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.

BACKGROUND: We previously reported that sequential teriparatide followed by denosumab substantially increases BMD in premenopausal idiopathic osteoporosis (PremenIOP).
OBJECTIVE: To determine whether administration of bisphosphonates after denosumab cessation is associated with stable BMD in PremenIOP.
METHODS: Open-label extension study.
METHODS: 24 PremenIOP Teriparatide-Denosumab Study participants.
METHODS: Oral alendronate (ALN), 70mg weekly, or IV zoledronic acid (ZOL), 5mg once (patient choice), was administered 7 months (M) after final denosumab dose.
RESULTS: BMD by DXA and serum C-telopeptide (CTX) q6M; vertebral fracture assessment (VFA) and HR-pQCT q12M.
RESULTS: 24 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 12M.Women choosing ZOL (n = 6) versus ALN (n = 18) did not differ by baseline age, BMI, fractures, BMD, or CTX. On ZOL, there were small LSBMD declines and CTX increases, particularly between 6M and 12M, while greater stability was observed on ALN.Changes in BMD and CTX did not differ by duration of denosumab (36M vs <36M) 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 VFA screening) or non-vertebral fractures occurred.
CONCLUSIONS: BMD remained stable in women with PremenIOP who received bisphosphonates after sequential teriparatide-denosumab therapy.

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.
OBJECTIVE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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.

Pregnancy- and lactation-associated osteoporosis (PLO) is a rare type of premenopausal osteoporosis that occurs mainly in the third trimester or immediately after delivery; one of its most common symptoms is back pain caused by a vertebral fracture. The pathogenesis of PLO is unclear, and there is no accepted consensus regarding the treatment of PLO. Although treatments with drugs such as bisphosphonate, strontium ranelate, denosumab, and teriparatide were reported, there is no report of a patient with PLO treated with romosozumab. We present the first case of a patient with PLO treated with romosozumab following 4-month teriparatide treatment. A 34-year-old primiparous and breastfeeding Japanese woman experienced severe low back pain 1 month postdelivery. She was diagnosed with PLO on the basis of low bone marrow density (BMD) and multiple vertebral fractures with no identified cause of secondary osteoporosis. She was treated with teriparatide injection for 4 months, but the treatment was discontinued because of the patient feeling severe nausea after every teriparatide injection and the appearance of new vertebral fractures. Thereafter, we used romosozumab for 12 months. After the romosozumab treatment, her BMD was increased from the baseline by 23.6% at L1-L4, 6.2% at the femoral neck, and 11.2% at the total hip. Treating PLO with 12-month romosozumab after 4 months of teriparatide injection remarkably increased the BMD of the lumbar spine, femoral neck, and total hip without subsequent fracture. Romosozumab has potential as a therapeutic option to improve the BMD and reduce the subsequent fracture risk of patients with PLO.

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).

In contrast to postmenopausal women diagnostic process and treatment of premenopausal osteoporosis in young women reamin poorly defined. A low bone mineral density in premenopausal women is not associated with the same risk of fractures as in postmenopausal women, therefore diagnosis requires not only densitometric examination but depends on the consideration of other risk factors. Most cases of premenopausal osteoporosis are associated with chronic diseases affecting bone metabolism. Treatment of the underlying disease may improve bone density as well as bone quality. Rarely, a bone-specific antiporotic therapy may be used, although quality evidence is scarce. This article will review current opinion on definition, diagnosis and treatment of premenopausal osteoporosis.

Premenopausal women with idiopathic osteoporosis (PreMenIOP) have marked deficits in bone density, microstructure, and strength.
To define effects of treatment with teriparatide followed by denosumab on lumbar spine (LS) volumetric bone mineral density (vBMD) and stiffness by finite element analysis assessed on central quantitative computed tomography (cQCT) scans.
Ancillary analysis of baseline, post-teriparatide, and post-denosumab cQCT scans from a randomized trial of 41 women allocated to teriparatide (20 mcg daily; n = 28) or placebo (n = 11). After 6 months, those on teriparatide continued for 18 months, and those on placebo switched to teriparatide for 24 months. After completing teriparatide, 33 enrolled in a Phase 2B extension with denosumab (60 mg every 6 months) for 12 months.
Primary outcomes were percentage change from baseline in LS trabecular vBMD and stiffness after teriparatide and between end of teriparatide and completing denosumab. Percentage change from baseline in LS trabecular vBMD and stiffness after sequential teriparatide and denosumab were secondary outcomes.
There were large increases (all Ps < 0.001) in trabecular vBMD (25%), other vBMD parameters, and stiffness (21%) after teriparatide. Statistically significant increases in trabecular vBMD (10%; P < 0.001) and other vBMD parameters (P = 0.03-0.001) were seen after denosumab, while stiffness increased by 7% (P = 0.068). Sequential teriparatide and denosumab led to highly significant (all Ps < 0.001) increases LS trabecular vBMD (43%), other vBMD parameters (15-31%), and stiffness (21%).
The large and statistically significant increases in volumetric density and stiffness after sequential treatment with teriparatide followed by denosumab are encouraging and support use of this regimen in PreMenIOP.

BACKGROUND: We have previously reported that teriparatide is associated with substantial increases in bone mineral density (BMD) at the lumbar spine (LS), total hip (TH) and femoral neck (FN) and small declines at the distal radius (DR) in 41 premenopausal women with idiopathic osteoporosis (IOP), all severely affected with low trauma fractures and/or very low BMD. Effects of teriparatide dissipate if not followed by antiresorptives.
OBJECTIVE: To assess the effects of 12 and 24 months (M) of denosumab in premenopausal women with IOP completing 24M of teriparatide.
METHODS: Preplanned phase 2B extension study.
METHODS: Tertiary referral centers.
METHODS: Premenopausal women with IOP.
METHODS: Denosumab 60mg every 6 months for 12 and 24M.
METHODS: Within-group change in BMD at the LS at 12M. Secondary outcomes include change in 12M BMD at other sites, 24M BMD at all sites, trabecular bone score (TBS) and bone turnover markers (BTM).
RESULTS: After completing teriparatide, 32 participants took denosumab for 12M and 29 for 24M, with statistically significant increases in BMD at the LS (5.2±2.6% and 6.9±2.6%), TH (2.9±2.4% and 4.6±2.8%) and FN (3.0±3.8% and 4.7±4.9%). Over the entire 24M teriparatide and 24M denosumab treatment period, BMD increased by 21.9±7.8% at the LS, 9.8±4.6% at the TH and 9.5±4.7% at the FN (all p<0.0001). TBS increased by 5.8±5.6% (p<0.001). Serum BTM decreased by 75%-85% by 3M and remained suppressed through 12M of denosumab. Denosumab was generally well-tolerated.
CONCLUSIONS: These data support the use of sequential teriparatide and denosumab to increase BMD in premenopausal women with severe osteoporosis.

Pregnancy and lactation-related osteoporosis (PLO) is the development of osteoporosis in a premenopausal woman, usually in the third trimester of pregnancy or puerperium. The hormonal changes that allow for the maternal-fetal calcium gradient may be the underlying cause for bone loss, but it is not currently known why some women are affected so severely. Because osteoporosis does not cause symptoms until the condition is advanced, diagnosis is usually made upon the development of an osteoporotic fracture or incidentally when imaging is performed for other reasons. Spontaneous recovery is common once lactation is discontinued, as the underlying hormonal factors that caused the osteoporosis revert to the pre-pregnancy state. We used the research database TriNetX (TriNetX, LLC, Cambridge, MA) to perform a query selecting women between the ages of 10 and 50 years old who experienced an osteoporotic fracture within 12 months of pregnancy. We analyzed the cohort of patients to determine the incidence of fractures at different skeletal locations and evaluated the medications that were utilized in the patients who received treatment.

Osteoporosis in premenopausal women with intact gonadal function and no known secondary cause of bone loss is termed idiopathic osteoporosis (IOP). Women with IOP diagnosed in adulthood have profound bone structural deficits and often report adult and childhood fractures, and family history of osteoporosis. Some have very low bone formation rates (BFR/BS) suggesting osteoblast dysfunction. These features led us to investigate potential genetic etiologies of bone fragility. In 75 IOP women (aged 20-49) with low trauma fractures and/or very low BMD who had undergone transiliac bone biopsies, we performed Whole Exome Sequencing (WES) using our variant analysis pipeline to select candidate rare and novel variants likely to affect known disease genes. We ran rare-variant burden analyses on all genes individually and on phenotypically-relevant gene sets. For particular genes implicated in osteoporosis, we also assessed the frequency of all (including common) variants in subjects versus 6540 non-comorbid female controls. The variant analysis pipeline identified 4 women with 4 heterozygous variants in LRP5 and PLS3 that were considered to contribute to osteoporosis. All 4 women had adult fractures, and 3 women also had multiple fractures, childhood fractures and a family history of osteoporosis. Two women presented during pregnancy/lactation. In an additional 4 subjects, 4 different relevant Variants of Uncertain Significance (VUS) were detected in the genes FKBP10, SLC34A3, and HGD. Of the subjects with VUS, 2 had multiple adult fractures, childhood fractures, and presented during pregnancy/lactation, and 2 had nephrolithiasis. BFR/BS varied among the 8 subjects with identified variants; BFR/BS was quite low in those with variants that are likely to have adverse effects on bone formation. The analysis pipeline did not discover candidate variants in COL1A1, COL1A2, WNT, or ALPL. Although we found several novel and rare variants in LRP5, cases did not have an increased burden of common LRP5 variants compared to controls. Cohort-wide collapsing analysis did not reveal any novel disease genes with genome-wide significance for qualifying variants between controls and our 75 cases. In summary, WES revealed likely pathogenic variants or relevant VUS in 8 (11%) of 75 women with IOP. Notably, the genetic variants identified were consistent with the affected women\'s diagnostic evaluations that revealed histological evidence of low BFR/BS or biochemical evidence of increased bone resorption and urinary calcium excretion. These results, and the fact that the majority of the women had no identifiable genetic etiology, also suggest that the pathogenesis of and mechanisms leading to osteoporosis in this cohort are heterogeneous. Future research is necessary to identify both new genetic and non-genetic etiologies of early-onset osteoporosis.