical presentation of OP. Unlike major posttraumatic VCFs, which are invariably symptomatic, those caused by moderate trauma are frequently misunderstood and thus go undiagnosed. They are typically asymptomatic or present with symptoms such as back or low back pain that responds to analgesic therapy (15, 16). They primarily impact the dorsolumbar junction (T12-L1), followed by the mid-dorsal tract (T7-T8) and other locations (17). The Genant classification, which takes into account the level of vertebral body involvement by a semi-quantitative evaluation of its deformity, is used to categorize the severity of vertebral fractures (18). The reduction in the patient’s height, which can be partly attributed to antalgic posture and partially to the accentuation of the thoracic kyphosis, is the evident and immediately observable result of vertebral collapse. The latter causes a number of issues, including sleep disturbances caused by adopting analgesic positions, limitations on daily activities, respiratory (modest reduction of respiratory volumes due to reduction of rib cage support) and gastrointestinal (early satiety due to abdominal distension) disturbances. Neurological deficits occur rarely, even when they cause compression of the spinal cord (by sliding) (19). Hip fracture is a severe injury that necessitates hospitalization and immediate medical surgery (20). Such fractures account for a small percentage of fractures caused by OP (about 15%), but they have a greater impact on health expenditure (21) because they are associated with a higher rate of morbidity and mortality, particularly in the first three months after the fracture; numerous complications are in fact associated with this event: embolism, pulmonary disease, infections, sepsis, heart attack, and cardio-pulmonary problems in general (22). Hip fracture risk increases with age, and so does mortality (by 5-8 times): this connects with both BMD decline and an increase in the chance of falling (which accounts for around 90% of fractures in the elderly) (21). Colles fracture, or fractures of the distal epiphysis of the radius, are more common in persons with a higher performance level because they are more active and hence at a higher risk of falling. Its prevalence rises gradually after menopause, then levels out at the age of 65. In contrast, wrist fractures are uncommon in men, regardless of age (M:F 1:6-1:10 at 65 years) (21). This disparity is related to the male skeleton’s bigger cortex and lower endocortical resorption (23). Other types of fractures (humerus, pelvis, proximal radius, or distal femur) are more uncommon. Although the association with age is indisputable due to the loss in BMD, it is relatively weak for rib fractures and more meaningful for pelvic fractures (21).

Skin aging is not just an aesthetic problem. In fact, its effects also weaken the skin on a functional level, reducing the crucial protective properties of the skin. Since this growing knowledge in recent years, it has been necessary to coniate a term as DP that could focus the attention of clinicians on the urgency of preventing and treating this condition as well as OP.

DP is a clinical entity that includes the whole broad spectrum of skin alterations due to aging, including complications that can cause severe morbidity for the affected elderly person, taking the form of a real chronic skin frailty syndrome (2). People with dermatoporosis have particularly thin and fragile skin. This results in a poor tolerance to friction and shear forces, and consequent susceptibility to skin tears and more or less serious hematomas. DP also tends to delay the healing of wounds once they have formed. Additionally, skin failure leads to loss of temperature regulation combined with the incapacity of keeping the core body temperature. In more severe cases, it may result in percutaneous loss of fluid with electrolytes and protein, as well as an increased susceptibility to infection (24). For this reason, severe DP is a cause of death in intensive care units (25). Similarly to OP, DP is classified as ‘primary” and ‘secondary’. Primary DP is caused by chronological aging along with long-term, unprotected sun exposure. Although data on genes associated in DP pathogenesis are limited, genetic variables are known to play a substantial role in the regulation and loss of extracellular matrix (ECM) components, in the viscoelastic characteristics of the skin, and hence could be involved in DP susceptibility. Chronic use of topical and systemic corticosteroids causes the secondary type. These iatrogenic forms may appear earlier and be more severe in people predisposed to primary DP. Corticosteroids are known to affect the expression of genes encoding collagens I, III, IV, V, decorin, elastin, metalloproteinases (MMPs) 1, 2, 3, tenascin, and MMP 1 and 2 tissue inhibitors (2).

Data on the prevalence of the disease are currently scarce, however they show the high frequency among the elderly and especially in women. The frequency of dermatoporosis is 32%, based on a study of 202 hospitalized participants aged 60 to 80 years. DP was found in approximately 22% of females and 38% of males (26). Another French study evaluated 533 people over the age of 65 who went to see a dermatologist, resulting in an overall prevalence of dermatoporosis of 37.5%, which was prevalent in women (27). Finally, in a prospective analysis of 176 patients aged 60 years or more, Kluger et al. discovered DP in 30.7% of patients, mostly in the upper extremities (94%) (28).

There are many factors implicated in the development of DP. First of all, the decline with aging in dermal hyaluronic acid (HA). In the elderly there is a thinning of the skin, which loses its resistance to mechanical forces. The firmness of “healthy” skin is provided by the ECM, whose major constituent is HA, a non-sulfated glycosaminoglycan that is mostly produced by fibroblasts. HA is a very hydrophilic material that decreases friction between collagen fibers and provides shear force resistance. Yet, as people age, fibroblasts lose their ability to make HA; as a result, the ECM loses volume and consequently is protective mechanical function, determining skin laceration from minimal trauma (2). The lack of interaction between HA and the cell surface receptor CD44, which normally increases keratinocyte proliferation, is a second mechanism hypothesized. In mice models, the selective suppression of keratinocyte CD44 determines skin atrophy (29). This observation has served as the foundation for DP research: it has been shown that dermatoporotic skin has lower CD44 levels than “healthy” skin from young persons (30). Expression of CD44 is also decreased by UVA and UVB exposure (31) and topical corticosteroid application (30–32). Corticosteroids can also cause dermatoporotic alterations by modifying collagen I, collagen III, collagen IV, and matrix MMP gene expression (33). With age, the overexpression of MMP 1, 2, and 3 and the downregulation of the tissue inhibitor of MMP 1 leads to the degradation of collagen and elastin in the dermis (34). The malfunction of the hyalurosome, a multimeric macromolecule complex comprising of components involved in HA metabolism and cell signaling in keratinocytes such as CD44, heparin binding epidermal growth factor, and its receptor erbB, appears to be the most critical aspect of DP (35).

Clinical manifestation is variable and includes morphological and functional alteration of the skin. Skin atrophy, senile purpura, and stellate pseudoscars are morphological signs of skin fragility. Sun-exposed areas of skin atrophy include the pretibial zones, the back of the forearms, the dorsum of the hands, the presternal area, and the scalp. Dermatoporotic skin is clinically very thin and transparent, with many wrinkles, senile purpura, and pseudoscars as compared to younger skin. There is a significant reduction in skin thickness, demonstrated by ultrasound (1.4-1.5 mm “healthy” skin thickness vs 0.7-0.8 mm in dermatoporotic skin). The dermis, which contains the majority of the subcutaneous fat, shows substantial elastosis, while the epidermis displays linearization with lack of rete ridges (2). Senile purpura, also known as Bateman purpura, is a benign superficial hemorrhagic lesion caused by repeated spontaneous or minor trauma. Histologically, it is distinguished by erythrocyte extravasation and enhanced vascular fragility as a result of connective tissue injury and atrophy in the dermis. These dermal bleedings are not associated with any coagulation disorders (3). Senile purpura is very common in up to 10% of the elderly population between the ages of 70 and 90 and in 90% of cases it is associated with pseudoscars. As these purpuric plaques fade, a dark brownish pigmentation that resembles hemosiderin pigment is left behind (36). Vitamin C, whose protective role on blood vessels is well known, is often deficient in elderly people with dermatoporosis, leading to dermal hematomas; so acid ascorbic replacement therapy should be considered in this pattern (2). Stellate Pseudoscar is a superficial lesion of the skin with a star shape, deriving from spontaneous dermal laceration caused by minimal trauma. These lesions have a hypocellular dermal zone in a background of fibrosis and elastotic collagen fibers covered by an atrophic epidermis. As the senile purpura, Stellate Pseudoscar appears on the backs of elderly people’s hands and forearms and they show as pale lesions on medical inspection. Pseudoscars are classified into three kinds based on their shape: star-shaped, linear, and plaque (36).

Functional manifestations of DP are skin lacerations, delayed wound healing, and subcutaneous bleeding with the development of deep dissecting hematomas (DHH) and in the most serious cases even large areas of necrosis (3). DHH is the most serious DP complication. It occurs as a result of extensive bleeding between subcutaneous fat and muscle fascia following a small injury (37). DHH typically occurs in elderly patients with dermatoporosis who underwent anticoagulation therapy or topical or systemic corticosteroid therapy (33). Histologically, there is exposure of deep skin vessels to the skin surface in the context of significant skin thinning. Unlike the other clinical signs of DP, DHH occurs mostly in the lower limbs of elderly adults with severe DP (M/F ratio: 1/5) (38). Necrosis is caused by large hematomas that cut off the blood flow to the skin. As soon as possible to prevent severe skin damage in this situation, the bleeding area and necrotic tissue should be surgically removed. It may be essential to make large and deep incisions that reach the muscular tissue, determining a significant loss of skin surface (39). The exact mechanism causing the delay in wound healing in elderly is still unclear. Tissue deterioration is caused by a reduction in the ability of keratinocytes and fibroblasts to proliferate, a surplus of matrix MMPs, which delay the production of renewed ECM (40).

Besides being a lipid-soluble vitamin, VD is a steroid hormone. Humans obtain VD from either sunlight exposure to UVB rays or minimally from the introduction with plant or animal foods, dietary foods and supplements, as VD2 (or ergocalciferol) or VD3 (or cholecalciferol) (54). VD is produced in the skin via 7-dehydrocholesterol (7-DHC) present in keratinocytes; UVB rays mediate a photochemical reaction that converts 7-DHC in vitamin D3 (55). The latter is transported to the liver binded to a type of alpha-globulin called Vitamin D Binding Protein (VDPB), where it undergoes the first hydroxylation and is released in the form of 25(OH)D3. Finally, VD3 is activated with a second hydroxylation at the kidney level. The proximal tubule is the primary site of action for this mechanism, and it is vulnerable to both negative and positive feedback processes mediated by 1,25(OH)2D3, phosphorus, calcium, and FGF-23 (56). The 1,25(OH)2D3 acts through activation of the nuclear receptor of VD (VDR), a transcription factor and part of the steroid receptor family, with which VD has a high affinity. Although the primary function of VD, which is the control of calcium-phosphorus metabolism and the balance of bone mineral reserves, is well understood (57, 58), there is also ample evidence of its numerous other activities in extra-skeletal tissues (59, 60). In reality, the VDR is expressed everywhere (61), and VD is essential for the immune system’s physiology (62), for controlling the activity of other hormones like IGF-1 (63), in the prevention of many types of neoplasms (64), in the maintenance of a solid skeletal muscle (65), participates in carbohydrate metabolism (66), of the cardiovascular (67) and reproductive systems (68), of the neuro cognitive (69) and cell proliferation (70, 71). As we will see in more detail later, it is relevant also in the constitution of the skin (72). VD seems to act either directly on organs such as bone and skin, and indirectly through influencing the immune system and, in turn, inflammatory processes, which is a major factor in the development of many diseases like OP and skin aging. All immune system cells have VDR, and antigen-presenting cells (APC) can create 1,25(OH)2D3 in response to immunological stimuli by using the same enzyme that is produced in the kidney (62).

Both innate and acquired immunity are affected by 1,25(OH)2D3. VD and its metabolites influence innate immunity by promoting macrophage development and activation, which results in the production of defensins including cathelicidin and 2-defensin (73). Mice on a diet lacking in vitamin D produced less IL-6, TNF-, and IL-1, and their antibacterial activity was weak (74). The primary inhibitory effects of VD on acquired immunity result in a phenotypic shift in T cells from an effector phenotype, which is involved in autoimmune disorders, to a regulating and protecting one (75).

The interpretation of serum 25(OH)D has to take into account many factors, as levels can vary widely in different life periods, based on degree of exposure to sunshine (period of the year, latitude), phototype, and nutritional status (76). There is also a large variability in its dosage between different laboratories. In fact, there is still no unanimous consensus among scientific societies for the definition of the deficiency of VD, except for the condition of serious deficiency represented by values ​​of 25(OH)D <10 ng/mL which are linked with higher risk of rickets and osteomalacia. Since the observation that in the general population there is a relationship between values of serum 25(OH)D < 20 ng/mL and increased risk of fracture (77), the Italian Society for Osteoporosis, Mineral Metabolism and Bone Diseases (SIOMMMS) suggests to consider these cutoffs: “deficient” means a 25(OH)D level of 10 ng/mL; “insufficient” means a level of 20 ng/mL; and “optimal” means a level of 20-50 ng/mL (76). In patients with OP, especially those who necessitate a treatment with OP drugs and subjects at risk of hypovitaminosis D, an “optimal” level of at least 30 ng/mL is instead indicated. This value is related with a considerable reduction in the incidence of hip fractures in institutionalized women and a 4.5 times better response in bisphosphonate-treated patients (78). Globally, there are many people who have mild or severe VD deficiencies. Around 7% of the world’s population has severe VD deficit (serum 25(OH)D concentrations below 25/30 nmol/l (10/12 ng/ml)), while 37% has mild VD deficiency (serum 25(OH)D concentrations below 50 nmol/l (20 ng/ml)) (79).

Everyone in the aging population, regardless of bone health status, should get enough VD (together with an adequate calcium intake of 800-1000 mg/day as well) (4). The Bone Health and Osteoporosis Foundation (BHOF) advises 800 to 1000 international units (IU) of VD per day for persons over the age of 50, while the Institute of Medicine (IOM) recommends 600 IU per day till the age of 70 and 800 IU per day for adults over the age of 71. It is however very common that older individuals develop VD deficiency, which is caused mostly by being institutionalized or chronically ill with inadequate sun exposure, absorption problems, chronic renal illness. If enough and non-hazardous solar exposure is insufficient to obtain the necessary amounts of VD for skeletal occurrences (fractures and falls), oral supplements should be used. Treatment must be personalized. Cholecalciferol is the first line therapy in most patients. No one who requires supplementing will respond to a single set dose; instead, a dose between 800 and 2000 IU per day should be taken into consideration (141). The daily method of supplementing is the most physiological; however, from a pharmacological perspective, the use of similar weekly or monthly doses is recommended in order to increase adherence to therapy. In individuals who require quick vitamin D level normalization (symptomatic osteomalacia or zoledronic acid or denosumab initiators) it is recommended to use a initial loading dose of either cholecalciferol in a single dosage of 60,000 to 150,000 IU, followed by a maintenance dose, or 3,000–10,000 IU/day (mean 5,000 IU/day) for 1–2 months (142). As an alternative, it is feasible to utilize calcifediol for 20 to 30 days before moving to cholecalciferol for maintenance dose. Since its pharmacokinetics are different from the cholecalciferol’s one because it has a lower volume of distribution, calcifediol causes a 25(OH)D level increase more quickly. In obese subjects it is suggested to use either cholecalciferol at a dosage increased by approximately 30% of the usual dose or calcifediol. The latter can also be indicated in other conditions of 25-hydroxylation deficiency which are often observed in older people, such as severe liver failure, male hypogonadism or intestinal malabsorption (79). Chronic renal disease is another ailment that is typically common in aged persons. In this setting it is recommended to use cholecalciferol and to restrict the administration of active vitamin D compounds (calcitriol or synthetic analogues) to dialysis patients or those in the G4-G5 phase with severe and progressive hyperparathyroidism (143).