Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Effect of gender on the evolution of pain and quality of life after treatment of symptomatic vertebral fragility fractures.

The evolution of pain and quality of life after a symptomatic vertebral fracture differs according to patient gender, with a worse evolution in women independently of the treatment received. PURPOSE: In a previous randomized clinical study comparing the effect of vertebroplasty (VP) vs. conservative therapy (CT) on pain evolution and quality of life (QoL) of patients with symptomatic vertebral fractures (VF), we observed the development of chronic back pain in 23% of subjects, independently of the therapy received. This study analyses the effect of gender on the evolution of pain and QoL in these subjects. METHODS: 118/125 randomized patients (27 males/91 females) with recent symptomatic VFs were evaluated. All received a standardized analgesic and antiosteoporotic format of treatment. Pain and QoL were evaluated by VAS and Qualeffo-41, respectively, at baseline, at 2 weeks and 2 and 6 months. We compared pain evolution and QoL after treatment (CT vs. VP) according to gender, and analysed factors including age, time of evolution, treatment received, baseline VAS, previous VFs (total and recent), incidental VFs, lumbar and femoral T-scores, and analgesic and antiosteoporotic treatment. RESULTS: At baseline, there were no differences in age (males 74.8 ± 11.2 vs. females:73.2 ± 8.7 years), time of evolution, number of VFs (males:3.8 ± 2.4 vs. females: 3.1 ± 2.4), treatment received (VP, males:59%, females:45%), lumbar or femoral T-score, baseline VAS (males:6.8 ± 2.1 vs. females:6.8 ± 2.2) or Qualeffo score (males:52.2 ± 24.4 vs. females:59.7 ± 20.6). Pain and QoL evolution differed according to gender, being better in males. These differences were significant after two months independently of the treatment and the development of incidental VF during follow-up. CONCLUSIONS: Pain and QoL evolution after a symptomatic VF differs according to gender, with a worse evolution in women independently of the treatment received.

Osteoporosis related to WNT1 variants: a not infrequent cause of osteoporosis.

Nearly 10% of subjects with severe idiopathic osteoporosis present pathogenic WNT1 mutations. Clinical characteristics include a family history of osteoporosis, early adulthood onset, and fragility fractures which may evolve to pseudoarthrosis. WNT1 should be genetically screened in these patients as the phenotype is often variable and therapeutic approaches may differ. INTRODUCTION: Recent studies have shown that homozygous WNT1 gene mutations may be related to severe osteoporosis resembling osteogenesis imperfecta (OI). Conversely, heterozygous WNT1 mutations are linked to a milder phenotype of early-onset osteoporosis. Treatment with bisphosphonates is reported to be unsatisfactory. Our aim was to analyze the presence and prevalence of WNT1 mutations and the main associated clinical characteristics in subjects with primary early-onset osteoporosis. METHODS: A cohort comprising 56 subjects (aged 19-60 years) with severe, early-onset osteoporosis was screened by massive parallel sequencing with a 23-gene panel. The gene panel included 19 genes known to cause OI (including the WNT1 gene), three genes related to osteoporosis, and the gene related to hypophosphatasia (ALPL). RESULTS: We identified five patients (3 men) with heterozygous WNT1 variants. All presented severe osteoporosis with early fracture onset and a family history of fragility fractures. None presented a characteristic phenotype of OI or skeletal deformities. One patient was previously treated with bisphosphonates, presenting inadequate response to treatment and two developed pseudoarthrosis after upper arm fractures. All subjects were diagnosed in adulthood. CONCLUSIONS: Nearly 1/10 adult subjects with severe idiopathic osteoporosis may present pathogenic WNT1 mutations. Clinical characteristics commonly include a family history of osteoporosis, onset in early adulthood, marked decrease in bone mass, and prevalent fractures, particularly vertebral. WNT1 should be genetically screened in these subjects as the phenotype is often variable and the therapeutic approach may differ. The role of WNT1 mutations in the development of pseudoarthrosis should also be elucidated.

Trabecular bone score improves fracture risk assessment in glucocorticoid-induced osteoporosis.

OBJECTIVE: To analyse the clinical utility of trabecular bone score (TBS) evaluation for fracture risk assessment in glucocorticoid (GC)-treated patients compared with BMD assessment. METHODS: One hundred and twenty-seven patients on GC treatment were included [mean age 62 (18) years, 63% women] in this cross-sectional study. The medical history, anthropometric data, lumbar and femoral BMD (DXA) [considering osteoporosis (OP): T-score ⩽-2.5], TBS (considering degraded microarchitecture: <1.230) and dorsolumbar X-ray [to assess vertebral fractures (VF)] were evaluated. BMD and TBS sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were evaluated to determine the diagnostic accuracy of the two methods. RESULTS: All patients were receiving GC treatment for autoimmune diseases during 47.7 (68.9) months at a mean daily dose of 14.5 mg; 17% had VF, 28% any type of fragility fracture (VF + non-VF), 29% OP and 52% degraded microarchitecture. Degraded microarchitecture was significantly more frequent than densitometric OP in patients with VF (76% vs 38%) and with any fragility fracture (69% vs 36%). For VF, TBS and BMD sensitivity, specificity, PPV, and NPV were 0.76, 0.53, 0.25 and 0.92, and 0.38, 0.72, 0.22 and 0.85, respectively. Specificity increased to 0.89 for VF and 0.9 for any fragility fracture on combining BMD+TBS. TBS had better ability than BMD to discriminate between patients with fracture, especially VF (area under the curve = 0.73). CONCLUSION: TBS seems to have greater discriminative power than BMD for fracture risk assessment in GC-treated patients, confirming the utility of this method as a complementary tool in the diagnosis of GC-induced OP.

Bilirubin and bile acids in osteocytes and bone tissue. Potential role in the cholestatic-induced osteoporosis.

BACKGROUND AND AIMS: Osteoporosis is a common complication in patients with primary biliary cholangitis. Both bilirubin and lithocholic acid (LCA) result in detrimental effects on osteoblastic cells, and ursodeoxycholic acid (UDCA) counteracts these outcomes. However, there is no information on the consequences of these retained substances of cholestasis and sera from cholestatic patients in osteocytes. METHODS: The impact of bilirubin, LCA, UDCA and serum from jaundiced patients on viability, differentiation, mineralization and apoptosis has been assessed in MLO-Y4 and MLO-A5 osteocyte cell lines. Effects on gene expression were assessed in these cells and in human bone fragments. RESULTS: Lithocholic acid 10 µmol/L and bilirubin 50 µmol/L decreased viability in MLO-Y4 and MLO-A5 cells (11% and 53% respectively; P ≤ .01). UDCA alone or combined with LCA or bilirubin increased cell viability. Jaundiced sera decreased cell viability (56%), an effect which was reverted by UDCA. Bilirubin decreased differentiation by 47% in MLO-Y4 (P ≤ .01) and mineralization (87%) after 21 days in MLO-A5 (P ≤ .03). Both bilirubin and LCA increased apoptosis in MLO-Y4, and UDCA diminished the apoptotic effect. Moreover, bilirubin down-regulated RUNX2 and up-regulated RANKL gene expression in bone tissue, MLO-Y4 and MLO-A5 cells, and LCA up-regulated RANKL expression in bone tissue. UDCA 100 µmol/L increased the gene expression of all these genes in bone tissue and MLO-Y4 cells and neutralized the decreased RUNX2 expression induced by bilirubin. CONCLUSION: Bilirubin and LCA have damaging consequences in osteocytes by decreasing viability, differentiation and mineralization, increasing apoptosis and modifying gene expression, effects that are neutralized by UDCA.

Osteoporosis in chronic liver disease.

Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end-stages and in chronic cholestasis, in addition to non-alcoholic fatty liver disease, haemochromatosis and alcoholism. Mechanisms underlying osteoporosis are poorly understood, but osteoporosis mainly results from low bone formation. In this setting, sclerostin, a key regulator of the Wnt/ß-catenin signalling pathway which regulates bone formation, in addition to the effects of the retained substances of cholestasis such as bilirubin and bile acids on osteoblastic cells, may influence the decreased bone formation in chronic cholestasis. Similarly, the damaging effects of iron and alcohol on osteoblastic cells may partially explain bone disease in haemochromatosis and alcoholism. A role for proinflammatory cytokines has been proposed in different conditions. Increased bone resorption may occur in cholestatic women with advanced disease. Low vitamin D, poor nutrition and hypogonadism, may be contributing factors to the full picture of bone disorders in chronic liver disease.

Reference intervals for bone turnover markers in Spanish premenopausal women.

BACKGROUND: The aims of this study were to establish robust reference intervals and to investigate the factors influencing bone turnover markers (BTMs) in healthy premenopausal Spanish women. METHODS: A total of 184 women (35-45 years) from 13 centers in Catalonia were analyzed. Blood and second void urine samples were collected between 8 a.m. and 10 a.m. after an overnight fast. Serum procollagen type I amino-terminal propeptide (PINP) and serum cross-linked C-terminal telopeptide of type I collagen (CTX-I) were measured by two automated assays (Roche and IDS), bone alkaline phosphatase (bone ALP) by ELISA, osteocalcin (OC) by IRMA and urinary NTX-I by ELISA. PTH and 25-hydroxyvitamin D (25OHD) levels were measured. All participants completed a questionnaire on lifestyle factors. RESULTS: Reference intervals were: PINP: 22.7-63.1 and 21.8-65.5 µg/L, bone ALP: 6.0-13.6 µg/L, OC: 8.0-23.0 µg/L, CTX-I: 137-484 and 109-544 ng/L and NTX-I: 19.6-68.9 nM/mM. Oral contraceptive pills (OCPs) influenced PINP (p=0.007), and low body mass index (BMI) was associated with higher BTMs except for bone ALP. Women under 40 had higher median values of most BTMs. CTX-I was influenced by calcium intake (p=0.010) and PTH (p=0.007). 25OHD levels did not influence BTMs. Concordance between the two automated assays for PINP and particularly CTX-I was poor. CONCLUSIONS: Robust reference intervals for BTMs in a Southern European country are provided. The effects of OCPs and BMI on their levels are significant, whilst serum 25OHD levels did not influence BTMs. Age, calcium intake, BMI and PTH influenced CTX-I. The two automated assays for measuring PINP and CTX-I are not interchangeable.

Risk factors for the development of chronic back pain after percutaneous vertebroplasty versus conservative treatment.

In a recent randomized controlled trial comparing vertebroplasty (VP) versus conservative treatment (CT) in patients with symptomatic vertebral fractures (VF), we observed the development of chronic back pain (CBP) in nearly one-quarter of patients. The aim of this study was to identify the risk factors related to the development of severe CBP in these subjects. We evaluated risk factors including visual analog scale (VAS) at baseline and during the 1-year follow-up, age, gender, symptom onset time, number, type and severity of VF at baseline, number of vertebral bodies treated, incident VF, and antiosteoporotic treatment, among others. CBP was considered in patients with VAS ≥ 7 at 12 months. 91/125 patients completed the 12-months follow-up. CBP was observed in 23% of VP-treated patients versus 23% receiving CT. Patients developing CBP after VP showed a longer symptom onset time (82% ≥ 4 months in VP vs. 40% in CT, P = 0.03). On univariate analysis, female gender (OR 1.52; 95% CI 1.47-1.57, P < 0.0001), multiple acute VF (OR 1.79; 95% CI 1.71-1.87, P < 0.0001), VAS ≥ 7 two months after treatment (OR 11.04; 95% CI 6.71-18.17, P < 0.0001), and type of antiosteoporotic drug (teriparatide) (OR 0.12; 95% CI 0.03-0.60, P = 0.0236) were risk factors of CBP development in both groups. In the multivariate analysis, the main risk factors were baseline and post-treatment VAS ≥ 7, longer symptom onset time, and type of antiosteoporotic treatment. In conclusion, 23% of patients with symptomatic osteoporotic VF developed severe CBP independently of the type of treatment. Symptom onset time before VP and persistence of severe CBP after treatment were the main factors related to CBP with teriparatide treatment decreasing the risk of this complication.

Randomized trial comparing monthly ibandronate and weekly alendronate for osteoporosis in patients with primary biliary cirrhosis.

UNLABELLED: Osteoporosis resulting in bone fractures is a complication in patients with primary biliary cirrhosis (PBC). Once-weekly alendronate improves bone mass and is well tolerated in these patients, but there is a concern because of poor compliance. Therefore, the efficacy, adherence, and safety of monthly ibandronate (150 mg) with weekly alendronate (70 mg) were compared in a randomized, 2-year study in 42 postmenopausal women with PBC and osteoporosis. Bone mineral density (BMD) of the lumbar spine and proximal femur (by DXA), liver function, and bone markers were measured at entry and every 6 months over 2 years. Adherence to therapy was assessed by the Morisky-Green score. At enrollment, the two groups were similar with respect to age, BMD, severity of cholestasis, previous fractures, and bone markers. Thirty-three patients, 14 in the ibandronate group and 19 in the alendronate group, completed the trial. At 2 years both treatments resulted in a significant increase in BMD at the lumbar spine (from 0.875 ± 0.025 to 0.913 ± 0.026 g/cm(2), P < 0.001 with alendronate, and from 0.898 ± 0.024 to 0.949 ± 0.027 g/cm(2), P < 0.001 with ibandronate). The mean percentage change was 4.5% and 5.7%, respectively (P = not significant). BMD increased at the total hip by 2.0% and 1.2%, respectively. Changes in bone markers were similar in both groups and one patient with alendronate developed a new vertebral fracture. Adherence to therapy was higher with ibandronate (P = 0.009). Neither treatment impaired liver function or cholestasis. CONCLUSION: Both regimens, weekly alendronate and monthly ibandronate, improve bone mass and are comparable in safety for osteoporosis therapy in patients with PBC, although adherence is higher with the monthly regimen. Further larger studies are needed to assess fracture prevention.

Ursodeoxycholic acid decreases bilirubin-induced osteoblast apoptosis.

BACKGROUND: Low bone turnover osteoporosis is common in cholestatic diseases. Ursodeoxycholic acid (UDCA) counteracts the damaging effects of bilirubin or lithocholic acid (LCA) on osteoblast viability, proliferation and mineralisation. UDCA is anti-apoptotic in various cell lines, but this effect in bone cells is unknown. Therefore, the consequences of bilirubin and LCA on apoptosis, and whether UDCA has anti-apoptotic effects have been assessed on osteoblasts. MATERIALS AND METHODS: Human osteoblasts (hOB) and osteosarcoma cell line (Saos-2) were treated with camptothecin as a pro-apoptotic agent, and UDCA, LCA and bilirubin. Apoptosis was determined by DNA fragmentation, flow cytometry, caspase-3 activity and expression of pro-apoptotic (Bcl-2-associated X protein BAX) and anti-apoptotic (BCL2 and BCL2-like 1 protein, BCL2L) genes. RESULTS: Both LCA (10 µM) and bilirubin (50 µM) induced apoptosis as indicated by DNA fragmentation (4·7- and 3·7-fold, respectively, P < 0·001), caspase-3 activity and flow cytometry in Saos-2 and hOB. UDCA (10 µM) reduced the apoptotic effects of camptothecin (0·5 µM) by 61%, (P < 0·001) and counteracted the apoptotic effects of LCA and bilirubin determined by DNA fragmentation (56% and 60%, respectively, P < 0·001), cytometry and caspase-3 activity in Saos-2, with lower effects in hOB. UDCA (10 µM) downregulated BAX (75%), upregulated BCL2L (10-fold, P < 0·01) genes, and neutralised BAX upregulation (P < 0·01) and BCL2L downregulation (P < 0·01) induced by LCA and bilirubin. CONCLUSIONS: Bilirubin and LCA induce apoptosis in osteoblastic cells. UDCA counteracts the apoptotic consequences of these two substances, and therefore, it may have further beneficial effects on the decreased bone formation in the cholestasis.

The role of Wnt signaling and sclerostin in the pathogenesis of glucocorticoid-induced osteoporosis.

Bone formation is suppressed in glucocorticoid-induced osteoporosis. One of the mechanisms by which glucocorticoids depress bone formation is through their effects on the Wnt/ß-catenin signaling pathway, a critical regulator of osteoblastogenesis. Thus, Wnt signaling induces the differentiation of osteoblast precursors toward mature osteoblasts and prevents osteoblast and osteocyte apoptosis. Glucocorticoids increase the expression of Wnt signaling antagonists (sclerostin and Dkk-1) in experimental studies in rodents and cell cultures. However, the scarce data of their effects in humans are somewhat contradictory, probably due to the dose and duration of treatment as well as the characteristics of the patients. A progressive decrease in Dkk-1 serum levels and an increase in circulating sclerostin levels at long-term follow-up have recently been reported in patients treated with high doses of glucocorticoids. This review describes the most recent data on the effects of glucocorticoids on the Wnt signaling pathway, especially on their antagonists, sclerostin and Dkk-1.

Incidence of skeletal fractures after traumatic spinal cord injury: a 10-year follow-up study.

OBJECTIVE: To analyse the incidence and factors related to the development and clinical evolution of fractures in patients with traumatic spinal cord injury. DESIGN: A retrospective 10-year follow-up study. SETTING: Neurorehabilitation centre. SUBJECTS: Sixty-three patients (50M/13F) with a mean age of 36 ± 20 years with recent traumatic spinal cord injury attended over a one-year period (January to December 2000). MAIN MEASURES: Medical reports were reviewed, evaluating risk factors for osteoporosis, fracture incidence during the 10 years following spinal cord injury, severity (ASIA score) and level of spinal cord injury (paraplegia/tetraplegia), type of lesion (spastic/flaccid), weight-bearing standing activity, and the cause, location and evolution of the fracture. RESULTS: Of the 129 patients attending during the study period, 75 had traumatic spinal cord injury (7 died and 5 had no follow-up). Finally, 63 patients were included. Fifty-four per cent had complete motor injury (ASIA A). Twenty-five per cent of these patients developed fractures, with 2.9 fractures per 100 patient-years. The femur was the most frequent location of the fractures. Fractures were observed 6.4 ± 2.4 years after spinal cord injury (range 2-10 years), all in males. Most fractures (70%) were related to low-impact injuries. Fifty per cent presented with associated clinical complications and only 20% of the patients had received anti-osteoporotic treatment. Spinal cord injury severity was the only risk factor for the development of fractures (complete spinal cord injury (ASIA A)) (RR 4.043; 95% confidence interval (CI) 1.081-23.846, P = 0.037). CONCLUSION: The incidence of fractures after spinal cord injury is high, with severity and time since spinal cord injury being the main determinants for their development. Fractures were frequently associated with clinical complications. However, the use of anti-osteoporotic treatment was uncommon.

Clinical use of bone markers: a challenge to variability.

Bone markers are a group of substances released into circulation during bone formation and/or resorption. These substances can be measured in blood and urine to obtain information about metabolic bone disorders. This review provides an insight into factors influencing bone marker variability and describes different approaches to minimize variability and interpret results appropriately. Variability in bone marker concentrations results from biological and analytical variability across assays. Other influencing factors include gender, age, physical exercise, circadian rhythm, and diet. The multiplicity of influencing factors hinders the establishment of accurate reference values. Gaining a deep understanding of bone marker variability is the first step to ascertain their clinical usefulness. Bone marker variability can be minimized by controlling as many variables as it is possible and through the standardization of patient preparation and sample collection and handling.

Bone disease in patients awaiting liver transplantation. Has the situation improved in the last two decades?

In recent years, there has been speculation about the possibility of a reduction in the incidence of fractures after liver transplantation (LT) because of changes in the characteristics of candidates and the use of different immunosuppressive therapies. We analyzed the characteristics of LT candidates (CTC) and compared them with historical data from a group of LT candidate patients (HTC). Data from 60 CTC patients consecutively included in a screening program of metabolic bone disease were compared with data from 60 HTC patients prospectively evaluated between 1992 and 1993. In all patients, we analyzed the clinical and laboratory characteristics, bone mineral density (BMD) dual-energy X-ray absorptiometry, and skeletal fractures. Patients in the CTC group were older than patients in the HTC group. The CTC group had lower femoral neck T scores. No differences were observed between groups in the proportion of patients with osteoporosis (22 vs. 30 %, p = ns) or fractures (36 vs. 33 %, p = ns). The percentage of patients with normal BMD decreased from 38 to 20 %. 25(OH)D values were low in both groups. Only 7.5 % of the CTC patients received calcium and/or vitamin D supplementation. The prevalence of fractures among CTC patients was similar to that seen two decades ago. At present, candidates for LT are older and have lower femoral bone mass. Vitamin D deficiency remains frequent; however, calcium and/or vitamin D supplementation is uncommon.

Ursodeoxycholic acid increases differentiation and mineralization and neutralizes the damaging effects of bilirubin on osteoblastic cells.

BACKGROUND: Osteoporosis resulting from decreased bone formation is a common complication in patients with chronic cholestasis. Lithocholic acid (LCA) and bilirubin may play a role in osteoporosis given that both substances have detrimental effects on survival of human osteoblasts, the cells involved in bone formation. AIMS: As ursodeoxycholic acid (UDCA) improves cholestasis, we have assessed if this bile acid may neutralize the harmful effects of LCA, bilirubin and sera from jaundiced patients on osteoblastic cells. METHODS: The experiments were performed in primary human osteoblasts and human osteosarcoma cell line (Saos-2) at different times and concentrations of UDCA, LCA, cholic acid (CA), bilirubin and sera from jaundiced patients to assess cell viability, differentiation and mineralization. RESULTS: UDCA significantly decreased cell survival at concentrations 10 times higher (1 mM) than that observed with LCA, whereas CA did not decrease osteoblast survival. UDCA (100 µM) neutralized the damaging effects of bilirubin (50 µM) and sera from jaundiced patients on survival. Moreover, UDCA (1 µM and 10 µM) increased osteoblast differentiation in cells treated with harmful concentrations of LCA or bilirubin. UDCA (100 µM) increased cell differentiation in osteoblasts cultured with a mix of serum from cholestatic patients by 23%. Furthermore, UDCA increased osteoblast mineralization by 35% and neutralized the negative consequences of 50 µM bilirubin. CONCLUSIONS: UDCA increases osteoblast differentiation and mineralization, and neutralizes the detrimental effects of lithocholic acid, bilirubin and sera from jaundiced patients on osteoblastic cells. Therefore, UDCA may exert a favourable effect on bone in patients which chronic cholestasis.

Sequential management of postmenopausal health and osteoporosis: An update.

Increased life expectancy means that women are now in a hypoestrogenic state for approximately one-third of their lives. Overall health and specifically bone health during this period evolves in accordance with aging and successive exposure to various risk factors. In this review, we provide a summary of the approaches to the sequential management of osteoporosis within an integrative model of care to offer physicians a useful tool to facilitate therapeutic decision-making. Current evidence suggests that pharmacologic agents should be selected based on the risk of fractures, which does not always correlate with age. Due to their effect on bone turnover and on other hormone-regulated phenomena, such as hot flushes or breast cancer risk, we position hormone therapy and selective estrogen receptor modulators as an early postmenopause intervention for the management of postmenopausal osteoporosis. When the use of these agents is not possible, compelling evidence supports antiresorptive agents as first-line treatment of postmenopausal osteoporosis in many clinical scenarios, with digestive conditions, kidney function, readiness for compliance, or patient preferences playing a role in choosing between bisphosphonates or denosumab during this period. For patients at high risk of osteoporotic fracture, the "anabolic first" approach reduces that risk. The effect on bone health with these bone-forming agents or with denosumab should be consolidated with the subsequent use of antiresorptive agents. Regardless of the strategy, follow-up and treatment should be maintained indefinitely to help prevent fractures.