Osteoporosis is a bone degenerative condition characterized by low cortical and/or trabecular density of the hip, vertebrae, femoral neck, and/or distal forearm, expressed as a T-score ≤2.5 standard deviations (SD) as measured by bone densitometry (DXA). Postmenopausal osteoporosis occurs in the context of the physiological lowering of estrogen secretion, typical of this phase of life (biomechanical defects and aging are co-mechanisms) [1] [3] . Bone remodeling is accelerated, leading to a net loss of bone tissue with each cycle. Since trabecular bone is more susceptible to this phenomenon than cortical bone, one can assume that osteoporosis might be more common in bones where the former prevails such as the hip, vertebrae, and femoral neck. Subsequent deterioration of bone architecture and strength loss predispose either to fracture due to trauma

of lesser magnitude or to atypical fractures. It is a subclinical condition until complicated with bone fracture [2] [4] .

Women in their 6^th decade of life present a 40% risk of experiencing an osteoporotic fracture, with the vertebrae being the most commonly affected bones. The latter type of fracture is associated with the following rates: 1) two-thirds occur in women >75 years of age, 2) there is a 5-fold increased risk for additional vertebral fractures, and 3) there is 2- to 3-fold increased risk for hip, proximal femur or distal forearm fractures [3] . Despite their greater frequency, vertebral fractures can be asymptomatic [1] [7] . Hip fractures result in greater morbidity, mortality, and costs than all other osteoporotic fracture types combined, as 60% of patients do not regain their pre-fracture independence [1] [3] .

DXA of the total hip, femoral neck, or lumbar spine is considered the gold standard for osteoporosis diagnosis, therapeutic follow-up, and therapeutic change assessment [3] . Known limitations of this technique are:

· Poor precision for changes of <3% to 6% and <2% to 4% in BMD of hip and spine, respectively [3] .

· Measurement of crystalized inorganic mineral matrix density, disregarding osseous connective tissue (collagen fibers, osteocalcin, and other non-collagen proteins).

Based on this limitation, one can suppose that a T-score increase might not forcibly reflect a clinically significant bone microarchitectural improvement. In fact, even when BMD measurements have not significantly increased, fracture risk can decrease disproportionately, suggesting that other factors of bone strength different than the crystalized inorganic mineral matrix might play a role [3] [4] .

Even though biochemical markers of bone turnover (s-CTx, urinary N-telopeptide, propeptide type 1 procollagen, bone-specific alkaline phosphatase, and osteocalcin) are not recommended for postmenopausal osteoporosis diagnosis, they can be useful in predicting rapidity of bone loss, as a tool for estimating the magnitude of BMD post-therapeutic increases and to point out the timing for medication resumption during a “bisphosphonates holiday” (see further) [3] .

*FRAX model is an assessment tool for estimating 10-year bone fracture risk in treatment-naïve individuals, based on parameters such as a history of fractures, BMD, and parental history.

Indications for postmenopausal osteoporosis prophylaxis are [3] :

· primary fracture prevention: 1) T-score ≤2.5 at the femoral neck and total hip and 2) osteopenia (T-score between −1.0 and −2.5) at the femoral neck or hip plus either 10-year hip fracture risk ≥3% or a 10-year major osteoporosis-related fracture risk ≥20% (based on FRAX model*).

· secondary fracture prevention: 1) fracture of hip or vertebra (regardless of BMD) and 2) fracture of the proximal humerus, pelvis, or distal forearm under a T-score between −1.0 and −2.5.

Therapeutic classes and drugs approved for the prevention and/or treatment of postmenopausal osteoporosis are bisphosphonates, selective estrogen-receptor modulators (e.g., raloxifene), human monoclonal antibodies to sclerotin (e.g., romosozumab), strontium ranelate, recombinant parathyroid hormone (PTH analogs) (e.g., teriparatide), tissue-selective estrogen complex, receptor activator of nuclear factor kappa-B ligand (RANKL) inhibitors (denosumab), calcitonin and estrogen therapy [1] . Parameters for the best modality choice are fracture prevention efficacy, site of optimal fracture prevention (spine vs. hip), and the onset of effect [3] . Assuming that postmenopausal osteoporosis is an uncurable and inexorably evolving condition, treatment can never be stopped (even though “holidays” can be considered) and the achieved benefits can only be maintained as long as the therapy endures [3] .

Bisphosphonates represent a class of drugs that increases bone strength by inhibiting tissue resorption during its physiological remodeling process. They are mainly indicated as first-line therapy for postmenopausal osteoporosis prevention and management [4] . The following mechanisms of action are described for this class of drugs [1] [2] [3] [4] [5] .

· inhibition of osteocyte farnesyl diphosphate synthase (mevalonate pathway).

Osteocyte enzyme farnesyl diphosphate synthase (FDS) yields farnesyl pyrophosphate, which promotes prenylation (addition of hydrophobic molecules) of small GTPase signaling proteins, a phenomenon involved in osteoclast activation. By inhibiting FDS, bisphosphonates stop the prenylation of these GTPase signaling proteins, either preventing osteoclasts activation or leading to cell apoptosis [8] .

· hydroxyapatite crystals’ solubility decrease.

Bisphosphonates are chemically composed of two phosphate groups that allow binding to hydroxyapatite crystals composing the crystalized inorganic mineral matrix, decreasing the solubility of the latter and slowing down bone resorption.

· proosteoclasts signaling downregulation.

Reduced hydroxyapatite crystals solubility, as described above, prevents osteocyte cytokines from reaching proosteoclasts, stopping their differentiation into osteoclasts.

Bisphosphonates’ nadir effect on osteoclast activity is expected to be attained within 3 months of therapy and will inevitably lead to inhibition of osteoblasts activation and therefore bone remodeling. Nevertheless, within 3 additional months, an equilibrium is expected to take place, leading to a net result of either BMD preservation or gain. After this term, a clinically significant reduction of fracture risk is expected to be reached [4] . Bisphosphonates take longer to bring BMD and fracture risk to baseline levels than non-bisphosphonates, but their effect stands longer after interruption (this characteristic can be advantageous during the so-called “bisphosphonates holiday”) [3] .

Bisphosphonates’ immediate side effects are limited to the digestive system (esophageal irritation, dysphagia, and gastrointestinal symptoms) [4] . The drugs of this class are potentially nephrotoxic and therefore are contraindicated in patients with a glomerular filtration rate <30 mL/min. Inhibition of osteoclast activity caused by bisphosphonates is expected to lower calcium efflux to the blood, leading to one-week duration hypocalcemia, which is clinically unimportant in most cases. Nevertheless, bisphosphonates are contraindicated in patients with preexisting hypocalcemia or under other associated risky conditions, such as hypoparathyroidism [4] [5] . Prolonged suppression of bone resorption and its subsequent formation can lead to tissue microdamage accumulation and bone frailty [4] .

Bisphosphonates-related osteonecrosis of the jaw is a side effect that belongs to the broader group of medication-related osteonecrosis of the jaw (MRONJ) and it can occur under the following circumstances: 1) cancer patients undergoing odontological procedures reaching periodontal tissues; 2) poor fitting of dental appliances or poor oral health; 3) parenteral bisphosphonates used for prevention of bone complications due to cancer; 4) bisphosphonates use for longer than 3 to 5 years; 5) concomitant diabetes mellitus or corticosteroids use. It is not possible to grade individual risk for this side effect. There are no reports of such an adverse event during clinical trials [1] [3] [4] . Atypical femur fractures are a complication associated with bilateral chronic bone stress and triggered by minor trauma. They occur under the following circumstances, when associated with bisphosphonates use: a) patients with Asian ethnicity; b) coexistence with lateral bowing of the femur, autoimmune diseases, corticosteroids use; c) bisphosphonates use for longer than 3 years. Their rate declines with the discontinuation of the substances of the class [3] . The risk for jaw osteonecrosis as well as atypical femur fractures is expected to decrease during the “bisphosphonates holiday”.

“Bisphosphonates holiday” is feasible, based on the premise that these drugs are retained by the skeleton, extending anti-fracture benefits. The “holiday” can be considered either after 5 years or after 10 years of oral therapy (if T score ≤ −2.5 and/or there is a report of a recent fracture) of oral therapy. The effects of a “bisphosphonates holiday” on the risk of bone fracture are unknown [3] [4] . Concomitant supplementation with vitamin D and calcium is recommended, not only for bone health in general but also to reduce the risk of hypocalcemia [5] .

Ibandronate is a nitrogen-containing bisphosphonate with enough potency and skeletal binding capacity to enable a once-monthly interval dosage [1] [7] . Its pharmacological effect is a cumulative-dependent decrease of bone turnover biochemical markers, as it maintains tissue quality, strength, and architecture, without affecting mineralization and repair properties [1] . An ibandronate structural formula is depicted in Figure 2.

Clinical effects associated with ibandronate use are: 1) increased lumbar spine and proximal femur BMD and mechanical strength, 2) sustained decrease of bone absorption biochemical markers after three months, and 3) risk reduction of osteoporotic vertebral fractures. Ibandronate consolidated pharmacokinetics parameters are listed below [1] [5] :

· bioavailability: 0.63% (relative to IV administration; reduced by ~90% with food).

· intestinal absorption: impaired by food and beverages (other than plain water).

· Cmax: 49.7 ng/mL (10% of this value is attained after 8 h, due to bone binding, when a slower clearance phase starts as ibandronate returns to the blood to ongoing renal excretion).

· tmax: 0.5 to 2 h.

· bone sequestration rate: 40% to 50% (the remainder being excreted in the urine 24 hours after administration).

· Vd: 90 to 160 L.

· protein binding: 84% to 86% (steady under clinically relevant blood concentration).

· increases in plasma concentration (dose >50 mg): disproportionally greater than dosing.

· half-life: ~1.3 h.

· terminal half-life: 10 to 72 h.

· estimated bone half-life: years.

· renal clearance: 56.9 mL/min (urine excretion linearly related to creatinine clearance).

· fecal excretion: trace amounts.

Ibandronate is not biotransformed [1] .

In addition to prevention and first-line treatment of postmenopausal osteoporosis, ibandronate is used off-label for the reduction of skeletal events during glucocorticoid chronic use and malignancy hypercalcemia prevention (pathological bone resorption due to bone metastases) [5] [9] .

Postmenopausal osteoporosis is more common among elderly women and consequently, there is a higher likelihood of concurrent diseases requiring concomitant medication, increasing interactions risk as well as predisposing to adherence and safety concerns. The once-monthly dosage interval, feasible with ibandronate, could minimize these issues among treated patients [7] .

The most commonly reported adverse reactions with ibandronate are: 1) upper gastrointestinal ulcerations, 2) flu-like symptoms, 3) musculoskeletal symptoms, and 4) nervous system disorders [1] [7] . Immediate adverse events associated with ibandronate share the following characteristics: a) mild to moderate in intensity, b) last 1 to 4 days, and c) did not lead to withdrawal during clinical trials [1] . Once-monthly interval dosage can minimize oesophageal irritation, given the reduced administration frequency [7] . Ibandronate is contraindicated in the following circumstances: i) preexisting gastrointestinal symptoms and disorders (dysphagia, epigastralgia, gastroesophageal reflux disease, gastritis, hiatal hernia), ii) an inability to sit or stand upright for longer than 1 h after administration and iii) creatinine clearance <30 mL/min [1] [3] [4] [5] . No episodes of jaw osteonecrosis were reported with ibandronate [1] . No dose adjustment is necessary during hepatic failure or under a creatinine clearance >30 mL/min [1] . Intestinal absorption is impaired by multivalent cations such as calcium, aluminum, and iron. No pharmacokinetic interactions were demonstrated between ibandronate and other drugs commonly prescribed to postmenopausal women (e.g., tamoxifen and estrogen). Ibandronate interacts with bone-imaging agents used in bone scintigraphy [1] [5] .

A recommended regimen is 150 mg once monthly for 3 years [1] . Ibandronate should be taken after 6 hours of fasting (preferentially in the morning) and longer than 1 hour before a meal (with plain water and without any other medications). Patients should not lie down for 60 minutes afterward [1] [3] [5] .

Cholecalciferol (vitamin D3) is the major form of vitamin D in nature. It is attainable from the following sources: 1) corneocyte membrane 7-dehydrocolesterol, destined for photobiological transformation; 2) regular diet (cod liver oil, mackerel, salmon); 3) as the major form of vitamin D in pharmacological supplements. It can be considered simultaneously as a pre-hormone and a vitamin. Whatever its origin, cholecalciferol is destined to be converted to 25-hydroxyvitamin-D (calcidiol) in the liver by the action of vitamin D-25-hydroxylase. 25-hydroxyvitamin-D is destined to be converted to the biologically active 1,25-dihydroxy vitamin D (calcitriol) by the action of renal vitamin D-1-alpha-hydroxylase. Calcitriol stimulates the synthesis of 25-hydroxyvitamin D-24-hydroxylase, an enzyme that catalyzes the former to inactive calcitroic acid in peripheral cells, the latter destined to be excreted in the bile. Cholecalciferol to calcidiol enzymatic transformation obeys first-order kinetics, i.e., the conversion rate is proportional to the concentration of the former. Nevertheless, 1,25-dihydroxy vitamin D blood levels are strictly controlled through a balance of vitamin D-1-alpha-hydroxylase activity and 25-hydroxyvitamin D-24-hydroxylase catabolic rate in peripheral tissues [10] . On average, the skin releases 250 mcg of cholecalciferol daily, most of it destined either to be excreted in the bile or to be degraded to calcitroic acid, with only 2 mcg converted to bioavailable calcitriol. Physiological actions of calcitriol are: a) to facilitate the active absorption of calcium and phosphate in the small intestine and of calcium in the renal tubules to allow bone mineralization; b) to modulate parathyroid hormone secretion; c) to increase bone reabsorption of calcium and phosphate by increasing RANKL synthesis (a ligand to receptor activator of nuclear factor kappa-B), with subsequent nuclear factor kappa-light chain stimulation and proosteoclast to osteoclast differentiation (under hypocalcemia) [5] [10] [11] .

If vitamin D is abruptly interrupted and there is no sun exposure, calcitriol blood levels would still be maintained by two subsequent mechanisms: a) routine calcidiol to calcitriol conversion, the former having a terminal half-life of 2 months; b) cholecalciferol muscle and fat-storage retrieval by the organism [10] . Assuming its biological origin, it is possible to predict the physiological availability of cholecalciferol according to the following factors: 1) skin weight (by inference 7-dehydrocholesterol quantity, inversely proportional to age); 2) skin integrity (the dermal structure is compromised by aging); 3) UVB exposure (“vitamin D winter”, earth latitude, weather); 4) fish in the diet; 5) skin melanin quantity (a UVB absorbing molecule); 6) sunscreen use; 7) clothing; 8) glass shielding (a UVB absorbing material). Given the above factors, it is no wonder to verify that vitamin D deficiency is a highly prevalent condition in the western world and, by inference, bone metabolism complications associated with calcitriol decrease, especially among postmenopausal women [11] .

Cholecalciferol absorption takes place in the small intestine, it is fat-dependent and occurs readily. From the former, it is transported inside chylomicrons via the lymphatic system into the bloodstream, and linked to vitamin D binding protein (DBP) thereon. Cholecalciferol consolidated pharmacokinetics parameters are listed below [3] [5] [10] :

· time to conversion to 25-hydroxyvitamin-D3: 10 to 24 hours.

· protein binding rate: 50% to 80%.

· circulating half-life: 2 days.

· functional half-life: 2 to 3 months (influenced by DBP concentration and genetic polymorphisms).

· minimum serum levels for optimal calcium absorption: 30 ng/mL.

Oral cholecalciferol increases intestinal calcium and phosphate absorption in the range of 10% - 15% to 30% - 40% and 60% - 80% rates, respectively [5] . Vitamin D3 pharmacokinetics is unaltered by ibandronate under single dosages of 24,000 IU and 150 mg, respectively [12] .

Cholecalciferol side effects are generally associated with excessive doses and consist of hypercalcemia, nephrocalcinosis, osteoporosis, non-skeletal calcification, and pancreatitis [5] . According to the American Geriatric Society, 25-hydroxyvitamin D blood levels up to 100 ng/mL can be considered safe. Daily vitamin D dosage can be increased up to 10,000 IU in obese patients, due to fat distribution. Safety of doses ≥400 IU daily during pregnancy is not established. Maternal hypercalcemia may lead to supravalvular aortic stenosis syndrome and suppression of PTH release in the neonate. Excessive amounts of vitamin D in nursing mothers may result in hypercalcemia in infants [5] .

The Institutes of Medicine recommends 1500 to 2000 IU of vitamin D daily to treat and prevent postmenopausal osteoporosis [11] . Even though vitamin D and calcium supplementation are universally suggested, there is no consensus on the ideal daily regimens which vary from 600 IU to 1200 IU and 2000 to 2500 mg, respectively, depending on age and institutional recommendations. To attain calcidiol blood levels >30 ng/mL in vitamin D deficient adults in a 5 to 8 weeks term, vitamin D 50,000 IU once a week (or 7000 daily) regimen is suggested [3] .

Postmenopausal osteoporosis presents a complex pathophysiology, hinting the indication for different therapeutic modalities. Ibandronate and cholecalciferol fixed-dose combination can be considered clinically feasible for the following reasons: 1) both ibandronate and vitamin D influence at least two important pathophysiological elements related to osteoporosis, i.e., bone unbalanced resorption and low vitamin D availability, respectively; 2) both belong to first-line pharmacological classes recommended for this condition; 3) there is no know interaction between the two.

Ibandronate decreases the uptake of calcium from bone into the blood, an effect potentially associated with hypocalcemia. By increasing intestinal and renal calcium absorption, cholecalciferol could decrease this risk.

Combining both substances in the same pharmaceutical formulation can simplify the daily medical routine, especially in the setting of a chronic incurable condition, as well as improve adherence.