This observational study of teripar atide-treated PLO documents a substantial effect of postpartum treatment timing on BMD response. Women who initiated teriparatide < 12 months (M) postpartum had two–threefold larger BMD increases than those initiating teriparatide ≥ 12M postpartum. This study provides important data to inform treatment response expectations in clinical care of teriparatide-treated PLO. Pregnancy- and lactation-associated osteoporosis (PLO) describes an early-onset osteoporosis presentation with low- or no-trauma fractures associated with pregnancy/lactation; BMD at presentation is often extremely low. PLO fractures occur in the context of skeletal demineralization associated with pregnancy/lactation; natural BMD recovery is expected postpartum/postweaning, but BMD often remains quite low. Optimal management for PLO is uncertain. Teriparatide is the most common medication investigated. Observational studies document larger average BMD increases on teriparatide versus natural recovery—but individual response varies. Since treatment may overlap with the skeletally dynamic postweaning recovery period, we hypothesized that postpartum treatment timing would affect BMD response to teriparatide. Within our PLO Registry, BMD was assessed at baseline, 6M, and 12M in 31 women with PLO who initiated teriparatide either < 12M postpartum (EarlyRx, n = 10, initiation 7 ± 3 M postpartum) or ≥ 12M postpartum (DelayedRx, n = 21, initiation 36 ± 29 M postpartum). Groups were similar in terms of age, BMI, parity, number of fractures, and breastfeeding duration. As expected, based on known postpartum bone physiology, baseline BMD was lower in EarlyRx vs. DelayedRx. Teriparatide was associated with significant BMD increases in both timing groups—but response differed substantially. Increases at 12M in the EarlyRx group (LS:+ 21 ± 12

During pregnancy and lactation, changes in mineral metabolism provide fetuses with sufficient calcium. Eith a reported instance of 4–400 per 1 million pregnancies, the decrease in bone mineral density causes pregnancy and lactation associated osteoporosis (PLO). This the first systematic review conducted on this condition affecting the hip. A comprehensive literature search of the databases Embase, PubMed, and Web of Science was conducted. The articles included for review were case studies or case series that consisted of pregnant patients with PLO of the hip. Data extraction was performed on the resulting 64 studies, totaling 149 patient cases. The average age reported was 33.5 years, with an average BMI of 26.5 kg/m2 and an average height of 165.8 cm. Symptom onset was reported in 50

In premenopausal IOP, BMD gains on teriparatide-denosumab were maintained on bisphosphonate over 1 year. In 19 followed after bisphosphonate, there was a significant bone loss over 6M, leading to retreatment in some. BMD remained significantly above pretreatment baseline. In premenopausal IOP, the optimal duration of bisphosphonate after denosumab requires further study. We have previously reported that sequential teriparatide-denosumab resulted in large BMD increases in premenopausal women with idiopathic osteoporosis (IOP), and that BMD remained stable with bisphosphonate (alendronate or zoledronate) for 1 year after denosumab cessation (Bisphosphonate Extension Study; BES Year 1). To determine the durability of this effect, an observation year (BES Year 2) off therapy was planned. 19 women, aged 44 ± 8, with premenopausal IOP. BMD by DXA, serum CTX every 6 months (M). On sequential teriparatide-denosumab, BMD increased by 23 ± 9

Pregnancy- and lactation-associated osteoporosis (PLO) describes a fragility fracture presentation around pregnancy/lactation. Presentation often includes multiple vertebral fractures, but can also involve hip, sacral/pelvic, or other fractures. Substantial bone structural deficits and low bone formation rate have been documented. Most have no known secondary cause. Many have a history of childhood fracture and/or family history of osteoporosis. These characteristics, together with early onset and disease severity, lead to the hypothesis that genetic factors may contribute to PLO. We enrolled 110 women with PLO (mean #fractures = 6, vertebral fractures in 88 %) in an exome sequencing (ES) study. Analyses identified rare (<1 % allele frequency in gnomAD) predicted deleterious variants (RPDV) in 33/110 (30 %) women. All were heterozygous; two participants had multiple RPDV. No RPDV in COL1A1/COL1A2 were identified. 28/110 (25 %) had RPDV in genes related to WNT signaling, critical to bone formation: LRP5 (n = 19), LRP6 (n = 6), WNT1 (n = 2) or WNT1&LRP5 (n = 1). Seven had RPDV related to renal/calcium handling (SLC34A1, SLC34A3, SLC9A3), or other osteoporosis mechanisms (PLS3 (n = 3), HGD (n = 1)). Those with RPDV did not differ from those without in terms of BMD, fracture characteristics, and most clinical characteristics. Among 110 PLO women, exome sequencing analyses identified a potential genetic osteoporosis contribution in 30 %, suggesting that many genetic contributors to PLO have yet to be elucidated. The finding of variants related to WNT signaling in 25 % of the cohort is consistent with the predominantly low bone formation phenotype of PLO and may have implications for prognosis and treatment response.

Pregnancy and lactation-associated osteoporosis (PLO) is a rare presentation of early-onset osteoporosis characterized by low trauma and spontaneous fractures during late pregnancy/lactation. Herein, we report areal BMD (aBMD) by DXA and volumetric BMD (vBMD), microarchitecture, and strength at the distal radius and tibia by HR-pQCT in 59 women with PLO-in comparison to both healthy premenopausal controls (n = 28) and premenopausal women with idiopathic osteoporotic fractures not associated with pregnancy/lactation (non-PLO IOP; n = 50). Women with PLO (aged 34 ± 6 yr) had a more severe clinical presentation than non-PLO IOP: 80% had vertebral and 92% had multiple fractures (p<.001). They had lower DXA aBMD at all sites vs Controls (all p<.001) and non-PLO IOP (all p<.05). By HR-pQCT, PLO had deficits in all radial/tibial density and most microarchitecture parameters and lower bone strength than controls (all p<.001). Compared to non-PLO IOP, PLO had lower total and trabecular density at radius and tibia (all p ≤ .01) and significant deficits in trabecular microstructure and cortical thickness at the radius only. We studied PLO subgroups with clinical factors potentially related to bone physiology: Within PLO, women with vertebral fractures had lower spine aBMD and higher tibial cortical porosity but were otherwise structurally similar to the nonvertebral group. Those with prior heparin exposure had larger bone size and trabecular area, and those with renal stones had smaller bone size and lower 1/3 radius aBMD. We also compared groups based on postpartum timing: Recent PLO (n = 25) evaluated ≤12 M postpartum, before expected recovery of pregnancy/lactation bone loss, had significantly lower aBMD than distant PLO (n = 34) evaluated >12 M postpartum. However, radial/tibial HR-pQCT measures did not differ, suggesting pre-existing and/or persistent structural deficits. This structural study increases our mechanistic understanding of the severe bone fragility presentation that characterizes PLO and also highlights areas of potential mechanistic heterogeneity that require additional investigation.

Idiopathic osteoporosis (IOP) is a rare form of early-onset osteoporosis diagnosed in patients with no known metabolic or hormonal cause of bone loss and unknown pathogenesis. Patients with IOP commonly report both childhood fractures and family history of osteoporosis, raising the possibility of genetic etiologies of IOP. Whole-exome sequencing analyses of different IOP cohorts identified multiple variants in melatonin receptor 1A ( MTNR1A ) with a potential pathogenic outcome. A rare MTNR1A variant (rs374152717) was found in members of an Ashkenazi Jewish family with IOP, and an MTNR1A variant (rs28383653) was found in a nonrelated female IOP cohort (4%). Both variants occur at a substantially higher frequency in Ashkenazi Jewish individuals than in the general population. We investigated consequences of the heterozygous (rs374152717) variant [ MTNR1A c.184+1G>T ( MTNR1A c. 184+1G>T )] on bone physiology. A mouse model of the human rs374152717 variant reproduced the low bone mass (BM) phenotype of young-adult patients with IOP. Low BM occurred because of induction of senescence in mutant osteoblasts followed by compromised differentiation and function. In human cells, introduction of rs374152717 led to translation of a nonfunctional protein and subsequent dysregulation of melatonin signaling. These studies provide evidence that MTNR1A mutations entail a genetic etiology of IOP and establish the rs374152717 variant as a loss-of-function allele that impairs bone turnover by inducing senescence in osteoblasts. The higher prevalence of the MTNR1A variants identified in IOP cohorts versus the general population indicates a greater risk of IOP in those carrying these variants, especially Ashkenazi Jewish individuals bearing the rs374152717 variant.

This article reviews bone metabolism, bone mass, and bone structure changes expected during and after pregnancy and lactation, as well as the condition of pregnancy and lactation-associated osteoporosis (PLO)—a presentation with fragility fracture(s) in the context of these physiologic changes. Clinical implications of physiologic bone changes will be addressed, as will specific management considerations that apply to premenopausal women with PLO.

Context Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown.Methods We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics.Results In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median similar to 7 years of pegvisomant. In the cross-sectional study, patients on a median similar to 9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time.Conclusion In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.

Context: We previously reported that sequential teriparatide followed by denosumab substantially increases bone mineral density (BMD) in premenopausal idiopathic osteoporosis (PremenIOP). Objective: To determine whether administration of bisphosphonates after denosumab cessation is associated with stable BMD in PremenIOP Design: Open-label extension study. Participants: Twenty-four PremenIOP Teriparatide-Denosumab Study participants. Interventions: Oral alendronate (ALN), 70 mg weekly, or intravenous zoledronic acid (ZOL), 5 mg once (patient choice), was administered 7 months (M) after final denosumab dose. Outcomes: BMD by dual-energy x-ray absorptiometry and serum C-telopeptide (CTX) q6M; Vertebral Fracture Assessment (VFA), and high-resolution peripheral quantitative computed tomography (HR-pQCT) q12 M. Results: Twenty-four women with PremenIOP (aged 43 +/- 8 years), severely affected with low trauma adult fractures (range 0-12; 9 with vertebral fractures) and/or very low BMD, had large BMD increases on sequential teriparatide-denosumab (spine: 25 +/- 9%; total hip: 11 +/- 6%). During the Bisphosphonate Extension, mean BMD and CTX changes in the entire group were small and not statistically significant at 6 or 12 M. Women choosing ZOL (n = 6) vs ALN (n = 18) did not differ by baseline age, body mass index, fractures, BMD, or CTX. On ZOL, there were small lumbar spine BMD declines and CTX increases, particularly between 6 M and 12 M, while greater stability was observed on ALN. Changes in BMD and CTX did not differ by duration of denosumab (36 M vs <36 M) or between 20 women who remained premenopausal and 4 who transitioned into menopause. Higher pre-teriparatide CTX, likely reflecting baseline remodeling status, predicted more spine and hip bone loss. No new vertebral (clinical or vertebral fraction assessment screening) or nonvertebral fractures occurred. Conclusion: BMD remained stable in women with PremenIOP who received bisphosphonates after sequential teriparatide-denosumab therapy.

Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in skeletal microstructure. We have reported that sequential treatment with teriparatide and denosumab improves central skeletal bone mineral density (BMD) by dual‐energy X‐ray absorptiometry and central QCT in PreMenIOP. We conducted preplanned analyses of high‐resolution peripheral quantitative computed tomography (HR‐pQCT) scans from teriparatide and denosumab extension studies to measure effects on volumetric BMD (vBMD), microarchitecture, and estimated strength at the distal radius and tibia. Of 41 women enrolled in the parent teriparatide study (20 mcg daily), 34 enrolled in the HR‐pQCT study. HR‐pQCT participants initially received teriparatide (N = 24) or placebo (N = 10) for 6 months; all then received teriparatide for 24 months. After teriparatide, 26 enrolled in the phase 2B denosumab extension (60 mg q6M) for 24 months. Primary outcomes were percentage change in vBMD, microstructure, and stiffness after teriparatide and after denosumab. Changes after sequential teriparatide and denosumab were secondary outcomes. After teriparatide, significant improvements were seen in tibial trabecular number (3.3%, p = 0.01), cortical area and thickness (both 2.7%, p < 0.001), and radial trabecular microarchitecture (number: 6.8%, thickness: 2.2%, separation: −5.1%, all p < 0.02). Despite increases in cortical porosity and decreases in cortical density, whole‐bone stiffness and failure load increased at both sites. After denosumab, increases in total (3.5%, p < 0.001 and 3.3%, p = 0.02) and cortical vBMD (1.7% and 3.2%; both p < 0.01), and failure load (1.1% and 3.6%; both p < 0.05) were seen at tibia and radius, respectively. Trabecular density (3.5%, p < 0.001) and number (2.4%, p = 0.03) increased at the tibia, while thickness (3.0%, p = 0.02) increased at the radius. After 48 months of sequential treatment, significant increases in total vBMD (tibia: p < 0.001; radius: p = 0.01), trabecular microstructure (p < 0.05), cortical thickness (tibia: p < 0.001; radius: p = 0.02), and whole bone strength (p < 0.02) were seen at both sites. Significant increases in total vBMD and bone strength parameters after sequential treatment with teriparatide followed by denosumab support the use of this regimen in PreMenIOP. © 2022 American Society for Bone and Mineral Research (ASBMR).

Purpose Fractures are increased in patients with acromegaly, both before and after successful acromegaly treatment. Abnormalities of bone microstructure, which may underlie this fragility, are present in active acromegaly but to what extent these improve with acromegaly treatment or persist despite biochemical remission remains unclear. To examine these questions, we studied the effects of acromegaly treatment and remission on bone quality.Methods Sixty-five women and men with acromegaly were studied. Subgroups underwent assessments of areal bone mineral density by dual x-ray absorptiometry, trabecular bone score (TBS), and volumetric bone mineral density, microarchitecture, stiffness and failure load of the distal radius and tibia by high-resolution peripheral quantitative tomography in a longitudinal study before and after acromegaly treatment and in a cross-sectional study in which patients were compared to sex-, age-, and body mass index-matched healthy controls.Results In the longitudinal study, significant increases in total, cortical, and trabecular densities at the radius and tibia and increased stiffness and failure load of the tibia occurred with acromegaly treatment. In the cross-sectional study, patients in biochemical remission after surgery had larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to controls. TBS did not change with acromegaly treatment but correlated with some microstructural parameters.Conclusion We show, for the first time, that volumetric bone mineral density and microarchitecture of the peripheral skeleton improve with acromegaly treatment but remain abnormal in patients in remission after surgery compared to controls. These abnormalities, known to be associated with fractures in other populations, may play a role in the pathogenesis of persistent fragility in treated acromegaly.

Pregnancy and lactation associated osteoporosis is a rare and often severe osteoporosis presentation. Little information is available about etiology, clinical characteristics, risk factors and predictors of severity. Using an anonymized questionnaire, we defined clinical characteristics and potential risk factors for disease severity in PLO including primiparity, heparin exposure and celiac disease. Pregnancy and lactation associated osteoporosis (PLO) is a rare form of early-onset osteoporosis in which young women present with fractures, usually multiple vertebral fractures, during late pregnancy or lactation. Little information is available about etiology, clinical characteristics, risk factors and predictors of disease severity. PLO patients were recruited to complete an anonymized online questionnaire. Disease severity was defined as total number of fractures during or after the first pregnancy associated with a fracture(s). Analyses related disease severity to potential predictors including diseases/conditions or medication exposures. 177 completed surveys were received between 5/29/2018 and 1/12/2022. Average age at initial PLO fracture event was 32 ± 5 years. The majority were primiparous with singleton pregnancy and 79% fractured during lactation. Subjects reported 4.7 ± 2.7 total PLO fractures, with 48% reporting ≥ 5 fractures. Vertebral fractures, reported by 164/177 responders (93%), were the most common fracture type. Conditions and medications most commonly reported included vitamin D deficiency, amenorrhea unrelated to pregnancy, nephrolithiasis, celiac disease (CD), oral steroid use, heparin products during pregnancy and progestin only contraceptive after pregnancy. CD and heparins exposure during pregnancy were significantly related to disease severity. This is the largest study characterizing clinical features of PLO to date. The large number of participants and broad range of clinical and fracture characteristics queried has yielded novel information on the characteristics of PLO and potential risk factors for its severity, including primiparity, exposure to heparin and CD. These findings provide important preliminary data that can help target future mechanistic investigations.

Bone's ability to adapt is governed by the network of embedded osteocytes, which inhabit individual pores called lacunae. The morphology of these lacunae and their resident osteocytes are known to change with age and diseases such as postmenopausal osteoporosis. However, it is unclear whether alterations in lacunar morphology are present in younger populations with osteoporosis. To investigate this, we implemented a previously validated methodology to image and quantify the three-dimensional morphometries of lacunae on a large scale with ultrahigh-resolution micro-computed tomography (microCT) in transiliac bone biopsies from three groups of premenopausal women: control n = 39; idiopathic osteoporosis (IOP) n = 45; idiopathic low BMD (ILBMD) n = 19. Lacunar morphometric parameters were measured in both trabecular and cortical bone such as lacunar density (Lc.N/BV), lacunar volume (Lc.V), and lacunar sphericity (Lc.Sr). These were then compared against each other and also with previously measured tissue morphometries such as bone volume density (BV/TV), trabecular separation (Tb.Sp), trabecular number (Tb.N), and others. We detected no differences in lacunar morphology between the IOP, ILBMD and healthy premenopausal women. In contrast, we did find significant differences between lacunar morphologies including Lc.N/BV, Lc. V, and Lc. Sr in cortical and trabecular regions within all three groups (p < 0.001), which was consistent with our previous findings on a subgroup of the healthy group. Furthermore, we discovered strong correlations between Lc. Sr from trabecular regions with the measured BV/TV (R = -0.90, p < 0.05). The findings and comprehensive lacunar dataset we present here will be a crucial foundation for future investigations of the relationship between osteocyte lacunar morphology and disease.