Cannabidiol (CBD) effects on bone metabolism in postmenopausal osteoporosis remain unclear. While endocannabinoids and phytocannabinoids bind to receptors in bone cells, direct evidence of CBD’s bone-protective effects is lacking. We evaluated the effects of CBD on bone metabolism in ovariectomized (OVX) rat model of estrogen deficiency. Twelve-week study with treatment initiated 2 wk after the surgery was conducted. Five experimental groups were established: sham-operated with vehicle (SHM/VEH), sham with CBD (SHM/CBD5), OVX with vehicle (OVX/VEH), OVX with 17β-estradiol (OVX/E2), and OVX with CBD (OVX/CBD5). Cannabidiol was administered at 5 mg/kg/d via osmotic pumps. Micro-CT of the distal femur revealed that trabecular bone mass in OVX/CBD5 decreased similarly to OVX/VEH, indicating no protective effect. Serum bone turnover markers showed increased bone resorption in OVX/CBD5 compared to OVX/VEH. Gene expression analysis revealed that estrogen significantly reduced Ctsk gene expression compared to OVX/VEH, while CBD showed no significant differences. No significant changes were observed in cannabinoid receptor expression or bone metabolism in sham-operated rats receiving CBD. While CBD (5 mg/kg/d) was well-tolerated, it did not mitigate OVX-induced bone loss in skeletally mature rats. Consequently, CBD should not be considered a monotherapy for postmenopausal osteoporosis, though it appears safe for other potential medical applications.

Hypophosphatasia (HPP) is a rare, inherited, systemic disease characterized by skeletal and systemic manifestations. Asfotase alfa (AA) is the only US Food and Drug Administration-approved treatment for perinatal/infantile- and juvenile-onset HPP. Real-world data are scarce on fracture rates and healthcare resource utilization (HCRU) in patients treated with AA. This retrospective, observational study evaluated fracture-related outcomes and HCRU in patients with HPP treated with AA from January 2016 to December 2022 using the US Medicare Fee-for-Service and Inovalon Medical Outcomes Research for Effectiveness and Economics closed claims databases. Patients (≥2 yr of age) treated with AA (≥1 pharmacy claim for AA between January 2017 and December 2021 [identification period]) and ≥12 mo of continuous enrollment with medical and pharmacy coverage pre- and post-AA initiation were included. Clinical outcomes (change in fractures, types of fractures, and fracture event rates) and HCRU were assessed. Statistical analyses were performed to compare outcomes before and after initiation of AA. One hundred forty-nine patients (65.1% females, 69.1% adults; mean age, 39.6 yr) met the inclusion criteria. The proportion of patients experiencing fractures in the 12 mo following AA initiation significantly decreased compared to the 12 mo prior to treatment (18.1% vs 8.1%; p = .004). The mean fracture rate per patient per year nominally decreased post-AA initiation (0.24 vs 0.14; p = .096). The decrease was significant in fragility fracture rates (0.08 vs 0.02; p = .019). Most prescribed concomitant drugs at baseline were opioid analgesics (36.9%), nonopioid analgesics (34.2%), and antidepressants (34.9%). At baseline, 38.2% of patients were continuously using opioids and 21.8% were using high-dose opioids. Asfotase alfa initiation was associated with a statistically significant reduction in the proportion of patients experiencing fractures and fragility fracture rates, underscoring its potential therapeutic benefits.

Intravenous iron infusions (particularly ferric carboxymaltose) are associated with hypophosphatemia. This is mediated by increased fibroblast growth factor 23 (FGF-23), resulting in decreased activation of 25(OH)vitamin D to 1,25(OH)2 vitamin D and increased urinary phosphate excretion. Similarly, parenteral antiresorptive agents can lead to hypocalcemia due to reduced bone calcium mobilization, increasing parathyroid hormone (PTH) secretion, and exacerbating kidney phosphate excretion. When given concurrently, electrolyte disturbances can be severe and refractory to treatment, necessitating intravenous replacement, frequent monitoring, and prolonged hospitalization. We describe a case series of six patients with severe hypophosphatemia and hypocalcemia from concurrent administration of intravenous iron and antiresorptive therapy. The average time to hypophosphatemia following iron therapy in the presence of antiresorptives was 17.5 days. This is consistent with the nadir of phosphate 2 weeks following iron infusion and appears to be prolonged and exacerbated by antiresorptive therapy, increasing urinary phosphate loss through increased PTH activity. With the increasing popularity of intravenous iron infusions and parenteral antiresorptive agents, the interplay of these medications is an important consideration for clinicians. The emerging administration of these agents in the community and fragmentation of care across primary and specialist networks create the risk of unintentional concurrent use. Increased awareness of their impact on calcium-phosphate homeostasis is needed to mitigate the risk of severe electrolyte derangements with consideration of alternate iron formulations preferentially in those receiving medications for osteoporosis.

Osteitis fibrosa cystica (OFC) is an extreme manifestation of accelerated bone resorption in primary hyperparathyroidism (PHPT), rarely encountered nowadays. Bone mineral density gain following parathyroidectomy (PTx) is well documented, while little is known regarding the timeline of lytic lesions remineralization and recovery. We present three patients with OFC, surgically treated for PHPT, with clinical, biochemical, and advanced radiological (CT or MRI) post-PTx follow-up. Additionally, we review published OFC case reports that include serial imaging of bony lesions following PTx. All patients received calcium, magnesium and alphacalcidiol supplementation post-PTx with serum calcium, PTH, and alkaline phosphatase gradually normalizing. Patients 1 and 2 exhibited an impressive remineralization of pelvic lytic lesions within 6 and 12 mo following PTx, respectively. Patient 3 showed partial remineralization of C4-C5 vertebrae at 6 mo, with continued improvement at 18 mo post-PTx. Both Patients 1 and 3 required salvage orthopedic intervention. We summarize reports of 54 patients with PHPT and OFC, assessed for lytic lesion recovery after PTx using various imaging modalities. Most lesions showed partial remineralization within 6-12 mo. Near full and complete remineralization was evident in 38 (70.3%) of the patients on the last imaging follow-up. Substantial remineralization of lytic lesions in OFC can be observed within months of PTx, even in large or symptomatic lesions. This early skeletal recovery may obviate the need for orthopedic intervention in selected patients and supports a conservative management approach when lesion location permits.

When denosumab is discontinued, antiresorptive therapy is necessary to mitigate high bone turnover bone loss. While bisphosphonates have been investigated for this, alternatives have received less attention. In the Comparison of Alendronate and Raloxifene after Denosumab (CARD) randomized, controlled, open-label study, we previously reported alendronate better suppressed bone remodeling and maintained denosumab-induced areal BMD (aBMD) gains than raloxifene, though raloxifene maintained femoral neck aBMD and partially inhibited loss elsewhere. In this exploratory analysis, we now assess the comparative ability of these drugs to maintain denosumab-induced improvements in peripheral volumetric BMD (vBMD), microarchitecture, and estimated bone strength. CARD randomized 51 postmenopausal women (60–81y) at high fracture risk to receive denosumab 60-mg by subcutaneous injection every 6 mo for 12-mo followed by either 12-mo of oral alendronate (70 mg weekly, n = 26) or oral raloxifene (60 mg daily, n = 25). Total, trabecular, and cortical vBMD and skeletal microarchitecture were measured by high-resolution peripheral quantitative CT of the distal radius and distal tibia. After 12-mo of denosumab, mean total and cortical vBMD at the radius and tibia increased significantly in the cohort as a whole, whereas trabecular vBMD did not change significantly. Bone strength (stiffness and failure load as estimated by finite element analysis) also increased significantly at both sites. After the transition to alternate antiresorptive therapy, the gains observed in total and compartmental vBMD and estimated bone strength were maintained in both treatment groups with no significant between-group differences. No significant changes in cortical porosity or thickness were observed, either during denosumab treatment or after the transition to alternate antiresorptive therapy. We conclude that denosumab improved vBMD and bone strength, and these gains were maintained with both alendronate and raloxifene, supporting raloxifene as an option for those unable or unwilling to take bisphosphonates after short-term denosumab exposure.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic condition characterized by congenital malformations of the great toes and progressive heterotopic ossification (HO) in specific anatomic patterns. Present management summarized here is focused on early diagnosis, assiduous avoidance of injury and iatrogenic harm, symptomatic amelioration of painful flare-ups, and optimization of residual function. Twenty-one members of the International Clinical Council on FOP (ICC) and seven consultants from 15 countries, chosen for their clinical expertise in FOP, developed this summary statement. Further advances in therapeutics will be based on rigorous clinical trials to assess novel and emerging treatment and prevention strategies. A detailed and updated exploration of the topics outlined in this brief perspective can be found in “The Medical Management of Fibrodysplasia Ossificans Progressiva: Current Treatment Considerations” which can be found on the International Clinical Council on FOP (ICC) website (www.iccfop.org).

Bone damage occurs early in the progression of plasma cell disorders. Romosozumab (ROMO), a sclerostin inhibitor with both anabolic and antiresorptive effects, may provide therapeutic benefit for this fracture-prone population. We conducted a 12-mo prospective observational study on postmenopausal women with osteoporosis and multiple myeloma (MM) treated with monthly ROMO. BMD was assessed at baseline, 6, and 12 mo with DXA and HR-pQCT. Additionally, bone turnover markers (BTMs) and several MM markers were also monitored. Eight female patients with MM without evidence of CRAB completed 12 mo of ROMO. A significant BMD increase was observed at the LS (+5.8%, p = .048), FN (+4.2%, p = .020), and TH (+3.3%, p = .002). Procollagen I intact N-terminal peptide rose sharply at month 3 (+117.8%) and returned to baseline by month 12 (p = .006). C-terminal telopeptide of type I collagen decreased progressively, showing a trend toward significance (−53.6%, p = .060). Alkaline phosphatase and bone alkaline phosphatase significantly declined by month 12 (p = .020 and p = .022). No significant changes occurred in immunoglobulins, M-protein, or light chains. β2-microglobulin decreased at month 12 (from 2.35 to 2.1 mg/L, p = .042), but the overall trend was not significant (p = .092). Failure load increased at month 6 (p = .033), while the other HR-pQCT parameters remained stable throughout the study. In this exploratory study of postmenopausal women with MM and osteoporosis, ROMO significantly improved BMD and modulated BTMs, without any evidence of disease progression over the 12-mo period. These findings support ROMO as a potential bone-targeted therapy in patients with osteoporosis and MM.

More than 18% of the global population suffers from osteoporosis and its associated fracture risk each year. Among the many factors implicated in osteoporosis development, high iron levels have been implicated in bone loss in mice and patients. Here, we performed a comparative analysis of the effect of iron overload induced via diet, injections, or genetic factors, on overall bone health and mechanical bone strength. We used female mice, given the higher risk of osteoporosis and associated fractures in women than in men. We show that dietary iron overload induced trabecular remodeling in the spine but not in the femur, with potentially pre-pathogenic structural changes. By contrast, iron injections caused severe bone deficits across all sites measured. Interestingly, the loss of cortical bone emerged as a common hallmark of secondary iron overload and was associated with decreased mechanical strength in mice. However, no bone anomalies were observed in mice with genetic iron overload, demonstrating that iron overload per se does not suffice to induce bone loss in genetic hemochromatosis. Collectively, our study shows that iron overload-induced by diet and injections, but not genetically, induces selective and specific bone deficits, which are associated with decreased bone mechanical strength in mice.

Disruptions of the composition of the gut microbiome are linked to impaired bone tissue strength. Fecal microbiota transplantation (FMT) is an established clinical therapy that can restore a healthy gut microbiome and reduce systemic inflammation. However, whether FMT from a healthy donor could rescue bone fragility is unknown. As induced inflammation causes mineralization defects, we hypothesize that manipulations of the gut microbiota alter bone fracture resilience through changes in mineral quality. Here, we altered the compositions of the gut microbiome in mice via antibiotics (ampicillin and neomycin) and FMT. Mice were allocated to 5 groups (M/F, N = 13-18/group): Unaltered, Continuous (dosed 4-24 wk), Initial (dosed 4-16 wk), Reconstituted (dosed 4-16 wk with subsequent FMT from age- and sex-matched mice with unaltered gut microbiota), and Delayed (dosed 16-24 wk). Fracture toughness testing and Raman spectroscopy were conducted on the femora. The maximum toughness was greater in the Reconstituted group (for females, p < .05 compared to Continuous, Unaltered, and Delayed groups; for males, p < .05 compared to groups with antibiotic dosing). The Reconstituted group showed lower type-B carbonate substitution in the bone mineral (all p < .01 for both sexes), and lower mineral-to-matrix ratio (all p < .01 for males, for females, p < .01 compared to Unaltered, Initial, and Delayed groups). In females, mineral crystallinity was higher in the Reconstituted group than those dosed with antibiotics (all p < .05). Serum inflammation marker TNF-α was positively correlated with type-B carbonate substitutions (ρ = 0.66), mineral-to-matrix ratio (ρ = 0.71), and carboxymethyl-lysine (CML) in bone matrix (ρ = 0.43). Enhanced bone maximum fracture toughness was associated with reduced type-B carbonate substitution (r = −0.45), decreased mineral-to-matrix ratio (r = −0.40), increased mineral crystallinity (r = 0.33), and lower levels of bone CML (r = −0.49, all p < .01). These results suggest that the introduction of more beneficial gut microbiota can increase fracture resistance by modifying mineral composition and quality, likely through the reduction of systemic inflammation.